Autor(en) |
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Sabel M, Fleischhack G, Tippelt S, Gustafsson G, Doz F, Kortmann R, Massimino M, Navajas A, von Hoff K, Rutkowski S, Warmuth-Metz M, Clifford SC, Pietsch T, Pizer B, Lannering B, SIOP-E Brain Tumour Group |
Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study. |
Journal of neuro-oncology 2016, |
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The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76â±â2â% and 78â±â2â% respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18â%) were isolated local relapses in the posterior fossa (PF) and 59 (82â%) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (pâ=â0.24). Late relapse, i.e. >5 years from diagnosis, occurred in six patients (8â%). Relapse treatment consisted of combinations of surgery (25â%), focal radiotherapy (RT 22â%), high dose chemotherapy with stem cell rescue (HDSCR 21â%) and conventional chemotherapy (90â%). OS at 5 years after relapse was 6.0â±â4â%. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour. |
Sadick M, Müller-Wille R, Wildgruber M, Wohlgemuth WA |
Vascular Anomalies (Part I): Classification and Diagnostics of Vascular Anomalies. |
RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin 2018, 190: 825 |
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Salama A, Gaedicke G |
Autoimmunhaemolytische Anaemien. |
In: Helmut Gadner, Gerhard Gaedicke, Charlotte Niemeyer (Hrsg.): Pädiatrische Hämatologie und Onkologie 2005, p.147 |
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Die autoimmunhämolytischen Anämien sind bei Kindern selten. Wenn sie auftreten, sind sie meistens durch eine akute und schwere Hämolyse gekennzeichnet. Wichtigster diagnostischer Test ist neben dem Blutbild der positive direkte Coombs-Test. Nach dem Reaktionsoptimum der Autoantikörper unterscheidet man Wärmeautoantikörper und Kälteautoantikörper. In der Regel sind die autoimmunhämolytischen Anämien sekundäre Erkrankungen, so dass nach primären Grunderkrankungen, besonders solchen aus dem Formenkreis der Autoimmunerkrankungen und nach Immundefekten, gesucht werden muß. Auch im Rahmen von Infektionen können sie auftreten. Medikamentös induzierte Formen sind bei Kindern selten. Für eine adäquate Behandlung ist eine enge Zusammenarbeit zwischen Klinik und Transfusionsmedizin erforderlich, zumal sich die Transfusionstherapie, vor allem im Initialstadium, schwierig gestalten kann. |
Salzburg J, Burkhardt B, Zimmermann M, Wachowski O, Woessmann W, Oschlies I, Klapper W, Wacker HH, Ludwig WD, Niggli F, Mann G, Gadner H, Riehm H, Schrappe M, Reiter A |
Prevalence, clinical pattern, and outcome of CNS involvement in childhood and adolescent non-Hodgkin's lymphoma differ by non-Hodgkin's lymphoma subtype: a Berlin-Frankfurt-Münster Group Report. |
Journal of clinical oncology 2007, 25: 3915 |
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Salama A, Kiesewetter H, Kalus U, Movassaghi K, Meyer O |
Massive platelet transfusion is a rapidly effective emergency treatment in patients with refractory autoimmune thrombocytopenia. |
Thrombosis and haemostasis 2008, 100: 762 |
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Patients with refractory autoimmune thrombocytopenia (ITP) may develop life-threatening bleeding that cannot be immediately controlled by drug administration. To date, there have been no studies conducted to evaluate the efficacy of platelet transfusion alone in such cases. Ten patients with refractory ITP and bleeding or a high bleeding risk were consecutively transfused (one unit/30 min) with apheresis platelet concentrates (APC) without the administration of new drugs. The used APCs (average 3-7 units) contained 2.7 x 10(11) (medium) platelets and were leukodepleted (< or = 1 x 10(6) leukocytes/unit). Platelet serology was performed using standard techniques. Platelet transfusion resulted in an increase in the platelet count to 84 - 157 x 10(3)/microl, and the cessation of bleeding in all patients without any serious adverse effects. Although platelet counts gradually decreased within a few days post-transfusion, bleeding was stopped in all cases. These findings indicate that consecutive platelet transfusion using APCs is a rapidly effective emergency treatment in patients with refractory ITP. |
Salchow J, Mann J, Koch B, von Grundherr J, Jensen W, Elmers S, Straub LA, Vettorazzi E, Escherich G, Rutkowski S, Dwinger S, Bergelt C, Sokalska-Duhme M, Bielack S, Calaminus G, Baust K, Classen CF, Rössig C, Faber J, Faller H, Hilgendorf I, Gebauer J, Langer T, Metzler M, Schuster S, Niemeyer C, Puzik A, Reinhardt D, Dirksen U, Sander A, Köhler M, Habermann JK, Bokemeyer C, Stein A |
Comprehensive assessments and related interventions to enhance the long-term outcomes of child, adolescent and young adult cancer survivors - presentation of the CARE for CAYA-Program study protocol and associated literature review. |
BMC cancer 2020, 20: 16 |
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Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. |
Sander A, Zimmermann M, Dworzak M, Fleischhack G, von Neuhoff C, Reinhardt D, Kaspers GJ, Creutzig U |
Consequent and intensified relapse therapy improved survival in pediatric AML: results of relapse treatment in 379 patients of three consecutive AML-BFM trials. |
Leukemia 2010 |
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Relapse remains the major cause of treatment failure in pediatric acute myeloid leukemia (AML). We analyzed the clinical characteristics, treatment response to relapse treatment and overall survival (OS) of 379 children with AML relapse treated according to three consecutive frontline protocols of the AML-Berlin/Frankfurt/Muenster study group (AML-BFM-87/-93/-98). Of 313 treated patients with data on remission status, 198 children (63%) achieved a second complete remission (CR2). There were no significant differences in remission rates and OS for the intensive reinduction treatment schedules used. The 5-year OS rate was 23% for the total group and 29% for patients treated with curative intent. OS rates increased with study periods from 18 to 34% (P(log rank)=0.012), whereas the proportion of patients receiving only palliative treatment decreased from 23 to 11% (P(CMH)=0.005). Late relapse, no allogeneic stem cell transplantation (SCT) in CR1, age <10 years and favorable cytogenetics were independent favorable prognostic factors for survival. Achievement of CR2 was the most important prognostic factor (OS 44 vs 3%; P(log rank)<0.0001). Overall, one-third of children with relapsed AML can be cured today. SCT in CR2 is recommended for most patients, although its impact on CR2 is discussed.Leukemia advance online publication, 10 June 2010; doi:10.1038/leu.2010.127. |
Sasco AJ, Vainio H |
From in utero and childhood exposure to parental smoking to childhood cancer: a possible link and the need for action. |
Hum Exp Toxicol 1999, 18: 192 |
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Satge D, Sasco A, Carlsen N, Stiller C, Rubie H, Hero B, De Bernardi B, de Kraker J, Coze C, Kogner P, Langmark F, Hakvoort-Cammel F, Beck D, von der Weid, Parkes S, Hartmann O, Lippens R, Kamps W, Sommelet D |
A lack of neuroblastoma in Down syndrome. |
Cancer Res 1998, 58: 448 |
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Satty AM, Klein E, Mauguen A, Kunvarjee B, Boelens JJ, Cancio M, Curran KJ, Kernan NA, Prockop SE, Scaradavou A, Spitzer B, Tamari R, Ruggiero J, Torok-Castanza J, Mehta PA, O'Reilly RJ, Boulad F |
T-cell depleted allogeneic hematopoietic stem cell transplant for the treatment of Fanconi anemia and MDS/AML. |
Bone marrow transplantation 2023, |
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The only curative approach for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) arising in patients with Fanconi anemia (FA) is allogeneic hematopoietic stem cell transplantation (HCT); however, HCT approaches are inconsistent and limited data on outcomes exist. We retrospectively evaluated outcomes of thirty patients with FA and MDS/AML who underwent first allogeneic HCT with a T-cell depleted (TCD) graft at our institution. Patients were transplanted on successive protocols with stepwise changes in cytoreduction and GVHD prophylaxis. All but two patients (93%) experienced durable hematopoietic engraftment. With median follow-up of 8.7 years, 5-year OS was 66.8% and DFS 53.8%. No significant differences in survival were found in patients with high-risk prognostic features (age ≥20 years, AML diagnosis, alternative donor graft) or when stratified by conditioning regimen. The 5-year cumulative incidences of relapse and NRM were 24.3% and 21.9%, respectively. NRM was higher in patients ≥20 years at HCT but did not otherwise differ. We herein demonstrate promising outcomes following allogeneic HCT for patients with FA and MDS/AML using TCD grafts, particularly in a cohort of high-risk patients with 50% ≥20 years and a majority receiving mismatched grafts. Future prospective studies are needed to compare this approach with other HCT platforms. |
Sauerbrey A, Bielack S, Kempf-Bielack B, Zoubek A, Paulussen M, Zintl F |
High-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (ASCT) as salvage therapy for relapsed osteosarcoma. |
Bone Marrow Transplant 2001, 27: 933 |
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Sauerwein W et al. |
Brachytherapy of the orbit in young children. |
Radiotherapy and Oncology 2012, 103 : 164 |
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Scheer U, Schellong G |
The prognostic value of measuring cell size in acute childhood leukemia (author's transl). |
Klin Pädiatr 1979, 191: 127 |
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Scheer U, Schellong G, Riehm H |
Verbesserte Prognose der akuten myeloischen Leukämien bei Kindern nach intensivierter Anfangstherapie. |
Klinische Pädiatrie 1979, 191: 210 |
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Schellong G, Waubke A, Langermann H, Breu H, Kuhne B, Riehm H, Ritter J |
Significance of clinical and intraoperative findings for the prediction of splenic involvement in children with Hodgkin's disease. |
Klin Pädiatr 1982, 194: 242 |
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Schellong G, Creutzig U, Ritter J |
Treatment of acute myelogenous leukemia in children. |
Med Oncol Tumor Pharmacother 1985, 2: 17 |
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Schellong G, Bramswig J, Ludwig R, Gerein V, Jobke A, Jürgens H, Kabisch H, Stollmann B, Weinel P, Gadner H, |
Combined treatment strategy in over 200 children with Hodgkin's disease. |
Klin Pädiatr 1986, 198: 137 |
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Schellong G, Lietzke S, Strauch S, Kuhne B, Schneider B |
Results of ultrasonic, computer tomography and clinical findings for the detection of abdominal involvement in Hodgkin's disease in childhood--a retrospective statistical analysis of 145 patients in the therapeutic study DAL-HD-82. |
Klin Pädiatr 1986, 198: 147 |
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Schellong G, Waubke-Landwehr A, Langermann H, Riehm H, Bramswig J, Ritter J |
Prediction of splenic involvement in children with Hodgkin's disease. Significance of clinical and intraoperative findings. A retrospective statistical analysis of 154 patients in the German therapy study DAL-HD- 78. |
Cancer 1986, 57: 2049 |
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Schmidt RF, Thews G (Hrsg) |
Physiologie des Menschen. |
Springer Verlag 23. Aufl. 1987 |
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Schellong G, Bramswig J, Schwarze E, Wannenmacher M |
An approach to reduce treatment and invasive staging in childhood Hodgkin's disease. |
Bull Cancer 1988, 75: 41 |
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Schellong G, Hornig I, Bramswig J, Bokkerink J, Steinhoff A, Ludwig R, Niethammer D, Reiter A, von Lengerke H, Heinecke H, Schwarze E, Pötter R, Müller R, Wannenmacher M, |
Significance of procarbazine in the chemotherapy of Hodgkin's disease-- a report of the Cooperative Therapy Study DAL-HD-85. |
Klin Pädiatr 1988, 200: 205 |
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Schellong G, Hornig I, Schwarze E, Wannenmacher M |
Risk factor adapted treatment of Hodgkin's lymphoma in childhood. |
Recent Results Cancer Res 1989, 117: 205 |
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Schell MJ, McHaney VA, Green AA, Kun LE, Hayes FA, Horowitz M, Meyer WH |
Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation. |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1989, 7: 754 |
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One hundred seventy-seven children and young adults with various malignant neoplasms were prospectively tested for hearing loss after they had received cisplatin (n = 146), cranial irradiation (n = 18), or both (n = 13). Adequate renal function, no history of treatment with ototoxic drugs other than cisplatin, and availability for repeated audiometric testing were requirements for enrollment. Substantial hearing loss, defined as a hearing threshold of 50 dB or greater, was noted in only 11% of the cohort on tests conducted at the common speech frequencies (500 to 3,000 Hz). About half the patients had substantial deficits at higher frequencies (4,000 to 8,000 Hz). The probability of substantial hearing loss was directly related to the cumulative dose of cisplatin. In nonirradiated patients tested at the speech frequencies, there was a negligible risk of substantial deficits over the dose range of 90 to 360 mg/m2. As the dose increased to 720 mg/m2, the risk increased to 22%. In irradiated patients who later received cisplatin, cumulative drug doses as low as 270 mg/m2 were associated with a high probability of substantial hearing loss, suggesting potentiation of ototoxicity when these therapies are used together. Hearing acuity was either not affected or only minimally decreased in the irradiation-only group. Younger age, prior irradiation, and the presence of a CNS tumor each contributed significantly to the severity of hearing deficits at given cisplatin dose levels. We conclude that early increases in hearing threshold at a stimulus frequency of 4,000 Hz indicate probable subsequent deficits at lower frequencies, especially in young children with CNS tumors who have received cranial irradiation. The probability charts derived from this analysis should provide a useful tool for predicting hearing loss in the speech frequencies. |
Schellong G, Brämswig J, Hörnig-Franz I |
Treatment of children with Hodgkin's disease--results of the German Pediatric Oncology Group. |
Ann Oncol 1992, 3 Suppl 4: 73-6: 73 |
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Scholz R, Kabisch H, Weber B, Roser K, Delling G, Winkler K |
Studies of the RB1 gene and the p53 gene in human osteosarcomas. |
Pediatr Hematol Oncol 1992, 9: 125 |
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Schwerdtfeger R, Schmid H, Zingsem J, Beck J, Bender-Götze C, Döpfer R, Peters H, Henze G, Siegert W |
High-dose VP-16 and fractionated total body irradiation followed by autologous bone marrow transplantation in children with relapsed or high-risk acute lymphoblastic leukemia. |
Haematol Blood Transfus 1992, 34: 568 |
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Schmid H, Henze G, Schwerdtfeger R, Baumgarten E, Besserer A, Scheffler A, Serke S, Zingsem J, Siegert W |
Fractionated total body irradiation and high-dose VP-16 with purged autologous bone marrow rescue for children with high risk relapsed acute lymphoblastic leukemia. |
Bone Marrow Transplant 1993, 12: 597 |
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Schmidt D, Wischmeyer P, Leuschner I, Sprenger E, Langenau E, von Schweinitz D, Harms D |
DNA analysis in hepatoblastoma by flow and image cytometry. |
Cancer 1993, 72: 2914 |
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Schneider S, Wildhardt G, Ludwig R, Royer-Pokora B |
Exon skipping due to a mutation in a donor splice site in the WT-1 gene is associated with Wilms' tumor and severe genital malformations. |
Hum Genet 1993, 91: 599 |
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Schrappe M |
Acute leukemia in children. |
Kinderkrankenschwester 1993, 12: 106 |
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Schellong G, Brämswig J, Hörnig-Franz I, Schwarze E, Pötter R, Wannenmacher M |
Hodgkin's disease in children. |
Ann Oncol 1994, 5 Suppl 2: 113-5: 113 |
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Schellong G, Hornig-Franz I, Rath B, Ritter J, Riepenhausen M, Kabisch H, Goldschmitt-Wuttge B, Schmidt P, Niethammer D, Gaedicke G, Schwarze E, Pötter R, |
Reducing radiation dosage to 20-30 Gy in combined chemo-/radiotherapy of Hodgkin's disease in childhood. A report of the cooperative DAL-HD- 87 therapy study. |
Klin Pädiatr 1994, 206: 253 |
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Schellong G, Hörnig-Franz I, Rath B, Ritter J, Riepenhausen M, Kabisch H, Goldschmitt-Wuttge B, Schmidt P, Niethammer D, Gaedicke G |
Reducing radiation dosage to 20-30 Gy in combined chemo-/radiotherapy of Hodgkin's disease in childhood. A report of the cooperative DAL-HD-87 therapy study. |
Klin Pädiatr 1994, 206: 253 |
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Schmid H, Schwerdtfeger R, Henze G, Baumgarten E, Besserer A, Scheffler A, Gallardo J, Schmidt-Wolf I, Schwella N, Zingsem J, Siegert W |
Autologous and allogeneic bone marrow transplantation after identical high-dose chemo-radiotherapy in children with relapsed ALL. |
Haematol Blood Transfus 1994, 721 |
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Schrappe M, Reiter A, Sauter S, Ludwig W, Wormann B, Harbott J, Bender-Gotze C, Dörffel W, Dopfer R, Frey E, |
Concept and interim result of the ALL-BFM 90 therapy study in treatment of acute lymphoblastic leukemia in children and adolescents. |
Klin Pädiatr 1994, 206: 208 |
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Schweizer P |
Das Rhabdomyosarkom. |
Kinderheilkunde 1994, 10 |
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Schweizer P |
Resectability of malignant soft tissue tumors. Retrospective analysis of patients in the CWS 86 study. |
Klinische Pädiatrie 1994, 206: 263 |
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Schwella N, Schwerdtfeger R, Konig V, Blasczyk R, Schmid H, Schmidt-Wolf I, Henze G, Siegert W |
Allogeneic bone marrow transplantation for recurrence of leukemia after autologous bone marrow transplantation. |
Transplantation 1994, 57: 1263 |
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Scheurlen W, Krauss J, Kühl J |
No preferential loss of one parental allele of chromosome 17p13. 3 in childhood medulloblastoma. |
Int J Cancer 1995, 63: 372 |
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Schoch C, Rieder H, Freund M, Hoelzer D, Riehm H, Fonatsch C |
Twenty-three cases of acute lymphoblastic leukemia with translocation t(4;11)(q21;q23). |
Annals Hematology 1995, 70: 195 |
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Schellong G |
The balance between cure and late effects in childhood Hodgkin's lymphoma. |
Ann Oncol 1996, 7 Suppl 4: 67 |
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Schellong G |
Treatment of children and adolescents with Hodgkin's disease. |
Baillieres Clin Haematol 1996, 9: 619 |
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Schellong G, Riepenhausen M, Creutzig U, Ritter J, Harbott J, Mann G, Gadner H, Group for |
Incidence of Secondary Leukemias After Therapy of Childhood Hodgkin's Disease Without Nitrogen-Mustard. Results of the German-Austrian Study Group. |
Haematology and Blood Transfusion 1996, 38: 898 |
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Scheurlen W, Sörensen N, Roggendorf W, Kühl J |
Molecular analysis of medulloblastomas occurring simultaneously in monozygotic twins. |
Eur J Pediatr 1996, 155: 880 |
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Schlehofer B, Blettner M, Geletneky K, Haaf H, Kaatsch P, Michaelis J, Mueller-Lantzsch N, Niehoff D, Winkelspecht B, Wahrendorf J, Schlehofer J |
Sero-epidemiological analysis of the risk of virus infections for childhood leukaemia. |
Int J Cancer 1996, 65: 584 |
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Schlieben S, Borkhardt A, Reinisch I, Ritterbach J, Janssen J, Ratei R, Schrappe M, Repp R, Zimmermann M, Kabisch H, Janka-Schaub G, Bartram C, Ludwig W, Riehm H, Lampert F, Harbott J |
Incidence and clinical outcome of children with BCR/ABL-positive acute lymphoblastic leukemia (ALL). A prospective RT-PCR study based on 673 patients enrolled in the German pediatric multicenter therapy trials ALL-BFM-90 and CoALL-05-92. |
Leukemia 1996, 10: 957 |
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Schrappe M, Reiter A, Riehm H |
Cytoreduction and prognosis in childhood acute lymphoblastic leukemia. |
J Clin Oncol 1996, 14: 2403 |
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Schellong G, Riepenhausen M, Creutzig U, Ritter J, Harbott J, Mann G, Gadner H |
Low risk of secondary leukemias after chemotherapy without mechlorethamine in childhood Hodgkin's disease. German-Austrian Pediatric Hodgkin's Disease Group. |
J Clin Oncol 1997, 15: 2247 |
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Scheurlen W, Seranski P, Mincheva A, Kühl J, Sörensen N, Krauss J, Lichter P, Poustka A, Wilgenbus K |
High-resolution deletion mapping of chromosome arm 17p in childhood primitive neuroectodermal tumors reveals a common chromosomal disruption within the Smith-Magenis region, an unstable region in chromosome band 17p11. 2 |
Genes Chromosomes Cancer 1997, 18: 50 |
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Schrappe M, Creutzig U |
Akue lymphoblastische (ALL) und akute myeloblastische (AML) Leukämie, in Creutzig U, Henze G (Hrsg.) |
Diagnostische und therapeutische Standards in der Pädiatrischen Onkologie, München, Bern, Wien, New York, W Zuckschwerdt Verlag 1997 |
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Schrappe M, Reiter A |
Maligne Non-Hodgkin-Lymohome im Kindesalter, in Schmoll H-J, Höffken, K, Possinger K, (Hrsg.) |
Kompendium Internistische Onkologie, Berlin, Springer 1997, 1713 |
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Schrappe M, Reiter A, Welte K, Ludwig W, Harbott J, Lampert F, Henze G, Riehm H |
Risk adapted treatment in childhood acute lymphoblastic leukemia:data from the Berlin-Frankfurt-Münster group. |
Haematology and Blood Transfusion 1997 |
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Schrappe M, Riehm H |
Akute lymphoblastische Leukämie im Kindesalter in Schmoll,H-J, Höffken K,Possinger K (Hrsg.): |
Kompendium Internistische Onkologie, Berlin, Springer 1997 |
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Schumacher V, Schneider S, Figge A, Wildhardt G, Harms D, Schmidt D, Weirich A, Ludwig R, Royer-Pokora B |
Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology. |
Proc Natl Acad Sci U S A 1997, 94: 3972 |
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Schweinitz D |
Hepatoblastom. |
Diagnostische und therapeutische Standards in der Pädiatrischen Onkologie 1997, 76 |
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Scheurlen WG, Seranski P, Mincheva A, Kühl J, Sörensen N, Krauss J, Lichter P, Poustka A, Wilgenbus KK |
High-resolution deletion mapping of chromosome arm 17p in childhood primitive neuroectodermal tumors reveals a common chromosomal disruption within the Smith-Magenis region, an unstable region in chromosome band 17p11. 2. |
Genes, chromosomes & cancer 1997, 18: 50 |
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Loss of heterozygosity (LOH) on chromosome arm 17p is the most common genetic aberration in childhood primitive neuroectodermal tumors (PNETs). To determine the frequency and extent of 17p deletions, 29 loci on 17p were investigated in 24 tumors by using restriction fragment length polymorphism (RFLP) and microsatellite analysis. LOH on 17p was found in 9 of 24 tumors. In all tumors with LOH, a continuous stretch from the telomere to chromosome band 17p11.2 was completely deleted, and no interstitial or terminal small-scale deletions were detected in the remaining 15 tumors. In four tumors with LOH on 17p, the chromosomal breakpoint was located between D17S953 and D17S805. To identify this deletion breakpoint on the cytogenetic map of chromosome 17 and to exclude uniparental disomy, we verified our data by using fluorescence in situ hybridization (FISH) analyses. By using two yeast artificial chromosome (YAC) clones that were positive for D17S689 and D17S953, the same breakpoint was confirmed in two specimens of cerebrospinal fluid (CSF) metastases by using FISH on interphase preparations. We demonstrate that, in most childhood PNETs with LOH on 17p, the breakpoint is close to, but not within, the centromere. It varies, and it occurs predominantly between the two markers D17S689 and D17S953, which is an unstable chromosomal region that is deleted or duplicated in the Smith-Magenis syndrome. Because LOH of 17p is associated with the formation of isochromosome 17q in the majority of PNETs, this study provides entry points to determine the molecular nature of this phenomenon. |
Schilling RF |
Spherocytosis, splenectomy, strokes, and heat attacks. |
Lancet 1997, 350: 1677 |
|
Schellong G |
Pediatric Hodgkin's disease. |
Ann Oncol 1998, 9 Suppl 5:S115-S119 |
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Scheurlen W, Kühl J |
Current diagnostic and therapeutic management of CNS metastasis in childhood primitive neuroectodermal tumors and ependymomas. |
J Neurooncol 1998, 38: 181 |
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Scheurlen W, Schwabe G, Joos S, Mollenhauer J, Sörensen N, Kühl J |
Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome. |
J Clin Oncol 1998, 16: 2478 |
|
Schilling F, Berthold F, Erttmann R, Keding G, Michaelis J, Sander J, Treuner J |
Neuroblastom-Früherkennung. Krebsfrüherkennung im Kindesalter. |
Deutsches Ärzteblatt 1998, 95: 1485 |
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Schilling F, Spix C, Berthold F, Erttmann R, Hero B, Michaelis J, Sander J, Tafese T, Treuner J |
German Neuroblastoma Mass Screening Study at 12 Months of Age. |
Med Pediat Oncol 1998, 31: 435 |
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Schmandt S, Kühl J |
Chemotherapy as prophylaxis and treatment of meningosis in children less than 3 years of age with medulloblastoma. |
J Neurooncol 1998, 38: 187 |
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Schneider D, Göbel U |
Erhöhte Werte für Alpha-1-Fetoprotein und humanes Gonadotropin. |
Monatsschr Kinderheilkd 1998, 146: 1094 |
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Schneider D, Göbel U |
Differentialdiagnostische Bewertung erhöhter Werte für Alpa 1-Fetoprotein und humanes Choriogonadotropin im Kindesalter. |
Tumordiagnose und Therapie 1998, 19: 101 |
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Schott G, Sperling C, Schrappe M, Ratei R, Martin M, Meyer U, Riehm H, Ludwig W |
Immunophenotypic and clinical features of T-cell receptor gammadelta+ T-lineage acute lymphoblastic leukaemia. |
Br J Haematol 1998, 101: 753 |
|
Schrappe M, Arico M, Harbott J, Biondi A, Zimmermann M, Conter V, Reiter A, Valsecchi M, Gadner H, Basso G, Bartram C, Lampert F, Riehm H, Masera G |
Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia. |
Blood 1998, 92: 2730 |
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Schrappe M, Reiter A, Henze G, Niemeyer C, Bode U, Kühl J, Gadner H, Havers W, Pluss H, Kornhuber B, Zintl F, Ritter J, Urban C, Niethammer D, Riehm H |
Prevention of CNS recurrence in childhood ALL. |
Klin Pädiatr 1998, 210: 192 |
|
Schrappe M, Reiter A, Riehm H |
Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia. |
J Neurooncol 1998, 38: 159 |
|
Scheurlen W, Kühl J |
Current diagnostic and therapeutic management of CNS metastasis in childhood primitive neuroectodermal tumors and ependymomas. |
Journal of neuro-oncology 1998, 38(2-3): 181 |
|
Metastatic disease is a major problem in the management of the most frequent childhood brain tumors, in ependymoma and primitive neuroectodermal tumors (PNET). Today, contrast enhanced craniospinal MRI and careful analysis of craniospinal fluid are a prerequisite for correct staging of both tumors and imply therapeutic consequences. So far metastatic spread of medulloblastoma and some ependymomas is prevented by conventional chemotherapy and radiotherapy. However, some forms of diffuse metastatic dissemination in medulloblastoma are resistant to conventional therapeutic regimens and require new experimental strategies. |
Scheurlen WG, Schwabe GC, Joos S, Mollenhauer J, Sörensen N, Kühl J |
Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome. |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1998, 16: 2478 |
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PURPOSE: The diagnostic and prognostic significance of well-defined molecular markers was investigated in childhood primitive neuroectodermal tumors (PNET). MATERIALS AND METHODS: Using microsatellite analysis, Southern blot analysis, and fluorescence in situ hybridization (FISH), 30 primary tumors and six CSF metastasis specimens were analyzed for loss of heterozygosity (LOH) of chromosomes 1q31, 6q, 9q22, 10q, 11, 16q22, and 17p13.1 and/or high-level amplification of the c-myc gene. Experimental data were compared with clinical stage and outcome. RESULTS: LOH of chromosome 17p13.1 was found most frequently (14 of 30 tumors, six of six CSF metastasis specimens); LOH of chromosomes 10q, 16q22, 11, 6, 9q22, and 1q31 was observed in 20.6%, 20%, 14.3%, 12%, 10%, and 0%, respectively. Eight of 32 tumors and CSF specimens showed amplification of c-myc. All tumors with amplification of c-myc were resistant to therapy and had a fatal outcome (mean survival time, 9.3 months). Tumors that displayed LOH of chromosome 17p were associated with metastatic disease. The prognosis of these tumors was worse only when associated with amplification of c-myc. Three of three patients with LOH of 9q22 relapsed. CONCLUSION: In our study, amplification of c-myc was a poor-prognosis marker in PNET. LOH of chromosome 17p was associated with metastatic disease. Molecular analysis of primary tumors using these markers may be useful for stratification of children with PNET in future prospective studies. The other aberrations investigated were not of significant prognostic value, but may provide an entry point for future large-scale molecular studies. |
Schellong G, Dörffel W |
Morbus Hodgkin bei Kindern und Jugendlichen. |
Kompendium Internistische Onkologie 1999, 1: 2257 |
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Schellong G, Potter R, Bramswig J, Wagner W, Prott F, Dörffel W, Körholz D, Mann G, Rath B, Reiter A, Weissbach G, Riepenhausen M, Thiemann M, Schwarze E |
High cure rates and reduced long-term toxicity in pediatric Hodgkin's disease. |
J Clin Oncol 1999, 17: 3736 |
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Schmidt B, Koscielniak E, Pilz T, Treuner J |
Radiation therapy in juvenile aggressive fibromatosis. |
Klinische Pädiatrie 1999, 211: 296 |
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Schneider D, Göbel U |
Diagnostic and therapeutic pitfalls in infants with large sacrococcygeal tumors [letter; comment] [see comments]. |
Pediatr Hematol Oncol 1999, 16: 481 |
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Schneider D, Hilgenfeld E, Schwabe D, Behnisch W, Zoubek A, Wessalowski R, Göbel U |
Acute myelogenous leukemia after treatment for malignant germ cell tumors in children. |
J Clin Oncol 1999, 17: 3226 |
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Schuz J, Kaatsch P, Kaletsch U, Meinert R, Michaelis J |
Association of childhood cancer with factors related to pregnancy and birth. |
Int J Epidemiol 1999, 28: 631 |
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Schuz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J |
Association of childhood leukaemia with factors related to the immune system. |
Br J Cancer 1999, 80: 585 |
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Schwartz S, Heinecke A, Zimmermann M, Creutzig U, Schoch C, Harbott J, Fonatsch C, Löffler H, Buchner T, Ludwig W, Thiel E |
Expression of the C-kit receptor (CD117) is a feature of almost all subtypes of de novo acute myeloblastic leukemia (AML), including cytogenetically good-risk AML, and lacks prognostic significance. |
Leuk Lymphoma 1999, 34: 85 |
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Schweinitz D |
Hepatoblastom. |
Leitlinien Kinderheilkunde 1999 |
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Schweinitz D |
Hepatoblastom. |
Onkologisches Daten- und Informationssystem (H Link und H Poliwoda) ODIN 1999 |
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Schilling F, Berthold F, Erttmann R, Michaelis J, Spix C, Sander J, Schwarz K, Treuner J |
Population-based and controlled study to evaluate neuroblastoma screening at one year of age in Germany. |
Med Pediatr Oncol 2000, 35: 701 |
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Schilling F, Bihl H, Jacobsson H, Ambros P, Martinsson T, Borgstrom P, Schwarz K, Ambros I, Treuner J, Kogner P |
Combined (111)In-pentetreotide scintigraphy and (123)I-mIBG scintigraphy in neuroblastoma provides prognostic information. |
Med Pediatr Oncol 2000, 35: 688 |
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Schneider D, Calaminus G, Reinhard H, Gutjahr P, Kremens B, Harms D, Göbel U |
Primary mediastinal germ cell tumors in children and adolescents. |
J Clin Oncol 2000, 18: 832 |
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Schrappe M, Camitta B, Pui C, Eden T, Gaynon P, Gustafsson G, Janka-Schaub G, Kamps W, Masera G, Sallan S, Tsuchida M, Vilmer E |
Long-term results of large prospective trials in childhood acute lymphoblastic leukemia. |
Leukemia 2000, 14: 2193 |
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Schrappe M, Reiter A, Ludwig W, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H |
Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy. |
Blood 2000, 95: 3310 |
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Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig W, Henze G, Gadner H, Odenwald E, Riehm H |
Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster. |
Leukemia 2000, 14: 2205 |
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Schulz S, Becker K, Braungart E, Reichmuth C, Klamt B, Becker I, Atkinson M, Gessler M, Hofler H |
Molecular analysis of E-cadherin and cadherin-11 in Wilms' tumours. |
J Pathol 2000, 191: 162 |
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Schuz J, Grigat J, Stormer B, Rippin G, Brinkmann K, Michaelis J |
Extremely low frequency magnetic fields in residences in Germany. Distribution of measurements, comparison of two methods for assessing exposure, and predictors for the occurrence of magnetic fields above background level. |
Radiat Environ Biophys 2000, 39: 233 |
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Schuz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J |
Risk of childhood leukemia and parental self-reported occupational exposure to chemicals, dusts, and fumes. |
Cancer Epidemiol Biomarkers Prev 2000, 9: 835 |
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Schwabe J, Francke A, Gerharz C, Willnow U, Schneider D, Nürnberger W |
Immature teratoma arising from an intra-abdominal testis in a 5-month-old boy. |
Med Pediatr Oncol 2000 Aug ;35 (2 ):140 -1 2000, 35: 140 |
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Schmitt HJ, Jilg W, Rasch G |
Impfempfehlungen der Ständigen Impfkommission (STIKO) am Robert-Koch-Institut. |
Epidemiologisches Bulletin 2000, 2: 9 |
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Schilling F, Ambros P, Bihl H, Martinsson T, Ambros I, Borgstrom P, Jacobsson H, Falkmer U, Treuner J, Kogner P |
Absence of somatostatin receptor expression in vivo is correlated to di- or tetraploid 1p36-deleted neuroblastomas. |
Med Pediatr Oncol 2001, 36: 56 |
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Schneider D, Calaminus G, Göbel U |
Diagnostic value of alpha 1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. |
Pediatr Hematol Oncol 2001, 18: 11 |
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Scholz I, Popp S, Granzow M, Schoell B, Holtgreve-Grez H, Takeuchi S, Schrappe M, Harbott J, Teigler-Schlegel A, Zimmermann M, Fischer C, Koeffler H, Bartram C, Jauch A |
Comparative genomic hybridization in childhood acute lymphoblastic leukemia. |
Cancer Genet Cytogenet 2001, 124: 89 |
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Schrappe M |
Workshop on minimal residual disease. |
Leukemia 2001, 15 |
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Schrappe M, Creutzig U |
Akute lymphoblastische- (ALL) und akute myeloische (AML) Leukämie im Kindesalter. Interdisziplinäre Leitlinie der Deutschen Krebsgesellschaft und der Deutschen Gesellschaft für Pädiatrische Onkologie und Hämatologie. |
AWMF online 2001 |
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Schuz J, Kaletsch U, Kaatsch P, Meinert R, Michaelis J |
Risk factors for pediatric tumors of the central nervous system. |
Med Pediatr Oncol 2001, 36: 274 |
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Schuz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J |
High-birth weight and other risk factors for Wilms tumour. |
Eur J Pediatr 2001, 160: 333 |
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Schuz J, Kaletsch U, Meinert R, Kaatsch P, Spix C, Michaelis J |
Risk factors for neuroblastoma at different stages of disease. Results from a population-based case-control study in Germany. |
J Clin Epidemiol 2001, 54: 702 |
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Schneider DT, Schuster AE, Fritsch MK, Calaminus G, Harms D, Göbel U, Perlman EJ |
Genetic analysis of childhood germ cell tumors with comparative genomic hybridization. |
Klinische Padiatrie 2001, 213: 204 |
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BACKGROUND: Germ Cell Tumors (GCTs) in children and adolescents constitute a clinically and histologically heterogeneous group of tumors. Compared to GCTs in adults, the numbers of GCTs in children analyzed with cytogenetic and molecular genetic techniques is limited. However, the data available to date reveal a pattern of cytogenetic aberrations different from that in adults. Comparative genomic hybridization (CGH) is a valuable technique for the genetic profiling of tumors that allows screening for chromosomal imbalances consistent with amplification of oncogenes and loss of putative tumor suppressor genes. As CGH does not require tissue culture, it also allows analysing archival tissue samples. PATIENTS: This study focuses exclusively on GCTs in children younger than ten years of age and summarizes the genetic data of 51 tumors. Eighteen teratomas and 33 malignant GCTs were included. Primary sites were the testis (n=10), coccyx (n=13), mediastinum (n=20), ovary (n=5), CNS (n=2), and the face (n=1). METHODS: The experimental procedure includes differential enzymatic fluorescence labeling of tumor and control DNA followed by comparative hybridization to normal male chromosomes, karyotyping and computerized analysis of the fluorescence profiles. RESULTS: With the exception of one testicular and two ovarian tumors, malignant GCTs in children do not show chromosomal gain of 12p, which is characteristic of GCTs in adult patients. Irrespective of the primary site, childhood GCTs show chromosomal imbalances of chromosome 1 (loss of distal 1p, gain of 1q), deletion of 4q and 6q as well as gain of 20q at a high frequency. CONCLUSIONS: These studies will help guiding further investigations elucidating the role of putative tumor suppressor genes at e.g. 1p36 and 6q. In addition, further studies incorporated in prospective therapeutic protocols are necessary to evaluate the prognostic relevance of specific genetic aberrations. |
Schiller M, Böhm M, Zeidler C, Germeshausen M, Welte K, Luger TA, Bonsmann G |
[Cyclic neutropenia. Detection of a mutation in the gene for neutrophil elastase (ELA2)]. |
Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete 2001, 52: 790 |
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Cyclic neutropenia is a rare congenital hematopoietic disease which occurs sporadically or as an autosomal dominantly inherited disorder. Recently, the locus for cyclic neutropenia was mapped to chromosome 19p13.3. Autosomal dominant and sporadic cyclic neutropenia are now attributable to mutations of the ELA2 gene encoding neutrophil elastase. |
Schilling F, Spix C, Berthold F, Erttmann R, Fehse N, Hero B, Klein G, Sander J, Schwarz K, Treuner J, Zorn U, Michaelis J |
Neuroblastoma screening at one year of age. |
N Engl J Med 2002, 346: 1047 |
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Schilling F, Spix C, Berthold F, Erttmann R, Klein G, Sander J, Treuner J |
Neuroblastom-Früherkennung. |
Onkologe 2002, 10: 1103 |
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Schilling F, Spix C, Berthold F, Erttmann R, Klein G, Sander J, Treuner J |
Modellprojekt Neuroblastom-Früherkennung - Eine Krebsfrüherkennungsstudie im Kindesalter mit unerwartetem Ausgang. |
Monatschr Kinderheilkd 2002, 150: 934 |
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Schuck A, Ahrens S, Konarzewska A, Paulussen M, Frohlich B, Konemann S, Rube C, Rube C, Dunst J, Willich N, Jürgens H |
Hemithorax irradiation for Ewing tumors of the chest wall. |
Int J Radiat Oncol Biol Phys 2002, 54: 830 |
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Schuck A, Rube C, Konemann S, Rube C, Ahrens S, Paulussen M, Dunst J, Jürgens H, Willich N |
Postoperative radiotherapy in the treatment of Ewing tumors. |
Strahlenther Onkol 2002, 178: 25 |
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Schüz J, Kaatsch P |
Epidemiology of pediatric tumors of the central nervous system. |
Expert Rev Neurotherapeutics 2002, 2: 469 |
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Schrappe M, Beier R, Burger B |
New treatment strategies in childhood acute lymphoblastic leukaemia. |
Best Pract Res Clin Haematol 2002, 15: 729 |
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Schneider DT, Calaminus G, Wessalowski R, Pathmanathan R, Harms D, Göbel U |
Therapy of advanced ovarian juvenile granulosa cell tumors. |
Klinische Padiatrie 2002, 214: 173 |
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BACKGROUND: Gonadal sex cord-stromal tumors are rare tumors that develop from the gonadal non-germ cell component such as granulosa, Sertoli or Leydig cells. Among these, juvenile granulosa cell tumors (JGCT) constitute the largest subgroup of ovarian sex cord-stromal tumors during childhood and adolescence. In local disease (FIGO stage I), the beneficial role of tumor-ovarectomy is well established. In contrast, life expectancy in patients with advanced JGCT (FIGO stage >/= II) is short even after complete tumor resection. The current literature provides only limited and inconclusive data regarding the value of adjuvant chemotherapy in such patients with advanced disease. PATIENTS AND METHODS: Therefore, we analyzed the patients with FIGO stage >/= II JGCT who were prospectively documented as follow-up patients of the German MAKEI trials for non-testicular germ cell tumors and received the recommended cisplatin-based chemotherapy in an adjuvant setting. From 1988 until 2000, 7 patients (age, 4;2 - 18;11 years, median 14;8 years) were registered. Three patients were stage IIc, one stage IIIa, and three stage IIIc. 5 patients underwent laparatomy with adnectomy, which was complete in only two patients. Two patients received laparoscopic tumor resection, which was incomplete in both. All patients received 4 or 6 cycles of adjuvant cisplatin-based three-agent chemotherapy in analogy to the current therapeutic concept applied in malignant germ cell tumors. One patient with a large tumor and multiple peritoneal metastases additionally received 40 Gy abdominal irradiation. RESULTS: All patients achieved complete clinical remission after initial surgery and adjuvant chemotherapy. 4 out of 7 patients are currently remaining in first continuous complete remission after 15 to 111 months follow-up. One patient developed a metachronous tumor of the contralateral ovary after 126 months follow-up and is still alive but currently in therapy of another recurrence. Another patient suffered a tumor recurrence after 12 months but achieved a second complete remission with cisplatin chemotherapy after a follow-up of currently 4 months. One patient achieved complete clinical remission but suffered a diffuse peritoneal tumor recurrence with massive ascites and finally died as a result of tumor progression. In summary, at the time of this report 6 of 7 patients are alive after a median of 47 (15 - 138) months. CONCLUSION: This analysis clearly demonstrates that advanced JGCT can be successfully treated with surgery followed by adjuvant cisplatin-based chemotherapy. Therefore, this study reveals encouraging therapeutic perspectives in these otherwise fatal tumors that merit further investigation in a prospective cooperative trial. |
Schmidt P, Haas RJ, Göbel U, Calaminus G |
[Results of the German studies (MAHO) for treatment of testicular germ cell tumors in children--an update]. |
Klinische Padiatrie 2002, 214: 167 |
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BACKGROUND: The MAHO studies for treatment of testicular germ cell tumors in childhood and adolescence registered between 1982 and 1/2001 260 patients (pts.). Aims of the studies were: 1. Delay of chemotherapy in YST of stage I A. 2. Delay of modified lymphadenectomy for staging in I A tumors. 3. Stepwise reduction of therapy in low stage tumors but increasing therapy in tumors of metastatic pattern. Standard therapy consisted of 4 courses of vinblastine, bleomycin and cisplatin. In stage II C or higher chemotherapy included cisplatin, VP 16 and bleomycin. As salvage therapy VP16, ifosfamide and cisplatin was given. RESULTS: According to histology and stage only 75/260 pts. needed chemotherapy. Out of 140 pts. with YST 139 survived disease free according to a |
Schwabe J, Calaminus G, Vorhoff W, Engelbrecht V, Hauffa BP, Göbel U |
Sexual precocity and recurrent beta-human chorionic gonadotropin upsurges preceding the diagnosis of a malignant mediastinal germ-cell tumor in a 9-year-old boy. |
Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2002, 13: 975 |
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Numerous disorders are known to cause sexual precocity. Beta-human chorionic gonadotropin (beta-HCG)-secreting germ-cell tumors are one of the sources that have to be considered in the differential diagnosis of processes inducing a peripheral precocious puberty. Germ-cell tumors might be located in the ovaries or testes, retroperitoneum, mediastinum or the cranium. We present the case of a 9-year-old boy with sexual precocity and a recurrent transient beta-HCG elevation. After an interval of 2 years with repeated radiological examinations including the mediastinum, a mediastinal tumor was identified by magnetic resonance imaging. To our knowledge, this is the first case of a diagnosis of a mediastinal choriocarcinoma with a recurrent serum beta-HCG elevation. So far, factors that might be responsible for the repeated spontaneous beta-HCG decline are unknown. |
Schneider DT, Schuster AE, Fritsch MK, Calaminus G, Göbel U, Harms D, Lauer S, Olson T, Perlman EJ |
Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents. |
Genes, chromosomes & cancer 2002, 34: 115 |
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Primary mediastinal germ cell tumors (M-GCTs) represent a heterogeneous group of tumors that varies with regard to age at presentation, histologic differentiation, and outcome. We retrospectively analyzed archival tissue samples of mediastinal mature and immature teratomas (n = 15) and malignant nonseminomatous M-GCTs (n = 20) with comparative genomic hybridization (CGH). The aim of this study was to define distinct genetic subgroups of M-GCT among the pediatric cohort that may differ in their clinical behavior and prognosis. All pure teratomas showed normal CGH profiles. Malignant M-GCTs in infants and children < 8 years old most frequently showed a gain of 1q, 3, and 20q and a loss of 1p, 4q, and 6q. Gain of 12p and sex chromosomal abnormalities were not observed in this age group. In contrast, the gain of 12p was the most common aberration in M-GCTs that arose in children > or = 8 years old. Additional recurrent changes included the loss of chromosome 13 and the gain of chromosome 21. All ten adolescents with malignant M-GCT were male, and five showed a gain of the X chromosome. In two of these five patients, Klinefelter syndrome was confirmed by cytogenetic analysis or by fluorescence in situ hybridization (FISH). In conclusion, CGH analysis of M-GCTs defines distinct genetic subgroups. Mediastinal teratomas show no genetic gains or losses. Malignant M-GCTs in children < 8 years old show the same pattern of gains and losses identified in sacrococcygeal and testicular GCTs at this age, and they lack sex-chromosomal abnormalities. Malignant M-GCTs in children > or = 8 years old show the same genetic profile previously reported in gonadal GCTs at this age. In addition, approximately 50% demonstrate a gain of the X chromosome, consistent with Klinefelter syndrome. Cooperative group studies reveal a significantly better prognosis of malignant M-GCT arising in infants compared to that in adolescents, suggesting that these genetic differences are associated with differences in clinical behavior. |
Schaeffeler E, Stanulla M, Greil J, Schrappe M, Eichelbaum M, Zanger U, Schwab M |
A novel TPMT missense mutation associated with TPMT deficiency in a 5-year-old boy with ALL. |
Leukemia 2003, 17: 1422 |
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Schellong G, Riepenhausen M |
Spätfolgen nach Hodgkinscher Krankheit. |
WIR 2003, 1: 18 |
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Schilling F, Spix C, Berthold F, Erttmann R, Klein G, Sander J, Treuner J, Michaelis J |
Neuroblastom-Früherkennung im Alter von einem Jahr in Deutschland. |
Deutsches Ärzteblatt 2003, 25: 1442 |
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Schiltmeyer B, Hempel G, Schwab M, Ritter C, Klingebiel T, Boos J |
Population pharmacokinetics of oral busulfan in children. |
Int J Clin Pharmacol Ther 2003, 40: 385 |
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Schrappe M |
Prognostic factors in childhood acute lymphoblastic leukemia. |
Indian J Pediatr 2003, 70: 817 |
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Schrappe M, Beier R, Burger B |
New treatment strategies in childhood acute lymphoblastic leukaemia. |
Best Pract Res Clin Haematol 2003, 15: 729 |
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Schrappe M, Zimmermann M, Stanulla M, Schrauder A |
Stratifizierung der ALL mit Hilfe des Nachweises minimaler Resterkrankung , Rationale und klinische Rationalisierung. |
Monatsschrift Kinderheilkunde 2003, 2: 138 |
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Schuck A, Ahrens S, Paulussen M, Kuhlen M, Konemann S, Rube C, Winkelmann W, Kotz R, Dunst J, Willich N, Jürgens H |
Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. |
Int J Radiat Oncol Biol Phys 2003, 55: 168 |
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Schuz J, Morgan G, Bohler E, Kaatsch P, Michaelis J |
Atopic disease and childhood acute lymphoblastic leukemia. |
Int J Cancer 2003, 105: 255 |
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Schwab M, Westermann F, Hero B, Berthold F |
Neuroblastoma: biology and molecular and chromosomal pathology. |
Lancet Oncol 2003, 4: 472 |
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Schilling FH, Spix C, Berthold F, Erttmann R, Sander J, Treuner J, Michaelis J |
Children may not benefit from neuroblastoma screening at 1 year of age. Updated results of the population based controlled trial in Germany. |
Cancer letters 2003, 197(1-2): 19 |
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Neuroblastoma is the second most frequent malignancy in childhood. We investigated whether screening for neuroblastoma at 1 year of age reduces the incidence of metastatic disease or mortality. Screening was offered in 6 of the 16 German states from 1995 to 2000 with the remaining states serving as controls. We studied 2,581,188 children in the screening area born between 1994 and 1999 and 2,117,600 in the control area. We compared mortality from neuroblastoma and the incidence of disseminated disease in the two groups. The screened group and the control group had similar rates of stage 4 neuroblastoma and mortality due to neuroblastoma. Comparison of the screened group and the control area revealed substantial over diagnosis in the screened participants. The present findings provide no support for mass screening for neuroblastoma at 1 year of age. |
Schueler AO, Jurklies C, Heimann H, Wieland R, Havers W, Bornfeld N |
Thermochemotherapy in hereditary retinoblastoma. |
Br J Ophthalmol 2003, 87: 90 |
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BACKGROUND/AIM: The combination of chemotherapy and transpupillary thermotherapy, thermochemotherapy (TCT) has become an established part of the treatment plan in advanced retinoblastoma. The aim of this study was to identify safe indications, the complications as well as the limitations of this new treatment for retinoblastoma. METHODS: Tumour response and side effects of TCT with an indirect laser ophthalmoscope (spot size about 400 micro m) in 55 tumours of 26 children with bilateral retinoblastoma were analysed. Using the Reese-Ellsworth classification system, nine of 35 eyes were classified as type I, 13 eyes as type II, 10 eyes as type III, and three eyes as type V. The mean age of the children was 0.74 (SD 0.61) years. The mean tumour height was 3.5 (2.3) mm with a mean diameter of 6.1 (4.1) mm. Treatment parameters were 4.3 (1.6) (median 5) thermochemotherapy sessions with a mean energy of 539 (211) mW and a mean duration of 13.5 (5.6) minutes. Chemotherapy courses (vincristine, etoposide, and carboplatin) were repeated every 3 weeks. The mean follow up period was 1.25 (0.6) years. RESULTS: Local recurrence occurred in 21 tumours (38%), with a mean onset of 3.2 (2.9) months after TCT. The risk of tumour recurrence was correlated with tumour height. The recurrence rate was 17% for tumours with a height less than 2 mm, 37% for tumours with a height between 2 and 4 mm, and 63% for larger retinoblastomas. Multivariate analysis identified fish flesh regression after TCT (p = 0.0007) as the most important risk factor for tumour recurrence besides tumour height (p = 0.001) and the necessity of increased laser power during TCT sessions (p = 0.018). Complications during therapy included transient corneal opacification in two eyes (6%), focal iris atrophy (three eyes, 8.5%), peripheral lens opacity (two eyes, 6%), circumscribed transient retinal detachment (one eye, 3%) and diffuse choroidal atrophy (one eye, 3%). CONCLUSION: TCT using an indirect laser ophthalmoscope with a spot size of about 400 micro m was efficient for retinoblastoma with a tumour height less than 4 mm. In larger tumours, the recurrence rate was unacceptably high. Fish flesh regression after TCT correlates with a higher rate of local tumour recurrence. Treatment related complications occurred in less than 9% of the treated eyes. |
Schneider DT, Jänig U, Calaminus G, Göbel U, Harms D |
Ovarian sex cord-stromal tumors--a clinicopathological study of 72 cases from the Kiel Pediatric Tumor Registry. |
Virchows Archiv : an international journal of pathology 2003, 443: 549 |
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We analyzed 72 patients with ovarian sex cord-stromal tumors (OSCST) registered at the German Pediatric Tumor Registry in Kiel over a 20-year period. Juvenile granulosa cell tumors (JGCT, n=48) were the most frequent histological subtype. In addition, there were 14 Sertoli-Leydig cell tumors, 5 sclerosing stromal tumors, 2 sex cord tumors with annular tubules, 2 thecomas and 1 steroid cell tumor. Stage according to FIGO (International Federation of Gynecologists and Obstetricians) was Ia in 39 patients, Ic in 17 patients, II in 3 patients and III in 1 patient (60 patients with complete data). Compared with adult granulosa cell tumors, JGCT showed pronounced mitotic activity [mean 9.8 mitoses/10 high power field (HPF)], which was significantly higher than in other histological subtypes (2.7/10 HPF, P=0.001). Immunohistochemical analysis revealed frequent coexpression of vimentin (positive in 52/52 examined tumors), cytokeratin (27/33), and inhibin (19/20). Of patients, 12 with Ic or higher stage tumors received adjuvant cisplatinum-based chemotherapy. Event-free survival at 10 years was 0.88 +/- 0.05 (38/43 patients with follow-up data). Outcome significantly correlated with stage and mitotic activity (<20 versus > or =20 mitoses/10 HPF: event-free survival 1.0 versus 0.48 +/- 0.05, P=0.0001). In conclusion, this analysis confirms that the majority of patients with OSCST present at low tumor stage and that prognosis in these patients is excellent. Refractory tumors are characterized by high proliferative activity. Therefore, histopathological evaluation substantially contributes to risk assessment in patients with OSCST and might be useful for therapy stratification in prospective therapeutic protocols. |
Schreiber-Gollwitzer BM, Schröder H, Grießmeier B, Labouvie H, Lilienthal S |
Quantitative und qualitative Erfassung patientenbezogener psychosozialer Tätigkeiten in der pädiatrischen Onkologie und Hämatologie. |
Klin Pädiatr 2003; 215(3): 171 |
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Schenk J, Engelmann D, Rohrschneider W, Zieger B, Semler O, Graf N, Troger J |
Rhabdoid tumors of the kidney in childhood. |
Rofo 2004, 176: 965 |
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Schrappe M |
Evolution of BFM trials for childhood ALL. |
Annals Hematology 2004, 83 Suppl 1:S121-S123 |
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Schuck A, Mattke A, Schmidt B, Kunz D, Harms D, Knietig R, Treuner J, Koscielniak E |
Group II rhabdomyosarcoma and rhabdomyosarcomalike tumors. |
J Clin Oncol 2004, 22: 143 |
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Schellong G (Eds) |
Verhütung und Behandlung schwerer bakterieller Infektionen bei milzlosen Personen – Informationen und Empfehlungen für Ärzte und Patienten. |
Eigenverlag Münster 2004 |
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Schellong G, Riepenhausen M |
Late effects after therapy of Hodgkin's disease: update 2003/04 on overwhelming post-splenectomy infections and secondary malignancies. |
Klinische Padiatrie 2004, 216: 364 |
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BACKGROUND: For a long time, a main focus of paediatric therapy studies for Hodgkin's disease (HD) has been on diminishing adverse late effects. Consequently, the long-term follow-up of patients after HD is very important. The HD late effects project of the GPOH, which evolved from 5 consecutive German-Austrian DAL therapy studies, was aimed at establishing a basis for the further improvement of therapy concepts and of long-term surveillance. PATIENTS AND METHODS: The original cohort consisted of 1 245 study patients from 92 centres enrolled in the DAL studies HD-78 to HD-90 between 1978 and 1995. Initially, follow-up data were submitted by the participating study centres. When the majority of the patients had reached adult age and were no longer seen by the originally treating paediatric colleagues, we contacted them directly by mail every 2-3 years. At the time of analysis (March 2004) information from the preceding 6 years was available in 78.6 % of the patients alive. RESULTS: The median follow-up period of patients at the date of last information was 11.1 years (max. 25.5 years), the median age was 23.7 years (max. 41.1 years). The present report is focused on three out of a wide range of problems evaluated, namely cause of death in 14 patients expired after 10-21 years' follow-up, overwhelming post-splenectomy infections (18 events, 11 fatal), and 46 secondary malignancies. The OS rate after 24 years is 87 % (SE 3 %) in the total group, 83 % (SE 3 %) in 335 asplenic patients, and 93 % (SE 2 %) in 910 non- or partially splenectomised patients. We have initiated activities to improve the prophylactic measures against overwhelming infections in this risk group of asplenic patients. The cumulative incidences of secondary malignancies (SM) after 22 years is 11 % (SE 2 %) for all SM, 10 % (SE 2 %) for solid tumours, 0.8 % (SE 0.5 %) for NHL, and 0.6 % (SE 0.3 %) for leukaemias. The cumulative incidence of breast cancer in female patients at the age of 35 years is 4.0 % (SE 2 %). The effect of reducing the radiotherapy doses in the studies HD-87/HD-90 will become evident within the next years. |
Schenk JP, Waag KL, Graf N, Wunsch R, Jourdan C, Behnisch W, Troger J, Gunther P |
[3D-visualization by MRI for surgical planning of Wilms tumors]. |
RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin 2004, 176: 1447 |
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PURPOSE: To improve surgical planning of kidney tumors in childhood (Wilms tumor, mesoblastic nephroma) after radiologic verification of the presumptive diagnosis with interactive colored 3D-animation in MRI. MATERIALS AND METHODS: In 7 children (1 boy, 6 girls) with a mean age of 3 years (1 month to 11 years), the MRI database (DICOM) was processed with a raycasting-based 3D-volume-rendering software (VG Studio Max 1.1/Volume Graphics). The abdominal MRI-sequences (coronal STIR, coronal T1 TSE, transverse T1/T2 TSE, sagittal T2 TSE, transverse and coronal T1 TSE post contrast) were obtained with a 0.5T unit in 4 - 6 mm slices. Additionally, a phase-contrast-MR-angiography was applied to delineate the large abdominal and retroperitoneal vessels. A notebook was used to demonstrate the 3D-visualization for surgical planning before surgery and during the surgical procedure. RESULTS: In all 7 cases, the surgical approach was influenced by interactive 3D-animation and the information found useful for surgical planning. Above all, the 3D-visualization demonstrates the mass effect of the Wilms tumor and its anatomical relationship to the renal hilum and to the rest of the kidney as well as the topographic relationship of the tumor to the critical vessels. One rupture of the tumor capsule occurred as a surgical complication. For the surgeon, the transformation of the anatomical situation from MRI to the surgical situs has become much easier. CONCLUSION: For surgical planning of Wilms tumors, the 3D-visualization with 3D-animation of the situs helps to transfer important information from the pediatric radiologist to the pediatric surgeon and optimizes the surgical preparation. A reduction of complications is to be expected. |
Schuck A, Kuhlen M, von Schorlemer L, Ahrens S, Hunold A, Konemann S, Dunst J, Winkelmann W, Jürgens H, Willich N |
Radiotherapy in Ewing's tumors of the vertebral column - Results and analysis of local recurrences. |
STRAHLENTHERAPIE UND ONKOLOGIE 180: 24-24 Suppl. 1, JUN 2004 |
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Schneider DT, Calaminus G, Koch S, Teske C, Schmidt P, Haas RJ, Harms D, Göbel U |
Epidemiologic analysis of 1,442 children and adolescents registered in the German germ cell tumor protocols. |
Pediatric blood & cancer 2004, 42: 169 |
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BACKGROUND: Germ cell tumors (GCTs) constitute a heterogeneous group of tumors that significantly vary with respect to their clinical presentation and biology. The objective of this analysis was to analyze a large population-based pediatric cohort of GCTs and to evaluate the parameters age, sex, site of the tumor, histology, and potential correlations between these parameters. PROCEDURE: Between 1981 and 2000, 1,442 patients were prospectively enrolled onto the German protocols for testicular and non-testicular GCTs. Tumors were histologically classified according to the WHO. RESULTS: We observed a bimodal age distribution with a first peak during infancy and a second after the onset of puberty. At birth, almost all tumors were teratomas, sometimes with microfoci of yolk sac tumor, which on the other hand, was the predominant histology during childhood. After the onset of puberty, germinomatous GCTs represented the most frequent histological subtype, and malignant non-germinomatous GCTs often presented as mixed tumors with choriocarcinoma and embryonal carcinoma components. During infancy, non-gonadal GCTs accounted for the majority of GCTs, while after the onset of puberty, gonadal GCTs predominated. Notably, among non-gonadal GCTs, there was a female predominance during childhood and a strong male predominance during adolescence. CONCLUSIONS: Two separate groups of GCTs with distinct clinical features relevant for differential diagnosis and the diagnostic assessment can be distinguished. This observation correlates with genetic studies that reveal different genetic changes in childhood and adolescence GCTs. Further studies are needed to elucidate the molecular mechanisms of germ cell and GCT development that account for the age- and sex-dependent clinical manifestation. |
Schönberger S, Niehues T, Meisel R, Bernbeck B, Laws HJ, Kögler G, Enzmann J, Wernet P, Göbel U, Dilloo D |
Transplantation of haematopoietic stem cells derived from cord blood, bone marrow or peripheral blood: a single centre matched-pair analysis in a heterogeneous risk population. |
Klinische Padiatrie 2004 Nov-Dec; 216: 356 |
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Beside the transplantation of haematopoietic stem cells derived from bone marrow (BMT) and peripheral blood (PBSCT) in the absence of a well-matched donor, transplantation of cord blood (CBT) has been shown to be a valid alternative. To validate the efficacy of CBT in comparison to BMT and PBSCT we performed a single-centre based matched-pair analysis. |
Schuster FR, Simon A, Laws HJ, Beutel K, Groll AH, Jäger G, Schuster V |
Viral Infections in Pediatric Cancer Patients. |
Klin Pädiatr 2005, 217 Suppl 1:S67 |
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Schumacher-Kuckelkorn R, Hero B, Ernestus K, Berthold F |
Lacking immunocytological GD2 expression in neuroblastoma: report of 3 cases. |
Pediatric blood & cancer 2005, 45: 195 |
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Immunocytological bone marrow assessment for contamination with neuroblastoma cells is based on their characteristic GD2 surface staining. Neuroblastoma without GD2 expression have been rarely and only after antibody therapy reported. Conventional cytology was performed using Pappenheim staining. For immunocytology, the APAAP method was utilized with the 14G2a anti-GD2 mouse monoclonal antibody. 7 x 10(5) cells on cytospin preparations were investigated. In 2003, 288 bone marrow samples from 191 neuroblastoma patients were investigated by cytology and immunocytology. Three cases demonstrated GD2 negativity on cytologically unambiguous neuroblastoma cells. Two female cases (94 and 37 months of age) with stage 4 neuroblastoma had GD2 expressing neuroblastoma cells in bone marrow at diagnosis. At 2nd relapse 25 and 23 months after diagnosis and 8 months and 12 months after anti-GD2 antibody treatment (ch14.18), the bone marrow infiltrating neuroblastoma cells lacked GD2 staining. The third patient, a 63-month-old girl with bone marrow replacement by neuroblastoma cells showed at diagnosis a mixture of GD2-unstained tumor clumps and very weakly stained neuroblastoma cells. Neuroblastoma cells may lack GD2 expression at diagnosis and at recurrence. This observation has diagnostic and therapeutic implications. |
Schüz J, Blettner M, Michaelis J, Kaatsch P |
Ursachen von Leukämien im Kindesalter: Resümee einer Fallkontrollstudie des Deutschen Kinderkrebsregisters. |
Dtsch Arztebl 102: A2557-64, 2005. |
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Schenk JP, Engelmann D, Zieger B, Semler O, Wuhl E, Furtwangler R, Graf N, Troger J |
[Radiologic differentiation of rhabdoid tumor from Wilms' tumor and mesoblastic nephroma]. |
Der Urologe. Ausg. A 2005, 44: 155 |
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Differentiation between rhabdoid tumor (RT) and mesoblastic nephroma (MN) and Wilms' tumor (WT) by imaging studies in babies and young children before histological confirmation is useful to start optimal treatment early. Typical radiologic criteria (crescent-shaped subcapsular liquid areas, tumor lobules, blurred tumor borders, metastasis in the lung, and regional lymph nodes) are described.The results of 26 MRI, 30 CT, and 22 ultrasound examinations of 49 patients (22 RT, 19 WT, and 8 MN, age 2-57 months) were analyzed. The above-mentioned radiologic criteria were classified with score values. The score value distribution was analyzed between the tumor entities and by two investigators.RT had significantly higher score values than the MN and WT. The difference between the two investigators was not significant.As a group RT differentiates from the group of WT and MN, but this is not possible in single cases with the radiologic criteria employed. Only if more signs are observed together in one case can a RT be presumed, which may indicate an early biopsy before chemotherapy. |
Schlomm T, Gunawan B, Schulten HJ, Sander B, Thangavelu K, Graf N, Leuschner I, Ringert RH, Fuzesi L |
Effects of chemotherapy on the cytogenetic constitution of Wilms' tumor. |
Clinical cancer research 2005, 11: 4382 |
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The management of Wilms' tumors consists of a combination of surgery, chemotherapy, and possibly radiotherapy. To date, chemotherapy is being risk stratified according to histologic subtype and stage. Although the cytogenetic characteristics of Wilms' tumors are well established, the cytogenetic effects related to chemotherapy are widely unknown. We herein report on comparative genomic hybridization findings in 41 primary Wilms' tumors of blastemal type, of which 19 had received preoperative chemotherapy (PCT group) and 22 did not (non-PCT group). Overall, imbalances could be detected in 32 tumors, with +1q (17 cases), +7q (10 cases), +7p (6 cases), and -7p (6 cases) as the most common changes. Among these, +7q and -7p were both significantly associated with metastatic disease at the time of surgery (P = 0.002 and 0.007, respectively), and +7q was also associated with higher stage (stages III + IV; P = 0.003). There were significant differences in the cytogenetic constitution of tumors between the two treatment groups. As a trend, tumors in the preoperative-chemotherapy group had fewer changes (mean, 2.7) than those in the non-preoperative-chemotherapy group (mean, 3.8), and the frequencies of imbalances at 7p or +7q, respectively, were significantly lower compared with tumors in the non-preoperative-chemotherapy group (2 of 19 versus 10 of 22, P = 0.019; 1 of 19 versus 9 of 22, P = 0.011). In contrast, -1q was common in both the preop-CT group (10 of 19) and the non-preop-CT group (7 of 22). The results suggest that Wilms' tumor clones with +1q are not obliterated by preoperative chemotherapy, whereas cytogenetically more complex clones with +7q and/or imbalances at 7p seem more responsive and are more likely to be eliminated by chemotherapeutic treatment. |
Schenk JP, Schrader C, Furtwangler R, Ko HS, Leuschner I, Graf N, Troeger J |
[MRI-morphology and staging of congenital mesoblastic nephroma: evaluation of a collection with 20 patients]. |
RoFo 2005, 177: 1373 |
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PURPOSE: To differentiate classic and cellular type of congenital mesoblastic nephroma (CMN) in MRI and to evaluate MRI for staging according to the Societe Internationale de Oncologie Pediatrique (SIOP). MATERIAL AND METHODS: MRI examinations of 20 children with CMN (age 1st to 16th months, classic type n = 11, cellular type n = 7, mixed type n = 2) were analyzed retrospectively. Cysts, necrosis, hemmorhage in the tumor, signal intensity, tumor structure, thrombosis and dilatation of renal vein, crossing of the body midline, peripheral contrast-enhancement, tumor volume and existence of a tumor pseudocapsule in contrast to the residual kidney were described. The radiologic stage was compared with the histopathologic stage (infiltration of perirenal fat and infiltration of the renal sinus). RESULTS: Tumors of the classic type (mean volume 67.9 ml) had necrosis in 1 case, crossed the midline in 1 case, had no cysts or bleeding, and had a peripheral contrast-enhancement in 1 case, and were heterogeneous in 9 cases. The cellular type (mean volume 302.8 ml) had tumor necrosis in 6 cases, bleeding in 3 cases, cysts in 3 cases, crossed the midline in 4 cases, and peripheral contrast enhancement in 2 cases, and was predominantly heterogeneous. Mixed tumor types (7 ml and 202 ml) had tumor necrosis in 1 case and crossed the midline in 1 case, a peripheral contrast enhancement in 2 cases and a homogenous structure in 1 case. The signal intensity in T1 w and T2 w images was not specific. The renal vein was inconspicuous in all children. The evaluation of the infiltration in perirenal fatty tissue was true positive in 1 case, true negative in 10 cases, false negative in 4 cases and false positive in 5 cases. The infiltration of the renal hilus was true positive in 10 children, false positive in 8 cases and true negative in 2 cases. CONCLUSION: A typical finding of CMN in MRI is a heterogeneous tumor without demarcation from the rest of the kidney parenchyma by a pseudocapsule. The cellular type of CMN tends to have a higher tumor volume and shows more necrosis, bleeding and cysts than the classic type in MRI. A peripheral contrast-enhancement in MRI is not characteristic for any type of CMN. Local tumor staging is not possible with MRI. |
Schenk JP, Gunther P, Schrader C, Ley S, Furtwangler R, Leuschner I, Edelhauser M, Graf N, Troger J |
[Childhood kidney tumors - the relevance of imaging.] |
Der Radiologe 2005, 45: 1112 |
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Kidney tumors represent 6.2% of malignant tumors in children. History, clinical course and radiological findings are necessary elements in the differential diagnosis of the different renal tumors. In the case of nephroblastoma, chemotherapy is based solely on the radiological diagnosis without prior histology. In therapy-optimizing studies of the Society of Pediatric Oncology and Hematology, preoperative chemotherapy is performed. Therapy monitoring is performed in the course of and after preoperative chemotherapy to verify tumor response. Radiological staging plays a significant role in deciding on further treatment and in operative planning. Three-dimensional visualization of the abdominal situs can assist preoperative planning. In summary, diagnostic imaging in renal tumors in children plays a role in differential diagnosis, staging, monitoring of therapy, and surgical planning. |
Scheiderbauer J, Gnekow AK, Emser A, Hildebrandt G, Bamberg M, Kortmann RD |
Multizentrische prospektive kooperative Studie SIOP/GPOH „Low grade glioma„ im Kindesalter von 1996: Ergebnisse nach Strahlentherapie (Deutschland). |
Strahlenther Onkol 2005, 181 (Sondernr 1): 39 |
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Schrappe M, Creutzig U |
Akute lymphoblastische (ALL) und akute myeloische (AML) Leukämie im Kindesalter. Interdisziplinäre Leitlinie der Deutschen Krebsgesellschaft und der Deutschen Gesellschaft für Pädiatrische Onkologie und Hämatologie. |
AWMF online 2005 |
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Schmidt, RF |
Physiologie des Menschen. |
Springer Verlag 29., vollst. neu bearb. und aktualisierte Aufl., 2005 |
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Schuck A, Ahrens S, von Schorlemer I, Kuhlen M, Paulussen M, Hunold A, Gosheger G, Winkelmann W, Dunst J, Willich N, Jürgens H |
Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials. |
International journal of radiation oncology, biology, physics 2005, 63: 1562 |
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PURPOSE: Treatment results in patients with Ewing tumors of the vertebrae enrolled in the Cooperative Ewing's Sarcoma Study (CESS) 81, 86, and the European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) 92 trials were analyzed with special emphasis on radiation-associated factors. PATIENTS AND METHODS: A retrospective analysis was performed on 116 patients with primary tumors of the cervical, thoracic, or lumbar vertebrae treated between 1981 and 1999. Furthermore, a relapse analysis was done on those patients who underwent radiotherapy and subsequently had a local recurrence. RESULTS: A total of 64.6% of the patients received definitive radiotherapy; 27.5% of patients had surgery and radiotherapy. Only 4 patients (3.4%) underwent definitive surgery. Twenty-seven patients presented with metastases at diagnosis. 22.4% of the total group developed a local relapse. Among the subgroup with definitive radiotherapy, local recurrence was seen in 17 of 75 patients (22.6%). Event-free survival and survival at 5 years were 47% and 58%, respectively. Of the 14 evaluable patients with a local relapse after radiotherapy, 13 were in-field. No correlation between radiation dose and local control could be found. CONCLUSION: Surgery with wide resection margins is rarely possible. The results after definitive radiotherapy in vertebral tumors are comparable to those of other tumor sites when definitive radiotherapy is given. Nearly all local relapses after radiotherapy are in-field. |
Schuck A, Hamelmann V, Bramswig JH, Konemann S, Rube C, Hesselmann S, Riesenbeck D, Horst E, Bolling T, Paulussen M, Jürgens H, Willich N |
Ovarian function following pelvic irradiation in prepubertal and pubertal girls and young adult women. |
Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] 2005, 181: 534 |
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PURPOSE: To analyze the effect of pelvic radiotherapy on ovarian function in prepubertal and pubertal girls and young adult women. PATIENTS AND METHODS: In a retrospective monoinstitutional analysis, patients < 30 years of age at diagnosis were included who had been irradiated between 1979 and 1998. The main tumor types were Hodgkin's disease (38%), Ewing's sarcoma (20%) and nephroblastoma (11%). Patients were classified into three groups according to the position of the ovary in relation to the radiation portals. Group 1 was defined by direct irradiation of both ovaries. Group 2 patients were included with both ovaries potentially located in the radiation portals. In group 3, at least one ovary was not directly irradiated. The median follow-up was 128 months. RESULTS: 16 of 55 analyzed patients were categorized in group 1. In ten of these patients, hormone status was evaluable. The ovarian doses were >/= 15 Gy. Except for one patient treated with 15 Gy all developed hormone failure. Eight of 14 patients of group 2 were evaluable. Seven of these patients developed ovarian failure. 19 of 24 patients in group 3 were evaluable. Nine of these patients developed ovarian failure. The observed difference in the rate of ovarian failure between the groups is statistically significant (p = 0.045). CONCLUSION: All patients receiving > 15 Gy to the ovaries developed hormone failure. In one case of a patient receiving an ovarian dose of 15 Gy, hormone failure was not found. In case of pelvic irradiation excluding at least one ovary, approximately half of the patients developed ovarian dysfunction, probably also due to the effects of polychemotherapy. |
Schellong G, Dörffel W, Claviez A, Körholz D, Mann G, Scheel-Walter HG, Bokkerink JP, Riepenhausen M, Luders H, Potter R, Ruhl U, DAL/GPOH |
Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group. |
Journal of clinical oncology 2005, 23: 6181 |
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PURPOSE: To evaluate a salvage therapy (ST-HD-86) for patients with progressive and relapsed Hodgkin's disease after primary treatment in the pediatric DAL/GPOH studies. The essential chemotherapeutic regimens were ifosfamide, etoposide, and prednisone (IEP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: One hundred seventy-six patients with progression (n = 51) or first relapse (n = 125) were enrolled by 67 centers. The median time from initial diagnosis to progression/relapse was 1.1 year (range, 0.1 to 15.3 years), and the patients' median age was 14.7 years (range, 4.3 to 24.5 years). Salvage chemotherapy consisted of two to three cycles of IEP alternating with one to two cycles of ABVD supplemented in part by one to two cycles of cyclophosphamide, vincristine, procarbazine, and prednisone or lomustine (CCNU), etoposide, and prednimustine. Radiotherapy was given to involved areas using individualized doses. In the 1990s, additional high-dose chemotherapy with autologous stem-cell transplantation (SCT) was introduced for patients with unfavorable prognosis. RESULTS: Disease-free survival (DFS) and overall survival (OS) after 10 years are 62% and 75%, respectively (SE, 4% each). Of 176 patients, 73 suffered second events. The risk-factor analysis revealed the time to progression/relapse as the strongest prognostic factor (P = .0001). Patients with progression have an inferior outcome (DFS, 41%; OS, 51%), whereas patients with late relapse (> 12 months after end of therapy) do well (DFS, 86%; OS, 90%), although none of them received SCT in second remission. CONCLUSION: The result can be considered favorable. Whereas the salvage strategy for progressive disease has to be optimized further, it is possible to reduce intensity and avoid SCT in late relapses after Hodgkin's disease in childhood/adolescence. |
Schneider DT, Calaminus G, Harms D, Göbel U, German Maligne Keimzelltumoren Study Group |
Ovarian sex cord-stromal tumors in children and adolescents. |
The Journal of reproductive medicine 2005, 50: 439 |
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Ovarian sex cord-stromal tumors (OSCSTs) are a heterogeneous group of tumors that develop from the gonadal non-germ-cell component. Despite recent advances in the clinical and histopathologic diagnosis of OSCSTs, a high degree of uncertainty remains with regard to adequate therapy, particularly in patients presenting with microscopic or macroscopic tumor spread. We review the currently available data on the biology and histology of OSCST in children and adolescents. In addition, we summarize the data from our clinical, histopathologic and genetic analyses of patients that were prospectively reported to the German MAKEI protocols for treatment of nontesticular malignant germ cell tumors. Among these patients, juvenile granulosa cell tumors (JGCTs) constitute the most frequent histologic subtype, followed by Sertoli-Leydig cell tumors (SLCTs) and sclerosing stromal tumors. Patients with JGCT and SLCT show greater mitotic activity than do all those with other histologic types. Furthermore, high mitotic activity is associated with adverse outcome. In addition, prognosis correlates with tumor stage according to the International Federation of Obstetrics and Gynecology. Nevertheless, we observed a favorable response to cisplatin-based chemotherapy in the majority of stage II and III tumors. For the whole cohort of 62 patients, event-free survival was 0.87 +/- 0.05 months and overall survival 0.88 +/- 0.05. Genetic analysis of 27 tumors available for comparative genomic hybridization analysis revealed normal profiles in the majority of tumors and whole chromosomal gain, such as a gain of 12 in single tumors, with no consistent pattern with regard to histology or clinical outcome. This analysis confirmed that most OSCSTs present at a low tumor stage and that prognosis in these patients is excellent. Most important, patients at high risk can be identified through clinical and histopathologic analysis, and the majority can be treated successfully with adjuvant cisplatinum-based chemotherapy. Based on this analysis, a prospective study on OSCST in children and adolescents began recruiting cases in 2005. |
Schuck A, Hamelmann V, Brämswig JH, Könemann S, Rübe C, Hesselmann S, Riesenbeck D, Horst E, Bölling T, Paulussen M, Jürgens H, Willich N |
Ovarian function following pelvic irradiation in prepubertal and pubertal girls and young adult women. |
Strahlentherapie und Onkologie 2005, 181: 534 |
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To analyze the effect of pelvic radiotherapy on ovarian function in prepubertal and pubertal girls and young adult women. |
Schneppenheim R, Barthels M, Budde U |
[Inborn and acquired von Willebrand disease]. |
Hamostaseologie 2005, 25: 367 |
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Von Willebrand disease (VWD) is known for its marked heterogeneity which was already recognized by von Willebrand in 1926. The basis of phenotypic differentiation are quantitative and qualitative or functional differences between the different types and subtypes of VWD. Clinical relevant facts for the practitioner on diagnosis and therapy of von Willebrand disease and von Willebrand syndrome are presented. |
Schuck A, Ranft A, Dirksen U, Dunst J, Jürgens H, Willich, N |
Radiotherapy in Ewing tumours: Significance of fractionation. |
Strahlentherapie und Onkologie 2006, 182; 67 |
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Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M |
Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. |
Journal of clinical oncology 2006, 24: 5742 |
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PURPOSE: The role of hematopoietic stem-cell transplantation (SCT) in first complete remission (CR1) for children with very high-risk (VHR) acute lymphoblastic leukemia (ALL) is still under critical discussion. PATIENTS AND METHODS: In the ALL-Berlin-Frankfurt-Münster (BFM) 90 and ALL-BFM 95 trials, 387 patients were eligible for SCT if there was a matched sibling donor (MSD). T-cell ALL (T-ALL) patients with poor in vivo response to initial treatment represented the largest homogeneous subgroup within VHR patients. RESULTS: Of 191 high-risk (HR) T-ALL patients, 179 patients (94%) achieved CR1. Twenty-three patients received an MSD-SCT. Furthermore, in trial ALL-BFM 95, eight matched unrelated donors (MUDs) and five mismatched family donors (MMFDs) were used. The median time to SCT was 5 months (range, 2.4 to 10.8 months) from diagnosis. The 5-year disease-free survival (DFS) was 67% +/- 8% for 36 patients who received an SCT in CR1 and 42% +/- 5% for the 120 patients treated with chemotherapy alone having an event-free survival time of at least the median time to transplantation (Mantel-Byar, P = .01). Overall survival (OS) rate for the SCT group was 67% +/- 8% at 5 years, whereas patients treated with chemotherapy alone had an OS rate of 47% +/- 5% at 5 years (Mantel-Byar, P = .01). Outcome of patients who received MSD-SCT versus MUD-/MMFD-SCT was comparable (DFS, 65% +/- 10% v 69% +/- 13%, respectively). However, relapses only occurred after MSD-SCT (eight of 23 patients), whereas treatment-related mortality only occurred after MUD-/MMFD-SCT (four of 13 patients). CONCLUSION: SCT in CR1 is superior to treatment with chemotherapy alone for childhood HR-T-ALL. |
Schmidt M, Simon T, Hero B, Eschner W, Dietlein M, Sudbrock F, Bongartz R, Berthold F, Schicha H |
Is there a benefit of 131 I-MIBG therapy in the treatment of children with stage 4 neuroblastoma? A retrospective evaluation of The German Neuroblastoma Trial NB97 and implications for The German Neuroblastoma Trial NB2004. |
Nuklearmedizin. Nuclear medicine 2006, 45: 145-51; quiz N39 |
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AIM: (131)I-meta-iodobenzylguanidine ((131)I-MIBG) therapy has been used in neuroblastoma treatment for many years but its value in high intensive first line treatment protocols is not exactly known. PATIENTS, METHODS: Stage 4 neuroblastoma patients >1 year with (123)I-MIBG positive residual disease (primary tumour and/or metastasis) after complete induction chemotherapy according to the German neuroblastoma trial NB97 were retrospectively analyzed. RESULTS: One-hundred-eleven patients had (123)I-MIBG positive residual disease after complete induction chemotherapy. Forty patients received (131)I-MIBG therapy using a median activity of 0.44 GBq/kg body weight. By univariate analysis, patients who underwent (131)I-MIBG therapy had a better 3-year event free survival (3-y-EFS 46 +/- 8%) and 3-year overall survival (3-y-OS 58 +/- 9%) than 71 patients without (131)I-MIBG therapy (3-y-EFS 19 +/- 5%, p = 0.003; 3-y-OS 43 +/- 6%, p = 0.037). However, subgroup analysis of 66 patients who underwent high dose chemotherapy with autologous stem cell transplantation (ASCT) during treatment found a very similar outcome with (131)I-MIBG therapy (3-y-EFS 49 +/- 9%, 3-y-OS 59 +/- 10%) and without (131)I-MIBG therapy (3-y-EFS 33 +/- 9%, p = 0.171; 3-y-OS 59 +/- 9%, p = 0.285) due to the dominating effect of ASCT. By multivariate analysis, (131)I-MIBG therapy had no impact on EFS (p = 0.494) and OS (p = 0.891). Only ASCT, external beam radiation therapy and MYCN amplification were important for EFS and OS. CONCLUSIONS: An independent advantage of I-131-MIBG therapy could not be proven in this retrospective analysis. The ongoing German Neuroblastoma Trial NB2004 will address the influence of (131)I-MIBG therapy with emphasis on tumour dosimetry. |
Schneider DT, Zahn S, Sievers S, Alemazkour K, Reifenberger G, Wiestler OD, Calaminus G, Göbel U, Perlman EJ |
Molecular genetic analysis of central nervous system germ cell tumors with comparative genomic hybridization. |
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2006, 19: 864 |
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The limited information available to date regarding the genetic alterations in germ cell tumors of the central nervous system has raised concerns about their biologic relationship to other germ cell tumor entities. We investigated fresh-frozen or archival tumor samples from 19 patients with central nervous system germ cell tumors (CNS-GCTs), including seven germinomas, eight malignant nongerminomatous germ cell tumors and four teratomas, using chromosomal comparative genomic hybridization to determine recurrent chromosomal imbalances. All 15 malignant CNS-GCTs and two of four teratomas showed multiple chromosomal imbalances. Chromosomal gains (median: 4 gains/tumor, range: 0-9 gains/tumor) were observed more frequently than losses (median: 1.6 losses/tumor, range: 0-6 losses/tumor). Gain of 12p, which is considered characteristic for germ cell tumors of the adult testis, was detected in 11 of 19 tumors and 10 of 15 malignant CNS-GCTs. In one tumor, gain of 12p was confined to an amplicon at 12p12, corresponding to the commonly amplified region on 12p. Other common gains were found on chromosome arms 1q and 8q (n = 9, each). Among the chromosomal losses, parts of chromosome 11 (n = 5), 18 (n = 4), and 13 (n = 3) were deleted most frequently. Notably, we observed no difference in the genetic profiles of germinomatous and nongerminomatous CNS-GCTs; however, the average number of imbalances was higher in the latter group. A meta-analysis comparing 116 malignant gonadal and extragonadal germ cell tumors revealed that the genomic alterations in CNS-GCTs are virtually indistinguishable from those found in their gonadal or other extragonadal counterparts of the corresponding age group. These data strongly argue in favor of common pathogenetic mechanisms in gonadal and extragonadal germ cell tumors. |
Schrappe M, Harbott J, Riehm H |
Akute lymphoblastische Leukämien. |
In: Gadner H, Gaedicke G, Niemeyer C, Ritter J, editors. Pädiatrische Hämatologie und Onkologie Berlin, Heidelberg, New York: Springer Verlag, 2006, 656-679. |
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Schneppenheim R, Zieger B |
Physiologie und Pathophysiologie von plasmatischer Gerinnung und Fibrinolyse. |
In: Gadner H, Gaedicke G, Niemeyer C, et al., editors. Pädiatrische Hämatologie und Onkologie Springer Medizin Verlag Heidelberg; 2006. p 373 |
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Schüz J, Weihkopf T, Kaatsch P |
Medication use during pregnancy and the risk of childhood cancer in the offspring. |
European journal of pediatrics 2007, 166: 433 |
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The young age at onset of many cancers in childhood has led to investigations on maternal exposures during pregnancy. Data from a population-based case-control study in Germany (1992-1997) that included 1,867 cases and 2,057 controls was used to investigate this question. Maternal use of vitamin, folate or iron supplementation was associated with a reduced risk of non-Hodgkin lymphoma and tumors and, less clearly, with leukemia, but not with CNS tumors. An increased risk of neuroblastoma was associated most markedly with diuretics and other antihypertensives, but also with vitamin, folate or iron supplementation. No associations were seen with pain relievers, antinauseants or cold medications, nor with delivery by Caesarian section. The strengths of this study are its population base, the large number of cases and the inclusion of different case groups to identify disease specificity of associations. The limitation of this study is an exposure assessment relying on maternal self-reports. In conclusion, these data indicate a potential influence of some maternal medication during pregnancy on the risk of childhood cancer in the offspring; however, no clear picture is seen. |
Schwartz S, Borner K, Müller K, Martus P, Fischer L, Korfel A, Auton T, Thiel E |
Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. |
Oncologist 2007, 12: 1299 |
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Leucovorin and extracorporeal removal of methotrexate (MTX) have limited efficacy in delayed MTX elimination after high-dose methotrexate (HD-MTX) therapy. Glucarpidase (carboxypeptidase G2) cleaves MTX into nontoxic metabolites, but experience with this enzyme is limited in adult patients. We evaluated the effects of glucarpidase intervention in adult and elderly patients with delayed MTX elimination. |
Schreiber-Gollwitzer BM, Rauscher-Lacher, H |
Kognitive Spätfolgen nach allogener oder autologer Stammzelltransplantation im Kindesalter. |
WIR - Die Zeitschrift der Deutschen Leukämie-Forschungshilfe e.V. und der Deutschen Kinderkrebsstiftung 4 / 2007 |
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Schaefer KL, Eisenacher M, Braun Y, Brachwitz K, Wai DH, Dirksen U, Lanvers-Kaminsky C, Jürgens H, Herrero D, Stegmaier S, Koscielniak E, Eggert A, Nathrath M, Gosheger G, Schneider DT, Bury C, Diallo-Danebrock R, Ottaviano L, Gabbert HE, Poremba C |
Microarray analysis of Ewing's sarcoma family of tumours reveals characteristic gene expression signatures associated with metastasis and resistance to chemotherapy. |
European journal of cancer (Oxford, England : 1990) 2008, 44: 699 |
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In Ewing's sarcoma family of tumours (ESFT), the clinically most adverse prognostic parameters are the presence of tumour metastasis at time of diagnosis and poor response to neoadjuvant chemotherapy. To identify genes differentially regulated between metastatic and localised tumours, we analysed 27 ESFT specimens using Affymetrix microarrays. Functional annotation of differentially regulated genes revealed 29 over-represented pathways including PDGF, TP53, NOTCH, and WNT1-signalling. Regression of primary tumours (n=20) induced by polychemotherapy was found to be correlated with the expression of genes involved in angiogenesis, apoptosis, ubiquitin proteasome pathway, and PI3 kinase and p53 pathways. These findings could be confirmed by in vitro cytotoxicity assays. A set of 46 marker genes correctly classifies these 20 tumours as responding versus non-responding. We conclude that expression signatures of initial tumour biopsies can help to identify ESFT patients at high risk to develop tumour metastasis or to suffer from a therapy refractory cancer. |
Schrauder A, von Stackelberg A, Schrappe M, Cornish J, Peters C, ALL-BFM Study Group, EBMT PD WP, I-BFM Study Group |
Allogeneic hematopoietic SCT in children with ALL: current concepts of ongoing prospective SCT trials. |
Bone marrow transplantation 2008, 41 Suppl 2:S71 |
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The definition of indications for allogeneic SCT in children with high-risk (HR) ALL in the first remission or after the first or subsequent relapse depends on biological features, response to treatment and survival after chemotherapy alone. As the results of frontline and relapse protocols are improving over time, there is a strong need for prospective SCT trials, ensuring a well-standardized procedure regarding all relevant components that are potentially responsible for heterogeneity in post-SCT outcome. Therefore, in 2003, the ALL-BFM and the ALL-REZ BFM Study Group initiated a prospective, international, multicenter trial (ALL-SCT-BFM 2003). This trial will now be extended to a larger consortium, trial ALL-SCT-BFM-international (ALL-SCT-BFMi). Strict rules define HLA-typing, donor selection, conditioning regimen, GvHD prophylaxis and therapy as well as standards of supportive care to reduce treatment-related mortality and establish an early GVL effect. Moreover, comprehensive and closely reviewed documentation and serious adverse event reporting shall ensure high study quality. Case-by-case discussions of any fatal or critical course during annual meetings will improve the culture of failure management and lead to modifications of guidelines of supportive care. Finally, the results of these prospective trials will determine the current potential of the different SCT procedures in HR or relapsed childhood ALL. |
Schmidt M, Simon T, Hero B, Schicha H, Berthold F |
The prognostic impact of functional imaging with (123)I-mIBG in patients with stage 4 neuroblastoma >1 year of age on a high-risk treatment protocol: results of the German Neuroblastoma Trial NB97. |
European journal of cancer (Oxford, England : 1990) 2008, 44: 1552 |
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AIM/PURPOSE: (123)I-meta-iodobenzylguanidine ((123)I-mIBG) scintigraphy is well established for staging and evaluation of response in children with high-risk neuroblastoma but its prognostic value in highly intensive first-line treatment protocols is uncertain. The presence of any (123)I-mIBG positive tumour tissue was correlated with event-free survival (EFS) and overall survival (OS). PATIENTS AND METHODS: The prognostic impact of residual (123)I-mIBG uptake into the primary tumour and metastases for predicting outcome in 113 stage 4 neuroblastoma patients >1 year of the German Neuroblastoma Trial NB97 was assessed using a univariate log-rank test and multivariate Cox regression analysis. RESULTS: All patients had (123)I-mIBG positive disease at initial staging. After four courses of induction chemotherapy, 71% of patients were still (123)I-mIBG positive for the primary tumour and 61% for metastases. After six courses, 39% of patients had (123)I-mIBG uptake by the primary tumour and 45% residual (123)I-mIBG positive metastatic disease. The (123)I-mIBG status of the primary tumour site had no bearing on outcome. Residual (123)I-mIBG positive metastatic disease after four (3-y-EFS 25.7+/-5.3% versus 55.9+/-7.6%, p=0.009; 3-y-OS 49.8+/-6.1% versus 65.0+/-7.3%; p=0.021) and after six chemotherapy cycles (3-y-EFS 27.5+/-6.2% versus 47.4+/-6.4%, p=0.011; 3-y-OS 50.5+/-7.1% vs 60.0+/-6.4%, p=0.031) was associated with poor outcome. CONCLUSION: Functional imaging with (123)I-mIBG scintigraphy can identify poor responders with any persistent metastatic (123)I-mIBG uptake who are at a high risk of disease relapse. (123)I-mIBG response of the primary tumour site had no bearing on outcome. |
Schrappe M |
Risk-adapted stratification and treatment of childhood acute lymphoblastic leukaemia. |
Radiation protection dosimetry 2008, 132: 130 |
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Systematic enrollment of children and adolescents with acute lymphoblastic leukaemia (ALL) into clinical trials has allowed the establishment of prognostic parameters derived from initial diagnostic findings. More important, these trials have significantly contributed to the reduction of disease recurrence as much as to the reduction of acute and late side effects. Some problems that are related to the specificity of the parameters used for risk assessment were not overcome: high tumour load by white blood cell count (WBC), age and (rare) cytogenetic subtypes (e.g. t9;22) may characterise a significant proportion of children and adolescents with high-risk ALL. Most patients who will eventually relapse do not present with characteristic features at initial diagnosis. It appears feasible through careful response assessment to identify these patients at risk of relapse, who present initially without specific features. Earlier trials of the ALL-BFM (Berlin/Frankfurt/Münster) study group and others have demonstrated that inadequate leukaemic blast reduction in the peripheral blood or bone marrow after the first few days of therapy is highly predictive of treatment failure. Using clone-specific polymerase chain reaction-based detection of minimal residual disease (MRD) as done in trial AIEOP-BFM ALL 2000 allowed a close surveillance of specific treatment elements when applied in MRD positive patients. This may facilitate innovative chemotherapy approaches and a more rational use of allogeneic haematopoetic stem cell transplantation. In addition, genetic signatures of treatment response or failure have been identified. |
Schneppenheim R, Budde U |
[Inborn and acquired von Willebrand disease]. |
Hamostaseologie 2008, 28: 312 |
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Von Willebrand disease (VWD) is known for its marked heterogeneity which was already recognized by von Willebrand in 1926. The basis of phenotypic differentiation are quantitative and qualitative or functional differences between the different types and subtypes of VWD. Clinical relevant facts for the practioner on diagnosis and therapy of von Willebrand disease and von Willebrand syndrome are presented. |
Schneppenheim R, Budde U |
Angeborenes und erworbenes von Willebrand-Syndrom. |
Hamostaseologie 2008, 28: 312 |
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Von Willebrand disease (VWD) is known for its marked heterogeneity which was already recognized by von Willebrand in 1926. The basis of phenotypic differentiation are quantitative and qualitative or functional differences between the different types and subtypes of VWD. Clinical relevant facts for the practioner on diagnosis and therapy of von Willebrand disease and von Willebrand syndrome are presented. |
Schüz J, Ahlbom A |
Exposure to electromagnetic fields and the risk of childhood leukaemia: a review. |
Radiation protection dosimetry 2008, 132: 202 |
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Schmid H, Jaeger B, Lohse J, Suttorp M |
Longitudinal growth retardation in a prepuberal girl with chronic myeloid leukemia on long-term treatment with imatinib. |
Haematologica 2009, 94: 1177 |
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Schwarz AK, Stanulla M, Cario G, Flohr T, Sutton R, Möricke A, Anker P, Stroun M, Welte K, Bartram CR, Schrappe M, Schrauder A |
Quantification of free total plasma DNA and minimal residual disease detection in the plasma of children with acute lymphoblastic leukemia. |
Annals of hematology 2009, 88: 897 |
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The analysis of total plasma DNA and the monitoring of leukemic clone-specific immunoglobulin and/or T-cell receptor gene rearrangements for the evaluation of minimal residual disease (MRD) in the plasma may be useful tools for prognostic purposes or for early detection of subclinical disease recurrence in children with acute lymphoblastic leukemia (ALL). The aim of this paper is to establish reference ranges for total plasma DNA concentrations and to test the feasibility of MRD measurements employing plasma DNA from children with ALL by using real-time quantitative (RQ)-PCR. Despite wide inter-individual variation, the median concentrations of total plasma DNA for 12 healthy donors (57 ng/ml), 21 children with ALL after day 4 of treatment initiation (62 ng/ml) and 13 children with other malignancies (76 ng/ml) were similar. However, ALL patients had significantly higher concentrations at diagnosis (277 ng/ml) and on treatment day 3 (248 ng/ml) before returning to normal afterwards. Early plasma DNA MRD kinetics could be established for 15 ALL patients and showed good concordance with bone marrow MRD. Plasma DNA was higher in children with ALL at diagnosis but returned to normal within the first four treatment days. Despite low concentrations of DNA, it is feasible to measure MRD kinetics in plasma DNA during ALL induction therapy by adapted real-time PCR methodologies. |
von Schweinitz, D |
Tumoren der Leber, des Pankreas und des Gastrointestinaltraktes. |
Kinderchirurgie |
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Primäre Tumoren der Leber, des Pankreas oder des Gastrointestinaltraktes kommen im Kindesalter sehr selten vor. Dabei kann man in allen drei Organen auf eine große Variabilität der Entitäten stoßen, von denen die Mehrzahl maligne ist. Säuglinge und junge Kinder erkranken außer an gutartigen Tumoren der Leber und des Pankreas vor allem an embryonalen malignen Tumoren dieser Organe, dem Hepatoblastom und dem Pankreatoblastom. Diese zeigen ein gutes Ansprechen auf Chemotherapie. Therapeutisch steht bei den benignen Tumoren, wie auch bei den übrigen malignen Neoplasien der Leber (hepatozelluläres Karzinom, Sarkome), des Pankreas (Pankreaskarzinom) und des Magen-Darm-Traktes (Karzinome) die komplette chirurgische Resektion im Vordergrund. Wie beim Erwachsenen wirken Chemotherapie und Bestrahlung bei den Karzinomen auch des Kindesalters nur schlecht. Während Kinder und Jugendliche mit benignen Tumoren eine gute, solche mit embryonalen malignen Tumoren eine mäßige Überlebenschance haben, ist diese bei Karzinompatienten in der Regel sehr schlecht. |
Schmitz N, Sureda A, Dini G, Claviez A, Lymphoma and Pediatric Diseases Working Parties |
Allogeneic transplantation for children and adolescents with Hodgkin lymphoma. |
Blood 2009 Nov 12; 114: 4605 |
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Schwarz K, Iolascon A, Verissimo F, Trede NS, Horsley W, Chen W, Paw BH, Hopfner KP, Holzmann K, Russo R, Esposito MR, Spano D, De Falco L, Heinrich K, Joggerst B, Rojewski MT, Perrotta S, Denecke J, Pannicke U, Delaunay J, Pepperkok R, Heimpel H |
Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. |
Nature genetics 2009, 41: 936 |
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Congenital dyserythropoietic anemias (CDAs) are phenotypically and genotypically heterogeneous diseases. CDA type II (CDAII) is the most frequent CDA. It is characterized by ineffective erythropoiesis and by the presence of bi- and multinucleated erythroblasts in bone marrow, with nuclei of equal size and DNA content, suggesting a cytokinesis disturbance. Other features of the peripheral red blood cells are protein and lipid dysglycosylation and endoplasmic reticulum double-membrane remnants. Development of other hematopoietic lineages is normal. Individuals with CDAII show progressive splenomegaly, gallstones and iron overload potentially with liver cirrhosis or cardiac failure. Here we show that the gene encoding the secretory COPII component SEC23B is mutated in CDAII. Short hairpin RNA (shRNA)-mediated suppression of SEC23B expression recapitulates the cytokinesis defect. Knockdown of zebrafish sec23b also leads to aberrant erythrocyte development. Our results provide in vivo evidence for SEC23B selectivity in erythroid differentiation and show that SEC23A and SEC23B, although highly related paralogous secretory COPII components, are nonredundant in erythrocyte maturation. |
Schrappe M, Nachman J, Hunger S, Schmiegelow K, Conter V, Masera G, Pieters R, Pui CH |
Educational symposium on long-term results of large prospective clinical trials for childhood acute lymphoblastic leukemia (1985-2000). |
Leukemia 2010, 24: 253 |
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Schrey D, Borghorst S, Lanvers-Kaminsky C, Hempel G, Gerss J, Möricke A, Schrappe M, Boos J |
Therapeutic drug monitoring of asparaginase in the ALL-BFM 2000 protocol between 2000 and 2007. |
Pediatric blood & cancer 2010, 54: 952 |
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BACKGROUND: On a voluntary basis therapeutic drug monitoring (TDM) was implemented in the ALL-BFM 2000 protocol for the three currently used asparaginase (ASNase) preparations (first line: native Escherichia coli ASNase; second line: pegylated ASNase and third line: Erwinia chrysanthemi ASNase). PROCEDURE: Between 2000 and 2007, 2,074 ASNase samples from 763 patients out of 114 hospitals were evaluated (5,000 U/m2 E. coli ASNase (n = 318), 1,000 U/m2 pegylated ASNase (n = 416) and 10,000 U/m2 Erwinia chrysanthemi ASNase (n = 29)). RESULTS: First-line therapy with 5,000 U/m2 E. coli ASNase resulted in an ASNase activity of <100 U/L in 10% of all samples from day +3 after administration. Second-line treatment with 1,000 U/m2 PEG ASNase led to activity values below 100 U/L in approximately 30% of all samples taken +7 days. Relating ASNase activity to route of administration, 10,000 U/m2 Erwinia ASNase IM compared to IV as third-line treatment, led to a higher median activity (IM: median 151.5 U/L, range (0-750 U/L); IV: median 115 U/L, range (0-884 U/L), P = 0.3) and fewer samples below 100 U/L (IM: 15% vs. IV: 45%) at day +2. CONCLUSION: The reduced dose of 5,000 U/m2 E. coli ASNase for induction treatment succeeded to achieve an activity level above 100 U/L in more than 90% of all samples. They confirm that dose reduction is reasonable and provide the basis for future treatment strategies employing ASNase. |
Schwarz R, Bruland O, Cassoni A, Schomberg P, Bielack S |
The role of radiotherapy in oseosarcoma. |
Cancer treatment and research 2010, 152: 147 |
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A survey of the literature shows that the experience with radiotherapy (RT) in the local treatment of osteosarcoma (OS) is limited. This is due to various reasons: OS is a rare tumor and surgery is the treatment of choice with high local control rate, and uncertainty exists in regard to the efficacy and tolerance of radiotherapy. Publications on this topic were analyzed and will be reviewed. Furthermore, experience from the Cooperative Osteosarkomstudiengruppe (COSS)-Registry, including 100 patients (pts) treated using radiotherapy for OS, was analyzed.The COSS-registry includes a total of 175 pts (5% of all pts) with histologically proven OS irradiated over the period of 1980-2007. 100 pts were eligible for analysis. The median age was 18 (3-66) years. Indication for RT was a primary tumor in 66, a local recurrence in 11, and metastases in 23 pts. 94 pts got external photontherapy; 2 pts, proton therapy; 2 pts, neutron therapy; and 2 pts, intraoperative RT. In addition, a group of 17 pts received bone-targeted radionuclide therapy by samarium-153-EDTMP-therapy alone or in combination with external RT. The median dose for external RT was 55.8 Gy (30-120). All the pts received chemotherapy in accordance with different COSS-protocols.The median follow-up was 1.5 (0.2-23) years. Survival and local control rates at 5 years were calculated, and univariate and multivariate analyses performed. 41 pts are alive, 59 pts died. The overall survival rate after biopsy was 41% at 5 years, while the overall survival rates after RT for the whole group, for treatment of primary tumors, local recurrence, and metastases were 36%, 55%, 15%, and 0% respectively.In 41 cases, local control was achieved, whereas local progression or local recurrence occurred in 59 cases, with a median time to local recurrence of 0.5 (0.1-4) years after RT. 15 pts were nonresponders to radiotherapy. Local control for the whole group was 30%. Local control rates for combined surgery and RT were significantly better than those for RT alone (48% vs. 22%, p=0.002). Local control for treatment of primary tumors, local recurrence, and metastases were 40%, 17%, and 0% respectively. Local control for pts given an addition of samarium-153-EDTMP was poor, though not statistically significant . A dose of over 60 Gy had no significant effect on local control. Prognostic factors for survival were indication for RT, RT plus surgery vs. RT alone and tumor location. Prognostic factors for local control were indication for RT, and RT plus surgery vs. RT alone.For the majority of pts, surgery remains the local treatment of choice. Radiotherapy is an important option as local treatment of unresectable tumors, following intralesional resection, or as palliation of symptomatic metastases. Survival prognosis of such pts, however, is poor. Despite the fact that many of these pts will eventually die, they may benefit in terms of prolonged survival and prolonged local control. The combination of surgery, radiotherapy, and chemotherapy can be curative. The consistent use of full-dose chemotherapy is of importance for the response to radiotherapy. Prognostic factors for survival are indication for RT, RT plus surgery vs. RT alone and tumor location. Prognostic factors for local control are indication for RT, and RT plus surgery vs. RT alone. |
Schneppenheim R, Frühwald MC, Gesk S, Hasselblatt M, Jeibmann A, Kordes U, Kreuz M, Leuschner I, Martin Subero JI, Obser T, Oyen F, Vater I, Siebert R |
Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. |
American journal of human genetics 2010, 86: 279 |
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Rhabdoid tumors of early infancy are highly aggressive with consequent poor prognosis. Most cases show inactivation of the SMARCB1 (also known as INI1 and hSNF5) tumor suppressor, a core member of the ATP-dependent SWI/SNF chromatin-remodeling complex. Familial cases, described as rhabdoid tumor predisposition syndrome (RTPS), have been linked to heterozygous SMARCB1 germline mutations. We identified inactivation of another member of the SWI/SNF chromatin-remodeling complex, its ATPase subunit SMARCA4 (also known as BRG1), due to a SMARCA4/BRG1 germline mutation and loss of heterozygosity by uniparental disomy in the tumor cells of two sisters with rhabdoid tumors lacking SMARCB1 mutations. SMARCA4 is thus a second member of the SWI/SNF complex involved in cancer predisposition. Its general involvement in other tumor entities remains to be established. |
Schellong G, Riepenhausen M, Bruch C, Kotthoff S, Vogt J, Bölling T, Dieckmann K, Pötter R, Heinecke A, Brämswig J, Dörffel W |
Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for hodgkin disease in children and adolescents: Report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD studies. |
Pediatric blood & cancer 2010, 55: 1145-52. |
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BACKGROUND: To analyze the impact of mediastinal irradiation on the incidence of cardiac late effects in long-term survivors of pediatric Hodgkin disease (HD). METHODS: The study cohort comprised 1,132 survivors of HD who received treatment before 18 years of age in consecutive trials between 1978 and 1995. They had maintained remission without secondary malignancy for 3.1-29.4 years. The cumulative doxorubicin dose was uniformly 160 mg/m(2), the mediastinal radiation dose (MedRD) was 36, 30, 25, 20, or 0 Gy. Follow-up questionnaires complemented by additional contacts served to collect information on late effects from patients and physicians. A central expert panel reviewed all reported cardiac abnormalities. RESULTS: By October 2008, cardiac diseases (CD) had been diagnosed in 50 of 1,132 patients aged 15.0-41.7 (median 32.2) years. The interval since HD therapy was 3.0-28.2 (median 19.5) years. Valvular defects were diagnosed most frequently, followed by coronary artery diseases, cardiomyopathies, conduction disorders, and pericardial abnormalities. The cumulative incidence of CD after 25 years was highest in the MedRD-36 group (21%) decreasing to 10%, 6%, 5%, and 3% in the lower MedRD groups (P < 0.001). Multivariate Cox analysis of several putative risk factors showed MedRD to be the only significant variable predicting for CD-free survival (P = 0.0025). CONCLUSIONS: Our results indicate that lower MedRDs are less cardiotoxic. Consequently, reduction of cardiac late effects may be expected with the lower radiation doses used in current HD protocols. Longer follow-up is needed to confirm the present results. Pediatr Blood Cancer. (c) 2010 Wiley-Liss, Inc. |
Schneider DT, Brecht IB |
Care for rare cancers: improved care requires improved communication. |
Klinische Padiatrie 2010, 222: 124 |
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Schneider DT, Brecht I |
Ein Netzwerk für besonders seltene Tumoren. |
WIR 2010, 3/10, 18 |
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Schädlich D, Friebel D, Schallner J, Gehrisch S, Siegert G, Kuhlisch E, Knöfler R |
[Evaluation of haemostasis in children treated with valproic acid]. |
Hamostaseologie 2010, 30 Suppl 1:S132 |
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Coagulation parameters were determined in children with valproic acid mono- and valproic acid-lamotrigin combination therapy. Patients, methods: Monotherapy group (n = 22; mean age: 10.5 years) was compared to combination therapy (n = 7; 12.9 years) and a control group (n = 22; 8.7 years). The following parameters were measured: aggregation and ATP-release in whole blood (ADP: 20 μmol/l, collagen: 1 μg/ml, thrombin: 0.5 U/ml), PFA-100® closure times (CT), blood cell counts, global tests, VWF:Ag, VWF:CBA, factors VIII and XIII as well as fibrinogen. Bleeding symptoms were evaluated by using a questionnaire. Results: For ADP- and collagen-induced aggregation as well as for ATP release no significant differences between the groups were detected. The combined therapy group showed significantly prolonged CT. Von Willebrand disease was not detected in any of the patients. The platelet count was significantly decreased in the monotherapy group. In six children a mild bleeding tendency was observed, mostly epistaxis. Conclusion: A clinically relevant influence of valproic acid on haemostasis was found only in few cases. However, before surgical procedures an extended coagulation diagnostics is recommended in patients with valproic acid therapy. |
Schramm W, Krebs H |
Hämophilie-Patienten in Deutschland 2008/2009 Morbidität und Mortalität. |
Hämostaseologie Supplement 2010 2010, 30: Supplementum 1: S9-S14 |
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Seit 1978 wird jährlich die multizentrische Untersuchung zur Epidemiologie bei Patienten mit Hämophilie mit der Unterstützung von Hämophiliezentren und Behandlungseinrichtungen jeglicher Größe durchgeführt. Auch die aktuelle Zusammenstellung beruht wieder auf einer breiten Datenbasis aus inzwischen über 30 Jahren und vermag sowohl den aktuellen als auch den retrospektiven Morbiditäts- und Mortalitäts-Status gut abzubilden. Abgefragt wurden dabei Informationen ausschließlich zu Patienten mit Hämophilie A, B und von Willebrand-Erkrankung. Im Einzelnen wurden anonymisierte Daten zur Gesamtzahl an behandelten Patienten, Typ und Schweregrad der Erkrankung, HIV-Status und Todesursachen abgefragt. Diese Datensätze wurden mit den vorhandenen Datensätzen zusammengeführt und statistisch ausgewertet. Insgesamt wurde für den Untersuchungszeitraum 2008/2009 eine Gesamtzahl von 9101 Patienten aus 66 Behandlungseinrichtungen gemeldet. Obwohl die Mortalität durch HIV/AIDS bei Patienten mit Hämophilie immer weiter abnimmt, bleibt HIV immer noch ein wichtiges Problem, insbesondere da eine HIV/HCV Koinfektion das Risiko einer schweren Lebererkrankung erhöhen kann. Die Altersstruktur unserer Patienten hat sich in im Laufe der letzten Jahrzehnte erheblich verändert und nähert sich zunehmend an die Normalbevölkerung an, so dass dies bei der Beurteilung der Mortalität und Morbidität beachtet werden muss. |
Schellong G, Riepenhausen M, Bruch C, Kotthoff S, Vogt J, Bölling T, Dieckmann K, Pötter R, Heinecke A, Brämswig J, Dörffel W |
Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for Hodgkin disease in children and adolescents: report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD studies. |
Pediatric blood & cancer 2010, 55: 1145 |
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To analyze the impact of mediastinal irradiation on the incidence of cardiac late effects in long-term survivors of pediatric Hodgkin disease (HD). |
Schmid S |
Der Zahlen-GAU. |
Neue Zürcher Zeitung am Sonntag Online 20.03.2011 |
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Schmitz M, Breithaupt P, Scheidegger N, Cario G, Bonapace L, Meissner B, Mirkowska P, Tchinda J, Niggli FK, Stanulla M, Schrappe M, Schrauder A, Bornhauser BC, Bourquin JP |
Xenografts of highly resistant leukemia recapitulate the clonal composition of the leukemogenic compartment. |
Blood 2011,Epub ahead of print |
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Clonal evolution of the leukemogenic compartment may contribute to alter the therapeutic response in acute lymphoblastic leukemia (ALL). Using xenotransplantation of primary leukemia cells we evaluated the phenotypic and genetic composition of de novo resistant very high risk (VHR) precursor B-cell ALL, a subgroup defined by the persistence of minimal residual disease (MRD) despite intensive chemotherapy. Analysis of copy number alterations (CNA) showed that the xenografted leukemia, even when reconstituted from hundred cells, remained highly related to the diagnostic sample, with minor changes in CNAs, mostly deletions, emerging in most cases in the first passage into mice. At the single cell level, the pattern of mono-and bi-allelic deletions of the CDKN2A locus revealed distinct leukemia subpopulations, which were reproducibly tracked in xenografts. In most VHR-ALL cases, the predominant diagnostic clones were reconstituted in xenografts, as shown by multiplex PCR analysis of Ig/TCR loci. In other cases, the pattern in CNAs and Ig/TCR rearrangement was less concordant in xenografts, suggesting the outgrowth of subclones. These results unequivocally demonstrate the existence of clonally closely related but distinct subsets of leukemia initiating cells in ALL, which has important implications for drug development and preclinical disease modeling. |
Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grümayer R, Möricke A, Parasole R, Zimmermann M, Dworzak M, Buldini B, Reiter A, Basso G, Klingebiel T, Messina C, Ratei R, Cazzaniga G, Koehler R, Locatelli F, Schäfer BW, Aricò M, Welte K, van Dongen JJ, Gadner H, Biondi A, Conter V |
Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. |
Blood 2011, 118: 2077 |
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The prognostic value of MRD in large series of childhood T-ALL has not yet been established. Trial AIEOP-BFM-ALL 2000 introduced standardized quantitative assessment of MRD for stratification, based on immunoglobulin and TCR gene rearrangements as polymerase chain reaction targets: Patients were considered MRD standard risk (MRD-SR) if MRD was negative at day 33 (time point 1 [TP1]) and day 78 (TP2), analyzed by at least 2 sensitive markers; MRD intermediate risk (MRD-IR) if positive either at day 33 or 78 and < 10(-3) at day 78; and MRD high risk (MRD-HR) if ≥ 10(-3) at day 78. A total of 464 patients with T-ALL were stratified by MRD: 16% of them were MRD-SR, 63% MRD-IR, and 21% MRD-HR. Their 7-year event-free-survival (SE) was 91.1% (3.5%), 80.6% (2.3%), and 49.8% (5.1%) (P < .001), respectively. Negativity of MRD at TP1 was the most favorable prognostic factor. An excellent outcome was also obtained in 32% of patients turning MRD negative only at TP2, indicating that early (TP1) MRD levels were irrelevant if MRD at TP2 was negative (48% of all patients). MRD ≥ 10(-3) at TP2 constitutes the most important predictive factor for relapse in childhood T-ALL. The study is registered at http://www.clinicaltrials.gov; |
Schüz J |
Exposure to extremely low-frequency magnetic fields and the risk of childhood cancer: update of the epidemiological evidence. |
Progress in biophysics and molecular biology 2011, 107: 339 |
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Schmid I, Häberle B, Albert MH, Corbacioglu S, Fröhlich B, Graf N, Kammer B, Kontny U, Leuschner I, Scheel-Walter HG, Scheurlen W, Werner S, Wiesel T, von Schweinitz D |
Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. |
Pediatric blood & cancer 2011, 58: 539 |
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PURPOSE: Overall survival is poor in children with primary unresectable hepatocellular carcinoma. Sorafenib has been shown to significantly improve progression-free survival in adult hepatocellular carcinoma (HCC) patients. We evaluated the experience of PLADO (cisplatin 80 mg/m(2) /day, doxorubicin 2 × 30 mg/m(2) /day) in combination with sorafenib in pediatric HCC patients. PATIENTS AND METHODS: Clinical data of 12 patients (7-16 years), 7 with unresectable tumor, were retrospectively assessed. RESULTS: In total 6/12 (50%) patients are in complete remission after a median follow-up of 20 months (4 with PLADO/sorafenib/resection, 2 with liver transplantation after local relapse). Of the seven patients with unresectable tumor, PLADO/sorafenib resulted in partial response (PR) in four, stable disease (SD) in two, and progression in one. Three are alive in CR after complete resection after 12 (alternative therapy after two cycles PLADO/sorafenib), 12 and 18 months (six cycles PLADO/sorafenib), respectively. All four patients with elevated alpha-fetoprotein levels had a marked drop after two cycles. Of the five patients with primary complete tumor resection one is alive disease-free at 27 months. Four had local or metastatic relapses (13, 7, 12, and 13 months), two of whom were rescued by liver transplantation (CR after 25 and 32 months). The main toxicity attributable to sorafenib was a hand-foot skin reaction (HFSR) in seven patients. CONCLUSION: Sorafenib in combination with PLADO may be a promising approach in pediatric HCC; HFSR was the most important toxicity. Data based on prospective studies are needed to evaluate pharmacokinetics, resectability rates, and survival in pediatric HCC treated with sorafenib. Pediatr Blood Cancer © 2011 Wiley-Liss, Inc. |
Schneppenheim R, Budde U |
Von Willebrand factor and ADAMTS13 balancing primary haemostasis. |
Hamostaseologie 2011, 31: 275 |
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Von Willebrand factor (VWF) is an adhesive, multi-functional huge multimerized protein with multiple domains harboring binding sites for collagen, platelet glycoprotein receptors and coagulation factor VIII (FVIII). The functional domains enable VWF to bind to the injured vessel wall, to recruit platelets to the site of injury by adhesion and aggregation and to bind and protect FVIII, an important cofactor of the coagulation cascade. VWF function in primary haemostasis is located in particular in the arterial and micro-circulation. This environment is exposed to high shear forces with hydrodynamic shear rates ranging over several orders of magnitude from 10⁻¹ to 10⁵ s-1 and requires particular mechanisms to enable platelet adhesion and aggregation under these variable conditions. The respective VWF function is strictly correlating with its multimer size. Lack or reduction of large VWF multimers is seen in patients with von Willebrand disease (VWD) type 2A which correlates with reduction of both VWF:platelet GPIb-binding and VWF:collagen binding and a bleeding phenotype. To prevent unlimited platelet adhesion and aggregation which is the cause of the microangiopathic disorder thrombotic thrombocytopenic purpura (TTP), VWF function is regulated by its specific protease ADAMTS13. Whereas a particular susceptibility of VWF to ADAMTS13 proteolysis is the cause of a frequent VWD type 2A phenotype, lack or dysfunction of ADAMTS13, either acquired by ADAMTS13 antibodies or by inherited ADAMTS13 deficiency (Upshaw-Schulman Syndrome), causes TTP. Therefore VWD and TTP represent the opposite manifestations of VWF related disorders, tightly linked to each other. |
Schmidt R, Baumann U, Botzug K, Henning C, Stoll M, Witte, T |
Primäre und sekundäre Immundefekte. |
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Schneider DT, Brecht IB, Olson ThA, Ferrari A (Eds) |
Rare Tumors In Children and Adolescents. |
Series: Pediatric Oncology, Springer-Verlag 2012 |
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This is the first book to be devoted exclusively to rare tumors in children and adolescents, and its aim is to provide up-to-date information on their diagnosis and clinical management. |
Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A, Conter V, Otten J, Ohara A, Versluys AB, Escherich G, Heyman M, Silverman LB, Horibe K, Mann G, Camitta BM, Harbott J, Riehm H, Richards S, Devidas M, Zimmermann M |
Outcomes after induction failure in childhood acute lymphoblastic leukemia. |
N Engl J Med 2012, 366: 1371 |
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Failure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL). |
von Schweinitz D |
Hepatoblastoma: recent developments in research and treatment. |
Seminars in pediatric surgery 2012, 21: 21 |
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Hepatoblastoma is the most common liver tumor of early childhood. According to recent studies its incidence seems to be increasing in North America and Europe. Since new histological variants have been described recently the formerly clear-cut distinction of hepatoblastoma and hepatocellular carcinoma may not be valid anymore and a new histological classification will be inaugurated by an international working group. Recent research identified prognostically relevant gene signatures as well as potential molecular targets for therapy of hepatoblastoma. The multicentric study groups in the USA, Europe and Japan recommend cisplatin based chemotherapy for neoadjuvant and adjuvant treatment. However, their risk stratification systems and general treatment strategies differ substantially. Therefore the four groups agreed to pool their patients' data for an analysis of prognostic criteria which can be used for defining common risk groups. While 90% of standard risk and 65% of high risk hepatoblastomas can be cured, the still dismal outcome of multifocal disseminated and metastasising tumors warrants the investigation of new cytotoxic drugs and substances against specific molecular targets. |
Schmid I, Häberle B, Albert MH, Corbacioglu S, Fröhlich B, Graf N, Kammer B, Kontny U, Leuschner I, Scheel-Walter HG, Scheurlen W, Werner S, Wiesel T, von Schweinitz D |
Sorafenib and cisplatin/doxorubicin (PLADO) in pediatric hepatocellular carcinoma. |
Pediatric blood & cancer 2012, 58: 539 |
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Overall survival is poor in children with primary unresectable hepatocellular carcinoma. Sorafenib has been shown to significantly improve progression-free survival in adult hepatocellular carcinoma (HCC) patients. We evaluated the experience of PLADO (cisplatin 80 mg/m(2) /day, doxorubicin 2 × 30 mg/m(2) /day) in combination with sorafenib in pediatric HCC patients. |
Schenk, M |
Spätfolgen von Krebs im Kindesalter - Langzeit-Nachsorge muss noch besser strukturiert werden. |
Dtsch Med Wochenschr 2012, 137: S7-S10, Georg Thieme Verlag KG Stuttgart, New York |
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Schüz J, Grell K, Kinsey S, Linet MS, Link MP, Mezei G, Pollock BH, Roman E, Zhang Y, McBride ML, Johansen C, Spix C, Hagihara J, Saito AM, Simpson J, Robison LL, Dockerty JD, Feychting M, Kheifets L, Frederiksen K |
Extremely low-frequency magnetic fields and survival from childhood acute lymphoblastic leukemia: an international follow-up study. |
Blood cancer journal 2012 Dec 21; 2:e98 |
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Schöning, M |
Sinus – und Hirnvenenthrombosen. |
Pädiatrie (Hrsg. Speer,C P, Gaar, M), 4. Auflage 2012 |
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Schönberger S, Okpanyi V, Calaminus G, Heikaus S, Leuschner I, Nicholson JC, Stoecklein NH, Schneider DT, Borkhardt A |
EPCAM-A novel molecular target for the treatment of pediatric and adult germ cell tumors. |
Genes, chromosomes & cancer 2013, 52: 24 |
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Germ cell tumors (GCTs) are thought to develop from totipotent primordial germ cells. Although the epithelial cell adhesion molecule (EPCAM) is expressed on embryonic stem cells as well as different tumor cells, it has not yet been extensively studied in GCTs. We analyzed EPCAM expression by quantitative RT-PCR in 48 fresh-frozen GCT specimens of different histology (10 mature teratoma, MT; 6 immature teratoma, IT; 7 dysgerminoma; 6 mixed malignant GCTs; 19 yolk sac tumor, YST) and in the GCT cell lines NCCIT, TE76.T, JAR and 2102Ep, and correlated its expression with AFP and hCG protein levels, histologic differentiation, and clinical follow-up data. EPCAM protein was visualized by immunohistochemistry of selected corresponding paraffin embedded tumor tissues. EPCAM was expressed in malignant but not in benign GCTs irrespective of age, sex, site and clinical stage of tumor (P = 0.001). In primary teratomas, EPCAM expression increased with their grade of immaturity (mean 2(-ΔCt) values: MT 0.23, IT 1.61, P = 0.007) and significantly correlated with serum AFP (P = 0.03) and hCG (P = 0.03) levels in malignant GCTs. Particularly high EPCAM levels were found in nonseminomatous GCTs such as YSTs (8.49) and choriocarcinoma (13.54). Immunohistochemical analysis verified gene expression data showing a distinct EPCAM staining in YST. Similarly in vitro, highest EPCAM expression was measured in GCT cell lines comprising yolk sac (2102Ep: 5.59) or choriocarcinoma (JAR: 10.65) components. This first comprehensive analysis of EPCAM in GCTs revealed high EPCAM expression in YSTs and choriocarcinomas. Thus, these nonseminomatous GCTs may be interesting targets for EPCAM immunotherapy, which has to be evaluated in further studies. |
Schrappe M, Möricke A, Reiter A, Henze G, Welte K, Gadner H, Ludwig WD, Ritter J, Harbott J, Mann G, Klingebiel T, Gruhn B, Niemeyer C, Kremens B, Niggli F, Debatin KM, Ratei R, Stanulla M, Beier R, Cario G, Schrauder A, Zimmermann M |
Key Treatment Questions in Childhood Acute Lymphoblastic Leukemia: Results in 5 Consecutive Trials Performed by the ALL-BFM Study Group From 1981 to 2000. |
Klinische Padiatrie 2013, 225(S 01):S62-S72 |
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Between 1981 and 2000, 6 609 children (<18 years of age) were treated in 5 consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria, and Switzerland. Probability of 10-year event-free survival (survival) improved from 65% (77%) in study ALL-BFM 81-78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: 1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk ALL patients and eliminated in non-high-risk non-T-ALL patients, if it was replaced by high-dose and intrathecal methotrexate; 2) omission of delayed reintensification severely impaired outcome of low-risk patients; 3) 6 months less maintenance therapy caused an increase in systemic relapses; 4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; 5) condensed induction therapy resulted in a significant improvement of outcome; 6) the daunorubicin dose in induction could be safely reduced in low-risk patients; 7) intensification of consolidation/reintensification treatment led to considerable improvement of outcome in high-risk patients. |
Schuster S, Beck JD, Calaminus G, am Zehnhoff-Dinnesen A, Langer T |
Nachsorge von krebskranken Kindern, Jugendlichen und jungen Erwachsenen - Erkennen, Vermeiden und Behandeln von Spätfolgen. |
AWMF online 2013 |
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Schmidt P, Otto M, Hechler T, Metzing S, Wolfe J, Zernikow B |
Did increased availability of pediatric palliative care lead to improved palliative care outcomes in children with cancer? |
Journal of palliative medicine 2013, 16: 1034 |
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Awareness for pediatric palliative care in children with cancer increased in the last ten years in Germany. In this study we sought to determine whether this change in awareness led to improved palliative care outcomes in children dying due to cancer. |
Schellong G, Riepenhausen M, Ehlert K, Brämswig J, Dörffel W, Schmutzler R, Rhiem K, Bick U |
Brustkrebs bei jungen Frauen nach Therapie eines Hodgkin-Lymphoms im Kindes- und Jugendalter: Eine Beobachtungsstudie mit bis zu 33 Jahren Follow-up. |
Dtsch Arztebl Int 2014, 111(1-2): 3 |
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Schlitt A, Jordan K, Vordermark D, Schwamborn JR, Langer T, Thomssen C |
Cardiotoxicity and oncological treatments. |
Deutsches Arzteblatt international 2014 Mar 7; 111: 161 |
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Cardiotoxic and other side effects limit the usefulness of treatments for cancer. |
Schneider DT, Orbach D, Cecchetto G, Stachowicz-Stencel T, Brummel B, Brecht IB, Bisogno G, Ferrari A, Reguerre Y, Godzinski J, Calaminus G, Patte C, Göbel U |
Ovarian Sertoli Leydig cell tumours in children and adolescents: An analysis of the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). |
European journal of cancer (Oxford, England : 1990) 2014,Epub ahead of print |
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To analyse ovarian Sertoli-Leydig cell tumours (SLCTs) for potential prognostic markers and their use for treatment stratification. |
Schrappe, M |
Detection and management of minimal residual disease in acute lymphoblastic leukemia. |
Hematology Am Soc Hematol Educ Program 5; 2014, 244-9. |
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Schreiber JE, Gurney JG, Palmer SL, Bass JK, Wang M, Chen S, Zhang H, Swain M, Chapieski ML, Bonner MJ, Mabbott DJ, Knight SJ, Armstrong CL, Boyle R, Gajjar A |
Examination of risk factors for intellectual and academic outcomes following treatment for pediatric medulloblastoma. |
Neuro-oncology 2014, 16: 1129 |
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The aim of this study was to prospectively examine the effects of hearing loss and posterior fossa syndrome (PFS), in addition to age at diagnosis and disease risk status, on change in intellectual and academic outcomes following diagnosis and treatment in a large sample of medulloblastoma patients. |
Schultz KA, Chen L, Chen Z, Kawashima T, Oeffinger KC, Woods WG, Nicholson HS, Neglia JP |
Chronic Health Conditions and health-related quality of life in survivors of childhood acute myeloid leukemia (AML): A Report from the Children's Oncology Group. |
Pediatric Blood Cancer 2014, 61: 729 |
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Background
Therapy for childhood acute myeloid leukemia (AML) has historically included chemotherapy with or without autologous bone marrow transplant (autoBMT) or allogeneic hematopoietic stem cell transplantation (alloBMT). We sought to compare health-related quality-of-life (HRQOL) outcomes between these treatment groups.
Procedure
Five-year survivors of AML diagnosed before age 21 and enrolled and treated from 1979 to 1995 on one of 4 national protocols were interviewed. These survivors or proxy caregivers completed a health questionnaire and an HRQOL measure.
Results
Of 180 survivors, 100 were treated with chemotherapy only, 26 with chemotherapy followed by autoBMT, and 54 with chemotherapy followed by alloBMT. Median age at interview was 20 years (range 8 to 39). Twenty-one percent reported a severe or life-threatening chronic health condition (chemotherapy-only 16% vs. autoBMT 21% vs. alloBMT 33%; p=0.02 for chemotherapy-only vs. alloBMT). Nearly all (95%) reported excellent, very good or good health. Reports of cancer-related pain and anxiety did not vary between groups. HRQOL scores among 136 participants ≥ 14 years of age were similar among groups and to the normative population, though alloBMT survivors had a lower physical mean summary score (49.1 alloBMT vs. 52.2 chemotherapy-only; p=0.03). Multivariate analyses showed the presence of severe chronic health conditions to be a strong predictor of physical but not mental mean summary scores.
Conclusions
Overall HRQOL scores were similar among treatment groups, although survivors reporting more health conditions or cancer-related pain had diminished HRQOL. Attention to chronic health conditions and management of cancer-related pain may improve QOL. |
Schlegel P, Lang P, Zugmaier G, Ebinger M, Kreyenberg H, Witte KE, Feucht J, Pfeiffer M, Teltschik HM, Kyzirakos C, Feuchtinger T, Handgretinger R |
Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab. |
Haematologica 2014, 99: 1212 |
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We report on posttransplant relapsed pediatric patients with B-precursor acute lymphoblastic leukemia with no further standard of care therapy who were treated with the T-cell engaging CD19/CD3-bispecific single-chain antibody construct blinatumomab on a compassionate use basis. Blast load was assessed prior to, during and after blinatumomab cycle using flow cytometry to detect minimal residual disease, quantitative polymerase chain reaction for rearrangements of the immunoglobulin or T-cell receptor genes, and bcr/abl mutation detection in one patient with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dosage of 5 or 15 μg/m(2)/day. Nine patients received a total of 18 cycles. Four patients achieved complete remission after the first cycle of treatment; 2 patients showed a complete remission from the second cycle after previous reduction of blast load by chemotherapy. Three patients did not respond, of whom one patient proceeded to a second cycle without additional chemotherapy and again did not respond. Four patients were successfully retransplanted in molecular remission from haploidentical donors. After a median follow up of 398 days, the probability of hematologic event-free survival is 30%. Major toxicities were grade 3 seizures in one patient and grade 3 cytokine release syndrome in 2 patients. Blinatumomab can induce molecular remission in pediatric patients with posttransplant relapsed B-precursor acute lymphoblastic leukemia and facilitate subsequent allogeneic hematopoietic stem cell transplantation from haploidentical donor with subsequent long-term leukemia-free survival. |
Schütte P, Möricke A, Zimmermann M, Bleckmann K, Reismüller B, Attarbaschi A, Mann G, Bodmer N, Niggli F, Schrappe M, Stanulla M, Kratz CP |
Preexisting conditions in pediatric ALL patients: Spectrum, frequency and clinical impact. |
Eur J Med Genet 2015, S1769-721230063-X. [Epub ahead of print] |
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INTRODUCTION:
The etiology of acute lymphoblastic leukemia remains undisclosed in the majority of cases. A number of rare syndromic conditions are known to predispose to different forms of childhood cancer including ALL. The present study characterized the spectrum and clinical impact of preexisting diseases in a cohort of ALL patients from Germany, Austria and Switzerland with a focus on genetic diseases predisposing to cancer development.
METHODS:
Retrospective database and study chart review included all patients from Germany, Austria and Switzerland (n = 4939) enrolled into multicenter clinical trial AIEOP-BFM ALL 2000 between July 1999 and June 2009. Patients enrolled into study AIEOP-BFM ALL 2009 - which was initiated subsequent to AIEP-BFM ALL 2000 - who were reported with a cancer prone syndrome or chromosomal abnormality were additionally included in this study to increase conclusiveness of observations.
RESULTS:
A total of 233 patients with at least one reported condition could be identified. The following conditions were reported in more than one patient: Gilbert's disease (n = 13), neurofibromatosis type I (n = 8), ataxia telangiectasia (n = 8), thalassemia (n = 7), Nijmegen Breakage syndrome (n = 6), cystic fibrosis (n = 4), glucose-6-phosphate dehydrogenase deficiency (n = 4), Noonan syndrome (n = 2), Klinefelter syndrome (n = 2), alpha-1-antitrypsin deficiency (n = 2), primary ciliary dyskinesia (n = 2). Especially those syndromes with a known cancer predisposition (NF type I, Ataxia telangiectasia, Nijmegen Breakage syndrome etc.) were associated with certain general and ALL-related characteristics, high therapy-related toxicity and reduced survival.
CONCLUSION:
The spectrum of underlying diseases within ALL patients is dispersed. A small number of ALL patients are reported with cancer predisposition syndromes at initial diagnosis which are associated with high rates of therapy-related toxicity and a markedly reduced chance of survival. The true prevalence of these conditions within the ALL population remains unknown due to inapparent clinical presentation. A targeted clinical and/or genetic examination for certain diagnoses like NF type I, Ataxia telangiectasia or Nijmegen Breakage syndrome could identify patients who benefit from adjustment of antileukemic therapy or intensification of supportive care. |
Schebesch KM, Mueller S, Wendl C, Brawanski A, Riemenschneider MJ, Proescholdt M |
Recurrence rates and functional outcome after resection of intrinsic intramedullary tumors. |
Clinical neurology and neurosurgery 2015, 134: 60 |
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Intramedullary tumors account for 2-4% of all CNS neoplasms. Surgical resection is challenging because of aggravated neurological impairment in up to 64% of patients. We analyzed a consecutive series of patients with intramedullary tumors and focused on the extent of resection, functional outcome, and tumor recurrence. |
Schweitzer J, Zimmermann M, Rasche M, von Neuhoff C, Creutzig U, Dworzak M, Reinhardt D, Klusmann JH |
Improved outcome of pediatric patients with acute megakaryoblastic leukemia in the AML-BFM 04 trial. |
Journal of the European Academy of Dermatology and Venereology : JEADV |
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Schündeln MM, Hauffa PK, Bauer JJ, Temming P, Sauerwein W, Biewald E, Bornfeld N, Hauffa BP, Grasemann C |
Pediatric Survivors of Retinoblastoma Are at Risk for Altered Bone Metabolism After Chemotherapy Treatment Early in Life. |
Pediatric hematology and oncology 2015, 32: 455 |
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Survivors of childhood cancer frequently suffer from endocrine late effects, which are, at least partly, attributed to toxic effects of chemotherapy. Treatment of retinoblastoma typically involves chemotherapy at a very young age. The authors conducted a cross-sectional study to assess bone health in a pediatric cohort of 33 survivors of retinoblastoma (mean age: 4.4 years) who had undergone chemotherapy treatment at an especially young age (mean age: 0.76 years). Of these patients, 14 had unilateral and 19 bilateral retinoblastoma. Polychemotherapy consisted of treatment with cyclophosphamide, etoposide, vincristine, and carboplatin. Ten patients had undergone external beam radiotherapy. Clinical and biochemical parameters of growth, pubertal development, and bone health were obtained. A vitamin D deficiency was found in 51.7% of the patients, and 13.7% of patients displayed severe vitamin D deficiency. Secondary hyperparathyroidism and altered readings for bone formation or resorption markers were present in 15%. Nine percent reported bone pain or experienced fractures of the long bones after primary diagnosis. No difference between children with bilateral and unilateral disease or irradiated versus nonirradiated children was observed. The parameters of thyroid function, growth, and pubertal development were within age-appropriate norms in almost all children. In conclusion, altered parameters of bone health can be present in survivors of retinoblastoma at a young age and warrant regular follow-up in these children. The endocrine hypothalamic-pituitary axes, however, were not impaired at this early age in this group of survivors of retinoblastoma. |
Schneider DT |
Sex Cord Stromal Tumors: It is Networking-or Not Working. |
Pediatric blood & cancer 2015, 62: 2065 |
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von Schweinitz D, Becker K |
Hepatoblastom. |
S1-Leitlinie 025/011 AWMF online 2016 |
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Schütte P, Möricke A, Zimmermann M, Bleckmann K, Reismüller B, Attarbaschi A, Mann G, Bodmer N, Niggli F, Schrappe M, Stanulla M, Kratz CP |
Preexisting conditions in pediatric ALL patients: Spectrum, frequency and clinical impact. |
European journal of medical genetics 2016, 59: 143 |
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The etiology of acute lymphoblastic leukemia remains undisclosed in the majority of cases. A number of rare syndromic conditions are known to predispose to different forms of childhood cancer including ALL. The present study characterized the spectrum and clinical impact of preexisting diseases in a cohort of ALL patients from Germany, Austria and Switzerland with a focus on genetic diseases predisposing to cancer development. |
Scheer M, Dantonello T, Hallmen E, Vokuhl C, Leuschner I, Sparber-Sauer M, Kazanowska B, Niggli F, Ladenstein R, Bielack SS, Klingebiel T, Koscielniak E |
Primary Metastatic Synovial Sarcoma: Experience of the CWS Study Group. |
Pediatric blood & cancer 2016, 63: 1198 |
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Prognostic factors for localized synovial sarcoma are well defined. However, few data exist regarding patients with metastases at diagnosis. Poor outcome is described but the optimal therapeutic regimen remains unclear. Our aim was to assess the outcome, identify prognostic factors, and analyze treatment strategies. |
Schmiegelow K, Attarbaschi A, Barzilai S, Escherich G, Frandsen TL, Halsey C, Hough R, Jeha S, Kato M, Liang DC, Mikkelsen TS, Möricke A, Niinimäki R, Piette C, Putti MC, Raetz E, Silverman LB, Skinner R, Tuckuviene R, van der Sluis I, Zapotocka E, Ponte di Legno toxicity working group |
Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. |
The Lancet. Oncology 2016, 17:e231 |
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Scheer C, Kratz C, Witt O, Creutzig U, Reinhardt D, Klusmann JH |
Hematologic Response to Vorinostat Treatment in Relapsed Myeloid Leukemia of Down Syndrome. |
Pediatric blood & cancer 2016, 63: 1677 |
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Children with Down syndrome are at high risk to develop myeloid leukemia (ML-DS). Despite their excellent prognosis, children with ML-DS particularly suffer from severe therapy-related toxicities and for relapsed ML-DS the cure rates are very poor. Here we report the clinical course of one child with ML-DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML-DS. |
Schmidt M, Hero B, Simon T |
I-131-mIBG therapy in neuroblastoma: established role and prospective applications. |
Clinical and Translational Imaging 2016, Volume 4, Issue 2, 87 |
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Schultz KA, Chen L, Kunin-Batson A, Chen Z, Woods WG, Gamis A, Kawashima T, Oeffinger KC, Nicholson HS, Neglia JP |
Health-related Quality of Life (HR-QOL) and Chronic Health Conditions in Survivors of Childhood Acute Myeloid Leukemia (AML) with Down Syndrome (DS): A Report From the Children's Oncology Group. |
Journal of pediatric hematology/oncology 2017, 39: 20 |
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Schwermer M, Dreesmann S, Eggert A, Althoff K, Steenpass L, Schramm A, Schulte JH, Temming P |
Pharmaceutically inhibiting polo-like kinase 1 exerts a broad anti-tumour activity in retinoblastoma cell lines. |
Clinical & experimental ophthalmology 2017, 45: 288 |
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Retinoblastoma is the most common malignant cancer of the eye in children. Although metastatic retinoblastoma is rare, cure rates for this advanced disease remain below 50%. High-level polo-like kinase 1 expression in retinoblastomas has previously been shown to be correlated with adverse outcome parameters. Polo-like kinase 1 is a serine/threonine kinase involved in cell cycle regulation at the G2/M transition. Polo-like kinase 1 inhibition has been demonstrated to have anti-tumour effects in preclinical models of several paediatric tumours. Here, we assessed its efficacy against retinoblastoma cell lines. |
Schuster S, Beck JD, Calaminus G, Zehnhoff-Dinnesen AA, Langer T |
Nachsorge von krebskranken Kindern, Jugendlichen und jungen Erwachsenen-Erkennen, Vermeiden und Behandeln von Spatfolgen. |
Kinderkrankenschwester : Organ der Sektion Kinderkrankenpflege 2017, 36: 20 |
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Schmid I, von Schweinitz D |
Pediatric hepatocellular carcinoma: challenges and solutions. |
Journal of hepatocellular carcinoma 2017, 4: 15 |
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Hepatocellular carcinoma (HCC) is a very rare entity in children, making it nearly impossible to orchestrate Phase II/III studies even as multinational cooperative trials. In contrast to adults, nearly 50% of the children have a response (α-fetoprotein decline and/or tumor shrinkage) to chemotherapeutic agents such as cisplatin and doxorubicin (PLADO), demonstrating that HCC in childhood can be chemotherapy sensitive. As a result, the main treatment options in pediatric HCC focus on systemic drug therapies and resection as the central therapy. In nonmetastatic patients with complete resection upfront, the 5-year event-free survival and overall survival has reached 80%-90%. In almost all reported studies, children received adjuvant chemotherapy (mostly PLADO), but it has never been proven that postoperative chemotherapy is superior to observation. No data are available for the effects of sorafenib. The 3-year survival is <20% in children with unresectable HCC independent of the chemotherapy given preoperatively. Currently, PLADO in combination with sorafenib is recommended with the goal of achieving operability status. Alternatively, data are promising for the combination of sorafenib with gemcitabine and oxaliplatin. For children with nonresectable and nonmetastastic liver tumors, it has been shown that the Milan criteria regarding liver transplantation are not applicable - individual decisions have to be made. Transarterial chemoembolization could be offered to patients with chemotherapy-resistant liver tumors for palliative care or potentially to achieve surgical resectability, and therefore cure. Information about the feasibility or effects of new agents or approaches as discussed in adult HCC patients is not available for childhood HCC. Research has to be done for characterizing the molecular and genomic mechanisms of pediatric HCC to support the development of novel therapeutic approaches and the implementation of personalized medicine. |
Schrappe M, Möricke A, Attarbaschi A, von Stackelberg A |
Akute lymphoblastische Leukämie. |
in: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie. Springer-Verlag GmbH Deutschland, 2. vollständig überarbeitete Auflage 2018, 269 |
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Schneider DT, Brecht IB |
Das STEP-Register für seltene Tumorerkrankungen in der Pädiatrie - It's networking – or not working. |
WiR - die Zeitschrift der Deutschen Leukämie-Forschungshilfe e.V. und der Deutschen Kinderkrebsstiftung 3/2018 |
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Schrappe M, Bleckmann K, Zimmermann M, Biondi A, Möricke A, Locatelli F, Cario G, Rizzari C, Attarbaschi A, Valsecchi MG, Bartram CR, Barisone E, Niggli F, Niemeyer C, Testi AM, Mann G, Ziino O, Schäfer B, Panzer-Grümayer R, Beier R, Parasole R, Göhring G, Ludwig WD, Casale F, Schlegel PG, Basso G, Conter V |
Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000). |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2018, 36: 244 |
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Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% ( P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% ( P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). Patients with ETV6-RUNX1-positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response. |
Schuster AJ, Kager L, Reichardt P, Baumhoer D, Csóka M, Hecker-Nolting S, Lang S, Lorenzen S, Mayer-Steinacker R, von Kalle T, Kevric M, Werner M, Windhager R, Wirth T, Bielack SS |
High-Grade Osteosarcoma of the Foot: Presentation, Treatment, Prognostic Factors, and Outcome of 23 Cooperative Osteosarcoma Study Group COSS Patients. |
Sarcoma 2018, 2018, 1632978 |
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Osteosarcoma of the foot is a very rare presentation of a rare tumor entity. In a retrospective analysis, we investigated tumor- and treatment-related variables and outcome of patients registered in the Cooperative Osteosarcoma Study Group (COSS) database between January 1980 and April 2016 who suffered from primary high-grade osteosarcoma of the foot. Among the 23 eligible patients, median age was 32 years (range: 6-58 years), 10 were female, and 13 were male. The tarsus was the most commonly affected site (n=16). Three patients had primary metastases. All patients were operated: 5 underwent primary surgery and 18 received surgery following preoperative chemotherapy. In 21 of the 23 patients, complete surgical remission was achieved. In 4 of 17 patients, a poor response to neoadjuvant chemotherapy was observed in the resected primary tumors. Median follow-up was 4.2 years (range: 0.4-18.5). At the last follow-up, 15 of the 23 patients were alive and 8 had died. Five-year overall and event-free survival estimates were 64% (standard error (SE) 12%) and 54% (SE 13%), which is similar to that observed for osteosarcoma in general. Event-free and overall survival correlated with primary metastatic status and completeness of surgery. Our findings show that high-grade osteosarcoma in the foot has a similar outcome as osteosarcoma of other sites. |
Scholz-Kreisel P, Kaatsch P, Spix C, Schmidberger H, Marron M, Grabow D, Becker C, Blettner M |
Second Malignancies Following Childhood Cancer Treatment in Germany From 1980 to 2014. |
Deutsches Arzteblatt international 2018 Jun 8; 115: 385 |
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Background: Because of improvements in cancer treatment, more than 80% of all children with cancer now survive at least five years from the time of diagnosis. As a result, late sequelae of cancer and its treatment have become more common, particularly second malignancies. We studied the current incidence of second malignancies among childhood cancer survivors in Germany.
Methods: This study is based on the cohort of the German Childhood Cancer Registry (Deutsches Kinderkrebsregister, DKKR). Persons given the diagnosis of a first malignancy at any time in the years 1980-2014 who were no more than 14 years old at the time of diagnosis and survived at least six months thereafter were included in the study. Cumulative incidences and hazard ratios were calculated, and comparisons with the general population were made with the aid of standardized incidence ratios (SIR).
Results: Among the 47 650 survivors included in the study, there were 1262 cases of second malignancies. After a follow-up interval of up to 35 years, the cumulative incidence of second malignancies was 8.27% (95% confidence interval [7.51; 9.03]). Second malignancies were more common in female patients (hazard ratio 1.29, [1.16; 1.44]) and in those who had had a systemic cancer as their initial malignancy (hazard ratio 1.22 [1.09; 1.36]). The SIR compared to the general population for the period 1955-2014 was 7.08 [6.42; 7.9] for female patients and 5.83 [5.27; 6.42] for male patients.
Conclusion: The cumulative incidence of second malignancies is 5.4% at 25 years and 8.3% at 35 years; these figures may be slight underestimates. The DKKR is an epidemiologic registry containing no data about treatment, so the effect of treatment on the risk of second malignancies could not be studied. The acquisition and evaluation of treatment data for the overall cohort is currently one of the main tasks for research on the late sequelae of childhood cancer. This may enable conclusions to be drawn about whether treatment strategies that have been introduced to lessen the risk of a second malignancy actually have the desired effect. |
von Schweinitz D, Schmid I |
Lebertumoren. |
in: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie. Springer-Verlag GmbH GDeutschland 2006, 2018 2. vollständig überarbeitete Auflage 2018, 465 |
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Schönberger S, van Beekum C, Götz B, Nettersheim D, Schorle H, Schneider DT, Casati A, Craveiro RB, Calaminus G, Dilloo D |
Brentuximab vedotin exerts profound antiproliferative and pro-apoptotic efficacy in CD30-positive as well as cocultured CD30-negative germ cell tumour cell lines. |
Journal of cellular and molecular medicine 2018, 22: 568 |
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Prognosis in patients suffering from high-risk, refractory and relapsed germ cell tumours (GCT) often comprising of CD30-positive embryonal carcinoma (EC) components remains poor. Thus, novel treatment strategies are warranted. The antibody-drug conjugate (ADC) brentuximab vedotin delivers the potent antimitotic drug monomethyl auristatin E (MMAE) to CD30-expressing tumour cells. After CD30 binding, internalization and intracellular linker cleavage cytotoxic MMAE can efflux and eradicate neighbouring CD30-negative cells. To analyse cytotoxicity and a potential bystander effect of brentuximab vedotin in GCT, we established an in vitro coculture model mimicking GCT of heterogeneous CD30 positivity and measured cell viability, proliferation and apoptosis after exposure to brentuximab vedotin and unbound MMAE by MTS- and flow cytometry-based CFSE/Hoechst assay. CD30 expression being assessed by quantitative RT-PCR and immunohistochemistry was apparent in all EC cell lines with different intensity. Brentuximab vedotin abrogates cell viability of CD30-positive GCT27 EC line exerting marked time-dependent antiproliferative and pro-apoptotic activity. CD30-negative JAR cultured alone barely responds to brentuximab vedotin, while in coculture with GCT27 brentuximab vedotin induces clear dose-dependent cytotoxicity. Cellular proliferation and cell death are significantly enhanced in CD30-negative JAR cocultured with CD30-positive GCT27 compared to JAR cultured alone in proof of substantial bystander activity of brentuximab vedotin in CD30-negative GCT. We present first evidence that in an in vitro model mimicking GCT of heterogeneous histology, brentuximab vedotin exerts potent antiproliferative and pro-apoptotic activity against both CD30-positive as well as CD30-negative GCT subsets. Our results strongly support translational efforts to evaluate clinical efficacy of brentuximab vedotin in high-risk GCT of heterogeneous CD30 positivity. |
Scholz-Kreisel P, Kaatsch P, Spix C, Schmidberger H, Marron M, Grabow D, Becker C, Blettner M |
Second Malignancies Following Childhood Cancer Treatment in Germany From 1980 to 2014. |
Deutsches Arzteblatt international 2018, 115: 385 |
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Because of improvements in cancer treatment, more than 80% of all children with cancer now survive at least five years from the time of diagnosis. As a result, late sequelae of cancer and its treatment have become more common, particularly second malignancies. We studied the current incidence of second malignancies among childhood cancer survivors in Germany. |
Schröder HM, Lilienthal S, Schreiber-Gollwitzer BM, Grießmeier B, Hesselbarth B, Lein-Köhler I, Nest A, Weiler-Wichte LJ Leiss U |
Psychosoziale Versorgung in der Pädiatrischen Onkologie und Hämatologie. |
S3-Leitlinie der Psychosozialen Arbeitsgemeinschaft in der Pädiatrischen Onkologie und Hämatologie (PSAPOH), AWMF online 2019 |
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Scholtes C, Baust K, Weinhold L, Creutzig U, Gnekow A, Hinz A, Kaatsch P, Kreitz K, Langer T, Rutkowski S, Singer S, Spix C, Teske C, Schmid M, Dilloo D, Calaminus G |
Health status, health-related quality of life, and socioeconomic outcome in childhood brain tumor survivors: a German cohort study. |
Neuro-oncology 2019, 21: 1069 |
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With rising numbers of childhood cancer survivors, somatic and socioeconomic outcome as well as health-related quality of life (QoL) gain increasing relevance. Based on the first nationwide German Survey on Life Situation, State of Health, and Quality of Life of Childhood Cancer Survivors, the VIVE survey, we report the outcome of survivors of childhood brain tumors localized in the posterior fossa. |
Schepke E, Tisell M, Kennedy C, Puget S, Ferroli P, Chevignard M, Doz F, Pizer B, Rutkowski S, Massimino M, Navajas A, Schwalbe E, Hicks D, Clifford SC, Pietsch T, Lannering B |
Effects of the growth pattern of medulloblastoma on short-term neurological impairments after surgery: results from the prospective multicenter HIT-SIOP PNET 4 study. |
Journal of neurosurgery. Pediatrics 2020, 1 |
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Extensive resection of a tumor in the posterior fossa in children is associated with the risk of neurological deficits. The objective of this study was to prospectively evaluate the short-term neurological morbidity in children after medulloblastoma surgery and relate this to the tumor's growth pattern and to the extent of resection. |
Schieck M, Lentes J, Thomay K, Hofmann W, Behrens YL, Hagedorn M, Ebersold J, Davenport CF, Fazio G, Moericke A, Buchmann S, Alten J, Cario G, Schrappe M, Bergmann AK, Stanulla M, Steinemann D, Schlegelberger B, Cazzaniga G, Goehring G |
Implementation of RNA sequencing and array CGH in the diagnostic workflow of the AIEOP-BFM ALL 2017 trial on acute lymphoblastic leukemia. |
Annals of hematology 2020, 99: 809 |
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Risk-adapted therapy has significantly contributed to improved survival rates in pediatric acute lymphoblastic leukemia (ALL) and reliable detection of chromosomal aberrations is mandatory for risk group stratification. This study evaluated the applicability of panel-based RNA sequencing and array CGH within the diagnostic workflow of the German study group of the international AIEOP-BFM ALL 2017 trial. In a consecutive cohort of 117 children with B cell precursor (BCP) ALL, array analysis identified twelve cases with an IKZF1 profile of gene deletions and one case of masked hypodiploidy. Genetic markers BCR-ABL1 (nâÂÂ=âÂÂ1), ETV6-RUNX1 (nâÂÂ=âÂÂ25), and rearrangements involving KMT2A (nâÂÂ=âÂÂ3) or TCF3 (nâÂÂ=âÂÂ3) were assessed by established conventional techniques such as karyotyping, FISH, and RT-PCR. Comparison of these results with RNA sequencing analysis revealed overall consistency in n=115/117 cases, albeit with one undetected AFF1-KMT2A fusion in RNA sequencing and one undetected ETV6-RUNX1 fusion in conventional analyses. The combined application of RNA sequencing, FISH, and CGH+SNP array reliably detected all genetic markers necessary for risk stratification and will be used as the diagnostic standard workflow for BCP-ALL patients enrolled in the AIEOP-BFM ALL 2017 study. Prospectively, consistent collection of genome-wide CGH+SNP array as well as RNA sequencing data will be a valuable source to elucidate new prognostic lesions beyond established markers of pediatric ALL. In this respect, RNA sequencing identified various gene fusions in up to half of the IKZF1 (nâÂÂ=âÂÂ6/12) and B-other (nâÂÂ=âÂÂ19/36) cases but not in cases with hyperdiploid karyotypes (nâÂÂ=âÂÂ35). Among these fusions, this study reports several previously undescribed in frame PAX5 fusions, including PAX5-MYO1G and PAX5-NCOA6. |
Scheer M, Blank B, Bauer S, Vokuhl C, Stegmaier S, Feuchtgruber S, Henssen A, Sparber-Sauer M, Eggert A, Handgretinger R, Pekrun A, Rossig C, Rutkowski S, Schlegel PG, Schrappe M, Simon T, Kazanowska B, Niggli F, Ladenstein R, Ljungman G, Jahnukainen K, Fuchs J, Bielack SS, Koscielniak E, Klingebiel T, Cooperative Weichteilsarkom Studiengruppe [CWS] |
Synovial sarcoma disease characteristics and primary tumor sites differ between patient age groups: a report of the Cooperative Weichteilsarkom Studiengruppe (CWS). |
Journal of cancer research and clinical oncology 2020, 146: 953 |
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Older age is associated with worse outcome in synovial sarcoma (SS) patients. Differences in disease presentation among distinct age groups, however, are currently unknown. |
Schönberger S, Kraft D, Nettersheim D, Schorle H, Casati A, Craveiro RB, Mohseni MM, Calaminus G, Dilloo D |
Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell Lines. |
Cancers 2020, 12 |
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Outcome in high-risk patients with refractory or relapsed germ cell tumours (GCT) remains poor. Novel strategies enhancing therapeutic efficacy whilst limiting therapeutic burden are warranted, yet immunotherapy approaches geared towards activating endogenous antitumor responses have not been successful thus far. Redirection of cytotoxic effector cells by bispecific antibodies represents a promising approach in this setting. We demonstrate that the Epithelial Cell Adhesion Molecule (EpCAM) is broadly expressed in GCT cell lines of different histologic origin including seminoma, choriocarcinoma (CHC), and embryonal carcinoma (EC). In these GCT lines of variable EpCAM surface expression, targeting T cells by the prototypic bispecific EpCAM/CD3-antibody (bAb) Catumaxomab together with natural killer (NK) cell engagement via the Fc domain promotes profound cytotoxicity across a broad range of antibody dilutions. In contrast, tumor cell lysis mediated by either immune cell subset alone is influenced by surface density of the target antigen. In the CHC line JAR, NK cell-dependent cytotoxicity dominates, which may be attributed to differential surface expression of immunomodulatory proteins such as MHC-I, CD24, and Fas receptors on CHC and EC. In view of redirecting T cell therapy mediated by bispecific antibodies, such differences in GCT immunophenotype potentially favoring immune escape are worth further investigation. |
Scheer M, Vokuhl C, Veit-Friedrich I, Münter M, von Kalle T, Greulich M, Loff S, Stegmaier S, Sparber-Sauer M, Niggli F, Ladenstein R, Kazanowska B, Ljungman G, Jahnukainen K, Fuchs J, Bielack SS, Koscielniak E, Klingebiel T, Cooperative Weichteilsarkom Studiengruppe (CWS) |
Low-grade fibromyxoid sarcoma: A report of the Cooperative Weichteilsarkom Studiengruppe (CWS). |
Pediatric blood & cancer 2020, 67:e28009 |
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Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue tumor with benign histologic appearance, though fully malignant behavior is possible. |
Schmidt M, Decarolis B, Franzius C, Hero B, Pfluger T, Rogasch J, Simon T |
DGN-Handlungsempfehlung (S1-Leitlinie) Durchführung und Befundung der 123I-mIBG-Szintigraphie bei Kindern und Jugendlichen - Deutsche Gesellschaft für Nuklearmedizin e. V. |
AWMF online 2/2020, AWMF-Registernummer: 031 |
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Schepke E, Tisell M, Kennedy C, Puget S, Ferroli P, Chevignard M, Doz F, Pizer B, Rutkowski S, Massimino M, Navajas A, Schwalbe E, Hicks D, Clifford SC, Pietsch T, Lannering B |
Effects of the growth pattern of medulloblastoma on short-term neurological impairments after surgery: results from the prospective multicenter HIT-SIOP PNET 4 study. |
Journal of neurosurgery. Pediatrics 2020, 1 |
|
Extensive resection of a tumor in the posterior fossa in children is associated with the risk of neurological deficits. The objective of this study was to prospectively evaluate the short-term neurological morbidity in children after medulloblastoma surgery and relate this to the tumor's growth pattern and to the extent of resection. |
Schroeter-Rupieper M |
Für immer anders. |
Patmos-Verlag 2020 |
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Schuster S, Hahn B, Beck JD, Calaminus G, Timmermann B, am Zehnhoff-Dinnesen A, Gebauer I, Langer T |
Langzeit-Nachsorge von krebskranken Kindern, Jugendlichen und jungen Erwachsenen – Vermeiden, Erkennen und Behandeln von Spätfolgen. |
AWMF online 025/003, 4/2021 |
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Schulte JH, Eggert A |
ALK Inhibitors in Neuroblastoma: A Sprint from Bench to Bedside. |
Clinical cancer research : an official journal of the American Association for Cancer Research 2021 Jul 1; 27: 3507 |
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Activating mutations of the anaplastic lymphoma kinase () gene were identified in the pediatric tumor neuroblastoma, in 2008. Rapid translation of this finding into targeted neuroblastoma therapy was facilitated by the availability of ALK inhibitors developed for adult malignancies and an efficient preclinical and clinical research program.. |
Schneider DT, Orbach D, Ben-Ami T, Bien E, Bisogno G, Brecht IB, Cecchetto G, Ferrari A, Godzinski J, Janic D, Lopez Almaraz R, Pourtsidis A, Roganovic J, Schultz KAP, Stachowicz-Stencel T, Fresneau B |
Consensus recommendations from the EXPeRT/PARTNER groups for the diagnosis and therapy of sex cord stromal tumors in children and adolescents. |
Pediatric blood & cancer 2021, 68 Suppl 4:e29017 |
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As part of the European Union-funded project designated Paediatric Rare Tumours Network - European Registry (PARTNER), the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) is continuously developing consensus recommendations in order to harmonize standard care for very rare solid tumors of children and adolescents. This paper presents the internationally recognized recommendations for the diagnosis and treatment of sex cord stromal tumors (SCST). The clinical approach to sex cord stromal tumors of the testis (TSCST) and ovary (OSCST) depends on histological differentiation and tumor stage. Virtually all TSCSTs present as localized nonmetastatic tumors, with excellent prognosis after complete resection. In contrast, the prognosis of OSCSTs may be adversely affected by tumor spillage during surgery or presence of metastases. In these cases, cisplatin-based chemotherapy is recommended. Of note, some SCSTs may develop in the context of tumor predisposition syndromes, for example, DICER-1, so that specific follow-up is indicated. SCSTs should be diagnosed and treated according to standardized recommendations that include reference pathology, genetic testing for tumor predisposition syndromes in selected cases, and stratified adjuvant chemotherapy in patients with unfavorable risk profile. To ensure high quality of diagnosis and therapy, patients should be enrolled into prospective registries. |
Scheer M, Vokuhl C, Bauer S, Fuchs J, Loff S, Timmermann B, Münter M, Henssen AG, Kazanowska B, Niggli F, Ladenstein R, Ljungman G, Koscielniak E, Klingebiel T, European Cooperative Weichteilsarkom Studiengruppe [CWS] |
The effect of adjuvant therapies on long-term outcome for primary resected synovial sarcoma in a series of mainly children and adolescents. |
Journal of cancer research and clinical oncology 2021 Jul 17; online ahead of print |
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The benefit of adjuvant therapy in synovial sarcoma (SS) treatment is under debate. Long-term follow-up data are missing. |
Schumacher-Kuckelkorn R, Atra A, Belli ML, den Engelsman G, Fréneaux P, Gauthier A, Heijlaerts-Klever A, Scuderi F, Senent Peris L, Tewari S, Zapletal O, Ernst A, Berthold F |
The reliability of bone marrow cytology as response criterion in metastatic neuroblastoma. |
Pediatric blood & cancer 2021, 68:e28819 |
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The quantitative assessment of neuroblastoma cell content in bone marrow aspirates for response evaluation has been introduced recently. Data on the concordance of interobserver reports are lacking so far. |
Schenk JP, Hötker A, Furtwängler R, Fuchs J, Warmann SW, Graf N |
[Imaging of renal tumors in children]. |
Der Radiologe 2021, 61: 619 |
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Renal tumors in children are treated according to the guidelines of the Renal Tumor Study Group of the International Society of Pediatric Oncology (SIOP-RTSG). Nephroblastoma is the most frequent renal tumor in children. |
Schneppenheim R, Brehm M, Budde U |
von Willebrand-Syndrom und von Willebrand-Faktor - Aktuelle Aspekte der Diagnostik und Therapie. |
UNI-MED Science 4.neubearb. Auflage 2021 |
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Die hereditäre von Willebrand-Erkrankung und das erworbene von Willebrand-Syndrom sind Krankheitsbilder, die mit einer mehr oder weniger starken Blutungsneigung durch eine signifikante Störung der primären Hämostase und oft auch der Blutgerinnung assoziiert sind. Sie beruhen auf quantitativen und/oder strukturellen Defekten des von Willebrand-Faktors (VWF).Demgegenüber steht die prothrombotische Seite des VWF, welcher mit seiner Überfunktion bei fehlender Regulation durch die Protease ADAMTS13 zu schweren thrombo-embolischen Ereignissen im Rahmen einer Thrombotisch-Thrombozytopenischen Purpura führt.Aktuelle Erkenntnisse bezüglich der Funktion und Regulation des VWF im Hinblick auf die Pathogenese der VWF-assoziierten Krankheitsbilder und deren molekulargenetische Grundlagen haben sowohl für die Diagnostik als auch für die Therapie große Bedeutung und werden hier aktualisiert zusammengefasst. Dabei ist die prothrombotische Seite des VWF in den letzten Jahren im Hinblick auf therapeutische Optionen in den Fokus intensiverer Forschung mit bereits guten Ergebnissen für die Patientenversorgung gerückt.
Bewertungen |
Schmelz K, Toedling J, Huska M, Cwikla MC, Kruetzfeldt LM, Proba J, Ambros PF, Ambros IM, Boral S, Lodrini M, Chen CY, Burkert M, Guergen D, Szymansky A, Astrahantseff K, Kuenkele A, Haase K, Fischer M, Deubzer HE, Hertwig F, Hundsdoerfer P, Henssen AG, Schwarz RF, Schulte JH, Eggert A |
Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions. |
Nature communications 2021, 12: 6804 |
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Intratumour heterogeneity is a major cause of treatment failure in cancer. We present in-depth analyses combining transcriptomic and genomic profiling with ultra-deep targeted sequencing of multiregional biopsies in 10 patients with neuroblastoma, a devastating childhood tumour. We observe high spatial and temporal heterogeneity in somatic mutations and somatic copy-number alterations which are reflected on the transcriptomic level. Mutations in some druggable target genes including ALK and FGFR1 are heterogeneous at diagnosis and/or relapse, raising the issue whether current target prioritization and molecular risk stratification procedures in single biopsies are sufficiently reliable for therapy decisions. The genetic heterogeneity in gene mutations and chromosome aberrations observed in deep analyses from patient courses suggest clonal evolution before treatment and under treatment pressure, and support early emergence of metastatic clones and ongoing chromosomal instability during disease evolution. We report continuous clonal evolution on mutational and copy number levels in neuroblastoma, and detail its implications for therapy selection, risk stratification and therapy resistance. |
Schlüter S, Bornfeld N, Valiyev E, Flühs D, Stuschke M, Bechrakis NE, Kiefer T, Ketteler P, Göricke S, Biewald EM |
Combination of Brachytherapy and Intravitreal Chemotherapy in the Treatment of Retinoblastoma with Vitreous Seeding. |
Ocular oncology and pathology 2022, 8: 64 |
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Schlüter S, Bornfeld N, Valiyev E, Flühs D, Stuschke M, Bechrakis NE, Kiefer T, Ketteler P, Göricke S, Biewald EM |
Combination of Brachytherapy and Intravitreal Chemotherapy in the Treatment of Retinoblastoma with Vitreous Seeding. |
Ocular oncology and pathology 2022, 8: 64 |
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The aim of this study was to report the efficacy of combined intravitreal chemotherapy (IVC) and ruthenium-106 brachytherapy in retinoblastoma, either as first-line or second-line treatment, following systemic chemoreduction or intra-arterial chemotherapy. |
Schmidt F, Erlacher M, Niemeyer C, Reinhardt D, Klusmann JH |
Leukoreductive response to the combination of sorafenib and chemotherapy in hyperleukocytosis of FLT3-ITD mutated pediatric AML. |
Frontiers in pediatrics 2022, 10: 1046586 |
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Twelve to 22% of pediatric acute myeloid leukemia (AML) patients present with hyperleukocytosis, which is one of the main risk factors of early death due to its clinical complications: leukostasis, causing pulmonary or central nervous system injuries, tumor lysis syndrome, and disseminated intravascular coagulation. Sorafenib is a multi-kinase inhibitor that blocks the Fms-Related Tyrosine Kinase 3 receptor () in AML patients with a -internal tandem duplication (-ITD), leading to a reduction of proliferation. Here we report four diagnosed or relapsed pediatric -ITD-positive AML patients with hyperleukocytosis, which were treated with sorafenib in combination with cytoreductive chemotherapy prior to the start of the induction phase. We observed a fast reduction of white blood cells in peripheral blood and bone marrow. This resulted in a rapid clinical stabilization of the patients. Adverse side effects-such as dermatologic toxicity, elevation of transaminases and hypertension-occurred but were mild and inductive chemotherapy could be started in parallel or subsequently. This implies sorafenib as a safe and effective treatment option in combination with chemotherapy during cytoreductive prephase for children with this life-threatening condition. |
Schweiger B, Göricke S, Ketteler P, Biewald E, Kottke R, Sirin S |
[Imaging of retinoblastoma : Current state-of-the-art and future prospects]. |
Radiologie (Heidelberg, Germany) 2022, 62: 1067 |
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Retinoblastoma is the most common malignant eye tumor in children and is associated with tumor predisposition syndrome (RB1 mutation) in up to 40% of cases. Imaging is an important part of the diagnostic workup of children with retinoblastoma both during the initial diagnosis and follow-up. |
Schmidt M, Decarolis B, Franzius C, Hero B, Pfluger T, Rogasch JMM, Simon T |
Durchführung und Befundung der 123I-mIBG-Szintigraphie bei Kindern und Jugendlichen mit Neuroblastom (Version 3) – DGN-Handlungsempfehlung (S1-Leitlinie), Stand: 2/2020 – AWMF-Registernummer: 031-040. |
Nuklearmedizin. Nuclear medicine 2022, 61: 96 |
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Scheer M, Hallmen E, Vokuhl C, Fuchs J, Tunn PU, Münter M, Timmermann B, Bauer S, Henssen AG, Kazanowska B, Niggli F, Ladenstein R, Ljungman G, Eggert A, Klingebiel T, Koscielniak E, Cooperative Weichteilsarkom Studiengruppe [CWS] |
Pre-operative radiotherapy is associated with superior local relapse-free survival in advanced synovial sarcoma. |
Journal of cancer research and clinical oncology 2023, 149: 1717 |
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Optimization of local therapies in synovial sarcoma (SS) considered unresectable at diagnosis is needed. We evaluated the effects of neoadjuvant versus adjuvant radiation versus surgery only on long-term outcomes. |
Schober SJ, Hallmen E, Reßle F, Gassmann H, Prexler C, Wawer A, von Luettichau I, Ladenstein R, Kazanowska B, Ljungman G, Niggli F, Lohi O, Hauer J, Gruhn B, Klingebiel T, Bader P, Burdach S, Lang P, Sparber-Sauer M, Koscielniak E, Thiel U |
No Improvement of Survival for Alveolar Rhabdomyosarcoma Patients After HLA-Matched Versus -Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Compared to Standard-of-Care Therapy. |
Frontiers in oncology 2022, 12: 878367 |
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Patients with stage IV alveolar rhabdomyosarcoma (RMA) have a 5-year-survival rate not exceeding 30%. Here, we assess the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for these patients in comparison to standard-of-care regimens. We also compare the use of HLA-mismatched vs. HLA-matched grafts after reduced vs. myeloablative conditioning regimens, respectively. |
Schönberger S, Mohseni MM, Ellinger J, Tran GVQ, Becker M, Claviez A, Classen CF, Hermes B, Driever PH, Jorch N, Lauten M, Mehlitz M, Schäfer N, Scheer-Preiss J, Schneider DT, Troeger A, Calaminus G, Dilloo D |
MicroRNA-profiling of miR-371~373- and miR-302/367-clusters in serum and cerebrospinal fluid identify patients with intracranial germ cell tumors. |
Journal of cancer research and clinical oncology 2023, 149: 791 |
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Intracranial germ cell tumors (iGCT) comprise germinoma and non-germinoma. Their diagnosis predominantly relies on biopsy as only one-fifth of patients present with elevated biomarkers (AFP/ß-HCG) in serum or cerebrospinal fluid (CSF). MicroRNAs (miR/miRNA) have emerged as non-invasive biomarkers in extracranial GCT and may potentially facilitate non-invasive diagnosis in iGCT. |
Schoot RA, van Ewijk R, von Witzleben AA, Kao SC, Merks JHMH, Morosi C, Pace E, Shulkin BL, Ferrari A, von Kalle T, van Rijn RR, Weiss AR, Sparber-Sauer M, Ter Horst SAJ, McCarville MB |
INternational Soft Tissue saRcoma ConsorTium (INSTRuCT) consensus statement: Imaging recommendations for the management of rhabdomyosarcoma. |
European journal of radiology 2023, 166: 111012 |
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Rhabdomyosarcoma is the most common soft-tissue neoplasm in the pediatric population. The survival of children with rhabdomyosarcoma has only marginally improved over the past 25 years and remains poor for those with metastatic disease. A significant challenge to advances in treatment of rhabdomyosarcoma is the relative rarity of this disease, necessitating years to complete clinical trials. Progress can be accelerated by international cooperation and sharing national experiences. This necessitates agreement on a common language to describe patient cohorts and consensus standards to guide diagnosis, treatment, and response assessment. These goals formed the premise for creating the INternational Soft Tissue saRcoma ConsorTium (INSTRuCT) in 2017. Multidisciplinary members of this consortium have since developed international consensus statements on the diagnosis, treatment, and management of pediatric soft-tissue sarcomas. Herein, members of the INSTRuCT Diagnostic Imaging Working Group present international consensus recommendations for imaging of patients with rhabdomyosarcoma at diagnosis, at staging, and during and after completion of therapy. The intent is to promote a standardized imaging approach to pediatric patients with this malignancy to create more-reliable comparisons of results of clinical trials internationally, thereby accelerating progress in managing rhabdomyosarcoma and improving survival. |
Schifferli A, Moulis G, Godeau B, Leblanc T, Aladjidi N, Michel M, Leverger G, Elalfy M, Grainger J, Chitlur M, Heiri A, Holzhauer S, Le Gavrian G, Imbach P, Kühne T |
Adolescents and young adults with newly diagnosed primary immune thrombocytopenia. |
Haematologica 2023, 108: 2783 |
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Current immune thrombocytopenia (ITP) guidelines target children and adults, leading to oversimplification. Adolescents and young adults (AYAS) comprise a separate group with distinct health and psychosocial issues. This study aimed to describe the clinical presentation and therapeutic strategies of ITP among AYAS. We analyzed data from two large ITP registries (PARC-ITP; CARMEN-France) and included newly diagnosed ITP patients (aged 12-25 years) with an initial platelet counts of <100×109/L. Patients with secondary ITP or non-immune thrombocytopenia (n=57) and pregnant women (n=10) were excluded. Of the 656 cases of AYAS with primary ITP registered from 2004 up to 2021, 12-month follow-up data were available for 72%. The initial median platelet count was 12×109/L. In 109 patients (17%), the diagnosis was incidental, without documented bleeding. Apart from gynecological bleeding, the clinical and therapeutical characteristics of females and males were similar. Platelet-enhancing drugs were reported in 66%, 45%, and 30% of patients at diagnosis, 1-6 months, and 6-12 months after diagnosis, respectively. Corticosteroids were the preferred treatment at all time points. At 12 months, 50% of all patients developed chronic ITP. In the subgroup of patients with initial severe thrombocytopenia (<20×109/L), those receiving frontline treatment had a higher remission rate at 1 year than those who followed an initial watch-and-wait strategy (53% and 32%; P<0.05). Our analysis indicates that the remission rate at 1 year may be associated with the initial treatment strategy. This hypothesis must be confirmed in prospective studies. |
Mannucci PM, Mancuso ME, Santagostino E |
How we choose factor VIII to treat hemophilia. |
Blood 2012, 119: 4108 |
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In high-income countries, the large availability of coagulation factors for replacement therapy of patients with hemophilia A has raised the life expectancy of these lifelong bleeders to that of males from the general population. The practicing clinician is offered a multitude of choices among several commercial brands of factor VIII extracted from human plasma or engineered from mammalian cell cultures by means of recombinant DNA technology. This article has the goal to offer our opinions on how to choose among the different products, that we consider interchangeable relevant to their clinical efficacy in the control of bleeding and safety from pathogen transmission. Hence, the main determinants of our choices are price and the risk of occurrence of factor VIII inhibitory alloantibodies. With this as background, we present the rationale underlying the choices for different categories of patients with severe hemophilia A: previously untreated patients, multiply treated patients, and patients undergoing immune tolerance induction with large doses of factor VIII to eradicate inhibitors. Mention is also made to the possible strategies that should be implemented to make available coagulation factors for replacement therapy in developing countries. |
Scobioala S, Ranft A, Wolters H, Jabar S, Paulussen M, Timmermann B, Jürgens H, Hassenpflug W, Klingebiel T, Elsayad K, Eich HT, Dirksen U |
Impact of Whole Lung Irradiation on Survival Outcome in Patients With Lung Relapsed Ewing Sarcoma. |
International journal of radiation oncology, biology, physics 2018 Nov 1; 102: 584 |
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There is no standard treatment procedure for relapsed Ewing sarcoma (EwS). This retrospective analysis evaluates the survival outcome in patients with an isolated pulmonary relapse of EwS treated with whole lung irradiation (WLI) in addition to second line chemotherapy (Ctx). |
Scobioala S, Parfitt R, Matulat P, Byrne J, Langer T, Troschel FM, Hesping AE, Clemens E, Kaatsch P, Grabow D, Kaiser M, Spix C, Kremer LC, Calaminus G, Baust K, Kuehni CE, Weiss A, Strebel S, Kuonen R, Elsner S, Haupt R, Garré ML, Gruhn B, Kepak T, Kepakova K, Winther JF, Kenborg L, Rechnitzer C, Hasle H, Kruseova J, Luks A, Lackner H, Bielack S, Beck JD, Jürgens H, van den Heuvel-Eibrink MM, Zolk O, Eich HT, Am Zehnhoff-Dinnesen A, PanCareLIFE Consortium |
The impact of the temporal sequence of cranial radiotherapy and platin-based chemotherapy on hearing impairment in pediatric and adolescent CNS and head-and-neck cancer patients: A report from the PanCareLIFE consortium. |
International journal of cancer 2023, |
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The impact of the temporal sequence by which cranial radiotherapy (CRT) and platin-based chemotherapy (PCth) are administered on sensorineural hearing loss (SNHL) in pediatric and adolescent central nervous system (CNS) and head-and-neck (HN) cancer patients has not yet been studied in detail. We examined the ototoxic effects of sequentially applied CRT and PCth. This study included children and adolescents with CNS and HN tumors who participated in the multicountry PanCareLIFE (PCL) consortium. Audiological outcomes were compared between patients who received CRT prior to PCth and those who received it afterwards. The incidence, degree and posttreatment progression of SNHL, defined as Muenster classification grade ≥MS2b, were evaluated in 141 patients. One hundred and nineteen patients were included in a time-to-onset analysis. Eighty-eight patients received CRT prior to PCth (Group 1) and 53 patients received PCth before CRT (Group 2). Over a median follow-up time of 1.6 years, 72.7% of patients in Group 1 experienced SNHL ≥ MS2b compared to 33.9% in Group 2 (P < .01). A time-to-onset analysis was performed for 74 patients from Group 1 and 45 patients from Group 2. Median time to hearing loss (HL) ≥ MS2b was 1.2 years in Group 1 and 4.4 years in Group 2 (P < .01). Thus, audiological outcomes were better for patients who received CRT after PCth than before. This finding should be further evaluated and considered within clinical practice in order to minimize hearing loss in children and adolescents with CNS and HN tumors. |
Seeger K, Adams H, Buchwald D, Beyermann B, Kremens B, Niemeyer C, Ritter J, Schwabe D, Harms D, Schrappe M, Henze G |
TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia. The Berlin-Frankfurt-Münster Study Group. |
Blood 1998, 91: 1716 |
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Seeger K, Buchwald D, Peter A, Taube T, Stackelberg A, Schmitt G, Henze G |
TEL-AML1 fusion in relapsed childhood acute lymphoblastic leukemia. |
Blood 1999, 94: 374 |
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Seeger K, Buchwald D, Taube T, Peter A, Stackelberg A, Schmitt G, Köchling J, Henze G |
TEL-AML1 positivity in relapsed B cell precursor acute lymphoblastic leukemia in childhood. Berlin-Frankfurt-Münster Study Group [letter] [see comments]. |
Leukemia 1999, 13: 1469 |
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Seeger K, Stackelberg A, Taube T, Buchwald D, Körner G, Suttorp M, Dörffel W, Tausch W, Henze G |
Relapse of TEL-AML1-positive acute lymphoblastic leukemia in childhood. |
J Clin Oncol 2001, 19: 3188 |
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Seeger K, Viehmann S, Buchwald D, Harbott J, Schrappe M, Stary J, Henze G, Trka J |
Treatment response and residual-disease monitoring in initial and relapsed TEL-AML1 positive childhood ALL. |
Leukemia 2001, 15: 280 |
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Seeringer A, Bartelheim K, Kerl K, Hasselblatt M, Leuschner I, Rutkowski S, Timmermann B, Kortmann RD, Koscielniak E, Schneppenheim R, Warmuth-Metz M, Gerß J, Siebert R, Graf N, Boos J, Frühwald MC |
Feasibility of intensive multimodal therapy in infants affected by rhabdoid tumors - experience of the EU-RHAB registry. |
Klinische Padiatrie 2014, 226: 143 |
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Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2-12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants. |
Seidemann K, Meyer U, Jansen P, Yakisan E, Rieske K, Führer M, Kremens B, Schrappe M, Reiter A |
Impaired renal function and tumor lysis syndrome in pediatric patients with non-Hodgkin's lymphoma and B-ALL. Observations from the BFM-trials. |
Klin Pädiatr 1998, 210: 279 |
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Seidemann K, Tiemann M, Henze G, Sauerbrey A, Muller S, Reiter A |
Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency. |
Med Pediatr Oncol 1999, 33: 536 |
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Seitz R, Dodt, J |
Virus Safety of Prothrombin Complex Concentrates and Factor IX Concentrates. |
Thromb Res 1999, Suppl 1, 95: S19-S23. |
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Substantial progress in virus safety has been achieved during the past 15 years. Therefore only a few virus transmissions with plasma-derived products have been observed since 1985. Specific steps to eliminate, remove, or inactivate viruses were developed. Although virus safety is of decisive importance, chemical or physical treatment during the manufacturing process need not activate labile coagulation factors that cause the risk of thrombogenicity nor need not create neoantigens that mediate the risk of inhibitor formation. Thus, any new virus elimination procedure has to be evaluated and validated for all safety aspects. A comprehensive framework of regulations and efforts has been set up involving plasma donors, donation centres, manufacturers, regulatory authorities, politicians responsible for legislation, physicians, and patients. Blood and plasma donation centres and pharmaceutic industry follow “Good Manufacturing Practice” and are subject to regular audits and official inspections. Every single donation as well as plasma pools are tested for virus markers. The final products need both a marketing authorization and official batch release; in Germany, supervised by the Paul-Ehrlich-Institute. European integration is the purpose of the European Medicines Evaluation Agency. An alert pharmacovigilance system enables scientifically adequate reactions in any case of a safety problem. The ultimate evidence of product safety is provided by clinical surveillance. By participating in clinical studies, patients themselves are able to contribute significantly to the safety of plasma-derived products. The currently achieved high level of safety should encourage us to take further steps to stabilize this success and to look for further progress, wherever possible. |
Seidemann K, Henze G, Beck J, Sauerbrey A, Kühl J, Mann G, Reiter A |
Non-Hodgkin's lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS). |
Ann Oncol 2000, 11 Suppl 1: 141 |
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Seidemann K, Tiemann M, Schrappe M, Yakisan E, Simonitsch I, Janka-Schaub G, Dörffel W, Zimmermann M, Mann G, Gadner H, Parwaresch R, Riehm H, Reiter A |
Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. |
Blood 2001, 97: 3699 |
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Seidemann K, Tiemann M, Lauterbach I, Mann G, Simonitsch I, Stankewitz K, Schrappe M, Zimmermann M, Niemeyer C, Parwaresch R, Riehm H, Reiter A |
Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients. |
J Clin Oncol 2003, 21: 1782 |
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Seidemann K, Zimmermann M, Book M, Meyer U, Burkhardt B, Welte K, Reiter A, Stanulla M |
Tumor necrosis factor and lymphotoxin alfa genetic polymorphisms and outcome in pediatric patients with non-Hodgkin's lymphoma: results from Berlin-Frankfurt-Münster Trial NHL-BFM 95. |
J Clin Oncol 2005, 23: 8414 |
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Seidel MG, Fritsch G, Matthes-Martin S, Lawitschka A, Lion T, Pötschger U, Rosenmayr A, Fischer G, Gadner H, Peters C |
In vitro and in vivo T-cell depletion with myeloablative or reduced-intensity conditioning in pediatric hematopoietic stem cell transplantation. |
Haematologica 2005, 90: 1405 |
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BACKGROUND AND OBJECTIVES: Anti-thymocyte globulin (ATG) is given in various conditioning regimens for children and young adults undergoing hematopoietic stem cell transplantation (HSCT) from HLA non-identical donors in order to reduce the risks of graft-versus-host disease (GvHD) and rejection after the transplant. The aim of this study was to define the effect of in vitro T-cell depletion in addition to ATG on the reconstitution of T-cell-mediated immunity. DESIGN AND METHODS: We retrospectively analyzed the engraftment kinetics and clinical performance of 134 patients (median age 5.80 years) who received ATG during myeloablative or reduced intensity conditioning, and either in vitro T-cell-depleted or unmanipulated grafts. RESULTS: T-cell reconstitution was significantly delayed after T-cell-depleted grafts, irrespectively of the conditioning intensity (p<0.001). The incidence of fatal viral and fungal infections was higher in recipients of T-cell-depleted grafts than in those receiving unmanipulated grafts (26.6-29% versus |
Seifert G, Jesse P, Laengler A, Reindl T, Lüth M, Lobitz S, Henze G, Prokop A, Lode HN |
Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro. |
Cancer letters 2008, 264: 218 |
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Viscum album (Mistletoe) is one of the most widely used alternative cancer therapies. Aqueous mistletoe extracts (MT) contain the three mistletoe lectins I, II and III as one predominant group of biologically active agents. Although MT is widely used, there is a lack of scientifically sound preclinical and clinical data. In this paper, we describe for the first time the in vivo efficacy and mechanism of action of MT in lymphoblastic leukemia. For this purpose, we first investigated both the cytotoxic effect and the mechanism of action of two standardized aqueous MTs (MT obtained from fir trees (MT-A); MT obtained from pine trees (MT-P)) in a human acute lymphoblastic leukemia (ALL) cell line (NALM-6). MT-A, MT-P and ML-I inhibited cell proliferation as determined by Casy Count analysis at very low concentrations with MT-P being the most cytotoxic extract. DNA-fragmentation assays indicated that dose-dependent induction of apoptosis was the main mechanism of cell death. Finally, we evaluated the efficacy of MT-A and MT-P in an in vivo SCID-model of pre-B ALL (NALM-6). Both MTs significantly improved survival (up to 55.4 days) at all tested concentrations in contrast to controls (34.6 days) without side effects. |
Seifert G, Rutkowski S, Jesse P, Madeleyn R, Reif M, Henze G, Längler A |
2. Anthroposophic Supportive Treatment in Children With Medulloblastoma Receiving First-line Therapy. |
J Pediatr Hematol Oncol 2011, Epub ahead of print |
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BACKGROUND: The use of anthroposophic medicine (AM) is popular in Central Europe, especially in German-speaking countries. Although these therapies are judged to be beneficial by many patients, there are few data with regard to the safety and efficacy in pediatric oncology. Several theoretical concerns have been published with regard to tumor enhancement or promotion of metastatic dissemination due to mistletoe. To test the indirect safety of supportive anthroposophic treatment accompanying the first-line treatment in children with medulloblastoma in this respect we performed a retrospective matched-pair analysis of patients with medulloblastoma treated by standard first-line radiochemotherapy with or without a concomitantly applied panel of AM including mistletoe. The question was whether the effectiveness of the first-line therapy is altered by AM.
PROCEDURE: Seventeen patients with AM were matched in a 1:2 ratio with 34 patients from the database of the German HIT study group with regard to the criteria of diagnosis, age, status of metastatic dissemination, resection status, and first-line therapy.
RESULTS: The overall survival after 10 years was 58.33% for the AM group and 57.14% for the control group, that is, showing no statistically significant difference (stratified Cox regression; P=0.6023). Event-free survival (including metastases) also did not differ between the groups (stratified Cox regression; P=0.4275).
CONCLUSIONS: AM consisting of different combinations of specific pharmacologic and nonpharmacologic interventions seems to be safe with respect to any potential negative impact on the first-line therapy. There is no evidence with regard to tumor enhancement. The effectiveness of the supportive AM cannot be assessed on the basis of these data. |
Seifert G, Kanitz JL, Pretzer K, Henze G, Witt K, Reulecke S, Voss A |
Improvement of Heart Rate Variability by Eurythmy Therapy After a 6-Week Eurythmy Therapy Training. |
Integr Cancer Ther 2011, [Epub ahead of print] |
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Background. Eurythmy therapy (EYT) is a mind-body therapy used in anthroposophic medicine. Recently, the authors were able to show that at comparable workloads, EYT stimulated heart rate variability (HRV) whereas conventional ergometer training attenuated HRV. Furthermore, a long-term improvement of quality of life (QoL) and stress coping strategies by EYT could be shown. Objective. This study aimed to evaluate the long-term effects of EYT training on HRV. Design: A total of 23 healthy women (mean age = 44.57 ± 8.04 years) performed 10 hours of EYT over a period of 6 weeks. Electrocardiograms were recorded before and after the EYT trial. HRV was quantified by the extent of high (HF), low (LF), very low (VLF), and ultra low frequency (ULF) oscillations of heart rate. RESULTS: Autonomic regulation was significantly changed following the EYT training compared with baseline. Especially the proportion referring to the total power (P) of HF/P and LF/P increased, whereas ULF/P and (ULF+VLF)/P decreased after the training period. CONCLUSION: EYT shifted the autonomic regulation proportionally referring to the total power mainly caused by changes of ULF and VLF components of HRV. The LF and HF spectral components were also decreased following EYT while their proportion in relation to the total variance of the power spectrum was increased. The proportional enhancement of the higher frequency and the decrease of the ULF and VLF components are probably an indicator of an improvement of autonomic regulation processes by more relaxed physical activity after the EYT training, thus supporting the plausibility of the improved QoL and better stress coping strategies. |
Seitz G, Dantonello TM, Int-Veen C, Blumenstock G, Godzinski J, Klingebiel T, Schuck A, Leuschner I, Koscielniak E, Fuchs J, on behalf of the CWS-96 Study Group |
Treatment efficiency, outcome and surgical treatment problems in patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma: A report from the cooperative soft tissue sarcoma trial CWS-96. |
Pediatr Blood Cancer 2011, 56: 718 |
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BACKGROUND: To analyze the clinical course, treatment modalities, complications and outcome of patients suffering from localized embryonal bladder/prostate rhabdomyosarcoma (BPRMS) treated on the CWS-96 trial.
PROCEDURE: There were 85 patients with BPRMS enrolled and 63 patients with embryonal non-metastatic BPRMS were analyzed. Fifty-six patients received neoadjuvant chemotherapy and response was assessed radiographically after 9 weeks. Local therapy with radiation and or surgery was performed based on age, tumor size, and response. Patients were treated with adjuvant chemotherapy following local control.
RESULTS: Patient's age ranged from 0 to 16 years with a median follow up of 5.3 years. Eighty nine percent of the patients had IRS group III disease. The 5-year overall survival (OS) for the whole group was 76.3 ± 5.6% and the 5-year event-free survival (EFS) 69.8 ± 6.2%. Seventeen patients underwent preoperative radiochemotherapy followed by tumor resection (5-year-OS: 87.8 ± 8.1%). Eight patients were treated with solely radiochemotherapy (87.5 ± 11.7%). Twenty-five patients received chemotherapy and tumor resection (OS: 83.6 ± 7.5%). Thirteen patients underwent incomplete tumor resection and were treated with radiochemotherapy postoperatively (OS: 39.9 ± 14.8%, P < 0.05 vs. other groups).
CONCLUSIONS: Local therapy is an important factor for prognosis of localized embryonal BPRMS. Inadequate primary or secondary surgery compromises the outcome and should be avoided. Radiotherapy alone, complete surgical tumor resection or combined preoperative radiotherapy with surgical resection lead to similar good local control rates and prognosis. Pediatr Blood Cancer 2011;56:718-724. © 2010 Wiley-Liss, Inc. |
Seifert G, Rutkowski S, Jesse P, Madeleyn R, Reif M, Henze G, Längler A |
Anthroposophic supportive treatment in children with medulloblastoma receiving first-line therapy. |
Journal of pediatric hematology/oncology 2011, 33:e105 |
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The use of anthroposophic medicine (AM) is popular in Central Europe, especially in German-speaking countries. Although these therapies are judged to be beneficial by many patients, there are few data with regard to the safety and efficacy in pediatric oncology. Several theoretical concerns have been published with regard to tumor enhancement or promotion of metastatic dissemination due to mistletoe. To test the indirect safety of supportive anthroposophic treatment accompanying the first-line treatment in children with medulloblastoma in this respect we performed a retrospective matched-pair analysis of patients with medulloblastoma treated by standard first-line radiochemotherapy with or without a concomitantly applied panel of AM including mistletoe. The question was whether the effectiveness of the first-line therapy is altered by AM. |
Seidel MG, Urban C, Sipurzynski J, Beham-Schmid C, Lackner H, Benesch M |
High response rate but short-term effect of romiplostim in paediatric refractory chronic immune thrombocytopenia. |
British journal of haematology 2014, E-pub ahead of print |
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Seitz G, Dantonello TM, Kosztyla D, Klingebiel T, Leuschner I, Fuchs J, Koscielniak E, Cooperative Soft Tissue Sarcoma Study Group |
Impact of Hemiscrotectomy on Outcome of Patients with Embryonal Paratesticular Rhabdomyosarcoma: Results from the Cooperative Soft Tissue Sarcoma Group Studies CWS-86, 91, 96 and 2002P. |
The Journal of urology 2014, Epub ahead of print |
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Children with paratesticular rhabdomyosarcoma have a favorable prognosis. Surgical treatment problems include inadequate primary transscrotal approaches, incomplete tumor resections and the need for secondary hemiscrotectomy. We evaluated the need for hemiscrotectomy regarding local relapse and outcome. |
Seitz G, Fuchs J, Sparber-Sauer M, Leuschner I, Godzinski J, Klingebiel T, Schuck A, Martus P, Dantonello TM, Koscielniak E |
Improvements in the Treatment of Patients Suffering from Bladder-Prostate Rhabdomyosarcoma: A Report from the CWS-2002P Trial. |
Annals of surgical oncology 2016, |
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Modern treatment concepts for bladder/prostate rhabdomyosarcoma (BPRMS) are designed to improve survival, to reduce therapy intensity, and to increase bladder preservation rates. Nevertheless, treatment is not optimal. The purpose of this study was to analyze BPRMS patients treated within the CWS-2002P trial regarding outcome, treatment modalities, complications, and to compare the data with the precursor trial CWS-96. |
Seidel C, von Bueren AO, Bojko S, Hoffmann M, Pietsch T, Gielen GH, Warmuth-Metz M, Bison B, Kortmann RD, Kramm CM |
Concurrent radiotherapy with temozolomide vs. concurrent radiotherapy with a cisplatinum-based polychemotherapy regimen : Acute toxicity in pediatric high-grade glioma patients. |
Strahlentherapie und Onkologie 2018, 194: 215 |
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As the efficacy of all pediatric high-grade glioma (HGG) treatments is similar and still disappointing, it is essential to also investigate the toxicity of available treatments. |
Selle B, Bar C, Hecker S, Schmidt-Rohr U, Viehmann S, Debatin K, Reinhardt D |
ABL-specific tyrosine kinase inhibitor imatinib as salvage therapy in a child with Philadelphia chromosome-positive acute mixed lineage leukemia (AMLL). |
Leukemia 2002, 16: 1393 |
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Selo N, Bölling T, Ernst I, Pape H, Martini C, Rübe C, Timmermann B, Fischedick K, Kortmann RD, Gerss J, Koch R, Willich N |
Acute toxicity profile of radiotherapy in 690 children and adolescents: RiSK data. |
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 2010, 97: 119 |
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BACKGROUND AND PURPOSE: The "Registry for the evaluation of side effects after radiation in childhood and adolescence" (risk) was introduced to characterize adverse effects of radiotherapy in childhood and adolescence prospectively. The aim of this analysis was to characterize the pattern of acute side effects. MATERIALS AND METHODS: Since 2001, patients receiving radiotherapy in one of the German pediatric therapy trials have been registered in RiSK with detailed information regarding radiation doses to organs at risk and characterization of acute toxicities. RESULTS: From 2001 to May 2009, 690 patients have been characterized for acute toxicity in primary therapy. Acute toxicity ≥ grade 1 was observed in 506 patients. In patients irradiated in their lung and liver, patients with grade 1 or 2 acute toxicities showed higher organ volumes exposed to radiation doses <20 Gray (Gy) compared to patients without toxicities. For the salivary glands, there was a positive correlation between the acute toxicity grade and the maximum radiation dose to the organ; the lower GI tract showed a similar trend. The impact of different chemotherapy regimens on these acute side effects remains unclear. Age did not have any impact on side effects. CONCLUSION: This analysis gives a comprehensive overview of the acute toxicities of radiotherapy in children and adolescents. With prolongation of follow-up, detailed analyses regarding late toxicities will be possible with the characterization of dose-volume-effect relationships. |
Selt F, Hohloch J, Hielscher T, Sahm F, Capper D, Korshunov A, Usta D, Brabetz S, Ridinger J, Ecker J, Oehme I, Gronych J, Marquardt V, Pauck D, Bächli H, Stiles CD, von Deimling A, Remke M, Schuhmann MU, Pfister SM, Brummer T, Jones DT, Witt O, Milde T |
Establishment and application of a novel patient-derived KIAA1549:BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing. |
Oncotarget 2017 Feb 14; 8: 11460 |
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Selt F, van Tilburg CM, Bison B, Sievers P, Harting I, Ecker J, Pajtler KW, Sahm F, Bahr A, Simon M, Jones DTW, Well L, Mautner VF, Capper D, Hernáiz Driever P, Gnekow A, Pfister SM, Witt O, Milde T |
Response to trametinib treatment in progressive pediatric low-grade glioma patients. |
Journal of neuro-oncology 2020, 149: 499 |
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A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy. |
Sessa C, Schneider DT, Planchamp F, Baust K, Braicu EI, Concin N, Godzinski J, McCluggage WG, Orbach D, Pautier P, Peccatori FA, Morice P, Calaminus G |
ESGO-SIOPE guidelines for the management of adolescents and young adults with non-epithelial ovarian cancers. |
The Lancet. Oncology 2020, 21:e360-e368 |
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The European Society of Gynaecological Oncology and the European Society for Paediatric Oncology jointly developed clinically relevant and evidence-based guidelines for the management of adolescents and young adults aged 15 to 25 years with non-epithelial ovarian cancers, including malignant ovarian germ cell tumours, sex cord-stromal tumours, and small cell carcinoma of the ovary of hypercalcaemic type. The developmental process of these guidelines is based on a systematic literature review and critical appraisal process involving an international multidisciplinary developmental group consisting of experts from relevant disciplines (paediatric oncology, paediatric surgery, medical oncology, pathology, psycho-oncology, gynaecological oncology, and reproductive endocrinology). Given the specific and often complex issues involved in treating this group of patients, fertility sparing surgery and decrease of acute and long-term toxicities from treatment were important criteria for guidelines definition. Prior to publication, the guidelines were reviewed by 54 independent international practitioners in cancer care delivery. |
Seuser A, Wallny T, Oldenburg J (Hrsg) |
Hämophilie und Schmerz. |
Weller Verlag 2008 |
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Sevenet N, Lellouch-Tubiana A, Schofield D, Hoang-Xuan K, Gessler M, Birnbaum D, Jeanpierre C, Jouvet A, Delattre O |
Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations. |
Hum Mol Genet 1999, 8: 2359 |
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Seyger M, Ritterbach J, Creutzig U, Gnekow A, Göbel U, Graf N, Reiter A, Lampert F, Harbott J |
12q13, a new recurrent breakpoint in acute non-lymphoblastic leukemia. |
Cancer Genet Cytogenet 1995, 80: 23 |
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Seyyedi S, Parlowsky T, Bucsky P |
Interimsanalyse der interdisziplinären multizentrischen Therapieoptimierungsstudie im Kindes- und Jugendalter, GPOH-MET 97. |
Monatsschr. Kinderheilk 2002, 150: 1303-1304. |
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Shannon KM, O'Connell P, Martin GA, Paderanga D, Olson K, Dinndorf P, McCormick F |
Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. |
N Engl J Med 1994, 330: 597 |
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Shalapour S, Eckert C, Seeger K, Pfau M, Prada J, Henze G, Blankenstein T, Kammertoens T |
Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia. |
Journal of molecular medicine 2010, 88: 249 |
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Childhood acute lymphoblastic leukemia (ALL) is caused by malignant immature lymphocytes. Even though childhood ALL can be cured in a large number of patients, around 20% of the patients suffer a relapse after chemotherapy. The origin of the relapse is unclear at the present time. Given the high plasticity of cells, we searched for leukemia-associated genetic aberrations and immunoglobulin (IG) gene rearrangements in mesenchymal stem cells (MSC) from childhood B-cell precursor ALL patients. MSC from all ten ALL patients analyzed presented the chromosomal translocations that had been detected in leukemia cells (TEL-AML1, E2A-PBX1, or MLL rearrangement). The proportions of translocation-positive MSC varied between 10% and 54% depending on the patients and the time point of analysis. Leukemia-specific IG gene rearrangements were detected in the MSC from three ALL patients. The detection of leukemia-associated genetic aberrations in MSC indicates a clonal relationship between MSC and leukemia cells and suggests their involvement in the pathogenesis and/or pathophysiology of childhood ALL. |
Shalapour S, Hof J, Kirschner-Schwabe R, Bastian L, Eckert C, Prada J, Henze G, von Stackelberg A, Seeger K |
High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse. |
Haematologica 2011, 96: 1627 |
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Resistance to therapy and subsequent relapse remain major challenges in the clinical management of relapsed childhood acute lymphoblastic leukemia. As the bone marrow environment plays an important role in survival and chemotherapy resistance of leukemia cells by activating different signaling pathways, such as the VLA-4 and PI3K/Akt pathways, we studied the prognostic and biological impact of VLA-4 expression in leukemia cells from children with relapsed B-cell precursor acute lymphoblastic leukemia and its influence on the sensitivity of the leukemia cells to drugs. |
Shen JJ, Williams BJ, Zipursky A, Doyle J, Sherman SL, Jacobs PA, Shugar AL, Soukup SW, Hassold TJ |
Cytogenetic and molecular studies of Down syndrome individuals with leukemia. |
Am J Hum Genet 1995, 56: 915 |
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Shenoy S, Eapen M, Panepinto JA, Logan BR, Wu J, Abraham A, Brochstein J, Chaudhury S, Godder K, Haight AE, Kasow KA, Leung K, Andreansky M, Bhatia M, Dalal J, Haines H, Jaroscak J, Lazarus HM, Levine JE, Krishnamurti L, Margolis D, Megason GC, Yu LC, Pulsipher MA, Gersten I, DiFronzo N, Horowitz MM, Walters MC, Kamani N |
A trial of unrelated donor marrow transplantation for children with severe sickle cell disease. |
Blood 2016, 128: 2561 |
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Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n = 12), transcranial Doppler velocity >200 cm/s (n = 2), ≥3 vaso-occlusive pain crises per year (n = 12), or ≥2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The BMT CTN #0601 trial was registered at www.clinicaltrials.gov as #NCT00745420. |
Shimizu Y, Schull WJ, Kato H |
Cancer risk among atomic bomb survivors: the RERF Life Span Study. Radiation Effects Research Foundation. |
JAMA 1990, 264: 601 |
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Shi L, Eichelbauer D, Borchard F, Jürgens H, Göbel U, Schneider E |
Specificity and function of monoclonal antibodies directed against Ewing sarcoma cells. |
Cancer Immunol Immunother 1994, 38: 208 |
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Shields CL, Shields JA, Baez K, Cater JR, De Potter P |
Optic nerve invasion of retinoblastoma. Metastatic potential and clinical risk factors. |
Cancer 1994, 73: 692 |
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BACKGROUND. Optic nerve invasion is one of the predictors for retinoblastoma metastases. This study was designed to investigate the risk of optic nerve invasion and clinical features that may identify those children with optic nerve invasion. METHODS. We reviewed the charts of 289 children with retinoblastoma treated initially with enucleation. Logistic regression analysis was performed to assess the risk for metastases from varying degrees of optic nerve invasion and to assess the clinical and histopathologic predictors of optic nerve invasion. RESULTS. There were 84 eyes (29%) with optic nerve invasion. The invasion was prelamina cribrosa in 44 cases (15%), up to but not posterior to the lamina cribrosa in 21 cases (7%), posterior to the lamina cribrosa but not to the cut end of the optic nerve in 17 cases (6%), and to the site of optic nerve transection in 2 cases (1%). Patients with optic nerve invasion were more likely to develop metastasis (P = 0.0016), particularly those with invasion to the postlaminar and cut section of the optic nerve (P = 0.0001). Development of metastasis was not statistically associated with laminar or prelaminar involvement. If those patients with choroidal invasion simultaneous with optic nerve invasion were excluded from evaluation, the presence of optic nerve invasion alone was not significant for development of metastasis. The clinical factors found to be predictive for optic nerve invasion from a univariate analysis included exophytic growth pattern (P = 0.011), elevated intraocular pressure (> 22 mm Hg) (P = 0.02), and tumor thickness greater than or equal to 15 mm (P = 0.03). The histopathologic factor significantly associated with optic nerve invasion (univariate analysis) was simultaneous choroidal invasion (P = 0.001). A trend toward an association with optic nerve invasion was found with vitreous hemorrhage (P = 0.06), iris neovascularization (P = 0.10), and poorly differentiated retinoblastoma (P = 0.07). A multivariate analysis showed the most significant clinical factors to be exophytic growth pattern (P = 0.002), tumor thickness greater than or equal to 15 mm (P = 0.01), and vitreous hemorrhage (P = 0.05). CONCLUSIONS. Optic nerve invasion of retinoblastoma beyond the lamina cribrosa is associated with a greater metastatic risk. Large exophytic retinoblastoma with secondary glaucoma is at highest risk for optic nerve invasion. |
Shields CL, Shields JA, Needle M, de Potter P, Kheterpal S, Hamada A, Meadows AT |
Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma. |
Ophthalmology 1997, 104: 2101 |
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OBJECTIVE: The purpose of the study is to investigate chemoreduction and adjuvant treatment (AT) for retinoblastoma and its effect on complete retinal tumor control, vitreous seed control, and subretinal seed control. DESIGN: The study design was a prospective, nonrandomized clinical trial. PARTICIPANTS: There were 130 intraocular retinoblastomas in 52 eyes of 32 consecutive patients observed for at least 1 year after initiation of treatment. INTERVENTION: Treatment with chemoreduction using vincristine, etoposide, and carboplatin (VEC) and adjuvant treatment (+ AT) (cryotherapy, laser photocoagulation, thermotherapy, chemothermotherapy, plaque radiation therapy, or external beam radiation therapy) were assessed. MAIN OUTCOME MEASURES: The effect of chemoreduction for 6 cycles (VEC x 6) versus fewer than 6 cycles (VEC x <6) on retinoblastoma control was analyzed. Furthermore, the impact of adjuvant treatment (+ AT) versus no adjuvant treatment (no AT) on retinoblastoma control was analyzed. RESULTS: Retinal tumors showed favorable initial regression with chemoreduction. Adjuvant treatment was applied to 93% of the retinal tumors after chemoreduction and only 2% recurred over the mean follow-up of 17 months (range 13-27 months). Vitreous seeds and subretinal seeds showed initial regression and often complete disappearance with chemoreduction. In those eyes with seeds before treatment, the addition of AT to VEC for 6 cycles decreased the vitreous seed recurrence from 75% to 0% (P = 0.04) and also decreased the subretinal seed recurrence from 67% to 0% (P = 0.003). More important, when considering that enucleation or external beam radiation therapy was the only other treatment option for these 52 eyes, the authors were successful in avoiding these methods in 42% of cases. Of the 36 eyes classified as Reese-Ellsworth group 5, there was 78% ocular salvage, and external beam radiation therapy was avoided in 25% of these eyes. There was a 100% ocular salvage in the group 5 eyes that received VEC for 6 cycles + AT to retinal tumors and seeds. CONCLUSIONS: Chemoreduction and AT to intraocular retinoblastoma and its seeds provides good retinal tumor control, even in eyes with advanced disease. Chemoreduction alone generally is not adequate to achieve complete tumor seed control. Cautious follow-up of affected patients is recommended because the risk for recurrent vitreous and subretinal seeds is substantial and proper treatment is critical for salvaging the eye. |
Shields JA |
Importance of early diagnosis of retinoblastoma. |
The British journal of ophthalmology 1999, 83: 1315 |
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Shields CL, Honavar SG, Meadows AT, Shields JA, Demirci H, Naduvilath TJ |
Chemoreduction for unilateral retinoblastoma. |
Archives of ophthalmology 2002, 120: 1653 |
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OBJECTIVE: To evaluate conservative management of unilateral retinoblastoma using chemoreduction and focal treatment. DESIGN: Prospective nonrandomized single-center clinical trial. SETTING: Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University, Philadelphia, Pa, in conjunction with the Division of Oncology at The Children's Hospital of Philadelphia. PARTICIPANTS: Thirty eyes of 30 patients with unilateral retinoblastoma treated with chemoreduction between June 1, 1994, and August 31, 1999, that would otherwise have been managed with enucleation or external beam radiotherapy. INTERVENTION: All patients received treatment for retinoblastoma with a planned 6 cycles of chemoreduction using vincristine sulfate, etoposide, and carboplatin, combined with focal treatment (cryotherapy or thermotherapy) to each retinal tumor. MAIN OUTCOME MEASURES: The main outcome measure was the postchemoreduction need for external beam radiotherapy or enucleation. The cumulative probability of each outcome was estimated using Kaplan-Meier survival analysis. A secondary outcome measure was final visual acuity in the affected eye. The clinical features at the time of patient presentation were analyzed for their impact on the main outcomes using a series of Fisher exact tests and Cox proportional hazards regressions. RESULTS: Eighteen eyes (60%) were classified as having Reese-Ellsworth (RE) groups I through IV retinoblastoma and 12 eyes (40%), group V retinoblastoma. By using Kaplan-Meier estimates, we found a need for either external beam radiotherapy or enucleation in 68% of eyes by 5 years. In fact, 38% of those in groups I through IV required either treatment, whereas all of those in group V required the additional use of either treatment. Specifically, the need for external beam radiotherapy occurred in 27% of eyes by 5 years. Eleven percent of those in groups I through IV and 50% of group V required external beam radiotherapy by 5 years. The factors predictive of the need for external beam radiotherapy included RE group V disease, tumor thickness greater than 5 mm, and presence of vitreous seeds. The need for enucleation occurred in 47% of eyes by 5 years using Kaplan-Meier analysis. Specifically, 29% of those in groups I through IV and 67% of group V required enucleation by 5 years. The factors predictive of the need for enucleation included age at diagnosis older than 12 months, RE group V disease, tumor base diameter greater than 15 mm, and tumor thickness greater than 5 mm. At a mean follow-up of 29 months, the final visual acuity was 20/200 or better in 6 eyes (20%) and worse than 20/200 in 14 (47%); enucleation was needed in 10 (33%). Of the 26 eyes with initial macular involvement of retinoblastoma, final visual acuity was 20/200 or better in 6 (23%). No patient developed retinoblastoma metastasis, pinealoblastoma, or second malignant neoplasms. CONCLUSIONS: Chemoreduction is an option for selected eyes with unilateral retinoblastoma. Those with advanced RE group V retinoblastoma showed poorest results, while those with less advanced groups I through IV disease showed best results, maintaining the globe in 71% of eyes, sometimes with satisfactory functional visual acuity. |
Shields CL, Shields JA |
Basic understanding of current classification and management of retinoblastoma. |
Current opinion in ophthalmology 2006, 17: 228 |
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The current classification and management strategies for retinoblastoma are discussed. |
Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, Shields JA |
The International Classification of Retinoblastoma predicts chemoreduction success. |
Ophthalmology 2006, 113: 2276 |
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To evaluate the reliability of the International Classification of Retinoblastoma (ICRB) for predicting treatment success with chemoreduction (CRD). |
Shields CL, Shields JA |
Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. |
Current opinion in ophthalmology 2010, 21: 203 |
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To provide an update on current management of retinoblastoma |
Shields CL, Shields JA |
Intra-arterial chemotherapy for retinoblastoma: the beginning of a long journey. |
Clinical & experimental ophthalmology 2010, 38: 638 |
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Conservative management of retinoblastoma has evolved from external beam radiotherapy to systemic chemotherapy by intravenous route and now to localized chemotherapy by intra-arterial route in some cases. With 16-year experience, systemic chemotherapy has been found effective for minimal to moderately advanced retinoblastoma with tumour control of 90% or better, few side effects and even hope for return of some vision. Localized intra-arterial chemotherapy with delivery under fluoroscopy and catheterization of the ophthalmic artery is now undergoing evaluation and appears to provide striking control for retinoblastoma, particularly recurrent tumour seeds following other therapies. The limitations and complications of this approach have yet to be defined. Toxicity of the chemotherapy to the delicate retinal vessels is unknown. Despite its allure, intra-arterial chemotherapy should be used with caution, as in other fields of paediatric oncology it has been found to provide no advantage over intravenous chemotherapy. Time will tell. |
Shimamura A, Alter BP |
Pathophysiology and management of inherited bone marrow failure syndromes. |
Blood reviews 2010, 24: 101 |
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The inherited marrow failure syndromes are a diverse set of genetic disorders characterized by hematopoietic aplasia and cancer predisposition. The clinical phenotypes are highly variable and much broader than previously recognized. The medical management of the inherited marrow failure syndromes differs from that of acquired aplastic anemia or malignancies arising in the general population. Diagnostic workup, molecular pathogenesis, and clinical treatment are reviewed. |
Shu XO, Stewart P, Wen WQ, Han D, Potter JD, Buckley JD, Heineman E, Robison LL |
Parental occupational exposure to hydrocarbons and risk of acute lymphocytic leukemia in offspring. |
Cancer Epidemiol Biomarkers Prev 1999, 8: 783 |
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Siemer S, Lehmann J, Reinhard H, Graf N, Loffler G, Hendrik H, Remberger K, Stockle M |
Prenatal diagnosis of congenital mesoblastic nephroma associated with renal hypertension in a premature child. |
International journal of urology : official journal of the Japanese Urological Association 2004, 11: 50 |
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In the present article, we report, for the first time, a prenatal diagnosis of a congenital mesoblastic nephroma in combination with a post-partum hyperreninemia with hypertension. A newborn was delivered at 35 weeks gestation who had an intrauterine diagnosis of a renal mass as early as 32 weeks gestational age by ultrasound examination. Tumor nephrectomy was performed on day 11 after delivery when an increase in hypertension was observed in the newborn. |
Siepermann M, Koscielniak E, Dantonello T, Klee D, Boos J, Krefeld B, Borkhardt A, Hoehn T, Asea A, Wessalowski R |
Oral low-dose chemotherapy: Successful treatment of an alveolar rhabdomyosarcoma during pregnancy. |
Pediatr Blood Cancer 2011, [Epub ahead of print] |
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We report for the first time the impact of neoadjuvant oral low-dose chemotherapy consisting of oral trofosfamide, idarubicin, and etoposide (O-TIE) in the case of alveolar rhabdomyosarcoma (RMS) in the lower jaw of an 18-year-old woman at 27 weeks of gestation, without fetal complications and a highly efficient anti-tumor response. Our study suggests the possible application of O-TIE treatment in a neoadjuvant setting during pregnancy and recommends a schedule that can be considered for the treatment of patients with high-risk sarcomas who cannot be treated with intensive chemotherapy for various reasons. Pediatr Blood Cancer © 2011 Wiley-Liss, Inc. |
Siepermann M, Koscielniak E, Dantonello T, Klee D, Boos J, Krefeld B, Borkhardt A, Hoehn T, Asea A, Wessalowski R |
Oral low-dose chemotherapy: successful treatment of an alveolar rhabdomyosarcoma during pregnancy. |
Pediatric blood & cancer 2012, 58: 104 |
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We report for the first time the impact of neoadjuvant oral low-dose chemotherapy consisting of oral trofosfamide, idarubicin, and etoposide (O-TIE) in the case of alveolar rhabdomyosarcoma (RMS) in the lower jaw of an 18-year-old woman at 27 weeks of gestation, without fetal complications and a highly efficient anti-tumor response. Our study suggests the possible application of O-TIE treatment in a neoadjuvant setting during pregnancy and recommends a schedule that can be considered for the treatment of patients with high-risk sarcomas who cannot be treated with intensive chemotherapy for various reasons. |
Sievers P, Henneken SC, Blume C, Sill M, Schrimpf D, Stichel D, Okonechnikov K, Reuss DE, Benzel J, Maaß KK, Kool M, Sturm D, Zheng T, Ghasemi DR, Kohlhof-Meinecke P, Cruz O, Suñol M, Lavarino C, Ruf V, Boldt HB, Pagès M, Pouget C, Schweizer L, Kranendonk MEG, Akhtar N, Bunkowski S, Stadelmann C, Schüller U, Mueller WC, Dohmen H, Acker T, Harter PN, Mawrin C, Beschorner R, Brandner S, Snuderl M, Abdullaev Z, Aldape K, Gilbert MR, Armstrong TS, Ellison DW, Capper D, Ichimura K, Reifenberger G, Grundy RG, Jabado N, Krskova L, Zapotocky M, Vicha A, Varlet P, Wesseling P, Rutkowski S, Korshunov A, Wick W, Pfister SM, Jones DTW, von Deimling A, Pajtler KW, Sahm F |
Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors. |
Acta neuropathologica 2021, 142: 827 |
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Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients. |
Signorello LB, Mulvihill JJ, Green DM, Munro HM, Stovall M, Weathers RE, Mertens AC, Whitton JA, Robison LL, Boice JD Jr |
Congenital anomalies in the children of cancer survivors: a report from the childhood cancer survivor study. |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012 Jan 20; 30: 239 |
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Children with cancer receive mutagenic treatments, which raises concern about the potential transmissibility of germline damage to their offspring. This question has been inadequately studied to date because of a lack of detailed individual treatment exposure assessment such as gonadal radiation doses. |
Silies H, Blaschke G, Hohenlochter B, Rossi R, Jürgens H, Boos J |
Excretion kinetics of ifosfamide side-chain metabolites in children on continuous and short-term infusion. |
Int J Clin Pharmacol Ther 1998, 36: 246 |
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Silva Junior GB, Vieira AP, Couto Bem AX, Alves MP, Meneses GC, Martins AM, Sanches TR, Andrade LC, Seguro AC, Libório AB, Daher EF |
Renal Tubular Dysfunction in Sickle Cell Disease. |
Kidney & blood pressure research 2014, 38: 1 |
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Background/Aims: Kidney abnormalities are one of the main chronic complications of sickle cell disease (SCD). The aim of this study is to investigate the occurrence of renal tubular abnormalities among patients with SCD. Methods: This is a prospective study with 26 SCD adult patients in Brazil. Urinary acidification and concentration tests were performed using calcium chloride (CaCl2), after a 12h period of water and food deprivation. Fractional excretion of sodium (FENa), transtubular potassium gradient (TTKG) and solute free water reabsorption (TcH2O) were calculated. The SCD group was compared to a group of 15 healthy volunteers (control group). Results: Patient`s average age and gender were similar to controls. Urinary acidification deficit was found in 10 SCD patients (38.4%), who presented urinary pH >5.3 after CaCl2 test. Urinary osmolality was significantly lower in SCD patients (355±60 vs. 818±202mOsm/kg, p=0.0001, after 12h period water deprivation). Urinary concentration deficit was found in all SCD patients (100%). FENa was higher among SCD patients (0.75±0.3 vs. 0.55±0.2%, p=0.02). The TTKG was higher in SCD patients (5.5±2.5 vs. 3.0±1.5, p=0.001), and TcH2O was lower (0.22±0.3 vs. 1.1±0.3L/day, p=0.0001). Conclusions: SCD is associated with important kidney dysfunction. The main abnormalities found were urinary concentrating and incomplete distal acidification defect. There was also an increase in the potassium transport and decrease in water reabsorption, evidencing the occurrence of distal tubular dysfunction. © 2014 S. Karger AG, Basel. |
Silva Junior GB, Vieira AP, Couto Bem AX, Alves MP, Meneses GC, Martins AM, Araújo SM, Libório AV, Daher EF |
Proteinuria in adults with sickle-cell disease: the role of hydroxycarbamide(hydroxyurea) as a protective agent. |
International journal of clinical pharmacy 2014, 36: 766 |
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Background Renal abnormalities are often seen in sickle cell disease (SCD). Objective To investigate the role of hydroxycarbamide as a protective agent in sickle cell nephropathy. Setting Patients with SCD followed at a Hematology outpatients clinic. Methods Prospective study with 26 SCD patients. Renal function evaluation was performed and a comparison between patients and control group was done. Patients using hydroxycarbamide were compared to those not taking this drug. Main outcome measure Effect of hydroxycarbamide on renal function. Results Patients mean age was 32.1 ± 9.9 years, and 16 (61 %) were males. Glomerular hyperfiltration was found in nine patients with SCD (34.6 %). GFR < 60 mL/min/1.73 m(2) was observed in three cases (11.5 %). Microalbuminuria (30-300 mg/day) was found in seven cases (27 %) and macroalbuminuria (>300 mg/dia) in one patient (3.8 %). All patients had urinary concentrating deficit, and inability to acidify urine was found in ten cases (38.4 %). The comparison of patients according to the use of hydroxycarbamide showed lower levels of serum creatinine in those using the drug (0.6 ± 0.1 vs. 0.8 ± 0.3 mg/dL, p = 0.03), as well as lower levels of 24 h-proteinuria (226 ± 16 vs. 414 ± 76 mg/dL, p = 0.0001), but not microalbuminuria (79 ± 15 vs. 55 ± 86 mg/dL, p = 0.35). Conclusion SCD is associated with important renal abnormalities. Hydroxycarbamide seems to protect kidney function in SCD by decreasing proteinuria but not microalbuminuria. |
Simone J, Aur R, Hustu HO, Pinkel D |
Total therapy” studies of acute lymphocytic leukemia in children. Current results and prospects for cure. |
Cancer 1972 30: 1488 |
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Simon T, Hero B, Berthold F |
Testicular and paratesticular involvement by metastatic neuroblastoma. |
Cancer 2000, 88: 2636 |
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Simon A, Fleischhack G, Marklein G, Ritter J |
Antimicrobial prophylaxis of bacterial infections in pediatric oncology patients. |
Klin Pädiatr 2001, 213 Suppl 1:A22-A37 |
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Simon T, Voth E, Berthold F |
Asymmetric salivary gland 123I-meta-iodobenzylguanidine uptake in a patient with cervical neuroblastoma and Horner syndrome. |
Med Pediat Oncol 2001, 36: 489 |
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Simon A, Fleischhack G |
Non-pharmacologic strategies to prevent and control infectious complications in pediatric hematology/oncology patients. |
Klin Pädiatr 2001, 213 Suppl 1:A9-A21 |
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Simon T, Hero B, Dupuis W, Selle B, Berthold F |
The incidence of hearing impairment after successful treatment of neuroblastoma. |
Klin Pädiatr 2002, 214: 149 |
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Simon A |
Evidenzbasierte Empfehlungen zur Anwendung dauerhafter, zentralvenöser intravaskulärer Zugänge in der pädiatrischen Onkologie. |
mhp-Verlag Wiesbaden 2002 |
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Simon T, Hero B, Berthold F |
Diagnostik und Therapie des Neuroblastoms. |
Kinder- und Jugendmedizin 2003, 1: 31 |
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Simon T, Hero B, Hunneman DH, Berthold F |
Tumour markers are poor predictors for relapse or progression in neuroblastoma. |
European journal of cancer (Oxford, England : 1990) 2003, 39: 1899 |
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The value of the tumour markers vanillylmandelic acid (VMA) and homovanillic acid (HVA) in urine (u) and serum (s), neurone-specific enolase (NSE), and lactate dehydrogenase (LDH) in the early prediction of relapse/progression in neuroblastoma is not known. We analysed the data of neuroblastoma patients who had successfully completed first-line treatment and had laboratory results available from their initial diagnosis and from relapse/progression (n=196). Patients' overall survival from relapse or progression was 21.5+/-4.2% (mean+/-standard deviation). At diagnosis, we found abnormal results in 75% for VMA and/or HVA (s), 92% for VMA and/or HVA (u), 90% for NSE, and 81% for LDH. We found a lower incidence of abnormal results at relapse or progression with 40% for VMA and/or HVA (s), 54% for HVA and/or VMA (u), 61% for NSE, and 48% for LDH. Sensitivity of all markers was higher for metastatic compared with local recurrence. NSE was the best, being able to detect 42% of the localised relapses, 77% of the combined local/metastatic relapses, and 69% of the metastatic recurrences. Relapse or progression in neuroblastoma cannot be detected reliably by monitoring tumour markers alone. Therefore, follow-up of neuroblastoma patients must include clinical assessment and imaging studies. |
Simon T, Spitz R, Faldum A, Hero B, Berthold F |
New definition of low-risk neuroblastoma using stage, age, and 1p and MYCN status. |
Journal of pediatric hematology/oncology : official journal of the American Society of Pediatric Hematology/Oncology 2004, 26: 791 |
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Data from patients with localized and stage 4S neuroblastoma were analyzed to define a new, extended low-risk group that does not require postoperative chemotherapy. Nine hundred eight patients with stage 1 to 3 and 4S disease without MYCN amplification were included. The prognostic impacts of age, stage, serum lactate dehydrogenase (LDH) activity, histology, and alterations of chromosomes 1p, 11q, and 3p were analyzed. By univariate analysis, alterations of chromosomes 1p and 11q were correlated with poor event-free survival (EFS) and overall survival (OS). Chromosome 3p alterations were prognostic only for EFS. Age, stage, and histology were found prognostic for EFS and OS. Stage 3 patients older than 2 years showed the worst outcome and were excluded from multivariate analysis. By multivariate analysis, status of 1p (P = 0.005, hazard ratio [HR] 3.6) and 11q (P = 0.024, HR 2.8) proved prognostic for EFS but only 1p status (P = 0.009, HR 3.0) for OS. The new low-risk group was defined as no MYCN amplification and either stage 1, stage 2 without 1p alterations, stage 3 two years of age or younger without 1p alteration, or stage 4S. These patients had a better outcome (3-year EFS 88.0 +/- 1.3%, 3-year OS 97.4 +/- 0.6%) than stage 2 and 3 patients with 1p alterations and stage 3 patients older than 2 years (3-year EFS 51.7 +/- 6.5%, P < 0.001; 3-year OS 83.4 +/- 4.5%; P < 0.001). The authors conclude that postoperative chemotherapy is required only in a small group of patients with localized and stage 4S disease without MYCN amplification. |
Simon T, Hero B, Faldum A, Handgretinger R, Schrappe M, Niethammer D, Berthold F |
Consolidation treatment with chimeric anti-GD2-antibody ch14. 18 in children older than 1 year with metastatic neuroblastoma. |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2004, 22: 3549 |
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PURPOSE: Antibody treatment is considered tolerable and potentially effective in the therapy of neuroblastoma. We have analyzed stage 4 neuroblastoma patients older than 1 year who underwent consolidation treatment with the chimeric monoclonal anti-GD2-antibody ch14.18. PATIENTS AND METHODS: Stage 4 patients older than 1 year who completed initial treatment without event were eligible. ch14.18 was scheduled in a dose of 20 mg/m2/d during 5 days in six cycles every 2 months. Patients who did not receive ch14.18 served as controls. RESULTS: Of 334 assessable patients, 166 received ch14.18, 99 received a 12-month low-dose maintenance chemotherapy (MT) instead, and 69 had no additional treatment. During 695 ch14.18 cycles, fever (55% of cycles), abnormal C-reactive protein without infection (35%), cough (24%), rash (22%), and pain (16%) were the main side effects. Univariate analysis found similar event-free survival (EFS) for the three groups (3-year EFS, 46.5% +/- 4.1%, 44.4% +/- 4.9%, 37.1% +/- 5.9% for patients treated with antibody ch14.18, MT, and no additional therapy, respectively; log-rank test, P =.314). For overall survival (OS), ch14.18 treatment (3-year OS, 68.5% +/- 3.9%) was superior to MT (3-year OS, 56.6% +/- 5.0%) or no additional therapy (3-year OS, 46.8% +/- 6.2%; log-rank test, P =.018). Separate univariate analysis of patients with autologous stem-cell transplantation revealed no difference between patients with ch14.18 treatment and no additional consolidation. Multivariate analysis failed to demonstrate an advantage of antibody treatment for EFS and OS. CONCLUSION: Consolidation treatment of stage 4 neuroblastoma with ch14.18 was associated with considerable but manageable side effects. Compared with oral maintenance chemotherapy and no consolidation treatment, ch14.18 had no clear impact on the outcome of patients. |
Simon A, Beutel K, Marklein G, Fleischhack G |
Bacterial infections in pediatric cancer patients. |
Klin Pädiatr 2005, 217 Suppl 1:S17 |
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Simon T, Hero B, Faldum A, Handgretinger R, Schrappe M, Niethammer D, Berthold F |
Infants with stage 4 neuroblastoma: the impact of the chimeric anti-GD2-antibody ch14. 18 consolidation therapy. |
Klinische Padiatrie 2005, 217: 147 |
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BACKGROUND: Antibody treatment is considered tolerable and potentially effective in the therapy of neuroblastoma. We have analyzed the clinical data of infants < 1 year with stage 4 neuroblastoma with regard to the consolidation treatment. PATIENTS AND METHODS: Infants < 1 year with stage 4 neuroblastoma who completed initial treatment (6-8 chemotherapy cycles followed either by 4 cycles low dose oral chemotherapy or high dose chemotherapy with stem cell transplantation) without event were eligible for this trial. Consolidation therapy consisted of 6 cycles of antibody ch14.18 (20 mg/m(2) x d ch14.18 for 5 days every 2 months) or 12 months oral maintenance chemotherapy (MT). RESULTS: Of 59 evaluable patients, 31 received a total of 159 ch14.18 cycles, 16 received MT instead, and 12 had no further treatment. Fever (47 % of cycles), abnormal CRP without infection (25 %), rash (23 %), cough (16 %), and pain (8 %) were the main side effects. Univariate analysis found no difference in event free survival (3-year-EFS 80.5 +/- 7.1 %, 87.5 +/- 8.3 %, and 75.0 +/- 12.5 % for patients treated with antibody ch14.18, MT, and no further therapy, p = 0.433) and overall survival (3-year-OS 90.1 +/- 5.4 %, 93.8 +/- 6.0 %, and 91.7 +/- 8.0 % for patients treated with antibody ch14.18, MT, and no further therapy, p = 0.931). Multivariate analysis failed to demonstrate an advantage of antibody treatment. CONCLUSION: The outcome of infants with stage 4 neuroblastoma is good. Consolidation treatment with ch14.18 was tolerable but associated with fever, elevated CRP, rash, cough, and pain as side effects. Compared to oral maintenance chemotherapy and no consolidation treatment, ch14.18 treatment had no impact on the patients' outcome which confirms the results found in children > 1 year. |
Simon T, Hero B, Bongartz R, Schmidt M, Müller RP, Berthold F |
Intensified external-beam radiation therapy improves the outcome of stage 4 neuroblastoma in children > 1 year with residual local disease. |
Strahlentherapie und Onkologie 2006, 182: 389 |
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BACKGROUND AND PURPOSE: In neuroblastoma, the value of radiation therapy in high-intensive first-line treatment protocols is still not exactly known but radiation-associated long-term effects need to be considered. The impact of external-beam radiation therapy (EBRT) on event-free (EFS) and overall survival (OS) of stage 4 neuroblastoma patients of the NB97 trial was analyzed. PATIENTS AND METHODS: The authors retrospectively analyzed data of 110 stage 4 neuroblastoma patients > or = 1 year who underwent induction therapy and high-dose chemotherapy with stem cell transplantation without relapse. Intensified local EBRT (36 Gy) of the residual tumor volume was reserved for patients with residual viable tumor documented by MRI and corresponding metaiodobenzylguanidine (MIBG) uptake. RESULTS: 13 patients who received EBRT for local residual disease had similar outcome (3-year EFS 85 +/- 10%, 3-year OS 92 +/- 7%) as 74 patients without any MIBG residual (3-year EFS 61 +/- 6%, 3-year OS 75 +/- 6%). Outcome was worse in 23 children without EBRT to residual primary (3-year EFS 25 +/- 10%, 3-year OS 51 +/- 11%). Separate analysis of 14 patients with isolated localized residual disease found far better outcome of eight patients with EBRT (3-year EFS 100%, 3-year OS 100%) compared to six patients without EBRT (3-year EFS 20 +/- 18%, 3-year OS 20 +/- 18%). Multivariate analysis identified EBRT as influential on EFS (hazard ratio 0.27) and OS (hazard ratio 0.17) in addition to MYCN amplification and presence of primary tumor site MIBG residual. CONCLUSION: EBRT appeared effective in high-intensive treatment of stage 4 neuroblastoma. It seems to compensate the disadvantage of incomplete response to induction chemotherapy. These retrospective results need confirmation by a prospective randomized trial. |
Simon T, Längler A, Berthold F, Klingebiel T, Hero B |
Topotecan and etoposide in the treatment of relapsed high-risk neuroblastoma: results of a phase 2 trial. |
Journal of pediatric hematology/oncology : official journal of the American Society of Pediatric Hematology/Oncology 2007, 29: 101 |
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We initiated a phase 2 trial with a combination of topotecan and etoposide (TE) in patients with relapse after intensive first line chemotherapy for neuroblastoma. TE chemotherapy consisted of topotecan (schedule A: 1.0 mg/m2/d 30-minute-infusion days 1 to 5, B: 0.7 mg/m2/d continuous infusion days 1 to 7, and C: 1.0 mg/m2/d continuous infusion days 1 to 7) followed by etoposide (100 mg/m2/d 1-hour-infusion days 8 to 10). TE was repeated every 28 days. The treatment was continued until severe nonhematopoietic toxicity or progression occurred or the treating physician chose alternative consolidation treatment after response to TE. Forty patients received 153 TE cycles. Grades 3 to 4 leukopenia was frequently observed in all schedules (A 51% of cycles, B 48%, and C 74%, P=0.141). Thrombocytopenia (A 69%, B 63%, and C 93%, P=0.004) and neutropenic fever (A 12%, B 29%, and C 37%, P=0.048) occurred more frequently in schedule C. No treatment-related fatal toxicity was observed. Among 36 patients evaluable for response, 4 patients achieved complete and 13 patients achieved partial remission (47%). We conclude that the combination of TE is effective and tolerable in the treatment of relapsed high-risk neuroblastoma. |
Simon T, Längler A, Harnischmacher U, Frühwald MC, Jorch N, Claviez A, Berthold F, Hero B |
Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. |
Journal of cancer research and clinical oncology 2007, 133: 653 |
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PURPOSE: Relapsed high-risk neuroblastoma patients still have a poor prognosis. This phase-II trial assessed a new topotecan containing chemotherapy approach in patients with active disease. METHODS: Chemotherapy consisted of topotecan (1.0 mg/m(2)/day 168-h continuous infusion), cyclophosphamide (100 mg/m(2)/day 1-h-infusion days 1-7 starting 6 h prior to topotecan), and etoposide (100 mg/m(2)/day 1-h-infusion days 8-10). Patients with relapsed neuroblastoma were scheduled for six cycles, untreated patients for two cycles followed by standard high-risk treatment. RESULTS: Main toxicity observed during 153 cycles were grade 3-4 leukopenia (97% of cycles), thrombocytopenia (92%), neutropenic fever (52%), and mucositis (10%). No treatment related fatal toxicity occurred. Complete or partial response was achieved in 19 of 31 (61%) evaluable relapsed patients and 8 of 11 (72%) untreated patients. CONCLUSIONS: The combination of topotecan, cyclophosphamide, and etoposide is tolerable and effective in relapsed and untreated neuroblastoma. Myelotoxicity is the main side effect but seems justified in view of the encouraging response rates. A randomized phase-III trial in primary disease has been commenced. |
Simon T, Berthold F, Borkhardt A, Kremens B, De Carolis B, Hero B |
Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: results of German trials. |
Pediatr Blood Cancer 2011, 56: 578 |
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BACKGROUND:
The prognosis of high-risk neuroblastoma patients has improved over the last decades. However, many patients experience relapse after successful initial treatment. We retrospectively analyzed the long-term outcome of relapsed patients of three consecutive national neuroblastoma trials.
METHODS:
Patients were included when they fulfilled all of the following criteria: Age at diagnosis being 1 year or older, first diagnosis between 1990 and 2007, stage 4 disease or stage 3 neuroblastoma with MYCN amplification, and relapse or progression after successful first-line autologous stem cell transplantation (ASCT).
RESULTS:
A total of 451 high-risk neuroblastoma patients 1 year or older underwent ASCT during first-line treatment, 253 experienced recurrence of disease, 158 received salvage chemotherapy, and 23 of them finally underwent a second ASCT. These 23 patients had a better median survival (2.08 years) and 3-year survival rate from recurrence (43.5 ± 10.9%) compared to 74 patients who had no second chemotherapy (median survival 0.24 years, 3-year survival rate 4.0 ± 2.6%) and 135 patients who underwent second-line chemotherapy but did not undergo second ASCT (median survival of 0.89 years, 3-year survival rate 9.6 ± 2.8%, P < 0.001). By February 2010, 3/23 patients were in complete remission, 3/23 in very good partial remission, 1/23 in partial remission, 14/23 patients died of disease after successful second ASCT, and 2/23 died of complications due to second ASCT.
CONCLUSION:
Intensive second-line therapy is feasible. A small subgroup of relapsed high-risk neuroblastoma patients may benefit from intensive relapse chemotherapy and second ASCT. The potential of long-term survival justifies clinical trials on intensive second-line treatment. |
Simon T, Hero B, Faldum A, Handgretinger R, Schrappe M, Klingebiel T, Berthold F |
Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14. 18 or oral metronomic chemotherapy. |
BMC Cancer 2011, 18; 11: 21. |
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BACKGROUND: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort.
METHODS: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls.
RESULTS: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found.
CONCLUSIONS: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective. |
Simon T, Niemann CA, Hero B, Henze G, Suttorp M, Schilling FH, Berthold F |
Short- and long-term outcome of patients with symptoms of spinal cord compression by neuroblastoma. |
Developmental medicine and child neurology 2012, 54: 347 |
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Prospective trials on neuroblastoma-induced myelopathy are lacking. Therefore, we retrospectively analysed patients in four national neuroblastoma trials. |
Simon T, Häberle B, Hero B, von Schweinitz D, Berthold F |
Role of surgery in the treatment of patients with stage 4 neuroblastoma age 18 months or older at diagnosis. |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013, 31: 752 |
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Although intensive multimodal treatment has improved the prognosis of patients with metastatic neuroblastoma, the impact of primary tumor resection on outcome is a matter of medical debate. |
Bomken S, Skinner R |
Secondary Malignant Neoplasms Following Haematopoietic Stem Cell Transplantation in Childhood. |
Children (Basel, Switzerland) 2015 Apr 21; 2: 146 |
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Simon T, Hero B, Schulte JH, Deubzer H, Hundsdoerfer P, von Schweinitz D, Fuchs J, Schmidt M, Prasad V, Krug B, Timmermann B, Leuschner I, Fischer M, Langer T, Astrahantseff K, Berthold F, Lode H, Eggert A |
2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors. |
Klinische Padiatrie 2017, 229: 147 |
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Simonin M, Dalissier A, Labopin M, Willasch A, Zecca M, Mouhab A, Chybicka A, Balduzzi A, Volin L, Peters C, Bader P, Dalle JH |
More chronic GvHD and non-relapse mortality after peripheral blood stem cell compared with bone marrow in hematopoietic transplantation for paediatric acute lymphoblastic leukemia: a retrospective study on behalf of the EBMT Paediatric Diseases Working Party. |
Bone marrow transplantation 2017, 52: 1071 |
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Simon T |
Leitlinie: Neuroblastom. |
S1-Leitlinie 025-008 (Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie) AWMF-online 2019 |
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K Singh V, Werner S, Hackstein H, Lennerz V, Reiter A, Wölfel T, Damm-Welk C, Woessmann W |
Analysis of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-reactive CD8(+) T cell responses in children with NPM-ALK(+) anaplastic large cell lymphoma. |
Clinical and experimental immunology 2016, 186: 96 |
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Cellular immune responses against the oncoantigen anaplastic lymphoma kinase (ALK) in patients with ALK-positive anaplastic large cell lymphoma (ALCL) have been detected using peptide-based approaches in individuals preselected for human leucocyte antigen (HLA)-A*02:01. In this study, we aimed to evaluate nucleophosmin (NPM)-ALK-specific CD8(+) T cell responses in ALCL patients ensuring endogenous peptide processing of ALK antigens and avoiding HLA preselection. We also examined the HLA class I restriction of ALK-specific CD8(+) T cells. Autologous dendritic cells (DCs) transfected with in-vitro-transcribed RNA (IVT-RNA) encoding NPM-ALK were used as antigen-presenting cells for T cell stimulation. Responder T lymphocytes were tested in interferon-gamma enzyme-linked immunospot (ELISPOT) assays with NPM-ALK-transfected autologous DCs as well as CV-1 in Origin with SV40 genes (COS-7) cells co-transfected with genes encoding the patients' HLA class I alleles and with NPM-ALK encoding cDNA to verify responses and define the HLA restrictions of specific T cell responses. NPM-ALK-specific CD8(+) T cell responses were detected in three of five ALK-positive ALCL patients tested between 1 and 13 years after diagnosis. The three patients had also maintained anti-ALK antibody responses. No reactivity was detected in samples from five healthy donors. The NPM-ALK-specific CD8(+) T cell responses were restricted by HLA-C-alleles (C*06:02 and C*12:02) in all three cases. This approach allowed for the detection of NPM-ALK-reactive T cells, irrespective of the individual HLA status, up to 9 years after ALCL diagnosis. |
Singh AK, McGuirk JP |
CAR T cells: continuation in a revolution of immunotherapy. |
The Lancet. Oncology 2020, 21:e168-e178 |
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The recent clinical successes of immunotherapy, as a result of a broader and more profound understanding of cancer immunobiology, and the leverage of this knowledge to effectively eradicate malignant cells, has revolutionised the field of cancer therapeutics. Immunotherapy is now considered the fifth pillar of cancer care, alongside surgery, chemotherapy, radiotherapy, and targeted therapy. Recently, the success of genetically modified T cells that express chimeric antigen receptors (CAR T cells) has generated considerable excitement. CAR T-cell therapy research and development has built on experience generated by laboratory research and clinical investigation of lymphokine-activated killer cells, tumour-infiltrating lymphocytes, and allogeneic haemopoietic stem-cell transplantation for cancer treatment. This Review aims to provide a background on the field of adoptive T-cell therapy and the development of genetically modified T cells, most notably CAR T-cell therapy. Many challenges exist to optimise efficacy, minimise toxicity, and broaden the application of immunotherapies based on T cells. |
Sirin S, de Jong MC, de Graaf P, Brisse HJ, Galluzzi P, Maeder P, Bornfeld N, Biewald E, Metz KA, Temming P, Castelijns JA, Goericke SL, European Retinoblastoma Imaging Collaboration |
High-Resolution Magnetic Resonance Imaging Can Reliably Detect Orbital Tumor Recurrence after Enucleation in Children with Retinoblastoma. |
Ophthalmology 2016, 123: 635 |
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Orbital tumor recurrence is a rare but serious complication in children with retinoblastoma, leading to a high risk of metastasis and death. Therefore, we assume that these recurrences have to be detected and treated as early as possible. Preliminary studies used magnetic resonance imaging (MRI) to evaluate postsurgical findings in the orbit. In this study, we assessed the diagnostic accuracy of high-resolution MRI to detect orbital tumor recurrence in children with retinoblastoma in a large study cohort. |
Skinner R, Mulder RL, Kremer LC, Hudson MM, Constine LS, Bardi E, Boekhout A, Borgmann-Staudt A, Brown MC, Cohn R, Dirksen U, Giwercman A, Ishiguro H, Jahnukainen K, Kenney LB, Loonen JJ, Meacham L, Neggers S, Nussey S, Petersen C, Shnorhavorian M, van den Heuvel-Eibrink MM, van Santen HM, Wallace WH, Green DM |
Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. |
The Lancet. Oncology 2017, 18:e75-e90 |
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Treatment with chemotherapy, radiotherapy, or surgery that involves reproductive organs can cause impaired spermatogenesis, testosterone deficiency, and physical sexual dysfunction in male pubertal, adolescent, and young adult cancer survivors. Guidelines for surveillance and management of potential adverse effects could improve cancer survivors' health and quality of life. Surveillance recommendations vary considerably, causing uncertainty about optimum screening practices. This clinical practice guideline recommended by the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium, developed using evidence-based methodology, critically synthesises surveillance recommendations for gonadotoxicity in male childhood, adolescent, and young adult (CAYA) cancer survivors. The recommendations were developed by an international multidisciplinary panel including 25 experts in relevant medical specialties, using a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. The aim of the recommendations is to enhance evidence-based care for male CAYA cancer survivors. The guidelines reveal the paucity of high-quality evidence, highlighting the need for further targeted research. |
Skolin I, Axelsson K, Ghannad P, Hernell O, Wahlin YB |
Nutrient intake and weight development in children during chemotherapy for malignant disease. |
Oral Oncol 1997, 33 : 364 |
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Skokowa J, Germeshausen M, Zeidler C, Welte K |
Severe congenital neutropenia: inheritance and pathophysiology. |
Current opinion in hematology 2007, 14: 22 |
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Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10/l. In this review we summarize our current knowledge on inheritance and pathophysiolgy of congenital neutropenia. |
Skokowa J, Lan D, Thakur BK, Wang F, Gupta K, Cario G, Brechlin AM, Schambach A, Hinrichsen L, Meyer G, Gaestel M, Stanulla M, Tong Q, Welte K |
NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD(+)-sirtuin-1-dependent pathway. |
Nature medicine 2009, 15: 151 |
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We identified nicotinamide phosphoribosyltransferase (NAMPT), also known as pre-B cell colony enhancing factor (PBEF), as an essential enzyme mediating granulocyte colony-stimulating factor (G-CSF)-triggered granulopoiesis in healthy individuals and in individuals with severe congenital neutropenia. Intracellular NAMPT and NAD(+) amounts in myeloid cells, as well as plasma NAMPT and NAD(+) levels, were increased by G-CSF treatment of both healthy volunteers and individuals with congenital neutropenia. NAMPT administered both extracellularly and intracellularly induced granulocytic differentiation of CD34(+) hematopoietic progenitor cells and of the promyelocytic leukemia cell line HL-60. Treatment of healthy individuals with high doses of vitamin B3 (nicotinamide), a substrate of NAMPT, induced neutrophilic granulocyte differentiation. The molecular events triggered by NAMPT include NAD(+)-dependent sirtuin-1 activation, subsequent induction of CCAAT/enhancer binding protein-alpha and CCAAT/enhancer binding protein-beta, and, ultimately, upregulation of G-CSF synthesis and G-CSF receptor expression. G-CSF, in turn, further increases NAMPT levels. These results reveal a decisive role of the NAD(+) metabolic pathway in G-CSF-triggered myelopoiesis. |
Skokowa J, Klimiankou M, Klimenkova O, Lan D, Gupta K, Hussein K, Carrizosa E, Kusnetsova I, Li Z, Sustmann C, Ganser A, Zeidler C, Kreipe HH, Burkhardt J, Grosschedl R, Welte K |
Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. |
Nature medicine 2012, 18: 1550 |
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We found that hematopoietic cell-specific Lyn substrate 1 (HCLS1 or HS1) is highly expressed in human myeloid cells and that stimulation with granulocyte colony-stimulating factor (G-CSF) leads to HCLS1 phosphorylation. HCLS1 binds the transcription factor lymphoid-enhancer binding factor 1 (LEF-1), transporting LEF-1 into the nucleus upon G-CSF stimulation and inducing LEF-1 autoregulation. In patients with severe congenital neutropenia, inherited mutations in the gene encoding HCLS1-associated protein X-1 (HAX1) lead to profound defects in G-CSF-triggered phosphorylation of HCLS1 and subsequently to reduced autoregulation and expression of LEF-1. Consistent with these results, HCLS1-deficient mice are neutropenic. In bone marrow biopsies of the majority of tested patients with acute myeloid leukemia, HCLS1 protein expression is substantially elevated, associated with high levels of G-CSF synthesis and, in some individuals, a four-residue insertion in a proline-rich region of HCLS1 protein known to accelerate intracellular signaling. These data demonstrate the importance of HCLS1 in myelopoiesis in vitro and in vivo. |
Skokowa J, Steinemann D, Katsman-Kuipers JE, Zeidler C, Klimenkova O, Klimiankou M, Unalan M, Kandabarau S, Makaryan V, Beekman R, Behrens K, Stocking C, Obenauer J, Schnittger S, Kohlmann A, Valkhof MG, Hoogenboezem R, Göhring G, Reinhardt D, Schlegelberger B, Stanulla M, Vandenberghe P, Donadieu J, Zwaan CM, Touw IP, van den Heuvel-Eibrink MM, Dale DC, Welte K |
Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. |
Blood 2014, 123: 2229 |
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Severe congenital neutropenia (CN) is a preleukemic bone marrow failure syndrome with a 20% risk of evolving into leukemia or myelodysplastic syndrome (MDS). Patterns of acquisition of leukemia-associated mutations were investigated using next-generation deep-sequencing in 31 CN patients who developed leukemia or MDS. Twenty (64.5%) of the 31 patients had mutations in RUNX1. A majority of patients with RUNX1 mutations (80.5%) also had acquired CSF3R mutations. In contrast to their high frequency in CN patients who developed leukemia or MDS, RUNX1 mutations were found in only 9 of 307 (2.9%) patients with de novo pediatric acute myeloid leukemia. A sequential analysis at stages prior to overt leukemia revealed RUNX1 mutations to be late events in leukemic transformation. Single-cell analyses in 2 patients showed that RUNX1 and CSF3R mutations were present in the same malignant clone. Functional studies demonstrated elevated granulocyte colony-stimulating factor (G-CSF)-induced proliferation with diminished myeloid differentiation of hematopoietic CD34(+) cells coexpressing mutated forms of RUNX1 and CSF3R. The high frequency of cooperating RUNX1 and CSF3R mutations in CN patients suggests a novel molecular pathway of leukemogenesis: mutations in the hematopoietic cytokine receptor (G-CSFR) in combination with the second mutations in the downstream hematopoietic transcription fator (RUNX1). The detection of both RUNX1 and CSF3R mutations could be used as a marker for identifying CN patients with a high risk of progressing to leukemia or MDS. |
Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K |
Severe congenital neutropenias. |
Nature reviews 2017, 3: 17032 |
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Severe congenital neutropenias are a heterogeneous group of rare haematological diseases characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life. The most frequent pathogenic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte colony-stimulating factor (G-CSF) signalling pathway. The pathophysiological mechanisms of these conditions are the object of extensive research and are not fully understood. Furthermore, severe congenital neutropenias may predispose to myelodysplastic syndromes or acute myeloid leukaemia. Molecular events in the malignant progression include acquired mutations in CSF3R (encoding G-CSF receptor) and subsequently in other leukaemia-associated genes (such as RUNX1) in a majority of patients. Diagnosis is based on clinical manifestations, blood neutrophil count, bone marrow examination and genetic and immunological analyses. Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophil count, reduction of infections and drastic improvement of quality of life. Haematopoietic stem cell transplantation is the alternative treatment. Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (for example, monosomy 7 and trisomy 21) as well as somatic pre-leukaemic mutations are recommended. |
Skowron MA, Vermeulen M, Winkelhausen A, Becker TK, Bremmer F, Petzsch P, Schönberger S, Calaminus G, Köhrer K, Albers P, Nettersheim D |
CDK4/6 inhibition presents as a therapeutic option for paediatric and adult germ cell tumours and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms. |
British journal of cancer 2020, 123: 378 |
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Germ cell tumours (GCTs) are the most common solid malignancies in young men. Although high cure rates can be achieved, metastases, resistance to cisplatin-based therapy and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In this study, we analysed the potential of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors palbociclib and ribociclib (PaRi) as molecular drugs to treat cisplatin-resistant and -sensitive paediatric and adult GCTs. |
Slavc I, Urban C, Ritter J, Ambros P, Haas O, Köller U, Kurz R |
Paraparesis secondary to a spinal mass as the presenting feature of erythroleukaemia in a 10-month-old child. |
Eur J Pediatr 1992, 151: 332 |
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Slatter MA, Boztug H, Pötschger U, Sykora KW, Lankester A, Yaniv I, Sedlacek P, Glogova E, Veys P, Gennery AR, Peters C |
Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in children with non-malignant diseases. |
Bone Marrow Transplant 2015, 50: 1536 |
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An increasing number of children with non-malignant diseases can be cured by allogeneic haematopoietic stem cell transplantation (HSCT). Treosulfan (L-treitol-1,4-bis-methanesulfonate) is being used more frequently for conditioning, owing to its' lower toxicity profile compared with conventional myeloablative regimens. A retrospective analysis was performed of children registered in the EBMT database, who received treosulfan before HSCT between January 2005 and 2010, to identify possible dose-related toxicity and determine the incidence of engraftment, treatment-related mortality and overall survival (OS). Results from 316 transplants from 11 different countries are presented. Ninety-five (30%) were under 1 year of age at the time of transplant. OS was 83% and event-free survival was 76%; 3-year OS and event-free survival of infants below 1 year were 79% and 73%, respectively. No association was found with age at transplant, dose of treosulfan given, other agents used in combination with treosulfan, donor type, stem cell source, or second or subsequent transplant. In this report of the largest number of children to date receiving treosulfan for non-malignant diseases, treosulfan is shown to be a safe and effective agent even for those under 1 year of age at the time of transplant. Further prospective studies are needed using precisely defined protocols with pharmacokinetic monitoring and detailed chimerism analysis. In addition, long-term studies will be vital to determine long-term effects, for example, on fertility in comparison with other regimens. |
Sluga M, Windhager R, Lang S, Heinzl H, Bielack S, Kotz R |
Local and systemic control after ablative and limb sparing surgery in patients with osteosarcoma. |
Clin Orthop 1999, 120 |
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van der Sluis IM, Vrooman LM, Pieters R, Baruchel A, Escherich G, Goulden N, Mondelaers V, Sanchez de Toledo J, Rizzari C, Silverman LB, Whitlock JA |
Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. |
Haematologica 2016, 101: 279 |
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L-asparaginase is an integral component of therapy for acute lymphoblastic leukemia. However, asparaginase-related complications, including the development of hypersensitivity reactions, can limit its use in individual patients. Of considerable concern in the setting of clinical allergy is the development of neutralizing antibodies and associated asparaginase inactivity. Also problematic in the use of asparaginase is the potential for the development of silent inactivation, with the formation of neutralizing antibodies and reduced asparaginase activity in the absence of a clinically evident allergic reaction. Here we present guidelines for the identification and management of clinical hypersensitivity and silent inactivation with Escherichia coli- and Erwinia chrysanthemi- derived asparaginase preparations. These guidelines were developed by a consensus panel of experts following a review of the available published data. We provide a consensus of expert opinions on the role of serum asparaginase level assessment, indications for switching asparaginase preparation, and monitoring after change in asparaginase preparation. |
van der Sluis IM, de Lorenzo P, Kotecha RS, Attarbaschi A, Escherich G, Nysom K, Stary J, Ferster A, Brethon B, Locatelli F, Schrappe M, Scholte-van Houtem PE, Valsecchi MG, Pieters R |
Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia. |
The New England journal of medicine 2023, 388: 1572 |
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-rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy. |
Smeland S, Bielack SS, Whelan J, Bernstein M, Hogendoorn P, Krailo MD, Gorlick R, Janeway KA, Ingleby FC, Anninga J, Antal I, Arndt C, Brown KLB, Butterfass-Bahloul T, Calaminus G, Capra M, Dhooge C, Eriksson M, Flanagan AM, Friedel G, Gebhardt MC, Gelderblom H, Goldsby R, Grier HE, Grimer R, Hawkins DS, Hecker-Nolting S, Sundby Hall K, Isakoff MS, Jovic G, Kühne T, Kager L, von Kalle T, Kabickova E, Lang S, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Mayer-Steinacker R, Meyers PA, Nagarajan R, Randall RL, Reichardt P, Renard M, Rechnitzer C, Schwartz CL, Strauss S, Teot L, Timmermann B, Sydes MR, Marina N |
Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. |
European journal of cancer 2019, 109: 36 |
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High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials. |
Smith MA, Seibel NL, Altekruse SF, Ries LA, Melbert DL, O'Leary M, Smith FO, Reaman GH |
Outcomes for children and adolescents with cancer: challenges for the twenty-first century. |
Journal of clinical oncology 2010, 28: 2625 |
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PURPOSE: This report provides an overview of current childhood cancer statistics to facilitate analysis of the impact of past research discoveries on outcome and provide essential information for prioritizing future research directions. METHODS: Incidence and survival data for childhood cancers came from the Surveillance, Epidemiology, and End Results 9 (SEER 9) registries, and mortality data were based on deaths in the United States that were reported by states to the Centers for Disease Control and Prevention by underlying cause. RESULTS: Childhood cancer incidence rates increased significantly from 1975 through 2006, with increasing rates for acute lymphoblastic leukemia being most notable. Childhood cancer mortality rates declined by more than 50% between 1975 and 2006. For leukemias and lymphomas, significantly decreasing mortality rates were observed throughout the 32-year period, though the rate of decline slowed somewhat after 1998. For remaining childhood cancers, significantly decreasing mortality rates were observed from 1975 to 1996, with stable rates from 1996 through 2006. Increased survival rates were observed for all categories of childhood cancers studied, with the extent and temporal pace of the increases varying by diagnosis. CONCLUSION: When 1975 age-specific death rates for children are used as a baseline, approximately 38,000 childhood malignant cancer deaths were averted in the United States from 1975 through 2006 as a result of more effective treatments identified and applied during this period. Continued success in reducing childhood cancer mortality will require new treatment paradigms building on an increased understanding of the molecular processes that promote growth and survival of specific childhood cancers. |
Smith-Whitley, Kim, Thompson, Alexis A |
Indications and complications of transfusions in sickle cell disease. |
Pediatric blood & cancer 2012, 59, 358 |
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Red cell transfusion remains an important part of the management of acute and chronic complications in SCD. The ongoing and emerging uses of transfusions in SCD may have significant benefits; however, the potential complications of transfusions also deserve careful consideration. In this report we review current indications for transfusions, transfusion complications, modifications of transfusion practices to mitigate risk, and potential considerations to improve transfusion outcomes. |
Smoots DW, Geyer JR, Lieberman DM, Berger MS |
Predicting disease progression in childhood cerebellar astrocytoma. |
Childs Nerv Syst 1998, 14: 636 |
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Sobota A, Sabharwal V, Fonebi G, Steinberg M |
How we prevent and manage infection in sickle cell disease. |
British journal of haematology 2015, 170: 757 |
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Sickle cell disease (SCD) affects approximately 100 000 people in the US, 12 500 in the UK, and millions worldwide. SCD is typified by painful vaso-occlusive episodes, haemolytic anaemia and organ damage. A secondary complication is infection, which can be bacterial, fungal or viral. Universal newborn screening, routine use of penicillin prophylaxis, availability of conjugated vaccines against S. pneumoniae and comprehensive care programmes instituted during the past few decades in industrialized countries have dramatically reduced childhood mortality and improved life expectancy. Yet patients with SCD remain at increased risk of infection. Unfortunately, the treatment of most bacterial infections that are common in SCD is not based on the results of randomized controlled clinical trials. In their absence, treatment decisions are based on consensus guidelines, clinical experience or adapting treatment applied in other diseases. This leads to wide variation in treatment among institutions and even between treating physicians in a single institution. Prevention of infection, when possible, is most important and we focus on prevention through targeted prophylaxis and vaccination. We will share our management strategies for managing the more common infections in SCD and provide the rationale for our recommendations. |
Sobas M, Kiladjian JJ, Beauverd Y, et al. |
Real-world study of children and young adults with myeloproliferative neoplasms: identifying risks and unmet needs. |
Blood advances 2022 Sep 13; 6: 5171 |
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Söntgerath R, Freier S, Wulftange M, Eckert K |
Qualitätsmerkmale und Verbreitungsgrad behandlungsbegleitender Sporttherapie bei pädiatrisch-onkologischen Erkrankungen in Deutschland. |
Klinische Pädiatrie 2017, 229: 126 |
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Söntgerath R, Küpper L, Wulftange M, Schepper F, Christiansen H |
Bewegungsförderung in der Pädiatrischen Onkologie – Strukturelle Voraussetzungen und Finanzierungsmöglichkeiten anhand des Leipziger Bewegungskonzepts. |
Klinische Pädiatrie 2019, 231 : 150 |
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Soling A, Schurr P, Berthold F |
Expression and clinical relevance of NY-ESO-1, MAGE-1 and MAGE-3 in neuroblastoma. |
Anticancer Res 1999, 19: 2205 |
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Sollena P, Mannino M, Tassone F, Calegari MA, D'Argento E, Peris K |
Efficacy of topical beta-blockers in the management of EGFR-inhibitor induced paronychia and pyogenic granuloma-like lesions: case series and review of the literature. |
Drugs in context 2019, 8: 212613 |
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Sommet J, Missud F, Holvoet L, Ithier G, Lorrot M, Benkerrou M, Faye A |
Morbidity among child travellers with sickle-cell disease visiting tropical areas: an observational study in a French tertiary care centre. |
Archives of disease in childhood 2013, epub ahead of print |
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OBJECTIVE: To examine morbidity among children with sickle-cell disease (SCD) during and after travel to a tropical area. DESIGN: Observational study. SETTING: Tertiary care children; Robert Debré Hospital, Paris, France. POPULATION: Children with SCD younger than 18 years old and managed in the SCD referral centre at the Robert Debré Hospital who travelled to a tropical or subtropical area between 1 June 2009 and 31 December 2009. MAIN OUTCOME: To assess morbidity, we used the number of clinical events requiring medical consultation during the trip as the primary outcome and the number of hospitalisations required after returning as the secondary outcome. RESULTS: Thirty-nine children were included. The median age was 7.8 years (4.3-11.7 years). All of the children and their parents attended a pretravel visit focusing on the prevention of travel-related diseases. Twelve children (30%) consulted a physician while they were abroad. Thirteen children (33%) were hospitalised, and 23 children (59%) consulted a physician while they were abroad or within 3 months after returning to France. Considering the 3 months before and after travel, the number of children hospitalised after travel (n=12, 30.7%) was significantly higher than the number hospitalised before (n=4, 10.2%; p=0.01). One child was hospitalised for multifocal osteoarthritis as a complication of Salmonella enterica septicaemia of gastrointestinal origin. CONCLUSIONS: Travels to tropical areas are associated with high morbidity in children with SCD. Salmonella infection is a particularly significant threat, and empirical antibiotic therapy should be prescribed routinely for traveller's diarrhoea in this population. |
Sommerhäuser G, Borgmann-Staudt A, Astrahantseff K, Baust K, Calaminus G, Dittrich R, Fernández-González MJ, Hölling H, König CJ, Schilling R, Schuster T, Lotz L, Balcerek M |
Health outcomes in offspring born to survivors of childhood cancers following assisted reproductive technologies. |
Journal of cancer survivorship : research and practice 2021, 15: 259 |
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An increasing number of childhood cancer survivors are using assisted reproductive technologies (ART) to overcome treatment-related fertility impairment. We report perinatal and health outcomes of offspring born to survivors following ART. |
Sonnemann J, Eckervogt V, Truckenbrod B, Boos J, Winkelmann W, van Valen F |
The bisphosphonate pamidronate is a potent inhibitor of Ewing's sarcoma cell growth in vitro. |
Anticancer Drugs 2003, 14: 767 |
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Sorrentino S, Ash S, Haupt R, Plantaz D, Schiff I, Hero B, Simon T, Kachanov D, Shamanskaya T, Kraal K, Littooij A, Wieczoreck A, Balwierz W, Laureys G, Trager C, Sertorio F, Erminio G, Fragola M, Beck Popovic M, De Bernardi B, Trahair T |
Presenting features of neuroblastoma with spinal canal invasion. A prospective study of the International Society of Pediatric Oncology Europe - Neuroblastoma (SIOPEN). |
Frontiers in pediatrics 2022, 10: 1023498 |
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Between 5 and 15% of children with neuroblastoma (NB) present with or develop spinal canal invasion (SCI). The majority of these children have symptoms of epidural compression of spinal cord and/or spinal nerves. Treatment of NB-SCI is considered an emergency but its modalities are not yet well-established. Independently of treatment, NB-SCI may result in significant long-term disabilities. We report on the first prospective study of NB-SCI focused on presenting characteristics of both symptomatic and asymptomatic patients and correlation between SCI-related symptoms and imaging features. |
Sowithayasakul P, Boekhoff S, Bison B, Müller HL |
Pregnancies after childhood craniopharyngioma - Results of KRANIOPHARYNGEOM 2000/2007 and review of the literature. |
Neuroendocrinology 2020, Epup ahead of print |
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Data on female fertility, pregnancy, and outcome of offspring after childhood-onset craniopharyngioma (CP) are rare. |
Sowithayasakul P, Buschmann LK, Boekhoff S, Müller HL |
Cardiac remodeling in patients with childhood-onset craniopharyngioma-results of HIT-Endo and KRANIOPHARYNGEOM 2000/2007. |
European journal of pediatrics 2021, 180: 1593 |
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Hypothalamic obesity caused by childhood-onset craniopharyngioma results in long-term cardiovascular morbidity. Knowledge about clinical markers and risk factors for cardiovascular morbidity is scarce. A cross-sectional study on transthoracic echocardiographic parameters was performed to determine the associations with clinical and anthropometric parameters in 36 craniopharyngioma patients. BMI correlated with the thickness of interventricular septum in diastole (IVSd) (r = 0.604, p < 0.001) and left ventricular posterior wall thickness in diastole (LVPWd) (r = 0.460, p = 0.011). In multivariate analyses on risk factors for cardiac remodeling, sex hormone replacement therapy, BMI, and male gender were positively correlated with increased left ventricular internal diameter in diastole (LVIDd), R = 0.596, F = 10.323, p < 0.001. BMI and insulin resistance were selected as significant independent determinants of IVSd, produced R = 0.655, F = 29.441, p < 0.001. Due to a wide range of disease duration, 17 pediatric and 19 adult patients were analyzed separately. In the adult subgroup (age at study ≥ 18 years), BMI correlated with IVSd (r = 0.707, p = 0.003), LVPWd (r = 0.592, p = 0.020), and LVIDd (r = 0.571, p = 0.026). In the pediatric subgroup (age at study < 18 years), no correlation between transthoracic echocardiography (TTE) parameters and BMI was observed. Only LVIDd correlated with disease duration (r = 0.645, p < 0.001). All cardiac functions were within the normal range, indicating no association with functional impairments.Conclusion: Cardiac remodeling in patients with craniopharyngioma correlated with the degree of hypothalamic obesity, disease duration, sex hormone replacement therapy, male gender, and insulin resistance. As echocardiography has limited sensitivity in patients with obesity, further research on more sensitive techniques for cardiac diagnostics in craniopharyngioma patients is warranted. What is Known: •Long-term prognosis in survivors of craniopharyngioma is impaired by obesity and cardiovascular disease. •Associations between echocardiographic findings and clinical and anthropometric parameters after craniopharyngioma are not yet analyzed. What is New: •In patients with childhood-onset craniopharyngioma, cardiac remodeling was associated with hypothalamic obesity, duration of disease, male gender sex hormone replacement, and insulin resistance. •Due to reduced echocardiographic sensitivity caused by obesity-related technical limitations, more sensitive cardiac diagnostics should be considered. |
Sowithayasakul P, Boekhoff S, Bison B, Müller HL |
Pregnancies after Childhood Craniopharyngioma: Results of KRANIOPHARYNGEOM 2000/2007 and Review of the Literature. |
Neuroendocrinology 2021, 111(1-2): 16 |
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Data on female fertility, pregnancy, and outcome of offspring after childhood-onset craniopharyngioma (CP) are rare. |
Sparber-Sauer M, Seitz G, Kirsch S, Vokuhl C, Leuschner I, Dantonello TM, Scheer M, von Kalle T, Ljungman G, Bielack SS, Klingebiel T, Fuchs J, Koscielniak E, CWS Study Group |
The impact of local control in the treatment of type II/III pleuropulmonary blastoma. Experience of the Cooperative Weichteilsarkom Studiengruppe (CWS). |
Journal of surgical oncology 2017, 115: 164 |
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This study aims at examining the potential survival benefits of primary versus secondary surgery in the management of children diagnosed with pleuropulmonary blastoma (PPB) type II/III. |
Sparber-Sauer M, Seitz G, von Kalle T, Vokuhl C, Leuschner I, Scheer M, Münter M, Ljungman G, Bielack SS, Niggli F, Ladenstein R, Klingebiel T, Fuchs J, Koscielniak E, CWS Study Group |
Systemic therapy of aggressive fibromatosis in children and adolescents: Report of the Cooperative Weichteilsarkom Studiengruppe (CWS). |
Pediatric blood & cancer 2018, 65:e26943 |
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Background: Treatment algorithms for patients with aggressive fibromatosis (AF) are challenging. There are limited data available about the use of systemic therapy (ST) in pediatric patients with AF.
Methods: Patient-, tumor-, and treatment-related factors of 90 children and adolescents with AF treated on multiple prospective trials of the Cooperative Weichteilsarkom Studiengruppe (1981-2015) were analyzed with focus on response and outcome of ST.
Results: Median age was 9.48 years (0.02-18.05). Primary resection was performed in 54 patients and ST was administered in 29 of 54 patients because of disease progression or relapse. In 35 patients, ST was the initial treatment modality. A secondary resection was performed in 21 of 35 patients after ST. A total of 64 patients received ST, mainly methotrexate and vinblastine (40%) with a median duration of 380 days. The most frequent radiological response to ST was stable disease at 3 months (39%) and partial response at 6 months (53%). Radiotherapy was administered to 15 of 90 patients. One patient remained on observation only. The 5-year overall survival was 100% and the 5-year event-free survival (EFS) was 44%. Patients who had a primary resection showed a 5-year EFS of 35% versus 59% in patients who had received primary ST (P = 0.08). Functional deficiencies as long-term sequelae following resection occurred in 11 patients. At a median follow-up of 5.05 years (0.25-14.88), complete remission was achieved in 51 patients and partial remission in 28 patients.
Conclusions: ST seems appropriate if a primary complete resection is not feasible and at relapse/progression after resection. |
Sparber-Sauer M, Koscielniak E, Vokuhl C, Seitz G, Hallmen E, von Kalle T, Scheer M, Münter M, Bielack SS, Ladenstein R, Fuchs J, Klingebiel T, CWS Study Group |
Epithelioid sarcoma in children, adolescents, and young adults: Localized, primary metastatic and relapsed disease. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. |
Pediatric blood & cancer 2019, 66:e27879 |
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Epithelioid sarcoma (ES) is a rare malignant soft-tissue tumor. Little is known about the optimal treatment of primary localized (LD), metastatic (MD), and relapsed disease (RD). |
Sparber-Sauer M, Stegmaier S, Vokuhl C, Seitz G, von Kalle T, Scheer M, Münter M, Bielack SS, Weclawek-Tompol J, Ladenstein R, Niggli F, Ljungman G, Fuchs J, Hettmer S, Koscielniak E, Klingebiel T, CWS Study Group |
Rhabdomyosarcoma diagnosed in the first year of life: Localized, metastatic, and relapsed disease. Outcome data from five trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS). |
Pediatric blood & cancer 2019, 66:e27652 |
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Rhabdomyosarcoma (RMS) diagnosed during the first year of life is reported to have poor outcome. Little is known about treatment and outcome data of relapsed disease (RD). |
Sparber-Sauer M, Koscielniak E, Vokuhl C, Schmid I, Bien E, Seitz G, Hallmen E, von Kalle T, Scheer M, Münter M, Bielack SS, Niggli F, Ljungman G, Fuchs J, Hettmer S, Rössler J, Klingebiel T, CWS Study Group |
Endothelial cell malignancies in infants, children and adolescents: Treatment results of three Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. |
Pediatric blood & cancer 2020, 67:e28095 |
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Endothelial cell malignancies are extremely rare in childhood. New identification of genetic abnormalities (WWTR1:CAMTA1 translocation) helps to recognize potential therapeutic targets. Little is known about treatment and outcome of these patients. |
Sparber-Sauer M, Vokuhl C, Seitz G, Stegmaier S, Hallmen E, von Kalle T, Scheer M, Münter M, Bielack SS, Ladenstein R, Niggli F, Ljungman G, Fuchs J, Klingebiel T, Koscielniak E, CWS Study Group |
The impact of local control in the treatment of children with advanced infantile and adult-type fibrosarcoma: Experience of the cooperative weichteilsarkom studiengruppe (CWS). |
Journal of pediatric surgery 2020, 55: 1740 |
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This study aims at examining the potential survival benefits of primary versus secondary surgery of children diagnosed with advanced infantile (iFS) and adult-type fibrosarcoma (aFS). |
Sparber-Sauer M, Seitz G, von Kalle T, Vokuhl C, Leuschner I, Scheer M, Münter M, Ljungman G, Bielack SS, Niggli F, Ladenstein R, Klingebiel T, Fuchs J, Koscielniak E, CWS Study Group |
Systemic therapy of aggressive fibromatosis in children and adolescents: Report of the Cooperative Weichteilsarkom Studiengruppe (CWS). |
Pediatric blood & cancer 2018, 65:e26943 |
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Treatment algorithms for patients with aggressive fibromatosis (AF) are challenging. There are limited data available about the use of systemic therapy (ST) in pediatric patients with AF. |
Sparber-Sauer M, Tagarelli A, Seitz G, Sorg B, Bien E, Bel-Ami T, Pourtsidis A, Lopez Almaraz R, Koscielniak E, Ferrari A, Orbach D, Bisogno G, EXPeRT and CWS Study Groups |
Children with progressive and relapsed pleuropulmonary blastoma: A European collaborative analysis. |
Pediatric blood & cancer 2021, 68:e29268 |
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Children with progressive (PD) or relapsed disease (RD) of pleuropulmonary blastoma (PPB) type II/III are known to have a very poor outcome. |
Sparber-Sauer M, Matle M, Vokuhl C, Hallmen E, von Kalle T, Münter M, Timmermann B, Bielack SS, Klingebiel T, Koscielniak E, Seitz G, CWS Study Group |
Rhabdomyosarcoma of the female genitourinary tract: Primary and relapsed disease in infants and older children. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. |
Pediatric blood & cancer 2021, 68:e28889 |
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Rhabdomyosarcoma (RMS) of the female genitourinary tract (FGU-RMS) located at the vagina or uterus is one of the most favorable RMS sites. Little is known about treatment and outcome in infants and relapsed disease (RD). |
Sparber-Sauer M, Orbach D, Navid F, Hettmer S, Skapek S, Corradini N, Casanova M, Weiss A, Schwab M, Ferrari A |
Rationale for the use of tyrosine kinase inhibitors in the treatment of paediatric desmoid-type fibromatosis. |
British journal of cancer 2021, 124: 1637 |
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In children with desmoid-type fibromatosis (DTF) in whom disease progression occurs after an initial watch-and-wait strategy, prolonged low-dose chemotherapy using vinblastine and methotrexate (VBL-MTX) is currently the standard of care. These conventional drugs have been prospectively evaluated but their efficacy and safety profiles are limited, and alternative therapeutic options are therefore essential. Based on the results of clinical trials, the use of tyrosine kinase inhibitors (TKIs) in the treatment of DTF is currently considered only in adult patients. TKIs such as imatinib show superior therapeutic efficacy to VBL-MTX and tolerable short-term side effects for the treatment of adult DFT, supporting the concept of the use of TKIs for the treatment of paediatric DFT. Moreover, new-generation TKIs, such as pazopanib and sorafenib, have shown improved therapeutic efficacy compared to imatinib in adult non-comparative studies. A tolerable safety profile of TKI therapy in children with disease entities other than DTF, such as leukaemia, has been reported. However, the efficacy and, in particular, the long-term safety of TKIs, including childhood-specific aspects such as growth and fertility, for the treatment of children with DTF should be investigated prospectively, as DFT therapy requires long-term drug exposure. |
Sparber-Sauer M, Ferrari A, Kosztyla D, Ladenstein R, Cecchetto G, Kazanowska B, Scarzello G, Ljungman G, Milano GM, Niggli F, Alaggio R, Vokuhl C, Casanova M, Klingebiel T, Zin A, Koscielniak E, Bisogno G |
Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults. |
Pediatric blood & cancer 2022 Apr 19;:e29691 |
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Background: CWS/RMS-96 was an international multicenter trial with randomization between two therapy arms of the standard four-drug therapy (vincristine, ifosfamide, adriamycin, dactinomycin [VAIA]) versus an intensified six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide [CEVAIE]) for high-risk rhabdomyosarcoma (RMS), extraskeletal Ewing sarcoma (EES), and undifferentiated sarcoma (UDS) in children, adolescents, and young adults aiming to improve their survival. Intensified chemotherapy with CEVAIE did not improve outcome.
Methods: Patients younger than 21 years with a previously untreated localized HR-RMS, EES, and UDS were enrolled from Cooperative Weichteilsarkom Studiengruppe (CWS) centers in Germany, Austria, Poland, Switzerland, and from Italian Soft Tissue Sarcoma Committee (STSC) centers. Randomization (1:1) to receive either 9 × 21 days cycles of VAIA or CEVAIE was performed separately in CWS and STSC. Hyperfractionated accelerated radiotherapy (32-44.8 Gy) was added at week 9-12 according to histology and response to chemotherapy. A secondary microscopically complete nonmutilating resection was performed if possible. Primary endpoints were response to chemotherapy, event-free (EFS) and overall survival (OS).
Results: Five hundred fifty-seven patients (HR-RMS: n = 416, EES and UDS: n = 141) underwent randomization: VAIA (n = 273) or CEVAIE (n = 284). Radiotherapy was given to 70% of patients in both groups. A secondary resection was performed in 47% and 48% patients, respectively. The 5-year EFS and OS for the VAIA and CEVAIE treatment arms were 59.8% and 60.8% (p = .89), and 74.2% and 68.3% (p = .16), respectively. No differences in response, toxicity, or second malignancies emerged in the two groups.
Conclusion: The use of an intensified regimen failed to show a significant improvement in tumor response and outcome of patients with localized HR-RMS, EES, and UDS. |
Sparber-Sauer M |
[Genomic classification and survival of patients with rhabdomyosarcoma: a report from an international consortium]. |
Strahlentherapie und Onkologie 2022, 198: 404 |
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Sparber-Sauer M, Vokuhl C, Seitz G, Sorg B, Tobias M, von Kalle T, Münter M, Bielack SS, Ladenstein R, Ljungman G, Niggli F, Frühwald M, Loff S, Klingebiel T, Koscielniak E |
Infantile myofibromatosis: Excellent prognosis but also rare fatal progressive disease. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. |
Pediatric blood & cancer 2022, 69:e29403 |
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Infantile myofibromatosis (IM) is a rare benign soft tissue tumor and often a self-limiting disease but rarely includes life-threatening complications. Little is known about optimal treatment of primary localized (LD) and multifocal disease (MFD). |
Sparber-Sauer M |
The future of rhabdomyosarcoma trials. |
The Lancet 2022, 6: 510 |
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Sparber-Sauer M, Dietzschold M, Schönstein A, Heinz A, Vokuhl C, Pajtler KW, Harrabi S, Lin YL, Kalle TV, Hagen R, Ladenstein R, Kazanowska B, Ljungman G, Klingebiel T, Ebinger M, Koscielniak E, Münter M, Timmermann B, CWS Study Group |
Radiotherapy and long-term sequelae in pediatric patients with parameningeal rhabdomyosarcoma: Results of two Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. |
Pediatric blood & cancer 2023,:e30742 |
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Parameningeal location of rhabdomyosarcoma (PM RMS) is known to be an unfavorable prognostic factor. Scarce data are available on radiotherapy (RT) concepts with regard to outcome. |
Sparber-Sauer M, Ferrari A, Spunt SL, Vokuhl C, Casey D, Lautz TB, Meyer WH, Walterhouse DO, Pajtler KW, Alaggio R, Schmidt A, Safwat A, Timmermann B, Dall'Igna P, Chen S, Weiss AR, Orbach D |
The significance of margins in pediatric Non-Rhabdomyosarcoma soft tissue sarcomas: Consensus on surgical margin definition harmonization from the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT). |
Cancer medicine 2023, 12: 11719 |
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Margin status following surgery in children, adolescents, and young adults with soft tissue sarcomas is controversial and has been defined differently by various specialties, with definitions changing over time and by cooperative group. The International Soft Tissue Sarcoma Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, European pediatric Soft Tissue sarcoma Study Group (EpSSG), and the European Cooperative Weichteilsarkom Studiengruppe (CWS) devoted to improving patient outcomes by pooling and mining cooperative group clinical trial data. |
Sparber-Sauer M, Corradini N, Affinita MC, Milano GM, Pierron G, Carton M, Tirode F, Pissaloux D, Alaggio R, Vokuhl C, Bisogno G, Berlanga P, Ferrari A, Orbach D |
Clinical characteristics and outcomes for children, adolescents and young adults with "CIC-fused" or "BCOR-rearranged" soft tissue sarcomas: A multi-institutional European retrospective analysis. |
Cancer medicine 2023, 12: 14346 |
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In certain rare undifferentiated small round cell sarcomas new specific molecular CIC-DUX4/other partner, BCOR-CCNB3/other partner, YWHAE fusions, or BCOR-ITD (internal tandem duplication) were identified. These new "CIC fused" (CIC-fused/ATXN1::NUTM1) and "BCOR rearranged" (BCOR fused/ITD/ YWHAE) soft tissue sarcomas (STS) are not well described. |
Sperling C, Büchner T, Creutzig U, Ritter J, Harbott J, Fonatsch C, Sauerland C, Mielcarek M, Löffler H, Ludwig W |
Clinical, morphologic, cytogenetic and prognostic implications of CD34 expression in childhood and adult de novo AML. |
Leukemia and Lymphoma 1995, 17: 417 |
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Spentzouris G, Scriven RJ, Lee TK, Labropoulos N |
Pediatric venous thromboembolism in relation to adults. |
Journal of vascular surgery 2012, 55: 1785 |
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Spix C, Aareleid T, Stiller C, Magnani C, Kaatsch P, Michaelis J |
Survival of children with neuroblastoma. time trends and regional differences in Europe, 1978--1992. |
Eur J Cancer 2001, 37: 722 |
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Spitz R, Hero B, Westermann F, Ernestus K, Schwab M, Berthold F |
Fluorescence in situ hybridization analyses of chromosome band 1p36 in neuroblastoma detect two classes of alterations. |
Genes Chromosomes Cancer 2002, 34: 299 |
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Spitz R, Hero B, Ernestus K, Berthold F |
FISH analyses for alterations in chromosomes 1, 2, 3, and 11 define high-risk groups in neuroblastoma. |
Med Pediatr Oncol 2003, 41: 30 |
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Spitz R, Hero B, Ernestus K, Berthold F |
Deletions in chromosome arms 3p and 11q are new prognostic markers in localized and 4s neuroblastoma. |
Clin Cancer Res 2003, 9: 52 |
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Spix C, Michaelis J, Berthold F, Erttmann R, Sander J, Schilling F |
Lead-time and overdiagnosis estimation in neuroblastoma screening. |
Stat Med 2003, 22: 2877 |
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Spix C, Schüz J, Klein G, Kaatsch P |
Epidemiologie solider Tumoren im Kindes- und Jugendalter. |
Kinder- und Jugendmedizin 2003, 4 |
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Spitz R, Hero B, Ernestus K, Berthold F |
Gain of distal chromosome arm 17q is not associated with poor prognosis in neuroblastoma. |
Clinical cancer research : an official journal of the American Association for Cancer Research 2003, 9: 4835 |
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PURPOSE: In several studies, gain of the distal long arm of chromosome 17 was shown to be a frequent and prognostically relevant factor in neuroblastoma, in addition to MYCN amplification (MNA) or 1p deletion. We asked whether this observation could be confirmed in a German cohort. EXPERIMENTAL DESIGN: To evaluate the frequency and prognostic impact of 17q gain, we investigated tissue samples from 193 neuroblastoma patients by the use of fluorescence in situ hybridization. The DNA probe (MPO) was located in distal 17q in the region of interest as used by several groups. To analyze the association of patients' outcome with the breakpoint position within 17q, we used the more proximal DNA probe ERBB2 in 17q21 on a selected number of cases. Gain was defined as an excess of 17q material compared with the chromosome 17 centromere in at least 50% of the analyzed tumor cells. In addition, alterations in chromosomes 1p, 3p, and 11q, as well as MYCN status, were determined to describe the interrelationship between the different parameters and to evaluate an independent prognostic influence. RESULTS: Gain of 17q was found in 61% of the investigated tumors. An additional 23% displayed an excess of 17q in less than half of all cells. Gain correlated with stage 4 disease (P = 0.003) and with other chromosomal alterations, such as 1p (P < 0.001), 3p (P = 0.01), 11q (P = 0.001), and MNA (P = 0.016), as well as with increased patient age (P = 0.01). Outcome was not different between patients with 17q gain compared with those without, however. A prognostic influence could not be delineated in all stages or in localized or in stage 4 subgroups or in the MYCN nonamplified patient cohort. Outcome did not differ between patients with additional 17q material in <10% of the cells or in >70%. Patients showing a breakpoint in the more proximal part of 17q could not be described as having a more favorable outcome compared with patients with a more distal breakpoint. Prognosis was poor in patients with MNA and/or 11q loss either with or without 17q gain. A multivariate analysis including the chromosomal parameters 17q, 11q, and MYCN status, as well as stage, showed MYCN and 11q status (P < 0.001), but not 17q or stage as significant prognostic factors. CONCLUSION: Although the most frequent aberration in neuroblastoma to date, we found no association between 17q gain and an inferior prognosis in our cohort; the status of MYCN and 11q, however, allowed reliable prediction of patients' outcomes. |
Spitz R, Hero B, Skowron M, Ernestus K, Berthold F |
MYCN-status in neuroblastoma: characteristics of tumours showing amplification, gain, and non-amplification. |
European journal of cancer (Oxford, England : 1990) 2004, 40: 2753 |
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While the role of MYCN-amplification (MNA) for risk assessment in neuroblastoma is undisputed, the phenomenon of gene copy excess below the amplification threshold is rarely described. To discuss biological characteristics and the clinical impact of the so-called MYCN-gain versus amplified or non-amplified cases, we investigated the MYCN status of 659 patients uniformly analysed by fluorescence in situ hybridisation. The number of MYCN-amplified tumours in our cohort was 18% (116/659); an additional 38 tumours (6%) displayed MYCN-gain. Both alterations were associated with an advanced stage disease, an increased patient age and further chromosomal alterations. Most of the amplified neuroblastomas displayed 1p aberrations, whereas MYCN-gain tumours correlated with 11q alterations. In contrast to the amplified cases, tumours with gain displayed no increased MYCN RNA levels. MNA versus non-amplification discriminated between good and poor outcomes, independent of stage, age and the degree of amplification. However, patients with amplified tumours showed a significantly better outcome when this was combined with non-stage 4 disease and age <1 year versus stage 4 and age < 1 year. Although MYCN-gain was associated with poor event-free-survival (EFS) in stages 1-3, 4S (P=0.005), this might be related to associated genetic aberrations and not to the MYCN-gain itself. A survival difference between neuroblastomas with gain and single copy MYCN could not be delineated. In conclusion, MNA predicts a poor outcome for neuroblastoma patients of all stages and age. MYCN-gain is also a characteristic feature of advanced stage tumours and older patients, but is not associated with higher MYCN expression and appears not to be discriminative in predicting patient outcome. |
Spitz R, Hero B, Simon T, Berthold F |
Loss in chromosome 11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. |
Clinical cancer research 2006, 12(11 Pt 1): 3368 |
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PURPOSE: To improve risk prediction in neuroblastoma and to specify the type of a possible relapse, alterations in the long arm of chromosome 11 were analyzed. EXPERIMENTAL DESIGN: A representative cohort of 611 neuroblastomas was investigated for deletion events in distal chromosome 11q using interphase fluorescence in situ hybridization. RESULTS: Alterations in 11q were found in 159 of 611 tumors in the whole cohort (26%) and were associated with stage 4 disease (P < 0.001) and age at diagnosis of >2.5 years (P < 0.001). Event-free survival and overall survival were significantly poorer for patients with 11q loss in the whole cohort (event-free survival and overall survival, P < 0.001) and in different subsets: neuroblastoma without MYCN amplification (MNA) (event-free survival and overall survival, P < 0.001), with MNA (event-free survival, P = 0.03; overall survival, P = 0.02), and MYCN-nonamplified stage 1, 2, 3, and 4S tumors with and without del 1p (event-free survival and overall survival, P < 0.001). In stage 4, the 11q status did not discriminate outcome. By multivariate analysis, the 11q status proved prognostic for event-free survival in the whole cohort (P = 0.008; hazard ratio, 1.573) and in the subgroup of stages 1, 2, 3, and 4S without MNA (P < 0.001; hazard ratio, 3.534). Moreover, 11q alterations were strongly correlated with the occurrence of metastatic relapses (P < 0.001). CONCLUSION: In addition to the current risk stratification, the status of 11q enables the identification of patients with an increased risk for relapses in general and metastatic relapses in particular. |
Spitz R, Oberthuer A, Zapatka M, Brors B, Hero B, Ernestus K, Oestreich J, Fischer M, Simon T, Berthold F |
Oligonucleotide array-based comparative genomic hybridization (aCGH) of 90 neuroblastomas reveals aberration patterns closely associated with relapse pattern and outcome. |
Genes, chromosomes & cancer 2006, 45: 1130 |
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The study of genomic alterations in neuroblastoma is of particular importance since several cytogenetic markers proved to be closely associated with the clinical phenotype. To disclose patterns of gains and losses, we performed high-resolution oligonucleotide array-based comparative genomic hybridization (aCGH). A total cohort of 90 patients was classified into 6 subsets according to tumor stage and outcome: Stages 1-3+ (with event), Stage 1-3- (no event), Stage 4+/-, and Stage 4S+/-. The aberration patterns in Stages 1-3- and 4S- tumors differed from all other groups as they were predominantly characterized by losses (3, 4, 14, X) and gains (7, 17) of whole chromosomes. However, 59/65 (91%) tumors of Stages 1-3+ or Stage 4 revealed numerous structural copy number alterations (sCNA). While deletions in chromosomes 1, 3, and 11 discriminated outcome in Stage 4, there were no specific sCNA that distinguished tumor stage within the subgroup of unfavorable tumors. sCNA in 1p, 3p, 11q, 17q, or MYCN amplification (MNA) was seen among 22/24 patients who died, 10/12 with metastatic relapses, and 5/9 with local recurrences. Detailed breakpoint analyses on chromosomes 1, 3, 11, and 17 disclosed preferred breaking areas, although breakpoints were not identical. Amplifications were found in 18 patients and involved 2p24 (MYCN) and other segments of chromosome 2, as well as regions on chromosome arms 6q, 12q, and 17q. One single feature in 21q21.1 (BU678720, without known function yet) attracted particular attention since five patients showed a homozygous loss of this sequence. |
Spitz R, Betts DR, Simon T, Boensch M, Oestreich J, Niggli FK, Ernestus K, Berthold F, Hero B |
Favorable outcome of triploid neuroblastomas: a contribution to the special oncogenesis of neuroblastoma. |
Cancer genetics and cytogenetics 2006, 167: 51 |
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There is a well-known association between patient outcome and tumor ploidy in neuroblastoma. To date, however, most clinical trials have not used this parameter for therapy stratification. Using conventional cytogenetics and fluorescence in situ hybridization (FISH), we investigated 36 tumors in terms of ploidy and chromosome 1 copy number (polysomy). In addition, interphase FISH for polysomy was performed on a second cohort of 440 neuroblastomas, together with the status of 1p, MYCN, and 11q. The main goals were as follows: (1) to assess the reliability of FISH to determine ploidy; (2) to illustrate associations between somy 1 and clinical/biologic factors; and (3) to investigate the role of somy 1 for predicting outcome. The comparison between karyotyping and FISH in the smaller cohort revealed 86% consistency between ploidy and polysomy (31/36). According to FISH, trisomic tumors in the second cohort showed structural chromosomal aberrations less frequently compared to di-/tetrasomic tumors (15 vs. 60%, P < 0.001). The portion of trisomic neuroblastomas was higher in stages 1, 2, and 4S versus stages 3 and 4 (55 vs. 24%, P < 0.001) and in children 18 months or younger versus those older than 18 months (55 vs. 19%, P < 0.001). Prognosis was significantly better for trisomic tumors versus di-/tetrasomic in the whole cohort [event-free (EFS) and overall survival (OS), P < 0.001]. In the subgroup without abnormalities of other molecular markers, EFS of trisomic neuroblastomas was better (P = 0.048), but was most likely due to an unequal stage distribution. In further subgroups, in terms of age and stage, significance between the somy groups was not reached, neither for EFS nor OS. The multivariate analyses including age, stage, chromosomal markers, and somy 1 confirmed the lack of independent prognostic power for the copy number of chromosome 1. This study demonstrates the following: (1) FISH is a practical alternative to other more labor-intensive techniques for determining ploidy; (2) trisomic tumors correlate with younger age at diagnosis, localized stage, and the lack of structural alterations; and (3) polysomy is not an independent prognostic marker. The sharp decline of trisomic tumors after the age of 18 months supports the idea of different genetic tumor entities. |
Spix C, Schmiedel S, Kaatsch P, Schulze-Rath R, Blettner M |
Case-control study on childhood cancer in the vicinity of nuclear power plants in Germany 1980-2003. |
European journal of cancer (Oxford, England : 1990) 2008, 44: 275 |
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The 1984 Windscale study raised concern about a possible association between living in the vicinity of nuclear power plants and childhood cancer. No such effect for all cancers was seen in ecological studies in Germany (1980-1995). Results from exploratory analyses led to a new study. Pre-selected areas around all 16 major nuclear power plants in Germany formed the study area. The design is a matched case-control study; cases are all cancers under five years diagnosed in 1980-2003: 1592 cases, and 4735 controls. Inverse distance of place of residence to the nearest nuclear power plant at the time of diagnosis was used as the independent variable in a conditional logistic regression model. Results show an increased risk for childhood cancer under five years when living near nuclear power plants in Germany. The inner 5-km zone shows an increased risk (odds ratio 1.47; lower one-sided 95% confidence limit 1.16). The effect was largely restricted to leukaemia. The results are compatible with the corresponding subgroups in the previous German ecological studies, with which this study shares most of the cases. They contrast with the lack of an effect observed or expected from other studies due to low doses from routine nuclear power plant operation. |
Spix C, Spallek J, Kaatsch P, Razum O, Zeeb H |
Cancer survival among children of Turkish descent in Germany 1980-2005: a registry-based analysis. |
BMC cancer 2008, 8: 355 |
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BACKGROUND: Little is known about the effect of migrant status on childhood cancer survival. We studied cancer survival among children of Turkish descent in the German Cancer Childhood Registry, one of the largest childhood cancer registries worldwide. METHODS: We identified children of Turkish descent among cancer cases using a name-based approach. We compared 5-year survival probabilities of Turkish and other children in three time periods of diagnosis (1980-87, 1988-95, 1996-2005) using the Kaplan-Meier method and log-rank tests. RESULTS: The 5-year survival probability for all cancers among 1774 cases of Turkish descent (4.76% of all 37.259 cases) was 76.9% compared to 77.6% in the comparison group (all other cases; p = 0.15). We found no age- or sex-specific survival differences (p-values between p = 0.18 and p = 0.90). For the period 1980-87, the 5-year survival probability among Turkish children with lymphoid leukaemia was significantly lower (62% versus 75.8%; p < 0.0001), this remains unexplained. For more recently diagnosed leukaemias, we saw no survival differences for Turkish and non-Turkish children. CONCLUSION: Our results suggest that nowadays Turkish migrant status has no bearing on the outcome of childhood cancer therapies in Germany. The inclusion of currently more than 95% of all childhood cancer cases in standardised treatment protocols is likely to contribute to this finding. |
Spix C, Schulze-Rath R, Kaatsch P, Blettner M |
Case-control study on risk factors for leukaemia and brain tumours in children under 5 years in Germany. |
Klinische Padiatrie 2009, 221: 362 |
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In the context of a case control study on the cancer risk for children under five by distance to the nearest nuclear power plant, we collected information on other risk factors in a subset. We present the interview study as if it had been an independent study. Parents of 471 cases with Leukaemia, Lymphoma or CNS (Central Nervous System)-tumour from the German Childhood Cancer Registry, diagnosed at age under 5 in the years 1993-2003, and 1,457 matched controls were to be interviewed. For Leukaemia, 243 cases/604 controls, and for CNS 102 cases/246 controls participated, lymphoma cases were too few. Questions related to social status, ionizing radiation, pregnancy and birth, immune system, and selected toxins. The analysis is exploratory in nature; variables were selected by backward elimination. For leukaemia we found a significant protective effect of social contacts (OR=0.50, 95% CI [0.29;0.87]) and a risk for high birth weight (OR=1.96 95% CI [1.12;3.41] comparing >4,000 g to |
Spix C, Mergenthaler A, Kaatsch P |
[Data exchange between the German Childhood Cancer Registry and the Epidemiological Cancer State Registries]. |
Klinische Padiatrie 2009, 221: 398 |
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Spix C, Kaatsch P, Blettner M |
The German and the French studies on childhood leukemia and nuclear power: differences and similarities. |
International journal of cancer 2012, [Epub ahead of print] |
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Spix C |
Fertility in survivors of childhood cancer. |
Deutsches Arzteblatt international 2012, 109: 124 |
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Sposto R, Ertel IJ, Jenkin RD, Boesel CP, Venes JL, Ortega JA, Evans AE, Wara W, Hammond D |
The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group. |
J Neurooncol 1989, 7: 165 |
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Spreafico F, Dalissier A, Pötschger U, Locatelli F, Michon JM, Peters C, Bader P, Bisogno G, Yeomanson D, Willasch A, van den Heuvel Eibrink M, Graf N, Dallorso S, EBMT Paediatric Diseases Working Party |
High dose chemotherapy and autologous hematopoietic cell transplantation for Wilms tumor: a study of the European Society for Blood and Marrow Transplantation. |
Bone marrow transplantation 2020, 55: 376 |
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Survival for subgroups of patients with Wilms tumor (WT), such as those who suffer from relapse, is disappointing. Some patients' treatment plans include high-dose chemotherapy (HDT) with autologous hematopoietic cell transplantation (aHCT), although proof for its benefit is lacking. To increase the level of evidence regarding children with WT receiving aHCT as consolidation of first or second remission (after first relapse), we extracted relevant data from the European Blood and Marrow Transplantation Registry concerning 69 patients. Different HDT regimens were administered, mostly either melphalan-containing (n = 34) or thiotepa-containing (n = 14). For the whole population, 5-year overall survival (OS) and event-free survival (EFS) probabilities were 0.67 (±0.06) and 0.63 (±0.06), respectively (median observation time 7.8 years); for children transplanted in first remission, OS and EFS were 0.69 (±0.09) and 0.72 (±0.08). In univariate analysis, male gender and relapse in multiple sites were associated with lower OS probabilities. The use of a given pretransplant regimen (i.e. melphalan alone versus regimens with multiple drugs) did not seem to influence EFS/OS probability after aHCT, but significantly influenced platelet engraftment (more delayed with thiotepa). We here provide further data to improve the basis for future evidence-based clinical decision-making when using HDT and aHCT in relapsed/refractory WT. |
Spurny C, Kailayangiri S, Altvater B, Jamitzky S, Hartmann W, Wardelmann E, Ranft A, Dirksen U, Amler S, Hardes J, Fluegge M, Meltzer J, Farwick N, Greune L, Rossig C |
T cell infiltration into Ewing sarcomas is associated with local expression of immune-inhibitory HLA-G. |
Oncotarget 2018 Jan 19; 9: 6536 |
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Spycher BD, Feller M, Zwahlen M, Röösli M, von der Weid NX, Hengartner H, Egger M, Kuehni CE |
Childhood cancer and nuclear power plants in Switzerland: A census based cohort study. |
Int J Epidemiol 2011 Jul 12. [Epub ahead of print] |
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Stansfeld AG, Diebold J, Noel H, Kapanci Y, Rilke F, Kelenyi G, Sundstrom C, Lennert K, van Unnik JA, Mioduszewska O, et al. |
Updated Kiel classification for lymphomas. |
Lancet 1988, 1: 292 |
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Stahnke K, Ritter J, Schellong G, Beck J, Kabisch H, Lampert F, Creutzig U |
Rezidivbehandlung bei akuter myeloischer Leukämie im Kindesalter. Eine retrospektive Analyse der in der Studie AML-BFM- 83 aufgetretenen Rezidive. |
Klinische Pädiatrie 1992, 204: 253 |
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Stahnke K, Creutzig U, Ritter J, Group for |
Second remission in relapsed childhood acute myelogenous leukemia after pretreatment with the AML-BFM-83 protocol. |
Haematology and Blood Transfusion 1993, 36: 500 |
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Stahnke K, Ritter J, Boos J, Creutzig U |
Mitoxantrone-etoposide or HD-Ara-C/mitoxantrone for remission induction in children with first relapse of AML. |
Haematology and Blood Transfusion 1996,V: 200 |
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Stahnke K, Boos J, Bender-Götze C, Ritter J, Zimmermann M, Creutzig U |
Duration of first remission predicts remission rates and longterm survival in children with relapsed acute myelogenous leukemia. |
Leukemia 1998, 12: 1543 |
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Stanulla M, Loning L, Welte K, Schrappe M |
Secondary brain tumours in children with ALL. |
Lancet 1999, 354: 1126 |
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Stanulla M, Kasper B, Schrappe M, Viehmann S, Harbott J, Ludwig W, Welte K |
Granulocyte colony-stimulating factor receptor expression and 11q23/MLL genotype in childhood acute lymphoblastic leukemia developing during the first 18 months of life. |
Leukemia 2000, 14: 337 |
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Stanulla M, Schrappe M, Brechlin A, Zimmermann M, Welte K |
Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia. |
Blood 2000, 95: 1222 |
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Stanulla M, Stumm M, Dieckvoss B, Seidemann K, Schemmel V, Müller-Brechlin A, Schrappe M, Welte K, Reiter A |
No evidence for a major role of heterozygous deletion 657del5 within the NBS1 gene in the pathogenesis of non-Hodgkin's lymphoma of childhood and adolescence. |
Br J Haematol 2000, 109: 117 |
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Stanulla M, Schrauder A, Welte K, Schrappe M |
Tumor necrosis factor and lymphotoxin-alpha genetic polymorphisms and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia. |
BMC Blood Disord 2001, 1 |
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Stam R, Den Boer M, Meijerink J, Ebus M, Peters G, Noordhuis P, Janka-Schaub G, Armstrong S, Korsmeyer S, Pieters R |
Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia. |
Blood 2003, 101: 1270 |
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Stams W, Den Boer M, Beverloo H, Meijerink J, Stigter R, van Wering E, Janka-Schaub G, Slater R, Pieters R |
Sensitivity to L-asparaginase is not associated with expression levels of asparagine synthetase in t(12;21)+ pediatric ALL. |
Blood 2003, 101: 2743 |
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Stam R, MM van, Den Boer M, Ebus M, Janka-Schaub G, Allen J, Pieters R |
Multidrug resistance genes in infant acute lymphoblastic leukemia. |
Leukemia 2004, 18: 78 |
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Stams WA, den Boer ML, Holleman A, Appel IM, Beverloo HB, van Wering ER, Janka-Schaub GE, Evans WE, Pieters R |
Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia. |
Blood 2005, 105: 4223 |
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Resistance to L-asparaginase in leukemic cells may be caused by an elevated cellular expression of asparagine synthetase (AS). Previously, we reported that high AS expression did not correlate to L-asparaginase resistance in TEL-AML1-positive B-lineage acute lymphoblastic leukemia (ALL). In the present study we confirmed this finding in TEL-AML1-positive patients (n = 28) using microarrays. In contrast, 35 L-asparaginase-resistant TEL-AML1-negative B-lineage ALL patients had a significant 3.5-fold higher AS expression than 43 sensitive patients (P < .001). Using real-time quantitative polymerase chain reaction (RTQ-PCR), this finding was confirmed in an independent group of 39 TEL-AML1-negative B-lineage ALL patients (P = .03). High expression of AS was associated with poor prognosis (4-year probability of disease-free survival [pDFS] 58% +/- 11%) compared with low expression (4-year pDFS 83% +/- 7%; P = .009). We conclude that resistance to l-asparaginase and relapse risk are associated with high expression of AS in TEL-AML1-negative but not TEL-AML1-positive B-lineage ALL. |
Stams WA, den Boer ML, Beverloo HB, Meijerink JP, van Wering ER, Janka-Schaub GE, Pieters R |
Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia. |
Clinical cancer research 2005, 11: 2974 |
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PURPOSE: t(12;21)(p13; q22), present in approximately 25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients. EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL. CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL. |
Stanulla M, Seidemann K, Schnakenberg E, Book M, Mehles A, Welte K, Schrappe M, Reiter A |
Methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and risk of pediatric non-Hodgkin lymphoma in a German study population. |
Blood 2005, 105: 906 |
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Stanulla M, Schaeffeler E, Flohr T, Cario G, Schrauder A, Zimmermann M, Welte K, Ludwig WD, Bartram CR, Zanger UM, Eichelbaum M, Schrappe M, Schwab M |
Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. |
JAMA 2005, 293: 1485 |
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CONTEXT: Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for children with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) is involved in the metabolism of mercaptopurine and subject to genetic polymorphism, with heterozygous individuals having intermediate and homozygous mutant individuals having very low TPMT activity. OBJECTIVE: To assess the association of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL. DESIGN, SETTING, AND PATIENTS: TPMT genotyping of childhood ALL patients (n = 814) in Germany consecutively enrolled in the ALL-BFM (Berlin-Frankfurt-Münster) 2000 study from October 1999 to September 2002. Minimal residual disease was analyzed on treatment days 33 and 78 for risk-adapted treatment stratification. A 4-week cycle of mercaptopurine was administered between these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analyses. MAIN OUTCOME MEASURES: Minimal residual disease load before (day 33) and after (day 78) mercaptopurine treatment. Loads smaller than 10(-4) were defined as negative. RESULTS: Patients (n = 55) heterozygous for allelic variants of TPMT conferring lower enzyme activity had a significantly lower rate of minimal residual disease positivity (9.1%) compared with patients (n = 755) with homozygous wild-type alleles (22.8%) on day 78 (P = .02). This translated into a 2.9-fold reduction in risk for patients with wild-type heterozygous alleles (relative risk, 0.34; 95% confidence interval, 0.13-0.86). CONCLUSIONS: TPMT genotype has a substantial impact on minimal residual disease after administration of mercaptopurine in the early course of childhood ALL, most likely through modulation of mercaptopurine dose intensity. Our findings support a role for minimal residual disease analyses in the assessment of genotype-phenotype associations in multiagent chemotherapeutic trials. |
von Stackelberg A, Henze G |
Rezidive der akuten lymphoblastischen Leukämie. |
In: Gadner H, Gaedicke G, Niemeyer C, Ritter J, editors. Pädiatrische Hämatologie und Onkologie Berlin, Heidelberg, New York: Springer Verlag Springer Verlag, 2006, 680 |
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Stanulla M, Cario G, Meissner B, Schrauder A, Möricke A, Riehm H, Schrappe M |
Integrating molecular information into treatment of childhood acute lymphoblastic leukemia--a perspective from the BFM Study Group. |
Blood cells, molecules & diseases 2007, 39: 160 |
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Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood and is treated with chemotherapy alone or, in particular subgroups, with additional radiation therapy and/or stem cell transplantation. The treatment intensity is adjusted according to prognostic factors associated with the risk of ALL recurrence. On Berlin-Frankfurt-Münster (BFM) protocols, the widely applicable early in vivo response to treatment as measured by the reduction of leukemic cells in the blood or bone marrow is currently the most important prognostic factor. However, although overall long-term cure rates for childhood ALL treated on risk-adapted protocols have dramatically improved over the last decades and, to date, are higher than 75%, a significant number of patients still die due to recurrent disease or the toxicity of treatment applied. One goal in future BFM trials will be to take advantage of a better molecular understanding of leukemia and host characteristics to dissect the mechanisms underlying the differences in treatment response. This short review focuses on the evolution of treatment response in BFM trials and provides a perspective on our strategy for improving molecular characterization of childhood ALL and implementing more individualized and novel therapeutic approaches. |
Staege MS, Banning-Eichenseer U, Weissflog G, Volkmer I, Burdach S, Richter G, Mauz-Körholz C, Föll J, Körholz D |
Gene expression profiles of Hodgkin's lymphoma cell lines with different sensitivity to cytotoxic drugs. |
Experimental hematology 2008, 36: 886 |
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OBJECTIVE: The prognosis of patients with Hodgkin's lymphoma (HL) has been significantly improved as a result of combination treatment including chemotherapy. However, some patients are refractory to chemotherapy. Therefore, identification of new targets might be useful for development of alternative treatment strategies. In addition, identification of markers associated with chemoresistance can be used to identify patients with increased risk of relapse. MATERIALS AND METHODS: By using high-density DNA microarrays, we analyzed the gene-expression profile of HL-cell lines in comparison to a set of normal tissues. Furthermore, we tested the sensitivity of HL cells for cytotoxic drugs (cisplatin, etoposide, melphalan) and compared the gene-expression profile of chemotherapy-resistant and -sensitive cell lines. Differentially expressed genes were validated by polymerase chain reaction and flow cytometry. RESULTS: In addition to genes with high expression in all cell lines, we observed differences between the gene-expression profile of chemotherapy-resistant and -sensitive cells. Genes upregulated in resistant cells include cytokine receptors (IL5RA, IL13RA1), markers expressed on antigen-presenting cells (CD40, CD80), as well as genes with known association to chemoresistance, e.g., myristoylated alanine-rich protein kinase C substrate. In addition, the tumor antigen PRAME (preferentially expressed antigen in melanoma) was expressed in resistant cell lines only. CONCLUSION: Genes with high expression in HL cells might be potential targets for development of future therapeutic interventions. Expression of tumor antigens together with costimulatory molecules in chemotherapy-resistant HL cells might become targets for cytotoxic T-cell responses against HL cells. |
von Stackelberg A, Hartmann R, Bührer C, Fengler R, Janka-Schaub G, Reiter A, Mann G, Schmiegelow K, Ratei R, Klingebiel T, Ritter J, Henze G, ALL-REZ BFM Study Group |
High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. |
Blood 2008, 111: 2573 |
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High-dose methotrexate (MTX) has been extensively used for treatment of acute lymphoblastic leukemia (ALL). To determine the optimal dose of MTX in childhood relapsed ALL, the ALL Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group performed this prospective randomized study. A total of 269 children with a first early/late isolated (n = 156) or combined (n = 68) bone marrow or any isolated extramedullary relapse (n = 45) of precursor B-cell (PBC) ALL (excluding very early marrow relapse within 18 months after initial diagnosis) were registered at the ALL-REZ BFM90 trial and randomized to receive methotrexate infusions at either 1 g/m(2) over 36 hours (intermediate dose, ID) or 5 g/m(2) over 24 hours (high dose, HD) during 6 (or 4) intensive polychemotherapy courses. Intensive induction/consolidation therapy was followed by cranial irradiation, and by conventional-dose maintenance therapy. Fifty-five children received stem-cell transplants. At a median follow-up of 14.1 years, the 10-year event-free survival probability was .36 (+/- .04) for the ID group (n = 141), and .38 (+/- .04) for the HD group (n = 128, P = .919). The 2 groups did not differ in terms of prognostic factors and other therapeutic parameters. In conclusion, methotrexate infusions at 5 g/m(2) per 24 hours, compared with 1 g/m(2) per 36 hours, are not associated with increased disease control in relapsed childhood PBC acute lymphoblastic leukemia. |
Stanulla M, Schaeffeler E, Möricke A, Coulthard SA, Cario G, Schrauder A, Kaatsch P, Dördelmann M, Welte K, Zimmermann M, Reiter A, Eichelbaum M, Riehm H, Schrappe M, Schwab M |
Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Münster protocols. |
Blood 2009, 114: 1314 |
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Thiopurine methyltransferase (TPMT)is involved in the metabolism of thiopurines such as 6-mercaptopurine and 6-thioguanine. TPMT activity is significantly altered by genetics, and heterozygous and even more homozygous variant people reveal substiantially decreased TPMT activity. Treatment for childhood acute lymphoblastic leukemia (ALL) regularly includes the use of thiopurine drugs. Importantly, childhood ALL patients with low TPMT activity have been considered to be at increased risk of developing therapy-associated acute myeloid leukemia and brain tumors. In the present study, we genotyped 105 of 129 patients who developed a secondary malignant neoplasm after ALL treatment on 7 consecutive German Berlin-Frankfurt-Münster trials for all functionally relevant TPMT variants. Frequencies of TPMT variants were similarly distributed in secondary malignant neoplasm patients and the overall ALL patient population of 814 patients. Thus, TPMT does not play a major role in the etiology of secondary malignant neoplasm after treatment for childhood ALL, according to Berlin-Frankfurt-Münster strategies. |
Stanulla M, Schrappe M |
Treatment of childhood acute lymphoblastic leukemia. |
Seminars in hematology 2009, 46: 52 |
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Childhood acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. Studies in ALL have been a model for clinical and basic research beyond pediatric hemato-oncology. As a result of sustained and well-organized research efforts since the early 1960s, childhood ALL now can be successfully treated in about 80% of patients by the application of intensive combination chemotherapy regimens, which in specific patient subgroups may need to be supplemented with radiation therapy and/or hematopoietic stem cell transplantation. Triggered by the observation of specific clinical presenting features, biological characteristics, and early treatment response being associated with treatment outcome, therapy intensity in contemporary ALL protocols is adjusted according to prognostic factors predicting the risk of relapse. While the goal of effective therapy for the majority of children with ALL has been achieved, significant numbers of patients still die due to recurrent disease or the toxicity of treatment. Thus, future research must extend our molecular understanding of leukemia and host factors in order to even more specifically identify the mechanisms underlying the differences in treatment response and outcome, and to finally address the therapeutic needs of the individual child. |
Staege MS, Körholz D |
New treatment strategies for Hodgkin's lymphoma. |
Leukemia research 2009, 33: 886 |
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von Stackelberg A, Völzke E, Kühl JS, Seeger K, Schrauder A, Escherich G, Henze G, Tallen G, for the ALL-REZ BFM Study Group |
Outcome of children and adolescents with relapsed acute lymphoblastic leukaemia and non-response to salvage protocol therapy: A retrospective analysis of the ALL-REZ BFM Study Group. |
European journal of cancer 2011, 47: 90 |
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AIM OF THE STUDY: Non-response (NR) to treatment of childhood relapsed acute lymphoblastic leukaemia (ALL) is an end-point of protocol therapy. Subsequent management has not yet been standardised. This study analyses different approaches after NR to aid optimising future strategies. PATIENTS AND METHODS: Ninety-three children with NR to treatment according to ALL relapse-protocols of the Berlin/Frankfurt/Muenster (BFM) Study Group (03/1990-2006/1999) were retrospectively assigned to a curative (C: intensive polychemotherapies, stem cell transplantation (SCT); n=51), palliative (P: 1-2 antineoplastic agents; n=23) or supportive (S: no antineoplastic therapy; n=19) treatment approach. RESULTS: Median survival after diagnosis of NR were 121 (C), 89 (P) and 42 (S) days, respectively (p<0.001). In cohort C, a complete remission (2ndCR) was obtained in 16/51 patients, among these 13 only after SCT, and nine children achieved partial remission. Ten of the 51 patients died from treatment-related complications, 39/51 from disease progression. Today, two patients are still in continuous CR after SCT. Adverse prognostic factors were overrepresented in the non-curative cohorts. Time-point of relapse and treatment after NR were independent predictors of survival duration. Most patients without antineoplastic treatment died at home, the majority of the others in the hospital. CONCLUSIONS: Treatment after NR has been heterogeneous and customised. Therapies with curative intent are capable of inducing 2ndCR but associated with high treatment-related morbidity, -mortality and minimal survival. NR patients may, therefore, be ideal candidates for controlled phase I/II trials, thus offering them a chance to benefit from new drugs and promoting drug development for cohorts with better prognosis. |
Stahl M, Ranft A, Paulussen M, Bölling T, Vieth V, Bielack S, Görtitz I, Braun-Munzinger G, Hardes J, Jürgens H, Dirksen U |
19. Risk of recurrence and survival after relapse in patients with Ewing sarcoma. |
Pediatr Blood Cancer 2011,Epub ahead of print |
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BACKGROUND:
The prognosis in patients with relapsed Ewing sarcoma is unfavorable. Our investigation identifies factors predicting for the outcome following relapse.
PROCEDURE:
We analyzed type of relapse, time to relapse and overall survival after relapse (OSr) in 714 patients with first recurrence. All patients had been treated within the Cooperative Ewing Sarcoma Studies (CESS) 81 or 86, or the European Intergroup CESS (EICESS 92). OSr time was calculated from diagnosis of first relapse to last follow-up or death.
RESULTS:
Median follow-up time from diagnosis of primary disease was 2.2 years (mean = 4.0; range: 0.2-24.9). Relapse sites were local in 15%, combined local and systemic in 12%, and systemic in 73%. Among patients with a localized primary tumor, 20% relapsed locally, while 12% showed combined and 68% systemic relapse. When the primary disease was disseminated, 82% developed systemic, 13% combined, and 5% local relapse. Five-year OSr was 0.13 (SE = 0.01). Outcome following local relapse, with a 5-year survival rate of 0.24 (P < 0.001), was superior to outcome after systemic or combined recurrence. Five-year OSr was 0.07 (SE = 0.01) in patients who relapsed 0-2 years after the diagnosis of primary disease, as compared to a 5-year OSr of 0.29 (SE = 0.03) when relapse occurred later.
CONCLUSIONS:
5-year OSr in Ewing sarcoma is poor (<0.2). Prognostically favorable factors are: late onset (>2 years) and strictly localized relapse. |
Stanulla M, Bourquin JP |
Behandlung der akuten lymphoblastischen Leukämie im Kindesalter. |
Pharm unserer Zeit 2012, 3 |
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Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S, Gonzalez A, Izraeli S, Janic D, Jazbec J, Konja J, Kaiserova E, Kowalczyk J, Kovacs G, Li CK, Magyarosy E, Popa A, Stark B, Jabali Y, Trka J, Hrusak O, Riehm H, Masera G, Schrappe M |
Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. |
Journal of clinical oncology 2014, 32: 174 |
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From 2002 to 2007, the International Berlin-Frankfurt-Münster Study Group conducted a prospective randomized clinical trial (ALL IC-BFM 2002) for the management of childhood acute lymphoblastic leukemia (ALL) in 15 countries on three continents. The aim of this trial was to explore the impact of differential delayed intensification (DI) on outcome in all risk groups. |
Stankov MV, El Khatib M, Kumar Thakur B, Heitmann K, Panayotova-Dimitrova D, Schoening J, Bourquin JP, Schweitzer N, Leverkus M, Welte K, Reinhardt D, Li Z, Orkin SH, Behrens GM, Klusmann JH |
Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy. |
Leukemia 2014, 28: 577 |
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Histone deacetylase (HDAC) inhibitors (HDACis) are well-characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome-associated myeloid leukemia (DS-AMKL) blasts. Investigating the antileukemic function of HDACis revealed their transcriptional and post-translational regulation of key autophagic proteins, including ATG7. This leads to suppression of autophagy, a lysosomal degradation process that can protect cells against damaged or unnecessary organelles and protein aggregates. DS-AMKL cells exhibit low baseline autophagy due to mammalian target of rapamycin (mTOR) activation. Consequently, HDAC inhibition repressed autophagy below a critical threshold, which resulted in accumulation of mitochondria, production of reactive oxygen species, DNA damage and apoptosis. Those HDACi-mediated effects could be reverted upon autophagy activation or aggravated upon further pharmacological or genetic inhibition. Our findings were further extended to other major acute myeloid leukemia subgroups with low basal level autophagy. The constitutive suppression of autophagy due to mTOR activation represents an inherent difference between cancer and normal cells. Thus, via autophagy suppression, HDACis deprive cells of an essential pro-survival mechanism, which translates into an attractive strategy to specifically target cancer cells. |
Stapleton JL, Tatum KL, Devine KA, Stephens S, Masterson M, Baig A, Hudson SV, Coups EJ |
Skin Cancer Surveillance Behaviors Among Childhood Cancer Survivors. |
Pediatric blood & cancer 2016, 63: 554 |
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The risk of developing skin cancer is elevated among childhood cancer survivors (CCS), particularly among those treated with radiation. This survey study examined the skin cancer surveillance behaviors of 94 CCS. Approximately 48% of CCS had ever conducted skin self-examination (SSE) and 31% had ever received a physician skin examination. Rates of physician skin examination were 2.5 times higher among CCS treated with radiation compared to those without radiation. However, rates of SSEs did not differ based on treatment history. These findings highlight the need to promote skin cancer surveillance as an important aspect of CCS survivorship care. |
Stadt UZ, Escherich G, Indenbirken D, Alawi M, Adao M, Horstmann MA |
Rapid Capture Next-Generation Sequencing in Clinical Diagnostics of Kinase Pathway Aberrations in B-Cell Precursor ALL. |
Pediatric blood & cancer 2016, 63: 1283 |
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Comprehensive next-generation sequencing (NGS) applications have recently identified various recurrent kinase and cytokine receptor rearrangements in Ph-like B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) amenable to tyrosin kinase inhibitor treatment. For rapid diagnostics of kinase pathway aberrations in minimal residual disease (MRD) high-risk BCP-ALL, we developed a PCR-independent NGS custom enrichment capture panel targeting recurrent genomic alterations, which allows for the identification of unknown 5' fusion partner genes and precise mapping of variable genomic breakpoints. Using a standardized bioinformatics algorithm, we identified kinase and cytokine receptor rearrangements in the majority of ALL patients with high burden of postinduction MRD and enrichment of IKZF1 mutation or deletion (IKZF1(del) ). |
von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM, Barnette P, Messina C, Michel G, DuBois SG, Hu K, Zhu M, Whitlock JA, Gore L |
Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016, 34: 4381 |
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Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m/d for the first 7 days, followed by 15 µg/m/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications. |
Stanulla M, Dagdan E, Zaliova M, Moericke A, Palmi C, Cazzaniga G, Eckert C, Te Kronnie G, Bourquin JP, Bornhauser B, Koehler R, Bartram CR, Ludwig WD, Bleckmann K, Groeneveld-Krentz S, Schewe D, Junk SV, Hinze L, Klein N, Kratz CP, Biondi A, Borkhardt A, Kulozik A, Muckenthaler MU, Basso G, Valsecchi MG, Izraeli S, Petersen BS, Franke A, Dörge P, Steinemann D, Haas OA, Panzer-Grümayer R, Cavé H, Houlston RS, Cario G, Schrappe M, Zimmermann M, TRANSCALL Consortium, International BFM Study Group |
IKZF1plus Defines a New Minimal Residual Disease-Dependent Very-Poor Prognostic Profile in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia. |
Journal of clinical oncology 2018, 36: 1240 |
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Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 ± 6% compared with 79 ± 5% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion ( P ≤ .001). Respective 5-year cumulative relapse incidence rates were 44 ± 6%, 11 ± 4%, and 10 ± 1% ( P ≤ .001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 ± 5% versus 40 ± 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients ( P ≤ .001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% ( P ≤ .001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BFM treatment is largely ineffective for MRD-positive IKZF1plus patients, new experimental treatment approaches will be evaluated in our upcoming trial AIEOP-BFM ALL 2017. |
Stanulla M, Kratz C |
Genetische Prädispositionen für Krebserkrankungen, in Niemeyer CH, Eggert A (Hrsg.): |
Pädiatrische Hämatologie und Onkologie 2018, 2. Aufl.: 169 |
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Zur Stadt U, Alawi M, Adao M, Indenbirken D, Escherich G, Horstmann MA |
Characterization of novel, recurrent genomic rearrangements as sensitive MRD targets in childhood B-cell precursor ALL. |
Blood cancer journal 2019, 9: 96 |
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B-cell precursor (BCP) ALL carry a variety of classical V(D)J rearrangements as well as genomic fusions and translocations. Here, we assessed the value of genomic capture high-throughput sequencing (gc-HTS) in BCP ALL (nâÃÂÃÂ=âÃÂÃÂ183) for the identification and implementation of targets for minimal residual disease (MRD) testing. For TRÃÂô, a total of 300 clonal rearrangements were detected in 158 of 183 samples (86%). Beside clonal VÃÂô2-DÃÂô3, DÃÂô2-DÃÂô3, and VÃÂô2-JÃÂñ we identified a novel group of recurrent DÃÂô-JÃÂñ rearrangements, comprising DÃÂô2 or DÃÂô3 segments fused predominantly to JÃÂñ29. For IGH-JH, 329 clonal rearrangements were identified in 172 of 183 samples (94%) including novel types of V(D)J joining. Oligoclonality was found in ~1/3 (nâÃÂÃÂ=âÃÂÃÂ57/183) of ALL samples. Genomic breakpoints were identified in 71 BCP-ALL. A distinct MRD high-risk subgroup of IGH-V(D)J-germline ALL revealed frequent deletions of IKZF1 (nâÃÂÃÂ=âÃÂÃÂ7/11) and the presence of genomic fusions (nâÃÂÃÂ=âÃÂÃÂ10/11). Quantitative measurement using genomic fusion breakpoints achieved equivalent results compared to conventional V(D)J-based MRD testing and could be advantageous upon persistence of a leukemic clone. Taken together, selective gc-HTS expands the spectrum of suitable MRD targets and allows for the identification of genomic fusions relevant to risk and treatment stratification in childhood ALL. |
Stachowicz-Stencel T, Synakiewicz A, Cornet M, Ferrari A, Garassino M, Masip JR, Julien R, Virgone C, Schneider DT, Brecht IB, Ben-Ami T, Bien E, Reguerre Y, Godzinski J, Bisogno G, Orbach D, Sarnacki S |
Thymoma and thymic carcinoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations. |
Pediatric blood & cancer 2021, 68 Suppl 4:e29042 |
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Thymic tumors are epithelial tumors arising from the anterior mediastinum and constitute 0.2-1.5% of all adult malignancies but are exceptional in pediatric population. Thymic epithelial tumors (TETs) encompass a variety of histologic subtypes associated with different clinical outcomes. Due to its rarity in children, TETs' management requires a multidisciplinary approach. However, prognosis remains still poor, especially among patients with thymic carcinoma. This study presents the internationally recognized recommendations for the diagnosis and treatment of thymic tumors in children and adolescents, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) group within the EU-funded project Paediatric Rare Tumours Network - European Registry (PARTNER). |
Stanulla M, Erdmann F, Kratz CP |
Risikofaktoren für Krebserkrankungen im Kindes- und Jugendalter. |
Monatsschrift Kinderheilkunde 169, 30-38 2021 |
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Stanulla M, Schewe DM, Bornhauser B, Bourquin JP, Eckert C, Eberl W, Wolf S, Wolf J, Vogiatzi F, Bergmann AK, Cario G, Beier R, Sauer M, Kratz CP, Maecker-Kolhoff B |
Molecular complete remission following combination treatment of daratumumab and venetoclax in an adolescent with relapsed mixed phenotype acute leukemia. |
Annals of hematology 2023, 102: 669 |
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Steinberg S, Hartmann R, Wisniewski S, Berger K, Beck J, Henze G |
Late sequelae of CNS recurrence of acute lymphoblastic leukemia in childhood. |
Klin Pädiatr 1998, 210: 200 |
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Steiner M, Burkart W, Grosche B, Kaletsch U, Michaelis J |
Trends in infant leukaemia in West Germany in relation to in utero exposure due to Chernobyl accident. |
Radiat Environ Biophys 1998, 37: 87 |
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Steinbach D, Dörffel W, Eggers G, Holfeld E, Kluba U, Krause I, Lauterbach I, Reiss T, Rieske K, Scharfe V, Schumacher R, Weigel H, Weinmann G, Zintl F, Hermann J |
Improved results in the treatment of acute myeloid leukemia - Results of study AML-BFM-93 in East Germany with comparisons to the preceding studies AML-I-82 and AML-II-87. |
Klin Pädiatr 2001, 213: 162 |
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Steinbach D, Hermann J, Littlewood T, Zintl F |
Risk group definition in children with acute myeloid leukemia by calculating individual risk factors on the basis of a multivariate stepwise Cox regression analysis. |
Leuk Lymphoma 2001, 42: 1289 |
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Steliarova-Foucher E, Berrino F, Coebergh J, Kaatsch P, Lacour B, Michaelis J, Mitlon N, Stiller C, Parkin D |
ACCISpass 1. 01, software for analysis and presentation of data on incidence and survival of children and adolescents in Europe. |
European Network of Cancer Registries 2002 |
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Steliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, Coebergh J, Lacour B, Parkin M |
Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since 1970s. |
Lancet 2004 |
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Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P |
International Classification of Childhood Cancer, third edition. |
Cancer 2005, 103: 1457 |
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BACKGROUND: The third edition of the International Classification of Diseases for Oncology (ICD-O-3), which was published in 2000, introduced major changes in coding and classification of neoplasms, notably for leukemias and lymphomas, which are important groups of cancer types that occur in childhood. This necessitated a third revision of the 1996 International Classification of Childhood Cancer (ICCC-3). METHODS: The tumor categories for the ICCC-3 were designed to respect several principles: agreement with current international standards, integration of the entities defined by newly developed diagnostic techniques, continuity with previous childhood classifications, and exhaustiveness. RESULTS: The ICCC-3 classifies tumors coded according to the ICD-O-3 into 12 main groups, which are split further into 47 subgroups. These 2 levels of the ICCC-3 allow standardized comparisons of the broad categories of childhood neoplasms in continuity with the previous classifications. The 16 most heterogeneous subgroups are broken down further into 2-11 divisions to allow study of important entities or homogeneous collections of tumors characterized at the cytogenetic or molecular level. Some divisions may be combined across the higher-level categories, such as the B-cell neoplasms within leukemias and lymphomas. CONCLUSIONS: The ICCC-3 respects currently existing international standards and was designed for use in international, population-based, epidemiological studies and cancer registries. The use of an international classification system is especially important in the field of pediatric oncology, in which the low frequency of cases requires rigorous procedures to ensure data comparability. |
Steliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, Coebergh JW, ACCIS Scientific Committee |
Trends in childhood cancer incidence in Europe, 1970-99. |
Lancet 2005, 365: 2088 |
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Steffens J, Treiyer A, Calaminus G |
[Management of pediatric testicular tumors : diagnosis, therapy, and follow-up]. |
Der Urologe. Ausg. A 2009, 48: 359 |
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Based on findings from the Prepubertal Testis Tumor Registry by the Urologic Section of the American Academy of Pediatrics and collaborative data in the literature, a modern algorithm for the surgical management of prepubertal testis tumors is presented. Following testicular surgery, patients with universally benign tumors, such as teratoma, may be released from oncological follow-up. Children with stage I yolk sac tumors should be monitored closely with periodic AFP tumor marker evaluation and imaging according to the primary dissemination (e.g., ultrasound, chest x-ray, and computed tomography). Patients with recurrent or metastatic yolk sac tumors should be treated with platinum-based chemotherapy and appropriate follow-up. Retroperitoneal lymph node dissection is not recommended except for patients with residual retroperitoneal masses following chemotherapy. Aggressive treatment is warranted for metastatic Sertoli cell and metastatic undifferentiated stromal tumors. |
Stegmaier S, Poremba C, Schaefer KL, Leuschner I, Kazanowska B, Békássy AN, Bielack SS, Klingebiel T, Koscielniak E |
Prognostic value of PAX-FKHR fusion status in alveolar rhabdomyosarcoma: A report from the cooperative soft tissue sarcoma study group (CWS). |
Pediatr Blood Cancer 2011, 57: 406 |
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BACKGROUND: Alveolar Rhabdomyosarcomas (RMA) are characterized by chromosomal translocations, fusing the PAX3 or PAX7 gene with FKHR in about 85%. Previous studies have suggested that the fusion type is associated with prognosis. In order to investigate the predictive value of the PAX-FKHR fusion status on disease outcome of patients with RMA treated in the CWS trials we performed a retrospective analysis.
PROCEDURE: Between 1986 and 2004, out of 446 patients with RMA treated in four consecutive CWS trials, tumor samples from 126 patients were available for RT-PCR analysis. Survival depending on fusion status in context with known clinical risk-factors was analyzed.
RESULTS: Out of 126 samples, 121 had adequate quality for PAX-FKHR fusion status analysis. PAX-FKHR fusions were detected in 101 samples: 60% PAX3-FKHR and 24% PAX7-FKHR fusions, 17% were fusion-negative. There was no significant difference in survival between patients with PAX3-FKHR versus PAX7-FKHR positive tumors. The fusion transcript negative cohort showed a more favorable outcome than the fusion transcript positive cohort among patients with metastatic disease. From the established clinical risk-factors none was associated with a significantly higher risk of failure or death in a multivariate analysis.
CONCLUSIONS: PAX-FKHR fusion type was not a significant predictor for survival in our analysis. More extensive molecular analyses are needed to identify features with prognostic relevance and useful therapeutic impact. Pediatr Blood Cancer © 2011 Wiley-Liss, Inc. |
Steinbach D, Wilhelm B, Kiermaier HR, Creutzig U, Schrappe M, Zimmermann M, Debatin KM, Gruhn B, von Stackelberg A, Jürgens H, Strahm B, Reinhardt D, Möricke A |
35. Long term survival in children with acute leukaemia and complications requiring mechanical ventilation. |
Arch Dis Child 2011, [Epub ahead of print] |
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Objective Previous reports have indicated that the short term prognosis for patients with malignant diseases and serious adverse events requiring mechanical ventilation (SAEV) is improving. The purpose of this study was to determine whether these patients can be cured of malignant disease or whether they survive SAEV only to subsequently relapse. Patients and methods The authors report the outcome of children with SAEV treated in the multicentre studies ALL-BFM 95 and AML-BFM 98. Data from 1182 patients with acute lymphoblastic leukaemia (ALL) and 334 patients with acute myeloid leukaemia (AML) were analysed. 88 patients (51 ALL and 37 AML) developed SAEV. Results The prognosis was almost identical in ALL and AML patients (survival of SAEV patients: 48%, 95% CI 38% to 58%; overall survival after 5 years: 31%, 95% CI 21% to 41%). Prognosis was independent of the time between leukaemia diagnosis and SAEV. Approximately 20% of children who required haemodialysis (n=14) or cardiac resuscitation (n=16) achieved long term survival, but no patient who fulfilled more than three of six identified risk factors (age ≥10 years, high risk leukaemia, C reactive protein ≥150 mg/l, administration of inotropic infusion, cardiac resuscitation and haemodialysis) survived (n=16; 0%, 95% CI 0% to 20%). Conclusions Intensive care improves the short and long term survival of children with leukaemia. 64% (95% CI 50% to 78%) of children with acute leukaemia who survived SAEV achieved long term survival. Prognosis mainly depends on age and leukaemia risk group. |
Steinlin M |
A clinical approach to arterial ischemic childhood stroke: increasing knowledge over the last decade. |
Neuropediatrics 2012, 43: 1 |
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Steinbach D, Bader P, Willasch A, Bartholomae S, Debatin KM, Zimmermann M, Creutzig U, Reinhardt D, Gruhn B |
Prospective validation of a new method of monitoring minimal residual disease in childhood acute myeloid leukemia. |
Clinical cancer research : an official journal of the American Association for Cancer Research 2014, epub ahead of print |
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Purpose: This study evaluated the prognostic impact of a novel, simple and standardized assay for monitoring minimal residual disease (MRD) in pediatric acute myeloid leukemia (AML). Experimental Design: The expression of seven leukemia associated genes (WT1, PRAME, CCL23, GAGED2, MSLN, SPAG6, ST18) was measured by TaqMan Low Density Arrays in 112 patients and 52 healthy controls. Patients were treated according to multicenter study AML-BFM 2004. Samples were collected prospectively at standard time points. The lab that measured MRD was blinded to patient outcome. Results: Relapse free survival (RFS) was 95% (N=19; SE=5%) if expression of all genes was down to normal on day15, 63% (N=41; SE=8%) if expression was normalized on day28, and 38% (N=21; SE=11%) in patients who still showed elevated expression on day28. The prognostic impact of MRD remained significant (p=0.002) when patients were stratified for AML-BFM 2004 risk group. Multivariate analysis identified MRD risk group and day28 cytology as the only independent prognostic factors. Patients with a cytological non-remission on day28 which was confirmed by MRD had a dismal prognosis. Only one out of eight patients survived without relapse. Conclusions: This novel method of monitoring MRD has a strong prognostic impact which is independent from established risk factors in childhood AML. |
Sterkenburg AS, Hoffmann A, Reichel J, Lohle K, Eveslage M, Warmuth-Metz M, Mueller HL |
Nuchal Skinfold Thickness: A Novel Parameter for Assessment of Body Composition in Childhood Craniopharyngioma. |
The Journal of clinical endocrinology and metabolism 2016, 101: 4922 |
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Hypothalamic obesity, cardiovascular disease (CVD), and relapse/progression have a major impact on prognosis in childhood-onset craniopharyngioma (CP). We analyzed nuchal skinfold thickness (NST) on magnetic resonance imaging performed for follow-up monitoring as a novel parameter for body composition (BC) and CVD in CP. |
Streetly A, Sisodia R, Dick M, Latinovic R, Hounsell K, Dormandy E |
Evaluation of newborn sickle cell screening programme in England: 2010-2016. |
Archives of disease in childhood 2017 |
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OBJECTIVE:
To evaluate England's NHS newborn sickle cell screening programme performance in children up to the age of 5 years.
DESIGN:
Cohort of resident infants with sickle cell disease (SCD) born between 1 September 2010 and 31 August 2015 and followed until August 2016.
PARTICIPANTS:
1317 infants with SCD were notified to the study from all centres in England and 1313 (99%) were followed up.
INTERVENTIONS:
Early enrolment in clinical follow-up, parental education and routine penicillin prophylaxis.
MAIN OUTCOME MEASURES:
Age seen by a specialist clinician, age at prescription of penicillin prophylaxis and mortality.
RESULTS:
All but two resident cases of SCD were identified through screening; one baby was enrolled in care after prenatal diagnosis; one baby whose parents refused newborn screening presented symptomatically. There were 1054/1313 (80.3%, 95% CI 78% to 82.4%) SCD cases seen by a specialist by 3 months of age and 1273/1313 (97%, 95% CI 95.9% to 97.8%) by 6 months. The percentage seen by 3 months increased from 77% in 2010 to 85.4% in 2015. 1038/1292 (80.3%, 95% CI 78.1% to 82.5%) were prescribed penicillin by 3 months of age and 1257/1292 (97.3%, 95% CI 96.3% to 98.1%) by 6 months. There were three SCD deaths <5 years caused by invasive pneumococcal disease (IPD) sensitive to penicillin.
CONCLUSION:
The SCD screening programme is effective at detecting affected infants. Enrolment into specialist care is timely but below the programme standards. Mortality is reducing but adherence to antibiotic prophylaxis remains important for IPD serotypes not in the current vaccine schedule. |
Stenzel E, Göricke S, Temming P, Biewald E, Zülow S, Göbel J, Wanke I, Umutlu L, Kleinschnitz C, Bornfeld N, Forsting M, Radbruch A, Mönninghoff C |
Feasibility of intra-arterial chemotherapy for retinoblastoma: experiences in a large single center cohort study. |
Neuroradiology 2019, 61: 351 |
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Steinbügl M, Nemes K, Johann P, Kröncke T, Tüchert S, da Costa MJG, Ebinger M, Schüller U, Sehested A, Hauser P, Reinhard H, Sumerauer D, Hettmer S, Jakob M, Hasselblatt M, Siebert R, Witt O, Gerss J, Kerl K, Frühwald MC |
Clinical evidence for a biological effect of epigenetically active decitabine in relapsed or progressive rhabdoid tumors. |
Pediatric blood & cancer 2021,:e29267 |
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Refined therapy has helped to improve survival rates in rhabdoid tumors (RT). Prognosis for patients with chemoresistant, recurrent, or progressive RT remains dismal. Although decitabine, an epigenetically active agent, has mainly been evaluated in the management of hematologic malignancies in adults, safety in children has also been demonstrated repeatedly. |
Stegmaier S, Sparber-Sauer M, Aakcha-Rudel E, Münch P, Reeh T, Feuchtgruber S, Hallmen E, Blattmann C, Bielack S, Klingebiel T, Koscielniak E |
Fusion transcripts as liquid biopsy markers in alveolar rhabdomyosarcoma and synovial sarcoma: A report of the Cooperative Weichteilsarkom Studiengruppe (CWS). |
Pediatric blood & cancer 2022, 69:e29652 |
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The possible application of gene fusion transcripts as tumor-specific noninvasive liquid biopsy biomarkers was investigated in blood plasma from patients with alveolar rhabdomyosarcoma (ARMS) and synovial sarcoma (SS). |
Stiller CA, Nectoux J |
International incidence of childhood brain and spinal tumours. |
Int J Epidemiol 1994, 23: 458 |
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Stöhr M, Brandt T, Einhäupl KM (Hrsg) |
Neurologische Syndrome in der Intensivmedizin. Differentialdiagnose und Akuttherapie. |
Kohlhammer Verlag 1190 |
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Stohr W, Langer T, Kremers A, Brecht I, Treuner J, Dinnesen A, Beck J |
Hearing function in soft tissue sarcoma patients after treatment with carboplatin. |
Oncology Reports 2004, 12: 767 |
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Stohr W, Langer T, Kremers A, Bielack S, Lamprecht-Dinnesen A, Frey E, Beck JD, German Late Effects Working Group in the German Society of Pediatric Oncology and Hematology |
Cisplatin-induced ototoxicity in osteosarcoma patients: a report from the late effects surveillance system. |
Cancer investigation 2005, 23: 201 |
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The aim of this study was to analyze cisplatin-induced ototoxicity in a recent study trial. Seventy-four patients who had received cisplatin for the treatment of osteosarcoma (median cumulative dose: 360 mg/m2) were investigated prospectively for ototoxicity in a multicenter trial. Hearing function was tested by audiometry. We evaluated the incidence and dependencies of hearing loss. After cessation of therapy, 51% of the patients showed a hearing loss of >20 dB in the frequency range of 4-8 kHz. Only in one patient a hearing loss was found at 2 kHz, and in none at 1 kHz. At a cumulative cisplatin dose of < or = 240 mg/m2, almost no ototoxicity was found. Incidence and magnitude of hearing loss increased significantly with a higher cumulative dose. Furthermore, hearing thresholds were significantly poorer in children <12 years. A further follow-up investigation showed only a marginal change in hearing function. We conclude that ototoxicity is moderate in our group of patients and probably irreversible. |
Stohr W, Paulides M, Brecht I, Kremers A, Treuner J, Langer T, Beck JD |
Comparison of epirubicin and doxorubicin cardiotoxicity in children and adolescents treated within the German Cooperative Soft Tissue Sarcoma Study (CWS). |
Journal of cancer research and clinical oncology 2006, 132: 35 |
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Purpose: Up to now, cardiotoxicity of epirubicin has been studied almost exclusively in adult cancer patients. The aim of this study was to investigate epirubicin in children and adolescents, in comparison with doxorubicin. Methods: About 172 soft tissue sarcoma patients (mean age at diagnosis: 8.3 years), treated with epirubicin (median cumulative dose: 450 mg/m(2)) or doxorubicin (median cumulative dose: 240 mg/m(2)) within the high-risk group of the CWS-96 study, were examined in a prospective multicentre study. Heart function was analysed by echocardiography, measuring left-ventricular fractional shortening (FS). The median follow up was 27.7 months. Results: Incidence of clinically manifest cardiomyopathy was 0% (0/60; 95% CI: 0-6.0%) in patients treated with epirubicin, and 0.9% (1/108; 95% CI: 0-5.1%) in patients treated with doxorubicin. A further three patients showed subclinical cardiomyopathy. There was no difference in FS between the two treatment arms. Conclusions: Cardiotoxicity was low in our study. For the short term, cardiotoxicity seems to be only a minor problem in patients treated with epirubicin as applied in this cohort. |
Stöhr W, Paulides M, Bielack S, Jürgens H, Treuner J, Rossi R, Langer T, Beck JD |
Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System. |
Pediatric blood & cancer 2007, 48: 447 |
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BACKGROUND: Ifosfamide is widely used in paediatric oncology, but its use is limited by nephrotoxic side effects. The aim of this study was to evaluate the incidence and risk factors of tubulopathy, with special emphasis on the influence of age, where different findings have been published so far. PROCEDURE: Five hundred ninety three children and adolescents treated for Ewing, osteo- or soft-tissue sarcoma (median age at diagnosis: 11.7 years) were prospectively investigated for nephrotoxicity in the Late Effects Surveillance System (LESS) study. Tubulopathy was diagnosed in case of continuing hypophosphatemia and proteinuria. RESULTS: After a median follow up of 19 months, 27 patients (4.6%; 95% CI: 3.0-6.6%) had newly developed tubulopathy. This incidence was 0.4% (95% CI: 0-2.4%) in patients treated with a cumulative ifosfamide dose of < or =24 g/m2, 6.5% (95% CI: 3.6-10.7%) after 24-60 g/m2, and 8.0% (95% CI: 4.2-13.6%) after > or = 60 g/m2. In multivariate analysis, children younger than 4 years at time of diagnosis had an 8.7-fold (95% CI: 3.5-21.8) higher risk for tubulopathy than older patients. Neither carboplatin treatment nor abdominal irradiation showed any significant influence. CONCLUSION: Ifosfamide-induced nephrotoxicity was found in 4.6% of patients. Risk factors were the cumulative ifosfamide dose and young age at treatment. |
Stöhr W, Paulides M, Bielack S, Jürgens H, Koscielniak E, Rossi R, Langer T, Beck JD |
Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system. |
Pediatric blood & cancer 2007, 48: 140 |
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BACKGROUND: Cisplatin and carboplatin are both nephrotoxic and can induce, to a different degree, impairment in glomerular function and hypomagnesemia. Prospective longitudinal studies on these renal impairments are rare in children and adolescents. PROCEDURE: Six hundred and fifty one sarcoma patients were investigated prospectively for nephrotoxicity in the Late Effects Surveillance System (LESS) network (median follow-up 2 years). Median cumulative dose was 360 mg/m(2) for cisplatin, and 1,500 mg/m(2) for carboplatin. Patients not treated with any platinum derivative were used as controls. Most patients (including controls) also received ifosfamide. Renal function was tested by serum magnesium, serum creatinine, and the GFR as estimated by the Schwartz formula. We evaluated incidence, dependencies, and the course of impairments. RESULTS: There was no observed platinum-induced reduction of glomerular function over time. After cessation of antineoplastic therapy, hypomagnesemia (<0.7 mmol/L) occurred in 12.1% (95% CI: 6.8%-19.4%) of patients after cisplatin therapy, and in 15.6% (95% CI: 5.3%-32.8%) after carboplatin therapy, in comparison with 4.5% (95% CI: 2.0%-8.7%) in patients without any treatment with platinum derivatives (P = 0.008). In all groups, the frequency of hypomagnesemia decreased with ongoing follow-up, but serum magnesium remained lower in platinum treated patients throughout the study period. CONCLUSION: Nephrotoxicity after treatment with cisplatin and carboplatin was mild in our study. Further studies have to show if serum magnesium is permanently decreased in platinum treated patients and if this will result in any clinically relevant impairment. |
Stokland T, Liu JF, Ironside JW, Ellison DW, Taylor R, Robinson KJ, Picton SV, Walker DA |
A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: a population-based cohort study (CCLG CNS9702). |
Neuro-oncology 2010, 12: 1257 |
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The purpose of this study was to identify risk factors for the progression of low-grade glioma in children from a large population-based cohort. Patient and tumor details of a national cohort of children with low-grade glioma, recruited into an international multidisciplinary clinical strategy, were subjected to univariate and multivariate analyses of progression-free survival and overall survival. From the cohort of 798 patients, 639 patients were eligible, with a median age 6.71 years (0.26-16.75 years); 49% were males; 15.9% had neurofibromatosis type 1, 63.7% pilocytic astrocytoma, 5.9% fibrillary astrocytoma, 4.2% mixed neuronal-glial tumors, and 3.6% others; 21.1% were diagnosed clinically. Anatomically implicated were 31.6% cerebellum, 24.6% chiasma/hypothalamus, 16.0% cerebral hemispheres, 9.9% brain stem, 6.1% other supratentorial midline structures, 5.9% optic nerve only, 4.5% spinal cord, and 1.4% others. The 5-year overall survival and progression-free survival in the whole cohort were 94.6% and 69.4%, respectively. There was a significant association between age and site (P < .001) and extent of tumor resection and site (P < .001). Multivariate analysis identified young age, fibrillary astrocytoma, and extent of surgical resection as significant independent risk factors for progression. Hypothalamic/chiasmatic tumors demonstrated the most sustained tendency to progress. In conclusion, the influence of age and anatomical site upon the risk of tumor progression suggests that these factors strongly influence tumor behavior for the majority of pilocytic tumors. Age <1 year and 1-5 years, fibrillary histology, completeness of resection, and chiasmatic location are candidates for stratification in future studies. |
Stoepker C, Hain K, Schuster B, Hilhorst-Hofstee Y, Rooimans MA, Steltenpool J, Oostra AB, Eirich K, Korthof ET, Nieuwint AW, Jaspers NG, Bettecken T, Joenje H, Schindler D, Rouse J, de Winter JP |
SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. |
Nat Genet 2011, 43: 138 |
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DNA interstrand crosslink repair requires several classes of proteins, including structure-specific endonucleases and Fanconi anemia proteins. SLX4, which coordinates three separate endonucleases, was recently recognized as an important regulator of DNA repair. Here we report the first human individuals found to have biallelic mutations in SLX4. These individuals, who were previously diagnosed as having Fanconi anemia, add SLX4 as an essential component to the FA-BRCA genome maintenance pathway. |
Stock A, Mynarek M, Pietsch T, Pfister SM, Clifford SC, Goschzik T, Sturm D, Schwalbe EC, Hicks D, Rutkowski S, Bison B, Pham M, Warmuth-Metz M |
Imaging Characteristics of Wingless Pathway Subgroup Medulloblastomas: Results from the German HIT/SIOP-Trial Cohort. |
AJNR 2019, 40: 1811 |
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In addition to the 4 histopathologically defined entities of medulloblastoma, 4 distinct genetically defined subgroups have been included in the World Health Organization classification of 2016. The smallest subgroup is the medulloblastoma with activated wingless pathway. The goal of this study was to identify a typical MR imaging morphology in a larger number of pediatric patients with wingless pathway medulloblastoma. |
Stockklausner C, Duffert CM, Cario H, Knöfler R, Streif W, Kulozik AE, THROMKID-Plus Studiengruppe der Gesellschaft für Thrombose- und Hämostaseforschung (GTH) and of Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) |
Thrombocytosis in children and adolescents-classification, diagnostic approach, and clinical management. |
Annals of hematology 2021, 100: 1647 |
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Secondary thrombocytosis is a frequent secondary finding in childhood infection and inflammation. Primary hereditary thrombocytosis may be caused by germline mutations within the genes encoding key regulators of thrombopoiesis, i.e., thrombopoietin (THPO) and its receptor c-MPL (MPL) or the receptor's effector kinase Januskinase2 (JAK2). Furthermore, somatic mutations in JAK2, MPL, and in the gene-encoding calreticulin (CALR) have been described to act as driver mutations within the so-called Philadelphia-negative myeloproliferative neoplasms (MPNs), namely essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Increasing knowledge on the molecular mechanisms and on the clinical complications of these diseases is reflected by the WHO diagnostic criteria and European LeukemiaNet (ELN) recommendations on the management of adult MPN. However, data on childhood thrombocytosis are rare, and no consensus guidelines for pediatric thrombocytosis exist. Current literature has highlighted differences in the epidemiology and molecular pathogenesis of childhood thrombocytosis as compared to adults. Furthermore, age-dependent complications and pharmacological specificities suggest that recommendations tailored to the pediatric population are necessary in clinical practice. Here we summarize literature on classification, diagnostics, and clinical management of childhood thrombocytosis. |
Stork T, Boemans R, Hardes J, Streitbürger A, Dirksen U, Pöttgen C, Schildhaus HU, Bauer S, Collaud S, Aigner C |
Number of metastases and their response to chemotherapy impact survival of patients with isolated lung metastases from bone-derived sarcoma. |
BMC cancer 2021, 21: 375 |
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Pulmonary metastasectomy (PM) is an established treatment for selected patients with metastatic sarcomas. The aim of this study was to examine our institutional experience and evaluate factors predicting outcome. |
Stock A, Hancken CV, Kandels D, Kortmann RD, Dietzsch S, Timmermann B, Pietsch T, Bison B, Schmidt R, Pham M, Gnekow AK, Warmuth-Metz M |
Pseudoprogression Is Frequent After Front-Line Radiation Therapy in Pediatric Low-Grade Glioma: Results From the German Low-Grade Glioma Cohort. |
International journal of radiation oncology, biology, physics 2022, 112: 1190 |
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Expansion of magnetic resonance imaging T2- or T1-tumor lesion volume after radiation therapy (RT) may indicate pseudoprogression (PsPD). The differentiation between true progression and PsPD is a clinical challenge and underinvestigated in pediatric low-grade glioma (LGG). We evaluated radiologic criteria for PsPD after front-line RT and investigated the frequency and duration of PsPD after 3 RT-modalities within the framework of the German pediatric multicenter LGG-studies. |
St Pierre TG, Clark PR, Chua-anusorn W, Fleming AJ, Jeffrey GP, Olynyk JK, Pootrakul P, Robins E, Lindeman R |
Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. |
Blood 2005, 105: 855 |
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Measurement of liver iron concentration (LIC) is necessary for a range of iron-loading disorders such as hereditary hemochromatosis, thalassemia, sickle cell disease, aplastic anemia, and myelodysplasia. Currently, chemical analysis of needle biopsy specimens is the most common accepted method of measurement. This study presents a readily available noninvasive method of measuring and imaging LICs in vivo using clinical 1.5-T magnetic resonance imaging units. Mean liver proton transverse relaxation rates (R2) were measured for 105 humans. A value for the LIC for each subject was obtained by chemical assay of a needle biopsy specimen. High degrees of sensitivity and specificity of R2 to biopsy LICs were found at the clinically significant LIC thresholds of 1.8, 3.2, 7.0, and 15.0 mg Fe/g dry tissue. A calibration curve relating liver R2 to LIC has been deduced from the data covering the range of LICs from 0.3 to 42.7 mg Fe/g dry tissue. Proton transverse relaxation rates in aqueous paramagnetic solutions were also measured on each magnetic resonance imaging unit to ensure instrument-independent results. Measurements of proton transverse relaxivity of aqueous MnCl2 phantoms on 13 different magnetic resonance imaging units using the method yielded a coefficient of variation of 2.1%. |
Strother D, Ashley D, Kellie SJ, Patel A, Jones-Wallace D, Thompson S, Heideman R, Benaim E, Krance R, Bowman L, Gajjar A |
Feasibility of four consecutive high-dose chemotherapy cycles with stem-cell rescue for patients with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: results of a collaborative study. |
J Clin Oncol 2001, 19: 2696 |
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PURPOSE: This study was designed to determine the feasibility and safety of delivering four consecutive cycles of high-dose cyclophosphamide, cisplatin, and vincristine, each followed by stem-cell rescue, every 4 weeks, after completion of risk-adapted craniospinal irradiation to children with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor (PNET). PATIENTS AND METHODS: Fifty-three patients, 19 with high-risk disease and 34 with average-risk disease, were enrolled onto this study. After surgical resection, high-risk patients were treated with topotecan in a 6-week phase II window followed by craniospinal radiation therapy and four cycles of high-dose cyclophosphamide (4,000 mg/m2 per cycle), with cisplatin (75 mg/m2 per cycle), and vincristine (two 1.5-mg/m2 doses per cycle). Support with peripheral blood stem cells or bone marrow and with granulocyte colony-stimulating factor was administered after each cycle of high-dose chemotherapy. Treatment of average-risk patients consisted of surgical resection and craniospinal irradiation, followed by the same chemotherapy given to patients with high-risk disease. The expected duration of the chemotherapy was 16 weeks, with a cumulative cyclophosphamide dose of 16,000 mg/m2 and a planned dose-intensity of 1,000 mg/m2/wk. RESULTS: Fifty of the 53 patients commenced high-dose chemotherapy, and 49 patients completed all four cycles. The median length of chemotherapy cycles one through four was 28, 27, 29, and 28 days, respectively. Engraftment occurred at a median of 14 to 15 days after infusion of stem cells or autologous bone marrow. The intended dose-intensity of cyclophosphamide was 1,000 mg/m2/wk; the median delivered dose-intensity was 1,014, 1,023, 974, and 991 mg/m2/wk for cycles 1 through 4, respectively; associated median relative dose-intensity was 101%, 102%, 97%, and 99%. No deaths were attributable to the toxic effects of high-dose chemotherapy. Early outcome analysis indicates a 2-year progression-free survival of 93.6% +/- 4.7% for the average-risk patients. For the high-risk patients, the 2-year progression-free survival is 73.7% +/- 10.5% from the start of therapy and 84.2% +/- 8.6% from the start of radiation therapy. CONCLUSION: Administering four consecutive cycles of high-dose chemotherapy with stem-cell support after surgical resection and craniospinal irradiation is feasible in newly diagnosed patients with medulloblastoma/supratentorial PNET with aggressive supportive care. The early outcome results of this approach are very encouraging |
Sträter R, Becker S, von Eckardstein A, Heinecke A, Gutsche S, Junker R, Kurnik K, Schobess R, Nowak-Göttl U |
Prospective assessment of risk factors for recurrent stroke during childhood--a 5-year follow-up study. |
Lancet 2002 Nov 16; 360: 1540 |
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Streif W, Knöfler R, Eberl W |
Inherited disorders of platelet function in pediatric clinical practice: a diagnostic challenge. |
Klinische Padiatrie 2010, 222: 203 |
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Hereditary disorders of platelet function are a heterogeneous group of diseases that are often complex and tend to go undetected until clinically relevant bleeding occurs. Hallmarks are epistaxis, easy bruising, mucous membrane bleeding, perioperative bleeding and menorrhagia. Bleeding may be intermittent and unpredictable. After decades of successful research on platelet biology and genetics, research findings have not been satisfactorily translated to clinical practice. The lack of robust and well- standardized test systems continues to make the diagnosis of platelet defects cumbersome for the practising clinician. Patient history and description of clinical bleeding symptoms are essential. Exclusion of von Willebrand disease, platelet count and investigation of blood smears may provide a tentative diagnosis. Light transmission aggregometry is still considered the gold standard for assessing platelet function. Due to the wide range of possible genetic defects molecular biological analyses can complement but do not substitute for other tests. The true incidence of inherited disorders of platelet function is unknown. A survey in Germany revealed that receptor-defects including Glanzmann's thrombasthenia and Bernard-Soulier syndrome and aspirin-like defects were the most frequently diagnosed platelet disorders. Of affected children 60% presented with mild and 40% with moderate to severe bleeding tendency. Epistaxis, cutaneous and mucous membrane bleeding were the most frequent symptoms. The paediatric competence network of the GTH e.V. comprises 44 collaborating centres that are caregivers to over 150 children with well-defined inherited platelet defects. A major goal of this network is to promote diagnosis of children with inherited disorders of platelet function. |
Strahm B, Nöllke P, Zecca M, Korthof ET, Bierings M, Furlan I, Sedlacek P, Chybicka A, Schmugge M, Bordon V, Peters C, O'Marcaigh A, de Heredia CD, Bergstraesser E, Moerloose BD, van den Heuvel-Eibrink MM, Starý J, Trebo M, Wojcik D, Niemeyer CM, Locatelli F, EWOG-MDS study group |
Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome in children: results of the EWOG-MDS 98 study. |
Leukemia 2011, 25: 455 |
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We report on the outcome of children with advanced primary myelodysplastic syndrome (MDS) transplanted from an HLA-matched sibling (MSD) or an unrelated donor (UD) following a preparative regimen with busulfan, cyclophosphamide and melphalan. Ninety-seven patients with refractory anemia with excess blasts (RAEB, n=53), RAEB in transformation (RAEB-T, n=29) and myelodysplasia-related acute myeloid leukemia (MDR-AML, n=15) enrolled in the European Working Group of MDS in Childhood (EWOG-MDS) 98 study and given hematopoietic stem cell transplantation (HSCT) were analyzed. Median age at HSCT was 11.1 years (range 1.4-19.0). Thirty-nine children were transplanted from an MSD, whereas 58 were given the allograft from a UD (n=57) or alternative family donor (n=1). Stem cell source was bone marrow (n=69) or peripheral blood (n=28). With a median follow-up of 3.9 years (range 0.1-10.9), the 5-year probability of overall survival is 63%, while the 5-year cumulative incidence of transplantation-related mortality (TRM) and relapse is 21% each. Age at HSCT greater than 12 years, interval between diagnosis and HSCT longer than 4 months, and occurrence of acute or extensive chronic graft-versus-host disease were associated with increased TRM. The risk of relapse increased with more advanced disease. This study indicates that HSCT following a myeloablative preparative regimen offers a high probability of survival for children with advanced MDS. |
Strahm B, Nöllke P, Zecca M, Korthof ET, Bierings M, Furlan I, Sedlacek P, Chybicka A, Schmugge M, Bordon V, Peters C, O'Marcaigh A, de Heredia CD, Bergstraesser E, Moerloose BD, van den Heuvel-Eibrink MM, Starý J, Trebo M, Wojcik D, Niemeyer CM, Locatelli F, EWOG-MDS study group |
Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome in children: results of the EWOG-MDS 98 study. |
Leukemia 2011, 25: 455 |
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We report on the outcome of children with advanced primary myelodysplastic syndrome (MDS) transplanted from an HLA-matched sibling (MSD) or an unrelated donor (UD) following a preparative regimen with busulfan, cyclophosphamide and melphalan. Ninety-seven patients with refractory anemia with excess blasts (RAEB, n=53), RAEB in transformation (RAEB-T, n=29) and myelodysplasia-related acute myeloid leukemia (MDR-AML, n=15) enrolled in the European Working Group of MDS in Childhood (EWOG-MDS) 98 study and given hematopoietic stem cell transplantation (HSCT) were analyzed. Median age at HSCT was 11.1 years (range 1.4-19.0). Thirty-nine children were transplanted from an MSD, whereas 58 were given the allograft from a UD (n=57) or alternative family donor (n=1). Stem cell source was bone marrow (n=69) or peripheral blood (n=28). With a median follow-up of 3.9 years (range 0.1-10.9), the 5-year probability of overall survival is 63%, while the 5-year cumulative incidence of transplantation-related mortality (TRM) and relapse is 21% each. Age at HSCT greater than 12 years, interval between diagnosis and HSCT longer than 4 months, and occurrence of acute or extensive chronic graft-versus-host disease were associated with increased TRM. The risk of relapse increased with more advanced disease. This study indicates that HSCT following a myeloablative preparative regimen offers a high probability of survival for children with advanced MDS. |
Strouse JJ, Heeney MM |
Hydroxyurea for the treatment of sickle cell disease: efficacy, barriers, toxicity, and management in children. |
Pediatric blood & cancer 2012, 59: 365 |
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Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on-going and planned studies in children. |
Streif W, Knöfler R, Eberl W, Andres O, Bakchoul T, Bergmann F, Beutel K, Dittmer R, Gehrisch S, Gottstein S, Halimeh S, Haselböck J, Hassenpflug WA, Heine S, Holzhauer S, King S, Kirchmaier CM, Krause M, Kreuz W, Lösche W, Mahnel R, Maurer M, Nimtz-Talaska A, Olivieri M, Rott H, Schambeck ChM, Schedel A, Schilling FH, Schmugge M, Schneppenheim R, Scholz U, Scholz T, Schulze H, Siegemund A, Strauß G, Sykora KW, Wermes C, Wiegering V, Wieland I, Zieger B, Zotz RB, Paediatric Committee of the Society of Thrombosis and Haemostasis Research |
[Therapy of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. |
Hamostaseologie 2014, 34: 269-75, quiz 276 |
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Inherited disorders of platelet function are a heterogeneous group. For optimal prevention and management of bleeding, classification and diagnosis of the underlying defect are highly recommended. An interdisciplinary guideline for a diagnostic approach has been published (AWMF # 086-003 S2K; Hämostaseologie 2014; 34: 201-212). Underlying platelet disorder, platelet count, age and clinical situation modify treatment. Exclusive transfusion of platelet concentrates may be inappropriate as potentially adverse effects can outweigh its benefit. A stepwise and individually adjusted approach for restitution and maintenance of haemostasis is recommended. Administration of antifibrinolytics is generally endorsed, but is of particular use in Quebec disease. Restricted to older children, desmopressin is favourable in storage pool disease and unclassified platelet disorders. Although licensed only for patients with Glanzmann thrombasthenia and alloantibodies, in clinical practice rFVIIa is widely used in inherited platelet disorders with severe bleeding tendency. This guideline aims at presenting the best available advice for the management of patients with inherited platelet function disorders. |
Streif W, Knöfler R |
S2k-Leitlinie: Diagnose von Thrombozytenfunktionsstörungen - Thrombozytopathien. |
AWMF-Registernummer 086-003 Stand Februar 2018 |
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Streif W, Knöfler R, Meyer O |
S2k-Leitlinie: Therapie angeborener thrombozytärer Erkrankungen. |
AWMF-Registernummer 086-004 Stand April 2020 |
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Strahm B, Loewecke F, Niemeyer CM, Albert M, Ansari M, Bader P, Bertrand Y, Burkhardt B, Da Costa LM, Ferster A, Fischer A, Güngör T, Gruhn B, Hainmann I, Kapp F, Lang P, Müller I, Schulz A, Szvetnik A, Wlodarski M, Noellke P, Leblanc T, Dalle JH |
Favorable outcomes of hematopoietic stem cell transplantation in children and adolescents with Diamond-Blackfan anemia. |
Blood advances 2020, 4: 1760 |
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Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia associated with congenital abnormalities and cancer predisposition. Allogeneic hematopoietic stem cell transplantation (HSCT) can correct the hematological phenotype and is indicated in transfusion-dependent patients. In 70 children reported to the German DBA and French HSCT registries, HSCT was performed from 1985 to 2017. Median age at HSCT was 5.5 years (range, 0.9-17.3 years). Two-thirds of patients (64%) were transplanted from a matched sibling donor (MSD), and most procedures were performed after the year 1999 (73%). Primary engraftment was achieved in all patients. One patient developed secondary graft failure. Cumulative incidence of acute graft-versus-host disease (GVHD) was 24% for °II-IV (95% confidence interval [CI], 16% to 37%) and 7% for °III-IV (95% CI, 3% to 17%); cumulative incidence of chronic GVHD was 11% (95% CI, 5% to 22%). The probability of chronic GVHD-free survival (cGFS) was 87% (95% CI, 79% to 95%) and significantly improved over time (<2000: 68% [95% CI, 47% to 89%] vs ≥2000: 94% [95% CI, 87% to 100%], P < .01). cGFS was comparable following HSCT from a MSD and an unrelated donor (UD). Of note, no severe chronic GVHD or deaths were reported following MSD-HSCT after 1999. The difference of cGFS in children transplanted <10 years of age compared with older patients did not reach statistical significance (<10 years: 90% [95% CI, 81% to 99%] vs 10-18 years 78% [95% CI, 58% to 98%]). In summary, these data indicate that HSCT is efficient and safe in young DBA patients and should be considered if a MSD or matched UD is available. HSCT for transfusion dependency only must be critically discussed in older patients. |
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group |
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. |
N Engl J Med 2005, 352: 987 |
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Stutterheim J, Gerritsen A, Zappeij-Kannegieter L, Kleijn I, Dee R, Hooft L, van Noesel MM, Bierings M, Berthold F, Versteeg R, Caron HN, van der Schoot CE, Tytgat GA |
PHOX2B is a novel and specific marker for minimal residual disease testing in neuroblastoma. |
Journal of clinical oncology 2008, 26: 5443 |
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PURPOSE: Polymerase chain reaction (PCR)-based detection of minimal residual disease (MRD) in neuroblastoma can be used to monitor therapy response and to evaluate stem cell harvests. Commonly used PCR markers, tyrosine hydroxylase (TH) and GD2 synthase, have expression in normal tissues, thus limiting MRD detection. To identify a more specific MRD marker, we tested PHOX2B. PATIENTS AND METHODS: To determine PHOX2B, TH, and GD2 synthase expression in normal tissues, it was measured by real-time quantitative PCR in samples of normal bone marrow (BM; n = 51), peripheral blood (PB; n = 37), and peripheral-blood stem cells (PBSCs; n = 24). Then, 289 samples of 101 Dutch patients and 47 samples of 43 German patients were tested for PHOX2B and TH; these samples included 52 tumor, 214 BM, 32 BM, and 38 PBSC harvests. Of the 214 BM samples, 167 were compared with cytology, and 47 BM samples were compared with immunocytology (IC). RESULTS: In contrast to TH and GD2 synthase, PHOX2B was not expressed in any of the normal samples. In patient samples, PHOX2B was detected in 32% cytology-negative and in 14% IC-negative samples and in 94% of cytology-positive and in 90% of IC-positive BM samples. Overall, PHOX2B was positive in 43% compared with 31% for TH. In 24% of all samples, TH expression was inconclusive, which is similar to expression found in normal tissues. In 42% of these samples, PHOX2B expression was positive. CONCLUSION: PHOX2B is superior to TH and GD2 synthase in specificity and sensitivity for MRD detection of neuroblastoma by using real-time quantitative PCR. We propose to include PHOX2B in additional prospective MRD studies in neuroblastoma alongside TH and other MRD markers. |
Stutterheim J, Gerritsen A, Zappeij-Kannegieter L, Yalcin B, Dee R, van Noesel MM, Berthold F, Versteeg R, Caron HN, van der Schoot CE, Tytgat GA |
Detecting minimal residual disease in neuroblastoma: the superiority of a panel of real-time quantitative PCR markers. |
Clinical chemistry 2009, 55: 1316 |
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BACKGROUND: PCR-based detection of minimal residual disease (MRD) in neuroblastoma (NB) patients can be used for initial staging and monitoring therapy response in bone marrow (BM) and peripheral blood (PB). PHOX2B has been identified as a sensitive and specific MRD marker; however, its expression varies between tumors. Therefore, a panel of markers could increase sensitivity. METHODS: To identify additional MRD markers for NB, we selected genes by comparing SAGE (serial analysis of gene expression) libraries of healthy and NB tissues followed by extensive real-time quantitative PCR (RQ-PCR) testing in samples of tumors (n = 56), control BM (n = 51), PB (n = 37), and cell subsets. The additional value of a panel was determined in 222 NB samples from 82 Dutch stage 4 NB patients (54 diagnosis BM samples, 143 BM samples during/after treatment, and 25 PB samples). RESULTS: We identified 2 panels of specific RQ-PCR markers for MRD detection in NB patients: 1 for analysis of BM samples (PHOX2B, TH, DDC, CHRNA3, and GAP43) and 1 for analysis of PB samples (PHOX2B, TH, DDC, DBH, and CHRNA3). These markers all showed high expression in NB tumors and no or low expression in control BM or PB samples. In patients' samples, the PHOX2B marker detected most positive samples. In PB samples, however, 3 of 7 PHOX2B-negative samples were positive for 1 or more markers, and in BM examinations during treatment, 7% (6 of 86) of the PHOX2B-negative samples were positive for another marker. CONCLUSIONS: Because of differences in the sensitivities of the markers in BM and PB, we advise the use of 2 different panels to detect MRD in these compartments. |
Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tönjes M, Sill M, Bender S, Kool M, Zapatka M, Becker N, Zucknick M, Hielscher T, Liu XY, Fontebasso AM, Ryzhova M, Albrecht S, Jacob K, Wolter M, Ebinger M, Schuhmann MU, van Meter T, Frühwald MC, Hauch H, Pekrun A, Radlwimmer B, Niehues T, von Komorowski G, Dürken M, Kulozik AE, Madden J, Donson A, Foreman NK, Drissi R, Fouladi M, Scheurlen W, von Deimling A, Monoranu C, Roggendorf W, Herold-Mende C, Unterberg A, Kramm CM, Felsberg J, Hartmann C, Wiestler B, Wick W, Milde T, Witt O, Lindroth AM, Schwartzentruber J, Faury D, Fleming A, Zakrzewska M, Liberski PP, Zakrzewski K, Hauser P, Garami M, Klekner A, Bognar L, Morrissy S, Cavalli F, Taylor MD, van Sluis P, Koster J, Versteeg R, Volckmann R, Mikkelsen T, Aldape K, Reifenberger G, Collins VP, Majewski J, Korshunov A, Lichter P, Plass C, Jabado N, Pfister SM |
Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. |
Cancer cell 2012, 22: 425 |
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Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins. |
Stutterheim J, de Lorenzo P, van der Sluis IM, Alten J, Ancliffe P, Attarbaschi A, Aversa L, Boer JM, Biondi A, Brethon B, Diaz P, Cazzaniga G, Escherich G, Ferster A, Kotecha RS, Lausen B, Leung AW, Locatelli F, Silverman L, Stary J, Szczepanski T, van der Velden VHJ, Vora A, Zuna J, Schrappe M, Valsecchi MG, Pieters R |
Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol. |
European journal of cancer 2022, 160: 72 |
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The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study. |
Stutterheim J, de Lorenzo P, van der Sluis IM, Alten J, Ancliffe P, Attarbaschi A, Aversa L, Boer JM, Biondi A, Brethon B, Diaz P, Cazzaniga G, Escherich G, Ferster A, Kotecha RS, Lausen B, Leung AW, Locatelli F, Silverman L, Stary J, Szczepanski T, van der Velden VHJ, Vora A, Zuna J, Schrappe M, Valsecchi MG, Pieters R |
Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol. |
European journal of cancer (Oxford, England : 1990) 2022, 160: 72 |
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The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study. |
Stöhr W, Langer T, Kremers A, Bielack S, Dinnesen A, Frey E, Beck J |
Cisplatin-induced Ototoxicity in Osteosarcoma Patients. |
Cancer Investigation 2004,in press |
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Suarez F, Mahlaoui N, Canioni D, Andriamanga C, Dubois d'Enghien C, Brousse N, Jais JP, Fischer A, Hermine O, Stoppa-Lyonnet D |
Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2015 Jan 10; 33: 202 |
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Biallelic mutations in ATM cause ataxia-telangiectasia (AT), a rare inherited disease with a high incidence of cancer. Precise estimates of the risk, presentation, and outcomes of cancer in patients with AT need to be addressed in large series. |
Subbiah V, Ketonen L, Bruner JM, Nunez R, Weinberg J, Wolff JE |
99mTc-sestamibi scan differentiates tumor from other contrast enhancing tissue in choroid plexus tumors. |
J Clin Onco 2010, 32: 160 |
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Choroid plexus tumors are rare brain tumors which account for 0.4% to 0.6% among brain tumors. Tumor resection is known to be of large prognostic impact, and re-resection of residual tumors is a part of standard care. However, after multiple resections it can become difficult to differentiate tumor from reactive tissue. 99mTC-sestamibi scans may assist in differentiating neoplastic (99mTC-sestamibi positive) from non-neoplastic tissue (99mTC-sestamibi negative). Previous literature showed sestamibi to be helpful in detecting residual choroid plexus tumors resulting in further resection. Here, we report the first case to show that sestamibi scans can also help with the opposite decision. |
Sudbrock F, Schmidt M, Simon T, Eschner W, Berthold F, Schicha H |
Dosimetry for (131)I-MIBG therapies in metastatic neuroblastoma, phaeochromocytoma and paraganglioma. |
European journal of nuclear medicine and molecular imaging 2010, |
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PURPOSE: Radiation dosimetry is a basic requirement for targeted radionuclide therapies (TRT) which have become of increasing interest in nuclear medicine. Despite the significant role of the radiopharmaceutical (131)I-metaiodobenzylguanidine (MIBG) for the treatment of metastatic neuroblastoma, phaeochromocytoma and paraganglioma details for a reliable dosimetry are still sparse. This work presents our procedures, the dosimetric data and experiences with TRT using (131)I-MIBG. METHODS: A total of 21 patients were treated with (131)I-MIBG between 2004 and 2008 according to a clearly defined protocol. Whole-body absorbed doses were determined by a series of scintillation probe readings for all 21 cases. Tumour absorbed doses were calculated on the basis of quantitative imaging for an entity of 25 lesions investigated individually using the region of interest (ROI) technique based on five scans each. RESULTS: Typical whole-body absorbed doses are found in the region of 2 Gy (range: 1.0-2.9 Gy) whereas tumour absorbed doses in turn cover a span between 10 and 60 Gy. Nonetheless this variation of tumour absorbed doses is comparatively low. CONCLUSION: The trial protocol in use is a substantial advancement in terms of reliable dosimetry. A clearly defined modus operandi for MIBG therapies should involve precisely described dosimetric procedures, e.g. a minimum of 20 whole-body measurements using a calibrated counter and at least four gamma camera scans over the whole period of the inpatient stay should be carried out. Calculation of tumour volumes is accomplished best via evaluation of SPECT and CT images. |
Surico G, Muggeo P, Rigillo N, Gadner H |
Concurrent Langerhans cell histiocytosis and myelodysplasia in children. |
Med Pediatr Oncol 2000, 35: 421 |
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Surun A, Schneider DT, Ferrari A, Stachowicz-Stencel T, Rascon J, Synakiewicz A, Agaimy A, Martinova K, Kachanov D, Roganovic J, Bien E, Bisogno G, Brecht IB, Kolb F, Thariat J, Moya-Plana A, Orbach D |
Salivary gland carcinoma in children and adolescents: The EXPeRT/PARTNER diagnosis and treatment recommendations. |
Pediatric blood & cancer 2021, 68 Suppl 4:e29058 |
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Salivary gland carcinomas (SGCs) are rare during childhood and adolescence. Consequently, no standardized recommendations for the diagnosis and therapeutic management of pediatric SGC are available, and pediatric oncologists and surgeons generally follow adult guidelines. Complete surgical resection with adequate margins constitutes the cornerstone of treatment. However, the indications and modalities of adjuvant therapy remain controversial and may be challenging in view of the potential long-term toxicities in the pediatric population. This paper presents the consensus recommendations for the diagnosis and treatment of children and adolescents with SGCs, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER project (Paediatric Rare Tumours Network - European Registry). |
Sutor A, Niemeyer C, Sauter S, Witt I, Kaufmehl K, Rombach A, Brandis M, Riehm H |
Changes in blood coagulation in treatment with ALL-BFM-90 and NHL-BFM-90 protocols. |
Klin Pädiatr 1992, 204: 264 |
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Sutton LN, Molloy PT, Sernyak H, Goldwein J, Phillips PL, Rorke LB, Moshang T Jr, Lange B, Packer RJ |
Long-term outcome of hypothalamic/chiasmatic astrocytomas in children treated with conservative surgery. |
J Neurosurg 1995, 83: 583 |
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Sutor AH |
Abklärung einer Blutungsneigung. |
Hämostaseologie 2010, 20: 1 |
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Diagnostische Schwerpunkte sind eine ausführliche Anamnese und sorgfältige klinische Untersuchung. Die Familien- und die Eigenanamnese geben wichtige Hinweise auf hereditäre Blutungsdiathesen. Das Alter bei der Erstmanifestation, die Lokalisation, die Art und der Zeitpunkt der Blutung ermöglichen oft eine Verdachtsdiagnose. Eine Kombination von In-vivo-Testen, wie die Blutungszeit, die vor allem Störungen der primären Hämostase erfaßt, und von In-vitro-Testen, wie die aPTT und die PT, kann die Diagnose weitgehend einengen. Die Kenntnis des Informationswertes dieser Übersichtsteste ermöglicht eine gezielte Auswahl von Spezial-Testen (Einzelfaktoren, Plättchenfunktionsteste, Von-Willebrand-Faktor), mit denen die endgültige Diagnose gestellt werden kann. Eine primäre Labordiagnostik ist nicht zu empfehlen. Sie erfordert viel Blut, verursacht unnötig hohe Kosten und kann in Unkenntnis von Anamnese und Klinik sowie von alters- und situationsbedingten Veränderungen sogar zu Fehldiagnosen führen. |
Sutor AH |
Thrombocytosis in children. |
Semin Thromb Hemost 1995; 21(3): 330-339 1995, 21: 330 |
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Until recently, thrombocytoses in childhood were considered to be rare. The literature on this subject is scarce and contradictory. When thrombocytosis is defined as a platelet count of more than 500 × 109/L (500 000/mm3 or 500 000/μL), the occurrence in routine examinations at pediatric hospitals can be estimated as 3 to 13%. These are almost exclusively secondary thrombocytoses, which are the result of infections (most frequently), trauma and surgery, hypoxemia, immunologic disturbances, premature birth, gastrointestinal disorders, medications, stress situations, or previous loss of platelets. The secondary thrombocytosis usually has less than 800 × 109/L platelets, is temporary, and occurs predominantly in infants and young children. If only thrombocytosis is present, thrombotic complications are practically nonexistent. Antithrombotic prophylaxis is not necessary unless other risk factors for thrombosis are present, such as vessel damage, permanent iron deficiency, hyperviscosity, immobilization. Primary thrombocytoses due to a defect of stem cells are extremely infrequent in childhood. |
Suttorp M, Millot F |
Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation. |
Hematology 2010, 368 |
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Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the only proven cure for chronic myeloid leukemia (CML), a rare malignancy in childhood. With the excellent results induced by the tyrosine kinase inhibitor (TKI) imatinib in adults in the last decade, the appropriate management of children with CML has also changed radically, and only a minority are now transplanted as a front-line treatment. Data on pediatric experiences with imatinib in CML from controlled trials remain very limited, but this review of available data describes the role of imatinib in children with CML, addressing: 1) the starting dose; 2) pharmacokinetics in childhood; 3) possible adverse effects, with a focus on the still-growing skeleton; 4) early monitoring of treatment efficacy in an attempt to avoid failure; 5) the timing of allo-SCT in children; and 6) treatment of CML relapse after allo-SCT. Because the characteristics of CML in children seem to overlap extensively with what is described in adult internal medicine, most answers and pediatric algorithms are adapted from the treatment of CML in adults. Today in 2010, allo-SCT in children should be postponed until CML becomes refractory to imatinib. The approach for young patients with suboptimal responses is unclear because data on the efficacy and safety of second-generation TKIs in childhood are almost entirely missing. Other than being included in a formal trial on second-generation TKIs, allo-SCT for patients failing imatinib remains the first choice. |
Suttorp M, Yaniv I, Schultz KR |
Controversies in the treatment of CML in children and adolescents: TKIs versus BMT? |
Biology of blood and marrow transplantation 2011, 17(1 Suppl):S115 |
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Chronic myeloid leukemia (CML) is a relatively rare hematopoietic malignancy in the pediatric and adolescent population. This makes it difficult to perform clinic trials that can define the best therapeutic option when considering the impact of tyrosine kinase inhibitors (TKIs) versus the established approach of allogeneic hematopoietic cell transplantation (HCT). With the relatively low toxicity of TKIs, there are little data regarding when HCT or long-term TKI therapy is a better option. There are even less data regarding the duration of TKI treatment in the pediatric CML in chronic phase (CML-CP) patients who may receive over 60 years of therapy. As children and adolescent are treated for longer times with TKIs, it has become clear that toxicities may make long-term TKI therapy less attractive compared to allogeneic HCT. HCT has the long-term complications of growth failure, infertility, chronic graft-versus-host disease (GVHD), metabolic syndrome, and secondary malignancies, whereas prolonged TKIs may cause growth failure, hepatic, and cardiac complications. Moreover, HCT is a potentially curative intervention, whereas TKI is not curative, requiring prolonged exposure. In this article, we discuss the relative merit of the 2 therapeutic approaches and recommend that all children and adolescents with CML-CP should initially be treated with imatinib and maintained with TKI therapy indefinitely if there is a good response. We recommend that allogeneic HCT with an HLA-identical sibling donor or closely matched unrelated donor be considered for patients with treatment failure or recurrence after receiving salvage second-generation TKI treatment. We also conclude that randomized international trials are urgently needed to evaluate the best therapies for pediatric CML. |
Suttorp M, Eckardt L, Tauer JT, Millot F |
Management of chronic myeloid leukemia in childhood. |
Current hematologic malignancy reports 2012, 7: 116 |
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Childhood chronic myelogenous leukemia (CML) is a rare malignancy, and experience with optimal treatment is very limited. Traditionally, allogeneic hematopoietic stem cell transplantation was considered the only curative treatment. Imatinib, a small-molecule inhibitor of the BCR-ABL tyrosine kinase (TKI), has been proven highly successful in adults with CML, resulting in prolonged molecular response with limited drug toxicity. This drug is now included as front-line therapy for CML in pediatrics as well, though valid concerns about serious late sequelae remain unresolved. Specific pediatric treatment guidelines have not yet been formulated, and most algorithms are derived from experience in adult CML. This overview attempts to summarize pediatric studies on issues such as dose, duration, adverse effects, and steering criteria for TKI treatment, adapting guidelines developed in adult medicine to pediatrics. Most importantly, pediatric patients with CML receiving TKI treatment should be enrolled into formal trials. |
Suttorp M, Schulze P, Glauche I, Gaehring G, von Neuhoff N, Metzler M, Sedlacek P, de Bont ESJM, Balduzzi A, Lausen B, Aleinikova O, Sufliarska S, Henze G, Strauss G, Eggert A, Kremens B, Groll AH, Berthold F, Klein C, GroÃ-Wieltsch U, Sykora KW, Borkhardt A, Kulozik AE, Schrappe M, Nowasz C, Krumbholz M, Tauer JT, Claviez A, Harbott J, Kreipe HH, Schlegelberger B, Thiede C |
Front-line imatinib treatment in children and adolescents with chronic myeloid leukemia: results from a phase III trial. |
Leukemia 2018, ePup ahead of print |
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A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m2, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective. |
Suttorp M, Bornhäuser M, Metzler M, Millot F, Schleyer E |
Pharmacology and pharmacokinetics of imatinib in pediatric patients. |
Expert review of clinical pharmacology 2018, 11: 219 |
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The tyrosine kinase inhibitor (TKI) imatinib was rationally designed to target BCR-ABL1 which is constitutively activated in chronic myeloid leukemia (CML). Following the tremendous success in adults, imatinib also became licensed for treatment of CML in minors. The rarity of pediatric CML hampers the conduction of formal trials. Thus, imatinib is still the single TKI approved for CML treatment in childhood. Areas covered: This review attempts to provide an overview of the literature on pharmacology, pharmacokinetic, and pharmacogenetic of imatinib concerning pediatric CML treatment. Articles were identified through a PubMed search and by reviewing abstracts from relevant hematology congresses. Additional information was provided from the authors' libraries and expertise and from our own measurements of imatinib trough plasma levels in children. Pharmacokinetic variables (e.g. alpha 1-acid glycoprotein binding, drug-drug/food-drug interactions via cytochrome P450 3A4/5, cellular uptake mediated via OCT-1-influx variations and P-glycoprotein-mediated drug efflux) still await to be addressed in pediatric patients systematically. Expert commentary: TKI response rates vary among different individuals and pharmacokinetic variables all can influence CML treatment success. Adherence to imatinib intake may be the most prominent factor influencing treatment outcome in teenagers thus pointing towards the potential benefits of regular drug monitoring. |
Suttorp M |
Chronische myeloische Leukämie, in: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie. |
Springer-Verlag GmbH Deutschland, 2. vollständig überarbeitete Auflage 2018, 303 |
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Suttorp M, Metzler M, Millot F, Shimada H, Bansal D, Guenes AM, Kalwak K, Sedlacek P, Baruchel A, Biondi A, Hijiya N, Schultz KR, Schrappe M |
Generic formulations of imatinib for treatment of Philadelphia chromosome-positive leukemia in pediatric patients. |
Pediatric blood & cancer 2018, 65:e27431 |
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Since the patent for imatinib has expired, the role of generic imatinib (GI) in the management of Philadelphia chromosome-positive (Ph+) leukemia in pediatric patients has had ongoing discussion. Some studies in adults demonstrated that equivalent doses of GI and branded imatinib (BI) result in comparable plasma concentrations and clinical efficacy. However, other studies found that GI users are more likely to stop imatinib, with intolerance and decreased persistence as the main causes. Economic factors also heavily influence GI selection. This article aims to review the present knowledge to support further discussion on the role of GI in the management of pediatric Ph+ leukemia. |
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (Eds) |
WHO Classification of Tumours of the Haematopoetic and Lymphoid Tissues. |
Lyon, France: IARC Press 2008, 109 |
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Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H et al. |
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. |
2017, revised 4th edition |
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Sykora K, Tomeczkowski J, Kirchhoff K, Yakisan E, Reiter A, Welte K |
Growth inhibition of IL-7 receptor positiv childhood Burkitt's lymphoma cells is due to induction of apoptosis. |
Molecular Biology of Hematopoiesis 1996, 191 |
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Sykora K, Tomeczkowski J, Reiter A |
C-kit receptors in childhood malignant lymphoblastic cells. |
Leuk Lymphoma 1997, 25: 201 |
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Szavay P, Luithle T, Semler O, Graf N, Fuchs J |
Surgery of cavoatrial tumor thrombus in nephroblastoma. |
Pediatr Blood Cancer 2004, 43: 40 |
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Szavay P, Fuchs J, Leuschner I, Selle B, Graf N |
Nierentumoren, in: Fuchs J (Hrsg.): Solide Tumoren im Kindesalter, Grundlagen – Diagnostik – Therapie. |
Schauttauer GmbH 2012, 111 |
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Szczepański T, van der Velden VHJ, Waanders E, Kuiper RP, Van Vlierberghe P, Gruhn B, Eckert C, Panzer-Grümayer R, Basso G, Cavé H, zur Stadt U, Campana D, Schrauder A, Sutton R, van Wering E, Meijerink JPP, van Dongen JJM |
Late Recurrence of Childhood T-Cell Acute Lymphoblastic Leukemia Frequently Represents a Second Leukemia Rather Than a Relapse: First Evidence for Genetic Predisposition. |
Journal of Clinical Oncology 2011, 1643 |
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