Literatur

Zuletzt geändert: 04.11.2024 https://kinderkrebsinfo.de/doi/e8952

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Autor(en)	Titel	Quelle
Eapen M, Brazauskas R, Williams DA, Walters MC, St Martin A, Jacobs BL, Antin JH, Bona K, Chaudhury S, Coleman-Cowger VH, DiFronzo NL, Esrick EB, Field JJ, Fitzhugh CD, Kanter J, Kapoor N, Kohn DB, Krishnamurti L, London WB, Pulsipher MA, Talib S, Thompson AA, Waller EK, Wun T, Horowitz MM	Secondary Neoplasms After Hematopoietic Cell Transplant for Sickle Cell Disease.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2023, 41: 2227
To report the incidence and risk factors for secondary neoplasm after transplantation for sickle cell disease.
European Association for the Study of the Liver	EASL clinical practice guidelines for HFE hemochromatosis.	Journal of Hepatology Published:April 19, 2010, aufgerufen 10.12.2020
Ebeling A	Untersuchung zur psychosozialen Problemlage leukämiekranker Kinder und ihrer Familien.	Philos Diss Universität Hamburg 1981
Eber S	Angeborene Erythrozytenmembrandefekte.	In: Gadner, H, Gaedicke, G, Niemeyer, C, Ritter, J (Hrsg.): Pädiatrische Hämatologie und Onkologie 2006, 125
Ebell W	Hämatopoetische Stammzelltransplantation. in: Gadner H, Gaedicke G, Niemeyer CH, Ritter J:.	Pädiatrische Hämatologie und Onkologie Springer-Verlag, 2006, 66
Eber S	Leitlinie der Gesellschäft für Pädiatrische Onkologie und Hämatologie Hereditäre Sphärozytose.
Eberherr C, Beck A, Vokuhl C, Becker K, Häberle B, Von Schweinitz D, Kappler R	Targeting excessive MYCN expression using MLN8237 and JQ1 impairs the growth of hepatoblastoma cells.	International journal of oncology 2019, 54: 1853
Hepatoblastoma (HB) is the most common liver tumor in children under the age of 3 years worldwide. While many patients achieve good outcomes with surgical resection and conventional chemotherapy, there is still a high‑risk population that exhibits a poor treatment response and unfavorable prognosis, which warrants the search for novel treatment options. In recent years, it has become clear that genetic events alone are not sufficient to explain the aggressive phenotype of this embryonal malignancy. Instead, epigenetic modifications and aberrant gene expression seem to be key drivers of HB. In the present study, expression analyses such as reverse transcription‑quantitative polymerase chain reaction revealed that the oncogene, MYCN proto‑oncogene basic‑helix‑loop‑helix transcription factor (MYCN) was upregulated in HB and other pediatric liver tumors, due to the transcriptional activity of its antisense transcript MYCN opposite strand (MYCNOS). Pyrosequencing demonstrated the hypomethylated regions in the promoter of MYCN and MYCNOS, suggesting that an epigenetic mechanism may underlie the induction of aberrant expression. Transient MYCN knockdown in HB cells resulted in growth inhibition over time. In addition, treating HB cells with the MYCN inhibitors JQ1 and MLN8237 led to the significant downregulation of MYCN either at the mRNA or protein levels, respectively. The underlying mechanism of action of the two inhibitors was revealed to be associated with the induction of dose‑dependent growth arrest, by arresting cells at either the G1/G0 or G2 phase. Furthermore, MLN8237 and JQ1 were able to cause spindle disturbances and/or apoptosis in HB cells. The present results suggest that MYCN may be a promising biomarker for HB and a potential therapeutic target in patients with tumors overexpressing MYCN.
Eckert C, Landt O, Taube T, Seeger K, Beyermann B, Proba J, Henze G	Potential of LightCycler technology for quantification of minimal residual disease in childhood acute lymphoblastic leukemia.	Leukemia 2000, 14: 316
Eckert C, Biondi A, Seeger K, Cazzaniga G, Hartmann R, Beyermann B, Pogodda M, Proba J, Henze G	Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia.	Lancet 2001, 358: 1239
Eckert C, Einsiedel HG, Hartmann R, von Stackelberg A, Volpel S, Guggemos A, Hanzsch N, Kawan L, Seeger K, Henze G	Clonal stability of initial leukemia in a child with CNS relapse 7. 4 years after bone marrow relapse of common acute lymphoblastic leukemic.	haematologica 2004, 89:ECR23.
Eckert C, Flohr T, Koehler R, Hagedorn N, Moericke A, Stanulla M, Kirschner-Schwabe R, Cario G, Stackelberg A, Bartram CR, Henze G, Schrappe M, Schrauder A	Very early/early relapses of acute lymphoblastic leukemia show unexpected changes of clonal markers and high heterogeneity in response to initial and relapse treatment.	Leukemia 2011, May, Epub ahead of print
Minimal residual disease (MRD) quantified after induction treatment of childhood acute lymphoblastic leukemia (ALL) predicts risk of relapse. It has been assumed that early relapses derive from a residual population of leukemic cells, which is still present after induction and that relapsed disease will consequently be more resistant to treatment. To test these hypotheses, we performed a prospective study on patients treated according to the frontline-trial ALL-BFM 2000, which used MRD response for risk-group stratification. Patients (n=45) showed a median time to relapse of 1.5 years. In 89% of patients at least one T-cell-receptor/immunoglobulin gene rearrangement chosen for initial MRD quantification remained stable; however, at least one of the preferred markers for MRD stratification at relapse was different to diagnosis in 50% of patients. A similar proportion of very early, early and late relapses appeared to gain a marker at relapse although backtracking-analysis revealed that in 77% of cases, the gained markers were present as small sub-clones at initial diagnosis. Comparing initial and relapse MRD response to induction, 38% of patients showed a similar, 38% a better and 25% a poorer response after relapse. These data demonstrate an unexpectedly high clonal heterogeneity among very early/early relapses and challenge some current assumptions about relapsed ALL.
Eckert C, von Stackelberg A, Seeger K, Groeneveld TW, Peters C, Klingebiel T, Borkhardt A, Schrappe M, Escherich G, Henze G	Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia - long-term results of trial ALL-REZ BFM P95/96.	European journal of cancer 2013, 49: 1346
This blinded prospective study was performed to optimise the risk assessment of children with a late isolated, combined or an early combined bone marrow (BM) relapse of precursor B-cell acute lymphoblastic leukaemia (ALL). The aim was to develop a reliable tool to identify patients with an intermediate risk relapse who are in need of haematopoietic stem cell transplantation (HSCT).
Eckert C, Henze G, Seeger K, Hagedorn N, Mann G, Panzer-Grümayer R, Peters C, Klingebiel T, Borkhardt A, Schrappe M, Schrauder A, Escherich G, Sramkova L, Niggli F, Hitzler J, von Stackelberg A	Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group.	Journal of clinical oncology 2013, 31: 2736
PURPOSE In children with intermediate risk of relapse of acute lymphoblastic leukemia (ALL), it is essential to identify patients in need of treatment intensification. We hypothesized that the prognosis of patients with unsatisfactory reduction of minimal residual disease (MRD) can be improved by allogeneic hematopoietic stem-cell transplantation (HSCT). PATIENTS AND METHODS In the Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 2002, patients with an MRD level of ≥ 10(-3) (n = 99) at the end of induction therapy were allocated to HSCT, whereas those with an MRD level less than 10(-3) (n = 109) continued to receive chemotherapy. MRD was quantified by real-time polymerase chain reaction for clone-specific T-cell receptor/immunoglobulin gene rearrangements. Results The probability of event-free survival for patients with MRD ≥ 10(-3) was 64% ± 5% in ALL-REZ BFM 2002 compared with 18% ± 7% in the predecessor study ALL-REZ BFM P95/96 (P < .001). This was mainly achieved by reducing the cumulative incidence of subsequent relapse (CIR) at 8 years from 59% ± 9% to 27% ± 5% (P < .001). The favorable prognosis of patients with MRD less than 10(-3) could be confirmed in those with a late combined or isolated bone marrow B-cell precursor (BCP) -ALL relapse (CIR, 20% ± 5%), whereas patients with an early combined BCP-ALL relapse had an unfavorable outcome (CIR, 63% ± 13%; P < .001). CONCLUSION Allogeneic HSCT markedly improved the prognosis of patients with intermediate risk of relapse of ALL and unsatisfactory MRD response. As a result, outcomes in this group approximated those of patients with favorable MRD response. Patients with early combined relapse require treatment intensification even in case of favorable MRD response, demonstrating the prognostic impact of time to relapse.
Eckert C, Hagedorn N, Sramkova L, Mann G, Panzer-Grümayer R, Peters C, Bourquin JP, Klingebiel T, Borkhardt A, Cario G, Alten J, Escherich G, Astrahantseff K, Seeger K, Henze G, von Stackelberg A	Monitoring minimal residual disease in children with high-risk relapses of acute lymphoblastic leukemia: prognostic relevance of early and late assessment.	Leukemia 2015, 29: 1648
The prognosis for children with high-risk relapsed acute lymphoblastic leukemia (ALL) is poor. Here, we assessed the prognostic importance of response during induction and consolidation treatment prior to hematopoietic stem cell transplantation (HSCT) aiming to evaluate the best time to assess minimal residual disease (MRD) for intervention strategies and in future trials in high-risk ALL relapse patients. Included patients (n=125) were treated uniformly according to the ALL-REZ BFM (Berlin-Frankfurt-Münster) 2002 relapse trial (median follow-up time=4.8 years). Patients with MRD ⩾10(-3) after induction treatment (76/119, 64%) or immediately preceding HSCT (19/71, 27%) had a significantly worse probability of disease-free survival 10 years after relapse treatment begin, with 26% (±6%) or 23% (±7%), respectively, compared with 58% (±8%) or 48% (±7%) for patients with MRD <10(-3). Conventional intensive consolidation treatment reduced MRD to <10(-3) before HSCT in 63% of patients, whereas MRD remained high or increased in the rest of this patient group. Our data support that MRD after induction treatment can be used to quantify the activity of different induction treatment strategies in phase II trials. MRD persistence at ⩾10(-3) before HSCT reflects a disease highly resistant to conventional intensive chemotherapy and requiring prospective controlled investigation of new treatment strategies and drugs.
Eckert C, Groeneveld-Krentz S, Kirschner-Schwabe R, Hagedorn N, Chen-Santel C, Bader P, Borkhardt A, Cario G, Escherich G, Panzer-GrÃ¼mayer R, Astrahantseff K, Eggert A, Sramkova L, Attarbaschi A, Bourquin JP, Peters C, Henze G, von Stackelberg A, ALL-REZ BFM Trial Group	Improving Stratification for Children With Late Bone Marrow B-Cell Acute Lymphoblastic Leukemia Relapses With Refined Response Classification and Integration of Genetics.	Journal of clinical oncology 2019 Dec 20; 37: 3493
Minimal residual disease (MRD) helps to accurately assess when children with late bone marrow relapses of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) will benefit from allogeneic hematopoietic stem-cell transplantation (allo-HSCT). More detailed dissection of MRD response heterogeneity and the specific genetic aberrations could improve current practice.
Eckert C, Groeneveld-Krentz S, Kirschner-Schwabe R, Hagedorn N, Chen-Santel C, Bader P, Borkhardt A, Cario G, Escherich G, Panzer-GrÃ¼mayer R, Astrahantseff K, Eggert A, Sramkova L, Attarbaschi A, Bourquin JP, Peters C, Henze G, von Stackelberg A, ALL-REZ BFM Trial Group	Improving Stratification for Children With Late Bone Marrow B-Cell Acute Lymphoblastic Leukemia Relapses With Refined Response Classification and Integration of Genetics.	Journal of clinical oncology 2019 Dec 20; 37: 3493
Minimal residual disease (MRD) helps to accurately assess when children with late bone marrow relapses of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) will benefit from allogeneic hematopoietic stem-cell transplantation (allo-HSCT). More detailed dissection of MRD response heterogeneity and the specific genetic aberrations could improve current practice.
Eckert C, Parker C, Moorman AV, Irving JA, Kirschner-Schwabe R, Groeneveld-Krentz S, Révész T, Hoogerbrugge P, Hancock J, Sutton R, Henze G, Chen-Santel C, Attarbaschi A, Bourquin JP, Sramkova L, Zimmermann M, Krishnan S, von Stackelberg A, Saha V	Risk factors and outcomes in children with high-risk B-cell precursor and T-cell relapsed acute lymphoblastic leukaemia: combined analysis of ALLR3 and ALL-REZ BFM 2002 clinical trials.	European journal of cancer (Oxford, England : 1990) 2021, 151: 175
Outcomes of children with high-risk (HR) relapsed acute lymphoblastic leukaemia (ALL) (N = 393), recruited to ALLR3 and ALL-REZ BFM 2002 trials, were analysed. Minimal residual disease (MRD) was assessed after induction and at predetermined time points until haematopoietic stem cell transplantation (SCT).
Eden T, Pui C, Schrappe M, Tognoni G, Masera G	All children have a right to full access to treatment for cancer.	Lancet 2004, 364: 1121
Effinger KE, Migliorati CA, Hudson MM, McMullen KP, Kaste SC, Ruble K, Guilcher GM, Shah AJ, Castellino SM	Oral and dental late effects in survivors of childhood cancer: a Children's Oncology Group report.	Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 2014, 22: 2009
Multi-modality therapy has resulted in improved survival for childhood malignancies. The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers provide practitioners with exposure- and risk-based recommendations for the surveillance and management of asymptomatic survivors who are at least 2Â years from completion of therapy. This review outlines the pathophysiology and risks for oral and dental late effects in pediatric cancer survivors and the rationale for oral and dental screening recommended by the Children's Oncology Group.
Egeler RM, Pritchard J, Gadner H, D'Angio GJ	An international histiocytic language.	Blood 1995, 85: 2281
Eggert A	Pädiatrische Onkologie - ein Überblick.	Onkologie heute 07/2016, 48
Eggert A, Zimmermann M	Konzepte klinischer Studien.	In: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie Springer Verlag GmbH Deutschland 2018, 257
Eggert A, Simon T, Hero B, Lode H, Ladenstein R, Fischer M, Berthold F	Neuroblastom.	in: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie Springer Verlag GmbH GDeutschland 2006, 2018, 2. vollständig überarbeitete Auflage 2018, 420
Ehlers S, Herbst C, Zimmermann M, Scharn N, Germeshausen M, von Neuhoff N, Zwaan CM, Reinhardt K, Hollink IH, Klusmann JH, Lehrnbecher T, Roettgers S, Stary J, Dworzak M, Welte K, Creutzig U, Reinhardt D	Granulocyte Colony-Stimulating Factor (G-CSF) Treatment of Childhood Acute Myeloid Leukemias That Overexpress the Differentiation-Defective G-CSF Receptor Isoform IV Is Associated With a Higher Incidence of Relapse.	Journal of clinical oncology 2010, 28: 2591
PURPOSE: This prospective, multicenter Acute Myeloid Leukemia Berlin-Frankfurt-Muenster (AML-BFM) 98 study randomly tested the ability of granulocyte colony-stimulating factor (G-CSF) to reduce infectious complications and to improve outcomes in children and adolescents with acute myeloid leukemia (AML). However, a trend toward an increased incidence of relapses in the standard-risk (SR) group after G-CSF treatment was observed. PATIENTS AND METHODS: Of 154 SR patients in the AML-BFM 98 cohort, 50 patients were tested for G-CSF receptor (G-CSFR) RNA isoform I and IV expression, G-CSFR cell surface expression, and acquired mutations in the G-CSFR gene. RESULTS: In patients randomly assigned to receive G-CSF after induction, 16 patients overexpressing the G-CSFR isoform IV showed an increased 5-year cumulative incidence of relapse (50% +/- 13%) compared with 14 patients with low-level isoform IV expression (14% +/- 10%; log-rank P = .04). The level of G-CSFR isoform IV had no significant effect in patients not receiving G-CSF (P = .19). Multivariate analyses of the G-CSF-treated subgroup, including the parameters G-CSFR isoform IV overexpression, sex, and favorable cytogenetics as covariables, revealed the prognostic relevance of G-CSFR isoform IV overexpression for 5-year event-free survival (P = .031) and the 5-year cumulative incidence of relapse (P = .049). CONCLUSION: Our results demonstrate that children and adolescents with AMLs that overexpress the differentiation-defective G-CSFR isoform IV respond to G-CSF administration after induction, but with a significantly higher incidence of relapse.
Ehl S	Etoposide for HLH: the limits of efficacy.	Blood 2017, 130: 2692
No abstract available
Ehl S, Bogdan C, Niehues T, Borchard G, Baumann U, Hecht J, Koch j, Neubert J, Wiese-Pochelt K, Zepp F	Impfen bei Immundefizienz : Anwendungshinweise zu den von der Ständigen Impfkommission empfohlenen Impfungen.(II) Impfen bei 1. Primären Immundefekterkrankungen und 2. HIV-Infektion.	Bundesgesundheitsblatt 2018, 61: 1034
Ehl S, Astigarraga I, von Bahr Greenwood T, Hines M, Horne A, Ishii E, Janka G, Jordan MB, La Rosée P, Lehmberg K, Machowicz R, Nichols KE, Sieni E, Wang Z, Henter JI	Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society.	The journal of allergy and clinical immunology. In practice 2018, 6: 1508
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome requiring aggressive immunosuppressive therapy. Following 2 large international studies mainly targeting pediatric patients with familial disease and patients without underlying chronic or malignant disease, the HLH-94 protocol is recommended as the standard of care when using etoposide-based therapy by the Histiocyte Society. However, in clinical practice, etoposide-based therapy has been widely used beyond the study inclusion criteria, including older patients and patients with underlying diseases (secondary HLH). Many questions remain around these extended indications and published reports do not address several practical issues. To tackle these concerns, the HLH Steering Committee of the Histiocyte Society decided to issue guidance for use of the HLH-94 protocol. The group convened in a structured consensus finding process to define recommendations that are based largely on expert opinion backed up by available data from the literature. The recommendations address all main elements of HLH-94 including corticosteroids, cyclosporin, etoposide, intrathecal therapy, and hematopoietic stem cell transplantation (HSCT) and consider various forms of HLH and all age groups. Aspects covered include indications, applications, dosing, side effects, duration of therapy, salvage therapy, and HSCT. These recommendations aim to provide a framework to guide treatment decisions in this severe disease.
Ehl S, von Bahr Greenwood T, Bergsten E, Fischer A, Henter JI, Hines M, Lehmberg K, Janka G, Moshous D, Nichols KE	Is neutralization of IFN-γ sufficient to control inflammation in HLH?	Pediatric blood & cancer 2021, 68:e28886
No abstract available
Eich H, Hero B, Staar S, Micke O, Seegenschmiedt H, Mattke A, Berthold F, Muller R	Multimodality therapy including radiotherapy and chemotherapy improves event-free survival in stage C esthesioneuroblastoma.	Strahlenther Onkol 2003, 179: 233
Eich HT, Muller RP, Micke O, Kocher M, Berthold F, Hero B	Esthesioneuroblastoma in childhood and adolescence. Better prognosis with multimodal treatment?	Strahlentherapie und Onkologie 2005, 181: 378
BACKGROUND AND PURPOSE: Only 3% of all malignant intranasal tumors are esthesioneuroblastomas (ENB) and only 20% of these rare neuroectodermal tumors are diagnosed up to 20 years of age. Radiotherapy and surgery are established treatment modalities for these patients, but the role of chemotherapy, especially in a multimodal approach, is not well defined. To investigate the influence of radio- and chemotherapy, the treatment and course of the disease in children and adolescents with ENB were analyzed retrospectively. PATIENTS AND METHODS: 19 unselected patients (nine male and ten female) diagnosed with ENB < or = 20 years of age were included in this analysis. Median age at diagnosis was 14.0 years (range, 5-20 years). The tumors were Kadish stage B in 4/19 patients and stage C in 15/19 patients. 17 patients underwent surgery, either without further therapy (n = 4), followed by radiotherapy (n = 1) or as part of multimodal regimens (n = 12). Two patients received radio- and chemotherapy without surgery. Complete resection (R0) was achieved in 15 out of 17 patients with surgery including all five patients with preoperative chemotherapy due to unresectable primary at diagnosis. RESULTS: The 5-year overall survival (OS) for the whole group was 73% +/- 12% and the 5-year event-free survival (EFS) 55% +/- 13%. None of the four patients with stage B experienced tumor progression so far, whereas seven out of 15 patients with stage C did (5-year EFS 47% +/- 14%; not significant). Patients with Kadish stage C and multimodal treatment strategies combing surgery, chemo- and radiotherapy had a significantly better outcome than patients with stage C and less than three treatment modalities (65% +/- 17% vs. 20% +/- 18%; p = 0.02). CONCLUSION: These data indicate a benefit of multimodal treatment regimens combining surgery, chemo- and radiotherapy for pediatric patients with ENB Kadish stage C. Chemotherapy appears to improve resectability, EFS, and OS. Radiotherapy is an integral part in the management of children and young adolescents with ENB in Kadish stage B and C.
Eichenmüller M, von Schweinitz D, Kappler R	Betulinic acid treatment promotes apoptosis in hepatoblastoma cells.	International journal of oncology 2009, 35: 873
Hepatoblastoma (HB) represents the most common malignant liver tumor in children with a dismal prognosis for patients with advanced disease. This study provides evidence that the naturally occurring pentacyclic triterpenoid betulinic acid (BA) is highly effective against HB. We demonstrate that BA has a strong cytotoxic effect on HB cells in a dose-dependent manner by impinging on cell viability and causing massive induction of programmed cell death. Apoptotic features including morphological changes, membrane asymmetry and proteolytic cleavage of caspase 3 and poly(ADP-ribose) polymerase were frequently found in BA-treated HB cells, which is suggestive of the mitochondrial intrinsic apoptotic pathway. In contrast, the hepatocellular carcinoma (HCC) cell line HepG2 was resistant to BA treatment. This insensitivity was dependent on the high expression of survival factors, such as Survivin and BCL2. Interestingly, BA treatment led to a significant decrease in expression of the hedgehog target genes GLI1, PTCH1 and IGF2 in HepT3 cells. In conclusion, we demonstrate that BA is capable of inducing apoptosis in HB cells and thereby might be a hopeful new strategy for treating HB, especially those with an activated hedgehog signaling pathway.
Eichenmüller M, Gruner I, Hagl B, Häberle B, Müller-Höcker J, von Schweinitz D, Kappler R	Blocking the hedgehog pathway inhibits hepatoblastoma growth.	Hepatology 2009, 49: 482
Recent evidence has indicated that Hedgehog (Hh) signaling significantly contributes to liver development and regeneration and that activation of the pathway may contribute to growth of hepatocellular carcinoma (HCC) in adults. However, the role of Hh signaling in pediatric liver tumors remains to be elucidated. In this study, we show that Hh signaling is activated in hepatoblastoma (HB), the most common liver tumor in childhood, with most occurrences before the age of 3 years. The Hh target genes glioma-associated oncogene homolog 1 (GLI1) and Patched (PTCH1) showed increased transcript levels in 65% and 30% of HB samples, respectively, compared with normal liver tissues. Most interestingly, the gene encoding the hedgehog interacting protein (HHIP) is transcriptionally silenced by cytosine-phospho-guanosine (CpG) island promoter hypermethylation in 26% of HB cases and treatment with the DNA-demethylating agent 5-aza-2'-deoxycytidine partially restored HHIP expression. Blocking Hh signaling with the antagonist cyclopamine had a strong inhibitory effect on cell proliferation of HB cell lines with an activated pathway. We further demonstrate that this decrease in cell viability is caused by a massive induction of apoptosis, as shown by morphological changes and phosphatidylserine membrane asymmetry. In cyclopamine-exposed HB cells, caspase 3 and poly(adenosine diphosphate-ribose) polymerase proteins were specifically activated by their proteolytic cleavage. Conclusion: This study demonstrates, for the first time, the frequent occurrence of GLI1 and PTCH1 overexpression and HHIP promoter methylation in early childhood HB, thus indicating a key role for Hh signaling activation in the malignant transformation of embryonal liver cells.
Eichinger A, Poetschger U, Glogova E, Bader P, Basu O, Beier R, Burkhardt B, Classen CF, Claviez A, Corbacioglu S, Deubzer HE, Greil J, Gruhn B, Güngör T, Kafa K, Kühl JS, Lang P, Lange BS, Meisel R, Müller I, Sauer MG, Schlegel PG, Schulz A, Stachel D, Strahm B, Wawer A, Peters C, Albert MH	Incidence of subsequent malignancies after total body irradiation-based allogeneic HSCT in children with ALL - long-term follow-up from the prospective ALL-SCT 2003 trial.	Leukemia 2022, 36: 2567
Total body irradiation (TBI)-based conditioning is associated with superior leukemia-free survival in children with ALL undergoing HSCT. However, the risk for subsequent malignant neoplasms (SMN) remains a significant concern. We analyzed 705 pediatric patients enrolled in the prospective ALL-SCT-BFM-2003 trial and its subsequent registry. Patients >2 years received conditioning with TBI 12 Gy/etoposide (n = 558) and children ≤2 years of age or with contraindications for TBI received busulfan/cyclophosphamide/etoposide (n = 110). The 5- and 10-year cumulative incidence of SMN was 0.02 ± 0.01 and 0.13 ± 0.03, respectively. In total, 39 SMN (34 solid tumors, 5 MDS/AML) were diagnosed in 33 patients at a median of 5.8 years (1.7-13.4), exclusively in the TBI group. Of 33 affected patients, 21 (64%) are alive at a median follow-up of 5.1 years (0-9.9) after diagnosis of their first SMN. In univariate analysis, neither age at HSCT, donor type, acute GVHD, chronic GVHD, nor CMV constituted a significant risk factor for SMN. The only significant risk factor was TBI versus non-TBI based conditioning. This analysis confirms and quantifies the increased risk of SMN in children with ALL after conditioning with TBI. Future strategies to avoid TBI will need careful tailoring within prospective, controlled studies to prevent unfavorable outcomes.
Eichholz T, Döring M, Giardino S, Gruhn B, Seitz C, Flaadt T, Schwinger W, Ebinger M, Holzer U, Mezger M, Teltschik HM, Sparber-Sauer M, Koscielniak E, Abele M, Handgretinger R, Lang P	Haploidentical hematopoietic stem cell transplantation as individual treatment option in pediatric patients with very high-risk sarcomas.	Frontiers in oncology 2023, 13: 1064190
Prognosis of children with primary disseminated or metastatic relapsed sarcomas remains dismal despite intensification of conventional therapies including high-dose chemotherapy. Since haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of hematological malignancies by mediating a graft versus leukemia effect, we evaluated this approach in pediatric sarcomas as well.
Einsiedel HG, von Stackelberg A, Hartmann R, Fengler R, Schrappe M, Janka-Schaub G, Mann G, Hahlen K, Göbel U, Klingebiel T, Ludwig WD, Henze G	Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87.	Journal of clinical oncology 2005, 23: 7942
PURPOSE: Approximately 20% of children with acute lymphoblastic leukemia (ALL) suffer a relapse, and their prognosis is unfavorable. Between 1987 and 1990, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 87 was conducted to establish a uniform treatment for these children in Germany and Austria. PATIENTS AND METHODS: Of 207 registered patients, 183 patients were stratified into three groups according to the protocol: A, early bone marrow (BM) relapse (n = 56); B, late BM relapse (n = 101); C, isolated extramedullary relapse (n = 26). Treatment consisted of risk-adapted alternating short-course multiagent systemic and intrathecal chemotherapy, cranial irradiation, if indicated, and conventional maintenance therapy. Additionally, 24 patients with an exceptionally poor prognosis (early BM or any relapse of T-cell ALL) were treated with individual regimens. In 35 patients, stem-cell transplantation was performed. RESULTS: The probability of event-free survival (EFS) and overall survival of all registered patients at 15 years was 0.30 +/- 0.03 and 0.37 +/- 0.03, respectively, with significant differences between the strategic groups (A, 0.18 +/- 0.05 and 0.20 +/- 0.05; B, 0.44 +/- 0.05 and 0.52 +/- 0.05; C, 0.35 +/- 0.09 and 0.42 +/- 0.10). Despite risk-adapted treatment, an early time point of relapse and T-lineage immunophenotype were significant predictors of inferior EFS in uni- and multivariate analyses. CONCLUSION: With the ALL-REZ BFM 87 protocol, more than one-third of patients may be regarded as cured from recurrent ALL with second complete remissions lasting more than 10 years. Immunophenotype and time point of relapse are important prognostic factors that allow us to adapt more precisely treatment intensity to individual prognosis in future trials.
Ejeskar K, Sjoberg R, Abel F, Kogner P, Ambros P, Martinsson T	Fine mapping of a tumour suppressor candidate gene region in 1p36. 2-3, commonly deleted in neuroblastomas and germ cell tumours.	Med Pediatr Oncol 2001, 36: 61
El-Ayadi M, Ansari M, Sturm D, Gielen GH, Warmuth-Metz M, Kramm CM, von Bueren AO	High-grade glioma in very young children: a rare and particular patient population.	Oncotarget 2017 Sep 8; 8: 64564
Eleftheriou A	About Thalassemia - English.	Thalassemia International Federation Publications 2007
Eleftheriou A	About Thalassemia - German.	Thalassemia International Federation Publications 2015
Ellinghaus E, Stanulla M, Richter G, Ellinghaus D, Te Kronnie G, Cario G, Cazzaniga G, Horstmann M, Panzer Grümayer R, Cavé H, Trka J, Cinek O, Teigler-Schlegel A, Elsharawy A, Häsler R, Nebel A, Meissner B, Bartram T, Lescai F, Franceschi C, Giordan M, Nürnberg P, Heinzow B, Zimmermann M, Schreiber S, Schrappe M, Franke A	Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia.	Leukemia 2012, 26: 902
Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) - the most common chromosomal translocation observed in childhood ALL - which leads to an ETV6-RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, P(CMH)=8.94 × 10(-9), OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10(-11), OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10(-9), OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10(-7), OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6-RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis.
Elmariah H, Garrett ME, De Castro LM, Jonassaint J, Ataga KI, Eckman J, Ashley-Koch AE, Telen MJ	Factors Associated with Survival in a Contemporary Adult Sickle Cell Disease Cohort.	American journal of hematology 2014, E-pub ahead of print
We examined the relationship of clinical differences among sickle cell disease (SCD) patients in order to understand the major contributors to early mortality in a contemporary cohort. Survival data were obtained for 542 adult subjects who were enrolled since 2002 at three university hospitals in the southeast United States. Subjects were followed for a median of 9.3 years. At enrollment, clinical parameters were collected, including hemoglobin (Hb) genotype, baseline laboratory values, comorbidities, and medication usage. Levels of soluble adhesion molecules were measured for a subset of 87 subjects. The relationship of clinical characteristics to survival was determined using regression analysis. Median age at enrollment was 32 years. Median survival was 61 years for all subjects. Median survival for Hb SS and Sβ(0) was 58 years and for Hb SC and Sβ(+) was 66 years. Elevated white blood count, lower estimated glomerular filtration rate, proteinuria, frequency of pain crises, pulmonary hypertension, cerebrovascular events, seizures, stroke, sVCAM-1 and short-acting narcotics use were significantly associated with decreased survival. 42% of subjects were on hydroxyurea therapy, which was not associated with survival. SCD continues to reduce life expectancy for affected individuals, particularly those with Hb Sβ(0) and SS. Not only were comorbidities individually associated with decreased survival, but an additive effect was observed, so that those with a greater number of negative endpoints had worse survival (p<0.0001). The association of higher sVCAM-1 levels with decreased survival suggests that targeted therapies to reduce endothelial damage and inflammation may also be beneficial.
Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, Cohen G, Davis S, Donnan G, Grotta J, Howard G, Kaste M, Koga M, von Kummer R, Lansberg M, Lindley RI, Murray G, Olivot JM, Parsons M, Tilley B, Toni D, Toyoda K, Wahlgren N, Wardlaw J, Whiteley W, del Zoppo GJ, Baigent C, Sandercock P, Hacke W, Stroke Thrombolysis Trialists' Collaborative Group	Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.	Lancet 2014, 384: 1929
Emmrich S, Rasche M, Schöning J, Reimer C, Keihani S, Maroz A, Xie Y, Li Z, Schambach A, Reinhardt D, Klusmann JH	miR-99a/100~125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling.	Genes Dev 2014, 28: 858
Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype. miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons on human chromosomes 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Here, we show that miR-99a/100∼125b tricistrons are transcribed as a polycistronic message transactivated by the homeobox transcription factor HOXA10. Integrative analysis of global gene expression profiling, miRNA target prediction, and pathway architecture revealed that miR-99a/100, let-7, and miR-125b functionally converge at the combinatorial block of the transforming growth factor β (TGFβ) pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, down-regulation of tumor suppressor genes adenomatous polyposis coli (APC)/APC2 stabilizes active β-catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFβ signaling, the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo while favoring megakaryocytic differentiation. Hence, our study explains the high phylogenetic conservation of the miR-99a/100∼125b tricistrons controlling stem cell homeostasis, the deregulation of which contributes to the development of AMKL.
Emmrich S, Streltsov A, Schmidt F, Thangapandi VR, Reinhardt D, Klusmann JH	LincRNAs MONC and MIR100HG act as oncogenes in acute megakaryoblastic leukemia.	Mol Cancer 2014, 13: 171
Long non-coding RNAs (lncRNAs) are recognized as pivotal players during developmental ontogenesis and pathogenesis of cancer. The intronic microRNA (miRNA) clusters miR-99a ~ 125b-2 and miR-100 ~ 125b-1 promote progression of acute megakaryoblastic leukemia (AMKL), an aggressive form of hematologic cancers. The function of the lncRNA hostgenes MIR99AHG (alias MONC) and MIR100HG within this ncRNA ensemble remained elusive.
Encke A, Haas S, Kopp I et al.	S3-Leitlinie Prophylaxe der venösen Thrombose (VTE).	AWMF Leitlinien-Register Nr. 003/001 2015
Eng C, Li FP, Abramson DH, Ellsworth RM, Wong FL, Goldman MB, Seddon J, Tarbell N, Boice JD Jr	Mortality from second tumors among long-term survivors of retinoblastoma.	Journal of the National Cancer Institute 1993, 85: 1121
BACKGROUND: Children diagnosed with retinoblastoma, a rare cancer of the eye, tend to develop and die of second primary cancers in childhood and adolescence, but few investigations have followed patients into adulthood. Retinoblastoma is frequently caused by inherited mutations of the RB1 tumor suppressor gene. Most patients with germline (hereditary) mutations have bilateral disease. PURPOSE: We sought to quantify the mortality from second malignancies among long-term survivors of retinoblastoma and to identify factors that predispose to these deaths. METHODS: A retrospective cohort study examined mortality among 1603 patients enrolled at 1 year after diagnosis of retinoblastoma during the period 1914-1984. Data on demography, family history, and retinoblastoma treatment were collected by medical chart review and questionnaire interview. Number of deaths, by cause, was compared with the corresponding expected figure based on U.S. mortality data for the general population for 1925-1990. RESULTS: Follow-up was complete for 1458 patients (91%) for a median of 17 years after retinoblastoma diagnosis. A total of 305 deaths occurred, 167 of them from retinoblastoma. There were 96 deaths from second primary tumors (relative risk [RR] = 30), 21 from other known causes (RR = 1.0), and 21 from ill-defined or unknown causes. Statistically significant excess mortality was found for second primary cancers of bone, connective tissue, and malignant melanoma and benign and malignant neoplasms of brain and meninges. Among 919 children with bilateral retinoblastoma, 90 deaths from second primary tumors occurred (RR = 60). Deaths from second tumors were more frequent among females (RR = 39) than males (RR = 22) (P = .007). The cumulative probability of death from second primary neoplasms was 26% at 40 years after bilateral retinoblastoma diagnosis, and additional cancer deaths occurred thereafter. Radiotherapy for retinoblastoma further increased the risk of mortality from second neoplasms. An excess of mortality from a second cancer, not seen in prior studies, was found among the 684 children with unilateral disease (RR = 3.1; 95% confidence interval = 1.0-7.3). CONCLUSIONS: These findings implicate germinal mutations in the retinoblastoma gene in second cancer mortality. Radiotherapy treatment for retinoblastoma appears to further enhance the inborn susceptibility to development of a second cancer. IMPLICATIONS: Patients with retinoblastoma, particularly bilateral retinoblastoma, should have careful follow-up, and interventions should be developed to reduce mortality from a second cancer.
US Environmental Protection Agency Office of Radiation and Indoor Air	EPA Radiogenic Cancer Risk Models and Projections for the U. S. Population.	December 2008
Erarslan-Uysal B, Kunz JB, Rausch T, Richter-Pechańska P, van Belzen IA, Frismantas V, Bornhauser B, Ordoñez-Rueada D, Paulsen M, Benes V, Stanulla M, Schrappe M, Cario G, Escherich G, Bakharevich K, Kirschner-Schwabe R, Eckert C, Loukanov T, Gorenflo M, Waszak SM, Bourquin JP, Muckenthaler MU, Korbel JO, Kulozik AE	Chromatin accessibility landscape of pediatric T-lymphoblastic leukemia and human T-cell precursors.	EMBO molecular medicine 2020, 12:e12104
We aimed at identifying the developmental stage at which leukemic cells of pediatric T-ALLs are arrested and at defining leukemogenic mechanisms based on ATAC-Seq. Chromatin accessibility maps of seven developmental stages of human healthy T cells revealed progressive chromatin condensation during T-cell maturation. Developmental stages were distinguished by 2,823 signature chromatin regions with 95% accuracy. Open chromatin surrounding SAE1 was identified to best distinguish thymic developmental stages suggesting a potential role of SUMOylation in T-cell development. Deconvolution using signature regions revealed that T-ALLs, including those with mature immunophenotypes, resemble the most immature populations, which was confirmed by TF-binding motif profiles. We integrated ATAC-Seq and RNA-Seq and found DAB1, a gene not related to leukemia previously, to be overexpressed, abnormally spliced and hyper-accessible in T-ALLs. DAB1-negative patients formed a distinct subgroup with particularly immature chromatin profiles and hyper-accessible binding sites for SPI1 (PU.1), a TF crucial for normal T-cell maturation. In conclusion, our analyses of chromatin accessibility and TF-binding motifs showed that pediatric T-ALL cells are most similar to immature thymic precursors, indicating an early developmental arrest.
Erb N, Harms D, Janka-Schaub G	Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine.	Cancer Chemother Pharmacol 1998, 42: 266
Erb N, Haverland U, Harms D, Escherich G, Janka-Schaub G	High-performance liquid chromatographic assay of metabolites of thioguanine and mercaptopurine in capillary blood.	J Chromatogr B Analyt Technol Biomed Life Sci 2003, 796: 87
Erdmann F, Kaatsch P, Grabow D, Spix C	German Childhood Cancer Registry - Annual Report 2019 (1980-2018).	Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at the University Medical Center of the Johannes Gutenberg University Mainz 2020
Erdmann F, Spix C, Katalinic A	Krebs in Deutschland für 2017/2018.	Gemeinsame Publikation des Robert Koch-Instituts (Hrsg) und der Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg) 13. Ausgabe; Berlin, 2021
Eriksson T, Frisk T, Gray S, von Schweinitz D, Pietsch T, Larsson C, Sandstedt B, Ekstrom T	Methylation changes in the human IGF2 p3 promoter parallel IGF2 expression in the primary tumor, established cell line, and xenograft of a human hepatoblastoma.	Exp Cell Res 2001, 270: 88
Erkek S, Johann PD, Finetti MA, Drosos Y, Chou HC, Zapatka M, Sturm D, Jones DTW, Korshunov A, Rhyzova M, Wolf S, Mallm JP, Beck K, Witt O, Kulozik AE, Frühwald MC, Northcott PA, Korbel JO, Lichter P, Eils R, Gajjar A, Roberts CWM, Williamson D, Hasselblatt M, Chavez L, Pfister SM, Kool M	Comprehensive Analysis of Chromatin States in Atypical Teratoid/Rhabdoid Tumor Identifies Diverging Roles for SWI/SNF and Polycomb in Gene Regulation.	Cancer cell 2019, 35: 95-110.e8
Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remodeling complex, is the hallmark genetic aberration of atypical teratoid rhabdoid tumors (ATRT). Here, we report how loss of SMARCB1 affects the epigenome in these tumors. Using chromatin immunoprecipitation sequencing (ChIP-seq) on primary tumors for a series of active and repressive histone marks, we identified the chromatin states differentially represented in ATRTs compared with other brain tumors and non-neoplastic brain. Re-expression of SMARCB1 in ATRT cell lines enabled confirmation of our genome-wide findings for the chromatin states. Additional generation of ChIP-seq data for SWI/SNF and Polycomb group proteins and the transcriptional repressor protein REST determined differential dependencies of SWI/SNF and Polycomb complexes in regulation of diverse gene sets in ATRTs.
Erker C, Mynarek M, Bailey S, Mazewski CM, Baroni L, Massimino M, Hukin J, Aguilera D, Cappellano AM, Ramaswamy V, Lassaletta A, Perreault S, Kline CN, Rajagopal R, Michaiel G, Zapotocky M, Santa-Maria Lopez V, La Madrid AM, Cacciotti C, Sandler ES, Hoffman LM, Klawinski D, Khan S, Salloum R, Hoppmann AL, Larouche V, Dorris K, Toledano H, Gilheeney SW, Abdelbaki MS, Wilson B, Tsang DS, Knipstein J, Oren MY, Shah S, Murray JC, Ginn KF, Wang ZJ, Fleischhack G, Obrecht D, Tonn S, Harrod VL, Matheson K, Crooks B, Strother DR, Cohen KJ, Hansford JR, Mueller S, Margol A, Gajjar A, Dhall G, Finlay JL, Northcott PA, Rutkowski S, Clifford SC, Robinson G, Bouffet E, Lafay-Cousin L	Outcomes of Infants and Young Children With Relapsed Medulloblastoma After Initial Craniospinal Irradiation-Sparing Approaches: An International Cohort Study.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2023, 41: 1921
Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy.
Erttmann R, Tafese T, Berthold F, Kerbl R, Mann J, Parker L, Schilling F, Ambros P, Christiansen H, Favrot M, Kabisch H, Hero B, Philip T	10 years' neuroblastoma screening in Europe.	Eur J Cancer 1998, 34: 1391
Escherich G, Göbel U, Jorch N, Spaar HJ, Janka-Schaub GE	Daunorubicin-induced cell kill with 1-hour versus 24-hour infusions: a randomized comparison in children with newly diagnosed acute lymphoblastic leukemia.	Klinische Padiatrie 2007, 219: 134
BACKGROUND: Daunorubicin (DNR) is one of the most important drugs in treatment of acute lymphoblastic leukemia (ALL). Prolonged infusions of anthracyclines are less cardiotoxic but it has not been investigated whether the in vivo leukemic cell kill is equivalent to short-term infusions. PROCEDURE: In the cooperative treatment study COALL-92 for childhood ALL 178 patients were randomized to receive in a therapeutic window a single dose of 36 mg/m (2) DNR either as a 1-h (85 patients) or 24-h infusion (93 patients). Daily measurements of white blood cell count (WBC) and peripheral blood smears for seven days could be evaluated centrally in 101 patients (1-h: 43 patients, 24-h: 58 patients). RESULTS: The proportional decline of blasts at day 7 after DNR infusion showed no statistically significant difference between the two treatment arms. At day 3 the median percentage of blasts was less than 10%, at day 7 less than 2% for either the 1-h or 24-h infusion. Twelve patients (1-h: 5 patients, 24-h: 7 patients) had an absolute number of more than 1000 blasts per mul peripheral blood (PB) at day 7 after DNR infusion (DNR poor responders). Kaplan-Meier analysis showed an equal probability of EFS for the short- and long-term infusion group (24-h: 83%+/-5; 1-h: 81+/-6) after a median observation time of 12.3 years. CONCLUSIONS: We conclude that in children with ALL a 24-h infusion of DNR has the same in vivo cytotoxicity for leukemic cells as a 1-h infusion. This offers the possibility to use prolonged infusions with hopefully less cardiotoxicity without loss of efficacy.
Escherich G, Horstmann MA, Zimmermann M, Janka-Schaub GE, COALL study group	Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97.	Leukemia : 2010, 24: 298
In this study, the long-term outcome of 1818 patients treated in five consecutive clinical trials (the cooperative study group for childhood acute lymphoblastic leukaemia (COALL) 82, 85, 89, 92 and 97) from 24 cooperating centres in Germany is reported. The probability of event-free survival (pEFS) improved significantly from the first two trials conducted in the 1980s (COALL 82 and COALL 85) to the three trials conducted in the 1990s (COALL 89, 92 and 97) (P=0.001). Through all COALL studies, age > or =10 years and initial white blood cell count (WBC) > or =50 x 10(9)/l and pro-B immunophenotype were of significant prognostic relevance. A refinement of risk assessment has been achieved by in vitro drug sensitivity testing in COALL 92 and 97. In patients with very sensitive leukaemic cells, therapy could be reduced without loss of efficacy. In COALL 97, a further improvement in risk stratification was gained by the molecular assessment of minimal residual disease (MRD) under treatment, which proved to have a superior prognostic effect when compared with in vitro drug sensitivity testing. Importantly, the gradual reduction in central nervous system (CNS) irradiation led to a decreased incidence of brain tumours as a second malignancy. In general, the prevention of treatment-related late effects will be one of the major issues in future studies. It remains to be shown whether prolonged infusions of anthracyclines, which have been implemented into the COALL studies after equal efficacy compared with short-time infusions was confirmed, will be associated with fewer cardiac late effects. Another way to prevent late effects may be a more refined risk assessment allowing for a reduction in cumulative treatment burden. A great challenge in the future will be to improve the overall treatment results, which very likely can only be achieved by the identification of molecularly defined subgroups to which novel, rational therapeutic strategies can be applied.
Escherich G, Troeger AF, Göbel U, Graubner U, Pekrun A, Jorch N, Kaspers G, Zimmermann M, Zur Stadt U, Kazemir K, Pieters R, Horstmann M, Denboer ML, Janka-Schaub G	The long-term impact of in vitro drug sensitivity testing on risk stratification and treatment outcome in acute lymphoblastic leukemia of childhood (CoALL 06-97).	Haematologica 2011, Epub ahead of print
Background. In study CoALL 06-97 in vitro sensitivity towards prednisolone, vincristine and asparaginase was implemented as a new additional risk parameter for treatment stratification of children with acute lymphoblastic leukemia. In parallel in vivo treatment response was assessed by minimal residual disease in a subset of patients (n= 224). Here we report the long-term impact of in vitro sensitivity based risk stratification according to survival and compare the results of in vitro sensitivity with in vivo response. Design and Methods. Patients with a sensitive in vitro profile were treated by a reduced intensity protocol (n = 167) whereas patients defined as Low Risk according to conventional parameters but with a resistant in vitro profile underwent an intensified therapy (n = 47). Results. At a median follow-up of 6.8 years event-free survival was 0.80 ±0.03 for patients with a sensitive, 0.73+/-0.03 with an intermediate and 0.67 ±0.08 with a resistant profile (p = 0.015). Overall, treatment results of the cases stratified according to in vitro sensitivity were similar to the historical control stratified based on conventional risk factors. Minimal residual disease at the end of induction was a strong predictor of outcome in B - Precursor and T-cell acute lymphoblastic leukemia. There was no correlation between in vitro and in vivo treatment response in B-Precursor (rspearman=0.13; p=0.15) in contrast to T-cell acute lymphoblastic leukemia (rspearman=0.63; p<0.001) Conclusions. Moderate reduction in treatment intensity for patients with a sensitive in vitro profile was possible without jeopardizing treatment outcome. However, in vitro drug testing was affected by a decrement in risk predictive power over time and revealed no correlation with in vivo assessment of minimal residual disease in B-Precursor acute lymphoblastic leukemia. Therefore it was abandoned in favor of the assessment of in vivo response in subsequent CoALL trials.
Escherich G, Zimmermann M, Janka-Schaub G, CoALL study group	Doxorubicin or daunorubicin given upfront in a therapeutic window are equally effective in children with newly diagnosed acute lymphoblastic leukemia. A randomized comparison in trial CoALL 07-03.	Pediatric blood & cancer 2013, 60: 254
The anthracyclines daunorubicin (DNR) and doxorubicin (DOX) are among the most important drugs in the treatment of childhood acute lymphoblastic leukemia, however there are conflicting in vitro data about the comparative efficacy and equivalent doses of both anthracyclines. To address the question of in vivo efficacy of both anthracyclines, patients enrolled in the CoALL 07-03 trial were randomized to receive one single dose of either doxorubicin 30 mg/m(2) , daunorubicin 30 mg/m(2) , or daunorubicin 40 mg/m(2) upfront induction therapy.
Escherich G, Schrappe M, Creutzig U	Akute lymphoblastische Leukämie – ALL – im Kindesalter.	AWMF online 2021
Escherich G, Schrappe M	[Updated AWMF Guideline on the Diagnosis and Treatment of Acute Lymphoblastic Leukaemia in Children].	Klinische Padiatrie 2022, 234: 363
Depending on the initial risk factors survival rates of childhood acute lymphoblastic leukemia (ALL) nowadays reach an average of 85%. The successful treatment of this severe disease is based on the development of multi-modal treatment concepts, on the basis of a continuously improving molecular genetic characteri-zation of the disease with the identification of new risk factors. The diagnosis of the response to therapy and the resulting stratification of patients into different therapy strata plays an essential role in this progress. These risk-adapted treatment approaches have minimized therapy-associated complications as well as late effects. In the upcoming years, the goal will be to improve the cure rate of patients with unfavorable prognosis. The development of im-munotherapeutic approaches, which are currently being tested in clinical trials in the con-text of ALL therapy, can play an important role in this context.
Eselgrim M, Grunert H, Kuhne T, Zoubek A, Kevric M, Burger H, Jürgens H, Mayer-Steinacker R, Gosheger G, Bielack SS	Dose intensity of chemotherapy for osteosarcoma and outcome in the Cooperative Osteosarcoma Study Group (COSS) trials.	Pediatric blood & cancer 2005,
BACKGROUND: The prognostic relevance of dose intensity in the treatment of osteosarcoma is still under discussion. The aim of this study was to investigate whether higher dose intensities of chemotherapy correlated with better outcomes. PROCEDURE: This study contains 917 consecutive Cooperative Osteosarcoma Study Group (COSS) patients <40 years with primary, high-grade central, nonmetastatic osteosarcoma of the extremities, who were in complete remission at least until day 200 after the start of chemotherapy. All COSS-protocols were based on a uniform treatment concept of aggressive polychemotherapy and definitive surgery. Chemotherapy dose intensity in the first 200 days of treatment (DI(200)) and possible correlations to overall and event-free survival were investigated. The study focused on methotrexate, doxorubicin, cisplatin, and ifosfamide, which are considered to be the most active drugs against osteosarcoma. Multivariate analyses including well-known prognostic factors were added to complete this investigation. RESULTS: Until day 200, patients received 80.7 +/- 26.1 g/m(2) methotrexate (MTX); 242 +/- 69 mg/m(2) doxorubicin (DOX); 324 +/- 133 mg/m(2) cisplatin (DDP); and 13.9 +/- 9.8 g/m(2) ifosfamide (IFO) (mean +/- SD). Median follow-up from day 200 was 6.6 (0.02-22.1) years. There was no correlation between a higher DI(200) of any one drug and better outcomes in uni- or multi-variate analyses. Total treatment intensity did not show such correlations either. CONCLUSIONS: In an overall setting of intensive multidrug treatment of osteosarcoma, we could not prove that higher dose intensities correlate with better outcomes. Pediatr Blood Cancer (c) 2005 Wiley-Liss, Inc.
Escherich G, Zur Stadt U, Zimmermann M, Horstmann MA, on behalf of the CoALL study group	Clofarabine in combination with pegylated asparaginase in the frontline treatment of childhood acute lymphoblastic leukaemia: a feasibility report from the CoALL 08-09 trial.	British journal of haematology 2013, epub ahead of print
Clofarabine was the latest new drug to be approved, in 2004, for relapsed or refractory acute lymphoblastic leukaemia (ALL). To investigate its value in the frontline treatment of ALL we applied clofarabine 5 × 40 mg/m(2) in combination with pegylated asparaginase (PEG-ASP) 1 × 2500 iu/m(2) in high risk ALL patients as a novel post-induction element in the German Co-operative Study Group for treatment of ALL (CoALL) trial 08-09. Newly diagnosed ALL patients, defined by a significant minimal residual disease (MRD) load at the end of induction (B-progenitor ALL at day 29 ≥ 10(-4) and T-ALL at day 43 ≥ 10(-3) ) were eligible for this phase II trial. All other patients received the standard treatment consisting of high-dose cytarabine (HIDAC) 4 × 3 g/m² in combination with Peg-ASP 2500 iu/m². Forty-two patients (39 B-progenitor; 3 T-ALL) fulfilled the criteria, were stratified and received the clofarabine/PEG-ASP treatment resulting in 24/39 (61%) MRD-negative B-progenitor patients compared to 18/39 (46%) after HIDAC/PEG-ASP in CoALL 07-03. Overall, the toxicity profile of clofarabine/PEG-ASP was similar to HIDAC/PEG-ASP without unexpected severe side effects. Clofarabine combined with PEG-ASP is safe and effective in the frontline treatment of ALL. A prospective, randomized trial is warranted to evaluate the antileukaemic efficacy of clofarabine versus HIDAC combined with PEG-ASP.
Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H	Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia.	Blood 2006 May 1; 107: 3469
We examined whether combining all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) might be an alternative to ATRA plus chemotherapy in untreated acute promyelocytic leukemia (APL). Twenty-five low-risk patients (white blood cell [WBC] count less than 10 x 10(9)/L [10,000/microL]) received ATRA (45 mg/m(2) daily) and ATO (0.15 mg/kg daily, beginning day 10 of ATRA), and in complete remission (CR) received ATO plus ATRA, without chemotherapy, unless they were reverse transcriptase-polymerase chain reaction (RT-PCR)-positive 3 months from CR date or had molecular relapse. Nineteen high-risk patients were treated identically, but received chemotherapy, generally 9 mg/m(2) gemtuzumab ozogamycin (GO) on day 1 of induction. The CR rate was 39 of 44 (24 of 25 in low-risk, 15 of 19 in high-risk). Disease recurred at 9, 9, and 15 months, respectively, in 3 high-risk patients. The median follow-up time from CR date in the 36 patients alive in first CR is 16 months (15 months in low-risk, 20 months in high-risk), with 9 patients followed for at least 24 months. Each of the 36 patients was PCR-negative at last follow-up. Thus, none of the low-risk patients has received chemotherapy, and only 3 high-risk patients (the 3 with relapsed disease) have received chemotherapy past induction. ATRA plus ATO may serve as an alternative to chemotherapy in low-risk untreated APL (eg, in older patients) and, when combined with GO, may improve outcome in high-risk patients.
Eveslage M, Calaminus G, Warmuth-Metz M, Kortmann, RD, Pohl F, Timmermann B, Schuhmann MU, Flitsch J, Faldum A, Müller HL	Postoperative Lebensqualität bei Kindern und Jugendlichen mit Kraniopharyngeom.	Dtsch Arztebl Int 2019, 116: 321
van Ewijk R, Cleirec M, Herold N, le Deley MC, van Eijkelenburg N, Boudou-Rouquette P, Risbourg S, Strauss SJ, Palmerini E, Boye K, Kager L, Hecker-Nolting S, Marchais A, Gaspar N, FOSTER Consortium (Fight OsteoSarcoma Through European Research), work package 3 on recurrent/refractory osteosarcoma trials	A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design?	Cancer treatment reviews 2023, 120: 102625
To analyze changes in recurrent/refractory osteosarcoma phase II trials over time to inform future trials in this population with poor prognosis.
Exner M, Engelhart S, Gebel J, Ilschner C, Pfeiffer R, Höller C, Dilloo D, Maschmeyer G, Simon A	Hygiene-Tipps für immunsupprimierte Patienten zur Vermeidung übertragbarer Infektionskrankheiten.	Hyg Med 2011, 36 – 1/2
Severely immunocompromised patients should also adopt a multitude of infection control measures at home and in their daily lives. The focus should be on a proactive approach which shows: Everybody can do something to prevent infections. The im - plementation of these measures requires the close cooperation of medical personnel with patients and relatives who need to be addressed directly as partners in infection control. Therefore, great emphasis was put on using common language and highlight - ing important points without neglecting the necessary background information. In order to achieve this goal, the text was proof-read by patients and relatives. The contents comprises the basic routes of pathogen transmission, hand hygiene, prevention of infection of the upper and the lower airways, personal hygiene, rules for visitors and public life, protection from food-borne diseases, vaccinations and con - tact with animals. These practical hygiene tips are also available in the format of an illustrated brochure with short summaries for each chapter and a subject index.
Eyrich M	Immuntherapie rezidivierter Gliome – ein individualisierter Therapieansatz.	WiR - die Zeitschrift der Deutschen Leukämie-Forschungshilfe e.V. und der Deutschen Kinderkrebsstiftung 2/2018
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