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Autor(en)	Titel	Quelle
Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, American Association for the Study of Liver Diseases	Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases.	Hepatology (Baltimore, Md.) 2011, 54: 328
Bader P, Beck J, Frey A, Schlegel P, Hebarth H, Handgretinger R, Einsele H, Niemeyer C, Benda N, Faul C, Kanz L, Niethammer D, Klingebiel T	Serial and quantitive analysis of mixed hematopoietic chimerism by PCR in patients with acute leukemias allows the prediction of relapse after allogenic BMT.	Bone Marrow Transplant 1998, 21: 487
Bader P, Stoll K, Huber S, Geiselhart A, Handgretinger R, Niemeyer C, Einsele H, Schlegel PG, Niethammer D, Beck J, Klingebiel T	Characterization of lineage-specific chimaerism in patients with acute leukaemia and myelodysplastic syndrome after allogeneic stem cell transplantation before and after relapse.	British journal of haematology 2000, 108: 761
Recently, we have shown that patients with acute leukaemias and myelodysplastic syndromes (MDS), who showed increasing mixed chimaerism (MC) upon serial PCR analysis after transplant, have a significantly increased risk of relapse. To determine whether the increasing MC in these patients is caused by the reappearance of normal recipient haematopoiesis or by the reoccurrence of malignant cells, we purified different leucocyte subpopulations and analysed these subfractions with regard to their donor-recipient ratio by a PCR-based method for the analysis of minisatellite DNA regions. In 14 patients [eight acute lymphoblastic leukaemia (ALL), three acute myelogenous leukaemia (AML) and three MDS] subfractions were analysed when increasing MC was first noted upon serial analysis of the peripheral blood. In seven of these 14 patients (four ALL, two AML and one MDS), subfractions were characterized at the time of frank haematological relapse. In all 14 patients investigated with increasing MC, recipient cells were detected in different mononuclear cell subpopulations. In patients characterized during frank relapse, two distinct distribution patterns were found. Patients who relapsed before day +300 (one ALL, two AML and one MDS) showed recipient-derived (normal) cells in addition to blast populations in different mononuclear subsets as well as granulocytes. In patients with acute leukaemias who relapsed after day +300 (two ALL and one AML), only leukaemic cells were found that were of recipient origin, whereas all other haematopoietic cell lines were donor derived. These data show that persistent MC in the early post-transplant period is caused predominantly by normal recipient haematopoietic cells. This finding further supports the hypothesis that a state of mixed haematopoietic chimaerism may reduce the clinical graft-versus-leukaemia (GVL) effect of alloreactive donor-derived effector cells in patients with acute leukaemias and MDS, and thus facilitate the proliferation of residual malignant cells that may have survived the preparative regimen.
Bader P, Kreyenberg H, Hoelle W, Dueckers G, Handgretinger R, Lang P, Kremens B, Dilloo D, Sykora KW, Schrappe M, Niemeyer C, Von Stackelberg A, Gruhn B, Henze G, Greil J, Niethammer D, Dietz K, Beck JF, Klingebiel T	Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation.	J Clin Oncol 2004, 22: 1696
Bader P, Kreyenberg H, Hoelle W, Dueckers G, Kremens B, Dilloo D, Sykora K, Niemeyer C, Reinhardt D, Vormoor J, Gruhn B, Lang P, Greil J, Handgretinger R, Niethammer D, Klingebiel T, Beck J	Increasing mixed chimerism defines a high-risk group of childhood acute myelogenous leukemia patients after allogeneic stem cell transplantation where pre-emptive immunotherapy may be effective.	Bone Marrow Transplant 2004, 33: 815
Bader P, Niemeyer C, Weber G, Coliva T, Rossi V, Kreyenberg H, Gerecke A, Biondi A	WT1 gene expression: useful marker for minimal residual disease in childhood myelodysplastic syndromes and juvenile myelo-monocytic leukemia?	European journal of haematology 2004, 73: 25
The WT1 gene is considered to be highly expressed in patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia and chronic myeloid leukemia and is thought to play a key role in maintaining the viability of leukemia cells. However, little is known about the WT1 gene expression levels in pediatric patients with juvenile myelo-monocytic leukemia (JMML) and myelodysplastic syndromes (MDS). We studied WT1 expression in diagnostic bone marrow (BM) and peripheral blood (PB) samples of 90 patients with JMML, low grade MDS, advanced MDS and myelodysplasia-related AML in BM (n = 20) and PB (n = 18) samples of normal healthy volunteer donors.
Bader P, Niemeyer C, Willasch A, Kreyenberg H, Strahm B, Kremens B, Gruhn B, Dilloo D, Vormoor J, Lang P, Niethammer D, Klingebiel T, Beck JF	Children with myelodysplastic syndrome (MDS) and increasing mixed chimaerism after allogeneic stem cell transplantation have a poor outcome which can be improved by pre-emptive immunotherapy.	British journal of haematology 2005, 128: 649
We recently reported that virtually all children with acute leukaemia and myelodysplastic syndrome (MDS) who develop the phenotype of increasing mixed chimaerism (MC) after allogeneic stem cell transplantation (allo-SCT) will relapse. We therefore performed a prospective, multi-centre study focused on children with MDS (n = 65; advanced MDS = 44, refractory cytopenia = 21) after allo-SCT in order to determine to what extent relapse can be prevented by pre-emptive immunotherapy on the basis of increasing MC. Analyses of chimaerism in 44 patients with advanced MDS revealed 31 cases with complete chimaerism (CC)/low-level MC/transient MC, 11 cases with increasing MC and two cases with decreasing MC. The same analyses in 21 MDS patients with refractory cytopenia revealed 17 cases with CC/low-level MC, one case with increasing MC and three cases with decreasing MC. Pre-emptive immunotherapy performed on each patient that showed increasing MC improved event-free survival from 0%, as seen in prior studies, to 50%. We therefore conclude that pre-emptive immunotherapy is an effective treatment option to prevent impending relapse in children with MDS after allo-SCT.
Bader P, Kreyenberg H, Henze GH, Eckert C, Reising M, Willasch A, Barth A, Borkhardt A, Peters C, Handgretinger R, Sykora KW, Holter W, Kabisch H, Klingebiel T, von Stackelberg A, ALL-REZ BFM Study Group	Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group.	Journal of clinical oncology 2009, 27: 377
PURPOSE: Minimal residual disease (MRD) before allogeneic stem-cell transplantation was shown to predict outcome in children with relapsed acute lymphoblastic leukemia (ALL) in retrospective analysis. To verify this, the Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster (ALL-REZ BFM) Study Group conducted a prospective trial. PATIENTS AND METHODS: Between March 1999 and July 2005, 91 children with relapsed ALL treated according to the ALL-REZ BFM 96 or 2002 protocols and receiving stem-cell transplantation in >or= second remission were enrolled. MRD quantification was performed by real-time polymerase chain reaction using T-cell receptor and immunoglobulin gene rearrangements. RESULTS: Probability of event-free survival (pEFS) and cumulative incidence of relapse (CIR) in 45 patients with MRD >or= 10(-4) leukemic cells was 0.27 and 0.57 compared with 0.60 and 0.13 in 46 patients with MRD less than 10(-4) leukemic cells (EFS, P = .004; CIR, P < .001). Intermediate-risk patients (strategic group S1) with MRD >or= 10(-4) leukemic cells (n = 14) had a pEFS of 0.20 and CIR of 0.73, whereas patients with MRD less than 10(-4) leukemic cells (n = 21) had a pEFS of 0.68 and CIR of 0.09 (EFS, P = .020; CIR, P < .001). High-risk patients (S3/4, third complete remission) who received transplantation with an MRD load of less than 10(-4) leukemic cells (n = 25) showed a pEFS and CRI of 0.53 and 0.18, respectively. In contrast, pEFS and CRI were 0.30 and 0.50 in patients who received transplantation with an MRD load of >or= 10(-4) leukemic cells. Multivariate Cox regression analysis revealed MRD as the only independent parameter predictive for EFS (P = .006). CONCLUSION: MRD is an important predictor for post-transplantation outcome. As a result, new strategies with modified stem-cell transplantation procedures will be evaluated in ALL-BFM trials.
Bader P, Kreyenberg H, von Stackelberg A, Eckert C, Salzmann-Manrique E, Meisel R, Poetschger U, Stachel D, Schrappe M, Alten J, Schrauder A, Schulz A, Lang P, Müller I, Albert MH, Willasch AM, Klingebiel TE, Peters C	Monitoring of Minimal Residual Disease After Allogeneic Stem-Cell Transplantation in Relapsed Childhood Acute Lymphoblastic Leukemia Allows for the Identification of Impending Relapse: Results of the ALL-BFM-SCT 2003 Trial.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2015, epub ahead of print
To elucidate the impact of minimal residual disease (MRD) after allogeneic transplantation, the Acute Lymphoblastic Leukemia Berlin-Frankfurt-Münster Stem Cell Transplantation Group (ALL-BFM-SCT) conducted a prospective clinical trial.
Bader P, Bornhäuser M, Grigoleit G-U, Kröger N	Monitoring, Chimärismusanalysen und Bestimmung der minimalen Resterkrankung (MRD) - Allogene Stammzelltransplantation.	Onkopedia Leitlinie - Empfehlungen der Fachgesellschaft zur Diagnostik und Therapie hämatologischer und onkologischer Erkrankungen 2016
Bader P, Rossig C, Hutter M, Ayuk FA, Baldus CD, Bücklein VL, Bonig H, Cario G, Einsele H, Holtick U, Koenecke C, Bakhtiar S, Künkele A, Meisel R, Müller F, Müller I, Penack O, Rettinger E, Sauer MG, Schlegel PG, Soerensen J, von Stackelberg A, Strahm B, Hauer J, Feuchtinger T, Jarisch A	CD19 CAR T cells are an effective therapy for posttransplant relapse in patients with B-lineage ALL: real-world data from Germany.	Blood advances 2023, 7: 2436
Patients with precursor B-cell acute lymphoblastic leukemia (pB-ALL) who have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT), have relapsed more than once, or are resistant upfront have a dismal prognosis. CD19-targeted chimeric antigen receptor (CAR) T cells have evolved as potent immune therapies. Tisagenlecleucel (Tisa-cel) is a commercially available autologous CD19-directed CAR T-cell product. We performed a retrospective study inviting all CAR T-cell centers in Germany to participate. Eighty-one patients with pB-ALL were included. Twenty-eight days after CAR T-cell infusion, 71 patients (87.7%) were in complete response, and 8 (9.9%) were in nonremission. At 2 years, the probabilities of event-free survival (pEFS), relapse-free survival (pRFS), and overall survival (pOS) were 45.3%, 51.7%, and 53.2%, respectively. pEFS was not different in patients without (n = 16, 55.0%) vs with prior allo-HSCT (n = 65, 43.4%). In patients treated after allo-HSCT, the time to relapse after allo-HSCT was a strong predictor of outcome. Patients relapsing within 6 months of allo-HSCT had a disappointing pEFS of 18.4% (pOS = 16.0%); the pEFS for those relapsing later was 55.5% (pOS = 74.8%). Our study provides real-world experience in pediatric, adolescent, and young adult patients with ALL treated with Tisa-cel, where most patients were treated after having relapsed after allo-HSCT. A total of 45.3% were rescued with a single dose of Tisa-cel. Our novel finding that patients with ALL after allo-HSCT had by far a better pEFS if relapse occurred beyond 6 months might be helpful in clinical decision-making and motivates studies to uncover the reasons.
Bagnasco F, Zimmermann SY, Egeler RM, Nanduri VR, Cammarata B, Donadieu J, Lehrnbecher T, Haupt R	Langerhans cell histiocytosis and associated malignancies: A retrospective analysis of 270 patients.	European journal of cancer 2022, 172: 138
The frequency of Langerhans cell histiocytosis (LCH) and associated malignancies (AM) is greater than statistically expected. Here, we analyze LCH-AM co-occurrence in both children and adults.
Bahar M, Kordes U, Tekautz T, Wolff J	Radiation therapy for choroid plexus carcinoma patients with Li-Fraumeni syndrome: advantageous or detrimental?	Anticancer research 2015, 35: 3013
Bailey S, André N, Gandola L, Massimino M, Rutkowski S, Clifford SC	Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial.	Cancers 2022, 14
Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront 'window' and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.
Baker KS, DeLaat CA, Steinbuch M, Gross TG, Shapiro RS, Loechelt B, Harris R, Filipovich AH	Successful correction of hemophagocytic lymphohistiocytosis with related or unrelated bone marrow transplantation.	Blood 1997, 89: 3857
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation leading to widespread lymphocytic and hemophagocytic infiltration of vital organs. Apparent cure has only been achieved with allogeneic bone marrow transplantation (BMT). This report describes 20 consecutive patients, who underwent either matched sibling donor (n = 4) or unrelated donor (URD; n = 16) BMT. Age at the time of BMT was 0.4 to 5.3 years (median, 0.8 years). Central nervous system disease was present at diagnosis in 13 patients. At BMT, 14 patients were in a clinical remission, whereas 6 patients had active HLH. All patients were engrafted after cytoreduction with busulfan, cyclophosphamide, and etoposide. The probability of grade II-III acute graft-versus-host disease (GVHD) for all patients was 57% (95% confidence limit [CL], 0.28, 0.86), and 73% (95% CL, 0.44, 1.0) in URD patients. The overall probability of survival at 3 years was 45% (95% CL, 0.23, 0.67) and 44% (95% CL, 0.19, 0.68) when URD BMT was evaluated separately. Favorable BMT outcome was associated with clinical remission status at the time of BMT. The preparative regimen was well tolerated, and in the 9 surviving patients it provided durable engraftment and was effective at eradicating the underlying disease.
Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL	New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2003 Apr 1; 21: 1352
To determine the incidence and risk factors for the development of new malignancies occurring after stem-cell transplantation (SCT).
Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P, Klingebiel T, Peters C, Stary J, Felice MS, Magyarosy E, Conter V, Reiter A, Messina C, Gadner H, Schrappe M	Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study.	Lancet 2005, 366: 635
BACKGROUND: The dismal prognosis of very-high-risk childhood acute lymphoblastic leukaemia could be improved by allogeneic haemopoietic cell transplantation. We compared this strategy with intensified chemotherapy protocols, with the aim to improve the outcome of children with very-high-risk acute lymphoblastic leukaemia in first complete remission. METHODS: A cooperative prospective study was set up in seven countries. Very-high-risk acute lymphoblastic leukaemia in first complete remission was defined by the presence of at least one of the following criteria: (1) failure to achieve complete remission after the first four-drug induction phase; (2) t(9;22) or t(4;11) clonal abnormalities; and (3) poor response to prednisone associated with T immunophenotype, white-blood-cell count of 100x10(9)/L or greater, or both. Children were allocated treatment by genetic chance, according to the availability of a compatible related donor, and assigned chemotherapy or haemopoietic-cell transplantation. The primary outcome was disease-free survival and analysis was by intention to treat. FINDINGS: Between April, 1995, and December, 2000, 357 children entered the study, of whom 280 were assigned chemotherapy and 77 related-donor haemopoietic-cell transplantation. 5-year disease-free survival was 40.6% (SE 3.1) in children allocated chemotherapy and 56.7% (5.7) in those assigned transplantation (hazard ratio 0.67 [95% CI 0.46-0.99]; p=0.02); 5-year survival was 50.1% (3.1) and 56.4% (5.9), respectively (0.73 [0.49-1.09]; p=0.12). INTERPRETATION: Children with very-high-risk acute lymphoblastic leukaemia benefit from related-donor haemopoietic-cell transplantation compared with chemotherapy. The gap between the two strategies increases as the risk profile of the patient worsens.
Balmer A, Zografos L, Munier F	Diagnosis and current management of retinoblastoma.	Oncogene 2006 Aug 28; 25: 5341
Retinoblastoma represents the prototypic model for inherited cancers. The RB1 gene was the first tumor suppressor gene to be identified. It represents the most frequent primary eye cancer in children under 15 years old, habitually occurring in infancy, even in utero, but can be observed in older children or young adults. Many other retinal lesions may also simulate retinoblastoma. The two major presenting signs are leukocoria and strabismus, but other ocular or general signs may be observed. A highly malignant tumor, retinoblastoma can nowadays be cured. The heritable form, however, carries a high risk of second nonocular tumors. Treatment in the early stages of disease holds a good prognosis for survival and salvage of visual function. In very late stages, however, the prognosis for ocular function and even survival is jeopardized.
Balduzzi A, De Lorenzo P, Schrauder A, Conter V, Uderzo C, Peters C, Klingebiel T, Stary J, Felice MS, Magyarosy E, Schrappe M, Dini G, Gadner H, Valsecchi MG	Eligibility for allogeneic transplantation in very high risk childhood acute lymphoblastic leukemia: the impact of the waiting time.	Haematologica 2008, 93: 925
The advantage of allogeneic transplant from compatible related donors versus chemotherapy in children with very-high-risk acute lymphoblastic leukemia in first complete remission was previously demonstrated in an international prospective trial. This study quantified the impact of time elapsed in first remission in the same cohort. Of 357 pediatric patients with very-high-risk acute lymphoblastic leukemia, 259 received chemotherapy, 55 transplantation from compatible related and 43 from unrelated donors. The 5-year disease-free survival was 44.2% overall and 42.5% for chemotherapy only patients. The chemotherapy conditional 5-year disease-free survival increased to 44.4%, 47.6%, 51.7%, and 60.4% in patients who maintained their first remission for at least 3, 6, 9, and 12 months respectively. The overall outcome was superior to that obtained with chemotherapy-only at any time-point. The relative advantage of transplant from compatible related donors in very-high-risk childhood acute lymphoblastic leukemia was consistent for any time elapsed in first remission.
Balgobind BV, Hollink IH, Reinhardt D, van Wering ER, de Graaf SS, Baruchel A, Stary J, Beverloo HB, de Greef GE, Pieters R, Zwaan CM, van den Heuvel-Eibrink MM	Low frequency of MLL-partial tandem duplications in paediatric acute myeloid leukaemia using MLPA as a novel DNA screenings technique.	European journal of cancer 2010,
Mixed-lineage leukaemia (MLL)-partial tandem duplications (PTDs) are found in 3-5% of adult acute myeloid leukaemia (AML), and are associated with poor prognosis. In adult AML, MLL-PTD is only detected in patients with trisomy 11 or internal tandem duplications of FLT3 (FLT3-ITD). To date, studies in paediatric AML are scarce, and reported large differences in the frequency of MLL-PTD, frequently utilising mRNA RT-PCR only to detect MLL-PTDs. We studied the frequency of MLL-PTD in a large cohort of paediatric AML (n=276) and the results from two different methods, i.e. mRNA RT-PCR, and multiplex ligation-dependent probe amplification (MLPA), a method designed to detect copy number differences of specific DNA sequences. In some patients with an MLL-rearrangement, MLL-PTD transcripts were detected, but were not confirmed by DNA-MLPA, indicating that DNA-MLPA can more accurately detect MLL-PTD compared to mRNA RT-PCR. In paediatric AML, MLL-PTD was detected in 7/276 patients (2.5%). One case had a trisomy 11, while the others had normal cytogenetics. Furthermore 4 of the 7 patients revealed a FLT3-ITD, which was significantly higher compared with the other AML cases (p=0.016). In conclusion, using DNA-MLPA as a novel screenings technique in combination with mRNA RT-PCR a low frequency of MLL-PTD in paediatric AML was found. Larger prospective studies are needed to further define the prognostic relevance of MLL-PTD in paediatric AML.
Balduzzi A, Galimberti S, Valsecchi MG, Bonanomi S, Conter V, Barth A, Rovelli A, Henze G, Biondi A, von Stackelberg A	Autologous purified peripheral blood stem cell transplantation compare to chemotherapy in childhood acute lymphoblastic leukemia after low-risk relapse.	Pediatric blood & cancer 2011, 57: 654
The treatment of childhood B-cell precursor acute lymphoblastic leukemia (ALL) after isolated extramedullary or late relapse is mostly based on chemotherapy or allogeneic transplantation. The aim of this study is to provocatively assess the role of purified autologous transplantation compared with best chemotherapy results in the same setting.
Ball S	Diamond Blackfan anemia.	Hematology Am Soc Hematol Educ Program 2011, 2011, 487
Mutations affecting genes encoding ribosomal proteins cause Diamond Blackfan anemia (DBA), a rare congenital syndrome associated with physical anomalies, short stature, red cell aplasia, and an increased risk of malignancy. p53 activation has been identified as a key component in the pathophysiology of DBA after cellular and molecular studies of knockdown cellular and animal models of DBA and other disorders affecting ribosomal assembly or function. Other potential mechanisms that warrant further investigation include impaired translation as the result of ribosomal insufficiency, which may be ameliorated by leucine supplementation, and alternative splicing leading to reduced expression of a cytoplasmic heme exporter, the human homolog of the receptor for feline leukemia virus C (FVLCR). However, the molecular basis for the characteristic steroid responsiveness of the erythroid failure in DBA remains unknown. This review explores the clinical and therapeutic implications of the current state of knowledge and delineates important but as-yet-unanswered questions.
Balcerek M, Reinmuth S, Hohmann C, Keil T, Borgmann-Staudt A	Suspected infertility after treatment for leukemia an solid tumors in childhood and adolescence.	Dtsch Arztebl Int 2012, 109
Background: With improved cure rates of cancer in children and adolescents, the long-term effects of oncological treatment, including impaired fertility, have become an important clinical issue. Methods: In 2008, we conducted a nationwide survey in Germany in which we asked 4689 female and male patients who had been treated for cancer in childhood or adolescence for information on menstruation, previous fertility testing (if any), attempts to conceive, and pregnancies. In a complementary study carried out in 2009, 748 former cancer patients in Berlin were offered hormone testing and sperm analysis. The defined criteria for suspected infertility were, in women, anti-muellerian hormone levels below 0.1 ng/mL; in men, FSH levels above 10 IU/L and inhibin B levels below 80 pg/mL, or azoospermia. Results: The respondents to the nationwide survey included 1476 leukemia survivors and 1278 persons who had had a solid tumor. 104 former leukemia patients and 96 former solid tumor patients had already undergone fertility testing, leading to the suspicion of infertility in 26% and 34% of the persons in these respective groups (95% confidence intervals [CI], 18%–34% and 25%–43%). The patients who were tested in the Berlin study included 59 leukemia survivors and 104 persons who had had a solid tumor. The frequency of suspected infertility in these two groups was 25% and 27%, respectively (95% CI, 14%–36% and 18%–36%). Conclusion: Up to one-third of adults who undergo fertility testing after having been treated for cancer in childhood or adolescence have suspected infertility. Patients and their parents should be counseled about the possibility of infertility and about fertility-preserving measures.
Ballas SK, Gupta K, Adams-Graves P	Sickle cell pain: a critical reappraisal.	Blood 2012, 120: 3647
Sickle cell pain includes 3 types: acute recurrent painful crises, chronic pain syndromes, and neuropathic pain. The acute painful crisis is the hallmark of the disease and the most common cause of hospitalization and treatment in the emergency department. It evolves through 4 phases: prodromal, initial, established, and resolving. Each acute painful episode is associated with inflammation that worsens with recurrent episodes, often culminating in serious complications and organ damage, such as acute chest syndrome, multiorgan failure, and sudden death. Three pathophysiologic events operate in unison during the prodromal phase of the crisis: vaso-occlusion, inflammation, and nociception. Aborting the acute painful episode at the prodromal phase could potentially prevent or minimize tissue damage. Our hypothesis is that managing these events with hydration, anti-inflammatory drugs, aggressive analgesia, and possibly vasodilators could abort the crisis and prevent or minimize further damage. Chronic pain syndromes are associated with or accompany avascular necrosis and leg ulcers. Neuropathic pain is not well studied in patients with sickle cell disease but has been modeled in the transgenic sickle mouse. Management of sickle cell pain should be based on its own pathophysiologic mechanisms rather than borrowing guidelines from other nonsickle pain syndromes.
Balcerek M, Reinmuth S, Hohmann C, Keil T, Borgmann-Staudt A	Verdacht auf Infertilität nach Leukämien und soliden Tumoren im Kindes- und Jugendalter.	Dtsch Arztebl 2012, 109
Balcerek M, Schilling R, Schlack R, Borgmann-Staudt A	Nationwide Survey on the Health of Offspring from Former Childhood Cancer Patients in Germany - Studie zur Gesundheit von Nachkommen ehemaliger kinderonkologischer Patienten in Deutschland.	Klin Pädiatr 2015, 227: 350
Background: Increased risk for infertility from cancer treatment and fear of health impairment in their offspring may prevent survivors of childhood cancer from having own children. Even though most studies report no increased risk for malformations, in our German fertility study 2008 a higher occurrence of cleft lip and palate was found in offspring of former patients. Methods: Since 2010 we assess offspring's health in a survey-based multicenter study, comparing diseases, well-being, healthcare utilization and health-related behavior between offspring from survivors, siblings or the general population. Within a first nationwide survey wave survivors who were known to have at least one child by previous fertility studies, received a questionnaire supported by the German Childhood Cancer Registry. Questionnaires were based on the KiGGS study on children's health in the German general population conducted by the Robert-Koch Institute (n=17,641). Results: Questionnaires on 418 children were answered by 65% (254/393) of survivors contacted to participate in the first nationwide offspring study wave. Participants were more likely to be female (p<0.01), to have achieved higher educational levels (p<0.05) and to be a survivor of a soft tissue tumor (p<0.05). Former patients expressed moderate to high anxiety for the occurrence of cancer in 74% and feared other diseases in their children in 20%. Conclusion: Offspring health is a topic of major relevance to former patients. Our offspring study is currently being extended to ~1500 offspring of childhood cancer survivors in Europe.
Ballas SK	The Use of Cannabis by Patients with Sickle Cell Disease Increased the Frequency of Hospitalization due to Vaso-Occlusive Crises.	Cannabis and cannabinoid research 2017, 2: 197
Introduction: The objective of this study was to determine if patients with sickle cell disease using cannabis had decreased frequency of acute vaso-occlusive crises (VOCs) that required hospitalization. Method: This was a retrospective study in which 270 urine drug screen tests were done on 72 patients: 40 males and 32 females. Results: Cannabinoids were found in 144 urine tests from 37 patients and were negative in 126 tests from 35 patients. Males who used cannabis were significantly younger (p<0.001) than males who did not. Patients who tested positive used benzodiazepines, cocaine, and phencyclidine significantly more often than patients who tested negative. There was no significant difference in the amounts of opioids consumed by users and nonusers of cannabis. The cannabis cohort was seen in the clinic significantly (p<0.05) less often than controls, but hospital admissions were significantly greater in the cannabis group than controls (p<0.05). Conclusion: These data show an unexpected negative effect of cannabis on the frequency of VOCs. This may be due to the effect of cannabis on the brain and/or the severity of the disease in the cannabis users. More controlled studies are needed to clarify these findings.
Balcerek M, Schuster T, Korte E, Seidel J, Schilling R, Hölling H, Borgmann-Staudt A	Health-Related Behaviour Among Children of Childhood Cancer Survivors in Germany - Gesundheitsverhalten von Kindern ehemaliger kinderonkologischer Patienten in Deutschland.	Klin Pädiatr 2017, 229: 118
Purpose: Childhood cancer survivors fear that previous therapy could not only impair their own but also their children's health. We examined whether health-related behaviour in children of childhood cancer survivors differs from the general population. Methods: Our first nationwide survey wave (2013-2014) surveyed offspring health in 396 German childhood cancer survivors known to have a child of their own. Answers about health behaviour were analysed using descriptive statistics. Data were collected for 418 offspring and 394 could be integrated for matched-pair analyses with data from the German general population (KIGGS, n=17 641). Results: Teeth-cleaning routine, body-mass-index or subjective body image evaluation by parents were no different from children in the general population. Parents who included a cancer survivor smoked less in the presence of their children (p=0.01). During pregnancy, mothers in cancer survivor parent pairs abstained from drinking alcohol more often (p=0.01) and smoked less (p=0.05). While the calculated effect sizes (Phi) were generally low (0.135-0.247), children from cancer survivors played less outdoors than peers did (p=0.01). Boys participated in sports outside a club more often (p=0.05) and watched less TV on weekdays (p=0.01) and girls spent more time on the computer during weekdays than peers did (p=0.01). Conclusions: This study provides the first data for health-related behaviour in cancer survivors' offspring and sheds light on differences to parenting in the general population. Multivariate analyses in a larger study population are needed to relate these differences to fear issues in cancer survivors.
Ballas SK	The Evolving Pharmacotherapeutic Landscape for the Treatment of Sickle Cell Disease.	Mediterr J Hematol Infect Dis 2020, 12:e2020010
Sickle cell disease (SCD) is an extremely heterogeneous disease that has been associated with global morbidity and early mortality. More effective and inexpensive therapies are needed. During the last five years, the landscape of the pharmacotherapy of SCD has changed dramatically. Currently, 54 drugs have been used or under consideration to use for the treatment of SCD. These fall into 3 categories: the first category includes the four drugs (Hydroxyurea, L-Glutamine, Crizanlizumab tmca and Voxelotor) that have been approved by the United States Food and Drug Administration (FDA) based on successful clinical trials. The second category includes 22 drugs that failed, discontinued or terminated for now and the third category includes 28 drugs that are actively being considered for the treatment of SCD. Crizanlizumab and Voxelotor are included in the first and third categories because they have been used in more than one trial. New therapies targeting multiple pathways in the complex pathophysiology of SCD have been achieved or are under continued investigation. The emerging trend seems to be the use of multimodal drugs (i.e. drugs that have different mechanisms of action) to treat SCD similar to the use of multiple chemotherapeutic agents to treat cancer.
Bamberg M, Kortmann RD, Calaminus G, Becker G, Meisner C, Harms D, Göbel U	Radiation therapy for intracranial germinoma: results of the German cooperative prospective trials MAKEI 83/86/89.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1999, 17: 2585
PURPOSE: A multicenter prospective trial was conducted (Maligue Keimzelltümoren [MAKEI] 83/86/89) to assess outcome in intracranial germinoma after treatment with radiotherapy alone at reduced doses. PATIENTS AND METHODS: Between 1983 and 1993, 60 patients with histologically (n = 58) or cytologically (n = 2) confirmed germinoma were enrolled onto the study. Patients received radiotherapy alone (craniospinal axis/local boost). In the MAKEI 83/86 study (involving 11 patients), the dose to the craniospinal axis was 36 Gy and the dose to the tumor region was 14 Gy. In the MAKEI 89 study (involving 49 patients), doses were 30 and 15 Gy, respectively. RESULTS: Median patient age was 13 years (range, 6 to 31 years). Complete remission was achieved in all patients. The estimated (Kaplan-Meier) 5-year relapse-free survival rate was 91.0% +/- 3.9% at a mean follow-up of 59.5 months (range, 3 to 180 months); the estimated overall survival rate was 93.7% +/- 3.6%. Relapse occurred in five patients 10 to 33 months (mean, 18.4 months) after diagnosis (one patient developed a spinal canal metastasis and underwent salvage radiotherapy and chemotherapy; four patients had metastases outside the CNS and underwent salvage chemotherapy alone). Four patients died: one died from disease, two died from therapy-related complications, and one committed suicide. Acute complications with long-lasting sequelae were tumor or surgery related (three cases of blindness, six of reduced vision, two of hemiparesis). Psychosocial development was normal in the majority of patients. CONCLUSION: Radiotherapy directed toward the craniospinal axis or tumor site alone at decreased dose levels is effective. To reduce the risk of late side effects, further attempts to decrease total doses are justified. In cases of recurrent disease, chemotherapy administered outside the CNS is the treatment of choice.
Banning U, Barthel H, Mauz-Körholz C, Kluge R, Körholz D, Sabri O	Effect of drug-induced cytotoxicity on glucose uptake in Hodgkin's lymphoma cells.	European journal of haematology 2006, 77: 102
BACKGROUND: In Hodgkin's lymphoma, F-18-fluoro-deoxy-d-glucose positron emission tomography (FDG-PET) is used for staging and response evaluation after chemotherapy. However, drug-mediated downregulation of glucose uptake in viable Hodgkin's lymphoma cells might limit the use of FDG-PET. METHODS: We analyzed the effect of etoposide on cell viability and uptake of F-18-fluoro-deoxy-D-glucose or the glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) in vitro. RESULTS: Etoposide induced a dose-dependent cytotoxicity in HDLM-2 cells which was significantly correlated with reduced FDG uptake. However, it also significantly increased the portion of viable cells which did not take up 2-NBDG. Interestingly, etoposide-induced cytotoxicity was mainly mediated via caspase-dependent mechanisms, whereas the cell death induced by deprivation of glucose was mediated via caspase-independent mechanisms. CONCLUSION: Etoposide-mediated reduction of glucose uptake by Hodgkin's lymphoma cells is mainly caused by cell death. In a small fraction of viable cells, etoposide might downregulate glucose transporters and/or hexokinase activity and by that inhibit glucose uptake. This, however, might not lead to false-negative results of response evaluation in Hodgkin's lymphoma patients after chemotherapy, because inhibition of glucose uptake itself seems to be a strong inducer of cell death. Altogether, this study provides important in vitro evidence to clarify the mechanisms by which FDG-PET monitors the effect of anti-cancer treatment in Hodgkin's lymphoma patients.
Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD, Koehler R, Muckenthaler MU, Kulozik AE	NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia.	Haematologica 2013, Epub ahead of print
Abstract Background: Despite improvements of treatment results for pediatric T-cell acute lymphoblastic leukemia (T-ALL), approximately 20% of patients relapse with dismal prognosis. Phosphatase and tensin homolog (PTEN) inactivation and NOTCH1 activation are known frequent leukemogenic events but their effect on outcome have been controversial. Design and methods: We analysed the effect of PTEN inactivation and its interaction with NOTCH1 activation on treatment response and long term outcome in 301 ALL-BFM treated children with T-cell acute lymphoblastic leukemia. Results: We identified PTEN mutations in 52/301 (17.3%) of patients, which in univariate analyses was significantly associated with increased resistance to induction chemotherapy and a trend towards poor long-term outcome. By contrast, patients with inactivating PTEN and activating NOTCH1 mutations showed marked sensitivity to induction treatment and excellent long term outcome, which was similar to patients with NOTCH1 mutations only and more favorable than in patients with PTEN mutations only. Notably, in the subgroup of patients with a prednisone- and MRD-response based medium risk profile PTEN-mutations without co-existing NOTCH1-mutations represented an MRD-independent highly significant high risk biomarker. Conclusions: Mutations of PTEN highly significantly indicate a poor prognosis in patients who have been stratified to the medium risk group of the BFM-protocol. This effect is clinically neutralized by NOTCH1 mutations. Although these results are not yet explained by an obvious molecular mechanism, they contribute to the development of new molecularly defined stratification algorithms. Furthermore, these data have unexpected potential implications for the development of NOTCH1 inhibitors in the treatment of T-cell acute lymphoblastic leukemia in general and in those with a combination of PTEN and NOTCH1 mutations in particular.
Bandapalli OR, Schuessele S, Kunz JB, Rausch T, Stütz AM, Tal N, Geron I, Gershman N, Izraeli S, Eilers J, Vaezipour N, Kirschner-Schwabe R, Hof J, von Stackelberg A, Schrappe M, Stanulla M, Zimmermann M, Koehler R, Avigad S, Handgretinger R, Frismantas V, Bourquin JP, Bornhauser B, Korbel JO, Muckenthaler MU, Kulozik AE	The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse.	Haematologica 2014, Epub ahead of print
Brief Summary Precursor T-cell acute lymphoblastic leukemia represents one of the major challenges of pediatric oncology, because relapses are frequently fatal and the molecular understanding of leukemogenesis and maintenance is limited in this entity. Here, we aimed at identifying novel leukemogenic driver mutations and first analyzed trios of bone marrow DNA of 5 patients with T-cell acute lymphoblastic leukemia obtained at initial diagnosis, remission and relapse by whole exome sequencing. We identified a recurrent, leukemia-specific mutation resulting in a N642H amino acid substitution in the SH2-domain of STAT5B. We subsequently validated these results by sequencing the entire STAT5B gene in two independent large cohorts of patients and identified this mutation in 17 of 301 patients (6.3%) with primary T-cell acute lymphoblastic leukemia recruited from the ALL-BFM 2000 trial and in 7 of 78 relapsed T-cell acute lymphoblastic leukemia patients (9.0%) from the BFM-ALL-REZ trials. The analysis of clinical data revealed that the presence of this mutation was associated with a significantly increased risk of relapse (RR 2.47, p=0.038). Cell based assays in transduced BaF3 cells and in xenografted leukemic cells showed this mutation to confer constitutive STAT5 phosphorylation, cytokine independent growth characteristics. We conclude that the STAT5B N642H mutation is common in pediatric T-cell acute lymphoblastic leukemia and results in an activation of oncogenic pathways, conferring an increased risk of relapse.
Bartram C, Ludwig W, Hiddemann W, Lyons J, Buschle M, Ritter J, Harbott J, Fröhlich A, Janssen J	Acute myeloid leukemia: analysis of ras gene mutations and clonality defined by polymorphic X-linked loci.	Leukemia 1989, 3: 247
Bartram CR, Schrauder A, Köhler R, Schrappe M	Akute lymphoblastische Leukämie bei Kindern (Übersichtsarbeit).	Dtsch Arztebl Int 2012; 109: 652
Barthels M, Alban S, Bergmann F, Ganser A, Studt JD, Tiede A, Ziemer S	Das Gerinnungskompendium.	Georg Thieme Verlag Stuttgart 2. Auflage 2012
"Das Gerinnungskompendium“ erscheint in zweiter Auflage, jetzt dank der Zusammenarbeit mehrerer, im hämostaseologischen Alltag erfahrener Autoren, die – ein neuartiges Konzept – im Bedarfsfall sich untereinander austauschten. Unverändert blieb jedoch das Konzept des Buches, nämlich Informationen komprimiert und systematisch gegliedert anzubieten. Die primäre Aufgabe dieses Buches ist die Schnellorientierung in der Hämostaseologie, insbesondere in der Diagnostik von Gerinnungsstörungen und in der Interpretation von Messergebnissen.
Bartram T, Burkhardt B, Wössmann W, Seidemann K, Zimmermann M, Cario G, Lisfeld J, Ellinghaus E, Franke A, Houlston RS, Schrappe M, Reiter A, Stanulla M	Childhood acute lymphoblastic leukemia-associated risk-loci IKZF1, ARID5B and CEBPE and risk of pediatric non-Hodgkin lymphoma: a report from the Berlin-Frankfurt-Münster Study Group.	Leukemia & lymphoma 2014,: 1
Bartelheim K, Sumerauer D, Behrends U, Kodetova D, Kucera F, Leuschner I, Neumayer P, Oyen F, Rübe C, Siebert R, Schneppenheim R, Seeringer A, Vasovcak P, Frühwald MC	Clinical and genetic features of rhabdoid tumors of the heart registered with the European Rhabdoid Registry (EU-RHAB).	Cancer genetics 2014, Epub ahead of print
Rhabdoid tumors are rare but highly aggressive malignancies of infancy and early childhood with a generally unfavorable prognosis. Despite a wide variety of anatomic locations rhabdoid tumors share mutational inactivation of the SWI/SNF (SWItch/Sucrose NonFermentable) core component gene SMARCB1 (also known as INI1, hSNF5 or BAF47) in chromosome 22. As this inactivation usually results in loss of SMARCB1 expression, detectable by an antibody against the SMARCB1 protein, the accurate diagnosis of a rhabdoid tumor may be more distinctly and frequently made. Several reports on rhabdoid tumors presenting in various anatomic sites outside the kidneys and CNS are on record. We report two cases of rhabdoid tumors originating in the heart (cardiac tissue), which were entered into the European Rhabdoid Registry (EU-RHAB). The first case presented with intracardial and -cranial lesions as well as malignant ascites, while the second patient demonstrated an isolated cardiac tumor. This induced a different therapeutic approach and subsequently different clinical course (death 7 weeks after diagnosis in patient 1). Patient 2 presented with a bifocal intracardial tumor without metastases and remains in complete remission for 46 months since diagnosis following multimodal therapy. The second case demonstrates that even in a potentially futile clinical situation early and accurate diagnosis followed by prompt and intensive multimodal therapy may offer prolonged survival, potential cure and improved quality of life.
Baronciani D, Angelucci E, Potschger U, Gaziev J, Yesilipek A, Zecca M, Orofino MG, Giardini C, Al-Ahmari A, Marktel S, de la Fuente J, Ghavamzadeh A, Hussein AA, Targhetta C, Pilo F, Locatelli F, Dini G, Bader P, Peters C	Hemopoietic stem cell transplantation in thalassemia: a report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry, 2000-2010.	Bone Marrow Transplant 2016 [Epub ahead of print]
Allogeneic hemopoietic stem cell transplantation (HSCT) is the only method currently available to cure transfusion-dependent thalassemia major that has been widely used worldwide. To verify transplantation distribution, demography, activity, policies and outcomes inside the European Group for Blood and Marrow Transplantation (EBMT), we performed a retrospective non-interventional study, extracting data from the EBMT hemoglobinopathy prospective registry database. We included 1493 consecutive patients with thalassemia major transplanted between 1 January 2000 and 31 December 2010. In total, 1359 (91%) transplants were performed on patients <18 years old, 1061 were from a human leukocyte Ag-identical sibling donor. After a median observation time of 2 years, the 2-year overall survival (OS) and event-free survival (EFS; that is, thalassemia-free survival) were 88±1% and 81±1%, respectively. Transplantation from a human leukocyte Ag-identical sibling offered the best results, with OS and EFS of 91±1% and 83±1%, respectively. No significant differences in survival were reported between countries. The threshold age for optimal transplant outcomes was around 14 years, with an OS of 90-96% and an EFS of 83-93% when transplants were performed before this age. Allogeneic HSCT for thalassemia is a curative approach that is employed internationally and produces excellent results
Bartelheim K, Nemes K, Seeringer A, Kerl K, Buechner J, Boos J, Graf N, Dürken M, Gerss J, Hasselblatt M, Kortmann RD, Teichert von Luettichau I, Nagel I, Nygaard R, Oyen F, Quiroga E, Schlegel PG, Schmid I, Schneppenheim R, Siebert R, Solano-Paez P, Timmermann B, Warmuth-Metz M, Frühwald MC	Improved 6-year overall survival in AT/RT - results of the registry study Rhabdoid 2007.	Cancer medicine 2016,
Atypical teratoid rhabdoid tumors (AT/RT) are characterized by mutations and subsequent inactivation of SMARCB1 (INI1, hSNF5), a predilection for very young children and an unfavorable outcome. The European Registry for rhabdoid tumors (EU-RHAB) was established to generate a common European database and to establish a standardized treatment regimen as the basis for phase I/II trials. Thus, genetic analyses, neuropathologic and radiologic diagnoses, and a consensus treatment regimen were prospectively evaluated. From 2005 to 2009, 31 patients with AT/RT from four countries were recruited into the registry study Rhabdoid 2007 and treated with systemic and intraventricular chemotherapy. Eight patients received high-dose chemotherapy, 23 radiotherapy, and 17 maintenance therapy. Reference evaluations were performed in 64% (genetic analyses, FISH, MLPA, sequencing) up to 97% (neuropathology, INI1 stain). Germ-line mutations (GLM) were detected in 6/21 patients. Prolonged overall survival was associated with age above 3Â years, radiotherapy and achievement of a complete remission. 6-year overall and event-free survival rates were 46% (Â±0.10) and 45% (Â±0.09), respectively. Serious adverse events and one treatment-related death due to insufficiency of a ventriculo peritoneal shunt (VP-shunt) and consecutive herniation were noted. Acquisition of standardized data including reference diagnosis and a standard treatment schedule improved data quality along with a survival benefit. Treatment was feasible with significant but manageable toxicity. Although our analysis is biased due to heterogeneous adherence to therapy, EU-RHAB provides the best available basis for phase I/II clinical trials.
Barz MJ, Hof J, Groeneveld-Krentz S, Loh JW, Szymansky A, Astrahantseff K, von Stackelberg A, Khiabanian H, Ferrando AA, Eckert C, Kirschner-Schwabe R	Subclonal NT5C2 mutations are associated with poor outcomes after relapse of pediatric acute lymphoblastic leukemia.	Blood 2020, 135: 921
Activating mutations in cytosolic 5'-nucleotidase II (NT5C2) are considered to drive relapse formation in acute lymphoblastic leukemia (ALL) by conferring purine analog resistance. To examine the clinical effects of NT5C2 mutations in relapsed ALL, we analyzed NT5C2 in 455 relapsed B-cell precursor ALL patients treated within the ALL-REZ BFM 2002 relapse trial using sequencing and sensitive allele-specific real-time polymerase chain reaction. We detected 110 NT5C2 mutations in 75 (16.5%) of 455 B-cell precursor ALL relapses. Two-thirds of relapses harbored subclonal mutations and only one-third harbored clonal mutations. Event-free survival after relapse was inferior in patients with relapses with clonal and subclonal NT5C2 mutations compared with those without (19% and 25% vs 53%, P < .001). However, subclonal, but not clonal, NT5C2 mutations were associated with reduced event-free survival in multivariable analysis (hazard ratio, 1.89; 95% confidence interval, 1.28-2.69; P = .001) and with an increased rate of nonresponse to relapse treatment (subclonal 32%, clonal 12%, wild type 9%, P < .001). Nevertheless, 27 (82%) of 33 subclonal NT5C2 mutations became undetectable at the time of nonresponse or second relapse, and in 10 (71%) of 14 patients subclonal NT5C2 mutations were undetectable already after relapse induction treatment. These results show that subclonal NT5C2 mutations define relapses associated with high risk of treatment failure in patients and at the same time emphasize that their role in outcome is complex and goes beyond mutant NT5C2 acting as a targetable driver during relapse progression. Sensitive, prospective identification of NT5C2 mutations is warranted to improve the understanding and treatment of this aggressive ALL relapse subtype.
Baroni LV, Rugilo C, Lubieniecki F, Sampor C, Freytes C, Nobre L, Hansford JR, Malalasekera VS, Zapotocky M, Dodgshun A, Martinez OC, La Madrid AM, Lavarino C, Suñol M, Rutkowski S, Schuller U, Bouffet E, Ramaswamy V, Alderete D	Treatment response of CNS high-grade neuroepithelial tumors with MN1 alteration.	Pediatric blood & cancer 2020, 67:e28627
Central nervous system high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) is a rare recently described entity. Fourteen CNS HGNET-MN1 patients were identified using genome-wide methylation arrays/RT-PCR across seven institutions. All patients had surgery (gross total resection: 10; subtotal resection: four) as initial management followed by observation alone in three patients, followed by radiotherapy in eight patients (focal: five; craniospinal: two; CyberKnife: one) and systemic chemotherapy in three patients. Seven patients relapsed; five local and two metastatic, despite adjuvant radiotherapy, of which three died. Treatment of CNS HGNET-MN1 remains a major treatment challenge despite aggressive surgical resections and upfront radiotherapy, warranting new approaches to this rare malignancy.
Bardou-Jacquet E, Morandeau E, Anderson GJ, Ramm GA, Ramm LE, Morcet J, Bouzille G, Dixon J, Clouston AD, Lainé F, Turlin B, Powell LW, Deugnier YM	Regression of Fibrosis Stage With Treatment Reduces Long-Term Risk of Liver Cancer in Patients With Hemochromatosis Caused by Mutation in HFE.	Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2020, 18: 1851
Fibrosis stage can decrease following treatment in patients with hemochromatosis caused by mutations in the homeostatic iron regulator gene (HFE), but the effects on cirrhosis are not clear. We assessed regression of severe fibrosis and the ensuing risk of liver cancer after treatment.
Bastian L, Einsiedel HG, Henze G, Seeger K, Shalapour S	The sequence of application of methotrexate and histone deacetylase inhibitors determines either a synergistic or an antagonistic response in childhood acute lymphoblastic leukemia cells.	Leukemia 2010 Nov 12;
Bastian L, Hof J, Pfau M, Fichtner I, Eckert C, Henze G, Prada J, von Stackelberg A, Seeger K, Shalapour S	Synergistic activity of bortezomib and HDACi in preclinical models of B-cell precursor acute lymphoblastic leukemia via modulation of p53, PI3K/AKT, and NF-κB.	Clinical cancer research 2013, 19: 1445
Relapse of disease and subsequent resistance to established therapies remains a major challenge in the treatment of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). New therapeutic options, such as proteasome and histone deacetylase inhibitors (HDACi) with a toxicity profile differing from that of conventional cytotoxic agents, are needed for these extensively pretreated patients.
Bastida JM, Lozano ML, Benito R, Janusz K, Palma-Barqueros V, Del Rey M, Hernández-Sánchez JM, Riesco S, Bermejo N, González-García H, Rodriguez-Alén A, Aguilar C, Sevivas T, López-Fernández MF, Marneth AE, van der Reijden BA, Morgan NV, Watson SP, Vicente V, Hernández-Rivas JM, Rivera J, González-Porras JR	Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders.	Haematologica 2018, 103: 148
Baumgarten E, Schmid H, Pohl U, Brzoska J, Linderkamp C, Siegert W, Henze G	Low-dose natural interleukin-2 and recombinant interferon-gamma following autologous bone marrow grafts in pediatric patients with high-risk acute leukemia.	Leukemia 1994, 8: 850
Bauer A, Savelyeva L, Claas A, Praml C, Berthold F, Schwab M	Smallest region of overlapping deletion in 1p36 in human neuroblastoma.	Genes Chromosomes Cancer 2001, 31: 228
Bause, H	Kryotherapie lokalisierter klassischer Hämangiome.	Monatsschr Kinderheilkd 2004, 152: 16
Die Kryotherapie gilt als etablierte Methode zur Behandlung der lokalisierten klassischen Hämangiome bei Säuglingen. An der Heilbronner Kinderklinik wurde sie bis März 2000 mit Flüssigstickstoff (−196°C) durchgeführt. Es wurde untersucht, ob auch geringere Minustemperaturen zur Behandlung ausreichen. 673 Kinder mit Hämangiomen wurden im Zeitraum von April 2000–März 2003 mit einem neuen Kälteverfahren mittels Peltier-Elementen (−32°C) behandelt. Das Gerät ist netzbetrieben; die auf −32°C gekühlten Stäbe werden mit möglichst konstantem manuellem Druck auf die Haut aufgesetzt. Die Einwirkungszeit beträgt 20 s. Nach 4 Wochen wurden der Erfolg kontrolliert und ggf. Reste oder Rezidive erneut behandelt. Die Kältestifte lassen sich ebenso gut wie die herkömmliche Methode zur Behandlung der Säuglingshämangiome einsetzen und weisen zudem Vorteile auf: Ihre Applikation bereitet weniger Schmerzen, der Heilungsverlauf (Blase und Kruste) ist kürzer, und die kosmetischen Ergebnisse sind überzeugend.
Bauer J, Jürgens H, Frühwald MC	Important aspects of nutrition in children with cancer.	Advances in nutrition (Bethesda, Md.) 2011, 2: 67
Adequate nutrition during cancer plays a decisive role in several clinical outcome measures, such as treatment response, quality of life, and cost of care. However, the importance of nutrition in children and young adults with malignancies is still an underestimated topic within pediatric oncology. The importance of our work is to reinforce and indicate that malnutrition in children with cancer should not be accepted at any stage of the disease or tolerated as an inevitable process. Unique to our manuscript is the close collaboration, the exchange of knowledge and expertise between pediatric oncologists and a nutritional specialist, as well as the comprehension of the mechanisms during cancer cachexia and malnutrition. We provide a critical review of the current state of research and new knowledge related to nutritional management in childhood cancer.
Baumann U, et al.	Primäre Immundefekte-Warnzeichen und Algorithmen zur Diagnosefindung.	2010
Bauer S, Dirksen U, Schildhaus HU	[Systemic therapy of sarcomas : New biomarkers and therapeutic strategies].	Der Pathologe 2019, 40: 436
Diagnostics and treatment of mesenchymal tumors (i.e.ÃÂ soft tissue sarcomas, gastrointestinal stromal tumors, and bone sarcomas) have changed dramatically in the past few years. Molecular and immunohistochemical biomarkers contribute significantly to improved diagnostics. They also play an increasing role in terms of clinical treatment decisions.Grading and tumor type-specific outcome data provide the basis for adjuvant chemotherapy of localized sarcomas. Recurrent gene fusions become more important as predictive biomarkers for targeted therapies in the context of systemic treatments. Immuno-oncology-based approaches are currently being studied in clinical trials, and the first responses of selected patients have been demonstrated. However, the role of predictive biomarkers in this field, such as PD-L1, still needs to be elucidated. Comprehensive genetic analyses of metastatic sarcomas will continue to identify additional therapeutic targets and the corresponding biomarkers.
Baumann FT, Zavetta E	Körperliche Aktivität ist ein wichtiger Baustein der Krebstherapie und der Vorsorge.	Aktuelle Gesundheits-Nachrichten der Europäischen Akademie für Naturheilverfahren und Umweltmedizin 36, 2020, 14
Bauer J, Köhler N, Maringer Y, Bucher P, Bilich T, Zwick M, Dicks S, Nelde A, Dubbelaar M, Scheid J, Wacker M, Heitmann JS, Schroeder S, Rieth J, Denk M, Richter M, Klein R, Bonzheim I, Luibrand J, Holzer U, Ebinger M, Brecht IB, Bitzer M, Boerries M, Feucht J, Salih HR, Rammensee HG, Hailfinger S, Walz JS	The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma.	Nature communications 2022, 13: 6401
The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease lacking specific therapies. This study reports on the identification, characterization, and immunotherapeutic application of HLA-presented neoantigens specific for the DNAJB1-PRKACA fusion transcript in fibrolamellar hepatocellular carcinoma. DNAJB1-PRKACA-derived HLA class I and HLA class II ligands induce multifunctional cytotoxic CD8 and T-helper 1 CD4 T cells, and their cellular processing and presentation in DNAJB1-PRKACA expressing tumor cells is demonstrated by mass spectrometry-based immunopeptidome analysis. Single-cell RNA sequencing further identifies multiple T cell receptors from DNAJB1-PRKACA-specific T cells. Vaccination of a fibrolamellar hepatocellular carcinoma patient, suffering from recurrent short interval disease relapses, with DNAJB1-PRKACA-derived peptides under continued Poly (ADP-ribose) polymerase inhibitor therapy induces multifunctional CD4 T cells, with an activated T-helper 1 phenotype and high T cell receptor clonality. Vaccine-induced DNAJB1-PRKACA-specific T cell responses persist over time and, in contrast to various previous treatments, are accompanied by durable relapse free survival of the patient for more than 21 months post vaccination. Our preclinical and clinical findings identify the DNAJB1-PRKACA protein as source for immunogenic neoepitopes and corresponding T cell receptors and provide efficacy in a single-patient study of T cell-based immunotherapy specifically targeting this oncogenic fusion.
Beck D, Creutzig U, Riehm H	Myelodysplastic and myeloproliferative syndromes in children.	Monogr in Paediat 1986, 153
Becker K, Berthold F	Plasma neurotensin: lack of a differentiation and tumor marker in children with neuroblastoma.	Pediatr Hematol Oncol 1992, 9: 269
Beck J, Winkler K, Niethammer D, Brandis M, Hertzberg H, Hardt von, Greil J, Überall M, Rossi R, Lamprecht-Dinnesen A	After-care of children and young adults surviving cancer. Initial recommendations by the late sequelae study group.	Klin Pädiatr 1995, 207: 186
Beck J, Hertzberg H, Kochendörfer S, Meier W, Göbel U, Greil J, Langer T	Neuropsychologische Spätfolgen nach Behandlung einer akuten lymphoblastischen Leukämie im Kindesalter.	Klin Onkol 1997, 11
Beck J, Dopfer R, Gadner H, Hertzberg H, Langer T, Niethammer D, Zoubek A	Besondere Aspekte in der Onkologie. Spätfolgen nach antineoplastischer Therapie.	Jugendmedizin 1999, 792
Beck J, Dörr H, Langer T, Bielack S, Rossi R, Gutjahr P	Spätfolgen der antineoplastischen Behandlung im Kindesalter. Die Nachsorge der von einer Krebserkrankung geheilten Kinder und Jugendlichen, in Schmoll H-J, Höffken K, Possinger K (Hrsg.):	Kompendium Internistische Onkologie, Berlin, Springer 1999, 1462
Beck J	Secondary neoplasms in 5-year survivors of cancer in childhood.	Strahlenther Onkol 2002, 178: 167
Becker K, Furch C, Schmid I, von Schweinitz D, Häberle B	Impact of postoperative complications on overall survival of patients with hepatoblastoma.	Pediatric blood & cancer 2015, 62: 24
Complete resection of hepatoblastoma (HB) is a demanding procedure in advanced tumors. Perioperative complications are still common. The influence of complication rates on course of disease and survival of patients with HB has not been analyzed yet.
Beck A, Eberherr C, Hagemann M, Cairo S, Häberle B, Vokuhl C, von Schweinitz D, Kappler R	Connectivity map identifies HDAC inhibition as a treatment option of high-risk hepatoblastoma.	Cancer biology & therapy 2016, 17: 1168
Hepatoblastoma (HB) is the most common liver tumor of childhood, usually occurring in children under the age of 3 y. The prognosis of patients presenting with distant metastasis, vascular invasion and advanced tumor stages remains poor and children that do survive often face severe late effects from the aggressive chemotherapy regimen. To identify potential new therapeutics for high risk HB we used a 1,000-gene expression signature as input for a Connectivity Map (CMap) analysis, which predicted histone deacetylase (HDAC) inhibitors as a promising therapy option. Subsequent expression analysis of primary HB and HB cell lines revealed a general overexpression of HDAC1 and HDAC2, which has been suggested to be predictive for the efficacy of HDAC inhibition. Accordingly, treatment of HB cells with the HDAC inhibitors SAHA and MC1568 resulted in a potent reduction of cell viability, induction of apoptosis, reactivation of epigenetically suppressed tumor suppressor genes, and the reversion of the 16-gene HB classifier toward the more favorable expression signature. Most importantly, the combination of HDAC inhibitors and cisplatin - a major chemotherapeutic agent of HB treatment - revealed a strong synergistic effect, even at significantly reduced doses of cisplatin. Our findings suggest that HDAC inhibitors skew HB cells toward a more favorable prognostic phenotype through changes in gene expression, thus indicating a targeted molecular mechanism that seems to enhance the anti-proliferative effects of conventional chemotherapy. Thus, adding HDAC inhibitors to the treatment regimen of high risk HB could potentially improve outcomes and reduce severe late effects.
Beck A, Trippel F, Wagner A, Joppien S, Felle M, Vokuhl C, Schwarzmayr T, Strom TM, von Schweinitz D, Längst G, Kappler R	Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma.	Clinical epigenetics 2018, 10: 27
Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification.
Beck P, Selle B, Madenach L, Jones DTW, Vokuhl C, Gopisetty A, Nabbi A, Brecht IB, Ebinger M, Wegert J, Graf N, Gessler M, Pfister SM, Jäger N	The genomic landscape of pediatric renal cell carcinomas.	iScience 2022, 25: 104167
Pediatric renal cell carcinomas (RCC) differ from their adult counterparts not only in histologic subtypes but also in clinical characteristics and outcome. However, the underlying biology is still largely unclear. For this reason, we performed whole-exome and transcriptome sequencing analyses on a cohort of 25 pediatric RCC patients with various histologic subtypes, including 10 MiT family translocation (MiT) and 10 papillary RCCs. In this cohort of pediatric RCC, we find only limited genomic overlap with adult RCC, even within the same histologic subtype. Recurrent somatic mutations in genes not previously reported in RCC were detected, such as in , , , . Our papillary pediatric RCCs, which represent the largest cohort to date with comprehensive molecular profiling in this age group, appeared as a distinct genomic subtype differing in terms of gene mutations and gene expression patterns not only from MiT-RCC but also from their adult counterparts.
Beckhaus J, Boekhoff S, Scheinemann K, Schilling FH, Fleischhack G, Binder G, Bison B, Pietsch T, Friedrich C, Müller HL	Perinatally diagnosed congenital craniopharyngiomas in the KRANIOPHARYNGEOM trials.	Endocrine connections 2023,Oct
Craniopharyngiomas (CP) are rare embryonic tumors. Clinical presentation and outcome of patients perinatally diagnosed with congenital CP (cCP) are not clear and refer mainly to a few case reports in the literature. The aim of this study was to analyse clinical presentation and outcome in patients with cCP.
Beckhaus J, Friedrich C, Müller HL	Childhood-onset craniopharyngioma - a life-long family burden?	The Journal of clinical endocrinology and metabolism 2023,
Beckhaus J, Friedrich C, Boekhoff S, Calaminus G, Bison B, Eveslage M, Timmermann B, Flitsch J, Müller HL	Outcome after pediatric craniopharyngioma: the role of age at diagnosis and hypothalamic damage.	European journal of endocrinology 2023, 188
Craniopharyngiomas (CP) are rare malformational tumors. Clinical presentation and outcome of pediatric patients with CP with specific regard to age at diagnosis is not clear. The aim of this cohort study was to determine clinical presentation and outcome in these patients diagnosed at different ages at diagnosis.
Bedetti B, Wiebe K, Ranft A, Aebert H, Schmidt J, Jürgens H, Dirksen U	Local control in Ewing sarcoma of the chest wall: results of the EURO-EWING 99 trial.	Annals of surgical oncology 2015, 22: 2853
Primary Ewing sarcoma (ES) can sometimes present as a chest-wall tumor. Multidisciplinary management, including chemotherapy and local treatment consisting of surgery, radiotherapy (RT), or both, has improved the survival of patients with localized ES; however, the best approach to achieving local control remains controversial.
Beekman R, Valkhof MG, Sanders MA, van Strien PM, Haanstra JR, Broeders L, Geertsma-Kleinekoort WM, Veerman AJ, Valk PJ, Verhaak RG, Löwenberg B, Touw IP	Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia.	Blood 2012, 119: 5071
Severe congenital neutropenia (SCN) is a BM failure syndrome with a high risk of progression to acute myeloid leukemia (AML). The underlying genetic changes involved in SCN evolution to AML are largely unknown. We obtained serial hematopoietic samples from an SCN patient who developed AML 17 years after the initiation of G-CSF treatment. Next- generation sequencing was performed to identify mutations during disease progression. In the AML phase, we found 12 acquired nonsynonymous mutations. Three of these, in CSF3R, LLGL2, and ZC3H18, co-occurred in a subpopulation of progenitor cells already in the early SCN phase. This population expanded over time, whereas clones harboring only CSF3R mutations disappeared from the BM. The other 9 mutations were only apparent in the AML cells and affected known AML-associated genes (RUNX1 and ASXL1) and chromatin remodelers (SUZ12 and EP300). In addition, a novel CSF3R mutation that conferred autonomous proliferation to myeloid progenitors was found. We conclude that progression from SCN to AML is a multistep process, with distinct mutations arising early during the SCN phase and others later in AML development. The sequential gain of 2 CSF3R mutations implicates abnormal G-CSF signaling as a driver of leukemic transformation in this case of SCN.
van der Beek JN, Geller JI, de Krijger RR, Graf N, Pritchard-Jones K, Drost J, Verschuur AC, Murphy D, Ray S, Spreafico F, Dzhuma K, Littooij AS, Selle B, Tytgat GAM, van den Heuvel-Eibrink MM	Characteristics and Outcome of Children with Renal Cell Carcinoma: A Narrative Review.	Cancers 2020, 12
Pediatric renal cell carcinoma (RCC) is a rare type of kidney cancer, most commonly occurring in teenagers and young adolescents. Few relatively large series of pediatric RCC have been reported. Knowledge of clinical characteristics, outcome and treatment strategies are often based on the more frequently occurring adult types of RCC. However, published pediatric data suggest that clinical, molecular and histological characteristics of pediatric RCC differ from adult RCC. This paper summarizes reported series consisting of ≥10 RCC pediatric patients in order to create an up-to-date overview of the clinical and histopathological characteristics, treatment and outcome of pediatric RCC patients.
van der Beek JN, Hol JA, Coulomb-l'Hermine A, Graf N, van Tinteren H, Pritchard-Jones K, Houwing ME, de Krijger RR, Vujanic GM, Dzhuma K, Schenk JP, Littooij AS, Ramírez-Villar GL, Murphy D, Ray S, Al-Saadi R, Gessler M, Godzinski J, Ruebe C, Collini P, Verschuur AC, Frisk T, Vokuhl C, Hulsbergen-van de Kaa CA, de Camargo B, Sandstedt B, Selle B, Tytgat GAM, van den Heuvel-Eibrink MM	Characteristics and outcome of pediatric renal cell carcinoma patients registered in the International Society of Pediatric Oncology (SIOP) 93-01, 2001 and UK-IMPORT database: A report of the SIOP-Renal Tumor Study Group.	International journal of cancer 2021, 148: 2724
In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93-01, 2001 and UK-IMPORT databases, were included. Event-free survival (EFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT-RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE-cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5-year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%-80.6%) and 84.5% (95% CI = 77.5%-92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE-testing.
Beger C, Gerdes K, Lauten M, Tissing W, Fernandez-Munoz I, Schrappe M, Welte K	Expression and structural analysis of glucocorticoid receptor isoform gamma in human leukaemia cells using an isoform-specific real-time polymerase chain reaction approach.	Br J Haematol 2003, 122: 245
Begemann M, Waszak SM, Robinson GW, Jäger N, Sharma T, Knopp C, Kraft F, Moser O, Mynarek M, Guerrini-Rousseau L, Brugieres L, Varlet P, Pietsch T, Bowers DC, Chintagumpala M, Sahm F, Korbel JO, Rutkowski S, Eggermann T, Gajjar A, Northcott P, Elbracht M, Pfister SM, Kontny U, Kurth I	Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.	Journal of clinical oncology 2020, 38: 43
The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete.
Behrends U, Jandl T, Golbeck A, Lechner B, Muller-Weihrich S, Schmid I, Till H, Berthold F, Voltz R, Mautner J	Novel products of the HUD, HUC, NNP-1 and alpha-internexin genes identified by autologous antibody screening of a pediatric neuroblastoma library.	Int J Cancer 2002, 100: 669
Behnisch W, Muckenthaler M, Kuloz ik, A	Eisenmangelanämie.	AWMF-Leitlinien 2010
Behrens YL, Göhring G, Bawadi R, Cöktü S, Reimer C, Hoffmann B, Sänger B, Käfer S, Thol F, Erlacher M, Niemeyer CM, Baumann I, Kalb R, Schindler D, Kratz CP	A novel classification of hematologic conditions in patients with Fanconi anemia.	Haematologica 2021, Online ahead of print
Not available.
BEIR Committee	Health Risks From Exposure to Low Levels of Ionizing Radiation.	BEIR VII Phase 2 2006
Beird HC, Bielack SS, Flanagan AM, Gill J, Heymann D, Janeway KA, Livingston JA, Roberts RD, Strauss SJ, Gorlick R	Osteosarcoma.	Nature reviews. Disease primers 2022, 8: 77
Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases.
Beishuizen A, Mellgren K, Andrés M, Auperin A, Bacon CM, Bomken S, Burke GAA, Burkhardt B, Brugieres L, Chiang AKS, Damm-Welk C, d'Amore E, Horibe K, Kabickova E, Khanam T, Kontny U, Klapper W, Lamant L, Le Deley MC, Loeffen J, Macintyre E, Mann G, Meyer-Wentrup F, Michgehl U, Minard-Colin V, Mussolin L, Oschlies I, Patte C, Pillon M, Reiter A, Rigaud C, Roncery L, Salaverria I, Simonitsch-Klupp I, Uyttebroeck A, Verdu-Amoros J, Williams D, Woessmann W, Wotherspoon A, Wrobel G, Zimmermann M, Attarbaschi A, Turner SD, European Intergroup for Childhood Non-Hodgkin Lymphoma	Improving outcomes of childhood and young adult non-Hodgkin lymphoma: 25 years of research and collaboration within the framework of the European Intergroup for Childhood Non-Hodgkin Lymphoma.	The Lancet. Haematology 2023, 10:e213-e224
The European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) was established 25 years ago with the goal to facilitate clinical trials and research collaborations in the field both within Europe and worldwide. Since its inception, much progress has been made whereby major improvements in outcomes have been achieved. In this Review, we describe the different diagnostic entities of non-Hodgkin lymphoma in children and young adults describing key features of each entity and outlining clinical achievements made in the context of the EICNHL framework. Furthermore, we provide an overview of advances in biopathology with an emphasis on the role of biological studies and how they have shaped available treatments. Finally, for each entity, we describe future goals, upcoming clinical trials, and highlight areas of research that require our focus going forward.
Bielack SS, Kager L, Kühne T, Langer T, Reichardt P, Blattmann C, Kevric M, Mettmann V, Sorg B, Hecker-Nolting S	Establishment, Maintenance, and Performance of the Cooperative Osteosarcoma Study Group (COSS).	Cancers 2023, 15
Osteosarcoma treatment has benefitted greatly from collaborative research. This paper describes the history and accomplishments of the Cooperative Osteosarcoma Study Group (COSS), mainly dedicated to clinical questions, as well as remaining challenges.
Beltinger C, Bohler T, Karawajew L, Ludwig W, Schrappe M, Debatin K	Mutation analysis of CD95 (APO-1/Fas) in childhood B-lineage acute lymphoblastic leukaemia.	Br J Haematol 1998, 102: 722
Beltinger C, Kurz E, Bohler T, Schrappe M, Ludwig W, Debatin K	CD95 (APO-1/Fas) mutations in childhood T-lineage acute lymphoblastic leukemia.	Blood 1998, 91: 3943
Bellaton E, Bertozzi AI, Behar C, Chastagner P, Brisse H, Sainte-Rose C, Doz F, Desjardins L	Neoadjuvant chemotherapy for extensive unilateral retinoblastoma.	The British journal of ophthalmology 2003, 87: 327
The role of neoadjuvant chemotherapy was studied when first line enucleation cannot be safely performed in unilateral extensive retinoblastoma (major buphthalmia or radiologically detectable optic nerve involvement).
Belson M, Kingsley B, Holmes A	Risk factors for acute leukemia in children: a review.	Environmental health perspectives 2007, 115: 138
Although overall incidence is rare, leukemia is the most common type of childhood cancer. It accounts for 30% of all cancers diagnosed in children younger than 15 years. Within this population, acute lymphocytic leukemia (ALL) occurs approximately five times more frequently than acute myelogenous leukemia (AML) and accounts for approximately 78% of all childhood leukemia diagnoses. Epidemiologic studies of acute leukemias in children have examined possible risk factors, including genetic, infectious, and environmental, in an attempt to determine etiology. Only one environmental risk factor (ionizing radiation) has been significantly linked to ALL or AML. Most environmental risk factors have been found to be weakly and inconsistently associated with either form of acute childhood leukemia. Our review focuses on the demographics of childhood leukemia and the risk factors that have been associated with the development of childhood ALL or AML. The environmental risk factors discussed include ionizing radiation, non-ionizing radiation, hydrocarbons, pesticides, alcohol use, cigarette smoking, and illicit drug use. Knowledge of these particular risk factors can be used to support measures to reduce potentially harmful exposures and decrease the risk of disease. We also review genetic and infectious risk factors and other variables, including maternal reproductive history and birth characteristics.
Bennett MH, MacLennan KA, Easterling MJ, Vaughan Hudson B, Vaughan Hudson G, Jelliffe AM	Analysis of histological subtypes in Hodgkin’s disease in relation to prognosis and survival, in Quaglino D, Hayhoe FGJ (eds.): The cytobiology of leukaemias and lymphomas.	Serono symposia publications from Raven press, New York 1985
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C	Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7). A report of the French-American-British Cooperative Group.	Annals Internal Medicine 1985, 103: 460
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C	Proposed revised criteria for the classification of acute myeloid leukemia.	Annals Internal Medicine 1985, 103: 626
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C	Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-M0).	Br J Haematol 1991, 78: 325
Benk V, Rodary C, Donaldson S, Flamant F, Maurer H, Treuner J, Carli M, Gehan E	Parameningeal rhabdomyosarcoma.	Int J Radiat Oncol Biol Phys 1996, 36: 533
Bénard J, Raguénez G, Kauffmann A, Valent A, Ripoche H, Joulin V, Job B, Danglot G, Cantais S, Robert T, Terrier-Lacombe MJ, Chassevent A, Koscielny S, Fischer M, Berthold F, Lipinski M, Tursz T, Dessen P, Lazar V, Valteau-Couanet D	MYCN-non-amplified metastatic neuroblastoma with good prognosis and spontaneous regression: a molecular portrait of stage 4S.	Molecular oncology 2008, 2: 261
Stage 4 neuroblastoma (NB) are heterogeneous regarding their clinical presentations and behavior. Indeed infants (stage 4S and non-stage 4S of age <365days at diagnosis) show regression contrasting with progression in children (>365days). Our study aimed at: (i) identifying age-based genomic and gene expression profiles of stage 4 NB supporting this clinical stratification; and (ii) finding a stage 4S NB signature. Differential genome and transcriptome analyses of a learning set of MYCN-non amplified stage 4 NB tumors at diagnosis (n=29 tumors including 12 stage 4S) were performed using 1Mb BAC microarrays and Agilent 22K probes oligo-microarrays. mRNA chips data following filtering yielded informative genes before supervised hierarchical clustering to identify relationship among tumor samples. After confirmation by quantitative RT-PCR, a stage 4S NB's gene cluster was obtained and submitted to a validation set (n=22 tumors). Genomic abnormalities of infant's tumors (whole chromosomes gains or loss) differ radically from that of children (intra-chromosomal rearrangements) but could not discriminate infants with 4S from those without this presentation. In contrast, differential gene expression by looking at both individual genes and whole biological pathways leads to a molecular stage 4S NB portrait which provides new biological clues about this fascinating entity.
Benz-Bohm G, Hero B, Gossmann A, Simon T, Körber F, Berthold F	Focal nodular hyperplasia of the liver in longterm survivors of neuroblastoma How much diagnostic imaging is necessary?	European journal of radiology 2009,
OBJECTIVES: Focal nodular hyperplasia of the liver is a tumor-like lesion, uncommon in children, but it has recently been more frequently observed in children treated for malignant diseases, especially neuroblastoma. The aetiology is unclear, the pathogenesis remains controversial. Focal nodular hyperplasia of the liver is suspected to be a sequela of tumor therapy. METHODS: Besides the clinical data we evaluated the imaging modalities needed to diagnose focal nodular hyperplasia of the liver in children with neuroblastoma who have been followed in our institution for more than 5 years. RESULTS: Out of 60 children six developed focal nodular hyperplasia at a median time of 10.5 years after diagnosis of neuroblastoma and 9.4 years after the end of treatment. The diagnosis of focal nodular hyperplasia was based on imaging criteria which are variable in ultrasonography and specific in MRI. Only one child underwent surgical biopsies to rule out liver metastases. CONCLUSIONS: Longterm survivors of neuroblastoma are at risk of developing focal nodular hyperplasia, especially if they underwent toxic chemotherapy and/or radiotherapy to the liver during initial treatment. The recommended diagnostic imaging tools are ultrasonography for detecting liver lesions and MRI for confirming and characterizing these lesions as focal nodular hyperplasia.
Benesch M, Siegler N, Hoff K, Lassay L, Kropshofer G, Müller H, Sommer C, Rutkowski S, Fleischhack G, Urban C	Safety and toxicity of intrathecal liposomal cytarabine (Depocyte) in children and adolescents with recurrent or refractory brain tumors: a multi-institutional retrospective study.	Anti-cancer drugs 2009, 20: 794
This retrospective study aimed to evaluate the safety and toxicity of intrathecal liposomal cytarabine (Depocyte) in children and adolescents with refractory or recurrent brain tumors. Nineteen heavily pretreated patients (males, n = 14; females, n = 5; median age at diagnosis 8.5 years; range, 1.4-22 years) were given intrathecal liposomal cytarabine on a compassionate use basis for recurrent refractory medulloblastoma (n = 12), mixed germ cell tumor (n = 2), central nervous system primitive neuroectodermal tumors of the pons (n = 1), anaplastic ependymoma (n = 1), anaplastic oligodendroglioma (n = 1), atypical teratoid rhabdoid tumor (n = 1), or rhabdoid papillary meningioma (n = 1). Eighteen patients received concomitant systemic radiochemotherapy. A total of 88 intrathecal injections of liposomal cytarabine (dose range, 20-50 mg) were administered with concomitant dexamethasone prophylaxis. The median number of doses per patient was four (range, 1-10). Duration of treatment ranged from (1/2) to 10 months. Eleven patients (57.9%) did not show any side effects, whereas eight patients (42.1%) developed side effects related to either chemical arachnoiditis (n = 4) or neurological progression (n = 2). Less typical treatment-related symptoms (e.g. lethargy, ataxia, and slurred speech) were observed in two patients. Treatment with intrathecal liposomal cytarabine was discontinued twice because of side effects. In conclusion, although intrathecal liposomal cytarabine was generally well tolerated, it should be used cautiously and only with dexamethasone prophylaxis in extensively pretreated patients with recurrent brain tumors. Proof of efficacy requires a prospective single-agent phase II study.
Benesch M, Sperl D, von Bueren AO, Schmid I, von Hoff K, Warmuth-Metz M, Ferrari R, Lassay L, Kortmann RD, Pietsch T, Rutkowski S	Primary central nervous system primitive neuroectodermal tumors (CNS-PNETs) of the spinal cord in children: four cases from the German HIT database with a critical review of the literature.	J Neurooncol 2010, Epub ahead of print
Approximately 30-50% of patients with intracranial primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS) develop spinal metastases. In contrast, primary spinal CNS-PNETs are extremely uncommon. The database and study records of the German/Austrian brain tumor trials HIT 91, HIT SKK 92, and HIT 2000 were retrospectively reviewed to describe clinical features, treatment modalities, and outcome of children with primary CNS-PNETs of the spinal cord who were registered as observational patients. Out of 1,248 patients with medulloblastomas or CNS-PNETs registered in the HIT database four patients (female, n = 3) with primary CNS-PNETs of the spinal cord were identified. Age at diagnosis was 10, 16, 23, and 174 months. Location of primary tumors was medulla oblongata-T3, C2-T1, T10-L2, T7-T10. Two patients had metastatic disease at diagnosis. Complete and incomplete resection was performed in one patient each, whereas two patients underwent a biopsy only. Two patients received chemotherapy only, in accordance with the HIT 91 trial (sandwich chemotherapy arm). They developed disease progression and died six months after diagnosis. One patient was given chemotherapy in accordance with the HIT 2000 trial followed by craniospinal radiotherapy and four courses of maintenance chemotherapy. The patient is in complete remission almost four years after diagnosis. The fourth patient developed disease progression while receiving induction chemotherapy. Hence, chemotherapy was switched to a modified Head Start protocol. After three cycles he underwent double autologous stem cell transplantation and craniospinal irradiation. Forty months after diagnosis the patient is alive and well, but surveillance MRIs still show nodular enhancing lesions in the area of the primary tumor and intracranial meningeal enhancement. Primary CNS-PNETs of the spinal cord probably require multimodal treatment including radiotherapy to achieve sustained tumor control.
Benesch M, Weber-Mzell D, Gerber NU, von Hoff K, Deinlein F, Krauss J, Warmuth-Metz M, Kortmann RD, Pietsch T, Driever PH, Quehenberger F, Urban C, Rutkowski S	Ependymoma of the spinal cord in children and adolescents: a retrospective series from the HIT database.	J Neurosurg Pediatr 2010, 6: 137
OBJECT: Reports on spinal cord ependymoma in children are rare. The aim of this study was to evaluate the clinical spectrum, treatment, and outcome of children with primary ependymoma of the spinal cord who were registered in the database of the pediatric German brain tumor studies Hirntumor (HIT) '91 and HIT 2000. METHODS: Between 1991 and 2007, 29 patients (12 male and 17 female, median age at diagnosis 13.6 years) with primary spinal cord ependymoma (myxopapillary ependymoma WHO Grade I, II, and III tumors in 6, 17, and 6 patients, respectively) were identified. Four patients had neurofibromatosis Type 2. RESULTS: With a median follow-up of 4.2 years (range 0.48-15 years), 28 patients (96.6%) were alive. Seven patients (24.1%) developed progressive disease or relapse, 2 after gross-total resection (GTR) and 5 after incomplete resection or biopsy. One patient with anaplastic ependymoma (WHO Grade III) died 65 months after diagnosis of disease progression. Primary adjuvant treatment (radiotherapy, chemotherapy, or both) was used in 8 (50%) of 16 patients following GTR and in 9 (82%) of 11 patients who underwent less than a GTR. Three additional patients were treated adjuvantly following progression. Estimated progression-free survival and overall survival rates at 5 years were 72.3% (95% CI 50%-86%) and 100%, respectively. Progression-free survival at 5 years is 84.4% (95% CI 50%-96%) for patients following GTR compared with 57.1% (95% CI 25%-69%) for patients who achieved a less than GTR (p = 0.088, log-rank test). A high relapse incidence (4 of 6) was observed among patients with myxopapillary ependymoma. CONCLUSIONS: Gross-total resection is the mainstay of treatment for patients with primary spinal cord ependymoma and may be achieved in about 50% of the patients using modern surgical techniques. Primary adjuvant treatment was commonly used in children with spinal cord ependymoma irrespective of the extent of resection or tumor grade. The impact of adjuvant treatment on progression-free and overall survival has to be investigated in a prospective trial.
Benesch M, Leuschner I, Wardelmann E, Thielen M, Schmid I, Kontny U, Ebetsberger G, Frey E, Graf N, Schneider DT, Kremens B, Amann G, Urban C, Schlemmer M, Quehenberger F, Klingebiel T, Dantonello T, Koscielniak E	Gastrointestinal stromal tumours in children and young adults: A clinicopathologic series with long-term follow-up from the database of the Cooperative Weichteilsarkom Studiengruppe (CWS).	Eur J Cancer 2011, 47: 1692-8. Epub 2011 Apr 11.
Studies on gastrointestinal stromal tumours (GIST) in the paediatric population are limited to case reports or small case series. PATIENTS AND METHODS: We conducted a retrospective study to describe the long-term outcome of children and adolescents with GIST registered in the database of the Cooperative Weichteilsarkom Studiengruppe (CWS). RESULTS: Sixteen patients (female, n=11) were identified. Median age at diagnosis was 13.5years. In four female patients presence of thoracic masses in addition to GIST led to the diagnosis of complete or incomplete Carney triad. Three female patients had metastatic disease at diagnosis, the remaining thirteen GIST were localised. The stomach was the most common primary site of the tumour, followed by the small bowel and colon/abdomen. All patients underwent tumour resection. Receptor tyrosine kinase inhibitors (RTKI) were administered in five patients. With a median follow-up of 96months all patients are alive, nine of them in first CR. Four female patients developed local or distant recurrence; three of them achieved second CR and one a PR. Two individuals have extensive progressive (n=1) or stable (n=1) disease. Estimated progression-free survival at 5years is 0.63 (95%CI: 0.50-0.86). CONCLUSIONS: Although long-term overall survival is favourable, approximately 30 percent of patients develop disease progression. International cooperation in registration, tissue collection and molecular studies are required to obtain reliable data on the clinical course of these rare tumours in the paediatric population. Biological studies are a prerequisite for initiation of studies with RTKI.
Bento C, Percy MJ, Gardie B, Maia TM, van Wijk R, Perrotta S, Della Ragione F, Almeida H, Rossi C, Girodon F, Aström M, Neumann D, Schnittger S, Landin B, Minkov M, Randi ML, Richard S, Casadevall N, Vainchenker W, Rives S, Hermouet S, Ribeiro ML, McMullin MF, Cario H, ECE-Consortium, Chauveau A, Gimenez-Roqueplo AP, Bressac-de-Paillerets B, Altindirek D, Lorenzo F, Lambert F, Dan H, Gad-Lapiteau S, Catarina Oliveira A, Rossi C, Fraga C, Taradin G, Martin-Nuñez G, Vitória H, Diaz Aguado H, Palmblad J, Vidán J, Relvas L, Ribeiro ML, Luigi Larocca M, Luigia Randi M, Pedro Silveira M, Percy M, Gross M, Marques da Costa R, Beshara S, Ben-Ami T, Ugo V, ECE-Consortium	Genetic basis of congenital erythrocytosis: mutation update and online databases.	Human mutation 2014, 35: 15
Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3-bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive Internet-based database focusing on the registration of clinical history, hematological, biochemical, and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database.
Benesch M, Bartelheim K, Fleischhack G, Gruhn B, Schlegel PG, Witt O, Stachel KD, Hauch H, Urban C, Quehenberger F, Massimino M, Pietsch T, Hasselblatt M, Giangaspero F, Kordes U, Schneppenheim R, Hauser P, Klingebiel T, Frühwald MC	High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): a report from the European Rhabdoid Registry (EU-RHAB).	Bone marrow transplantation 2014, 49: 370
A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n=9; following progression, n=5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n=1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (ÃÂ±11%) and 50% (ÃÂ±12%), respectively. At last follow-up, eight patients were alive (first CR, n=4; second CR, n=2; PR, n=1; PD, n=1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial.
Bento C, Cario H, Gardie B, Hermouet S, McMullin MF	Congenital Erythrocytosis and Hereditary Thrombocytosis. Clinical presentation, diagnosis, treatment and follow-up A practical guide with clinical cases.
Benesch M, Mynarek M, Witt H, Warmuth-Metz M, Pietsch T, Bison B, Pfister SM, Pajtler KW, Kool M, Schüller U, Pietschmann K, Juhnke BO, Tippelt S, Fleischhack G, Schmid I, Kramm CM, Vorwerk P, Beilken A, Classen CF, Hernáiz Driever P, Kropshofer G, Imschweiler T, Lemmer A, Kortmann RD, Rutkowski S, von Hoff K	Newly Diagnosed Metastatic Intracranial Ependymoma in Children: Frequency, Molecular Characteristics, Treatment, and Outcome in the Prospective HIT Series.	The oncologist 2019, 24:e921-e929
Data on frequency, clinical presentation, and outcome of primary metastatic intracranial ependymoma in children are scarce.
Ben-Ami T, Kontny U, Surun A, Brecht IB, Almaraz RL, Dragomir M, Pourtsidis A, Casanova M, Fresneau B, Bisogno G, Schneider DT, Reguerre Y, Bien E, Stachowicz-Stencel T, Österlundh G, Wygoda M, Janssens GO, Zsiros J, Jehanno N, Brisse HJ, Gandola L, Christiansen H, Claude L, Ferrari A, Rodriguez-Galindo C, Orbach D	Nasopharyngeal carcinoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.	Pediatric blood & cancer 2021, 68 Suppl 4:e29018
Nasopharyngeal carcinoma (NPC) is a rare pediatric tumor. Collaborative studies performed over the last decades showed improved results compared to historical data, but standardized guidelines for diagnosis and management of pediatric NPC are still unavailable. This study presents a European consensus guideline for the diagnosis and treatment of pediatric NPC developed by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT). Main recommendations include induction chemotherapy with cisplatin and 5-flurouracil, concomitant chemoradiotherapy in advanced disease, and to consider maintenance treatment with interferon beta (IFN-β) for selected high-risk patients. Dose adjustments of radiotherapy based on response to induction chemotherapy may decrease the rates of long-term treatment-related complications that affect most of the survivors.
Benetton M, Merli P, Walter C, Hansen M, Da Ros A, Polato K, Tregnago C, Abrahamsson J, Strocchio L, Sonneveld E, Fogelstrand L, Von Neuhoff N, Reinhardt D, Hasle H, Pigazzi M, Locatelli F	Molecular Measurable Residual Disease Assessment before Hematopoietic Stem Cell Transplantation in Pediatric Acute Myeloid Leukemia Patients: A Retrospective Study by the I-BFM Study Group.	Biomedicines 2022, 10
Hematopoietic stem cell transplantation (HSCT) is a curative post-remission treatment in patients with acute myeloid leukemia (AML), but relapse after transplant is still a challenging event. In recent year, several studies have investigated the molecular minimal residual disease (qPCR-MRD) as a predictor of relapse, but the lack of standardized protocols, cut-offs, and timepoints, especially in the pediatric setting, has prevented its use in several settings, including before HSCT. Here, we propose the first collaborative retrospective I-BFM-AML study assessing qPCR-MRD values in pretransplant bone marrow samples of 112 patients with a diagnosis of AML harboring t(8;21)(q22; q22), or inv(16)(p13q22), or t(9;11)(p21;q23) or -ITD genetic markers. We calculated an ROC cut-off of 2.1 × 10 that revealed significantly increased OS (83.7% versus 57.1%) and EFS (80.2% versus 52.9%) for those patients with lower qPCR-MRD values. Then, we partitioned patients into three qPCR-MRD groups by combining two different thresholds, 2.1 × 10 and one lower cut-off of 1 × 10, and stratified patients into low-, intermediate-, and high-risk groups. We found that the 5-year OS (83.7%, 68.6%, and 39.2%, respectively) and relapse-free survival (89.2%, 73.9%, and 67.9%, respectively) were significantly different independent of the genetic lesion, conditioning regimen, donor, and stem cell source. These data support the PCR-based approach playing a clinical relevance in AML transplant management.
Berry MP, Jenkin RD, Keen CW, Nair BD, Simpson WJ	Radiation treatment for medulloblastoma. A 21-year review.	J Neurosurg 1981, 43
One hundred and twenty-two patients with medulloblastoma received postoperative irradiation at the Princess Margaret Hospital, Toronto, from 1958 to 1978, inclusive. The surgical procedure in these patients was total resection (44 patients), subtotal resection (66 patients), or biopsy alone (12 patients). Twenty-five patients received adjuvant chemotherapy. Overall 5- and 10-year survival rates were 56% and 43%, respectively. Improved survival rates were associated with an increased degree of resection and with posterior fossa radiation doses of 5200 rads or more. The posterior fossa was the common site of first relapse (in 56 patients, 46%). Systemic metastases at first relapse occurred in 18 of 52 patients (35%), and were associated with the use of ventriculosystemic shunts. Millipore filters did not prevent systemic relapse in shunted patients. A subset of 15 patients who received a posterior fossa dose of 5200 rads or more after a total resection had a 5-year survival rate of 77%, which remained constant to 10 years. This result is considered to be the upper limit that can be achieved by current treatment methods.
Berthold F, Creutzig U, Lampert F	Effective remission induction in children with recurrent acute myeloid leukemia by mAMSA, Ara-C, and VP 16.	Haematology and Blood Transfusion 1987, 30: 406
Berthold F	Neuroblastom-Screening.	Münchn Med Wschr 1991, 22
Berthold F, Engelhardt-Fahrner U, Schneider A, Schumacher R, Zieschang J	Age dependence and prognostic impact of neuron specific enolase (NSE) in children with neuroblastoma.	In Vivo 1991, 5: 245
Berthold F, Himmelmann U, Pohl U	Natural interleukin-2 and lymphokine activated killer cells in the treatment of neuroblastoma in vitro and in vivo.	Prog Clin Biol Res 1991, 366: 417
Berthold F, Hunneman D, Kaser H, Harms D, Bertram U, Erttmann R, Schilling F, Treuner J, Zieschang J	Neuroblastoma screening: arguments from retrospective analysis of three German neuroblastoma trials.	American Journal Pediatric Hematology Oncology 1991, 13: 8
Berthold F, Hunneman D, Harms D, Kaser H, Zieschang J	Serum vanillylmandelic acid/homovanillic acid contributes to prognosis estimation in patients with localised but not with metastatic neuroblastoma.	Eur J Cancer 1992, 28A: 1950
Berthold F, Sander J, Baillot A, Hunneman D, Michaelis J	The "Lower Saxony/Northern Rhine-Westphalia" Neuroblastoma Screening Project.	Klin Pädiatr 1992, 204: 288
Berthold F, Trechow R, Utsch S, Zieschang J	Prognostic factors in metastatic neuroblastoma. A multivariate analysis of 182 cases.	Am J Pediatr Hematol Oncol 1992, 14: 207
Bergsagel DJ, Finegold MJ, Butel JS, Kupsky WJ, Garcea RL	DNA sequences similar to those of simian virus 40 in ependymomas and choroid plexus tumors of childhood.	N Engl J Med 1992, 326: 988
Berthold F	Neuroblastom. Modelltumor und Herausforderung für den Kinderarzt.	Monatschr Kinderheilkd 1994, 142: 296
Berthold F, Kassenbohmer R, Zieschang J	Multivariate evaluation of prognostic factors in localized neuroblastoma.	Am J Pediatr Hematol Oncol 1994, 16: 107
Berthold F, Hero B, Breu H, Christiansen H, Erttmann R, Gnekow A, Herrmann F, Klingebiel T, Lampert F, Muller-Weihrich S, Weinel P	The recurrence patterns of stages I, II and III neuroblastoma.	Ann Oncol 1996, 7: 183
Berthold F	Commentary on.	Eur J Cancer 1997, 33: 1437
Berthold F, Sahin K, Hero B, Christiansen H, Gehring M, Harms D, Horz S, Lampert F, Schwab M, Terpe J	The current contribution of molecular factors to risk estimation in neuroblastoma patients.	Eur J Cancer 1997, 33: 2092
Berthold F, Hero B	Neuroblastom in Huber/Hiddemann/Batram (Hrsg.)	Klinische Onkologie 1998
Berthold F, Hero B, Horz S, Jobke B, Boos J, Bretz R, Burdach S, Claviez A, Henze G, Jorch N, Klingebiel T, Kremens B, Kühl J, Schwabe D	Sind Spontanregressionen beim Neuroblastom verspätete embryofetale Involutionen?	Spontanremissionen bei Krebserkrankungen 1998
Berthold F	Maligne Erkrankungen des lymphatischen und histiozytären Systems, in Niessen K (Hrsg.), Maligne Tumoren, Thieme.	Pädiatrie 1999, 369
Berthold F, Baillot A, Hero B, Schurr P, Nerenz A, Hunneman D, Sander J	Which cases are found and missed by neuroblastoma screening at 1 year?	J Clin Oncol 1999, 17
Berthold F, Hero B	Neuroblastoma.	Drugs 2000, 59: 1261
Berthold F, Herold R	Die Pädiatrische Onkologie und Hämatologie auf dem Weg in die neue Krankenhausfinanzierung.	Klinische Pädiatrie 2002, 214: 145
Berthold F, Hero B, Kremens B, Handgretinger R, Henze G, Schilling FH, Schrappe M, Simon T, Spix C	Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age.	Cancer letters 2003, 197(1-2): 11
During the last two decades new diagnostic and therapeutic tools have been utilized to improve the poor survival chances of children with stage 4 neuroblastoma. This study reviews the risk profiles and the long-term outcome of patients from five consecutive German neuroblastoma trials. A total of 96% of all German patients registered at the German childhood cancer registry with neuroblastoma stage 4 over 1 year of age at diagnosis entered one of the trials during 1979-2001. Eight hundred and twenty-eight consecutive children were analyzed retrospectively. In spite of having significantly improved diagnostic tools like bone marrow superstaging and mIBG scintigraphy the stage 4 incidence did not increase after reaching completeness of the registry (5.4 cases/100,000 children at 1-14 years of age; P=0.52). The distribution of the primary tumors and of metastases was constant over the periods. The amount of bone marrow infiltration did not change with time. The risk factors lactate dehydrogenase, ferritin and MYCN, and the clinical risk groups 4A, 4B, 4C also remained constant over the trials with a few exceptions for NB97. The 5-year event free survival increased from 0.01+/-0.01 (NB79) to 0.14+/-0.03 (NB85), 0.16+/-0.04 (NB82), 0.27+/-0.02 (NB90), and 0.33+/-0.04 (NB97). The overall survival rates improved similarly from 0.04 (NB79) to 0.44 (NB97). In conclusion, the improved survival was associated with better treatment and not caused by lower risk profiles in stage 4 neuroblastoma patients.
Berthold F, Boos J, Burdach S, Erttmann R, Henze G, Hermann J, Klingebiel T, Kremens B, Schilling FH, Schrappe M, Simon T, Hero B	Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial.	The lancet oncology 2005, 6: 649
BACKGROUND: Myeloablative megatherapy is commonly used to improve the poor outlook of children with high-risk neuroblastoma, yet its role is poorly defined. We aimed to assess whether megatherapy with autologous stem-cell transplantation could increase event-free survival and overall survival compared with maintenance chemotherapy. METHODS: 295 patients with high-risk neuroblastoma (ie, patients with stage 4 disease aged older than 1 year or those with MYCN-amplified tumours and stage 1, 2, 3, or 4S disease or stage 4 disease and <1 year old) were randomly assigned to myeloablative megatherapy (melphalan, etoposide, and carboplatin) with autologous stem-cell transplantation (n=149) or to oral maintenance chemotherapy with cyclophosphamide (n=146). The primary endpoint was event-free survival. Secondary endpoints were overall survival and the number of treatment-related deaths. Analyses were done by intent to treat, as treated, and treated as randomised. FINDINGS: Intention-to-treat analysis showed that patients allocated megatherapy had increased 3-year event-free survival compared with those allocated maintenance therapy (47% [95% CI 38-55] vs 31% [95% CI 23-39]; hazard ratio 1.404 [95% CI 1.048-1.881], p=0.0221), but did not have significantly increased 3-year overall survival (62% [95% CI 54-70] vs 53% [95% CI 45-62]; 1.329 [0.958-1.843], p=0.0875). Improved 3-year event-free survival and 3-year overall survival were also recorded for patients given megatherapy in the as-treated group (n=212) and in the treated-as-randomised group (n=145). Two patients died from therapy-related complications during induction treatment. No patients given maintenance therapy died from acute treatment-related toxic effects. Five patients given megatherapy died from acute complications related to megatherapy. INTERPRETATION: Myeloablative chemotherapy with autologous stem-cell transplantation improves the outcome for children with high-risk neuroblastoma despite the raised risk of treatment-associated death.
Bernstein M, Kovar H, Paulussen M, Randall RL, Schuck A, Teot LA, Jürgens H	Ewing's sarcoma family of tumors: current management.	The oncologist 2006, 11: 503
Ewing's sarcoma is the second most frequent primary bone cancer, with approximately 225 new cases diagnosed each year in patients less than 20 years of age in North America. It is one of the pediatric small round blue cell tumors, characterized by strong membrane expression of CD99 in a chain-mail pattern and negativity for lymphoid (CD45), rhabdomyosarcoma (myogenin, desmin, actin) and neuroblastoma (neurofilament protein) markers. Pathognomonic translocations involving the ews gene on chromosome 22 and an ets-type gene, most commonly the fli1 gene on chromosome 11, are implicated in the great majority of cases. Clinical presentation is usually dominated by local bone pain and a mass. Imaging reveals a technetium pyrophosphate avid lesion that, on plain radiograph, is destructive, diaphyseal and classically causes layered periosteal calcification. Magnetic resonance best defines the extent of the lesion. Biopsy should be undertaken by an experienced orthopedic oncologist. Approximately three quarters of patients have initially localized disease. About two thirds survive disease-free. Management, preferably at a specialist center with a multi-disciplinary team, includes both local control-either surgery, radiation or a combination-and systemic chemotherapy. Chemotherapy includes cyclic combinations, incorporating vincristine, doxorubicin, cyclophosphamide, etoposide, ifosfamide and occasionally actinomycin D. Topotecan in combination with cyclophosphamide has shown preliminary activity. Patients with initially metastatic disease fare less well, with about one quarter surviving. Studies incorporating intensive therapy followed by stem cell infusion show no clear benefit. New approaches include anti-angiogenic therapy, particularly since vascular endothelial growth factor is an apparent downstream target of the ews-fli1 oncogene.
Bernstein M, Kovar H, Paulussen M, Randall, RL, Schuck A, Teot, LA, Juergens, H	Ewing Sarcoma Family of Tumors: Ewing Sarcoma of Bone and Soft Tissue and the Peripheral Primitive Neuroectodermal Tumors.	Buch: Principles and Practice of Pediatric Oncology (Ed. Pizzo,P.A.; Poplack,D.G.) 2006, 5th Ed.;Ch.33; 1002
Berthold F	Neuroblastom, in Schmoll H-J, Höffken K, Possinger K (Hrsg) : Kompendium Internistische Onkologie.	Springer Verlag 2006, XIII, 5567
Bernbeck B, Schneider DT, Bernbeck B, Koch S, Teske C, Lentrodt J, Harms D, Göbel U, Calaminus G, MAKEI-Study Group	Germ cell tumors of the head and neck: report from the MAKEI Study Group.	Pediatric blood & cancer 2009, 52: 223
BACKGROUND: Germ cell tumors (GCTs) of the head and neck region are rare but may pose significant problems for perinatal management as well as surgical and adjuvant therapy. PROCEDURE: Thirty-two prospectively reported patients from the German MAKEI studies (Maligne Keimzelltumoren) were analyzed with regard to perinatal management and long-term survival. RESULTS: Twenty-three tumors were diagnosed around birth and four during the first 3 months of life. All were primarily diagnosed as teratomas, but in two tumors, yolk sac tumor (YST) foci were identified. Another pure teratoma was diagnosed at 12 months. Four tumors were diagnosed after the first year of life and showed YST as leading histology. Most neonates presented with huge tumors causing external airway obstruction. All tumors were resected (complete resection, 16/26 patients with complete surgical information; incomplete resection, 10/26 patients). Eight tumors including five of six YSTs were treated with chemotherapy. In total, six patients relapsed. Relapse rate was higher after incomplete (5/10 patients) than after complete resection (1/16 patients). Accordingly, more relapses were observed in pharyngeal than in neck tumors due to incomplete resection. Nevertheless, half of the patients with incomplete resection remained in remission. One patient with YST died after multiple relapses. CONCLUSIONS: GCTs of the head and neck region require a multidisciplinary approach in specialized centers. Most patients with antenatal tumor growth are identified by ultrasound and delivered preterm by cesarian section. After delivery, immediate intubation and ventilation aim for respiratory stabilization, followed by elective resection. With this approach, outcome was favorable.
Berrak SG, Liu DD, Wrede B, Wolff JE	Which therapy works better in choroid plexus carcinomas?	J Neurooncol 2010, Epub ahead of print
Choroid plexus carcinomas (CPCs) are rare tumors with dismal outcome. While it has been established that surgery, radiotherapy, and chemotherapy improve survival, the best chemotherapy drugs for treating this disease still need to be identified. Since CPC is too rare to permit a prospective clinical trial, we performed a meta-analysis to evaluate the effects of individual drugs in patients with CPCs. We expanded a pre-existing database and included all cases of choroid plexus tumors, identified in PubMed through the end of 2007, for a total of 906 patients. At first, we restricted the analysis to patients with histologically confirmed CPC (n = 361) and with residual tumor after surgery (n = 130/361 patients), and we compared response and survival between patients who received a particular drug and those who did not. Response to chemotherapy was documented in 43 patients. Of the drugs used in these patients, etoposide was associated with the highest response rate (17/36). Next survival was compared among all CPC. Kaplan-Meier curves and log-rank tests suggested a statistically significant treatment benefit for cyclophosphamide, etoposide, and carboplatin, while the effect of vincristine was found to be marginally significant (P = 0.07, log rank). Of these, only etoposide's effect could be confirmed in a limited Cox multiple regression analysis. In conclusion, etoposide should be included in future standard treatment protocols. However the survival rates are still unsatisfactory, and additional novel drugs should be studied in prospective multicenter studies.
Berrak SG, Liu DD, Wrede B, Wolff JE	Which therapy works better in choroid plexus carcinomas?	J Neurooncol 2011, 103: 155
Choroid plexus carcinomas (CPCs) are rare tumors with dismal outcome. While it has been established that surgery, radiotherapy, and chemotherapy improve survival, the best chemotherapy drugs for treating this disease still need to be identified. Since CPC is too rare to permit a prospective clinical trial, we performed a meta-analysis to evaluate the effects of individual drugs in patients with CPCs. We expanded a pre-existing database and included all cases of choroid plexus tumors, identified in PubMed through the end of 2007, for a total of 906 patients. At first, we restricted the analysis to patients with histologically confirmed CPC (n = 361) and with residual tumor after surgery (n = 130/361 patients), and we compared response and survival between patients who received a particular drug and those who did not. Response to chemotherapy was documented in 43 patients. Of the drugs used in these patients, etoposide was associated with the highest response rate (17/36). Next survival was compared among all CPC. Kaplan-Meier curves and log-rank tests suggested a statistically significant treatment benefit for cyclophosphamide, etoposide, and carboplatin, while the effect of vincristine was found to be marginally significant (P = 0.07, log rank). Of these, only etoposide's effect could be confirmed in a limited Cox multiple regression analysis. In conclusion, etoposide should be included in future standard treatment protocols. However the survival rates are still unsatisfactory, and additional novel drugs should be studied in prospective multicenter studies.
Berentsen S, Tjønnfjord GE	Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia.	Blood reviews 2012, [Epub ahead of print]
Exact diagnosis of the subtype has essential therapeutic consequences in autoimmune hemolytic anemia. Cold-antibody types include primary chronic cold agglutinin disease (CAD) and rare cases of cold agglutinin syndrome (CAS) secondary to cancer or acute infection. Primary CAD is a clonal lymphoproliferative disorder. Not all patients require pharmacological therapy, but treatment seems indicated more often than previously thought. Corticosteroids should not be used to treat primary CAD. Half of the patients respond to rituximab monotherapy; median response duration is 11months. The most efficient treatment to date is fludarabine and rituximab in combination, resulting in responses in 75%, complete responses in 20% and median response duration of more than 66months. Toxicity may be a concern, and an individualized approach is discussed. Erythrocyte transfusions can be given provided specific precautions are undertaken. No evidence-based therapy exists in secondary CAS, but optimal treatment of the underlying disorder is essential when feasible.
Berger M, Fernandez-Pineda I, Cabello R, Ramírez-Villar GL, Márquez-Vega C, Nustede R, Linderkamp C, Schmid I, Neth O, Graf N, Agustin JC, Schweinitz DV, Lacher M, Hubertus J	The Relationship Between the Site of Metastases and Outcome in Children With Stage IV Wilms Tumor: Data From 3 European Pediatric Cancer Institutions.	Journal of pediatric hematology/oncology 2013, Epub ahead of print
The aim of this study was to analyze in detail the site of metastasis of stage 4 Wilms tumor (WT) and its correlation with outcome. The databases from 3 major European pediatric cancer institutions were screened for children with WT between 1994 and 2011. Of 208 children identified, 31 (14.9%) had metastases at diagnosis. The lung was affected in 29 children (93.5%) and the liver in 6 children (19.4%). Twenty-seven children (87.1%) had metastases isolated to 1 organ, with the lung being the most common site (80.7%). Five-year overall survival was significantly better in those children with distant disease in either lung or liver (95.8%) compared with those affected in both lung and liver (57.1%, P=0.028). Further, prognostic markers were the response of metastases to preoperative chemotherapy (P=0.0138), high-risk histology (P=0.024), and local stage (P=0.026). Five-year overall survival was 82.1% and 5-year event-free survival was 67.9%. The overall follow-up time was 74.1 and 87.2 (2 to 151) months among survivors, and the treatment-related complication rate was 16.7%. In conclusion, in our series of stage 4 WT, prognosis was excellent if histology was favorable, metastatic disease was isolated to either lungs or liver, and if metastases responded to preoperative chemotherapy.
van den Berg H, Paulussen M, Le Teuff G, Judson I, Gelderblom H, Dirksen U, Brennan B, Whelan J, Ladenstein RL, Marec-Berard P, Kruseova J, Hjorth L, Kühne T, Brichard B, Wheatley K, Craft A, Jürgens H, Gaspar N, Le Deley MC, Euro-EWING99 Group	Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: secondary analysis of the Euro-Ewing99-R1 trial.	European journal of cancer 2015, 51: 2453
Based on the randomised Euro-EWING99-R1 trial, vincristine, adriamycin, cyclophosphamide (VAC) may be able to replace vincristine, adriamycin, ifosfamide (VAI) in the treatment of standard-risk Ewing sarcoma. However some heterogeneity of treatment effect by gender was observed. The current exploratory study aimed at investigating the influence of gender on treatment efficacy and acute toxicity.
Berthold F, Hömberg M, Proleskovskaya I, Mazanek P, Belogurova M, Ernst A, Sterba J	Metronomic therapy has low toxicity and is as effective as current standard treatment for recurrent high-risk neuroblastoma.	Pediatric hematology and oncology 2017, 34: 308
The metronomic therapy concept uses low doses of continuously applied chemotherapeutic, anti-angiogenetic, and immunomodulating drugs. Twenty patients with recurrent and 3 with refractory high-risk neuroblastoma were treated by the metronomic concept using celecoxib, cyclophosphamide, vinblastine, and etoposide for up to 24 months. The outcome was compared to 274 matched patients with a first recurrence from stage 4 neuroblastoma using the variables time from diagnosis to first recurrence, number of organs involved, and MYCN amplification. All were treated with dose-intensive conventional chemotherapy. The study patients experienced 1-3 recurrences and had 1-3 sites involved (osteomedullary, primary tumor, central nervous system, lymph nodes, liver, lungs) before the metronomic therapy started. Two patients in complete remission and three with active refractory disease following recurrence treatment were excluded from the outcome analysis. The curves for secondary event-free and overall survival demonstrated no significant differences. The toxicity was minimal except for ≥ 3 grade thrombocytopenia and leukopenia (all heavily pretreated). The treatment was realized in an outpatient setting. The metronomic approach is similarly effective as standard treatment in recurrent high-risk neuroblastoma, has low toxicity, and is applicable in an outpatient setting. A prospective study including propranolol as a fifth drug is underway.
Berthold F, Spix C, Kaatsch P, Lampert F	Incidence, Survival, and Treatment of Localized and Metastatic Neuroblastoma in Germany 1979-2015.	Paediatric drugs 2017, 19: 577
BACKGROUND: A comprehensive clinical long-term survey over the complete spectrum of neuroblatoma disease is lacking in the literature. OBJECTIVE: Our objective was to describe the incidence, risk profiles, therapies, and outcomes for the total cohort of German patients with neuroblastoma including all clinical stages and risk groups. METHODS: Epidemiological, clinical, and outcome data of neuroblastoma patients who participated in one of the six consecutive national trials between 1979 and 2015 were analyzed retrospectively. RESULTS: Of all German neuroblastoma patients known to the national childhood cancer registry, ninety seven percent enrolled in one of the trials. The absolute neuroblastoma rate has increased slightly, whereas the median age at diagnosis has decreased. Except for the screening period (1995-2000), the risk factors lactate dehydrogenase (LDH), ferritin, chromosome 1p, and the MYCN oncogene have remained largely constant, with the exception of an increase in MYCN amplification at stage 4 for those aged ≥18 months between trials NB97 (27%) and NB2004 (35%). The 10-year overall survival increased in patients with stage 1-3 neuroblastoma from 83 to 91%, for stage 4S from 80 to 85%, and for stage 4 aged ≥18 months from 2 to 38%. The fraction of patients in stages 1-3 who never received chemotherapy (neither for frontline nor at recurrence) increased from 35 to 60%. The proportion of macroscopically complete surgical resections of the primary tumor decreased for the total population as well as for patients with stage 4 aged ≥18 months. The impact of chemotherapy response on the outcome was trial dependent. The overall proportion of toxic death during the time of the protocol therapy was 6% for stage 4 patients aged ≥18 months and 2% for low-/intermediate-risk patients. The most frequently reported late sequelae in stage 4 patients aged ≥18 months were renal dysfunctions, hypothyroidism, major hearing impairment, and second malignancies. CONCLUSION: The body of data for incidences, risk profiles, and survival rates from this survey of more than 37 years provides a useful perspective for future studies on neuroblastoma sub-cohorts.
Berthold F, Ernst A, Hero B, Klingebiel T, Kremens B, Schilling FH, Simon T	Long-term outcomes of the GPOH NB97 trial for children with high-risk neuroblastoma comparing high-dose chemotherapy with autologous stem cell transplantation and oral chemotherapy as consolidation.	British journal of cancer 2018, 119: 282
This study was done to investigate the long-term event free and overall survival of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), compared to maintenance chemotherapy (MT). Patterns of recurrences and late sequelae of both arms were analysed.
Bergsträsser E	Palliativmedizin in der pädiatrischen Onkologie und Hämatologie.	in: Niemeyer C., Eggert A. (Hrsg.), Pädiatrische Hämatologie und Onkologie Springer-Verlag GmbH Deutschland 2018
Berthold F, Ernst A, Hero B, Klingebiel T, Kremens B, Schilling FH, Simon T	Correction: Long-term outcomes of the GPOH NB97 trial for children with high-risk neuroblastoma comparing high-dose chemotherapy with autologous stem cell transplantation and oral chemotherapy as consolidation.	British journal of cancer 2019 Sep 24;
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Berthold F	From a single meeting to a scientific community: Quantification of the .	Pediatric blood & cancer 2019, 66:e27696
Berthold F, Faldum A, Ernst A, Boos J, Dilloo D, Eggert A, Fischer M, Frühwald M, Henze G, Klingebiel T, Kratz C, Kremens B, Krug B, Leuschner I, Schmidt M, Schmidt R, Schumacher-Kuckelkorn R, von Schweinitz D, Schilling FH, Theissen J, Volland R, Hero B, Simon T	Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR.	Annals of oncology : official journal of the European Society for Medical Oncology 2020, 31: 422
Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients.
Berthold F, Spix C, Erttmann R, Hero B, Michaelis J, Treuner J, Ernst A, Schilling FH	Neuroblastoma Screening at 1 Year of Age: The Final Results of a Controlled Trial.	JNCI cancer spectrum 2021, 5:pkab041
Neuroblastoma screening aims to reduce neuroblastoma-related mortality. A controlled trial showed no reduction in stage 4 disease incidence and preliminary mortality data. This article presents epidemiologic and clinical data 20 years after cessation of the screening program.
Berthold F, Rosswog C, Christiansen H, Frühwald M, Hemstedt N, Klingebiel T, Fröhlich B, Schilling FH, Schmid I, Simon T, Hero B, Fischer M, Ernst A	Clinical and molecular characterization of patients with stage 4(M) neuroblastoma aged less than 18 months without MYCN amplification.	Pediatric blood & cancer 2021, 68:e29038
The survival of children with stage 4(M) neuroblastoma without MYCN amplification and below the age of 18 months is considered better than the still dismal outcome of older high-risk neuroblastoma patients. This study analyzes the impact of clinical and molecular characteristics on the long-term outcome.
Berlak M, Tucker E, Dorel M, Winkler A, McGearey A, Rodriguez-Fos E, da Costa BM, Barker K, Fyle E, Calton E, Eising S, Ober K, Hughes D, Koutroumanidou E, Carter P, Stankunaite R, Proszek P, Jain N, Rosswog C, Dorado-Garcia H, Molenaar JJ, Hubank M, Barone G, Anderson J, Lang P, Deubzer HE, Künkele A, Fischer M, Eggert A, Kloft C, Henssen AG, Boettcher M, Hertwig F, Blüthgen N, Chesler L, Schulte JH	Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells.	Molecular cancer 2022, 21: 126
Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations.
Bergengruen PM, Hernaíz Driever P, Budach V, Zips D, Grün A	Second course of re-irradiation in pediatric diffuse intrinsic pontine glioma : A case study.	Strahlentherapie und Onkologie 2023,
Concomitant chemoradiation followed by repeat (dose-deescalated) irradiation has become standard of care in treating childhood diffuse intrinsic pontine glioma (DIPG) during first line treatment and at first progression. Progression after re-irradiation (re-RT) is in most cases symptomatic and either treated systemically with chemotherapy or new innovative approaches including targeted therapy. Alternatively, the patient receives best supportive care. Data on second re-irradiation in DIPG patients with second progression and good performance status are sparse. This is a case report of second short-term re-irradiation to shed further light on this option.
Bethke M, Varga G, Weinhage T, Sabharwal H, Mellgren K, Randau G, Rolfing M, Wittkowski H, Foell D, Michgehl U, Burkhardt B	Patient parameters and response after administration of rituximab in pediatric mature B-cell non-Hodgkin lymphoma.	Pediatric blood & cancer 2022, 69:e29514
Mature aggressive B-cell lymphomas are heterogenous malignancies that make up more than half of all diagnosed non-Hodgkin lymphoma in children and adolescents. The overall survival rate increased over the last decades to 80%-90% due to fine tuning of polychemotherapy. However, new therapeutic implications are needed to further increase the overall survival. Current clinical trials analyze the therapeutic effect of rituximab in pediatric patients, while the mechanism of action in vivo is still not fully understood.
Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T	Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA.	Lancet 2002, 359: 211
There has been much interest in screening populations for disease-associated mutations. A favoured candidate has been the HFE gene, mutations of which are the most common cause of haemochromatosis in the European population. About five people in 1000 are homozygotes for the 845G-->A mutation, but little is known of how many have mutation-caused clinical manifestations.
Beutel K, Simon A	Diagnostics and management of central venous line infections in pediatric cancer patients.	Klin Pädiatr 2005, 217 Suppl 1:S91
Beyermann B, Agthe A, Adams H, Seeger K, Linderkamp C, Goetze G, Ludwig W, Henze G	Clinical features and outcome of children with first marrow relapse of acute lymphoblastic leukemia expressing BCR-ABL fusion transcripts. BFM Relapse Study Group.	Blood 1996, 87: 1532
Beyermann B, Adams H, Henze G	Philadelphia chromosome in relapsed childhood acute lymphoblastic leukemia.	J Clin Oncol 1997, 15: 2231
Beyer R, Dörr H	Observations of reported and measured heights of mothers of short statured children.	Ann Hum Biol 1998, 25: 387
Bundesamt für Strahlenschutz	Grenzwerte und Dosisbegriffe im Strahlenschutz .	Webseite des Bundesamtes für Strahlenschutz Stand vom 08.04.2010, aufgerufen 24.06.2011
Bundesamt für Strahlenschutz	Krebs und Leukämie .	Webseite des Bundesamtes für Strahlenschutz aufgerufen 24.06.2011
Bundesamt für Strahlenschutz (BfS)	Entwarnung mit Einschränkung - Kein erhöhtes Risiko für erwachsene Handynutzer.	in: WIR - die Zeitschrift der Deutschen Leukämie-Forschungshilfe e.V. und der Deutschen Kinderkrebsstiftung 1/2011
Bundesamt für Strahlenschutz	UV-Strahlung.	Webseite des Bundesamtes für Strahlenschutz aufgerufen 23.05.2019
Bhatia S, Neglia JP	Epidemiology of childhood acute myelogenous leukemia.	Journal of pediatric hematology/oncology 1995, 17: 94
Acute myelogenous leukemia (AML) is the second most common leukemia in children, with approximately 400 new cases occurring annually in the United States. Worldwide, the highest rates of childhood AML occur in Asia and the lowest rates are reported from India and South America. Numerous genetic risk factors for childhood AML have been defined, including Down syndrome, neurofibromatosis, and Fanconi anemia. Research into environmental risk factors has been limited by the rarity of this disease; however, studies of AML in adults have implicated ionizing radiation, solvents, and petroleum products as potential etiologic agents. The largest analytic study of childhood AML found that occupational exposures of either parent to pesticides, paternal exposure to petroleum products, and postnatal exposures to pesticides are increased in children with AML. In addition, maternal use of marijuana during pregnancy was associated with an increased risk of AML, especially the monocytic subtypes. Further study of childhood AML, including occurrence of the disease as a second malignancy, is needed in order to confirm these findings and to increase our understanding of this leukemia.
Bhatia S, Yasui Y, Robison LL, Birch JM, Bogue MK, Diller L, DeLaat C, Fossati-Bellani F, Morgan E, Oberlin O, Reaman G, Ruymann FB, Tersak J, Meadows AT	High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group.	J Clin Oncol 2003, 21: 4386
Bhatia S, Landier W, Shangguan M, Hageman L, Schaible AN, Carter AR, Hanby CL, Leisenring W, Yasui Y, Kornegay NM, Mascarenhas L, Ritchey AK, Casillas JN, Dickens DS, Meza J, Carroll WL, Relling MV, Wong FL	Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children's oncology group.	J Clin Oncol 2012 Jun 10; 30: 2094
Systemic exposure to mercaptopurine (MP) is critical for durable remissions in children with acute lymphoblastic leukemia (ALL). Nonadherence to oral MP could increase relapse risk and also contribute to inferior outcome in Hispanics. This study identified determinants of adherence and described impact of adherence on relapse, both overall and by ethnicity.
Bhatia M, Sheth S	Hematopoietic stem cell transplantation in sickle cell disease: patient selection and special considerations.	Journal of blood medicine 2015, 6: 229
Hematopoietic stem cell transplantation remains the only curative treatment currently in use for patients with sickle cell disease (SCD). The first successful hematopoietic stem cell transplantation was performed in 1984. To date, approximately 1,200 transplants have been reported. Given the high prevalence of this disorder in Africa, and its emergence in the developed world through immigration, this number is relatively small. There are many reasons for this; primary among them are the availability of a donor, the risks associated with this complex procedure, and the cost and availability of resources in the developing world. Of these, it is fair to say that the risks associated with the procedure have steadily decreased to the point where, if currently performed in a center with experience using a matched sibling donor, overall survival is close to 100% and event-free survival is over 90%. While there is little controversy around offering hematopoietic stem cell transplantation to symptomatic SCD patients with a matched sibling donor, there is much debate surrounding the use of this modality in
Bhatt NS, Baassiri MJ, Liu W, Bhakta N, Chemaitilly W, Ehrhardt MJ, Inaba H, Krull K, Ness KK, Rubnitz JE, Srivastava D, Robison LL, Hudson MM, Mulrooney DA	Late outcomes in survivors of childhood acute myeloid leukemia: a report from the St. Jude Lifetime Cohort Study.	Leukemia 2021 Jan 25;
Bhoopalan SV, Suryaprakash S, Sharma A, Wlodarski MW	Hematopoietic cell transplantation and gene therapy for Diamond-Blackfan anemia: state of the art and science.	Frontiers in oncology 2023, 13: 1236038
Diamond-Blackfan anemia (DBA) is one of the most common inherited causes of bone marrow failure in children. DBA typically presents with isolated erythroid hypoplasia and anemia in infants. Congenital anomalies are seen in 50% of the patients. Over time, many patients experience panhematopoietic defects resulting in immunodeficiency and multilineage hematopoietic cytopenias. Additionally, DBA is associated with increased risk of myelodysplastic syndrome, acute myeloid leukemia and solid organ cancers. As a prototypical ribosomopathy, DBA is caused by heterozygous loss-of-function mutations or deletions in over 20 ribosomal protein genes, with being involved in 25% of patients. Corticosteroids are the only effective initial pharmacotherapy offered to transfusion-dependent patients aged 1 year or older. However, despite good initial response, only ~20-30% remain steroid-responsive while the majority of the remaining patients will require life-long red blood cell transfusions. Despite continuous chelation, iron overload and related toxicities pose a significant morbidity problem. Allogeneic hematopoietic cell transplantation (HCT) performed to completely replace the dysfunctional hematopoietic stem and progenitor cells is a curative option associated with potentially uncontrollable risks. Advances in HLA-typing, conditioning regimens, infection management, and graft-versus-host-disease prophylaxis have led to improved transplant outcomes in DBA patients, though survival is suboptimal for adolescents and adults with long transfusion-history and patients lacking well-matched donors. Additionally, many patients lack a suitable donor. To address this gap and to mitigate the risk of graft-versus-host disease, several groups are working towards developing autologous genetic therapies to provide another curative option for DBA patients across the whole age spectrum. In this review, we summarize the results of HCT studies and review advances and potential future directions in hematopoietic stem cell-based therapies for DBA.
Bidlingmaier C, Olivieri M,Kurnik, K	Hautblutungen bei Kindern Ist es eine Gerinnungsstörung?	Monatsschrift Kinderheilkunde 2012, 160 , 538
Hämatome im Kindesalter sind häufig. Meist sind sie Folge kleinerer Verletzungen und harmlos. Andererseits können sie erste Hinweise auf eine angeborene Gerinnungsstörung sein. Es ist daher wichtig, zu entscheiden, ob es sich um normale blaue Flecken oder aber eine relevante Blutungsneigung handelt. Neben der körperlichen Untersuchung spielen hierbei die Anamnese des Kindes und der Familie eine wichtige Rolle. Bei Verdacht auf eine Gerinnungsstörung muss sich eine ausgedehnte Labordiagnostik anschließen, da die Globalwerte der Gerinnung [aktivierte partielle Thromboplastinzeit (aPTT) und Quick-Wert] nicht hinreichend geeignet sind, häufige Gerinnungsstörungen wie ein Von-Willebrand-Syndrom auszuschließen. Im vorliegenden Beitrag wird das diagnostische Vorgehen mit Schwerpunkt auf relativ häufigen Gerinnungsstörungen beschrieben.
Bielack S, Bieling P, Erttmann R, Winkler K	Intraarterial chemotherapy for osteosarcoma.	Cancer Treat Res 1993, 62: 85
Bielack S, Bieling P, Fuchs N, Winkler K	Bone tumors in children.	Kinderkrankenschwester 1993, 12: 114
Bielack S, Beck J, Winkler K	Spätfolgen nach Krebsbehandlung im Kindesalter.	Monatsschr Kinderheilkd 1995, 649
Bielack S, Erttmann R	Anthracycline-induced cardiotoxicity in children.	Late Sequelae in Oncology 1995, 175
Bielack S, Wulff B, Delling G, Göbel U, Kotz R, Ritter J, Winkler K	Osteosarcoma of the trunk treated by multimodal therapy.	Med Pediatr Oncol 1995, 24: 6
Bielack S, Erttmann R, Kempf-Bielack B, Winkler K	Impact of scheduling on toxicity and clinical efficacy of doxorubicin: what do we know in the mid-nineties?	Eur J Cancer 1996, 32A: 1652
Bielack S, Kempf-Bielack B, Winkler K	Osteosarcoma.	J Clin Oncol 1996, 14: 683
Bieling P, Rehan N, Winkler P, Helmke K, Maas R, Fuchs N, Bielack S, Heise U, Jürgens H, Treuner J, Romanowski R, Exner U, Kotz R, Winkler K	Tumor size and prognosis in aggressively treated osteosarcoma.	J Clin Oncol 1996, 14: 848
Bielack S, Beron G, Winkler K	Influence of methotrexate dose intensity on outcome of patients with high grade osteogenic osteosarcoma.	Cancer 1997, 80: 516
Bielack S, Kempf-Bielack B, Heise U, Schwenzer D, Winkler K	Combined modality treatment for osteosarcoma occurring as a second malignant disease. Cooperative German-Austrian-Swiss Osteosarcoma Study Group.	J Clin Oncol 1999, 17
Bielack S, Kempf-Bielack B, Schwenzer D, Birkfellner T, Delling G, Ewerbeck V, Exner G, Fuchs N, Göbel U, Graf N, Heise U, Helmke K, von Hochstetter A, Jürgens H, Maas R, Munchow N, Salzer-Kuntschik M, Treuner J, Veltmann U, Werner M, Winkelmann W, Zoubek A, Kotz R	Neoadjuvant therapy for localized osteosarcoma of extremities. Results from the Cooperative osteosarcoma study group COSS of 925 patients.	Klin Pädiatr 1999, 211: 260
Bielack S, Schroeders A, Fuchs N, Bacci G, Bauer H, Mapeli S, Tomeno B, Winkler K	Malignant fibrous histiocytoma of bone.	Acta Orthop Scand 1999, 70: 353
Bielack S, Flege S, Kempf-Bielack B	Behandlungskonzept des Osteosarkoms.	Onkologe 2000, 6: 747
Bielack S, Kempf-Bielack B, Delling G, Exner G, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jürgens H, Winkler K	Prognostic factors in high-grade osteosarcoma of the extremities or trunk.	J Clin Oncol 2002, 20: 776
Bielack S, Hunold A, Kempf-Bielack B, Jürgens H	Maligne Knochentumoren.	Kinder- und Jugendmedizin 2003, 3: 13
Bielack S, Rerin J, Dickerhoff R, Dilloo D, Kremens B, Von Stackelberg A, Vormoor J, Jürgens H	Osteosarcoma after allogeneic bone marrow transplantation. A report of four cases from the Cooperative Osteosarcoma Study Group (COSS).	Bone Marrow Transplant 2003, 31: 353
Bielack S, Tabone M	Osteosarcomas occurring as second malignant neoplasms.	Radiother Oncol 2003, 68
Bielack S, Jürgens H	Surgical expertise and outcome in osteosarcoma trials.	J Clin Oncol 2004, 22: 2511
Bielack S, Machatschek J, Flege S, Jürgens H	Delaying surgery with chemotherapy for osteosarcoma of the extremities.	Expert Opin Pharmacother 2004, 5: 1243
Bielack S, Paulussen M, Kohler G	A patient with two Ewing's sarcomas with distinct EWS fusion transcripts.	N Engl J Med 2004, 350: 1364
Bielack S, Carrle D	Diagnostik und multimodales Therapiekonzept des Osteosarkoms.	ärztliches journal reise & medizin onkologie, Otto Hoffmanns Verlag GmbH 3/2007, S: 34
Bielack SS, Carrle D	State-of-the-art approach in selective curable tumors: bone sarcoma.	Annals of oncology 2008, 19 Suppl 7:vii155
Bielack SS, Marina N, Ferrari S, Helman LJ, Smeland S, Whelan JS, Reaman GH	Osteosarcoma: the same old drugs or more?	Journal of clinical oncology 2008, 26: 3102-3; author reply 3104
Bielack S	Pediatric extraskeletal osteosarcoma.	Pediatric radiology 2008, 38: 1033
Bielack S	Pediatric extraskeletal osteosarcoma.	Pediatric radiology 2008, 38: 1033
Bielack SS, Carrle D, Hardes J, Schuck A, Paulussen M	Bone tumors in adolescents and young adults.	Current treatment options in oncology 2008, 9: 67
OPINION STATEMENT: Bone tumors, particularly osteosarcomas and members of the Ewing Sarcoma Family of Tumors (ESFT), are typical malignancies of adolescents and young adults. Current diagnostic and therapeutic guidelines for patients of all ages were developed in this specific age group. The aim of bone sarcoma therapy should be to cure the patient from both the primary tumor and all (micro-)metastatic deposits while maintaining as much (extremity) function and causing as few treatment-specific late effects as possible. Bone sarcoma therapy requires close multidisciplinary cooperation. Usually, it consists of induction chemotherapy, followed by local therapy of the primary tumor (and, if present, primary metastases) and further, adjuvant chemotherapy. Local treatment for osteosarcoma should be surgery whenever feasible. Surgery is also gaining importance in ESFT, which was long considered a domain of radiotherapy. Modern reconstructive techniques continue to expand the indications for limb salvage, particularly for patients who have not yet reached skeletal maturity. Treatment within the framework of prospective, multi-institutional trials should be considered standard of care not only for children, but also for affected adolescents and (young) adults. Such trials are essential in guaranteeing that all patients have access to appropriate care and that progress from biological studies can be translated into prognostic improvements without undue delay. The rarity of bone sarcomas increasingly requires trials to be multinational.
Bielack SS, Kempf-Bielack B, Branscheid D, Carrle D, Friedel G, Helmke K, Kevric M, Jundt G, Kühne T, Maas R, Schwarz R, Zoubek A, Jürgens H	Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive cooperative osteosarcoma study group patients.	Journal of clinical oncology 2009, 27: 557
PURPOSE: To evaluate patient and tumor characteristics, treatment, and outcomes in a large cohort of unselected patients with second and subsequent recurrences of osteosarcoma. PATIENTS AND METHODS: Two hundred forty-nine consecutive patients who had originally received combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group protocols and went on to develop a total of 409 second and subsequent osteosarcoma recurrences were analyzed for patient-, tumor-, and treatment-related factors and outcomes. RESULTS: Five-year overall and event-free survival rates were 16% and 9% for 249 second, 14% and 0% for 93 third, 13% and 6% for 38 fourth, and 18% and 0% for 14 fifth recurrences, respectively. The proportion of recurrences confined to the lungs decreased and the proportion of those with chest wall involvement increased with increasing numbers of recurrences. The duration of relapse-free intervals and the number of lesions at recurrence correlated with outcomes. While only one of 205 patients with rerecurrence survived past 5 years without surgical remission, 5-year overall and event-free survival rates were 32% and 18% for 119 second, 26% and 0% for 45 third, 28% and 13% for 20 fourth, and 53% and 0% for five fifth recurrences, respectively, in which a renewed surgical remission was achieved. The use of chemotherapy correlated with longer survival in patients without surgical remissions. CONCLUSION: To our knowledge, this is the first report of survival estimates derived from large cohorts of unselected patients with second and subsequent osteosarcoma recurrences. It confirms the overwhelming importance of surgical clearance. Prognostic indicators after rerecurrences resemble those known from first recurrence. The exact role of re-treatment with chemotherapy, particularly in the adjuvant situation, remains to be defined.
Bielack SS, Franke M	Re: Late recurrence in pediatric cancer: a report from the childhood cancer survivor study.	Journal of the National Cancer Institute 2010, 102: 828; author reply 828
Bielack SS	Osteosarcoma: time to move on?	European journal of cancer 2010, 46: 1942
Bielack S, Jürgens H, Jundt G, Kevric M, Kühne T, Reichardt P, Zoubek A, Werner M, Winkelmann W, Kotz R	Osteosarcoma: The COSS Experience.	Cancer treatment and research 2010, 152: 289
COSS, the interdisciplinary Cooperative German-Austrian-Swiss Osteosarcoma Study Group, was founded in 1977 and has since registered some 3,500 bone sarcoma patients from over 200 institutions. For the purpose of the Pediatric and Adolescent Osteosarcoma Conference in Houston, March 2008, the outcomes of 2,464 consecutive patients with high-grade central osteosarcoma, who had been diagnosed between 1980 and 2005 and had been treated on neoadjuvant COSS protocols, were reviewed. Intended treatment had included surgery and multidrug chemotherapy, with high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide being used in most protocols. After a median follow-up of 7.31 years for 1,654 survivors, 5- and 10-year survival estimates were 0.748/0.695 for 2,017 patients with localized extremity tumors and 0.369/0.317 for 444 patients with axial tumors or/and primary metastases, respectively. Tumor response to preoperative chemotherapy was of independent prognostic significance. Over the years, there was a major shift from amputation towards limb-salvage. This development was least evident for patients below the age of 10. While survival expectancies improved from the first to the second half of the recruitment period, no further improvement was evident within the latter period. In the manuscript, the results described above are discussed based on the findings of the previous analyses of our group.
Bien E, Kazanowska B, Dantonello T, Adamkiewicz-Drozynska E, Balcerska A, Madziara W, Rybczynska A, Nurzynska-Flak J, Solarz E, Kurylak A, Zalewska-Szewczyk B, Krawczyk M, Izycka-Swieszewska E, Rapala M, Koscielniak E	Factors predicting survival in childhood malignant and intermediate vascular tumors : retrospective analysis of the Polish and German cooperative paediatric soft tissue sarcoma study groups and review of the literature.	Ann Surg Oncol 2010, 17: 1878
BACKGROUND: The rarity of malignant and intermediate vascular tumors in children means that little is known about their clinical course, optimal treatment, and variables predicting survival. METHODS: A total of 32 children with malignant vascular tumors (14 angiosarcomas [AS], 5 epithelioid hemangioendotheliomas, and 13 intermediate vascular tumors, including other hemangioendotheliomas plus adult-type hemangiopericytomas), registered in the German and Polish Paediatric Soft Tissue Sarcomas Study Groups, were treated following the Cooperative Weichteilsarkom Studiengruppe (CWS)-81, -86, -91, and -96 protocols. RESULTS: Male sex, AS histology, tumor size >5 cm, and T2 invasiveness were independent predictors of inferior 5-year overall survival, while AS histology and T2 invasiveness were predictors of inferior 5-year event-free survival. AS histology was the most important negative prognostic factor for overall survival and event-free survival. Completeness of primary tumor excision was a good prognostic factor for survival in univariate, but not multivariate, analysis. Local therapy (radiotherapy and delayed surgery) were provided to the minority of patients (28% and 38%, respectively) late in the course of disease (after a mean of 9 and 6 months, respectively) and did not prevent local relapses. Response to systemic treatment was poor (44%) and did not prevent local and distant relapses. CONCLUSIONS: The clinical course and outcome in childhood epithelioid HE seems to be similar to intravascular tumors and less aggressive than AS. RTX and delayed surgery should be performed more frequently and earlier in the disease course. An urgent need for modification of systemic therapy is needed because of the development of many metastatic and/or combined relapses and poor response to classic chemotherapy. The problem of effective therapy for childhood AS is the most appaling: 13 of 14 patients died of progression despite multimodal treatment.
Bielack S	Osteosarkome.	Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie AWMF online, 2010
Bielack SS, Marina N, Bernstein M	High-intensity focused ultrasound (HIFU) is not indicated for treatment of primary bone sarcomas.	Cancer 2011, 117: 2822, author reply 2822
Bielack SS, Hecker-Nolting S, Kevric M, Jürgens H	Osteosarcoma and Phyllodes Tumor.	Journal of pediatric hematology/oncology 2014,
Bielack S, Kevric M	High BMI at diagnosis is not associated with inferior survival in patients with osteosarcoma. A report from the Cooperative Osteosarcoma Study Group.	Pediatric blood & cancer 2014, 61: 952
Bielack SS, Smeland S, Whelan JS, Marina N, Jovic G, Hook JM, Krailo MD, Gebhardt M, Pápai Z, Meyer J, Nadel H, Randall RL, Deffenbaugh C, Nagarajan R, Brennan B, Letson GD, Teot LA, Goorin A, Baumhoer D, Kager L, Werner M, Lau CC, Sundby Hall K, Gelderblom H, Meyers P, Gorlick R, Windhager R, Helmke K, Eriksson M, Hoogerbrugge PM, Schomberg P, Tunn PU, Kühne T, Jürgens H, van den Berg H, Böhling T, Picton S, Renard M, Reichardt P, Gerss J, Butterfass-Bahloul T, Morris C, Hogendoorn PC, Seddon B, Calaminus G, Michelagnoli M, Dhooge C, Sydes MR, Bernstein M, EURAMOS-1 investigators	Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial.	Journal of clinical oncology 2015, 33: 2279
EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-Î±-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy.
Bielack SS, Hecker-Nolting S, Blattmann C, Kager L	Advances in the management of osteosarcoma.	F1000Research 2016 Nov 25; 5: 2767
Osteosarcoma, a bone cancer most commonly seen in adolescents and young adults, is usually a high-grade malignancy characterized by a very high risk for the development of pulmonary metastases. High-grade osteosarcomas are usually treated by preoperative and postoperative chemotherapy and surgery, with a very limited number of active agents available. Rarer lower-grade variants such as parosteal and periosteal osteosarcoma or low-grade central osteosarcoma are treated by surgery only. Imaging to search for possible metastases focuses on the lung. Computed tomography is the most sensitive method but cannot reliably distinguish small metastases from benign lesions. Advances of local imaging and surgical reconstruction now allow the use of limb-salvage in an ever-increasing proportion of patients. While still troubled by complications, non-invasive endoprosthesis-lengthening mechanisms have led to an increased uptake of limb-salvage, even for young, skeletally immature patients. Radiotherapy is employed when osteosarcomas cannot be removed with clear margins, but very high doses are required, and both proton and carbon-ion radiotherapy are under investigation. Unfortunately, the past 30 years have witnessed few, if any, survival improvements. Novel agents have not led to universally accepted changes of treatment standards. In patients with operable high-grade osteosarcomas, the extent of histological response to preoperative chemotherapy is a significant predictive factor for both local and systemic control. Attempts to improve prognosis by adapting postoperative treatment to response, recently tested in a randomized, prospective setting by the European and American Osteosarcoma Study Group, have not been proven to be beneficial. Many agree that only increased knowledge about osteosarcoma biology will lead to novel, effective treatment approaches and will be able to move the field forward.
Bien E, Roganovic J, Krawczyk MA, Godzinski J, Orbach D, Cecchetto G, Barthlen W, Defachelles AS, Ferrari A, Weldon CB, Brecht IB, Schneider DT, Bisogno G, Kolenova A, Ben-Ami T, Martinova K, Virgone C, Stachowicz-Stencel T, Kachanov D, Reguerre Y	Pancreatoblastoma in children: EXPeRT/PARTNER diagnostic and therapeutic recommendations.	Pediatric blood & cancer 2021, 68 Suppl 4:e29112
Pancreatoblastoma (PBL) is a rare malignant epithelial neoplasm that affects typically young children. Signs related to advanced upper-abdominal tumor accompanied by elevated serum α-fetoprotein levels in a young child suggest PBL, however histopathological confirmation is mandatory. The mainstay of the treatment is a complete surgical resection. Unresectable and/or metastatic PBL may become amenable to complete delayed surgery after neoadjuvant chemotherapy. This manuscript presents the international consensus recommendations for the diagnosis and treatment of children with PBL, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER (Paediatric Rare Tumors Network - European Registry) project.
Biewald E, Kiefer T, Geismar D, Schlüter S, Manthey A, Westekemper H, Wulff J, Timmermann B, Ketteler P, Schönberger S, Metz KA, Ting S, Göricke S, Bechrakis NE, Bornfeld N	Feasibility of Proton Beam Therapy as a Rescue Therapy in Heavily Pre-Treated Retinoblastoma Eyes.	Cancers 2021 Apr 13; 13
Despite the increased risk of subsequent primary tumors (SPTs) external beam radiation (EBRT) may be the only therapeutic option to preserve a retinoblastoma eye. Due to their physical properties, proton beam therapy (PBT) offers the possibility to use the effectiveness of EBRT in tumor treatment and to decisively reduce the treatment-related morbidity. We report our experiences of PBT as rescue therapy in a retrospectively studied cohort of 15 advanced retinoblastoma eyes as final option for eye-preserving therapy. The average age at the initiation of PBT was 35 (14-97) months, mean follow-up was 22 (2-46) months. Prior to PBT, all eyes were treated with systemic chemotherapy and a mean number of 7.1 additional treatments. Indication for PBT was non-feasibility of intra-arterial chemotherapy (IAC) in 10 eyes, tumor recurrence after IAC in another 3 eyes and diffuse infiltrating retinoblastoma in 2 eyes. Six eyes (40%) were enucleated after a mean time interval of 4.8 (1-8) months. Cataract formation was the most common complication affecting 44.4% of the preserved eyes, yet 77.8% achieved a visual acuity of >20/200. Two of the 15 children treated developed metastatic disease during follow-up, resulting in a 13.3% metastasis rate. PBT is a useful treatment modality as a rescue therapy in retinoblastoma eyes with an eye-preserving rate of 60%. As patients are at lifetime risk of SPTs consistent monitoring is mandatory.
Bielack SS, Blattmann C, Borkhardt A, Csóka M, Hassenpflug W, Kabíčková E, Kager L, Kessler T, Kratz C, Kühne T, Kevric M, Lehrnbecher T, Mayer-Steinacker R, Mettmann V, Metzler M, Reichardt P, Rossig C, Sorg B, von Luettichau I, Windhager R, Hecker-Nolting S	Osteosarcoma and causes of death: A report of 1520 deceased patients from the Cooperative Osteosarcoma Study Group (COSS).	European journal of cancer (Oxford, England : 1990) 2022, 176: 50
Most aspects of osteosarcoma have been addressed in detail, but there is no comprehensive analysis of deceased patients and causes of death.
Bielack SS, Blattmann C, Hassenpflug W, Kager L, Kuhne T, Kevric M, Schlegel PG, Mettmann V, Sorg B, Hecker-Nolting S	Osteosarcoma Arising After Ewing Sarcoma or Vice Versa: A Report of 20 Affected Patients from the Cooperative Osteosarcoma Study Group (COSS).	Anticancer research 2023, 43: 4975
Ewing sarcoma can arise in patients after osteosarcoma or vice versa. Our aim was to learn more about which patients develop these secondary tumors, which treatments may be effective, and which patients might survive.
Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jürgens H, Winkler K	Prognostic Factors in High-Grade Osteosarcoma of theExtremities or Trunk: An Analysis of 1,702 Patients Treatedon Neoadjuvant Cooperative Osteosarcoma Study GroupProtocols.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2023, 41: 4323
To define prognostic factors for response and long-term outcome for a wide spectrum of osteosarcomas, extending well beyond those of the typical young patient with seemingly localized extremity disease.
Bielack SS, Kager L, Kühne T, Langer T, Reichardt P, Blattmann C, Kevric M, Mettmann V, Sorg B, Hecker-Nolting S	Establishment, Maintenance, and Performance of the Cooperative Osteosarcoma Study Group (COSS).	Cancers 2023, 15
Osteosarcoma treatment has benefitted greatly from collaborative research. This paper describes the history and accomplishments of the Cooperative Osteosarcoma Study Group (COSS), mainly dedicated to clinical questions, as well as remaining challenges.
Biggar RJ, Frisch M, Goedert JJ	Risk of cancer in children with AIDS. AIDS-Cancer Match Registry Study Group.	JAMA 2000, 284: 205
Biondi A, Valsecchi M, Seriu T, D'Aniello E, Willemse M, Fasching K, Pannunzio A, Gadner H, Schrappe M, Kamps W, Bartram C, van Dongen J, Panzer-Grumayer E	Molecular detection of minimal residual disease is a strong predictive factor of relapse in childhood B-lineage acute lymphoblastic leukemia with medium risk features. A case control study of the International BFM study group.	Leukemia 2000, 14: 1939
Biondi A, Baruchel A, Hunger S, Masera G, Schmiegelow K, Schrappe M, Pui CH	The Eleventh International Childhood Acute Lymphoblastic Leukemia Workshop Report: Ponte di Legno, Italy, 6-7 May 2009.	Leukemia 2009, 23: 2318
An international childhood acute lymphoblastic leukemia (ALL)working group was formed during the 27th annual meeting of the International Society of Pediatric Oncology in 1995. Since then, 10 workshops have been held to address many issues that help advance treatment outcome of childhood ALL but require international collaboration (Table 1). The group was fondly named after 'Ponte di Legno,' a place in Lombardy, Italy, because the first major workshop was held there. In celebration of the 10th anniversary of the first major meeting, the group returned to Ponte di Legno on 6 and 7 May 2009 for its 11th meeting (Figure 1). During the meeting, Professor Giuseppe Masera was honored for his vision and contributions to further develop the International-BFM study group and to co-found the Ponte di Legno working group. The meeting began with greetings by Professor Andrea Biondi. This report summarizes the data presented and the discussion in the meeting.
Biondi A, Schrappe M, De Lorenzo P, Castor A, Lucchini G, Gandemer V, Pieters R, Stary J, Escherich G, Campbell M, Li CK, Vora A, Aricò M, Röttgers S, Saha V, Valsecchi MG	Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study.	The lancet oncology 2012, 13: 936
Trials of imatinib have provided evidence of activity in adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (ALL), but the drug's role when given with multidrug chemotherapy to children is unknown. This study assesses the safety and efficacy of oral imatinib in association with a Berlin-Frankfurt-Munster intensive chemotherapy regimen and allogeneic stem-cell transplantation for paediatric patients with Philadelphia-chromosome-positive ALL.
Biondi A, Cario G, De Lorenzo P, Castor A, Conter V, Leoni V, Gandemer V, Pieters R, Stary J, Escherich G, Campbell M, Attarbaschi A, Li CK, Vora A, Bradtke J, Saha V, Valsecchi MG, Schrappe M	Long-term follow up of pediatric Philadelphia positive acute lymphoblastic leukemia treated with the EsPhALL2004 study: high white blood cell count at diagnosis is the strongest prognostic factor.	Haematologica 2019, 104:e13-e16
Bird MG, Greim H, Snyder R, Rice JM	International symposium: Recent advances in benzene toxicity.	Chemico-biological interactions 2005 May 30; 153-154: 1
The symposium overview describes the recent succession of scientific meetings to further understand the adverse effects of benzene. It reviews the epidemiological evidence for hematological changes including leukemias and non-Hodgkins lymphoma, the progress in molecular biology and mechanism of action as well as ongoing studies in these fields. Various national occupational and community exposure monitoring data show that there has been significant progress in reducing benzene exposures globally. Biomarkers and biomonitoring have been used to provide information on biological plausibility, mode of action and susceptibility, and in the discrimination of co-exposures. Current research should help to further clarify cell type specificity, relationship to exposure, and the molecular elements involved in mechanism.
Bisogno G, Carli M, Stevens M, Oberlin O, Treuner J, Scarzello G, Colombatti R, De Zen L, Pinkerton C	Intensive chemotherapy for children and young adults with metastatic primitive neuroectodermal tumors of the soft tissue.	Bone Marrow Transplant 2002, 30: 297
Bisogno G, Pilz T, Perilongo G, Ferrari A, Harms D, Ninfo V, Treuner J, Carli M	Undifferentiated sarcoma of the liver in childhood.	Cancer 2002, 94: 252
Biskup W, Calaminus G, Schneider DT, Leuschner I, Göbel U	Teratoma with malignant transformation: experiences of the cooperative GPOH protocols MAKEI 83/86/89/96.	Klinische Padiatrie 2006 Nov-Dec; 218: 303
BACKGROUND: The designation of a teratoma with malignant transformation (TMT) refers to the occurrence of somatic non-germ cell malignancies within a teratoma. While TMT is a rare but well recognised phenomenon in adult germ cell tumors (GCT), data on TMT in pediatric GCTs are lacking. PATIENTS AND METHODS: Between 1982 and 2003, 641 patients with extracranial nontesticular pure teratoma (256 coccygeal, 246 ovarian, 139 other sites) were reported to the MAKEI protocols 83/86/89/96 by various, mainly German centres. Patients with teratoma and somatic malignancy were identified by database queries. Patients with malignant germ cell tumor components were excluded from this analysis. The clinical files were reviewed and re-evaluated centrally. Information was actualized by requisition to the participating hospitals. RESULTS: We identified nine patients (all female, age 0-39 years) meeting the histological criteria of TMT. Two patients had coccygeal teratomas and seven ovarian tumors. Carcinoma was the dominating malignancy (five of nine cases). Tumors with glial differentiation and embryonal tumors occurred in two cases each. Resection was performed in seven patients (including both coccygeal tumors) and adjuvant chemotherapy was administered in one of them. Two patients relapsed after resection, but both were cured with chemotherapy. Two patients suffered from advanced tumors and both were treated with primary chemotherapy. One patient was cured from the malignant component (astrocytoma), but the teratomatous components persisted. The other patient died as a result of progression of her malignant medulloepithelioma. CONCLUSIONS: Malignant transformation of pure teratomas constitutes a very rare entity in children and adolescents that is most commonly observed in postpubertal girls with ovarian teratoma. Compared to adult patients, similar malignant entities can be observed in association with teratoma. However, in our series, no sarcoma was diagnosed. In localised tumors, complete resection appears to be adequate, whereas chemotherapy should be considered in patients with R1- or R2-resection. Cisplatinum-based chemotherapy was effective as two of four relapsed patients survived tumor free. However, the ideal regimen has not yet been established and the known sensitivity of the histologic components to cytostatic drugs has to be considered in the choice of treatment. Further molecular biologic studies are necessary to understand the origin of these tumors.
Bisogno G, Ferrari A, Bien E, Brecht IB, Brennan B, Cecchetto G, Godzinski J, Orbach D, Reguerre Y, Stachowicz-Stencel T, Schneider DT	Rare Cancers in Children - The EXPeRT Initiative: A Report from the European Cooperative Study Group on Pediatric Rare Tumors.	Klin Pädiatr 2012, 224: 416
The low incidence and the heterogeneity of very rare tumors (VRTs) demand for international cooperation. In 2008, EXPeRT (European Cooperative Study Group for Pediatric Rare Tumors) was founded by national groups from Italy, France, United Kingdom, Poland and Germany. The first aims of EXPeRT were to agree on a uniform definition of VRTs and to develop the currently most relevant scientific questions. Current initiatives include international data exchange, retrospective and prospective studies of specific entities, and the development of harmonized and internationally recognized guidelines. Moreover, EXPeRT established a network for expert consultation to assist in clinical decision in VRTs.
Bisogno G, Sarnacki S, Stachowicz-Stencel T, Minard Colin V, Ferrari A, Godzinski J, Gauthier Villars M, Bien E, Hameury F, Helfre S, Schneider DT, Reguerre Y, Lopez Almaraz R, Janic D, Cesen M, Kolenova A, Rascon J, Martinova K, Cosnarovici R, Pourtsidis A, Ben Ami T, Roganovic J, Koscielniak E, Schultz KAP, Brecht IB, Orbach D	Pleuropulmonary blastoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.	Pediatric blood & cancer 2021, 68 Suppl 4:e29045
Pleuropulmonary blastoma (PPB) is a rare cancer occurring mainly during early childhood and often associated with germline DICER1 mutations. It is classified by the macroscopic appearance into three interrelated clinico-pathologic entities on a developmental continuum. Complete tumor resection is a main prognostic factor and can be performed at diagnosis or after neoadjuvant treatment that includes chemotherapy and in some cases radiotherapy. Optimal modalities of neo- or adjuvant treatments can be challenging taking into account potential long-term toxicities in this young population. This paper presents the recommendations for diagnosis and treatment of children and adolescents with PPB elaborated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the European Union-funded project PARTNER (Paediatric Rare Tumours Network - European Registry).
Bisogno G, Fuchs J, Dasgupta R, Ferrari A, Haduong JH, Rogers T, Walterhouse DO, Coppadoro B, Xue W, Vokuhl C, Hawkins DS, Seitz G, Merks JHM, Sparber-Sauer M, Venkatramani R	Patients with completely resected nongenitourinary low-risk embryonal rhabdomyosarcoma are candidates for reduced duration low-intensity chemotherapy.	Cancer 2022, 128: 4150
The survival of patients with localized embryonal rhabdomyosarcoma (RMS) completely resected at diagnosis is greater than 90%. Most patients have paratesticular, uterine, or vaginal RMS, limiting specific analyses of RMS localized in other anatomic regions. This international study was conducted to define the outcome for completely resected embryonal RMS at sites other than paratesticular, uterine, or vaginal primary sites.
Bitzer M, Voesch S, Albert J, Bartenstein P, Bechstein W, Blödt S, Brunner T, Dombrowski F, Evert M, Follmann M, La Fougère C, Freudenberger P, Geier A, Gkika E, Götz M, Hammes E, Helmberger T, Hoffmann RT, Hofmann WP, Huppert P, Kautz A, Knötgen G, Körber J, Krug D, Lammert F, Lang H, Langer T, Lenz P, Mahnken A, Meining A, Micke O, Nadalin S, Nguyen HP, Ockenga J, Oldhafer K, Paprottka P, Paradies K, Pereira P, Persigehl T, Plauth M, Plentz R, Pohl J, Riemer J, Reimer P, Ringwald J, Ritterbusch U, Roeb E, Schellhaas B, Schirmacher P, Schmid I, Schuler A, von Schweinitz D, Seehofer D, Sinn M, Stein A, Stengel A, Steubesand N, Stoll C, Tannapfel A, Taubert A, Trojan J, van Thiel I, Tholen R, Vogel A, Vogl T, Vorwerk H, Wacker F, Waidmann O, Wedemeyer H, Wege H, Wildner D, Wittekind C, Wörns MA, Galle P, Malek N	S3-Leitlinie: Diagnostik und Therapie biliärer Karzinome.	Zeitschrift fur Gastroenterologie 2022, 60: 219
Blanche S, Caniglia M, Girault D, Landman J, Griscelli C, Fischer A	Treatment of hemophagocytic lymphohistiocytosis with chemotherapy and bone marrow transplantation: a single-center study of 22 cases.	Blood 1991, 78: 51
Twenty-two children with hemophagocytic lymphohistiocytosis were treated with a chemotherapy regimen consisting of VP16-213, corticosteroids, and intrathecal methotrexate. A sustained clinical and biologic complete remission was obtained in 15 children and a partial remission in one child; six children died early of opportunistic infection (n = 4) or of disease progression (n = 2). Of the 16 children who were placed in first remission, 10 received maintenance chemotherapy alone, while six underwent bone marrow transplantation (HLA matched in five, HLA mismatched in one). Of the children who received chemotherapy alone, only two are in long-term remission after cessation of treatment. The remaining eight patients relapsed after a mean period of 5.4 months (range 2 to 8 months). Further treatment using the same regimen induced second remissions of short duration; death occurred after a median period of 2.3 months (range 0.5 to 6 months). A total of nine patients received allogeneic bone marrow transplantation (BMT). Among the six children transplanted in remission, four are in long-term unmaintained remission, 1 to 6 years after HLA-matched BMT. However, the relapse that occurred in one patient 1 year post BMT is difficult to interpret because the donor, the patient's 5-year-old sister, also developed the disease 1 year later. An HLA-nonidentical BMT resulted in unmaintained remission for 1 year, with autologous hematologic reconstitution followed by disease relapse. HLA-nonidentical BMT failed in three other patients with active disease at time of transplant. The poor long-term results of chemotherapy alone justify the use of related HLA-matched BMT in complete remission.
Blackall D, Dolatshahi L	Autoimmune Hemolytic Anemia in Children: Laboratory Investigation, Disease Associations, and Treatment Strategies.	Journal of pediatric hematology/oncology 2022, 44: 71
Autoimmune hemolytic anemia is a relatively uncommon pediatric clinical condition. As such, the evaluation and management of these cases can be challenging for even the most seasoned pediatrician. In this review, the 3 major forms of autoimmune hemolytic anemia in children will be discussed: warm autoimmune hemolytic anemia, cold agglutinin disease, and paroxysmal cold hemoglobinuria. After a general description of the laboratory approach to these entities, the pathophysiology of these disease processes, including important disease associations, will be described, and treatment strategies will be discussed. This will provide the reader with a rational approach to identifying and managing pediatric patients with these uncommon autoimmune conditions.
Bleckmann K, Schrappe M	Advances in therapy for Philadelphia-positive acute lymphoblastic leukaemia of childhood and adolescence.	Br J Haematol 2016, [Epub ahead of print]
The presence of the BCR/ABL1 fusion gene in childhood acute lymphoblastic leukaemia (ALL) is a rare finding and has been an adverse prognostic factor associated with a high risk of therapeutic failure. The current key components of treatment are intensive polychemotherapy and a BCR/ABL1 kinase domain inhibitor. This treatment approach has been applied in a few clinical trials by paediatric leukaemia study groups. Thus, this subtype of ALL serves as the first model system for truly targeted treatment. The role of haematopoietic stem cell transplantation (HSCT) is increasingly called into question, at least in a favourable, though not yet clearly defined, subset of patients. Currently, the choice of the most effective tyrosine kinase inhibitor is not yet settled, in particular, in view of potential reduction of overall treatment intensity.
Blohm M, Vesterling-Horner D, Calaminus G, Göbel U	Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age.	Pediatr Hematol Oncol 1998, 15: 135
Blohm M, Calaminus G, Gnekow A, Heidemann P, Bolkenius M, Weinel P, Schweinitz D, Ambros P, Schneider D, Harms D, Göbel U	Disseminated choriocarcinoma in infancy is curable by chemotherapy and delayed tumour resection.	Eur J Cancer 2001, 37: 72
Blume KG, Forman SJ, Appelbaum F	Thomas' Hematopoietic Cell Transplantation.	Blackwell Scientific Publications, Cambridge 3. Aufl. 2004
Blümel L, Qin N, Berlandi J, Paisana E, Cascão R, Custódia C, Pauck D, Picard D, Langini M, Stühler K, Meyer FD, Göbbels S, Malzkorn B, Liebau MC, Barata JT, Jeibmann A, Kerl K, Erkek S, Kool M, Pfister SM, Johann PD, Frühwald MC, Borkhardt A, Reifenberger G, Faria CC, Fischer U, Hasselblatt M, Bartl J, Remke M	Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors.	Cell death & disease 2022, 13: 806
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Additionally, apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. We also found significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis. Taken together, our findings indicate that primary ciliogenesis or its downstream signaling contributes to the aggressiveness of AT/RT and, therefore, may constitute a novel therapeutic target.
Boccon-Gibod L, Rey A, Sandstedt B, Delemarre J, Harms D, Vujanic G, de Kraker J, Weirich A, Tournade M	Complete necrosis induced by preoperative chemotherapy in Wilms tumor as an indicator of low risk.	Med Pediatr Oncol 2000, 34: 183
Boccara O, Blanche S, de Prost Y, Brousse N, Bodemer C, Fraitag S	Cutaneous hematologic disorders in children.	Pediatric blood & cancer 2012, 58: 226
To determine and list the clinical and pathological features of cutaneous hematologic diseases in childhood.
Bochennek K, Allwinn R, Langer R, Becker M, Keppler OT, Klingebiel T, Lehrnbecher T	Differential loss of humoral immunity against measles, mumps, rubella and varicella-zoster virus in children treated for cancer.	Vaccine 2014, 32: 3357
Intensive chemotherapy in children with cancer results in long-term impairment of humoral immunity. Whereas most studies to date focused on children with acute lymphoblastic leukemia (ALL), little data have been published on patients suffering from Hodgkin disease or from solid tumors. We therefore analyzed the loss of protective immunity (defined as immunity at the time of diagnosis and lack of immunity after completion of therapy) against vaccine-preventable diseases in children treated for various malignancies.
Bochennek K, Hassler A, Perner C, Gilfert J, Schöning S, Klingebiel T, Reinhardt D, Creutzig U, Lehrnbecher T	Infectious complications in children with acute myeloid leukemia: decreased mortality in multicenter trial AML-BFM 2004.	Blood Cancer J 2016, 15; 6:e382
Infections are an important cause for morbidity and mortality in pediatric acute myeloid leukemia (AML). We therefore characterized infectious complications in children treated according to the trial AML-BFM 2004. Patients with Down syndrome were excluded from the analysis. Data were gathered from the medical records in the hospital where the patients were treated. A total of 405 patients (203 girls; median age 8.4 years) experienced 1326 infections. Fever without identifiable source occurred in 56.1% of the patients and clinically and microbiologically documented infections in 17.5% and 32.4% of the patients, respectively. In all, 240 Gram-positive (112 viridans group streptococci) and 90 Gram-negative isolates were recovered from the bloodstream. Invasive fungal infection was diagnosed in 3% of the patients. Three children each died of Gram-negative bacteremia and invasive aspergillosis, respectively. As compared with the results of AML-BFM 93 with lower dose intensity, infection-related morbidity was slightly higher in AML-BFM 2004 (3.3. versus 2.8 infections per patient), whereas infection-related mortality significantly decreased (1.5% versus 5.4%; P=0.003). Specific anti-infective recommendations included in the treatment protocol, regular training courses for pediatric hematologists and increasing experience may be the reason for reduced infection-related mortality in children with AML. Further studies are needed to decrease infection-related morbidity.
Bode U, Hasan C	Supportivmaßnahmen, akute Komplikationen und Notfälle, in Gutjahr P: Krebs bei Kindern und Jugendlichen.	Deutscher Ärzte-Verlag Köln 5. Aufl. 2004, 173
Bodas P, Huang A, O Riordan MA, Sedor JR, Dell KM	The prevalence of hypertension and abnormal kidney function in children with sickle cell disease --a cross sectional review.	BMC nephrology 2013, 14: 237
Renal disease is a known contributor to mortality in adults with sickle cell disease (SCD) and renal abnormalities are evident in childhood. Hyperfiltration (evidenced by elevated glomerular filtration rate, GFR) occurs in children with SCD early in disease. However, the incidence of low GFR (<90 ml/min/1.73 m2) suggestive of chronic kidney disease (CKD), is not well established. The prevalence of hypertension is also not well known. The goal of this study was to determine the prevalence of hypertension and CKD in a cohort of children with SCD.
Bode, G	Nachsorge verbessern - Meeting in Genua.	WIR - Die Zeitschrift der Deutschen Kinderkrebsstiftung und der Deutschen Leukämie-Forschungshilfe e.V 3.2013
Bode U, Zimmermann M, Moser O, Rutkowski S, Warmuth-Metz M, Pietsch T, Kortmann RD, Faldum A, Fleischhack G	Treatment of recurrent primitive neuroectodermal tumors (PNET) in children and adolescents with high-dose chemotherapy (HDC) and stem cell support: results of the HITREZ 97 multicentre trial.	Journal of neuro-oncology 2014, 120: 635
Early studies with high-dose chemotherapy for treatment of relapsed cerebral PNET had shown modest efficacy but considerable toxicity. The HIT97 national trial tested a nonrandomized but stratified relapse protocol using either intensive chemotherapy, potentially high dose, or oral chemotherapy. 72 patients (59 disseminated) whose primary treatment had been surgery (97 %), radiotherapy (88 %), and/or chemotherapy (95 %) were enrolled in the intensive chemotherapy arm at diagnosis of relapse or resistance. As a window for this study they received two courses of a 96-hour infusion with carboplatin and etoposide. A response (complete or partial remission) was documented by MRI. Responders received two more cycles of this therapy and stem cell collection, before they received HDC (carboplatin, etoposide, thiotepa) and stem cell support. All possibilities of local therapy were to be explored and applied. After two courses of chemotherapy there was a 52 % response rate (41/72 patients). The median PFS and OS for all 72 patients were 11.6 and 21.1 months. Patients with medulloblastoma had a longer PFS and OS (12.6 and 22.6 months) than those with other PNETs (3.1 and 12.3 months). Favourable prognostic features were no new signs of clinical impairment and localised disease at relapse diagnosis. For the 27 patients who received HDC the median PFS and OS were 8.4 and 20.2 months, respectively. HDC did not benefit patients with resistant cerebral PNET and was associated with profound haematological and mucosal toxicity (90-100 % grade III, IV), infections (50 % grade III and IV) and severe ototoxicity (50 % grade III, 12.5 % grade IV). Treatment related mortality was 8 %. There was low long-term survival and only 2/72 patients are in continuous remission. Adding HDC in patients who responded to the initial courses of chemotherapy did not improve survival. Patients with relapsed cerebral PNET who respond to conventional chemotherapy do not profit from further augmentation to HDC.
Bodmer N, Hecker-Nolting S, Friedel G, Blattmann C, Kager L, Kessler T, Kevric M, Kühne T, Mettmann V, Müller-Abt P, Sorg B, Theobald M, Bielack SS	Primary osteosarcoma of the ribs: A report from the Cooperative Osteosarcoma Study Group.	Cancer 2023, 129: 1895
Primary rib osteosarcoma has not been investigated extensively, and clinical characteristics and optimal therapeutic strategies have not been defined. The authors used the database of the Cooperative Osteosarcoma Study Group (COSS) to analyze this tumor-site in depth.
Boensch M, Oberthuer A, Fischer M, Skowron M, Oestreich J, Berthold F, Spitz R	Quantitative real-time PCR for quick simultaneous determination of therapy-stratifying markers MYCN amplification, deletion 1p and 11q.	Diagnostic molecular pathology 2005, 14: 177
Amplification of the oncogene MYCN as well as deletions in 1p and 11q are important prognostic and in part therapy-stratifying factors in human neuroblastoma. Due to the increasing clinical relevance of these molecular markers, accurate and fast assessment of the status of MYCN, 1p, and 11q is essential. As 2 techniques are recommended to avoid artefacts and to circumvent technical limitations, we developed a real-time q-PCR assay using genomic DNA from frozen and paraffin-embedded tissue as template as an alternative to LOH analyses and Southern blot (SB) and in addition to fluorescence in situ hybridization (FISH). Determination of deletion or amplification was achieved by comparing the copy number of a target gene (TG from the region of interest) to an unaffected reference gene (RG) within the same chromosome. PCR raw data were normalized to a serial dilution standard curve and a ratio TG/RG was created. The ratio to define a deletion was set as 0.5 (= expected ratio 1 TG copy/2 RG copies), the amplification threshold was set as >10.0. Data were compared to results obtained by FISH and were consistent in 10 of 13 (77%) tumors with deletion 1p, 18 of 20 (90%) with deletion 11q, 12 of 12 (100%) with MYCN amplification, and 146 of 151 (97%) samples without any aberration. Three tumors with aberrations in 1p and 2 tumors with aberrations in 11q were detectable by FISH but not by PCR. Three cases indicated a deletion 11q, 1 tumor a deletion 1p by PCR only. Specificity was 98% for 1p and MYCN each and 92% for 11q. Sensitivity was 77% for 1p, 90% for 11q, and 100% for MYCN. The discrepant results were mostly caused by heterogeneous cell populations of the investigated tissue; the use of real-time q-PCR for the detection of chromosomal aberrances in NB enables a fast and reliable assessment of the 3 most relevant chromosomal aberrations simultaneously. As the assay does not require reference tissue, can be performed with small amounts of DNA, and allows the investigation of paraffin-embedded material for the MYCN-status, it can be regarded alternative to LOH or SB analyses and in addition to FISH.
Bölling T, Schuck A, Willich N	RiSK – Register zur Erfassung strahlentherapiebedingter Spätfolgen bei Kindern und Jugendlichen.	WIR - DLFH - Dachverband - Aktion für krebskranke Kinder e.V 2005, 4
Bölling T, Schuck A, Rübe C, Hesselmann S, Pape H, Dieckmann K, Pöllinger B, Kortmann RD, Speiser-Held I, Meyer FM, Martini C, Asadpour B, Timmermann B, Beck JD, Langer T, Paulides M, Schmidt B, Willich N	[Therapy-associated late effects after irradiation of malignant diseases in childhood and adolescence. Feasibility analyses of a prospective multicenter register study].	Strahlentherapie und Onkologie 2006, 182: 443
Radiogenic late effects in children and adolescents have been evaluated retrospectively in most analyses, with small patient numbers. The German Group of Pediatric Radiation Oncology (APRO) has generated a concept for a prospective evaluation of radiation-associated late effects in childhood. The aim of this study was to evaluate the feasibility of a nationwide central database for the documentation of radiation parameters and side effects of all children treated within therapy protocols of the German Society of Pediatric Oncology and Hematology (GPOH).
Bölling T, Schuck A, Pape H, Rübe C, Meyer FM, Martini C, Timmermann B, Asadpour B, Kortmann RD, Beck JD, Langer T, Paulides M, Willich N	German register for detection of late sequelae after radiotherapy for children and adolescents (RiSK): present status and first results.	Strahlentherapie und Onkologie 2007, 183 Spec No 2: 7
Bölling T, Schuck A, Pape H, Rübe C, Meyer FM, Martini C, Timmermann B, Asadpour B, Kortmann RD, Beck JD, Langer T, Paulides M, Könemann S, Willich N	[Register for the evaluation of side effects after radiation in childhood and adolescence--first results].	Klinische Padiatrie 2007, 219: 139
Late effects after radiotherapy in childhood and adolescence have mainly been characterized retrospectively with small patient numbers. Therefore the German Group of Pediatric Radiation Oncology (APRO) established the
Bölling T, Schuck A, Paulussen M, Dirksen U, Ranft A, Könemann S, Dunst J, Willich N, Jürgens H	Whole lung irradiation in patients with exclusively pulmonary metastases of Ewing tumors. Toxicity analysis and treatment results of the EICESS-92 trial.	Strahlentherapie und Onkologie 2008, 184: 193
BACKGROUND: In the European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) 92, whole lung irradiation (WLI) was performed in patients with primary lung metastases. This retrospective analysis evaluates the pulmonary function and the outcome of patients with exclusively pulmonary metastases. PATIENTS AND METHODS: Between 1990 and 1999, 99 patients were registered into the EICESS-92-study trial with exclusively pulmonary metastases of Ewing tumors. The multimodal treatment regimen included polychemotherapy and local therapy to the primary tumor. WLI was performed with a dose between 12-21 Gy. 70 patients were treated with WLI, 13 of them received a further boost to their primary tumor in the thorax up to a cumulative dose of 54 Gy. RESULTS: Pulmonary function tests were available for 37 patients treated with WLI (+/- boost). None, mild, moderate or severe pulmonary complications were seen in 43%, 29%, 21% and 7% of patients treated with WLI without further boost (median follow-up 25.2 months). Patients with an additional radiation boost or surgery to the thorax showed slightly higher rates of complications. Overall survival (OAS) showed a trend towards better results for patients with WLI (5-year-OAS: 0.61 for WLI vs. 0.49 for no WLI, p = 0.36). CONCLUSION: These data indicate a benefit and acceptable toxicity for WLI in the presented collective of patients. As long as there is no randomized prospective analysis, the present data confirm the indication for WLI in Ewing tumor patients with primary exclusively lung metastases.
Boelling T, Schuck A, Pape H, Rube C, Pollinger B, Timmermann B, Kortmann RD, Dieckmann K, Willich N	Study protocol of the German .	Radiation oncology 2008, 3: 10
Late effects after radiotherapy in childhood and adolescence have mainly been characterized retrospectively with small patient numbers. However, these analyses are limited due to little information regarding organ dose levels in many cases. To overcome this limitation, the German Group of Paediatric Radiation Oncology (APRO) established the "Registry for the evaluation of late side effects after radiation in childhood and adolescence" (RiSK). The study protocol and the documentation forms are given in this publication.
Bölling T, Könemann S, Ernst I, Willich N	Late effects of thoracic irradiation in children.	Strahlentherapie und Onkologie 2008, 184: 289
To summarize the literature regarding the late effects of radiotherapy to the thorax in childhood and adolescence with special emphasis on cardiac and pulmonary impairment.
Bölling T, Ernst I, Könemann S, Willich N	Pediatric radiation oncology in Germany: a study of availability and application.	Klinische Padiatrie 2008, 220: 178
Radiotherapy plays a pivotal role in many multimodal therapy concepts in pediatric oncology. However, the absolute number of irradiated children is estimated to be quite low. The aim of this study was to evaluate the availability and application of pediatric radiation oncology in Germany.
Bölling T, Dirksen U, Ranft A, Ernst I, Jürgens H, Willich N	Radiation toxicity following busulfan/melphalan high-dose chemotherapy in the EURO-EWING-99-trial: review of GPOH data.	Strahlenther Onkol 2009, 185 Suppl 2: 21
Bölling T, Ernst I, Pape H, Martini C, Rübe C, Timmermann B, Fischedick K, Kortmann RD, Willich N	Dose-Volume Analysis of Radiation Nephropathy in Children: Preliminary Report of the RiSK Consortium.	International journal of radiation oncology, biology, physics 2010,
PURPOSE: To characterize kidney function in children and adolescents who had undergone radiation treatment that included parts of the kidney. METHODS AND MATERIALS: Patients receiving radiotherapy during childhood or adolescence were prospectively registered in Germany's Registry for the Evaluation of Side Effects after Radiation in Childhood and Adolescence (RiSK). Detailed information was recorded regarding radiation doses at the organs at risk since 2001 all over Germany. Toxicity evaluation was performed according to standardized Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS: Up to May 2009, 1086 patients from 62 centers were recruited, including 126 patients (median age, 10.2 years) who underwent radiotherapy to parts of the kidneys. Maximal late toxicity (median follow-up 28.5 months in 74 patients) was characterized as Grade 0 (n = 65), 1 (n = 7) or 2 (n = 2). All patients with late effects had received potentially nephrotoxic chemotherapy. A statistically significant difference between patients with and without Grade 1 toxicity, revealing higher exposed kidney volumes in patients with toxicity, was seen for the kidney volume exposed to 20 Gy (V20; p = 0.031) and 30 Gy (V30; p = 0.003). CONCLUSIONS: Preliminary data indicate that radiation-induced kidney function impairment is rare in current pediatric multimodal treatment approaches. In the future, RiSK will be able to provide further detailed data regarding dose-volume effect relationships of radiation-associated side effects in pediatric oncology patients.
Bölling T, Willich N	Long-term overall and cardiovascular mortality after childhood cancer: the problem of retrospective estimated radiation doses.	Journal of clinical oncology 2010, 28:e436; author reply e437
Bölling T, Willich N, Ernst I	Late effects of abdominal irradiation in children: a review of the literature.	Anticancer research 2010, 30: 227
To comprehensively summarize the most important literature regarding the late effects of radiotherapy to the abdomen in childhood and adolescence.
Bölling T, Geisenheiser A, Pape H, Martini C, Rübe C, Timmermann B, Fischedick K, Kortmann RD, Gerss J, Koch R, Willich N	Hypothyroidism after head-and-neck radiotherapy in children and adolescents: preliminary results of the Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence" (RiSK).	International journal of radiation oncology, biology, physics 2011, 81:e787
The "Registry for the Evaluation of Side Effects After Radiotherapy in Childhood and Adolescence" (RiSK) has been established to prospectively characterize dose-volume effects of radiation in terms of side effects. The aim of this analysis was to characterize the function of the thyroid gland after radiotherapy to the head-and-neck region in children and adolescents.
Bölling T, Weege J, Eich HT, Timmermann B, Meyer FM, Rübe C, Kortmann RD, Fischedick K, Rödel C, Koch R, Willich N	Acute and late side effects to salivary glands and oral mucosa following head/neck radiotherapy in children and adolescents.	Head Neck 2014 Apr 25;[Epub ahead of print]
Background:
Bölling T, Braun-Munzinger G, Burdach S, Calaminus G, Craft A, Delattre O, Deley MC, Dirksen U, Dockhorn-Dworniczak B, Dunst J, Engel S, Faldum A, Fröhlich B, Gadner H, Göbel U, Gosheger G, Hardes J, Hawkins DS, Hjorth L, Hoffmann C, Kovar H, Kruseova J, Ladenstein R, Leuschner I, Lewis IJ, Oberlin O, Paulussen M, Potratz J, Ranft A, Rössig C, Rübe C, Sauer R, Schober O, Schuck A, Timmermann B, Tirode F, van den Berg H, van Valen F, Vieth V, Willich N, Winkelmann W, Whelan J, Womer RB	Development of curative therapies for Ewing sarcomas by interdisciplinary cooperative groups in Europe.	Klinische Padiatrie 2015, 227: 108
Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.
Boer JM, van der Veer A, Rizopoulos D, Fiocco M, Sonneveld E, de Groot-Kruseman HA, Kuiper RP, Hoogerbrugge P, Horstmann M, Zaliova M, Palmi C, Trka J, Fronkova E, Emerenciano M, do Socorro Pombo-de-Oliveira M, Mlynarski W, Szczepanski T, Nebral K, Attarbaschi A, Venn N, Sutton R, Schwab CJ, Enshaei A, Vora A, Stanulla M, Schrappe M, Cazzaniga G, Conter V, Zimmermann M, Moorman AV, Pieters R, den Boer ML	Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study.	Leukemia 2016, 30: 32
Deletions in IKZF1 are found in ~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4-7 and exons 1-8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case-control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P<0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2-7 (P=0.03), DEL 2-8 (P=0.002) and DEL-Other (P<0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4-7 and DEL 1-8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.
Boekhoff S, Bogusz A, Sterkenburg AS, Eveslage M, Müller HL	Long-term Effects of Growth Hormone Replacement Therapy in Childhood-onset Craniopharyngioma: Results of the German Craniopharyngioma Registry (HIT-Endo).	European journal of endocrinology 2018, 179: 331
Quality of survival, prognosis and long-term outcome are often severely impaired in childhood-onset craniopharyngioma patients (CP). Identification of risk factors for sequelae such as growth hormone (GH) deficiency is important for appropriate treatment and rehabilitation.
Boekhoff S, Bison B, Eveslage M, Sowithayasakul P, MÃ¼ller HL	Craniopharyngiomas presenting as incidentalomas: results of KRANIOPHARYNGEOM 2007.	Pituitary 2019, 22: 532
Childhood-onset craniopharyngiomas (CP) are diagnosed due to clinical symptoms (symCP) or incidentally (incCP). We investigated clinical manifestations and outcome in incCPs and symCPs.
Boekhoff S, Bison B, Genzel D, Eveslage M, Otte A, Friedrich C, Flitsch J, Müller HL	Cerebral Infarction in Childhood-Onset Craniopharyngioma Patients: Results of KRANIOPHARYNGEOM 2007.	Frontiers in oncology 2021, 11: 698150
Cerebral infarction (CI) is a known vascular complication following treatment of suprasellar tumors. Risk factors for CI, incidence rate, and long-term prognosis are unknown for patients with childhood-onset craniopharyngioma (CP).
Boekhoff S, Eveslage M, Beckhaus J, Friedrich C, Müller HL	[Legal Degree of Disability in Childhood-Craniopharyngioma Survivors During Long-Term Follow-Up].	Klinische Padiatrie 2023, 235: 151
Cranioparyngiomas are rare low-grade embryonic malformational tumors of the sellar/parasellar region. The prognosis after diagnosis during childood and adolescence is influenced by (neuro)endocrine long-term sequelae. A legal status of the degree of disability (GdB), according to the German Social Code Book V that is worthy of support provides financial means for psychosocial integration and participation of craniopharyngioma survivors.
Böhm S, Wustrau K, Pachlopnik Schmid J, Prader S, Ahlman M, Yacobovich J, Beier R, Speckmann C, Behnisch W, Ifversen M, Jordan MB, Marsh RA, Naumann-Bartsch N, Mauz-Koerholz C, Honig M, Schulz AS, Malinowska I, Hines MR, Nichols KE, Gil-Herrera J, Talano JA, Crooks B, Formankova R, Jorch N, Bakhtiar S, Kühnle I, Streiter M, Nathrath M, Russo A, Duerken M, Lang P, Lindemans CA, Henter JI, Lehmberg K, Ehl S	Survival in primary hemophagocytic lymphohistiocytosis 2016-2021: etoposide is better than its reputation.	Blood 2023 Nov 22;
Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 50-59% 5-year survival. Contemporary data are lacking. We evaluated 88 pHLH patients documented in the international HLH Registry between 2016-2021 with follow-up until 6/2023. In 12/88 patients, the diagnosis was made without HLH activity, based on index siblings or partial albinism. Major HLH-directed drugs (etoposide, ATG, alemtuzumab, emapalumab, ruxolitinib) were given to 66/76 symptomatic patients (86% first-line etoposide); 16/57 etoposide-treated and 3/9 patients with other first-line treatment received salvage therapy. HSCT was performed in 75 patients, 7 symptomatic patients died before HSCT. 3-year probability of survival (pSU) was 82% (CI 72%-88%) for the entire cohort and 77% (CI 64-86%) for symptomatic patients receiving first-line etoposide. Compared to the HLH-2004 study, both pre-HSCT survival (83% to 91%) and post-HSCT survival of patients receiving first-line etoposide improved (70% to 88%). Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (148 to 88 days). 3-year pSU was lower with haploidentical (44%, 4/9 patients) than with other types of donors (94%, 4/66, p<0.001). Importantly, also in this study, early HSCT of asymptomatic patients resulted in excellent survival (100%), emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of pHLH patients reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.
Bogusz A, Müler HL	Childhood-onset craniopharyngioma: latest insights into pathology, diagnostics, treatment, and follow-up.	Expert review of neurotherapeutics 2018, 18: 793
Childhood-onset craniopharyngiomas are rare embryonic tumors of low-grade histological malignancy. Severe obesity, physical fatigue, and psychosocial deficits due to hypothalamic tumor involvement have negative impact on quality of life. Initial pretreatment involvement of hypothalamic structures and/or treatment-related lesions result in sequelae clinically associated with impaired social and physical functionality and severe neuroendocrine deficiencies. Overall and progression-free survival rates are not associated with the degree of surgical resection. However, reduced overall survival rates were observed in patients with primary hypothalamic tumor involvement. Areas covered: This review discusses new perspectives on diagnostics, treatment, and follow-up of patients with childhood-onset craniopharyngioma, which were mostly published after 2010 and presented at the 5th International Multidisciplinary Postgraduate Course on Childhood Craniopharyngioma, 19-22 April 2018, at Bad Zwischenahn, Germany. Expert commentary: Percutaneous radio-oncological treatment options are effective in prevention of relapses and tumor progressions. Initial experience with proton beam therapy in childhood-onset craniopharyngioma patients shows promising results in terms of more protective radiological treatment. Recent reports on the molecular pathogenesis of craniopharyngioma open perspectives on the possibility of testing novel treatments targeting pathogenic pathways. As long as effective treatment options for hypothalamic syndrome are not available, hypothalamus-sparing treatment strategies are recommended.
Bogusz A, Boekhoff S, Warmuth-Metz M, Calaminus G, Eveslage M, MÃ¼ller HL	Posterior hypothalamus-sparing surgery improves outcome after childhood craniopharyngioma.	Endocrine connections 2019, 8: 481
Quality of life (QoL) is frequently impaired in childhood-onset craniopharyngioma (CP) by hypothalamic syndrome. The debate, whether pretreatment hypothalamic involvement (HI) has apriori prognostic impact or surgical hypothalamic lesions (HL) determine outcome, is controversial.
Boguszewski MCS, Boguszewski CL, Chemaitilly W, Cohen LE, Gebauer J, Higham C, Hoffman AR, Polak M, Yuen KCJ, Alos N, Antal Z, Bidlingmaier M, Biller BMK, Brabant G, Choong CSY, Cianfarani S, Clayton PE, Coutant R, Cardoso-Demartini AA, Fernandez A, Grimberg A, Guðmundsson K, Guevara-Aguirre J, Ho KKY, Horikawa R, Isidori AM, Jørgensen JOL, Kamenicky P, Karavitaki N, Kopchick JJ, Lodish M, Luo X, McCormack AI, Meacham L, Melmed S, Mostoufi Moab S, Müller HL, Neggers SJCMM, Aguiar Oliveira MH, Ozono K, Pennisi PA, Popovic V, Radovick S, Savendahl L, Touraine P, van Santen HM, Johannsson G	Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement.	European journal of endocrinology 2022, 186:P35-P52
Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.
Bohn G, Welte K, Klein C	Severe congenital neutropenia: new genes explain an old disease.	Current opinion in rheumatology 2007, 19: 644
This review summarizes the recent advances in the diagnosis and molecular characterization of isolated and syndromal forms of severe congenital neutropenia.
Bokemeyer A, Eckert C, Meyr F, Koerner G, von Stackelberg A, Ullmann R, Türkmen S, Henze G, Seeger K	Copy number genome alterations are associated with treatment response and outcome in relapsed childhood ETV6/RUNX1-positive acute lymphoblastic leukemia.	Haematologica 2014, 99: 706
The clinical heterogeneity among first relapses of childhood ETV6/RUNX1-positive acute lymphoblastic leukemia indicates that further genetic alterations in leukemic cells might affect the course of salvage therapy and be of prognostic relevance. To assess the incidence and prognostic relevance of additional copy number alterations at relapse of the disease, we performed whole genome array comparative genomic hybridization of leukemic cell DNA from 51 patients with first ETV6/RUNX1-positive relapse enrolled in and treated according to the relapse trials ALL-REZ of the Berlin-Frankfurt-Münster Study Group. Within this cohort of patients with relapsed ETV6/RUNX1-positive acute lymphoblastic leukemia, the largest analyzed for genome wide DNA copy number alterations to date, alterations were present in every ETV6/RUNX1-positive relapse and a high proportion of them occurred in recurrent overlapping chromosomal regions. Recurrent losses affected chromosomal regions 12p13, 6q21, 15q15.1, 9p21, 3p21, 5q and 3p14.2, whereas gains occurred in regions 21q22 and 12p. Loss of 12p13 including CDKN1B was associated with a shorter remission duration (P=0.009) and a lower probability of event-free survival (P=0.001). Distribution of X-chromosomal copy number alterations was gender-specific: whole X-chromosome loss occurred exclusively in females, gain of Xq only in males. Loss of the glucocorticoid receptor gene NR3C1 (5q31.3) was associated with a poor response to induction treatment (P=0.003), possibly accounting for the adverse prognosis of some of the ETV6/RUNX1-positive relapses.
Bolton-Maggs PH, Dickerhoff R, Vora AJ	The nontreatment of childhood ITP (or .	Seminars in thrombosis and hemostasis 2001, 27: 269
The management of childhood acute idiopathic thrombocytopenic purpura is controversial, with recent guidelines highlighting the lack of suitable evidence upon which to base management decisions. Three European centers have used an expectant policy and results over the past decade demonstrate that this is safe and convenient for the majority of children. Adequate parental education about the condition from an experienced specialist is essential, together with open access for children should they develop any problems. A clinical stratification of such patients must be incorporated into any future trials, together with quality of life assessment to discover the impact of restrictions on lifestyle, particularly in adolescents with chronic ITP who may need a different approach.
Bomelburg T, Roos N, von Lengerke H, Ritter J	Invasive aspergillosis complicating induction chemotherapy of childhood leukaemia.	Eur J Pediatr 1992, 151: 485
Bomken S, Skinner R	Secondary Malignant Neoplasms Following Haematopoietic Stem Cell Transplantation in Childhood.	Children (Basel, Switzerland) 2015 Apr 21; 2: 146
Improving survival rates in children with malignancy have been achieved at the cost of a high frequency of late adverse effects of treatment, especially in intensively treated patients such as those undergoing haematopoietic stem cell transplantation (HSCT), many of whom suffer the high burden of chronic toxicity. Secondary malignant neoplasms (SMNs) are one of the most devastating late effects, cause much morbidity and are the most frequent cause of late (yet still premature) treatment-related mortality. They occur in up to 7% of HSCT recipients by 20 years post-HSCT, and with no evidence yet of a plateau in incidence with longer follow-up. This review describes the epidemiology, pathogenesis, clinical features and risk factors of the three main categories of post-HSCT SMNs. A wide range of solid SMNs has been described, usually occurring 10 years or more post-HSCT, related most often to previous or conditioning radiotherapy. Therapy-related acute myeloid leukaemia/myelodysplasia occurs earlier, typically three to seven years post-HSCT, mainly in recipients of autologous transplant and is related to previous alkylating agent or topoisomerase II inhibitor chemotherapy. Post-transplant lymphoproliferative disorders occur early (usually within two years) post-HSCT, usually presenting as Epstein-Barr virus-related B cell non-Hodgkin lymphoma.
Bonn BR, Rohde M, Zimmermann M, Krieger D, Oschlies I, Niggli F, Wrobel G, Attarbaschi A, Escherich G, Klapper W, Reiter A, Burkhardt B	Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence.	Blood 2013, 18; 121: 3153
Probability of event-free survival (pEFS) in pediatric T-cell lymphoblastic lymphoma is about 80%, whereas survival in relapsed patients is very poor. No stratification criteria have been established so far. Recently, activating NOTCH1 mutations were reported to be associated with favorable prognosis, and loss of heterozygosity at chromosome 6q (LOH6q) was reported to be associated with increased relapse risk. The current project was intended to evaluate the prognostic effect of these markers. Mutations in hot spots of NOTCH1 and FBXW7 were analyzed in 116 patients. Concerning LOH6q status, 118 patients were investigated, using microsatellite marker analysis, in addition to an earlier reported cohort of 99 available patients. Ninety-two cases were evaluable for both analyses. All patients were treated with T-cell lymphoblastic lymphoma-Berlin-Frankfurt-Münster group (BFM)-type treatment. LOH6q was observed in 12% of patients (25/217) and associated with unfavorable prognosis (pEFS 27% ± 9% vs 86% ± 3%; P < .0001). In 60% (70/116) of the patients, NOTCH1 mutations were detected and associated with favorable prognosis (pEFS 84% ± 5% vs 66% ± 7%; P = .021). Interestingly, NOTCH1 mutations were rarely observed in patients with LOH in 6q16. Both prognostic markers will be used as stratification criteria in coming Non-Hodgkin Lymphoma-BFM trials.
Bonaventure A, Harewood R, Stiller CA, Gatta G, Clavel J, Stefan DC, Carreira H, Spika D, Marcos-Gragera R, Peris-Bonet R, Piñeros M, Sant M, Kuehni CE, Murphy MFG, Coleman MP, Allemani C, CONCORD Working Group	Worldwide comparison of survival from childhood leukaemia for 1995-2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries.	The Lancet. Haematology 2017 Apr 11;
Boos J, Real E, Schulze-Westhoff P, Pröbsting B, Wolff J, Jürgens H	Pharmacokinetics of etoposide short-term infusions within the scope of the GPOH therapy protocol.	Klin Pädiatr 1993, 205: 288
Boos J, Krumpelmann S, Schulze-Westhoff P, Euting T, Berthold F, Jürgens H	Steady-state levels and bone marrow toxicity of etoposide in children and infants.	J Clin Oncol 1995, 13: 2954
Boos J, Krümpelmann S, Schulze-Westhoff, Euting T, Berthold F, Jürgens H	Steady-state levels and bone marrow toxicity of etoposide in children and infants.	J Clin Oncol 1995, 13: 2954
Boos J, Silies H, Hohenlöchter B, Jürgens H, Blaschke G	Short-term versus continuous infusion.	Eur J Cancer 1995, 31A: 2417
Boos J, Schulze-Westhoff, Lanvers C, May-Manke A, Hohenlöchter B, Hempel G, Jürgens H	Pharmacokinetics of antineoplastic drugs in in vitro assays.	Med Pediatr Oncol 1996, 27
Boos J, Hohenlochter B, Schulze-Westhoff P, Schiller M, Zimmermann M, Creutzig U, Ritter J, Jürgens H	Intracellular retention of cytosine arabinoside triphosphate in blast cells from children with acute myelogenous and lymphoblastic leukemia.	Med Pediatr Oncol 1996, 26: 397
Boos J, Schiller M, Pröbsting B, Creutzig U, Ritter J	Intracellular retention of cytosine-arabinoside-triphosphate in leukemic blast cells from children.	Haematology and Blood Transfusion 1996, 37: 50
Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM	Mutations in SBDS are associated with Shwachman-Diamond syndrome.	Nature genetics 2003, 33: 97
Bopp A, Kameda G	Unser Kind hat Krebs.	Verlag Urachhaus 2011
Borgmann A, Emminger W, Emminger-Schmidmeier W, Peters C, Gatterer-Menz I, Henze G, Gadner H	Influence of fractionated total body irradiation on mucosal toxicity in intensified conditioning regimens for autologous bone marrow transplantation in pediatric cancer patients.	Klin Pädiatr 1994, 206: 299
Borgmann A, Hartmann R, Schmid H, Klingebiel T, Ebell W, Göbel U, Peters C, Gadner H, Henze G	Isolated extramedullary relapse in children with acute lymphoblastic leukemia.	Bone Marrow Transplant 1995, 15: 515
Borgmann A, Schmid H, Hartmann R, Baumgarten E, Hermann K, Klingebiel T, Ebell W, Zintl F, Gadner H, Henze G	Autologous bone-marrow transplants compared with chemotherapy for children with acute lymphoblastic leukaemia in a second remission.	Lancet 1995, 346: 873
Borgmann A, Baumgarten E, Schmid H, Döpfer R, Ebell W, Göbel U, Niethammer D, Gadner H, Henze G	Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission.	Bone Marrow Transplant 1997, 20: 939
Borkhardt A, Cazzaniga G, Viehmann S, Valsecchi M, Ludwig W, Burci L, Mangioni S, Schrappe M, Riehm H, Lampert F, Basso G, Masera G, Harbott J, Biondi A	Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Study Group.	Blood 1997, 90: 571
Bornfeld N, Schuler A, Bechrakis N, Henze G, Havers W	Preliminary results of primary chemotherapy in retinoblastoma.	Klin Pädiatr 1997, 209: 216
BACKGROUND: Eye retention rates after external beam therapy for advanced retinoblastoma are close to 90% with very few ocular side effects like radiation retinopathy or radiation induced optic neuropathy. Late complications, however, comprise a sixfold increase of secondary non-ocular cancers like soft tissue sarcomas demanding alternative treatment options in the management of advanced retinoblastoma. PURPOSE: A phase I study on primary chemotherapy using vincristine, cyclophosphamide, etoposide and carboplatin in advanced bilateral retinoblastoma was undertaken to evaluate the potential of a treatment regimen not including external beam therapy. PATIENTS AND METHODS: 12 eyes with 17 tumors in 9 children were treated with primary chemotherapy as first treatment option with a mean follow-up of 16.7 months. Planned enucleation of a tumor containing eye was performed in 2 eyes. In one of these enucleated eyes no viable tumor cells were visible on histopathological examination while in the other eye marked tumor regression was detectable. Of the remaining 10 eyes clinical regression of the intraocular tumors was present in all eyes; on average the tumor size was reduced by 50% within 3-6 weeks. Most of the tumors showed a type I (cottage cheese) regression indistinguishable from regression patterns found after external beam radiotherapy. Ancillary treatments including laser photocoagulation, beta-ray brachytherapy, external beam radiotherapy and cryotherapy were performed in 15 out of the 17 tumors. CONCLUSION: Based on the results of this study and on the results published by others primary chemotherapy may result in the same eye retention rate as conventional external beam therapy avoiding the unacceptable high rate of secondary non-ocular cancers in the latter. A prospective study to be undertaken by the GPOH (Gesellschaft für Pädiatrische Onkologie und Hämatologie) and the RG (Retinologische Gesellschaft) is planned to further evaluate this new and promising approach.
Bork, K	Rezidivierende Angioödeme durch C1-Inhibitor-Mangel: Erstickungsrisiko – Aktuelle Aspekte bei Diagnostik und Therapie der Angioödeme.	Dtsach arztebl 1997, 94: A-726 / B-588 / C
Angioödeme sind flüchtige, oft massive Schwellungen, die meistens Lidregion oder Lippen betreffen, oft aber auch andere Hautregionen und innere Organe. Ein Glottisödem dabei bedeutet drohende Erstickungsgefahr. Wichtig ist eine exakte Zuordnung, da es zwei Krankheiten mit verschiedenartiger Pathogenese gibt, die in dasselbe klinische Bild der Angioödeme münden, aber ein unterschiedliches therapeutisches Vorgehen erfordern, vor allem auch im Notfall eines Glottisödems.
Borowski A, van Valen, Ulbrecht M, Weiss E, Blasczyk R, Jürgens H, Göbel U, Schneider E	Monomorphic HLA class I-(non-A, non-B) expression on Ewing's tumor cell lines, modulation by TNF-alpha and IFN-gamma.	Immunobiology 1999, 200: 1
Borgmann A, Baldy C, Von Stackelberg A, Beyermann B, Fichtner I, Nürnberg P, Henze G	Childhood all blasts retain phenotypic and genotypic characteristics upon long-term serial passage in NOD/SCID mice.	Pediatr Hematol Oncol 2000, 17: 635
Bork K, Siedlecki K, Bosch S, Schopf RE, Kreuz W	Asphyxiation by laryngeal edema in patients with hereditary angioedema.	Mayo Clin Proc 2000, 75: 349-54.
OBJECTIVE: To describe the occurrence of fatal laryngeal edema in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. PATIENTS AND METHODS: We describe 6 patients from various regions of Germany who died from laryngeal edema within the last 10 years. Furthermore, we conducted a retrospective survey of 58 patients with hereditary angioedema, originating from 46 affected families. The data were obtained from the attending physicians and from the patients' relatives. RESULTS: Among the 6 reported patients, aged 9 to 78 years, hereditary angioedema had been diagnosed in 3 and was undiagnosed in 3. None of them had an emergency cricothyrotomy or received C1 inhibitor concentrate. The interval between onset of the laryngeal edema and asphyxiation was 20 minutes in a 9-year-old boy, and in the other patients, the interval was 1 to 14 hours (mean for all, 7 hours). The retrospective survey of 58 patients with hereditary angioedema revealed 23 deaths by asphyxiation (40%). The average age of all 29 patients at the time of asphyxiation was 39 years. CONCLUSION: Laryngeal edema in hereditary angioedema may be fatal. Most of the patients asphyxiated between their 20th and 50th years of life, but asphyxiation can occur even in children. The possibility that the first episode of laryngeal edema may be fatal must be emphasized to the relatives, and attending physicians must have a high degree of awareness.
Borkhardt A, Wuchter C, Viehmann S, Pils S, Teigler-Schlegel A, Stanulla M, Zimmermann M, Ludwig W, Janka-Schaub G, Schrappe M, Harbott J	Infant acute lymphoblastic leukemia - combined cytogenetic, immunophenotypical and molecular analysis of 77 cases.	Leukemia 2002, 16: 1685
Borgmann A, Von Stackelberg A, Hartmann R, Ebell W, Klingebiel T, Peters C, Henze G	Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission.	Blood 2003, 101: 3835
Bork K Hardt J, Schicketanz KH, Ressel N	Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency.	Archives of internal medicine 2003, 163: 1229
Hereditary angioedema due to C1 esterase inhibitor deficiency is clinically characterized by recurrent and self-limiting skin, intestinal, and laryngeal edema. Asphyxiation by laryngeal edema is the main cause of death among patients who die of hereditary angioedema. This study describes the age at which laryngeal edema first occurs, the time between onset and full development, and the effectiveness of therapy and prophylaxis.
Bork K, Fischer B, Dewald G	Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy.	The American journal of medicine 2003, 114: 294
Recurrent angioedema, characterized by skin swelling, colicky attacks of abdominal pain, and life-threatening laryngeal edema, can be either hereditary or acquired. According to anecdotal reports, it may be associated with use of oral contraceptives and hormone replacement therapy. We investigated potential interactions between these medications and various types of recurrent angioedema in a large cohort of women.
Borowski A, Dirksen U, Lixin L, Shi RL, Göbel U, Schneider EM	Structure and function of ETAA16: a novel cell surface antigen in Ewing's tumours.	Cancer Immunol Immunother Vol.55; 2006, 363
Immunoscreening of an Ewing's family of tumour (EFT)-derived cDNA library using formerly described EFT-specific antibodies led to the isolation of a 3.5 kb cDNA, named Ewing's tumour-associated antigen 16 (ETAA16). The ETAA16 cDNA shows no homology to any functionally characterised human gene. Only a bovine cDNA expressed in bovine testis and hepatocytes is functionally characterised as it encodes for a junction plaque associated protein and showed a homology of 69.9% at amino acid level to ETAA16. The human cDNA encodes for a 926 amino acid tumour antigen with a calculated molecular weight of 103 kDa. The epitope of the ETAA16-specific antibody, Ak16, covers the central region of the protein which is part of an extra cellular domain. The human ETAA16 gene locus has been assigned to chromosome 2p13-15 by FISH analyses and is confirmed by the human genome sequencing project. As demonstrated by flow cytometry, the cell surface expression of ETAA16 antigen is restricted to ET cell lines and not expressed on other small blue round cell tumours or other kind of tumour. RT-PCR analysis revealed a high expression of ETAA16 in brain, liver and kidney while lung and heart were negative. Immunohistochemistry showed an intracellular expression of ETAA16 in different kind of non-Ewing tumour tissues. These results suggest that ETAA16 may function as a tumour-specific cell surface antigen in EFTs.
Borgna-Pignatti C	Modern treatment of thalassaemia intermedia.	British journal of haematology 2007, 138: 291
The term thalassaemia intermedia includes a large spectrum of conditions of varying severity. Blood transfusion and chelation are necessary in some patients, especially during childhood, in order to promote growth and prevent bone deformities. Alloimunisation, however, is frequent and can be difficult to control. Splenectomy is usually needed at some time because of hypersplenism and mechanical encumbrance. Reactivation of HbF is possible only in a small proportion of patients: hydroxycarbamide (also known as hydroxyurea) appears to be the most effective drug for this purpose. Antioxidant agents, although theoretically useful, do not improve haemoglobin levels. Stem cell transplantation is an option limited to the severe forms. Gene therapy and other molecular approaches are subjects of intense study. Numerous complications, including pulmonary hypertension, thrombotic events, pseudoxanthoma elasticum and osteoporosis, have been described and all contribute to complicate the treatment of a disease that represents a significant burden for the patients and their families.
Borgmann A, Zinn C, Hartmann R, Herold R ,Kaatsch P, Escherich G, Möricke A, Henze G, von Stackelberg A, ALL-REZ BFM Study Group	Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood.	European journal of cancer (Oxford, England : 1990) 2008, 44: 257
PURPOSE: To investigate the cumulative incidence of and the risk factors for developing second malignant neoplasms (SMN) in children and adolescents following treatment for relapse of acute lymphocytic leukaemia (ALL). METHODS: Patients (1376) up to 18 years of age with first relapse of non-B-cell ALL were treated and achieved a 2nd complete remission (CR). The treatment followed trial protocol in five consecutive multicentre trials of the ALL-REZ BFM Study Group between March 1983 and December 2001. The incidence of SMN was analysed, correlated with clinical and therapeutic parameters, and compared to the age-specific incidence rates of cancers as cited in German cancer registries. RESULTS: Out of the 1376 patients 21 were diagnosed with SMN including non-lymphoblastic leukaemia/myelodysplastic syndrome (n=6), osteo-/Ewing's-/fibroblastic sarcoma (n=4), B-cell ALL/lymphoma (n=2), thyroid carcinoma (n=2), basal cell carcinoma, adeno carcinoma, squamous cell carcinoma, meningioma, malignant histiocytosis, glioblastoma and anaplastic astrocytoma (n=1 each). The overall cumulative risk of SMN at 15 years (median follow-up of 13.1 years) was 1.26%+/-0.38% (SE). SMN was found to be significantly associated with stem cell transplantation (SCT), and high cumulative doses of cranial irradiation, etoposide and cyclophosphamide. In multivariate analysis etoposide (VP16) and cyclophophamide (CY) were found to be independently associated with SMN (p=0.047 and 0.002). Compared to the incidence of neoplasm in the age-matched population, there was a 10-fold increase of neoplasia. CONCLUSIONS: Despite repeated exposure to intense frontline and relapse treatment (including multiagent chemotherapy, cranial irradiation and stem cell transplantation in some patients) the cumulative incidence of SMN was unexpectedly low, though significantly higher than in the general age-matched population. The association of SMN to SCT seemed to be a secondary effect at least partially mediated by exposure to high doses of VP16 and CY given for conditioning therapy.
Boria I, Garelli E, Gazda HT, Aspesi A, Quarello P, Pavesi E, Ferrante D, Meerpohl JJ, Kartal M, Da Costa L, Proust A, Leblanc T, Simansour M, Dahl N, Fröjmark AS, Pospisilova D, Cmejla R, Beggs AH, Sheen MR, Landowski M, Buros CM, Clinton CM, Dobson LJ, Vlachos A, Atsidaftos E, Lipton JM, Ellis SR, Ramenghi U, Dianzani I	The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update.	Human mutation 2010, 31: 1269
Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database.
Borg K	Recurrent angioedema and the threat of asphyxiation.	Dtsach arztebl int 2010, 107: 408
BACKGROUND: Recurrent angioedema may affect the skin or, less commonly, the tongue, gastrointestinal tract, and larynx. Angioedema is a clinical sign that can be produced by a variety of diseases. Asphyxiation due to edematous obstruction of the upper airway is rare, but, for the affected patients, it is a permanent risk.
Bornfeld N, Holdt M, Biewald E, Wieland R, Eggert A, Göricke S, Lohmann D	[New developments in molecular genetics and treatment of retinoblastoma].	Klinische Monatsblatter fur Augenheilkunde 2011, 228: 593
Retinoblastomas are the most frequent primary malignant intraocular tumours worldwide. Conventional and new treatment modalities have significantly improved the chance for survival and preservation of vision. The armamentarium of treatment modalities has been broadened recently by new techniques like intraarterial chemotherapy, which still has to be considered as experimental since long-term follow-up results are not yet available. The excellent prognosis for retinoblastomas in countries with a well developed health system is contrasted by the miserable prognosis for retinoblastomas in developing countries, which must be changed by a joint effort of all centres.
Bork K, Hardt J, Staubach-Renz P, Witzke G	Risk of laryngeal edema and facial swellings after tooth extraction in patients with hereditary angioedema with and without prophylaxis with C1 inhibitor concentrate: a retrospective study.	Oral Surg 2011, 112: 58-64.
OBJECTIVE: Tooth extractions may trigger clinical symptoms of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH). The aim of this study was to determine how many tooth extractions were followed by symptoms of HAE-C1-INH in patients with and without preoperative short-term prophylaxis with C1 inhibitor concentrate. STUDY DESIGN: Tooth extractions and clinical symptoms of HAE-C1-INH were determined from clinical record files of 171 patients with HAE-C1-INH. RESULTS: Facial swelling or potentially life-threatening laryngeal edema, or both, occurred in 124/577 tooth extractions (21.5%) without prophylaxis. Similar symptoms occurred in a fewer proportion of patients undergoing extractions (16/128; 12.5%) after short-term prophylaxis with C1 inhibitor concentrate. The graded dose-response relationship was significant at P < .05. CONCLUSIONS: Short-term prophylaxis with C1 inhibitor concentrate significantly reduces the risk of HAE-C1-INH symptoms after tooth extraction. In some patients, however, facial swellings and laryngeal edema symptoms may occur despite prophylaxis.
Borgmann-Staudt A, Rendtorff R, Reinmuth S, Hohmann C, Keil T, Schuster FR, Holter W, Ehlert K, Keslova P, Lawitschka A, Jarisch A, Strauss G	Fertility after allogeneic haematopoietic stem cell transplantation in childhood and adolescence.	Bone marrow transplantation 2012, 47: 271
Infertility is a major late effect in patients receiving haematopoietic stem cell transplantation (HSCT). The aim of this study was to determine the proportion of patients having fertility impairment after allogeneic HSCT in childhood/adolescence and to identify the potential risk factors. Treatment and fertility data of paediatric patients with malignant and non-malignant diseases treated with allogeneic HSCT between 2000 and 2005 were collected from seven European centres. Data were obtained for 138 female and 206 male patients after a median follow-up of 6 years (range 3-12). The patients' median age was 13 years (range 4-28) at the time of HSCT and 19 (range 12-35) years at the time of the enquiry. Seven children were born to the overall group, all at term and healthy. Fertility impairment was suspected in 69% males and 83% females. Start of treatment at age 13 years was a risk factor in females (odds ratio (OR) 4.7; 95% confidence interval (CI), 1.5 to 14.9), whereas pre-pubertal therapy was a risk factor in males (OR 0.4; 95% CI, 0.2 to 0.8). The major treatment-related risk factors were BU in females (OR 47.4; 95% CI, 5.4 to 418.1) and TBI in males (OR 7.7; 95% CI, 2.3 to 25.4). In light of the significant proportion of HSCT patients reviewed with impaired fertility, fertility conservation procedures should be considered for all patients undergoing HSCT, particularly those receiving TBI or BU-based preparative regimens.
Bork K, Maurer M, Bas M, Hartmann K, Biedermann T, Kreuz W, Aygören - Pürsün E, Martinez - Saguer I, Ott H, Wedi B	Leitlinie Leitlinie Hereditäres Angioödem durch C1-Inhibitor-Mangel.	Allergologie 2013, 36: 140
Leitlinie HAE
Bornfeld N, Biewald E, Bauer S, Temming P, Lohmann D, Zeschnigk M	The Interdisciplinary Diagnosis and Treatment of Intraocular Tumors.	Deutsches Arzteblatt international 2018 Feb 16; 115: 106
Background: Recent years have seen major changes in the diagnosis and treatment of solid intraocular tumors, mainly owing to an improved molecular biological understanding of their pathogenesis, new therapeutic approaches for the local treatment of tumors in children, and long-term follow-up observations in clinical trials. Methods: This review is based on pertinent publications retrieved by a selective search in PubMed. Results: Retinoblastoma is the most common type of primary intraocular tumor, with approximately 8000 new cases per year around the world, while malignant melanoma of the uvea is the most common primary intraocular tumor in adults, with approximately 7000 new cases per year around the world. Intraocular metastases of malignant tumors are ten times more common, in terms of incidence, than primary intraocular tumors and are therefore the most common intraocular tumors overall. Improved methods of intraocular biopsy, diagnostic imaging, and molecular genetic investigation have led to steady improvement in clinical and predictive diagnostic assessment. In the treatment of retinoblastoma, local techniques including brachytherapy and intra-arterial and intravitreal chemotherapy play a prominent role. Prognostic molecular-genetic testing now enables the highly selective identification of uveal melanomas that have a high potential to metastasize. Cutaneous and uveal melanomas differ both in their clinical behavior and in their basic biological features; to date, effective systemic treatment has been established for melanoma of the skin, but not for metastatic melanoma of the uvea. Intraocular metastases are common and often the initial manifestation of an extraocular tumor, particularly lung cancer. Conclusion: Modern diagnostic and therapeutic concepts for intraocular tumors can only be implemented through the close interdisciplinary collaboration of ophthal - mologists, oncologists, radiologists, radiotherapists, pathologists, and human geneticists.
Borgmann-Staudt A, Kunstreich M, Schilling R, Balcerek M, Dirksen U, Cario H, Kepakova K, Klco-Brosius S, Korte E, Kruseova J, Lackner H, Langer T, Roslan KM, Stefanowicz J, Strauß G, Byrne J, PanCareLIFE	Fertility knowledge and associated empowerment following an educational intervention for adolescent cancer patients.	Psycho-oncology 2019, 28: 2218
Fertility preservation is a major concern for adolescent cancer patients; yet, educational gaps remain. Our intervention study examined whether specially designed educational materials regarding fertility preservation increase knowledge and empowerment of patients and parents.
Borgmann-Staudt A, Balcerek M, Jantke A, Hinz S	Beeinträchtigung der Gonadenfunktion nach Chemo- und Strahlentherapie im Kindes- und Jugendalter: Risiken, Diagnostik, Prophylaxe- und Behandlungsmöglichkeiten.	Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie AWMF online 2020
Bornhauser B, Cario G, Rinaldi A, Risch T, Rodriguez Martinez V, Schütte M, Warnatz HJ, Scheidegger N, Mirkowska P, Temperli M, Möller C, Schumich A, Dworzak M, Attarbaschi A, Brüggemann M, Ritgen M, Mejstrikova E, Hofmann A, Buldini B, Scarparo P, Basso G, Maglia O, Gaipa G, Skoblyn TL, Te Kronnie G, Vendramini E, Panzer-Grümayer R, Barz MJ, Marovca B, Hauri-Hohl M, Niggli F, Eckert C, Schrappe M, Stanulla M, Zimmermann M, Wollscheid B, Yaspo ML, Bourquin JP	The hematopoietic stem cell marker VNN2 is associated with chemoresistance in pediatric B-cell precursor ALL.	Blood advances 2020, 4: 4052
Most relapses of acute lymphoblastic leukemia (ALL) occur in patients with a medium risk (MR) for relapse on the Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL protocol, based on persistence of minimal residual disease (MRD). New insights into biological features that are associated with MRD are needed. Here, we identify the glycosylphosphatidylinositol-anchored cell surface protein vanin-2 (VNN2; GPI-80) by charting the cell surface proteome of MRD very high-risk (HR) B-cell precursor (BCP) ALL using a chemoproteomics strategy. The correlation between VNN2 transcript and surface protein expression enabled a retrospective analysis (ALL-BFM 2000; N = 770 cases) using quantitative polymerase chain reaction to confirm the association of VNN2 with MRD and independent prediction of worse outcome. Using flow cytometry, we detected VNN2 expression in 2 waves, in human adult bone marrow stem and progenitor cells and in the mature myeloid compartment, in line with proposed roles for fetal hematopoietic stem cells and inflammation. Prospective validation by flow cytometry in the ongoing clinical trial (AIEOP-BFM 2009) identified 10% (103/1069) of VNN2+ BCP ALL patients at first diagnosis, primarily in the MRD MR (48/103, 47%) and HR (37/103, 36%) groups, across various cytogenetic subtypes. We also detected frequent mutations in epigenetic regulators in VNN2+ ALLs, including histone H3 methyltransferases MLL2, SETD2, and EZH2 and demethylase KDM6A. Inactivation of the VNN2 gene did not impair leukemia repopulation capacity in xenografts. Taken together, VNN2 marks a cellular state of increased resistance to chemotherapy that warrants further investigations. Therefore, this marker should be included in diagnostic flow cytometry panels.
Bortnick R, Wlodarski M, de Haas V, De Moerloose B, Dworzak M, Hasle H, Masetti R, Starý J, Turkiewicz D, Ussowicz M, Kozyra E, Albert M, Bader P, Bordon V, Cario G, Beier R, Schulte J, Bresters D, Müller I, Pichler H, Sedlacek P, Sauer MG, Zecca M, Göhring G, Yoshimi A, Noellke P, Erlacher M, Locatelli F, Niemeyer CM, Strahm B, for EWOG-MDS	Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome.	Bone marrow transplantation 2021, E-pub ahead of printg
GATA2 deficiency is a heterogeneous multi-system disorder characterized by a high risk of developing myelodysplastic syndrome (MDS) and myeloid leukemia. We analyzed the outcome of 65 patients reported to the registry of the European Working Group (EWOG) of MDS in childhood carrying a germline GATA2 mutation (GATA2) who had undergone hematopoietic stem cell transplantation (HSCT). At 5 years the probability of overall survival and disease-free survival (DFS) was 75% and 70%, respectively. Non-relapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased incidence of graft-versus-host-disease or excessive rates of infections or organ toxicities. Advanced disease and monosomy 7 (-7) were associated with worse outcome. Patients with refractory cytopenia of childhood (RCC) and normal karyotype showed an excellent outcome (DFS 90%) compared to RCC and -7 (DFS 67%). Comparing outcome of GATA2 with GATA2 patients, there was no difference in DFS in patients with RCC and normal karyotype. The same was true for patients with -7 across morphological subtypes. We demonstrate that HSCT outcome is independent of GATA2 germline mutations in pediatric MDS suggesting the application of standard MDS algorithms and protocols. Our data support considering HSCT early in the course of GATA2 deficiency in young individuals.
Bosma SE, Rueten-Budde AJ, Lancia C, Ranft A, Dirksen U, Krol AD, Gelderblom H, van de Sande MAJ, Dijkstra PDS, Fiocco M	Individual risk evaluation for local recurrence and distant metastasis in Ewing sarcoma: A multistate model: A multistate model for Ewing sarcoma.	Pediatric blood & cancer 2019, 66:e27943
We investigated the effects of surgical margins, histological response, and radiotherapy on local recurrence (LR), distant metastasis (DM), and survival in Ewing sarcoma.
Bosma SE, Lancia C, Rueten-Budde AJ, Ranft A, Gelderblom H, Fiocco M, van de Sande MAJ, Dijkstra PDS, Dirksen U	Easy-to-use clinical tool for survival estimation in Ewing sarcoma at diagnosis and after surgery.	Scientific reports 2019 Jul 29; 9: 11000
Accurate survival estimations in Ewing sarcoma are necessary to develop risk- and response adaptive treatment strategies allowing for early decision-making. We aim to develop an easy-to-use survival estimation tool from diagnosis and surgery. A retrospective study of 1314 Ewing sarcoma patients was performed. Associations between prognostic variables at diagnosis/surgery and overall survival (OS), were investigated using Kaplan-Meier and multivariate Cox models. Predictive accuracy was evaluated by cross-validation and Harrell C-statistics. Median follow-up was 7.9 years (95%CI 7.6-8.3). Independent prognostic factors at diagnosis were age, volume, primary tumor localization and disease extent. 5 risk categories (A-E) were identified with 5-year OS of 88% (86-94), 69% (64-74), 57% (50-64), 51% (42-60) and 28% (22-34) respectively. Harrell C-statistic was 0.70. Independent prognostic factors from surgery were age, volume, disease extent and histological response. In categories A-B, 5y OS increased to 92% (87-97) and 79% (71-87) respectively for 100% necrosis and decreased to 76% (67-85) and 62% (55-69) respectively for <100% necrosis. In categories C-E, 5y OS increased to 65% (55-75), 65% (52-78) and 52% (38-66) respectively for Ã¢ÂÂ¥90% necrosis and decreased to 38% (22-54), 11% (0-26) and 7% (0-19) respectively for <90% necrosis. We present an easy-to-use survival estimation tool from diagnosis in Ewing sarcoma based on age, volume, primary tumor localization and disease extent. Histological response is a strong additional prognostic factor for OS.
Bourne JP, Geyer R, Berger M, Griffin B, Milstein J	The prognostic significance of postoperative residual contrast enhancement on CT scan in pediatric patients with medulloblastoma.	J Neurooncol 1992, 14: 263
The clinical and therapeutic features of 20 patients with medulloblastoma treated at Children's Hospital and Medical Center, Seattle, from 1980 to 1987, were retrospectively analyzed with regard to prognosis. The overall actuarial 5-year survival rate was 63%, with 57% of patients free from recurrence at 5 years. Residual contrast enhancement on CT scans taken immediately postoperatively was associated with a significantly decreased 5-year recurrence-free survival rate; the 5-year recurrence-free survival rate was 100% for those patients without post-operative residual enhancement compared to 41% for those patients with residual enhancement. A high risk group of patients with residual contrast enhancement persisting one year following diagnosis was identified. No patient in this group survived without disease progression. Other factors, including sex, age at diagnosis, evidence of tumor dissemination, or extent of surgical resection as reported by the neurosurgeon, did not significantly influence prognosis.
Bourquin JP, Subramanian A, Langebrake C, Reinhardt D, Bernard O, Ballerini P, Baruchel A, Cave H, Dastugue N, Hasle H, Kaspers GL, Lessard M, Michaux L, Vyas P, van Wering E, Zwaan CM, Golub TR, Orkin SH	Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling.	Proceedings of the National Academy of Sciences of the United States of America 2006, 103: 3339
Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used cross-species comparison with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.
Bouchoucha Y, Matet A, Berger A, Carcaboso AM, Gerrish A, Moll A, Jenkinson H, Ketteler P, Dorsman JC, Chantada G, Beck-Popovic M, Munier F, Aerts I, Doz F, Golmard L, European Retinoblastoma Group EuRbG	Retinoblastoma: From genes to patient care.	European journal of medical genetics 2023, 66: 104674
Retinoblastoma is the most common paediatric neoplasm of the retina, and one of the earliest model of cancer genetics since the identification of the master tumour suppressor gene RB1. Tumorigenesis has been shown to be driven by pathogenic variants of the RB1 locus, but also genomic and epigenomic alterations outside the locus. The increasing knowledge on this "mutational landscape" is used in current practice for precise genetic testing and counselling. Novel methods provide access to pre-therapeutic tumour DNA, by isolating cell-free DNA from aqueous humour or plasma. This is expected to facilitate assessment of the constitutional status of RB1, to provide an early risk stratification using molecular prognostic markers, to follow the response to the treatment in longitudinal studies, and to predict the response to targeted therapies. The aim of this review is to show how molecular genetics of retinoblastoma drives diagnosis, treatment, monitoring of the disease and surveillance of the patients and relatives. We first recap the current knowledge on retinoblastoma genetics and its use in every-day practice. We then focus on retinoblastoma subgrouping at the era of molecular biology, and the expected input of cell-free DNA in the field.
Boztug K, Welte K, Zeidler C, Klein C	Congenital neutropenia syndromes.	Immunology and allergy clinics of North America 2008, 28: 259-75, vii-viii
Congenital neutropenia syndromes comprise a heterogeneous group of inherited disorders. Hereditary conditions associated with low neutrophil counts are persistent and need to be differentiated from neutropenia secondary to autoimmune processes or other pathologic conditions, such as myelodysplasia or leukemia. Clinically, congenital neutropenia is characterized by recurrent bacterial infections. Recently, several novel genetic defects were described in patients with congenital neutropenia, shedding light on the pathophysiology of these rare diseases.
Boxberger N, Redlich A, Böger C, Leuschner I, von Schweinitz D, Dralle H, Vorwerk P	Neuroendocrine tumors of the appendix in children and adolescents.	Pediatric blood & cancer 2012,
BACKGROUND: Neuroendocrine tumors (NET) of the appendix in children and adolescents are rare and mostly detected postoperatively by a histopathological examination. Since the malignant potential of these tumors remains unclear, therapeutic recommendations are not evidence based. The Society of Pediatric Oncology and Hematology (GPOH) has prospectively registered and followed children with appendical NET since 1997 (GPOH-MET trial). The objective of this study was to critically evaluate the therapeutic recommendations for appendical NET in children. PROCEDURE: Clinical data of 237 children with appendical NET were prospectively analyzed. RESULTS: The mean age at presentation was 13.0 years, while the mean follow-up time was 2.9 (0.0-12.8) years. The majority of tumors (70.9%) were located at the apex, and were smaller than or equal to 10 mm (72.7%). Tumor size was directly correlated with age. A second operation or primary lymph node sampling was done in 25.3% (N = 60) of the patients, and infiltration of the lymph nodes by tumor cells was found in nine of these patients (15%). All 237 patients are alive without tumor symptoms. CONCLUSIONS: ROC analysis and subsequent calculations identified a tumor size of >15 mm as the optimal cut-off point for the prediction of metastatic spread into the lymph system, with a sensitivity of 77.8% and a specificity of 66.7%. Therefore, secondary right hemicolectomy in completely removed appendical NET is recommended only in tumors >15 mm in size. For incompletely removed tumors ≤15 mm a local follow-up resection with lymph node sampling is recommended. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
Boztug K, Welte K, Zeidler C, Klein C	Congenital neutropenia syndromes.	Immunology and allergy clinics of North America 2008, 28: 259-75, vii-viii
Congenital neutropenia syndromes comprise a heterogeneous group of inherited disorders. Hereditary conditions associated with low neutrophil counts are persistent and need to be differentiated from neutropenia secondary to autoimmune processes or other pathologic conditions, such as myelodysplasia or leukemia. Clinically, congenital neutropenia is characterized by recurrent bacterial infections. Recently, several novel genetic defects were described in patients with congenital neutropenia, shedding light on the pathophysiology of these rare diseases.
Boztug H, Sykora KW, Slatter M, Zecca M, Veys P, Lankester A, Cant A, Skinner R, Wachowiak J, Glogova E, Pötschger U, Peters C	European Society for Blood and Marrow Transplantation Analysis of Treosulfan Conditioning Before Hematopoietic Stem Cell Transplantation in Children and Adolescents With Hematological Malignancies.	Pediatr Blood Cancer 2016, 63: 139
BACKGROUND: Standard myeloablative conditioning regimens for children with hematological malignancies undergoing allogeneic HSCT are based mainly on total body irradiation or busulfan. Their serious short- and long-term side effects warranted the exploration of less toxic alternatives. Treosulfan is increasingly used for adults and children before HSCT due to its potent immunosuppressive and cytotoxic effects combined with low organ toxicity. PROCEDURE: To further investigate the role of treosulfan conditioning in children, the EBMT Pediatric diseases working party performed a retrospective analysis of 193 children with hematological malignancies (ALL n = 71, AML n = 47, MDS/MPS n = 40, other leukemia/lymphoma n = 25) undergoing allogeneic HSCT following treosulfan between January 2005 and July 2010. RESULTS: Early regimen-related toxicity was low and mainly gastrointestinal. Veno-occlusive disease and neurological toxicity were rare. There was no association of toxicity with type of disease or treosulfan dose. High-grade early toxicity was not higher in infants or patients undergoing second or later transplantation. Treatment related mortality was low at 14%. Three-year event-free survival was 45 ± 4% and not significantly influenced by number of transplants, however it appeared to be significantly better for infants (P = 0.022). When compared to treosulfan plus fludarabine, the combination of treosulfan, fludarabine and an alkylator (either thiotepa or melphalan) resulted in significantly better overall survival (OS, P = 0.048) and a trend toward better EFS. CONCLUSIONS: Treosulfan based conditioning is a safe and effective approach for children with hematological malignancies, including and importantly for infants and those patients undergoing second or later transplantation.
Brämswig JH, Heimes U, Heiermann E, Schlegel W, Nieschlag E, Schellong G	The effects of different cumulative doses of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin's disease during childhood or adolescence.	Cancer 1990, 65: 1298
Testicular function was evaluated in 75 boys after treatment for Hodgkin's disease with involved-field or extended-field irradiation and stage-dependent chemotherapy (vincristine, prednisone, procarbazine, Adriamycin [doxorubicin], and cyclophosphamide [OPPA/COPP]). Although pubertal development and testosterone levels were normal in all patients, 18 of 75 (24.0%) had elevated basal and 65/74 (87.8%) elevated stimulated luteinizing hormone (LH) levels, demonstrating chemotherapy-induced Leydig cell damage. In addition, there was a 40.5% and 53.4% incidence of elevated basal and stimulated FSH values, respectively, indicating severe impairment of spermatogenesis as confirmed by azoospermia in four patients. Testicular dysfunction was observed in patients treated before as well as during puberty. The incidence of elevated basal follicle stimulating hormone (FSH) and LH values was significantly higher in patients who had received higher cumulative doses of chemotherapy, i.e., 28.9% and 13.2% with two OPPA, 45.5% and 36.4% with two OPPA/two COPP, and 62.5% and 43.8% with two OPPA/four to six COPP, respectively. Chemotherapy for Hodgkin's disease causes a high and apparently dose-related incidence of testicular dysfunction in prepubertal as well as in pubertal boys affecting Leydig cell function as well as spermatogenesis. Circumstantial evidence indicates that procarbazine is the major gonadotoxic agent involved.
Brämswig J, Dübbers A	Störungen der Pubertätsentwicklung.	Deutsches Ärzteblatt Jg. 1ß06, Heft 17, 2009
Brasme JF, Chalumeau M, Doz F, Lacour B, Valteau-Couanet D, Gaillard S, Delalande O, Aghakhani N, Sainte-Rose C, Puget S, Grill J	Interval between onset of symptoms and diagnosis of medulloblastoma in children: distribution and determinants in a population-based study.	European journal of pediatrics 2012, 171: 25
Hospital-based studies have reported long delays in the diagnosis of paediatric brain tumours. Our objective was to describe the duration between onset of symptoms and diagnosis of medulloblastoma in children and study their clinical determinants in a population-based study. This retrospective cohort study included all paediatric medulloblastoma from a region of France from 1990 to 2005. The median interval from symptom onset until diagnosis for these 166 patients was 65 days and did not decrease during the study period. The most frequent manifestations were: vomiting (88%), headaches (79%), psychomotor regression (60% of children under 3 years), psychological symptoms (27%), strabismus (26%), and asthenia (25%). For one third of the children under 3 years, the diagnosis was made only after life-threatening signs of intracranial hypertension appeared. The prediagnosis interval was significantly longer (median 91 vs. 60 days, p = 0.001) in children with psychological symptoms (27%). Causes for intervals that exceeded the median (65 days) included inconsistent (25%) or late (36%) combination of headaches and vomiting, a period of spontaneous symptom remission (14%-20%), no (24%) or late (57%) neurological signs, psychological symptoms (35%), and a normal neurological examination (27%). Time to medulloblastoma diagnosis in children remains fairly long, despite advances in imaging. Primary-care physicians must be suspicious not only of suggestive neurological signs, but also of non-specific symptoms that persist or are multiple. A meticulous neurological examination and cerebral imaging for such patients might facilitate earlier diagnosis.
Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M, Modlich U, Beier R, Göhring G, Steinemann D, Fronza R, Ball CR, Haemmerle R, Naundorf S, Kühlcke K, Rose M, Fraser C, Mathias L, Ferrari R, Abboud MR, Al-Herz W, Kondratenko I, Maródi L, Glimm H, Schlegelberger B, Schambach A, Albert MH, Schmidt M, von Kalle C, Klein C	Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity.	Science translational medicine 2014, 6: 227ra33
Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a Î³-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of Î³-retroviral vectors is associated with a substantial risk of leukemogenesis.
Brandow AM, Farley RA, Panepinto JA	Early insights into the neurobiology of pain in sickle cell disease: A systematic review of the literature.	Pediatric blood & cancer 2015, 62: 1501
Novel insights into the neurobiology of sickle cell disease (SCD) pain have recently been discovered. We systematically reviewed the literature focusing on original research that examined the biology of pain in SCD and/or addressed assessment or treatment of neuropathic pain in SCD. This review of 15 articles that met inclusion criteria provides epidemiological, basic, and clinical data that support central and/or peripheral nervous system abnormalities likely contribute to sickle cell pain. Continued basic and clinical investigation into pain neurobiology is imperative to translate these discoveries into novel ways to assess and treat neuropathic pain and decrease patient suffering.
Braam KI, van der Torre P, Takken T, Veening MA, van Dulmen-den Broeder E, Kaspers GJ	Physical exercise training interventions for children and young adults during and after treatment for childhood cancer.	The Cochrane database of systematic reviews 2016 Mar 31; 3:CD008796
A decreased physical fitness has been reported in patients and survivors of childhood cancer. This is influenced by the negative effects of the disease and the treatment of childhood cancer. Exercise training for adult cancer patients has frequently been reported to improve physical fitness. In recent years, literature on this subject has also become available for children and young adults with cancer, both during and after treatment. This is an update of the original review that was performed in 2011.
Breu H, Schellong G, Grosch-Wörner I, Jobke A, Riehm H, Ritter J, Treuner J, Schwarze E, Wannenmacher M	Abgestufte Chemotherapie und reduzierte Strahlendosis beim Morbus Hodgkin im Kindesalter - Ein Bericht über 170 Patienten der kooperativen Therapiestudie HD-78.	Klin Pädiatr 1982, 194: 233
Brenner H, Kaatsch P, Burkhardt-Hammer T, Harms D, Schrappe M, Michaelis J	Long-term survival of children with leukemia achieved by the end of the second millennium.	Cancer 2001, 92: 1977
Brennan BM, Shalet SM	Endocrine late effects after bone marrow transplant.	British J Haematol 2002, 118: 58
Brecht I, Treuner J	Weichteilsarkome im Kindes- und Jugendalter. Erfahrungen der Cooperativen Weichteilsarkom-Studie (CWS). Handchirurgie, Mikrochirurgie, Plastische Chirurgie.	in press 2004
Brecht IB, Graf N, Schweinitz D, Frühwald MC, Bielack SS, Schneider DT	Networking for children and adolescents with very rare tumors: foundation of the GPOH Pediatric Rare Tumor Group.	Klinische Padiatrie 2009, 221: 181
In comparison to cancer in adults, virtually all cancers of childhood and adolescence are rare. Nevertheless, there is a rather ill-defined group of tumors that are not only exceptionally rare but also do not fall into the major clinical categories of childhood cancers. Thus, a substantial proportion of these exceptionally rare tumors are not registered within clinical registries or prospective therapy optimization studies. Only recently, major attention has been drawn to the diagnostic assessment and treatment of children and adolescents with such orphan diseases. In 2006, the RARE TUMOR GROUP has been established within the German Society of Pediatric Oncology and Hematology (GPOH). This working group includes experts from Pediatric Oncology, Pediatric Surgery, Pediatric Pathology, Medical, Dermatologic and Radiation Oncology as well as Pediatric Epidemiology. The major aim of the rare tumor group is to integrate these patients into the diagnostic and therapeutic network successfully established in the pediatric oncologic society. Thus, the group aims at fostering the exchange of experience in the treatment of rare tumors between medical centers and to include patients in the diagnostic and therapeutic reference network. In addition, an information platform shall be established that will be accessible to treating physicians, patients and their parents. More information and better registration shall be established by active data accrual on a regular basis and by the implementation of a data base including diagnostic and therapeutic data of patients with rare tumors. These efforts as presented in this article as well as an intensified international collaboration will allow us to provide children and adolescents with rare tumors the best possible care.
Brecht IB, Schneider DT, Klöppel G, von Schweinitz D, Barthlen W, Hamre MR	Malignant Pancreatic Tumors in Children and Young Adults: Evaluation of 228 Patients Identified through the Surveillance, Epidemiology, and End Result (SEER) Database.	Klinische Padiatrie 2011, 223: 341
Malignant pancreatic tumors are rare in young patients, few epidemiologic data are available. We reviewed prognostic factors and outcome of 228 patients <30 years with malignant pancreatic tumors identified through the U.S. National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) Public-use Database from 1973 to 2004.Cases were grouped using the ICD-O-3. 5-year overall survival (OAS) was assessed by gender, ethnicity, SEER stage, and 5-year age intervals using univariate and Cox regression analysis.228 patients with malignant pancreatic tumors were identified, resulting in an incidence of 0.46/million (100 carcinomas, 85 endocrine tumors, 8 solid pseudopapillary neoplasms (SPN), 11 pancreatoblastomas) in the USA. OAS was worse in males than females (37% vs. 55%, p=0.005). OAS according to stage was 87%, 68%, 21% for local (n=54), regional (n=42), distant metastatic disease (n=108), respectively. OAS of patients with carcinoma was 33%, endocrine tumors 58%, SPNs 88%, pancreatoblastomas 66%. Cox regression revealed stage (p=< 0.001), histology (p=< 0.001), age group (p=0.05) to be independent prognostic factors.Malignant pancreatic tumors are extremely rare in children and young adults. Entities change over the age groups towards more carcinomas with worse outcome in older patients. Tumor stage, histology and age group are important predictors for outcome. International collaboration is needed to learn more about pediatric pancreatic tumors.
Breuer S, Preuner S, Fritsch G, Daxberger H, Koenig M, Poetschger U, Lawitschka A, Peters C, Mann G, Lion T, Matthes-Martin S	Early recipient chimerism testing in the T- and NK-cell lineages for risk assessment of graft rejection in pediatric patients undergoing allogeneic stem cell transplantation.	Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 2012, 26: 509
Timely diagnosis of impending graft rejection is crucial for effective therapeutic intervention after allogeneic hematopoietic stem cell transplantation (SCT). We have investigated the predictive potential of early leukocyte subset-specific chimerism for graft loss in children undergoing SCT. In total, 192 pediatric patients transplanted for the treatment of malignant and non-malignant diseases after reduced-intensity or myeloablative conditioning were investigated. Surveillance of lineage-specific chimerism was initiated upon first appearance of leukocyte counts amenable to cell sorting. Graft rejection occurred in 23 patients between 24 and 492 days post-transplant (median 63 days). The first chimerism analysis of T and NK cells performed at a median of 20 days after SCT identified three different risk groups that were independent from the conditioning regimen: recipient chimerism (RC) levels in T cells below 50% indicated a very low risk of rejection (1.4%), whereas high levels of RC (>90%) both in T and NK cells heralded graft loss in the majority of patients (90%) despite therapeutic interventions. RC >50% in T cells and ≤90% in NK cells defined an intermediate-risk group in which timely immunotherapy frequently prevented rejection. Early assessment of T- and NK-cell chimerism can therefore be instrumental in the risk assessment and therapeutic management of imminent graft rejection.
Brecht IB, Agaimy A, Besendörfer M, Carbon R, Thiel FC, Rompel O, Osinski D, Langer T, Metzler M, Holter W	Malignant Peritoneal Mesothelioma in a 16-Year-Old Girl: Presentation of a Rare Disease.	Klinische Padiatrie 2012, 224: 170
Malignant peritoneal mesothelioma is extremely rarely seen in young patients.A 16 year-old girl presented with appendicitis-like acute abdominal pain. Intra-operatively, multiple confluent peritoneal nodules were seen on the entire greater omentum and in the pelvis infiltrating the uterus and both ovaries. Biopsies were obtained and interpreted as serous ovarian carcinoma. Radical surgical resection and hyperthermic intraperitoneal chemotherapy -(HIPEC) with carboplatin was performed and followed by 2 cycles of carboplatin/paclitaxel. Histological reevaluation showed characteristic features of epithelioid peritoneal mesothelioma and ruled out serous ovarian cancer. Therapy was continued with 6 cycles of pemetrexed/cisplatin.3 months after end of chemotherapy vital tumor tissue was found in the recess behind the liver, which could be resected completely. The patient is currently disease-free 17 months after initial diagnosis.Malignant peritoneal mesothelioma in young female patients might be under-recognized and possibly misdiagnosed as ovarian serous carcinoma in some cases. International and interdisciplinary cooperation is necessary in order to provide evidence based guidelines for diagnosis and treatment in the future.
Brecht IB, Bremensdorfer C, Schneider DT, Frühwald MC, Offenmüller S, Mertens R, Vorwerk P, Koscielniak E, Bielack SS, Benesch M, Hero B, Graf N, von Schweinitz D, Kaatsch P	Rare malignant pediatric tumors registered in the German Childhood Cancer Registry 2001-2010.	Pediatric blood & cancer 2014, 61: 1202
The German Childhood Cancer Registry (GCCR) annually registers approximately 2,000 children diagnosed with a malignant disease (completeness of registration >95%). While most pediatric cancer patients are diagnosed and treated according to standardized cooperative protocols of the German Society for Pediatric Oncology and Hematology (GPOH), patients with rare tumors are at risk of not being integrated in the network including trials and reference centers.
Brecht IB, Garbe C, Gefeller O, Pfahlberg A, Bauer J, Eigentler TK, Offenmueller S, Schneider DT, Leiter U	443 paediatric cases of malignant melanoma registered with the German Central Malignant Melanoma Registry between 1983 and 2011.	European journal of cancer (Oxford, England : 1990) 2015, 51: 861
Malignant melanoma is a very rare paediatric tumour. This study was performed in order to understand clinical features and prognosis of malignant melanoma in children and adolescents.
Brecht IB, Garbe C, Gefeller O, Pfahlberg A, Bauer J, Eigentler TK, Offenmueller S, Schneider DT, Leiter U	443 paediatric cases of malignant melanoma registered with the German Central Malignant Melanoma Registry between 1983 and 2011.	European journal of cancer (Oxford, England : 1990) 2015, 51: 861
Malignant melanoma is a very rare paediatric tumour. This study was performed in order to understand clinical features and prognosis of malignant melanoma in children and adolescents.
Bresters D, Lawitschka A, Cugno C, Pötschger U, Dalissier A, Michel G, Vettenranta K, Sundin M, Al-Seraihy A, Faraci M, Sedlacek P, Versluys AB, Jenkins A, Lutz P, Gibson B, Leiper A, Diaz MA, Shaw PJ, Skinner R, O'Brien TA, Salooja N, Bader P, Peters C	Incidence and severity of crucial late effects after allogeneic HSCT for malignancy under the age of 3 years: TBI is what really matters.	Bone marrow transplantation 2016, 51: 1482
Younger children are considered to be more vulnerable to late effects (LE), which prompted us to study LE in patients after haematopoietic stem cell transplantation (HSCT) for a haematological malignancy before the age of 3. In this multicentre EBMT study, cumulative incidence (CI) and severity of endocrine LE, central nervous system complications and secondary malignancies at 5, 10, 15 and 20 years of follow-up were assessed. Risk factors (RF) like gender, diagnosis, age at and year of HSCT, TBI- or chemo-conditioning and GVHD were analysed. CI of any LE was 0.30, 0.52, 0.66 and 0.72 at 5, 10, 15 and 20 years after HSCT, respectively. In 25% of the patients, LE were severe at a median follow-up of 10.4 years. In multivariate analysis, only TBI was a RF for having any LE and for thyroid dysfunction and growth disturbance. Female gender was a RF for delayed pubertal development. Some more insight could be gained by descriptive analysis regarding the role of TBI and GVHD on the severity of LE. Although only five selected LE have been studied and median follow-up is relatively short, the incidence and severity of these LE are considerable but not different from what has been found in older children and TBI is the main RF.
Brecht IB, De Paoli A, Bisogno G, Orbach D, Schneider DT, Leiter U, Offenmueller S, Cecchetto G, Godzinski J, Bien E, Stachowicz-Stencel T, Ben-Ami T, Chiaravalli S, Maurichi A, De Salvo GL, Sorbara S, Bodemer C, Garbe C, Reguerre Y, Ferrari A	Pediatric patients with cutaneous melanoma: A European study.	Pediatric blood & cancer 2018, 65:e26974
Cutaneous melanoma is rare in childhood and published studies have mainly been retrospective single-institution series or small case series. Given the absence of clinical protocols dedicated to pediatric melanoma, the treatment approach is generally extrapolated from the ones applied to adults.
Brisse HJ, McCarville MB, Granata C, Krug KB, Wootton-Gorges SL, Kanegawa K, Giammarile F, Schmidt M, Shulkin BL, Matthay KK, Lewington VJ, Sarnacki S, Hero B, Kaneko M, London WB, Pearson AD, Cohn SL, Monclair T, International Neuroblastoma Risk Group Project	Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project.	Radiology 2011, 261: 243
Neuroblastoma is an enigmatic disease entity; some tumors disappear spontaneously without any therapy, while others progress with a fatal outcome despite the implementation of maximal modern therapy. However, strong prognostic factors can accurately predict whether children have
Briggs BJ, Dickerman JD	Bleeding disorders in Noonan syndrome.	Pediatric blood & cancer 2012, 58: 167
Noonan Syndrome (NS) is a common genetic disease with multiple organ defects including bleeding disorders, which was last reviewed in 1997. Since then significant information has been acquired regarding bleeding problems in NS, specifically on the underlying genetics. Associations between mutated genes and bleeding disorders are reviewed along with prevalence and underlying etiologies. Between 50-89% of NS patients will have a bleeding disorder and since a significant number will require surgery it is important to identify which ones are at risk prior to their procedure. Recommendations regarding screening for bleeding disorders and their treatment are discussed. Pediatr Blood Cancer 2012; 58: 167-172. © 2011 Wiley Periodicals, Inc.
Brierley JD, Gospodarowicz MK, Wittekind CH (Hrsg)	TNM Klassifikation maligner Tumoren.	8. Aufl., Wiley-Blackwell, Oxford (UK) 2017
Brivio E, Locatelli F, Lopez-Yurda M, Malone A, Díaz-de-Heredia C, Bielorai B, Rossig C, van der Velden VHJ, Ammerlaan ACJ, Thano A, van der Sluis IM, den Boer ML, Chen Y, Sleight B, Brethon B, Nysom K, Sramkova L, Øra I, Vinti L, Chen-Santel C, Zwaan CM	A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study).	Blood 2021, 137: 1582
This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or <18 years) received 3 doses of InO (days 1, 8, and 15) per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71.
Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM	Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage.	Science (New York, N.Y.) 1984 Jun 8; 224: 1121
A domain of DNA designated N-myc is amplified 20- to 140-fold in human neuroblastoma cell lines but not in cell lines from other tumor types. N-myc has now been found to be amplified in neuroblastoma tissue from 24 of 63 untreated patients (38 percent). The extent of amplification appears to be bimodal, with amplification of 100- to 300-fold in 12 cases and 3- to 10-fold in 10 others. Amplification was found in 0 of 15 patients with stage 1 or 2 disease, whereas 24 of 48 cases (50 percent) with stage 3 or 4 had evidence of N-myc amplification. These data indicate that N-myc amplification is a common event in untreated human neuroblastomas. Furthermore, N-myc amplification is highly correlated with advanced stages of disease (P less than 0.001) and with the ability to grow in vitro as an established cell line, both of which are associated with a poor prognosis.
Brodeur G, Pritchard J, Berthold F, Carlsen N, Castel V, Castelberry R, De Bernardi B, Evans A, Favrot M, Hedborg F,	Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment.	J Clin Oncol 1993, 11: 1466
Brodeur G, Pritchard J, Berthold F, Carlsen N, Castel V, Castelberry R, De Bernardi B, Evans A, Favrot M, Hedborg F,	Revisions of the international criteria for neuroblastoma diagnosis, staging and response to treatment.	Prog Clin Biol Res 1994, 385: 363
Broadbent V, Gadner H	Current therapy for Langerhans cell histiocytosis.	Hematol Oncol Clin North Am 1998, 12: 327
Brodeur GM	Neuroblastoma: biological insights into a clinical enigma.	Nature reviews. Cancer 2003, 3: 203
Neuroblastoma is a tumour derived from primitive cells of the sympathetic nervous system and is the most common solid tumour in childhood. Interestingly, most infants experience complete regression of their disease with minimal therapy, even with metastatic disease. However, older patients frequently have metastatic disease that grows relentlessly, despite even the most intensive multimodality therapy. Recent advances in understanding the biology and genetics of neuroblastomas have allowed classification into low-, intermediate- and high-risk groups. This allows the most appropriate intensity of therapy to be selected - from observation alone to aggressive, multimodality therapy. Future therapies will focus increasingly on the genes and biological pathways that contribute to malignant transformation or progression.
Broniscer A, Gajjar A	Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist.	Oncologist 2004, 9: 197-206. Review
Broniscer A, Nicolaides TP, Dunkel IJ, Gardner SL, Johnson J Jr, Allen JC, Sposto R, Finlay JL	High-dose chemotherapy with autologous stem-cell rescue in the treatment of patients with recurrent non-cerebellar primitive neuroectodermal tumors.	Pediatr Blood Cancer 2004, 261
BACKGROUND: Recurrent non-cerebellar primitive neuroectodermal tumors (PNETs) carry a dismal prognosis when treated with conventional chemotherapy alone. XSWe tested the efficacy of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in this setting. PROCEDURE: Eligibility mandated either minimal residual disease or evidence of chemosensitivity before HDC. Conditioning consisted of carboplatin (CBDCA) (500 mg/m(2) or AUC = 7 mg/ml min using the Calvert formula) on days -8 to -6, thiotepa (300 mg/m(2)), and etoposide (250 mg/m(2)) on days -5 to -3. Irradiation was given post HDC selectively. RESULTS: Among 17 patients treated in this study, there were eight pineoblastoma(s) (pineo), seven cortical PNETs, and two arising elsewhere. Relapse was either local (nine) or metastatic to the brain (four) or spine (four). Two patients received HDC as the sole therapy for recurrence; additionally, eight underwent surgical debulking before HDC, and nine received irradiation, including six after HDC. Median age at ASCR was 3.9 years. Two patients died of toxicity (11%) and ten experienced tumor relapse (range: 23-361 days post ASCR). Five patients with cortical PNETs remain alive disease-free (median follow-up: 8.3 years); four of them received irradiation post HDC. The difference in 5-year event-free survival (EFS) between patients with pineo and other supratentorial PNETs was significant (0 vs. 62.5 +/- 17%, P = 0.0065). Both surgery at relapse and irradiation post HDC were favorable prognostic factors (P = 0.006 and 0.01, respectively). CONCLUSIONS: Patients with recurrent cortical PNETs can be cured with this strategy. Surgical debulking before, and irradiation after HDC play an important role in treatment success. Copyright 2003 Wiley-Liss, Inc.
Brodin NP, Vogelius IR, Maraldo MV, Munck af Rosenschöld P, Aznar MC, Kiil-Berthelsen A, Nilsson P, Björk-Eriksson T, Specht L, Bentzen SM	Life years lost--comparing potentially fatal late complications after radiotherapy for pediatric medulloblastoma on a common scale.	Cancer 2012 Nov 1; 118: 5432
The authors developed a framework for estimating and comparing the risks of various long-term complications on a common scale and applied it to 3 different techniques for craniospinal irradiation in patients with pediatric medulloblastoma.
Brown MC, Levitt GA, Frey E, Bárdi E, Haupt R, Hjorth L, Kremer L, Kuehni CE, Lettner C, Mulder RL, Michel G, Skinner R, on behalf of the PanCareSurFup Consortium	The views of European clinicians on guidelines for long-term follow-up of childhood cancer survivors.	Pediatr Blood Cancer 2014 Nov 8;[Epub ahead of print]
Evidence-based guidelines are needed to guide effective long-term follow-up (LTFU) of childhood cancer survivors (CCS) at risk of late adverse effects (LAEs). We aimed to ascertain the use of LTFU guidelines throughout Europe, and seek views on the need for pan-European LTFU guidelines.
Brousse V, Buffet P, Rees D	The spleen and sickle cell disease: the sick(led) spleen.	British journal of haematology 2014, 166: 165
The spleen has a combined function of immune defence and quality control of senescent or altered red cells. It is the first organ injured in sickle cell anaemia (SCA) with evidence of hyposplenism present before 12 months in the majority of children. Repeated splenic vaso-occlusion leads to fibrosis and progressive atrophy of the organ (autosplenectomy), which is generally complete by 5 years in SCA. The precise sequence of pathogenic events leading to hyposplenism is unknown. Splenic injury is generally silent and progressive. It can be clinically overt with acute splenic sequestration of red cells, an unpredictable and life-threatening complication in infants. Splenomegaly, with or without hypersplenism, can also occur and can coexist with loss of function. Hyposplenism increases the susceptibility of SCA children to infection with encapsulated bacteria, which is notably reduced by penicillin prophylaxis and immunization. Whether hyposplenism indirectly increases the risk of vaso-occlusion or other circulatory complications remains to be determined.
Brown P, Zugmaier G, Gore L, Tuglus CA, von Stackelberg A	Day 15 bone marrow minimal residual disease predicts response to blinatumomab in relapsed/refractory paediatric B-ALL.	British journal of haematology 2020, 188:e36-e39
No abstract avialable
Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML	Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.	JAMA 2021, 325: 833
Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile.
Brok J, Mavinkurve-Groothuis AMC, Drost J, Perotti D, Geller JI, Walz AL, Geoerger B, Pasqualini C, Verschuur A, Polanco A, Jones KP, van den Heuvel-Eibrink M, Graf N, Spreafico F	Unmet needs for relapsed or refractory Wilms tumour: Mapping the molecular features, exploring organoids and designing early phase trials - A collaborative SIOP-RTSG, COG and ITCC session at the first SIOPE meeting.	European journal of cancer 2021, 144: 113
Wilms tumour (WT) accounts for about 6% of all childhood cancers and overall survival of WT is about 90% in international protocols. However, for WT subgroups with much poorer prognoses, i.e. typically high-risk (unfavorable) histology and/or relapse, there is an unmet need to better understand the biology of WT and to translate biological findings into clinics through early phase clinical trials that evaluate innovative therapies. The main challenges are the small numbers of children suitable for early phase trials, the genetic heterogeneity of WT and the low number of somatic mutations that are currently considered 'druggable'. Accordingly, a joint meeting between clinical and biology experts from the international cooperative groups of the Renal Tumour Study Group of the International Society of Paediatric Oncology, the Renal Tumour Committee of the Children's Oncology Group and the European Innovative Therapies for Children with Cancer consortium and parents representatives was organised during the first SIOPE meeting in Prague, 2019. We reviewed WT molecular features, ongoing/planned early phase trials and explored available knowledge on organoid technology. The key messages were: (1) relapsed WT should undergo whenever possible thorough molecular characterization and be enrolled in protocols or trials with systematic data collecting and reporting; (2) WT displays few known 'actionable' targets and currently no novel agent has appeared promising; (3) we need to improve the enrolment rate of WT candidates in early phase trials especially for the relatively small subgroup of relapses with an adverse prognostic signature; (4) despite some agnostic early phase trials existing, development of WT-focused trials are warranted; (5) growing organoids with parallel testing of drug panels seems feasible and may direct individual treatment and encourage clinical researchers to incorporate the most promising agents into early phase trials.
Bruckner AL, Frieden IJ	Infantile hemangiomas.	Journal of the American Academy of Dermatology 2006, 55: 671
Infantile hemangiomas (IHs), also known as “hemangiomas of infancy,” are common benign tumors of endothelial cells characterized by a unique pattern of rapid proliferation that occurs in the first months of life, followed by slow involution that may take years to complete. They reportedly occur in as many as 10% of children and are frequently brought to the attention of both pediatricians and dermatologists. Although most are ultimately of little significance, a portion have the potential to produce complications of concern.
Brugières L, Le Deley MC, Rosolen A, Williams D, Horibe K, Wrobel G, Mann G, Zsiros J, Uyttebroeck A, Marky I, Lamant L, Reiter A	Impact of the Methotrexate Administration Dose on the Need for Intrathecal Treatment in Children and Adolescents With Anaplastic Large-Cell Lymphoma: Results of a Randomized Trial of the EICNHL Group.	Journal of clinical oncology 2009, 27: 897
PURPOSE To compare the efficacy and safety of two methotrexate doses and administration schedules in children with anaplastic large-cell lymphoma (ALCL). PATIENTS AND METHODS This randomized trial for children with ALCL was based on the Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Muenster 90 (NHL-BFM90) study protocol and compared six courses of methotrexate 1 g/m(2) over 24 hours and an intrathecal injection (IT) followed by folinic acid rescue at 42 hours (MTX1 arm) with six courses of methotrexate 3 g/m(2) over 3 hours followed by folinic acid rescue at 24 hours without IT (MTX3 arm). This trial involved most European pediatric/lymphoma study groups and a Japanese group. Results Overall, 352 patients (96% ALK positive) were recruited between 1999 and 2005; 175 were randomly assigned to the MTX1 arm, and 177 were assigned to the MTX3 arm. Ninety-two percent of patients received protocol treatment. Median follow-up time is 3.7 years. Event-free survival (EFS) curves were superimposed with 2-year EFS rates (73.6% and 74.5% in the MTX1 and MTX3 arms, respectively; hazard ratio = 0.98; 91.76% CI, 0.69 to 1.38). Two-year overall survival rates were 90.1% and 94.9% in MTX1 and MTX3, respectively. Only two CNS relapses occurred (both in the MTX1 arm). Toxicity was assessed after 2,050 courses and included grade 4 hematologic toxicity after 79% and 64% of MTX1 and MTX3 courses, respectively (P < .0001); infection after 50% and 32% of courses, respectively (P < .0001); and grade 3 to 4 stomatitis after 21% and 6% of courses, respectively (P < .0001). CONCLUSION The results of the NHL-BFM90 study were reproduced in this large international trial. The methotrexate schedule of the NHL-BFM90 protocol including IT therapy can be safely replaced by a less toxic schedule of methotrexate 3 g/m(2) in a 3-hour infusion without IT therapy.
Brüggemann M, Schrauder A, Raff T, Pfeifer H, Dworzak M, Ottmann OG, Asnafi V, Baruchel A, Bassan R, Benoit Y, Biondi A, Cavé H, Dombret H, Fielding AK, Foà R, Gökbuget N, Goldstone AH, Goulden N, Henze G, Hoelzer D, Janka-Schaub GE, Macintyre EA, Pieters R, Rambaldi A, Ribera JM, Schmiegelow K, Spinelli O, Stary J, von Stackelberg A, Kneba M, Schrappe M, van Dongen JJ, European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL),International Berlin-Frankfurt-Münster Study Group (I-BFM-SG)	Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008.	Leukemia 2010, 24: 521
Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms 'complete MRD response', 'MRD persistence' and 'MRD reappearance'. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.
Bruce M, Gumley D, Isham L, Fearon P, Phipps K	Post-traumatic stress symptoms in childhood brain tumour survivors and their parents.	Child: care, health and development 2011, 37: 244
This study aimed to investigate post-traumatic stress symptoms (PTSS) in childhood brain tumour survivors and their parents. A further aim was to explore the relationship between objective illness parameters, parent-child interactions, coping styles and PTSS.
Brämswig J, Heiermann E, Heimes U, Hengst K, Schellong G	Radiation induced thyroid dysfunction in pediatric Hodgkin's disease (HD).	Med Pediat Oncol ; 15
Brämswig J, Heimes U, Heiermann E, Schlegel W, Nieschlag E, Schellong G	The effects of different cumulative doses of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin's disease during childhood or adolescence.	Cancer 1990, 65: 1298
Brämswig J, Hörnig-Franz I, Riepenhausen M, Schellong G	The challenge of pediatric Hodgkin's disease - Where is the balance between cure and long-term toxicity?	Leukemia and Lymphoma 1990, 3: 183
Brämswig J, Schellong G, Schlegel W, Hassel U, Heimes U	Testicular function in boys after treatment for Hodgkin's Disease with or without procarbazine.	Exp Clin Endocrinol 1993, 101, Suppl
Bucsky P, Parlowsky T	Epidemiology and therapy of thyroid cancer in childhood and adolescence.	Exp Clin Endocrinol Diabetes 1997, 105 Suppl 4: 70
Buckley JD, Meadows AT, Kadin ME, Le Beau MM, Siegel S, Robison LL	Pesticide exposures in children with non-Hodgkin lymphoma.	Cancer 2000, 89: 2315
Buchholz C, Hartmann J, SchueÃler-Lenz M, Keller-Stanislawski B	CAR-T-Zell-Therapie: Aussichten und Risiken.	Dtsch. Arztebl 2018, 115: [38]
CAR-T-Zellen lÃ¶sen ein zentrales Problem der Krebstherapie: die BekÃ¤mpfung von Tumoren, die fÃ¼r das Immunsystem unsichtbar sind. Bei dieser Therapie kommen gentechnologisch verÃ¤nderte T-Zellen mit synthetischen antigenspezifischen Rezeptoren zur Anwendung.
Buchholz C, Hartmann J, SchueÃÂler-Lenz M, Keller-Stanislawski B	CAR-T-Zell-Therapie: Aussichten und Risiken.	Dtsch. Arztebl 2018, 115: [38]
CAR-T-Zellen lÃÂ¶sen ein zentrales Problem der Krebstherapie: die BekÃÂ¤mpfung von Tumoren, die fÃÂ¼r das Immunsystem unsichtbar sind. Bei dieser Therapie kommen gentechnologisch verÃÂ¤nderte T-Zellen mit synthetischen antigenspezifischen Rezeptoren zur Anwendung.
Budde U, Schneppenheim R	Von Willebrand factor and von Willebrand disease.	Reviews in clinical and experimental hematology 2001, 5: 335-68; quiz following 431
von Willebrand disease (vWD) is caused by quantitative and/or qualitative defects of the von Willebrand factor (vWF), a multimeric high molecular weight glycoprotein. Typically, it affects the primary hemostatic system, which results in a mucocutaneous bleeding tendency simulating a platelet function defect. The vWF promotes its function in two ways: (i) by initiating platelet adhesion to the injured vessel wall under conditions of high shear forces, and (ii) by its carrier function for factor VIII in plasma. Accumulating knowledge of the different clinical phenotypes and the pathophysiological basis of the disease translated into a classification that differentiated between quantitative and qualitative defects by means of quantitative and functional parameters, and by analyzing the electrophoretic pattern of vWF multimers. The advent of molecular techniques provided the opportunity for conducting genotype-phenotype studies which have recently helped, not only to elucidate or confirm important functions of vWF and its steps in post-translational processing, but also many disease causing defects. Acquired von Willebrand syndrome (avWS) has gained more attention during the recent years. An international registry was published and recommendation by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis in 2000. It concluded that avWS, although not a frequent disease, is nevertheless probably underdiagnosed. This should be addressed in future prospective studies. The aim of treatment is the correction of the impaired hemostatic system of the patient, ideally including the defects of both primary and secondary hemostasis. Desmopressin is the treatment of choice in about 70% of patients, mostly with type 1, while the others merit treatment with concentrates containing vWF.
Buergin, D	Das Kind, die lebensbedrohende Krankheit und der Tod.	Hrsg.: Hogrefe AG 1981
Bürger B, Zimmermann M, Mann G, Kühl J, Loning L, Riehm H, Reiter A, Schrappe M	Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia.	J Clin Oncol 2003, 21: 184
von Bueren AO, von Hoff K, Benesch M, Rutkowski S	Dose reductions of vincristine in children with medulloblastoma treated in the maintenance arm of the prospective multicenter trial HIT'91.	Klinische Padiatrie 2009, 221: 396
von Bueren AO, Warmuth-Metz M, Schlegel PG, Soerensen N, Krauss J, Roggendorf W, Pietsch T, Feiden W, Graf N, Pohl F, Flentje M, Kuehl J, Rutkowski S	Late complete remission of supratentorial primitive neuroectodermal tumor (CNS-PNET) after multiple relapses.	Pediatr Blood Cancer 2011, 56: 503
No abstract available
von Bueren AO, von Hoff K, Pietsch T, Gerber NU, Warmuth-Metz M, Deinlein F, Zwiener I, Faldum A, Fleischhack G, Benesch M, Krauss J, Kuehl J, Kortmann RD, Rutkowski S	Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology.	Neuro-oncology 2011, 13: 669
This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with nonmetastatic medulloblastoma (MB) treated with postoperative chemotherapy alone. Patients who received a diagnosis during the period January 2001 through December 2005 and who were aged <4 years received 3 cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In cases of complete remission, treatment was terminated after 2 additional cycles of chemotherapy. Otherwise, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended. At a median follow-up of 4.5 years, the 5-year event-free survival (EFS) and overall survival (OS) rates (± standard error) for 45 patients (median age, 2.5 years) were 57% ± 8% and 80% ± 6%, respectively. Nineteen patients with desmoplastic/nodular MB variants had better 5-year EFS and OS rates (90% ± 7% and 100% ± 0%, respectively) than did 23 patients with classic MB (30% ± 11% and 68% ± 10%, respectively; P < .001 for EFS; P = .008 for OS). Five-year EFS and OS rates for 3 children with anaplastic MB were 33% ± 27%. Desmoplastic/nodular histology was an independent prognostic factor for EFS. Twenty-nine of 30 patients without postoperative residual tumor remained in continuous complete remission. Our results confirm that histology of MB variants is a strong prognostic factor in this age group. Sustained tumor control can be achieved by this chemotherapy regimen in young children with desmoplastic/nodular MB variants. For children with non-desmoplastic/nonnodular MB variants, for which predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006.
von Bueren AO, von Hoff K, Pietsch T, Gerber NU, Warmuth-Metz M, Deinlein F, Zwiener I, Faldum A, Fleischhack G, Benesch M, Krauss J, Kuehl J, Kortmann RD, Rutkowski S	Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology.	Neuro Oncol 2011, 13: 669
This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with nonmetastatic medulloblastoma (MB) treated with postoperative chemotherapy alone. Patients who received a diagnosis during the period January 2001 through December 2005 and who were aged <4 years received 3 cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In cases of complete remission, treatment was terminated after 2 additional cycles of chemotherapy. Otherwise, secondary surgery, radiotherapy, and consolidation chemotherapy were recommended. At a median follow-up of 4.5 years, the 5-year event-free survival (EFS) and overall survival (OS) rates (± standard error) for 45 patients (median age, 2.5 years) were 57% ± 8% and 80% ± 6%, respectively. Nineteen patients with desmoplastic/nodular MB variants had better 5-year EFS and OS rates (90% ± 7% and 100% ± 0%, respectively) than did 23 patients with classic MB (30% ± 11% and 68% ± 10%, respectively; P < .001 for EFS; P = .008 for OS). Five-year EFS and OS rates for 3 children with anaplastic MB were 33% ± 27%. Desmoplastic/nodular histology was an independent prognostic factor for EFS. Twenty-nine of 30 patients without postoperative residual tumor remained in continuous complete remission. Our results confirm that histology of MB variants is a strong prognostic factor in this age group. Sustained tumor control can be achieved by this chemotherapy regimen in young children with desmoplastic/nodular MB variants. For children with non-desmoplastic/nonnodular MB variants, for which predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006.
von Bueren AO, Bacolod MD, Hagel C, Heinimann K, Fedier A, Kordes U, Pietsch T, Koster J, Grotzer MA, Friedman HS, Marra G, Kool M, Rutkowski S	Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours.	British journal of cancer 2012, 107: 1399-408
Tumours are responsive to temozolomide (TMZ) if they are deficient in O(6)-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient.
Buehrlen M, Zwaan CM, Granzen B, Lassay L, Deutz P, Vorwerk P, Staatz G, Gademann G, Christiansen H, Oldenburger F, Tamm M, Mertens R	Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG.	Cancer 2012, 118: 4892
The authors report preliminary results from a prospective multicenter study (Nasopharyngeal Carcinoma [NPC] 2003 German Society of Pediatric Oncology and Hematology/German Children's Oncology Group [NPC-2003-GPOH/DCOG]).
von Bueren AO, Kortmann RD, von Hoff K, Friedrich C, Mynarek M, Müller K, Goschzik T, Zur Mühlen A, Gerber N, Warmuth-Metz M, Soerensen N, Deinlein F, Benesch M, Zwiener I, Kwiecien R, Faldum A, Bode U, Fleischhack G, Hovestadt V, Kool M, Jones D, Northcott P, Kuehl J, Pfister S, Pietsch T, Rutkowski S	Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters.	Journal of clinical oncology 2016, 34: 4151
von Bueren AO, Hagel C, Rutkowski S	Cerebrospinal fluid evaluation in adult patients with medulloblastoma.	The Lancet. Oncology 2020, 21:e120
Buffler PA, Kwan ML, Reynolds P, Urayama KY	Environmental and genetic risk factors for childhood leukemia: appraising the evidence.	Cancer Invest 2005, 23: 60
Bührer C, Hartmann R, Fengler R, Dopfer R, Gadner H, Gerein V, Göbel U, Reiter A, Ritter J, Henze G	Superior prognosis in combined compared to isolated bone marrow relapses in salvage therapy of childhood acute lymphoblastic leukemia.	Med Pediatr Oncol 1993, 21: 470
Buitenkamp TD, Izraeli S, Zimmermann M, Forestier E, Heerema NA, van den Heuvel-Eibrink MM, Pieters R, Korbijn CM, Silverman LB, Schmiegelow K, Liang DC, Horibe K, Arico M, Biondi A, Basso G, Rabin KR, Schrappe M, Cario G, Mann G, Morak M, Panzer-Grümayer R, Mondelaers V, Lammens T, Cavé H, Stark B, Ganmore I, Moorman AV, Vora A, Hunger SP, Pui CH, Mullighan CG, Manabe A, Escherich G, Kowalczyk JR, Whitlock JA, Zwaan CM	Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group.	Blood 2014, 123: 70
Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Münster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% ± 2% vs 15% ± 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% ± 1% vs 2.0% ± <1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% ± 2% vs 81% ± 2%, P < .0001) and overall survival (74% ± 2% vs 89% ± 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 × 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.
Buchanan GR, Adix L	Grading of hemorrhage in children with idiopathic thrombocytopenic purpura.	The Journal of pediatrics 2002, 141: 683
To develop an instrument to allow semiquantitative assessment of hemorrhage in children with idiopathic thrombocytopenic purpura (ITP).
Bunin GR	Nongenetic causes of childhood cancers: evidence from international variation, time trends, and risk factor studies.	Toxicol Appl Pharmacol 2004, 199: 91
Buchanan GR, Adix L	Current challenges in the management of children with idiopathic thrombocytopenic purpura.	Pediatric blood & cancer 2006, 47(5 Suppl): 681
Much progress has been made during the past several decades in the diagnosis and management of childhood idiopathic thrombocytopenic purpura (ITP). Although we do not yet know ITP's cause, opportunities for research discovery in other areas have blossomed in recent years. One major step forward has been realization that outcomes other than platelet count are important in children with ITP, most especially the severity of hemorrhage, cost and side effects of treatment, and overall quality of life. The classical definition of chronic ITP (thrombocytopenia lasting greater than 6 months) has been questioned. Debate continues whether ITP can truly be cured, especially when it lasts for years. Much excitement has recently been generated as a result of a new mechanism of ITP treatment, that is, enhancing platelet production. Yet problems continue regarding how best to conduct research involving newly diagnosed ITP patients, for a number of barriers are still to be overcome. Fortunately, however, abundant information and support for ITP patients and their families is now much more available than in years past.
Vorstand der Bundesärztekammer auf Empfehlung des Wissenschaftlichen Beirats (Hrsg)	Querschnitts-Leitlinien (BÄK) zur Therapie mit Blutkomponenten und Plasmaderivaten .	Deutscher Ärzteverlag Köln 2008
Burdach S, Jürgens H, Peters C, Nürnberger W, Mauz-Körholz C, Körholz D, Paulussen M, Pape H, Dilloo D, Koscielniak E, et al.	Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing's sarcoma.	J Clin Oncol 1993, 11: 1482
Burdach S, Müschenich M, Josephs W, Frisch J, Schulz G, Jürgens H, Göbel U	Granulocyte-macrophage-colony stimulating factor for prevention of neutropenia and infections in children and adolescents with solid tumors. Results of a prospective randomized study.	Cancer 1995, 76: 510
Burdach S, Nürnberger W, Laws H, Engel B, Dirksen U, Krauth K, Pape H, Kahn T, Körholz D, Gadner H, Göbel U, Jürgens H	Myeloablative therapy, stem cell rescue and gene transfer in advanced Ewing tumors.	Bone Marrow Transplant 1996, 18 Suppl 1:S67
Burdach S, van Kaick B, Laws H, Ahrens S, Haase R, Körholz D, Pape H, Dunst J, Kahn T, Willers R, Engel B, Dirksen U, Kramm C, Nurnberger W, Heyll A, Ladenstein R, Gadner H, Jürgens H, Go el	Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Dusseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria.	Ann Oncol 2000, 11: 1451
Burdach S, Jürgens H	High-dose chemoradiotherapy (HDC) in the Ewing family of tumors (EFT).	Crit Rev Oncol Hematol 2002, 41: 169
Burkhardt-Hammer T, Spix C, Brenner H, Kaatsch P, Berthold F, Hero B, Michaelis J	Long-term survival of children with neuroblastoma prior to the neuroblastoma screening project in Germany.	Med Pediatr Oncol 2002, 39: 156
Burdach S, Meyer-Bahlburg A, Laws H, Haase R, van Kaik B, Metzner B, Wawer A, Finke R, Göbel U, Haerting J, Pape H, Gadner H, Dunst J, Jürgens H	High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors.	J Clin Oncol 2003, 21: 3072
Burger B, Beier R, Zimmermann M, Beck JD, Reiter A, Schrappe M	Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)--experiences from trial ALL-BFM 95.	Pediatric blood & cancer 2005, 44: 220
BACKGROUND: Osteonecrosis (ON) as a complication during treatment of acute lymphoblastic leukemia (ALL) has gained rising attention over the past decade. Corticosteroids, representing an essential element of antileukemic therapy, are known to induce ON, which in turn may cause significant morbidity. Due to spontaneous reporting of affected patients with ON, a group-wide evaluation was performed to determine incidence, risk factors, and morbidity for ON. PROCEDURE: Patients were identified via spontaneous reporting to the study center and via questionnaire, addressing all 64 participating centers. We retrospectively analyzed 1,951 patients below 18 years of age who were treated according to trial ALL-BFM 95 between 01.01.1996 and 30.06.2000. RESULTS: Thirty-one patients (14 male, 17 female) affected by ON were identified. The overall 5-year cumulative incidence for ON is 1.8%. The incidence for patients <10 years is 0.2%, whereas for patients >/=10 years it is 8.9% (P = 0.00) and 16.7% (P = 0.003) for patients >/=15 years. The majority (n = 20) showed ON in two or more joints, and the joints most commonly affected were knees (14 patients, 24 affected knees) and hips (11 patients, 20 affected joints). Thirteen out of 31 patients had to undergo surgery in the course of their disease. CONCLUSIONS: Symptomatic ON is a rare event in patients treated with BFM-type chemotherapy with an overall 5-year cumulative incidence of 1.8%. The age group >/=10 years, and particularly adolescents >/=15 years have a significantly higher risk of developing ON.
Burkhardt B, Zimmermann M, Oschlies I, Niggli F, Mann G, Parwaresch R, Riehm H, Schrappe M, Reiter A, BFM Group	The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence.	Br J Haematol 2005, 131: 39
Burkhardt B, Woessmann W, Zimmermann M, Kontny U, Vormoor J, Doerffel W, Mann G, Henze G, Niggli F, Ludwig WD, Janssen D, Riehm H, Schrappe M, Reiter A	Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma.	J Clin Oncol 2006, 24: 491
Burkhardt B, Moericke A, Klapper W, Greene F, Salzburg J, Damm-Welk C, Zimmermann M, Strauch K, Ludwig WD, Schrappe M, Reiter A	Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact.	Leukemia & lymphoma 2008, 49: 451
Deletions on chromosome 6q are frequently reported in hematological malignancies. However, their biological or prognostic impact has not yet been clarified. This study analyzed loss of heterozygosity (LOH) at chromosome 6q and compared the LOH findings in pediatric precursor T lymphoblastic lymphoma (T-LBL) with the LOH findings in precursor-T lymphoblastic leukemia (T-ALL). For LOH analyses, a set of 25 microsatellite-markers on 6q14-q24 were examined. All patients were treated uniformly according to ALL-BFM-type treatment-strategy. A total of 1671 markers were successfully analyzed from 108 T-LBL patients. LOH was detected in 21 T-LBL patients. There was clear association between LOH at 6q and an increased risk of relapse. In comparison, 3109 markers were successfully analyzed from 127 T-ALL-patients. LOH was detected in 16 patients, but was not associated with increased relapse-rate. The localization of the common LOH regions identified for T-LBL and T-ALL samples did not overlap. Therefore patterns of LOH at 6q and the prognostic impact of LOH differ between T-ALL and T-LBL. These results hint at biologic differences between the two diseases.
Burkhardt B, Reiter A, Landmann E, Lang P, Lassay L, Dickerhoff R, Lakomek M, Henze G, von Stackelberg A	Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: a report from the berlin-frankfurt-muenster group.	Journal of clinical oncology 2009, 27: 3363
PURPOSE: Little is known about the outcome of pediatric patients with lymphoblastic lymphoma (LBL) who suffer from progressive disease or relapse. PATIENTS AND METHODS: We analyzed the pattern of LBL relapses after current non-Hodgkin's lymphoma Berlin-Frankfurt-Muenster (BFM) frontline therapy between April 1990 and March 2003. Relapse therapy was according to acute lymphoblastic leukemia (ALL) -Relapse-BFM protocols or ALL-BFM protocols for high-risk patients. RESULTS: Twenty-eight (11%) of 251 registered patients with precursor T-cell LBL (T-LBL) and six (8%) of 73 patients with precursor B-cell LBL (pB-LBL) suffered from relapse. Of the 28 patients with T-LBL, one died from infection during relapse chemotherapy, 18 failed to achieve stable remission and died from disease progression, and nine reached allogeneic stem-cell transplantation (SCT). Two of these nine patients who underwent SCT died from transplantation-associated toxicity, three died from disease progression, and four are still alive. These four patients are in second remission of their lymphoma for 48, 68, 125, and 131 months, respectively, after allogeneic SCT. One of the four patients developed colon adenocarcinoma 47 months after SCT. Of the six patients with pB-LBL who experienced relapse, one patient died as a result of toxicity of relapse chemotherapy, two died from disease progression after chemotherapy, and three received allogeneic SCT. Of these, two died from subsequent disease progression, and one is still alive 57 months after allogeneic SCT. CONCLUSION: Using modern conventional therapy in the frontline treatment of LBL, 10% of patients suffer from progressive disease or relapse. Because of the extremely poor reinduction success, the salvage rate for these patients is poor, with only a 14% (SE = 6%) overall survival. Long-term survival was only achieved in those few patients who were able to undergo an allogeneic SCT.
Burdach S, Thiel U, Schöniger M, Haase R, Wawer A, Nathrath M, Kabisch H, Urban C, Laws HJ, Dirksen U, Steinborn M, Dunst J, Jürgens H, Meta-EICESS Study Group	Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases.	Bone marrow transplantation 2010, 45: 483
We examined the role of total body magnetic resonance imaging (TB-MRI)-governed involved compartment irradiation (ICI) and high-dose chemotherapy (HDC), followed by stem cell rescue (SCR) in patients with high-risk Ewing tumors (ETs) with multiple primary bone metastases (high-risk ET-MBM). Eleven patients with high-risk ET-MBM receiving initial assessment of involved bones by TB-MRI were registered from 1995 to 2000 (group A). In all, 6 patients out of 11 had additional lung disease at initial diagnosis; all had multifocal bone disease with more than three bones involved. After systemic induction with etoposide, vincristine, adriamycin (doxorubicin), ifosfamide, and actinomycin D (EVAIA) or VAIA chemotherapy, ICI of all sites positive by TB-MRI was administered, followed by HDC and SCR. A second group matched for observation period and consisting of 26 patients with more than three involved bones at diagnosis was treated with the European Intergroup Cooperative Ewing Sarcoma Study-92 (EICESS-92) protocol (group B). These patients did not receive TB-MRI and consequently did not receive TB-MRI-governed ICI, or HDC and SCR. Survival in group A vs group B was 45 vs 8% at 5 years and 27 vs 8% at 10 years after diagnosis (log rank and Breslow: P<0.005). We conclude that TB-MRI-governed ICI followed by HDC and SCR in ET-MBM is feasible and warrants further evaluation in prospective studies.
Burkhardt B, Oschlies I, Klapper W, Zimmermann M, Woessmann W, Meinhardt A, Landmann E, Attarbaschi A, Niggli F, Schrappe M, Reiter A	Non-Hodgkin's lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols.	Leukemia 2011, 25: 153
Age-related differences in the distribution, biology and treatment response of non-Hodgkin's lymphoma (NHL) in adolescents remain to be elucidated. The current analyses present clinical parameters and outcomes of adolescents treated in pediatric NHL-BFM trials. Patients were stratified by histological subtype: lymphoblastic lymphoma (LBL); mature B-NHL, including Burkitt's lymphoma/leukemia (BL/B-AL), diffuse B-cell lymphoma (DLBCL-CB) and mediastinal B-cell lymphoma (PMLBL); and anaplastic large cell lymphoma (ALCL). Between October 1986 and December 2007, 2915 patients were registered, including 378 (13%) adolescents (15-18 years) with BL/B-AL (n=101), ALCL (n=74), DLBCL-CB (n=55), T-LBL (n=45), PMLBL (n=24), pB-LBL (n=13) and rare or not-specified NHL subtypes (n=66). The 5-year event-free survival (EFS) was 79±2% for adolescents compared with 85±1% for patients aged <15 years (P=0.014). EFS was 83±7% for adolescents with T-LBL, 82±4% with BL/B-AL, 85±5% with DLBCL-CB, 57±10% with PMLBL and 70±6% with ALCL. According to sex, the 5-year EFS in females versus males, respectively, was 70±5 versus 83±2% overall (P=0.004), 57±17 versus 92±6% (P=0.0036) for T-LBL patients and 71±9 versus 97±3% (P=0.0067) for DLBCL-CB patients. Adolescents with NHL treated according to pediatric NHL-BFM protocols had an EFS of 79±2%, which is marginally inferior to that of children. In adolescents with T-LBL and DLBCL-CB, female sex was associated with a worse prognosis.
Burkhardt B, Yavuz D, Zimmermann M, Schieferstein J, Kabickova E, Attarbaschi A, Lisfeld J, Reiter A, Makarova O, Worch J, Bonn BR, Damm-Welk C	Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia.	Annals of hematology 2016, 95: 1503
Burkhardt B, Mueller S, Khanam T, Perkins SL	Current status and future directions of T-lymphoblastic lymphoma in children and adolescents.	British journal of haematology 2016, 173: 545
Burkhardt B, Wössmann W	Non-Hodgkin-Lymphome.	S1-Leitlinie 025/013: Non-Hodgkin-Lymphome im Kindes- und Jugendalter 2017
Burkhardt B, Klapper W, Woessmann W	Non-Hodgkin-Lymphome.	in: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie. Springer-Verlag GmbH Deutschland, 2. vollständig überarbeitete Auflage 2018, 324
Burroughs LM, Petrovic A, Brazauskas R, Liu X, Griffith LM, Ochs HD, Bleesing JJ, Edwards S, Dvorak CC, Chaudhury S, Prockop SE, Quinones R, Goldman FD, Quigg TC, Chandrakasan S, Smith AR, Parikh S, Dávila Saldaña BJ, Thakar MS, Phelan R, Shenoy S, Forbes LR, Martinez C, Chellapandian D, Shereck E, Miller HK, Kapoor N, Barnum JL, Chong H, Shyr DC, Chen K, Abu-Arja R, Shah AJ, Weinacht KG, Moore TB, Joshi A, DeSantes KB, Gillio AP, Cuvelier GDE, Keller MD, Rozmus J, Torgerson T, Pulsipher MA, Haddad E, Sullivan KE, Logan BR, Kohn DB, Puck JM, Notarangelo LD, Pai SY, Rawlings DJ, Cowan MJ	Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report.	Blood 2020, 135: 2094
Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.).
Burkhardt B, Taj M, Garnier N, Minard-Colin V, Hazar V, Mellgren K, Osumi T, Fedorova A, Myakova N, Verdu-Amoros J, Andres M, Kabickova E, Attarbaschi A, Chiang AKS, Bubanska E, Donska S, Hjalgrim LL, Wachowiak J, Pieczonka A, Uyttebroeck A, Lazic J, Loeffen J, Buechner J, Niggli F, Csoka M, Krivan G, Palma J, Burke GAA, Beishuizen A, Koeppen K, Mueller S, Herbrueggen H, Woessmann W, Zimmermann M, Balduzzi A, Pillon M	Treatment and Outcome Analysis of 639 Relapsed Non-Hodgkin Lymphomas in Children and Adolescents and Resulting Treatment Recommendations.	Cancers 2021, 13
Despite poor survival, controversies remain in the treatment for refractory or relapsed pediatric non-Hodgkin lymphoma (r/r NHL). The current project aimed to collect international experience on the re-induction treatment of r/r NHL, hematopoietic stem cell transplantation (HSCT), risk factors associated with outcome, and to suggest treatment recommendations. Inclusion criteria were (i) refractory disease, disease progression or relapse of any NHL subtype except anaplastic large cell lymphoma, (ii) age < 18 years at initial diagnosis, (iii) diagnosis in/after January 2000. Data from 639 eligible patients were evaluable. The eight-year probability of overall survival was 34 ± 2% with highly significant differences according to NHL subtypes: 28 ± 3% for 254 Burkitt lymphoma/leukemia, 50 ± 6% for 98 diffuse large B-cell lymphomas, 57 ± 8% for 41 primary mediastinal large B-cell lymphomas, 27 ± 3% for 177 T-lymphoblastic lymphomas, 52 ± 10% for 34 precursor-B-cell lymphoblastic lymphomas and 30 ± 9% for 35 patients with rare NHL subtypes. Subtype-specific factors associated with survival and treatment recommendations are suggested. There were no survivors without HSCT, except in few very small subgroups. Conclusions: There is an urgent need to further improve survival in r/r NHL. The current study provides the largest real-world series, which underlines the role of HSCT and suggests treatment recommendations.
Burkhardt B, Michgehl U, Rohde J, Erdmann T, Berning P, Reutter K, Rohde M, Borkhardt A, Burmeister T, Dave S, Tzankov A, Dugas M, Sandmann S, Fend F, Finger J, Mueller S, Gökbuget N, Haferlach T, Kern W, Hartmann W, Klapper W, Oschlies I, Richter J, Kontny U, Lutz M, Maecker-Kolhoff B, Ott G, Rosenwald A, Siebert R, von Stackelberg A, Strahm B, Woessmann W, Zimmermann M, Zapukhlyak M, Grau M, Lenz G	Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age.	Nature communications 2022, 13: 3881
While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials.
Busch K, Borkhardt A, Wossmann W, Reiter A, Harbott J	Combined polymerase chain reaction methods to detect c-myc/IgH rearrangement in childhood Burkitt's lymphoma for minimal residual disease analysis.	haematologica 2004, 89: 818
Butturini A, Gale RP, Verlander PC, Adler-Brecher B, Gillio AP, Auerbach AD	Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study.	Blood 1994, 84: 1650
We analyzed data from 388 subjects with Fanconi anemia reported to the International Fanconi Anemia Registry (IFAR). Of those, 332 developed hematologic abnormalities at a median age of 7 years (range, birth to 31 years). Actuarial risk of developing hematopoietic abnormalities was 98% (95% confidence interval, 93% to 99%) by 40 years of age. Common hematologic abnormalities were thrombocytopenia and pancytopenia. These were often associated with decreased bone marrow (BM) cellularity (75% of cases studied). Clonal cytogenetic abnormalities developed in 23 of 68 persons with BM failure who had adequate studies. Actuarial risk of clonal cytogenetic abnormalities during BM failure was 67% (47% to 87%) by 30 years of age. Fifty-nine subjects developed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Actuarial risk of MDS or AML was 52% (37% to 67%) by 40 years of age. Risk was higher in persons with than in those without a prior clonal cytogenetic abnormality (3% [0% to 9%] v 35% [0% to 79%]; P = .006). One hundred twenty persons died of hematologic causes including BM failure, MDS or AML and treatment related complications. Actuarial risk of death from hematologic causes was 81% (67% to 90%) by 40 years of age.
Buttgereit T, Vera C, Weller K, Gutsche A, Grekowitz EM, Aykanat S, Wahn V, Krüger R, Maurer M, Magerl M	Lanadelumab Efficacy, Safety, and Injection Interval Extension in HAE: A Real-Life Study.	The journal of allergy and clinical immunology 2021, online ahaed of print
Lanadelumab has been available in Germany for the prophylactic treatment of hereditary angioedema since February 2019.
Butzer SK, Krug B, Reisberg M, Fuchs J, Warmann SW, Hubertus J, Körber F, Berthold F, Simon T, Hero B	Image-defined risk factors in localized thoracic neuroblastoma and ganglioneuroma.	Pediatric blood & cancer 2023, 70:e30605
The pretreatment International Neuroblastoma Risk Group Staging System (INRGSS) discriminates localized tumors L1/L2 depending on the absence/presence of image-defined risk factors (IDRFs) at diagnosis. Referring to this new staging system, we assessed initial imaging of localized thoracic neuroblastoma (NB) and ganglioneuroma (GN) and the extent of initial tumor resection.
Bührer C, Hartmann R, Fengler R, Döpfer R, Gadner H, Gerein V, Göbel U, Reiter A, Ritter J, Henze G	Superior prognosis in combined compared to isolated bone marrow relapses in salvage therapy of childhood acute lymphoblastic leukemia.	Med Pediatr Oncol 1993, 21: 470
Bührer C, Hartmann R, Fengler R, Schober S, Arlt I, Loewke M, Henze G	Importance of effective central nervous system therapy in isolated bone marrow relapse of childhood acute lymphoblastic leukemia. BFM (Berlin-Frankfurt-Münster) Relapse Study Group.	Blood 1994, 83: 3468
Bührer C, Hartmann R, Fengler R, Rath B, Schrappe M, Janka-Schaub G, Henze G	Peripheral blast counts at diagnosis of late isolated bone marrow relapse of childhood acute lymphoblastic leukemia predict response to salvage chemotherapy and outcome. Berlin-Frankfurt-Münster Relapse Study Group.	J Clin Oncol 1996, 14: 2812
Bürger D, von Schweinitz D, Weinel P, Mildenberger H	HB89.	Chirurg 1992, 63: 193
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