Literatur

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Autor(en)	Titel	Quelle
Haaf H, Kaatsch P, Keller B, Michaelis J	Regionale Analysen der Krebsinzidenz bei kleinen Fallzahlen.	Gesundheit und Umwelt 1992, 273
Haas R, Schmidt P, Göbel U, Harms D	Therapy of testicular germ cell tumors. Current status of the MAHO studies.	Klin Pädiatr 1993, 205: 225
Haas R, Schmidt P, Göbel U, Harms D	Treatment of malignant testicular tumors in childhood.	Med Pediatr Oncol 1994, 23: 400
Haas R, Schmidt P	Testicular germ-cell tumors in childhood and adolescence.	World J Urol 1995, 13: 203
Haas R, Schmidt P, Göbel U, Harms D	Testicular germ cell tumors. Results of the GPO MAHO studies -82-88-92.	Klin Pädiatr 1995, 207: 145
Haas R, Schmidt P, Göbel U, Harms D	Testicular germ cell tumors, an update. Results of the German cooperative studies 1982-1997.	Klin Pädiatr 1999, 211: 300
Haase R, Vilser C, Mauz-Körholz C, Hasenclever D, Kluge R, Ruschke K, Borkhardt A, Seeger K, Lehrnbecher T, Kulozik A, Rößler J, Burdach S, Jürgens H, Körholz D	Evaluation of the prognostic meaning of C-reactive protein (CRP) in children and adolescents with classical Hodgkin's lymphoma (HL).	Klinische Padiatrie 2012t; 224: 377
In adult cancer patients the negative predictive value of elevated CRP levels has been described for several malignancies. Only few studies have analyzed the prognostic role of CRP in children and adolescents with classical HL. In these studies elevated CRP levels correlate with the presence of classical risk factors and adverse outcome.
Haberle B, Hero B, Berthold F, von Schweinitz D	Characteristics and outcome of thoracic neuroblastoma.	Eur J Pediatr Surg 2002, 12: 145
Haberle B, Bode U, von Schweinitz D	Differentiated treatment protocols for high- and standard-risk hepatoblastoma--an interim report of the German Liver Tumor Study HB99.	Klin Pädiatr 2003, 215: 159
Habibi A, Mekontso-Dessap A, Guillaud C, Michel M, Razazi K, Khellaf M, Chami B, Bachir D, Rieux C, Melica G, Godeau B, Galacteros F, Bartolucci P, Pirenne F	Delayed hemolytic transfusion reaction in adult sickle-cell disease: presentations, outcomes, and treatments of 99 referral center episodes.	American journal of hematology 2016, 91: 989
Delayed hemolytic transfusion reaction (DHTR) is one of the most feared complications of sickle-cell disease (SCD). We retrospectively analyzed the clinical and biological features, treatments and outcomes of 99 DHTRs occurring in 69 referral center patients over 12 years. The first clinical signs appeared a median of 9.4 [IQR, 3-22] days after the triggering transfusion (TT). The most frequent DHTR-related clinical manifestation was dark urine/hemoglobinuria (94%). Most patients (89%) had a painful vaso-occlusive crisis and 50% developed a secondary acute chest syndrome (ACS). The median [IQR] hemoglobin-concentration nadir was 5.5 [4.5-6.3] g/dL and LDH peak was 1335 [798-2086] IU/L. Overall mortality was 6%. None of the patients had been receiving chronic transfusions. Among these DHTRs, 61% were developed in previously immunized patients, 28% in patients with prior DHTR. Among Abs detected after the TT in 62% of the episodes, half are classically considered potentially harmful. No association could be established between clinical severity and immunohematological profile and/or the type and specificity of Abs detected after the TT. Management consisted of supportive care alone (53%) or with adjunctive measures (47%), including recombinant erythropoietin and sometimes rituximab and/or immunosuppressants. Additional transfusions were either ineffective or worsened hemolysis. In some cases, severe intravascular hemolysis can be likely responsible for the vascular reaction and high rates of ACS, pulmonary hypertension and (multi)organ failure. In conclusion, clinicians and patients must recognize early DHTR signs to avoid additional transfusions. For patients with a history of RBC immunization or DHTR, transfusion indications should be restricted
Hadrich D, Berthold F, Steckhan E, Bonisch H	Synthesis and characterization of fluorescent ligands for the norepinephrine transporter.	J Med Chem 1999, 42: 3101
Haecker F, von Schweinitz D, Harms D, Buerger D, Graf N	Partial nephrectomy for unilateral Wilms tumor.	J Urol 2003, 170: 939
Haeusler J, Ranft A, Boelling T, Gosheger G, Braun-Munzinger G, Vieth V, Burdach S, van den Berg H, Jürgens H, Dirksen U	The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES).	Cancer 2010, 116: 443
Haeberle B, Rangaswami A, Krailo M, Czauderna P, Hiyama E, Maibach R, Lopez-Terrada D, Aronson DC, Alaggio R, Ansari M, Malogolowkin MH, Perilongo G, O'Neill AF, Trobaugh-Lotrario AD, Watanabe K, Schmid I, von Schweinitz D, Ranganathan S, Yoshimura K, Hishiki T, Tanaka Y, Piao J, Feng Y, Rinaldi E, Saraceno D, Derosa M, Meyers RL	The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database.	Pediatric blood & cancer 2020, 67:e28350
Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification.
Haggstrom AN, Lammer EJ, Schneider RA, Marcucio R, Frieden IJ	Patterns of infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development.	Pediatrics 2006, 117: 698
Large facial infantile hemangiomas have higher rates of complications than small localized hemangiomas, more often require treatment, and can be associated with neurological, ophthalmologic, and cardiac anomalies (PHACE syndrome). The anatomic patterns of these hemangiomas are often referred to as
Hagel C, Treszl A, Fehlert J, Harder J, von Haxthausen F, Kern M, von Bueren AO, Kordes U	Supra- and infratentorial pediatric ependymomas differ significantly in NeuN, p75 and GFAP expression.	Journal of neuro-oncology 2013, 112: 191
Ependymomas comprise 8 % of all intracranial tumors in children <15 years. Recent studies revealed that some supratentorial ependymomas express neuronal antigens and that high expression of neurofilament protein light polypeptide (NEFL) correlates with better clinical outcome. We retrospectively analyzed an expanded panel of proteins in 6 supratentorial, 15 posterior fossa and 4 spinal pediatric ependymomas by immunohistochemistry. Expression of high and low affinity neurotrophin receptors TrkA (NTRK1) and p75 (NGFR), pan-neuronal markers NeuN (RBFOX3) and synaptophysin, radial glial marker SOX9, adhesion molecules CD56 (NCAM) and CD44, junctional protein connexin 43 (GJA1), glial fibrillary acidic protein (GFAP), epithelial membrane antigen and proliferation associated antigen Ki-67 were evaluated in a semi-quantitative or quantitative (Ki-67 and NeuN-index) fashion. We found p75 and NeuN to be expressed at significantly higher levels in supratentorial versus infratentorial tumors and GFAP to be expressed at significantly higher levels in infratentorial lesions. In conclusion, immunohistochemical expression of p75, NeuN and GFAP differed in ependymomas depending on tumor topography supporting the view of divergent cells of origin. However, because of the small sample size the results are of preliminary nature and replication in a larger cohort would be desirable.
Halperin EC, Friedman HS, Schold SC Jr, Fuchs HE, Oakes WJ, Hockenberger B, Burger PC	Surgery, hyperfractionated craniospinal irradiation, and adjuvant chemotherapy in the management of supratentorial embryonal neuroepithelial neoplasms in children.	Surgical neurology 1993, 40: 278
Supratentorial embryonal neuroepithelial tumors are undifferentiated neoplasms. We have used this term in preference to the controversial classification primitive neuroectodermal tumors (PNET). These lesions in children are malignant neoplasms which are usually fatal within 2 years of diagnosis in spite of therapy with surgery, radiotherapy, and chemotherapy. We have adopted an aggressive approach to the treatment of these tumors with surgical resection, hyperfractionated craniospinal irradiation of 30.6-43.9 Gy followed by a tumor boost to a total dose of 50-63.7 Gy, and adjuvant chemotherapy with cyclophosphamide, vincristine, and cis-platinum. We have treated five children, aged 4-18 years, with this approach. In contrast to the results reported in the literature, four children are alive without evidence of tumor from 4.3 to 8.0 years following diagnosis. One has suffered a tumor relapse at 2.3 years following diagnosis but remains alive. The basis of our therapeutic strategy for childhood supratentorial embryonal neuroepithelial tumors and the implications of our clinical results are discussed.
Halimeh S	Menorrhagia and bleeding disorders in adolescent females.	Hamostaseologie 2012, 32: 45
In women, von Willebrand disease (VWD) is the most common inherited bleeding disorder. Since VWD and other inherited bleeding disorders are autosomal disorders, they affect women and men. Menorrhagia, or heavy menstrual bleeding (HMB), is the most common symptom of women with bleeding disorder experience. Objectively, it is defined as bleeding that lasts for more than seven days or results in the loss of more than 80 ml of blood per menstrual cycle. The prevalence of menorrhagia in a woman with a bleeding disorder ranges from 32 to 100% in patients with VWD, from 5 to 98% in patients with a platelet dysfunction and from 35 to 70% in women with a rare factor deficiency. A detailed history and a careful physical exam are the first steps towards a diagnosis in adolescents, adding a PBAC>100 increased the sensitivity of the screening tool further to 95%. Laboratory testing should be made at the time of menstrual bleeding in an effort to capture the lowest level of VWF:Ag and FVIII:C. Treatment options for menorrhagia in VWD: (1) antifibrinolytic therapy with tranexamic acid, (2) the non-transfusional agent desmopressin (DDAVP), (3) purified blood products that contain factor VIII and VWF concentrated from plasma and (4) hormonal preparations.
Halimeh S, Bidlingmaier C, Heller C, Gutsche S, Holzhauer S, Kenet G, Kurnik K, Manner D, Iorio A, Nowak-Göttl U	Risk factors for high-titer inhibitor development in children with hemophilia A: results of a cohort study.	BioMed research international 2013, 2013, 901975
Among the discussed risk factors for high-titre inhibitor (HRI) development in patients with hemophilia A (HA) are high dose FVIII replacement therapy and use of recombinant FVIII concentrates (rFVIII). The aim of this study was to evaluate the aforementioned risk factors for HRI development in children with hemophilia A â¤2%. About 288 ascertained PUPs (Israel and Germany) were followed after initial HA diagnosis over 200 exposure days. Inhibitor-free survival, hazard ratios (HR), and 95% confidence intervals (CIs) were calculated. Adjustment was performed for factor VIII concentrates, median single dose over the first three months of treatment, first FVIII administration before the age of three months, presence of risk HA gene mutations,
Hallberg B, Palmer RH	Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology.	Nature reviews. Cancer 2013, 13: 685
Hammerle K, Shayan P, Niemeyer CM, Flotho C	Expression analysis of alpha-NAC and ANX2 in juvenile myelomonocytic leukemia using SMART polymerase chain reaction and.	Cancer genetics and cytogenetics 2003, 142: 149
Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disease of early childhood with both myeloproliferative and myelodysplastic features. We had previously identified the genes for the alpha-chain of the nascent polypeptide-associated complex (NACA) and annexin II (ANX2) as potentially involved in the pathophysiology of JMML. Now we used SMART cDNA synthesis and subsequent
Hammer GP, Seidenbusch MC, Schneider K, Regulla DF, Zeeb H, Spix C, Blettner M	A cohort study of childhood cancer incidence after postnatal diagnostic X-ray exposure.	Radiation research 2009, 171: 504
Ionizing radiation is an established cause of cancer, yet little is known about the health effects of doses from diagnostic examinations in children. The risk of childhood cancer was studied in a cohort of 92.957 children who had been examined with diagnostic X rays in a large German hospital during 1976-2003. Radiation doses were reconstructed using the individual dose area product and other exposure parameters, together with conversion coefficients developed specifically for the medical devices and standards used at the radiology department. Newly diagnosed cancers occurring between 1980 and 2006 were determined through record linkage to the German Childhood Cancer Registry. The median radiation dose was 7 microSv. Eight-seven incident cases were found in the cohort: 33 leukemia, 13 lymphoma, 10 central nervous system tumors, and 31 other tumors. The standardized incidence ratio (SIR) for all cancers was 0.99 (95% CI: 0.79-1.22). No trend in the incidence of total cancer, leukemia or solid tumors with increasing radiation dose was observed in the SIR analysis or in the multivariate Poisson regression. Risk did not differ significantly in girls and boys. Overall, while no increase in cancer risk with diagnostic radiation was observed, the results are compatible with a broad range of risk estimates.
Hamideh D, Alvarez O	Sickle Cell Disease Related Mortality in the United States (1999-2009).	Pediatric blood & cancer 2013, epub ahead of print
BACKGROUND: Little is known about the national outcome of children and adults with sickle cell disease (SCD) given contemporary care. PROCEDURE: We investigated the number of deaths, standardized crude and age-adjusted mortality rates, and causes of death among individuals with SCD across the United States during 1999-2009 according to death certificates by using a publicly available website (http://wonder.cdc.gov/). Data were compared to mortality during 1979-1998. RESULTS: When compared to 1979-1998, mortality significantly decreased by 61% in infants <1 year of age, by 67% in children aged 1-4 years, and by 22-35% in children aged 5-19 years. After 19 years of age, mortality rates increased from 0.6 in the 15-19 year group to 1.4/100,000 in the 20-24 year group, corresponding to the transition period from pediatric to adult medical care, and this increase was similar during 1979-1998. Although the age groups with the highest mortality were 35-44 years for males and 45-54 years for females, there was a tendency for longer survival because there were more deaths among those individuals 55-74 years of age compared to previous years. For all individuals, the causes of deaths were cardiac disease (31.6%), respiratory (28.1%), renal (16.4%), infectious (14.4%), neurologic (11.9%), and gastrointestinal and hepatobiliary (9.2%) in nature. Cancer was the cause of death in <1%. CONCLUSION: Mortality during childhood has decreased significantly. However, the transition period from pediatric to adult care is critical. Risk-reduction, monitoring, and early treatment intervention of cardiovascular disease in adults is warranted. Pediatr Blood Cancer 2013;9999:XX-XX. © 2013 Wiley Periodicals, Inc.
Hammoudi N, Lionnet F, Redheuil A, Montalescot G	Cardiovascular manifestations of sickle cell disease.	Eur heart j 2020, 41: 1365
Sickle cell disease (SCD) is the most frequent genetic haemoglobinopathy worldwide. Early childhood mortality has dramatically decreased in high-income countries, and most patients now survive beyond the 5th decade. However, in the aging SCD population, the morbidity related to chronic organ damage, especially kidney and heart, has become a major concern. While pulmonary hypertension has attracted most attention, it appears that this condition is frequently linked to left heart failure (HF). Accordingly, SCD-associated cardiomyopathy is emerging as a major cause of reduced quality of life and early mortality in these patients. The diagnosis of this particular phenotype of high-output HF is challenging. Exercise intolerance and dyspnoea in SCD patients are linked to multiple causes including chronic anaemia. Moreover, echocardiographic features are unusual and can be misinterpreted. The classical diagnosis algorithm for HF is generally not suitable in SCD patients, and HF is poorly recognized and mostly diagnosed at a late congestive stage in routine practice. Such patients need to be identified at an earlier stage of myocardial dysfunction via improved phenotyping. This constitutes the first step towards further investigations in SCD needed to improve the prognosis and the quality of life. This article provides an updated review of the recent advances in the pathophysiology and diagnosis, and in addition, perspectives of new therapeutic approaches in SCD-related cardiac manifestations.
Hansmann C, Faber J, Lauth GW, Oldenburg M, Török M	Zwischenbericht zur „Untersuchung der heutigen Situation erwachsener Hämophiler“ im norddeutschen Raum.	Hämophilieblätter 1987, H.1: 27
Hanenberg H, Batish SD, Pollok KE, Vieten L, Verlander PC, Leurs C, Cooper RJ, Göttsche K, Haneline L, Clapp DW, Lobitz S, Williams DA, Auerbach AD	Phenotypic correction of primary Fanconi anemia T cells with retroviral vectors as a diagnostic tool.	Exp Hematol 2002, 30: 410
The aim of this study was to develop a rapid laboratory procedure that is capable of subtyping Fanconi anemia (FA) complementation groups FA-A, FA-C, FA-G, and FA-nonACG patients from a small amount of peripheral blood.
Hanke CA, Roessler J, Stegmaier S, Koscielniak E, Niemeyer CM, Kontny U	Alveolar rhabdomyosarcoma mimicking lymphoma with bone marrow involvement.	European journal of pediatrics 2007, 166: 505
Hanebutt FL, Rolf N, Loesel A, Kuhlisch E, Siegert G, Knoefler R	Evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders.	Haemophilia 2008, 14: 524
Desmopressin (DDAVP) affects haemostasis by the release of von Willebrand factor and coagulation factor VIII from endothelium. The aim of the study was to evaluate the results of DDAVP testing in paediatric patients with congenital bleeding disorders. Forty-one patients consisting of children with von Willebrand's disease (VWD, n = 26) and platelet function defects (PFD, n = 15) received DDAVP intravenously at a dosage of 0.3 mug/kg over 30 min. FVIII activity (FVIII), von Willebrand factor antigen (VWF:Ag), collagen-binding activity (VWF:CB) and PFA 100((R)) closure times (CT) were measured before, 60, 120 and 240 min after DDAVP. In VWD, the VWF:Ag increased threefold until 60 min and then it decreased continuously. Compared with baseline, VWF:Ag was significantly higher at 60 and 120 min but not at 240 min. In contrast, in PFD, the peak of VWF:Ag was reached after 120 min. Two hundred and forty minutes after DDAVP, the mean was still significantly elevated compared with baseline values. The course of VWF:CB corresponded to that of VWF:Ag. In patients with VWD and PFD, FVIII rose two- to threefold within 2 h after DDAVP. CT in patients with VWD shortened markedly within 120 min and then rose again. In all children with PFD, except one non-responder, the CT shortened within 240 min after DDAVP. Two non-responders with VWD were identified by the failed increase of VWF:Ag, VWF:CB and by prolonged CT. Haemostatic effects of DDAVP differ interindividually and dependent on the coagulation disorder. DDAVP was effective in most, but not in all patients. DDAVP testing is recommended to determine the individual haemostatic response.
Handgretinger R, Zugmaier G, Henze G, Kreyenberg H, Lang P, von Stackelberg A	Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia.	Leukemia 2010 Oct 14;
Hanahan D, Weinberg RA	Hallmarks of cancer: the next generation.	Cell 2011 Mar 4; 144: 646
Handgretinger R, Zugmaier G, Henze G, Kreyenberg H, Lang P, von Stackelberg A	Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia.	Leukemia 2011, 25: 181
No abstract available
Handgretinger R, Matthes-Martin S, Lang P	Hämatopoetische Stammzelltransplantation.	in: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie, Springer-Verlag GmbH Deutschland 2. vollständig überarbeitete Auflage 2018, 17
Hanitsch L, Baumann U, Boztug K, Burkhard-Meier U, Fasshauer M, Habermehl P, Hauck F, Klock G, Liese J, Meyer O, Müller R, Pachlopnik-Schmid J, Pfeiffer-Kascha D, Warnatz K, Wehr C, Wittke K, Niehues T, von Bernuth H	Treatment and management of primary antibody deficiency: German interdisciplinary evidence-based consensus guideline.	European journal of immunology 2020, 50: 1432
This evidence-based clinical guideline provides consensus-recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss, and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, and evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus-based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation, autoimmunity, and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g., antibiotic prophylaxis, management of bronchiectasis) and non-infectious manifestations (e.g., management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible, or unlikely benefit of IgG-replacement therapy. Summary and consensus-recommendations are provided for treatment indication, dosing, routes of administration, and adverse events of IgG-replacement therapy. Special aspects of concomitant impaired T-cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA-4-, and LRBA-deficiency).
Harisiadis L, Chang CH	Medulloblastoma in children: a correlation between staging and results of treatment.	Int J Radiat Oncol Biol Phys 1977 (9-10): 833
Harbott J, Budde M, Creutzig U, Engel R, Fengler R, Rudolph B, Lampert F	Prognostic meaning of chromosome aberrations in acute lymphocytic leukemia and acute nonlymphocytic leukemia patients of the BFM study group.	Haematology and Blood Transfusion 1987, 30: 497
Harbott J, Ritterbach J, Creutzig U, Riehm H, Lampert F	Cytogenetic findings in acute leukemias of infants.	Contrib Oncol 1990, 41: 50
Harms D, Gortitz I, Lambrecht W, Kabisch H, Erttmann R, Janka-Schaub G	Infectious risks of Broviac catheters in children with neoplastic diseases.	Pediatr Infect Dis J 1992, 11: 1014
Harbott J, Ritterbach J, Ludwig W, Bartram C, Reiter A, Lampert F	Clinical significance of cytogenetic studies in childhood acute lymphoblastic leukemia.	Recent Results Cancer Res 1993, 131: 123
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, et al.	A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group.	Blood 1994, 84: 1361-92.
Hartmann S, Schäper E, Lamprecht-Dinnesen A, Boos J	Ototoxizität von Cisplatin im Kindesalter.	Oto Rhino Laryng 1995, 222
Harbott J, Reinisch-Becker I, Ritterbach J, Creutzig U, Ludwig W, Gutjahr P, Borkhardt A, Lampert F	Karyotypic abnormalities in secondary leukemia of children.	Haematology and Blood Transfusion 1996, 38: 24
Harbott J, Viehmann S, Borkhardt A, Henze G, Lampert F	Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse.	Blood 1997, 90: 4933
Harms D, Jänig U, Göbel U	Pathology of germ cell tumors. Report of the Kiel pediatric tumor registry (KPTR).	Med Pediatr Oncol 1998, 31: 189
Harms D, Leuschner I, Krams M, Pilgrim T, Treuner J	Rhabdomyosarcoma and extraosseous Ewing's sarcoma.	Verh Dtsch Ges Pathol 1998, 82: 83
Harms D, Janka-Schaub G	Co-operative study group for childhood acute lymphoblastic leukemia (COALL).	Leukemia 2000, 14: 2234
Hartmann O, Berthold F	Treatment of advanced Neuroblastoma:the European Experience, in Brodeur G, M.; Sawada Y; Tsuchida Y; Voute,Pd (Hrsg.), Neuroblastoma.	Elsevier 2000, 437
Hartmann W, Waha A, Koch A, Goodyer C, Albrecht S, von Schweinitz D, Pietsch T	p57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2, and H19.	Am J Pathol 2000, 157: 1393
Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J	Lymphoma classification--from controversy to consensus: the R. E.A. L. and WHO Classification of lymphoid neoplasms.	Ann Oncol 2000, 11 Suppl 1: 3-10. Review.
Harms D, Göbel U, Spaar H, Graubner U, Jorch N, Gutjahr P, Janka-Schaub G	Thioguanine offers no advantage over mercaptopurine in maintenance treatment of childhood ALL.	Blood 2003, 102: 2736
Hartmann W, Küchler J, Koch A, Friedrichs N, Waha A, Endl E, Czerwitzki J, Metzger D, Steiner S, Wurst P, Leuschner I, von Schweinitz D, Buettner R, Pietsch T	Activation of phosphatidylinositol-3'-kinase/AKT signaling is essential in hepatoblastoma survival.	Clinical cancer research 2009, 15: 4538
PURPOSE: Hepatoblastoma represents the most frequent malignant liver tumor in childhood. The phosphatidylinositol-3'-kinase (PI3K)/AKT pathway is crucial in downstream signaling of multiple receptor tyrosine kinases of pathogenic importance in hepatoblastoma. Increased PI3K/AKT signaling pathway activity and activating mutations of PIK3CA, encoding a PI3K catalytic subunit, have been reported in different childhood tumors. The current study was done to analyze the role of PI3K/AKT signaling in hepatoblastoma. EXPERIMENTAL DESIGN: Immunohistochemical stainings of (Ser473)-phosphorylated (p)-AKT protein, its targets p-(Ser9)-GSK-3beta and p-(Ser2448)-mTOR, as well as the cell cycle regulators Cyclin D1, p27(KIP1), and p21(CIP1) were done and the PIK3CA gene was screened for mutations. In vitro, two hepatoblastoma cell lines treated with the PI3K inhibitor LY294002 were analyzed for AKT and GSK-3beta phosphorylation, cell proliferation, and apoptosis. Additionally, simultaneous treatments of hepatoblastoma with LY294002 and cytotoxic drugs were carried out. RESULTS: Most tumors strongly expressed p-AKT, p-GSK-3beta, and p-mTOR; subgroups showed significant Cyclin D1, p27(KIP1), and p21(CIP1) expression. One hepatoblastoma carried an E545A mutation in the PIK3CA gene. In vitro, PI3K inhibition diminished hepatoblastoma cell growth being accompanied by reduced AKT and GSK-3beta phosphorylation. Flow cytometry and 4', 6-diamidino-2-phenylindole stainings showed that PI3K pathway inhibition leads to a substantial increase in apoptosis and a decrease in cellular proliferation linked to reduced Cyclin D1 and increased p27(KIP1) levels. Simultaneous treatment of hepatoblastoma cell lines with LY294002 and cytotoxic drugs resulted in positive interactions. CONCLUSIONS: Our findings imply that PI3K signaling plays an essential role in growth control of hepatoblastoma and might be successfully targeted in multimodal therapeutic strategies.
Harrison CJ, Hills RK, Moorman AV, Grimwade DJ, Hann I, Webb DK, Wheatley K, de Graaf SS, van den Berg E, Burnett AK, Gibson BE	Cytogenetics of childhood acute myeloid leukemia: United Kingdom Medical Research Council Treatment trials AML 10 and 12.	Journal of clinical oncology 2010, 28: 2674
Karyotype is an independent indicator of prognosis in acute myeloid leukemia (AML) that is widely applied to risk-adapted therapy. Because AML is rare in children, the true prognostic significance of individual chromosomal abnormalities in this age group remains unclear.
Harigae H	Iron metabolism and related diseases: an overview.	International journal of hematology 2018, 107: 5
Hariharan N, Brunson A, Mahajan A, Keegan THM, Wun T	Bleeding in patients with sickle cell disease: a population-based study.	Blood advances 2020, 10; 4: 793
Bleeding is a known complication of sickle cell disease (SCD) and includes hemorrhagic stroke, hematuria, and vitreous hemorrhage. However, the incidence of bleeding events in patients with SCD has not been well described. We present a retrospective, population-based study examining the cumulative incidence of bleeding in 6423 patients with SCD from 1991 to 2014. We also studied risk factors associated with bleeding and the effects of bleeding on mortality, using Cox proportional hazards regression models. We used California emergency department and hospitalization databases to identify patients with SCD with intracranial hemorrhage, gastrointestinal (GI) bleeding, hemophthalmos, gross hematuria, epistaxis, menorrhagia, and other bleeding events. The cumulative incidence of any first bleeding event at age 40 years was 21% (95% confidence interval [CI], 19.8%-22.3%), increasing with age to 41% by age 60 years (95% CI, 38.8%-43.1%). The majority of bleeding events were GI (41.6%), particularly from the upper GI tract. A higher bleeding risk was associated with increased frequency of hospitalization (hazard ratio [HR], 2.16; 95% CI, 1.93-2.42), venous thromboembolism 180 days before bleeding event (HR, 4.24; 95% CI, 2.86-6.28), osteonecrosis of the femoral head (HR, 1.25; 95% CI, 1.08-1.46), and ischemic stroke (HR, 1.65; 95% CI, 1.20-2.26). Bleeding was also associated with a twofold increased risk for death (HR, 2.09; 95% CI, 1.82-2.41) adjusted for other SCD-related complications. Our novel finding of a high incidence of bleeding in patients with SCD, particularly from the upper GI tract, suggests that patients with SCD may be predisposed to bleeding, with possible etiologies including increased use of nonsteroidal anti-inflammatory drugs, mucosal infarction from vascular occlusion by sickled red blood cells, and increased stress ulceration from frequent hospitalization.
Hariz A, Priyanka T, Bhattacharya PT	Megaloblastic Anemia.	In: StatPearls [Internet]. Treasure Island (FL) StatPearls Publishing; 2020

Hasle H, Arico M, Basso G, Biondi A, Cantu Rajnoldi, Creutzig U, Fenu S, Fonatsch C, Haas O, Harbott J, Kardos G, Kerndrup G, Mann G, Niemeyer C, Ptoszkova H, Ritter J, Slater R, Stary J, Stollmann-Gibbels B, Testi A, van Wering E, Zimmermann M	Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS).	Leukemia 1999, 13: 376
Hasle H	Pattern of malignant disorders in individuals with Down's syndrome.	The Lancet. Oncology 2001, 2: 429
Hasle H, Niemeyer C, Chessells J, Baumann I, Bennett J, Kerndrup G, Head D	A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases.	Leukemia 2003, 17: 277
Hasle H, Niemeyer CM, Chessells JM, Baumann I, Bennett JM, Kerndrup G, Head DR	A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases.	Leukemia 2003, 17: 277
Myelodysplastic and myeloproliferative disorders are rare in childhood and there is no widely accepted system for their diagnosis and classification. We propose minimal diagnostic criteria and a simple classification scheme which, while based on accepted morphological features and conforming with the recent suggestions of the WHO, allows for the special problems of myelodysplastic diseases in children. The classification recognizes three major diagnostic groups: (1) juvenile myelomonocytic leukemia (JMML), previously named chronic myelomonocytic leukemia (CMML) or juvenile chronic myeloid leukemia (JCML); (2) myeloid leukemia of Down syndrome, a disease with distinct clinical and biological features, encompassing both MDS and AML occurring in Down syndrome; and (3) MDS occurring both de novo and as a complication of previous therapy or pre-existing bone marrow disorder (secondary MDS). The main subtypes of MDS are refractory cytopenia (RC) and refractory anemia with excess of blasts (RAEB). It is suggested retaining the subtype of RAEB-T with 20-30% blasts in the marrow until more data are available. Cytogenetics and serial assessments of the patients are essential adjuncts to morphology both in diagnosis and classification.
Hasle H, Baumann I, Bergstrasser E, Fenu S, Fischer A, Kardos G, Kerndrup G, Locatelli F, Rogge T, Schultz KR, Stary J, Trebo M, van den Heuvel-Eibrink MM, Harbott J, Nollke P, Niemeyer CM, European Working Group on childhood MDS	The International Prognostic Scoring System (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML).	Leukemia 2004, 18: 2008
The International Prognostic Scoring System (IPSS) for myelodysplastic syndrome (MDS) is based upon weighted data on bone marrow (BM) blast percentage, cytopenia, and cytogenetics, separating patients into four prognostic groups. We analyzed the value of the IPSS in 142 children with de novo MDS and 166 children with juvenile myelomonocytic leukemia (JMML) enrolled in retro- and prospective studies of the European Working Group on childhood MDS (EWOG-MDS). Survivals in MDS and JMML were analyzed separately. Among the criteria considered by the IPSS score, only BM blasts <5% and platelets >100 x 10(9)/l were significantly associated with a superior survival in MDS. In JMML, better survival was associated with platelets >40 x 10(9)/l, but not with any other IPSS factors including cytogenetics. In conclusion, the IPSS is of limited value in both pediatric MDS and JMML. The results reflect the differences between myelodysplastic and myeloproliferative diseases in children and adults.
Hasle H, Alonzo TA, Auvrignon A, Behar C, Chang M, Creutzig U, Fischer A, Forestier E, Fynn A, Haas OA, Harbott J, Harrison CJ, Heerema NA, van den Heuvel-Eibrink MM, Kaspers GJ, Locatelli F, Noellke P, Polychronopoulou S, Ravindranath Y, Razzouk B, Reinhardt D, Savva NN, Stark B, Suciu S, Tsukimoto I, Webb DK, Wojcik D, Woods WG, Zimmermann M, Niemeyer CM, Raimondi SC	Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: an international retrospective study.	Blood 2007, 109: 4641
Monosomy 7 (-7) and deletion 7q \del(7q)] are rare in childhood acute myeloid leukemia (AML). We retrospectively collected data on 258 children with AML or refractory anemia with excess blasts in transformation (RAEB-T) and -7 or del(7q) with or without other cytogenetic aberrations \+/- other]. Karyotypes included -7 (n = 90), -7 other (n = 82), del(7q) (n = 21), and del(7q) other (n = 65). Complete remission (CR) was achieved in fewer patients with -7 +/- other compared with del(7q) +/- other (61% versus 89%, P < .001). Overall, the 5-year survival rate was 39% (SE, 3%). Survival was superior in del(7q) +/- other compared with -7 +/- other (51% versus 30%, P < .01). Cytogenetic aberrations considered favorable in AML \t(8;21)(q22;q22), inv(16)(p13q22), t(15;17)(q22;q21), t(9;11)(p22;q23)] (n = 24) were strongly associated with del(7q) and a higher 5-year survival rate compared with del(7q) without favorable cytogenetics (75% versus 46%, P = .03). Patients with -7 and inv(3),-5/del(5q), or + 21 had a 5-year survival rate of 5%. Stem cell transplantation analyzed as a time-dependent variable had no impact on overall survival. However, patients not achieving CR had a 31% survival rate after stem cell transplantation. Childhood AML with chromosome 7 aberrations represents a heterogeneous group of disorders with additional cytogenetic aberrations having a major prognostic impact which should be reflected in future risk-group stratification.
Hasselblatt M, Mühlisch J, Wrede B, Kallinger B, Jeibmann A, Peters O, Kutluk T, Wolff JE, Paulus W, Frühwald MC	Aberrant MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation in choroid plexus tumors.	J Neurooncol 2009, 91: 151
Aberrant methylation of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene is a predictive marker for the response to chemotherapy with alkylating agents (e.g., temozolomide) in malignant gliomas. Since temozolomide is considered for the treatment of choroid plexus tumors, MGMT promoter methylation status was retrospectively assessed in 36 choroid plexus tumors using methylation specific PCR, combined bisulfite restriction analysis (COBRA), and clone sequencing. By methylation specific PCR, all samples demonstrated a signal for MGMT methylation. COBRA confirmed >10% methylation of CpGs 17 and 31 in 58% of tumors. Clone sequencing of six cases methylated by COBRA confirmed aberrant methylation including a previously recognized enhancer element. In conclusion, MGMT promoter methylation is frequent in choroid plexus tumors and can be quantified using COBRA. Determination of MGMT promoter methylation status might be useful for the stratification of patients for alkylator-based treatments in future clinical trials.
Hasle H, Niemeyer CM	Advances in the prognostication and management of advanced MDS in children.	Br J Haematol 2011, 154: 185
Advanced myelodysplastic syndrome (MDS) in children includes refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T) according to the paediatric modification of the World Health Organization classification. Clinical features and cytogenetics are essential to make a diagnosis because blast count alone is insufficient to differentiate MDS from acute myeloid leukaemia (AML). Little is known about molecular genetics in paediatric MDS but hypermethylation seem to be frequent. Monosomy 7 is the most common cytogenetic aberration but prognostic neutral whereas those with structural complex karyotype have a very poor outcome. Haematopoietic stem cell transplantation (HSCT) is the treatment of choice and results in cure rates of around 60%. Intensive chemotherapy prior to HSCT provides no survival benefit for children with RAEB and RAEB-T and can generally not be recommended. Intensive chemotherapy before HSCT should be considered in patients with myelodysplasia-related-AML (MDR-AML).
Hasselblatt M, Gesk S, Oyen F, Rossi S, Viscardi E, Giangaspero F, Giannini C, Judkins AR, Frühwald MC, Obser T, Schneppenheim R, Siebert R, Paulus W	Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression.	The American journal of surgical pathology 2011, 35: 933
Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive brain tumors of early childhood poorly responding to therapy. The majority of cases show inactivation of SMARCB1 (INI1, hSNF5, BAF47), a core member of the adenosine triphosphate (ATP)-dependent SWI/SNF chromatin-remodeling complex. We here report the case of a supratentorial AT/RT in a 9-month-old boy, which showed retained SMARCB1 staining on immunohistochemistry and lacked genetic alterations of SMARCB1. Instead, the tumor showed loss of protein expression of another SWI/SNF chromatin-remodeling complex member, the ATPase subunit SMARCA4 (BRG1) due to a homozygous SMARCA4 mutation [c.2032C>T (p.Q678X)]. Our findings highlight the role of SMARCA4 in the pathogenesis of SMARCB1-positive AT/RT and the usefulness of antibodies directed against SMARCA4 in this diagnostic setting.
Hashmi M, Wasay M	Caring for cerebral venous sinus thrombosis in children.	Journal of emergencies, trauma, and shock 2011, 4: 389
Hasenclever D, Kurch L, Mauz-Körholz C, Elsner A, Georgi T, Wallace H, Landman-Parker J, Moryl-Bujakowska A, Cepelová M, Karlén J,Álvarez Fernández-Teijeiro A, Attarbaschi A, Fosså A, Pears J, Hraskova A, Bergsträsser E, Beishuizen A, Uyttebroeck A, Schomerus E, Sabri O, Körholz D, Kluge R	qPET - a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma.	European journal of nuclear medicine and molecular imaging 2014, 41: 1301
Interim FDG-PET is used for treatment tailoring in lymphoma. Deauville response criteria consist of five ordinal categories based on visual comparison of residual tumor uptake to physiological reference uptakes. However, PET-response is a continuum and visual assessments can be distorted by optical illusions.
Hasselblatt M, Nagel I, Oyen F, Bartelheim K, Russell RB, Schüller U, Junckerstorff R, Rosenblum M, Alassiri AH, Rossi S, Schmid I, Gottardo NG, Toledano H, Viscardi E, Balbin M, Witkowski L, Lu Q, Betts MJ, Foulkes WD, Siebert R, Frühwald MC, Schneppenheim R	SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis.	Acta neuropathologica 2014, 128: 453
Hassler A, Bochennek K, Gilfert J, Perner C, Schöning S, Creutzig U, Reinhardt D, Lehrnbecher T	Infectious Complications in Children With Acute Myeloid Leukemia and Down Syndrome: Analysis of the Prospective Multicenter Trial AML-BFM 2004.	Pediatr Blood Cancer 2016, [Epub ahead of print]
BACKGROUND: Children with acute myeloid leukemia (AML) and Down syndrome have high survival rates with intensity-reduced chemotherapeutic regimens, although the optimal balance between dose intensity and treatment toxicity has not been determined. We, therefore, characterized infectious complications in children with AML and Down syndrome treated according to AML-BFM 2004 study (ClinicalTrials.gov NCT00111345; amended 2006 for Down syndrome with reduced intensity). PROCEDURE: Data on infectious complications were gathered from the medical records in the hospital where the patient was treated. Infectious complications were categorized as fever without identifiable source (FUO), or as microbiologically or clinically documented infections. RESULTS: A total of 157 infections occurred in 61 patients (60.5% FUO, 9.6% and 29.9% clinically and microbiologically documented infections, respectively). Almost 90% of the pathogens isolated from the bloodstream were Gram-positive bacteria, and approximately half of them were viridans group streptococci. All seven microbiologically documented episodes of pneumonia were caused by viruses. Infection-related mortality was 4.9%, and all three patients died due to viral infection. CONCLUSIONS: Our data demonstrate that a reduced-intensity chemotherapeutic regimen in children with AML and Down syndrome is still associated with high morbidity. Although no patient died due to bacteria or fungi, viruses were responsible for all lethal events. Future studies, therefore, have to focus on the impact of viruses on morbidity and mortality of patients with AML and Down syndrome.
Hasselblatt M, Thomas C, Hovestadt V, Schrimpf D, Johann P, Bens S, Oyen F, Peetz-Dienhart S, Crede Y, Wefers A, Vogel H, Riemenschneider MJ, Antonelli M, Giangaspero F, Bernardo MC, Giannini C, Ud Din N, Perry A, Keyvani K, van Landeghem F, Sumerauer D, Hauser P, Capper D, Korshunov A, Jones DT, Pfister SM, Schneppenheim R, Siebert R, Frühwald MC, Kool M	Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis.	Acta neuropathologica 2016, 132: 149
Hasle H	Myelodysplastic and myeloproliferative disorders of childhood.	Hematology. American Society of Hematology. Education Program 2016 Dec 2; 2016, 598
Myelodysplastic syndrome (MDS) and myeloproliferative disorders are rare in children; they are divided into low-grade MDS (refractory cytopenia of childhood [RCC]), advanced MDS (refractory anemia with excess blasts in transformation), and juvenile myelomonocytic leukemia (JMML), each with different characteristics and management strategies. Underlying genetic predisposition is recognized in an increasing number of patients. Germ line GATA2 mutation is found in 70% of adolescents with MDS and monosomy 7. It is challenging to distinguish RCC from aplastic anemia, inherited bone marrow failure, and reactive conditions. RCC is often hypoplastic and may respond to immunosuppressive therapy. In case of immunosuppressive therapy failure, hypercellular RCC, or RCC with monosomy 7, hematopoietic stem cell transplantation (HSCT) using reduced-intensity conditioning regimens is indicated. Almost all patients with refractory anemia with excess blasts are candidates for HSCT; children age 12 years or older have a higher risk of treatment-related death, and the conditioning regimens should be adjusted accordingly. Unraveling the genetics of JMML has demonstrated that JMML in patients with germ line PTPN11 and CBL mutations often regresses spontaneously, and therapy is seldom indicated. Conversely, patients with JMML and neurofibromatosis type 1, somatic PTPN11, KRAS, and most of those with NRAS mutations have a rapidly progressive disease, and early HSCT is indicated. The risk of relapse after HSCT is high, and prophylaxis for graft-versus-host disease and monitoring should be adapted to this risk.
Hasselblatt M, Johann PD, Kool M, Frühwald MC	Reduced histone H3 K27 trimethylation is encountered in about 50% of atypical teratoid/rhabdoid tumors (AT/RT) but is not associated with molecular subgroup status and outcome.	Acta neuropathologica 2017, 134: 817
Hastka J, Metzgeroth G, Gattermann N	Eisenmangel und Eisenmangelanämie.	Onkopedia Leitlinien Stand 2018, aufgerufen am 10.12.2020
Hasselblatt M, Thomas C, Nemes K, Monoranu CM, Riemenschneider MJ, Koch A, Sumerauer D, Hauser P, Paulus W, Johann PD, Kool M, Frühwald MC	Tyrosinase immunohistochemistry can be employed for the diagnosis of atypical teratoid/rhabdoid tumours of the tyrosinase subgroup (ATRT-TYR).	Neuropathology and applied neurobiology 2020, 46: 186
Hasselblatt M, Thomas C, Nemes K, Monoranu CM, Riemenschneider MJ, Koch A, Sumerauer D, Hauser P, Paulus W, Johann PD, Kool M, Frühwald MC	Tyrosinase immunohistochemistry can be employed for the diagnosis of atypical teratoid/rhabdoid tumours of the tyrosinase subgroup (ATRT-TYR).	Neuropathology and applied neurobiology 2020, 46: 186
No abstract available
Haupt R, Fears T, Heise A, Gadner H, Loiacono G, De Terlizzi M, Tucker M	Risk of secondary leukemia after treatment with etoposide (VP-16) for Langerhans' cell histiocytosis in Italian and Austrian-German populations.	Int J Cancer 1997, 71: 9
Haupt R, Spinetta JJ, Ban I, Barr RD, Beck JD, Byrne J, Calaminus G, Coenen E, Chesler M, D'Angio GJ, Eiser C, Feldges A, Gibson F, Lackner H, Masera G, Massimo L, Magyarosy E, Otten J, Reaman G, Valsecchi MG, Veerman AJ, Penn A, Thorvildsen A, van den Bos C, Jankovic M, International Berlin-Frankfurt-Münster Study Group Early and Late Toxicity Educational Committee (I-BFM-SG ELTEC)	Long term survivors of childhood cancer: cure and care. The Erice statement.	European journal of cancer (Oxford, England : 1990) 2007, 43: 1778
The number of subjects that have successfully completed treatment for a cancer diagnosed during childhood and are entering adulthood is increasing over time. Members of the International Berlin-Frankfurt-Munster (I-BFM) Early and Late Toxicity Educational Committee (ELTEC) invited 45 paediatric cancer experts (representing oncologists, psychologists, nurses, epidemiologists, parents, and survivors) from 13 European countries (with five additional experts from North America) to Erice, Sicily (from October 27 to 29, 2006) to discuss the circumstances in which the word 'cure' should be used when speaking about children with cancer, and when and why continuing follow-up and care may be required. The objective of the gathering was to generate from the personal and professional experience of the participants an overview statement of the group's philosophy of cure and care of survivors of childhood cancer. The ten points reflect what the group considers essential in the survivors' cure and care.
Hauffa BP, Scimic-Schleicher G	Pubertas tarda und Hypogonadismus.	Leitlinie der Deutschen Gesellschaft für Kinderheilkunde und Jugendmedizin AWMF online 2011
Haveman LM, Ranft A, Berg HVD, Klco-Brosius S, Ladenstein R, Paulussen M, Jürgens H, Dirksen U, Merks JHM	Primary and Metastatic Intracranial Ewing Sarcoma at Diagnosis: Retrospective International Study and Systematic Review.	Cancers 2020, 12
Intracranial Ewing sarcoma (EwS) is rare and publications on primary or metastatic intracranial EwS are minimal. The aim of this study was to describe incidence, clinical behavior, treatment, and factors associated with outcome in patients with primary intracranial EwS or patients with a primary extracranial EwS and cerebral metastases at diagnosis. We reviewed all patients with primary or with metastatic intracranial EwS at diagnosis registered in the International Clinical Trial Euro-E.W.I.N.G.99 (EE99). In total, 17 of 1435 patients (1.2%) presented with primary intracranial EwS; 3 of them had metastatic disease. Four patients (0.3%) with primary extracranial EwS presented with intracranial metastatic lesions. The 3-year event-free survival (EFS) was 64% and overall survival (OS) was 70% in patients with a primary intracranial EwS. Local control in patients with primary intracranial EwS consisted of surgery (6%), radiotherapy (RT) (18%), or both modalities (76%). Univariate analysis showed that patients < 15 years of age had significantly better outcome (EFS: 72%; OS: 76%) compared to those aged above 15 years (EFS: 13%; OS: 25%). In conclusion, primary intracranial EwS and extracranial EwS with cerebral metastases at diagnosis is rare, yet survival is comparable with local and metastatic EwS elsewhere in the body. Age and stage of disease are important prognostic factors. Besides chemotherapeutic treatment, local control with surgical resection combined with RT is recommended whenever feasible.
Hawkins DS, Schuetze SM, Butrynski JE, Rajendran JG, Vernon CB, Conrad EU 3rd, Eary JF	[18F]Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2005, 23: 8828
Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, LÃ³pez JA, Chen J, Chung D, Harju-Baker S, Cherian S, Chen X, Riddell SR, Maloney DG, Turtle CJ	Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy.	Blood 2017, 130: 2295
Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor-modified (CAR) T cells has produced impressive antitumor responses in patients with refractory CD19 B-cell malignancies but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation of and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR T cells. CRS developed in 70% of patients, including 62.5% with grade 1 to 3 CRS (grade 1, 26%; grade 2, 32%; grade 3, 4.5%), 3.8% with grade 4, and 3.8% with grade 5. A majority of cases of grade Ã¢ÂÂ¥4 CRS occurred during CAR T-cell dose finding. Multivariable analysis of baseline characteristics identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8 central memory T cells as independent predictors of CRS. Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. Angiopoietin-2 and von Willebrand factor, which are biomarkers of endothelial activation, were increased during severe CRS and also before lymphodepletion in patients who subsequently developed CRS. We describe a classification-tree algorithm to guide studies of early intervention after CAR T-cell infusion for patients at high risk of severe CRS. These data provide a framework for early intervention studies to facilitate safer application of effective CD19 CAR T-cell therapy.
Hebart H, Lang P, Woessmann W	Nivolumab for Refractory Anaplastic Large Cell Lymphoma: A Case Report.	Annals of internal medicine 2016, 165: 607
Hechler T, Chalkiadis GA, Hasan C, Kosfelder J, Meyerhoff U, Vocks S, Zernikow B	Sex differences in pain intensity in adolescents suffering from cancer: differences in pain memories?	The journal of pain 2009, 10: 586
Although sex differences have been investigated in chronic pain populations, little is known about sex differences in the pain experience of paediatric oncology patients and also whether their parents rate the pain experience differently for boys and girls. The aim of the present study was to determine if (1) boys and girls with cancer differ in current perception and past recollection of cancer-related pain and (2) if adolescents' and parents' pain ratings differ in relation to the sex of the adolescent. One hundred twelve adolescents with malignant diagnoses (12 to 18 years) and their parents participated in the study. Girls reported higher pain intensity within the last 7 days and 4 weeks despite similar diagnosis, physical status, duration of diagnoses, and main pain causes. When asked for pain intensity that dated back in time, parent and adolescent ratings diverged, with a trend for parents to reporting higher pain intensity in boys and lower pain intensity in girls, particularly for pain in the preceding 7 days. The present study provides preliminary evidence for sex differences in the recalled pain experience of adolescents with malignant diagnoses. Although boys and girls experience present pain similarly and hence should be treated similarly, girls recall higher pain intensity than boys. Future studies should address whether negative memories in girls play a significant role and may have an impact on girls' well-being and pain-related distress. Additionally, psychosocial factors such as gender role expectations may need to be investigated. Parental variables and their impact on parents' pain ratings, especially for ratings of precedent pain, warrants further investigation.
Hedborg F, Franklin G, Norrman J, Grimelius L, Wassberg E, Hero B, Schilling F, Berthold F, Harms D, Sandstedt B	Evidence of chromaffin oxygen sensing in neuroblastoma.	Med Pediatr Oncol 2001, 36: 149
Hedborg F, Ulleras E, Grimelius L, Wassberg E, Maxwell P, Hero B, Berthold F, Schilling F, Harms D, Sandstedt B, Franklin G	Evidence for hypoxia-induced neuronal-to-chromaffin metaplasia in neuroblastoma.	FASEB J 2003, 17: 598
Heerema N, Harbott J, Galimberti S, Camitta B, Gaynon P, Janka-Schaub G, Kamps W, Basso G, Pui C, Schrappe M, Auclerc M, Carroll A, Conter V, Harrison C, Pullen J, Raimondi S, Richards S, Riehm H, Sather H, Shuster J, Silverman L, Valsecchi M, Arico M	Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome.	Leukemia 2004, 18: 693
Heger S, Paetow U	S1-Leitlinie – Pubertas praecox: Leitlinie der Deutschen Gesellschaft für Kinderendokrinologie und -diabetologie (DGKED) e. V.	AWMF online 2019
Heinsohn S, Scholz R, Weber B, Wittenstein B, Werner M, Delling G, Kempf-Bielack B, Setlak P, Bielack S, Kabisch H	SV40 sequences in human osteosarcoma of German origin.	Anticancer Res 2000, 20: 4539
Heimpel H, Anselstetter V, Chrobak L, Denecke J, Einsiedler B, Gallmeier K, Griesshammer A, Marquardt T, Janka-Schaub G, Kron M, Kohne E	Congenital dyserythropoietic anemia type II: epidemiology, clinical appearance, and prognosis based on long-term observation.	Blood 2003, 102: 4576
Congenital dyserythropoietic anemia type II (CDA II) is the most frequent type of congenital dyserythropoietic anemia. More than 200 cases have been described, but with the exception of a report by the International CDA II Registry, these reports include only small numbers of cases and no data on the lifetime evolution of the disease. Since 1967, we were able to follow 48 cases of CDA II from 43 families for up to 35 years. All patients exhibit chronic anemia of variable severity requiring regular red cell transfusions only in a minority of children; 60% developed gallstones before the age of 30 years, and 16 patients had cholecystectomy between 8 and 34 years of age. Iron overload was a frequent complication. In 16 cases, iron depletion started between 7 and 36 years. Three patients died from secondary hemochromatosis. Splenectomy, performed in 22 cases, led to moderate increases in hemoglobin values and eliminated the need for transfusions but did not prevent further iron loading. The current recommendation is to consider splenectomy if the anemia compromises patients' performance, and to manage iron overload according to the guidelines derived from patients with thalassemia.
Heimpel H	Congenital dyserythropoietic anemias: epidemiology, clinical significance, and progress in understanding their pathogenesis.	Annals of hematology 2004, 83: 613
The congenital dyserythropoietic anemias (CDAs) comprise a group of rare hereditary disorders of erythropoiesis, characterized by ineffective erythropoiesis as the predominant mechanism of anemia and by distinct morphological abnormalities of the majority of erythroblasts in the bone marrow. The classification in three types as proposed in 1968 is still valid, but there is genetic heterogeneity within each type, and there are additional variants of unknown genetic basis. CDA II is the most frequent, and the nonfamilial type of CDA III the rarest group. The genes of CDA II and CDA III were mapped to chromosome 20 and 15, respectively, and the gene of CDA I on 15q was recently cloned. Therapeutic decision making requires definition of the type, an estimate of individual severity, and presence of or risk for complications. Therapeutic measures include interferon-alpha for CDA I, splenectomy for CDA II, and iron depletion for all individuals at risk for secondary hemochromatosis.
Heimpel H, Iolascon, A	Congenical dyserythropoietic anemias.	In: Beaument C, Beris, Ph, Beuzard, Y, Brugnara, C editors, ESH Handbook on Disorders of Erythropoiesis, Erythrocytes and Iron Metabolism 2009, 2nd edition, p178
Heinemann M, Ranft A, Jürgens H, Langer T, Vieth V, Timmermann B, Weckesser M, Dirksen U, Stegger L	Ewing sarcoma during follow-up.	Nuklearmedizin. Nuclear medicine 2017, 56: 233
To evaluate the performance of a prospectively defined follow-up imaging protocol that includes FDG-PET(/CT) to detect tumour recurrence in Ewing sarcoma (EwS) before becoming symptomatic.
Heinks K, Boekhoff S, Hoffmann A, Warmuth-Metz M, Eveslage M, Peng J, Calaminus G, Müller HL	Quality of life and growth after childhood craniopharyngioma: results of the multinational trialÂ KRANIOPHARYNGEOM 2007.	Endocrine 2018, 59: 364
Quality of life (QoL) after childhood-onset craniopharyngioma (CP) is frequently impaired due to tumor and/or treatment-related factors such as endocrine deficits and hypothalamic involvement/lesions.
Heinemann M, Ranft A, Langer T, Jürgens H, Kreyer J, Vieth V, Schäfers M, Weckesser M, Simon T, Hassenpflug W, Corbacioglu S, Bielack S, Mayer-Steinacker R, Kühne T, van den Berg H, Gelderblom H, Bauer S, Stegger L, Dirksen U	Recurrence of Ewing sarcoma: Is detection by imaging follow-up protocol associated with survival advantage?	Pediatric blood & cancer 2018, 65:e27011
The Cooperative Ewing Sarcoma Study and the Late Effects Surveillance System of the Society for Paediatric Oncology and Haematology recommend a structured follow-up imaging protocol (FUIP) for patients with Ewing sarcoma (EwS) with decreasing frequency of imaging over the first 5 years. The present study aims to assess the effectiveness of the FUIP for EwS patients regarding survival after relapse.
Heidelberg University Hospital	Protonentherapie und Schwerionentherapie – hochpräzise Behandlung gegen Krebs.	Webseite des Heidelberg University Hospital aufgerufen am 23.05.2019
Heinks K, De Schutter-NÃ¼sse C, Boekhoff S, Bogusz A, Zhu J, Peng J, MÃ¼ller HL	Periostin concentrations in childhood-onset craniopharyngioma patients.	Journal of endocrinological investigation 2019, 42: 815
Periostin is highly expressed in craniopharyngioma (CP)-associated fibroblasts and has been identified as a marker for non-alcoholic fatty liver disease (NAFLD). Half of CP patients with hypothalamic syndrome develop NAFLD. We hypothesized that periostin concentration is elevated in biological fluids of CP and associated with pathological hepatic parameters, indicating increased risk for NAFLD.
Heinemann M, Hoffmann C, Hardes J, Guder W, Streitbürger A, Götte M, Welz TL, Jürgens H, Ranft A, Vieth V, Weckesser M, Schäfers M, Stegger L, Dirksen U	Pain in survivors of Ewing sarcoma: Prevalence, associated factors and prediction of recurrence.	Pediatric blood & cancer 2021, 68:e28801
While the prognosis of patients with Ewing sarcoma (EwS) is improving, little is known about the frequency of pain and its risk factors in survivors of EwS. This study aims to analyse the prevalence and risk factors of pain and its predictive value for recurrence.
Hellenbrecht A	Kinderwunsch und Hormonhaushalt.	WIR 2005, 1
Hempel L, Kremens B, Weirich A, Graf N, Zintl F, Ludwig R	High dose consolidation with autologous stem cell rescue (ASCR) for nephroblastoma initially treated according to the SIOP 9/GPOH trial and study.	Klin Pädiatr 1996, 208: 186
Hempel G, Reinhardt D, Creutzig U, Boos J	Population pharmacokinetics of liposomal daunorubicin in children.	Br J Clin Pharmacol 2003, 56: 370
Hempel L, Sauerbrey A, Zintl F, Weirich A, Lemmer A, Graf N	Successful management of a child with clear cell sarcoma of the kidney (CCSK) and multifocal bone metastases at diagnosis.	Med Pediatr Oncol 2003, 41: 97
Hempel G, Müller HJ, Lanvers-Kaminsky C, Würthwein G, Hoppe A, Boos J	A population pharmacokinetic model for pegylated-asparaginase in children.	British journal of haematology 2010, 148: 119
We analysed 1221 serum activity measurements in 168 children from the Berlin-Frankfürt-Münster acute lymphoblastic leukaemia studies, ALL-BFM (Berlin-Frankfürt-Münster) 95 and ALL-BFM REZ, in order to develop a pharmacokinetic model describing the activity-time course of pegylated (PEG)-asparaginase for all dose levels. Patients received 500, 750, 1000 or 2500 U/m(2) PEG-asparaginase on up to nine occasions. Serum samples were analysed for asparaginase activity and data analysis was done using nonlinear mixed effects modelling (NONMEM Vers. VI, Globomax, Hanouet, MD, USA). Different linear and nonlinear models were tested. The best model applicable to all dosing groups was a one-compartmental model with clearance (Cl) increasing with time according to the formula: Cl=Cl(i) e((0.0793 t)) where Cl(i) = initial clearance and t = time after dose. The parameters found were: volume of distribution (V) 1.02 +/- 26% l/m(2), Cl(i) 59.9 +/- 59% ml/d per m(2) (mean +/- interindividual variability). Interoccasion variability was substantial with 0.183 l/m(2) for V and 44.7 ml/d per m(2) for Cl, respectively. A subgroup of the patients showed a high clearance, probably due to the development of inactivating antibodies. This is the first model able to predict the activity-time course of PEG-asparaginase at different dosing levels and can therefore be used for developing new dosing regimens.
Henter JI, Elinder G, Ost A	Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society.	Seminars in oncology 1991, 18: 29
Henze G, Fengler R, Hartmann R	Chemotherapy for relapsed childhood acute lymphoblastic leukemia.	Haematol Blood Transfus 1994, 36: 374
Henze G, Hartmann R, Fengler R	Salvage therapy of childhood ALL.	Haematol Blood Transfus 1995, 223
Henze G Agthe AG, Neuendank A, Hartmann R, Dörffel W, Brühmüller S, Klumper E, Pieters R, Veerman AJ	Tailored therapy for relapsed or refractory childhood acute lymphoblastic leukaemia.	Leukemia 1995, 9 : 538
Henze G	Autologe Knochenmarktransplantation versus Chemotherapie bei Kindern mit akuter lymphoblastischer Leukämie in zweiter Remission.	Deutsches Ärzteblatt 1996, 93: 935
Henter J, Arico M, Egeler R, Elinder G, Favara B, Filipovich A, Gadner H, Imashuku S, Janka-Schaub G, Komp D, Ladisch S, Webb D	HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society.	Med Pediatr Oncol 1997, 28: 342
Henze G	Chemotherapy for relapsed childhood acute lymphoblastic leukemia.	Int J Pediatr Hematol Oncol 1998, 5: 199
Henze G, Borgmann A, Stackelberg A, Baumgarten E, Uchanska-Ziegler B, Ziegler A, Wittig B	Immunotherapy of acute lymphoblastic leukemia by vaccination with autologoues leukemic cells transfected with a cDNA expression plasmid coding for an allogeneic HLA class I antigen combined with interleukin-2 treatment.	J Mol Med 1998, 76: 215
Hense H, Ahrens S, Paulussen M, Lehnert M, Jürgens H	Factors associated with tumor volume and primary metastases in Ewing tumors.	Ann Oncol 1999, 10: 1073
Hense H, Ahrens S, Paulussen M, Lehnert M, Jürgens H	Descriptive epidemiology of Ewing's tumor--analysis of German patients from (EI)CESS 1980-1997.	Klin Pädiatr 1999, 211: 271
Henze G	Leukämien.	In:Gutjahr, P , Krebs bei Kindern und Jugendlichen Deutscher Ärzte-Verlag, Köln, 4 Auflage 1999, 240
Henze G, Herold R, Creutzig U	Kompetenznetz Pädiatrische Onkologie und Hämatologie nach der ersten Förderperiode - zukünftige Pläne.	Monatsschrift für Kinderheilkunde 2002, 150
Henter JI, Samuelsson-Horne A, Aricò M, Egeler RM, Elinder G, Filipovich AH, Gadner H, Imashuku S, Komp D, Ladisch S, Webb D, Janka G, Histocyte Society	Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation.	Blood 2002, 100: 2367
Hemophagocytic lymphohistiocytosis (HLH) comprises familial (primary) hemophagocytic lymphohistiocytosis (FHL) and secondary HLH (SHLH), both clinically characterized by fever, hepatosplenomegaly, and cytopenia. FHL, an autosomal recessive disease invariably fatal when untreated, is associated with defective triggering of apoptosis and reduced cytotoxic activity, resulting in a widespread accumulation of T lymphocytes and activated macrophages. In 1994 the Histiocyte Society initiated a prospective international collaborative therapeutic study (HLH-94), aiming at improved survival. It combined chemotherapy and immunotherapy (etoposide, corticosteroids, cyclosporin A, and, in selected patients, intrathecal methotrexate), followed by bone marrow transplantation (BMT) in persistent, recurring, and/or familial disease. Between July 1, 1994, and June 30, 1998, 113 eligible patients aged no more than 15 years from 21 countries started HLH-94. All had either an affected sibling (n = 25) and/or fulfilled the Histiocyte Society diagnostic criteria. At a median follow-up of 3.1 years, the estimated 3-year probability of survival overall was 55% (95% confidence interval +/- 9%), and in the familial cases, 51% (+/- 20%). Twenty enrolled children were alive and off therapy for more than 12 months without BMT. For patients who received transplants (n = 65), died prior to BMT (n = 25), or were still on therapy (n = 3), the 3-year survival was 45% (+/- 10%). The 3-year probability of survival after BMT was 62% (+/- 12%). HLH-94 is very effective, allowing BMT in most patients. Survival of children with HLH has been greatly improved.
Henze G	Kryokonservierung von Nabelschnurstammzellen bei Neugeborenen zur eventuellen späteren Eigennutzung.	Die Mitteilungen von GPOH und KPOH 2003, 1: 7
Henze G	Leukämien, in Gutjahr P: Krebs bei Kindern und Jugendlichen.	Deutscher Ärzte-Verlag Köln 5. Aufl. 2004, 293
Henze G	20 Jahre Studien zur Behandlung von Kindern mit Rezidiv einer akuten lymphoblastischen Leukämie (ALL-REZ BFM).	WIR Informationsschrift der Aktion für krebskranke Kinder e.V. (Bonn) 2004, 3: 13
Henze G	Maligne Non-Hodgkin-Lymphome, in Gutjahr P: Krebs bei Kindern und Jugendlichen.	Deutscher Ärzte-Verlag Köln 5. Aufl. 2004, 328
Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G	HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.	Pediatric blood & cancer 2007, 48: 124
In HLH-94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease. In order to hopefully further improve diagnosis, therapy and biological understanding, participation in HLH studies is encouraged.
Hennes E, Zahn S, Lopes LF, Schönberger S, Leuschner I, Göbel U, Calaminus G, Schneider DT	Molecular genetic analysis of bilateral ovarian germ cell tumors.	Klinische Padiatrie 2012, 224: 359
Ovarian germ cell tumors (oGCTs) are rare and highly heterogeneous with regard to their clinical and histologic appearance. The risk of tumor development is higher in children with aberrant sexual differentiation. Development of gonadoblastomas is seen in young women with 46,XY gonadal dysgenesis. At least 50 % of gonadoblastomas may develop into malignant oGCTs, mostly dysgerminomas. In this study, we evaluated bilateral oGCTs in clinically inapparent patients for sex chromosomal aberrations.
Henrichs M-P, Hardes J, Jürgens H	Maligne Knochentumoren.	in: Solide Tumoren im Kindesalter. Fuchs J (Hrsg.), Schattauer GmbH Stuttgart 2012, 330
Henze G, v Stackelberg A, Eckert C	ALL-REZ BFM--the consecutive trials for children with relapsed acute lymphoblastic leukemia.	Klinische Padiatrie 2013, 225 Suppl 1:S73
The BFM studies for relapsed childhood acute lymphoblastic leukemia (ALL) were started in 1983, at a time when cure rates for ALL were still lower and the number of children with ALL relapse equaled about the number of children with newly diagnosed neuroblastoma. Today, relapses have become relatively rare events in ALL although, because of the frequency of ALL, they are still a significant cause of death in children and adolescents. With currently used treatment modalities, cure rates of about 50% after relapse can be achieved, and, together with the improved results of front-line therapy, the survival rate of childhood ALL is now about 90%. Most children with extramedullary and late bone marrow (BM) relapses achieve a second CR; remission rates in patients with high-risk features, however, remain still unsatisfactory. With improved techniques allogeneic hematopoietic stem cell transplant (HSCT) has become a relatively safe treatment but is not necessary for all patients as postremission therapy. HSCT is not required in children with isolated extramedullary and late BM relapses with rapid response to induction therapy measured by molecular techniques (minimal residual disease, MRD) but absolutely indicated in patients with early BM relapses and systemic relapses of T-cell ALL. For patients with insufficient response innovative therapies such as small molecules or targeted immunological or pharmacological approaches are urgently required. Efforts have to be made, therefore, in order to detect potential biological or molecular targets, which can be used for individualized, more effective and hopefully less toxic therapies in the future.
Hennewig U, Kaatsch P, Blettner M, Spix C	Local radiation dose and solid second malignant neoplasms after childhood cancer in Germany: a nested case-control study.	Radiation and environmental biophysics 2014, 53: 485
Radiotherapy (RT) has been associated with the development of solid second malignant neoplasms (SMNs) in childhood cancer survivors. The aim of this study was to analyse the effect of cumulative doses of previous RT received at the SMN body region, at all other body regions and at body regions adjacent to the SMN, on the risk of developing a solid SMN. A total of 190 cases diagnosed with a solid second malignant neoplasm in 1980-2002 were matched with 368 controls with single neoplasm from the database of the German Childhood Cancer Registry (GCCR) (33,809 patients at cut-off date). The GCCR registers approximately 97 % of all childhood malignancies which occur at an age of less than 15 years in Germany since 1980. It was found that 147 (77.4 %) cases had received RT compared to 208 (56.6 %) controls with cumulative focus doses from 8 to 110 Gy. Fifty per cent of the SMNs and 60 % of RT affected the head region. RT was shown to increase the risk of a solid second tumour within the body region of radiation by 5.3 % per Gy (odds ratio 1.053; 95 % confidence interval 1.036-1.071). With increasing age at diagnosis and with more recent treatment eras, this effect decreased. Cumulative RT doses received at all other body regions or only at body regions adjacent to the SMN did not show an additional effect on the risk of developing an SMN. It is thus concluded that RT is the main risk factor for the development of SMNs within the irradiated body region. Late effects surveillance of former patients should give special attention to the originally irradiated parts of the body.
Henry ER, Metaferia B, Li Q, Harper J, Best RB, Glass KE, Cellmer T, Dunkelberger EB, Conrey A, Thein SL, Bunn HF, Eaton WA	Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin.	Blood 2021, Online ahead of print
The issue of treating sickle cell disease with drugs that increase hemoglobin oxygen affinity has come to the fore with the FDA approval in 2019 of voxelotor, the only anti-sickling drug approved since hydroxyurea in 1998. Voxelotor reduces sickling by increasing the concentration of the non-polymerizing, high oxygen affinity R (oxy) conformation of HbS. Treatment of sickle cell patients with voxelotor increases Hb levels and decreases indicators of hemolysis, but with no indication as yet that it reduces the frequency of pain episodes. Here we use the allosteric model of Monod, Wyman, and Changeux to simulate whole blood oxygen dissociation curves and red cell sickling in the absence and presence of voxelotor under the in vivo conditions of rapid oxygen pressure decreases. Our modeling agrees with experiments using a new robust assay, which shows the very large, expected decrease in sickling from the drug. The modeling indicates, however, that the increase in oxygen delivery from reduced sickling is largely offset by the increase in oxygen affinity. The net result is that the drug increases overall oxygen delivery only at the very lowest oxygen pressures. Reduction of sickling does, however, mitigate against red cell damage and explains the observed decrease in hemolysis. More importantly, our modeling of in vivo oxygen dissociation, sickling, and oxygen delivery suggests that drugs that increase fetal hemoglobin or decrease MCHC, should be more therapeutically effective than drugs that increase oxygen affinity.
Hero B, Holschneider A, Berthold F	Risk and benefits of surgical interventions in localized neuroblastoma--experiences from cooperative studies in Germany.	Langenbecks Arch Chir Suppl Kongressbd 1996, 113: 1062
Hertzberg H, Langer T	Probleme der Chemotherapie im Kindesalter.	mta 1996, 796
Hero B, Kremens B, Klingebiel T, Bender-Gotze C, Burdach S, Schrappe M, Berthold F	Does megatherapy contribute to survival in metastatic neuroblastoma?	Klin Pädiatr 1997, 209: 196
Hertzberg H, Huk W, Überall M, Langer T, Meier W, Dopfer R, Skalej M, Lackner H, Bode U, Janssen G, Zintl F, Beck J	CNS late effects after ALL therapy in childhood. Part I	Med Pediatr Oncol 1997, 28: 387
Herold R, Creutzig U, Henze G	Kompetenznetz Pädiatrische Onkologie und Hämatologie.	humboldt spektrum 1999, 4: 4
Herold R, Creutzig U, Henze G	Kompetenznetz Pädiatrische Onkologie und Hämatologie.	InFoOnkologie 1999, 5: 292
Hero B, Berthold F	Neuroblastoma.	Leitlinien Kinderheilkunde und Jugendmedizin, D Reinhardt (Hrsg ), Urban & Fischer 2000, 1
Hero B, Simon T, Horz S, Berthold F	Metastatic neuroblastoma in infancy.	Med Pediatr Oncol 2000, 35: 683
Hero B, Hunneman D, Gahr M, Berthold F	Evaluation of catecholamine metabolites, mIBG scan, and bone marrow cytology as response markers in stage 4 neuroblastoma.	Med Pediatr Oncol 2001, 36: 220
Herold R, Henze G, Creutzig U	Kompetenznetz Pädiatrische Onkologie und Hämatologie.	Lebendige Wissenschaft - Medizin 2001,alpha Verlag Lampertheim
Herold Ralf, Creutzig Ursula, Pommerening Klaus	Use of an internet based knowledge Server for the Medical Research Network Pediatric Oncology and Hematology.	Onkologie 2001, 24: 169
Hertzberg H, Kremens B, Velten I, Beck JD, Greil J	Recurrent disseminated retinoblastoma in a 7-year-old girl treated successfully by high-dose chemotherapy and CD34-selected autologous peripheral blood stem cell transplantation.	Bone marrow transplantation 2001, 27: 653
A localized retinoblastoma of the left eye in a 7-year-old girl, was treated by enucleation. She received no additional therapy. Four months later, metastases of retinoblastoma in the lymph nodes, bone and bone marrow were diagnosed. Relapse chemotherapy consisting of three courses of vincristine, cyclophosphamide, etoposide and carboplatin led to a second complete remission. Subsequent high-dose chemotherapy with thiotepa, etoposide and carboplatin and autologous stem cell transplantation with CD34-selected stem cells were successful, with no adverse effects. No radiotherapy was given and the girl remains in continuous second remission with a follow-up of more than 4 years.
Hero B, Berthold F	Neuroblastom.	Monatschr Kinderheilkd 2002, 150: 775
Hero B, Graf N, Simon T, Weirich A, Troger J, Berthold F	Neuroblastoma preoperatively treated as nephroblastoma.	Klin Pädiatr 2002, 214: 157
Herold R, Berthold F	Erfahrungen und praktische Regeln beim Kodieren von Diagnosen und Prozeduren in der Pädiatrischen Onkologie und Hämatologie [Abstract].	Monatsschrift für Kinderheilkunde 2002, 150
Herold R, Grieámeier B, Tallen G, Henze G	Nicht mehr krank, doch gesund noch lange nicht - Zur Situation von krebskranken Kindern und Jugendlichen.	Forum Public Health 2002, 10: 13
Herold R, Stibenz D, Hartmann R, Henze G, Bührer C	Soluble l-selectin (sCD62L) in relapsed childhood acute lymphoblastic leukaemia.	Br J Haematol 2002, 119: 677
Herold R, Tallen G, Creutzig U	Neuer Informationsserver im Internet für Betroffene, Fachleute und Laien der Pädiatrischen Onkologie und Hämatologie.	Monatsschrift für Kinderheilkunde 2002, 150
Herold R, Zimmermann M	Konzepte und Perspektiven der elektronischen Unterstützung für die Medizinische Dokumentation in der Pädiatrischen Onkologie und Hämatologie [Abstract].	Monatsschrift für Kinderheilkunde 2002, 150
Herold R, Von Stackelberg A, Hartmann R, Eisenreich B, Henze G	Acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) experience.	J Clin Oncol 2004, 22: 569
Hero B, Berthold F	Neuroblastoma.	In: D. Reinhard (Hrsg.), Leitlinien Kinderheilkunde und Jugendmedizin Urban & Fischer, 2005, L5 1
Hering A, Michel S, Ernst G, Claussen U, Kloetzer Ch, Parlowsky T, Bucsky P, Loncarevic IF	Characteristic chromosomal imbalances in pediatric pheochromocytoma.	Genes Chromosomes and Cancer (accepted paper)
Hero B, Berthold F	Neuroblastome.	Interdisziplinäre Leitlinie der Deutschen Krebsgesellschaft und der Deutschen Gesellschaft für Pädiatrische Onkologie und Hämatologie 2005
Herold R, Reiche R, Creutzig U, Henze G	[Assessment of staffing and infrastructures of paediatric oncology and haematology centres in Germany].	Klinische Padiatrie 2007, 219: 380
BACKGROUND AND METHODS: At the end of 2003, the Competence Network Paediatric Oncology and Haematology conducted a survey of paediatric oncology centres in Germany as one of its measures to support and advance the collaboration of paediatric oncology centres and trials in science and health care. There was a lack of key figures to describe their combined position in the health care system. The survey aimed to quantify existing structures in terms of personnel, facilities, and patients as well as to collect preliminary information on patterns of care and on quality assurance. Starting with the largest patient numbers, 53 German centres were included, which cared for at least 10 patients under the age of 15 years with a newly diagnosed malignant disease per year. MAIN RESULTS: 49 (92%) centres contributed to the survey. 40 centres cared for a total of 1712 patients under the age of 15 years with a first occurrence of a malignant disease, which corresponds to 83% of all such patients registered in the German Childhood Cancer Registry in 2003. The total number of patients cared for in these centers, which also includes those with a relapse and the above 15-year olds, exceeds the Registry numbers by about 50%. The survey's outcome on staffing revealed about two work positions per bed (in-patient or day-clinic). A significant part of this personnel is financed by third-party funds. On average, the centres responding to the survey were equipped with 7 physician, 21 nursing and 4,4 psychologist, social worker, medical documentarist, and secretariat posts to care for a mean of 54 patients or 18 in-patient beds. Including those working positions financed by third-party funds, the majority of centres scored staffing as good or excellent. Yet, one out of ten centres scored the staffing of one or more occupational groups as poor. CONCLUSIONS: The survey provided for the first time a national assessment of the variable levels of staffing and facilities in the most relevant German paediatric oncology centres. The data indicate that the relationship between several key figures such as the Registry patient subset's numbers and in-patient bed numbers, for example, is weak, whereas physician post numbers, for example, correlate reasonably well with actual patient numbers. Further data include the variety of special health care offered and preliminary provisions for quality assurance per centre. According to a comparison with a seminal publication on needs in German paediatric oncology health care published in 1991 and with a needs survey of the UK National Institute for Health and Clinical Excellence (NICE), there seems to be an insufficient response to the needs, which is undermined by the centres survey responses. In view of the DRG reimbursement system being introduced throughout German health care, future surveys should also focus on key figures related to the DRG system such as case numbers, but such data should be merged with patient data in order to maintain a perspective on the course of health care provision to children and young adults with cancer.
Hero B, Simon T, Spitz R, Ernestus K, Gnekow AK, Scheel-Walter HG, Schwabe D, Schilling FH, Benz-Bohm G, Berthold F	Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97.	Journal of clinical oncology 2008, 26: 1504
PURPOSE: The excellent prognosis of localized neuroblastoma in infants, the overdiagnosis observed in neuroblastoma screening studies, and several case reports of regression of localized neuroblastoma prompted us to initiate a prospective cooperative trial on observation of localized neuroblastoma without cytotoxic treatment. PATIENTS AND METHODS: For infants with localized neuroblastoma without MYCN amplification, chemotherapy was scheduled only in cases with threatening symptoms; otherwise, the tumor was either resected or observed by ultrasound and magnetic resonance imaging (MRI). RESULTS: Of 340 eligible participants, 190 underwent resection, 57 were treated with chemotherapy, and 93 were observed with gross residual tumor. Of those 93 patients with unresected tumors, spontaneous regression was seen in 44, local progression in 28, progression to stage 4S in seven, and progression to stage 4 in four. Time to regression was quite variable, with first signs of regression noted 1 to 18 months after diagnosis and in 15 of 44 patients even after the first year of life. So far, complete regression was observed in 17 of 44 patients 4 to 20 months after diagnosis. Known clinical risk factors were not able to differentiate between patients with regression and regional or metastatic progression. Overall survival (OS; 3-year OS, 0.99 +/- 0.01) and metastases-free survival (rate at 3 years, 0.94 +/- 0.03) for patients with unresected tumors was excellent and was not different from patients treated with surgery or chemotherapy. CONCLUSION: Spontaneous regression is regularly seen in infants with localized neuroblastoma and is not limited to the first year of life. A wait-and-see strategy is justified in those patients.
Hernáiz Driever P, von Hornstein S, Pietsch T, Kortmann R, Warmuth-Metz M, Emser A, Gnekow AK	Natural history and management of low-grade glioma in NF-1 children.	J Neurooncol 2010,
Pediatric neurofibromatosis type 1 (NF-1) patients are prone to developing low-grade glioma (LGG). The HIT-LGG study 1996 aimed to observe the natural history of pediatric LGG and to postpone irradiation in younger children by using carboplatinum and vincristine in case non-surgical treatment was required. A total of 109 of 1,044 (10.4%) protocol patients had a genetic NF-1 trait [57 female patients; median age 5.1 years (range 1-15.4 years)]. Eighty-three patients (76%) suffered from an optic pathway tumor. Neuroimaging only allowed diagnosis in 67 patients. Histology revealed pilocytic astrocytoma WHO grade I in 38 of 42 biopsied patients. Sixty-five (60%) patients received non-surgical treatment, either chemotherapy (n = 55) or irradiation (n = 10). The overall survival rate of 96% after a median observation time of 5.25 years contrasts with an event free survival rate (EFS) of 0.24 at 5 years. Progressive LGG were observed even in children older than 11 years. Chiasmatic/postchiasmatic localization was a univariate risk factor for progressive disease. In the chemotherapy group, we observed a 5-year progression-free survival (PFS) rate of 0.73. Similarly, the PFS rate in the irradiation group was 0.78. Multivariate analysis revealed surgical intervention and localization within the optic pathway as factors that increased the risk of tumor progression. In this large prospective multinational study, LGG in NF-1 patients did progress in 75% of patients. Chemotherapy yielded acceptable PFS. The biological factors determining progression remain poorly understood.
Hero B, Papenheim H, Schuster U	Neuroblastom – Informationen für Eltern.	Fördergesellschaft Kinderkrebs-Neuroblastom-Forschung e.V., Baden 2011
Hero B, Clement N, Oera I, Pierron G, Lapouble E, Theissen J, Pasqualini C, Valteau-Couanet D, Plantaz D, Michon J, Delattre O, Tardieu M, Schleiermacher G	Genomic Profiles of Neuroblastoma Associated With Opsoclonus Myoclonus Syndrome.	Journal of pediatric hematology/oncology 2018, 40: 93
Opsoclonus myoclonus syndrome (OMS), often called
van den Heuvel-Eibrink MM, van Tinteren H, Rehorst H, Coulombe A, Patte C, de Camargo B, de Kraker J, Leuschner I, Lugtenberg R, Pritchard-Jones K, Sandstedt B, Spreafico F, Graf N, Vujanic GM	Malignant rhabdoid tumours of the kidney (MRTKs), registered on recent SIOP protocols from 1993 to 2005: A report of the SIOP renal tumour study group.	Pediatr Blood Cancer 2010 [Epub ahead of print]
BACKGROUND: Survival data of malignant rhabdoid tumour of the kidney (MRTK) registered in SIOP trials, advocating preoperative chemotherapy, are not available. Aim To evaluate characteristics, response and survival of MRTK patients registered in recent SIOP protocols. METHODS: An evaluation of all MRTK patients treated from 1993 to 2005 (SIOP trials 93-01 and 2001) was performed. Data were obtained from study specific case record forms and entered centrally in a database. RESULTS: Hundred and seven patients were identified (57 male), with a median age at diagnosis of 13 months (interquartile range 6-27 months), and a median follow-up time of 60 months. Left and right kidneys were equally affected. Tumour stage distribution was stage I (6%), stage II (22%), stage III (43%), stage IV (22%) and stage V (3%). Stage IV patients included 17 with pulmonary metastasis (8 lung-only) and 12 with multiple organ metastases (bone, brain and liver). Primary surgery was the upfront treatment approach in 22/107 patients (21%), by which 19 patients reached a complete remission (CR). Median difference in tumour volume before and after preoperative chemotherapy was 69 ml (interquartile range: 4.5-158.0, P < 0.0001), indicating marked chemosensitivity. The 5-year event-free survival (EFS) of the total group was 22% (95% CI: 15-33) and overall survival 26% (95% CI: 18-37). Most events (86%) occurred within the first 2 years after diagnosis. Younger age at diagnosis was an important adverse prognostic factors for survival. In contrast, tumour volume at diagnosis, nor volume reduction was associated with outcome. CONCLUSION: MRTK has a poor outcome especially in young and advanced-stage disease patients. Neither tumour volume at diagnosis, nor pre-operative chemosensitivity are prognostic factors for survival. Pediatr Blood Cancer © 2010 Wiley-Liss, Inc.
Heukamp LC, Thor T, Schramm A, De Preter K, Kumps C, De Wilde B, Odersky A, Peifer M, Lindner S, Spruessel A, Pattyn F, Mestdagh P, Menten B, Kuhfittig-Kulle S, Künkele A, König K, Meder L, Chatterjee S, Ullrich RT, Schulte S, Vandesompele J, Speleman F, Büttner R, Eggert A, Schulte JH	Targeted expression of mutated ALK induces neuroblastoma in transgenic mice.	Sci Transl Med 2012, 4: 141ra91
Activating anaplastic lymphoma kinase (ALK) mutations were recently detected in most familial and 10% of sporadic neuroblastomas. However, the role of mutated ALK in tumorigenesis remains elusive. We demonstrate that targeted expression of the most frequent and aggressive variant, ALK(F1174L), is tumorigenic in mice. Tumors resembled human neuroblastomas in morphology, metastasis pattern, gene expression, and the presence of neurosecretory vesicles as well as synaptic structures. This ALK-driven neuroblastoma mouse model precisely recapitulated the genetic spectrum of the disease. Chromosomal aberrations were syntenic to those in human neuroblastoma, including 17q gain and MYCN oncogene amplification. Targeted ALK(F1174L) and MYCN coexpression revealed a strong synergism in inducing neuroblastoma with minimal chromosomal aberrations, suggesting that fewer secondary hits are required for tumor induction if both oncoproteins are targeted. Treatment of ALK(F1174L) transgenic mice with the ALK inhibitor TAE-684 induced complete tumor regression, indicating that tumor cells were addicted to ALK(F1174L) activity. We conclude that an activating mutation within the ALK kinase domain is sufficient to induce neuroblastoma development, and ALK inhibitors show promise for treating human neuroblastomas harboring ALK mutations.
van den Heuvel-Eibrink MM, van Tinteren H, Bergeron C, Coulomb-L'Hermine A, de Camargo B, Leuschner I, Sandstedt B, Acha T, Godzinski J, Oldenburger F, Gooskens SL, de Kraker J, Vujanic GM, Pritchard-Jones K, Graf N	Outcome of localised blastemal-type Wilms tumour patients treated according to intensified treatment in the SIOP WT 2001 protocol, a report of the SIOP Renal Tumour Study Group (SIOP-RTSG).	European journal of cancer (Oxford, England : 1990) 2015,Epub ahead of print
Blastemal-type Wilms tumour (BT-WT) has been identified as a high risk histological subgroup in WT assessed after pre-nephrectomy chemotherapy in trials of the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group. Therefore, in SIOPWT2001, post-operative chemotherapy for BT-WT was intensified aiming to improve survival. Survival analysis of all unilateral BT-WT patients (SIOPWT2001) (n=238), was compared with historical BT-WT controls (SIOP93-01) (n=113). 351/4061 (8.6%) unilateral non-metastatic BT-WT patients (SIOP93-01/SIOPWT2001) were studied. Median age at diagnosis was 43months (Inter Quartile Range (IQR) 24-68months), stages: I (n=140, 40%), II (n=106, 30%), III (n=105, 30%). BT-WTs were higher staged, showed greater volume decrease after pre-operative chemotherapy and were diagnosed at an older median age compared to other WT patients. Patient characteristics did not differ substantially between SIOP93-01 and SIOPWT2001. Univariate analysis showed a 5-year event-free survival (EFS) of 80% (95% confidence interval (CI): 75-86%) (SIOPWT2001) compared to 67% in SIOP93-01 (95% CI: 59-76%; p=0.006) and overall survival (OS) of 88% (95% CI: 83-93%) (SIOPWT2001) compared to 84% (95% CI: 77-91%; p=0.4) in SIOP93-01. 95% of relapses were distant metastases (SIOP93-01/SIOPWT2001). Treatment protocol, age at diagnosis, tumour stage (III versus I/II) and volume (at surgery), were prognostic variables for EFS (uni- and multivariate Cox regression analysis). Independent prognosticators for OS were age at diagnosis, tumour stage and volume (at surgery). The most significant survival benefit of intensified treatment, was observed in Stage I (EFS 96% in SIOPWT2001 (OS 100%), 71% in SIOP93-01 (OS 90%)). BT-WT derived benefits from more intensive chemotherapy as reflected by a reduction in relapse risk. However, the benefit of the more intensive chemotherapy to improve OS was only observed in stage I BT-WTs, by adding doxorubicin.
van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, van Tinteren H, Furtwängler R, Verschuur AC, Vujanic GM, Leuschner I, Brok J, Rübe C, Smets AM, Janssens GO, Godzinski J, Ramírez-Villar GL, de Camargo B, Segers H, Collini P, Gessler M, Bergeron C, Spreafico F, Graf N, International Society of Paediatric Oncology -Renal Tumour Study Group (SIOP-RTSG)	Position paper: Rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol.	Nature reviews. Urology 2017, 14: 743
The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new protocol for the diagnosis and treatment of childhood renal tumours, the UMBRELLA SIOP-RTSG 2016 (the UMBRELLA protocol), to continue international collaboration in the treatment of childhood renal tumours. This protocol will support integrated biomarker and imaging research, focussing on assessing the independent prognostic value of genomic changes within the tumour and the volume of the blastemal component that survives preoperative chemotherapy. Treatment guidelines for Wilms tumours in the UMBRELLA protocol include recommendations for localized, metastatic, and bilateral disease, for all age groups, and for relapsed disease. These recommendations have been established by a multidisciplinary panel of leading experts on renal tumours within the SIOP-RTSG. The UMBRELLA protocol should promote international collaboration and research and serve as the SIOP-RTSG best available treatment standard.
Hicks LK, Bering H, Carson KR, Kleinerman J, Kukreti V, Ma A, Mueller BU, O'Brien SH, Pasquini M, Sarode R, Solberg L Jr, Haynes AE, Crowther MA	The ASH Choosing Wisely® campaign: five hematologic tests and treatments to question.	Blood 2013, 122: 3879
Choosing Wisely® is a medical stewardship and quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The ASH is an active participant in the Choosing Wisely® project. Using an iterative process and an evidence-based method, ASH has identified 5 tests and treatments that in some circumstances are not well supported by evidence and which in certain cases involve a risk of adverse events and financial costs with low likelihood of benefit. The ASH Choosing Wisely® recommendations focus on avoiding liberal RBC transfusion, avoiding thrombophilia testing in adults in the setting of transient major thrombosis risk factors, avoiding inferior vena cava filter usage except in specified circumstances, avoiding the use of plasma or prothrombin complex concentrate in the nonemergent reversal of vitamin K antagonists, and limiting routine computed tomography surveillance after curative-intent treatment of non-Hodgkin lymphoma. We recommend that clinicians carefully consider anticipated benefits of the identified tests and treatments before performing them.
Hicks LK, Bering H, Carson KR, Haynes AE, Kleinerman J, Kukreti V, Ma A, Mueller BU, O'Brien SH, Panepinto JA, Pasquini MC, Rajasekhar A, Sarode R, Wood WA	Five hematologic tests and treatments to question.	Blood 2014, 124: 3524
Choosing Wisely(®) is a medical stewardship initiative led by the American Board of Internal Medicine Foundation in collaboration with professional medical societies in the United States. The American Society of Hematology (ASH) released its first Choosing Wisely(®) list in 2013. Using the same evidence-based methodology as in 2013, ASH has identified 5 additional tests and treatments that should be questioned by clinicians and patients under specific, indicated circumstances. The ASH 2014 Choosing Wisely(®) recommendations include: (1) do not anticoagulate for more than 3 months in patients experiencing a first venous thromboembolic event in the setting of major, transient risk factors for venous thromboembolism; (2) do not routinely transfuse for chronic anemia or uncomplicated pain crises in patients with sickle cell disease; (3) do not perform baseline or surveillance computed tomography scans in patients with asymptomatic, early-stage chronic lymphocytic leukemia; (4) do not test or treat for heparin-induced thrombocytopenia if the clinical pretest probability of heparin-induced thrombocytopenia is low; and (5) do not treat patients with immune thrombocytopenia unless they are bleeding or have very low platelet counts.
Hiddemann W, Ritter J, Wormann B, Budde M, Creutzig U, Schellong G, Buchner T, Riehm H	DNA aneuploidy in children with acute leukemia.	Klin Pädiatr 1985, 197: 215
Hiddemann W, Harbott J, Ludwig W, Ritter J, Nehmer A, Reiter A, Kolkmeyer A, Laing T, Riehm H	DNA aneuploidy in childhood acute lymphoblastic leukemia.	Recent Results Cancer Res 1993, 131: 113
Hijiya N, Millot F, Suttorp M	Chronic myeloid leukemia in children: clinical findings, management, and unanswered questions.	Pediatric clinics of North America 2015, 62: 107
Chronic myelogenous leukemia (CML) is a rare disease in children. There is little evidence of biological differences between CML in children and adults, although host factors are different. Children develop distinct morbidities related to the off-target effects of tyrosine kinase inhibitors. The goal of treatment in children should be cure rather than suppression of disease, which can be the treatment goal for many older adults. This article reviews data from the literature on the treatment of CML, discusses the issues that are unique to CML in children, and recommends management that takes these issues into consideration.
Hijiya N, Schultz KR, Metzler M, Millot F, Suttorp M	Pediatric chronic myeloid leukemia is a unique disease that requires a different approach.	Blood 2016, 127: 392
Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic differences exist in pediatric and adult CML. Because children with CML may receive tyrosine kinase inhibitor (TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CML may be distinct from those in adults and require careful monitoring. Aggressive strategies, such as eradication of CML stem cells with limited duration and intensive regimens of chemotherapy and TKIs, may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects. Blood and marrow transplantation in pediatric CML is currently indicated only for recurrent progressive disease, and the acute and long-term toxicities of this option should be carefully evaluated against the complications associated with lifelong use of TKIs.
Hillmann A, Ozaki T, Rübe C, Hoffmann C, Schuck A, Blasius S, Haas A, Jürgens H, Winkelmann W	Surgical complications after preoperative irradiation of Ewing's sarcoma.	J Cancer Res Clin Oncol 1997, 123: 57
Hilgendorf I, Freund M, Jilg W, Einsele H, Gea-Banacloche J, Greinix H, Halter J, Lawitschka A, Wolff D, Meisel R	Vaccination of allogeneic haematopoietic stem cell transplant recipients: report from the international consensus conference on clinical practice in chronic GVHD.	Vaccine 2011 Apr 5; 29: 2825
Hing S, Lu Y, Summersgill B, King-Underwood L, Nicholson J, Grundy P, Grundy R, Gessler M, Shipley J, Pritchard-Jones K	Gain of 1q is associated with adverse outcome in favorable histology Wilms' tumors.	Am J Pathol 2001, 158: 393
Hirsch JF, Sainte Rose C, Pierre-Kahn A, Pfister A, Hoppe-Hirsch E	Benign astrocytic and oligodendrocytic tumors of the cerebral hemispheres in children.	J Neurosurg 1989, 70: 568
Hirst C, Owusu-Ofori S	Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease.	The Cochrane database of systematic reviews 2014, 11:CD003427
Background This is an update of a Cochrane Review first published in 2002, and previously updated in 2012. People with sickle cell disease are particularly susceptible to infection. Infants and very young children are especially vulnerable, and the 'Co-operative Study of Sickle Cell Disease' observed an incidence rate of 10 per 100 patient years of pneumococcal septicaemia in children under the age of three.Vaccines, including customary pneumococcal vaccines, may be of limited use in this age group. Therefore, prophylactic penicillin regimens may be advisable for this population.Objectives To assess the effects of prophylactic antibiotic regimens for preventing pneumococcal infection in children with sickle cell disease.Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which is comprised of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search: 26 June 2014.Selection criteria All randomised or quasi-randomised controlled trials comparing prophylactic antibiotics to prevent pneumococcal infection in children with sickle cell disease with placebo, no treatment or a comparator drug.Data collection and analysis Both authors independently extracted data and assessed trial quality.Main results Five trials were identified by the initial search, of which three trials met the inclusion criteria. All of the included trials showed a reduced incidence of infection in children with sickle cell disease (SS or Sβ0Thal) receiving prophylactic penicillin. In trials which investigated initiation of penicillin on risk of pneumococcal infection, the odds ratio was 0.37 (95% CI 0.16 to 0.86), while for withdrawal the odds ratio was 0.49 (95% CI 0.09 to 2.71). Adverse drug effects were rare and minor. Rates of pneumococcal infection were found to be relatively low in children over the age of five.Authors' conclusions Prophylactic penicillin significantly reduces risk of pneumococcal infection in children with homozygous sickle cell disease, and is associated with minimal adverse reactions. Further research may help to determine the ideal age to safely withdraw penicillin.
Hitzler JK, Cheung J, Li Y, Scherer SW, Zipursky A	GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome.	Blood 2003 Jun 1; 101: 4301
Children with constitutional trisomy 21 (Down syndrome) have an approximately 500-fold increased risk of developing acute megakaryoblastic leukemia (AMKL), a form of acute myeloid leukemia. Unique to newborn infants with Down syndrome is a transient leukemia (TL), also referred to as transient myeloproliferative syndrome, that undergoes spontaneous remission in the majority of cases but in approximately 20% is followed by AMKL later in life. Recently mutations of the gene encoding the hematopoietic transcription factor GATA1 were shown to be specific for AMKL of Down syndrome. Here, we demonstrate that GATA1 mutations are present in blasts of TL and show the identical GATA1 mutation in sequential samples collected from a patient during TL and subsequent AMKL. These findings suggest a model of malignant transformation in Down syndrome AMKL in which GATA1 mutations are an early event and AMKL arises from latent TL clones following initial apparent remission.
Holsten T, Tsiakas K, Kordes U, Bison B, Pietsch T, Rutkowski S, Santer R, SchÃ¼ller U	Group 3 medulloblastoma in a patient with a GYS2 germline mutation and glycogen storage disease 0a.	Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 2018, 34: 581
Glycogen storage disease (GSD) 0a is a rare congenital metabolic disease with symptoms in infancy and childhood caused by biallelic GYS2 germline variants. A predisposition to cancer has not been described yet. We report here a boy with GSD 0a, who developed a malignant brain tumor at the age of 4.5ÃÂ years. The tumor was classified as a group 3 medulloblastoma, and the patient died from cancer 27ÃÂ months after initial tumor diagnosis. This case appears interesting as group 3 medulloblastoma is so far not known to arise in hereditary syndromes and the biology of sporadic group 3 medulloblastoma is largely unknown.
Hochhaus A, Baerlocher GM, Brümmendorf TH, le Coutre P, Metzler M, Pelzer A, Saußele S, Suttorp M, Wolf D	Chronische Myeloische Leukämie (CML).	Onkopedia Leitlinien – Empfehlungen der Fachgesellschaft zur Diagnostik und Therapie hämatologischer und onkologischer Erkrankungen; Hrsg. DGHO Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e.V 2018
Hoene V, Fischer M, Ivanova A, Wallach T, Berthold F, Dame C	GATA factors in human neuroblastoma: distinctive expression patterns in clinical subtypes.	British journal of cancer 2009, 101: 1481
BACKGROUND: The aim of this study is to elucidate the expression patterns of GATA transcription factors in neuroblastoma and the developing sympathetic nervous system (SNS). METHODS: GATA-2, -3 and -4 and their cofactor friend-of-GATA (FOG)-2 were investigated in primary neuroblastoma by immunohistochemistry, real-time RT-PCR (n=73) and microarray analysis (n=251). In addition, GATA-2, -3 and FOG-2 expression was determined by northern-blot hybridisation. In the developing murine SNS, Gata-4 and Fog-2 were examined by immunohistochemistry. RESULTS: Although Gata-2, -3 and Fog-2 are expressed in the developing nervous system, Gata-4 was not detected. In contrast, protein expression of all factors was observed in human neuroblastoma. Northern-blot hybridisation and real-time RT-PCR suggested specific expression patterns of the four genes in primary neuroblastoma, but did not show unequivocal results. In the large cohort examined by microarrays, a significant association of GATA-2, -3 and FOG-2 expression with low-risk features was observed, whereas GATA-4 mRNA levels correlated with MYCN-amplification. CONCLUSION: The transcription factors GATA-2 and -3, which are essential for normal SNS development, and their cofactor FOG-2 are downregulated in aggressive but not in favourable neuroblastoma. In contrast, upregulation of GATA-4 appears to be a common feature of this malignancy and might contribute to neuroblastoma pathogenesis.
Hoell JI, Ginzel S, Kuhlen M, Kloetgen A, Gombert M, Fischer U, Hein D, Demir S, Stanulla M, Schrappe M, Zur Stadt U, Bader P, Babor F, Schuster F, Strahm B, Alten J, Moericke A, Escherich G, von Stackelberg A, Thiele R, McHardy AC, Peters C, Bornhauser B, Bourquin JP, Krause S, Enczmann J, Meyer LH, Eckert C, Borkhardt A, Meisel R	Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.	Blood advances 2019, 3: 3143
Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients' first relapses, which disappeared in the post-allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children's post-allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post-allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.
Hötker AM, Mazaheri Y, Lollert A, Schenk JP, Zheng J, Capanu M, Akin O, Graf N, Staatz G	Diffusion-weighted MRI and histogram analysis: assessment of response to neoadjuvant chemotherapy in nephroblastoma.	Abdominal radiology (New York) 2021, 46: 3317
To assess the value of diffusion-weighted MRI (DW-MRI) in the non-invasive prediction of blastemal remnant after neoadjuvant chemotherapy in nephroblastoma.
Hoffmann C, Jabar S, Ahrens S, Rödl R, Rübe C, Winkelmann W, Dunst J, Jürgens H	Prognosis in Ewing sarcoma patients with initial pathological fractures of the primary tumor site.	Klin Pädiatr 1995, 207: 151
Hoffmann C, Ahrens S, Dunst J, Hillmann A, Winkelmann W, Craft A, Göbel U, Rübe C, Voute P, Harms D, Jürgens H	Pelvic Ewing sarcoma. A retrospective analysis of 241 cases.	Cancer 1999, 85: 869
Hoffmann C, Gosheger G, Gebert C, Jürgens H, Winkelmann, N	Functional results and quality of life after treatment of pelvic sarcomas involving the acetabulum.	J Bone Joint Surg Am 88A; 3/2006, 575
Background: Limb salvage after resection of a pelvic sarcoma that involves the acetabulum represents a surgical challenge. The ideal method of reconstruction after acetabular resection remains a subject of controversy, and the outcome in terms of the impact of therapy is still unknown. The purpose of this study was to determine the impact of surgery on health-related quality of life and function after acetabular resection. Methods: Eighty-one patients with a pelvic sarcoma underwent acetabular resection at a single institution. Functional evaluation and quality-of-life examination were performed in forty-five patients, and these patients comprised the study group. Quality of life was assessed with use of the European Organization for Research and Treatment of Cancer core quality-of-life questionnaire. Function was assessed with use of the Musculoskeletal Tumor Society system. Results: The median age of the patients was 30.4 years at the time of the acetabular resection and 35.7 years at the time of follow-up. The median time interval from the index operation to the latest follow-up was sixty-nine months. At the latest follow-up evaluation, the mean functional status score was 14.5 points of a maximum of 30 points. In a comparison of endoprosthetic replacement and hip transposition following resection, significantly better functional results (p = 0.017) and a lower number of complications were found in patients who had a hip transposition. Quality-of-life assessment results were also better in patients with a hip transposition, especially in role functioning (p = 0.043). Conclusions: On the basis of the low complication rate and the good functional and quality-of-life results, hip transposition after acetabular resection seems to be the optimal technique for treating patients with a pelvic sarcoma involving the acetabulum.
von Hoff K, Hinkes B, Gerber NU, Deinlein F, Mittler U, Urban C, Benesch M, Warmuth-Metz M, Soerensen N, Zwiener I, Goette H, Schlegel PG, Pietsch T, Kortmann RD, Kuehl J, Rutkowski S	Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT'91.	European journal of cancer (Oxford, England : 1990) 2009, 45: 1209
PURPOSE: To analyse long-term outcome and clinical prognostic factors in medulloblastoma. METHODS: We analysed 280 patients with medulloblastoma (3-18 years) included from 1991 to 1997 in the randomised multicentre trial HIT'91 comparing pre-('sandwich') and postradiation ('maintenance') chemotherapy (median follow-up of survivors for 10 years). RESULTS: In 187 patients with complete staging, overall survival (OS) was higher after maintenance compared to sandwich treatment for M0 (10-year OS 91% and 62%, p=0.001) and M1 patients (10-year OS 70% and 34%, p=0.020). In M2/3 disease, 10-year OS was 42% and 45%. Incomplete staging, metastases, younger age and sandwich chemotherapy were independent adverse risk factors. Twelve percent of all relapses (13 of 107) occurred after more than five years, and 12 patients had secondary neoplasms. CONCLUSIONS: After maintenance therapy, long-term survival was excellent in fully assessable patients with localised medulloblastoma, and favourable for M1 patients. Patients should be followed longer for late relapses and secondary tumours.
von Hoff K, Hartmann W, von Bueren AO, Gerber NU, Grotzer MA, Pietsch T, Rutkowski S	Large cell/anaplastic medulloblastoma: outcome according to myc status, histopathological, and clinical risk factors.	Pediatric blood & cancer 2010, 54: 369
PURPOSE: To evaluate the prognostic impact of large cell/anaplastic (LC/A) histology together with molecular and clinical risk factors in childhood medulloblastoma. METHODS: Three consecutive prospective medulloblastoma trials were screened for patients with the histological diagnosis of LC/A medulloblastoma. Tumors were considered as LC/A if they displayed areas of severe cytological anaplasia or a significant or predominant large cell component. Histology was centrally confirmed. Genomic DNA amplification of c-myc and n-myc, and mRNA expression of c-myc and trkC were analyzed. RESULTS: Twenty-eight patients with LC/A medulloblastoma with a median age of 6.1 years (1.4-16.5 years) and a median follow-up of 4.5 years were identified (5% of all medulloblastoma). Four-year event-free (EFS) and overall survival (OS) were 58% and 67%. Young age and metastases (n = 13, 4-year EFS 31% vs. 82% in 15 children >4 years and without metastases, P = 0.001), large cell histology (n = 9, 4-year EFS 22% vs. 75%, P = 0.005) and c-myc amplification (n = 9, 4-year EFS 22% vs. 89%, P < 0.0001) were negative prognostic factors. C-myc amplification was highly correlated with young age (P < 0.001), metastases (P = 0.002) and large cell histology (P = 0.007). Outcome of 12 patients with severely anaplastic tumors without these risk factors was not impaired (4-year EFS 86%). CONCLUSION: In a subgroup of patients without clinical and molecular risk factors outcome was favorable despite severely anaplastic histology. In contrast, c-myc amplification and large-cell histology were associated with an inferior outcome. Intensified treatment strategies should be considered for children with LC/A medulloblastoma and these characteristics.
Hof J, Krentz S, van Schewick C, Körner G, Shalapour S, Rhein P, Karawajew L, Ludwig WD, Seeger K, Henze G, von Stackelberg A, Hagemeier C, Eckert C, Kirschner-Schwabe R	Mutations and Deletions of the TP53 Gene Predict Nonresponse to Treatment and Poor Outcome in First Relapse of Childhood Acute Lymphoblastic Leukemia.	J Clin Oncol 2011, [Epub ahead of print]
PURPOSE In the clinical management of children with relapsed acute lymphoblastic leukemia (ALL), treatment resistance remains a major challenge. Alterations of the TP53 gene are frequently associated with resistance to chemotherapy, but their significance in relapsed childhood ALL has remained controversial because of small studies. PATIENTS AND METHODS Therefore, we systematically studied 265 first-relapse patients enrolled in the German Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster 2002 (ALL-REZ BFM 2002) trial for sequence and copy number alterations of the TP53 gene by using direct sequencing and multiplex ligation-dependent probe amplification. Results We observed copy number and sequence alterations of TP53 in 12.4% (27 of 218) of patients with B-cell precursor ALL and 6.4% (three of 47) of patients with T-cell ALL relapse. Backtracking to initial ALL in 23 matched samples revealed that 54% of all TP53 alterations were gained at relapse. Within B-cell precursor ALL, TP53 alterations were consistently associated with nonresponse to chemotherapy (P < .001) and poor event-free survival (P < .001) and overall survival rates (P = .002). TP53 alterations also had a significant impact on survival within intermediate-risk (S2) and high-risk (S3/S4) relapse patients (P = .007 and P = .019, respectively). This prognostic significance of TP53 alterations was confirmed in multivariate analysis. Besides their clinical impact, TP53 alterations were associated with a higher fraction of leukemic cells in S/G(2)-M phase of the cell cycle at relapse diagnosis. CONCLUSION Alterations of the TP53 gene are of particular importance in the relapse stage of childhood ALL, in which they independently predict high risk of treatment failure in a significant number of patients. Therefore, they will aid in future risk assessment of children with ALL relapse.
von Hoff K, Hinkes B, Dannenmann-Stern E, von Bueren AO, Warmuth-Metz M, Soerensen N, Emser A, Zwiener I, Schlegel PG, Kuehl J, Frühwald MC, Kortmann RD, Pietsch T, Rutkowski S	Frequency, risk-factors and survival of children with atypical teratoid rhabdoid tumors (AT/RT) of the CNS diagnosed between 1988 and 2004, and registered to the German HIT database.	Pediatric blood & cancer 2011, 1; 57: 978
To analyze the frequency, prognostic factors, and outcome of children with atypical teratoid/rhabdoid tumors (AT/RT), a rare and highly malignant embryonal brain tumor.
Hofmann M, Schlegel PG, Hippert F, Schmidt P, von-Schweinitz D, Leuschner I, Göbel U, Calaminus G, Schneider DT, MAKEI study group	Testicular sex cord stromal tumors: Analysis of patients from the MAKEI study.	Pediatric blood & cancer 2013, 60: 1651
In children and adolescents, testicular sex cord stromal tumors (TSCSTs) are rare. There is only limited information available regarding their clinical presentation, biology, and prognosis.
Hoffmann A, Gebhardt U, Sterkenburg A, Warmuth-Metz M, Müller HL	Diencephalic syndrome in childhood craniopharyngioma -Results of German multicentre studies on 485 long-term survivors of childhood craniopharyngioma.	The Journal of clinical endocrinology and metabolism 2014,jc20141680
Context: Childhood craniopharyngiomas (CP) are known to be associated with an increased risk of excessive weight gain and hypothalamic obesity. Atypical clinical manifestations include the development of a diencephalic syndrome (DS) with a failure to thrive or maintain weight at appropriate BMI. Cases and Methods: In a retrospective study we analysed 21/485 childhood CP patients (4.3%) who presented with a low weight (<-2 BMI SD) at time of diagnosis. Eleven (11) of 21 patients were identified with a DS due to proven hypothalamic involvement. We show the clinical manifestations of DS and weight development before and after diagnosis in these 11 patients. First significant differences between patients with low weight at diagnosis and normal weight patients at diagnosis are observed at 5 years of age. Within the first 2 years after diagnosis, the weight of DS patients and normal weight patients converge to a similar level. Tumor size does not play a role with respect to DS development. Finally, tumor characteristics of DS patients were compared with magnetic resonance imaging (MRI) scans of obese CP patients at time of diagnosis. Conclusions: DS is a rare clinical manifestation in childhood CP and should be considered as a discrete diagnosis in failure to thrive. DS at the time of diagnosis does not preclude weight gain after diagnosis of a CP with hypothalamic involvement.
Hoffmann A, Warmth-Metz M, Gebhardt U, Pietsch T, Pohl F, Kortmann RD, Calaminus G, Müller HL	Childhood craniopharyngioma - changes of treatment strategies in the trials KRANIOPHARYNGEOM 2000/2007.	Klinische Padiatrie 2014, 226: 161
Prognosis in childhood cranio-pharyngioma, is frequently impaired due to sequelae. Radical surgery was the treatment of choice for decades. Even at experienced facilities radical surgery can result in hypothalamic disorders such as severe obesity.
Hoffmann A, Brentrup A, Mueller HL	First report on spinal metastasis in childhood-onset craniopharyngioma.	Journal of neuro-oncology 2016, 129: 193
Hoffmann A, Warmuth-Metz M, Lohle K, Reichel J, Daubenbuechel AM, Sterkenburg AS, Mueller HL	Fusiform dilatation of the internal carotid artery in childhood-onset craniopharyngioma: multicenter study on incidence and long-term outcome.	Pituitary 2016, 19: 422
Fusiform dilatations of the internal carotid artery (FDCA) represent a vascular complication following surgery for suprasellar tumors in children. Incidence rate and long-term prognosis of FDCA in terms of survival rates, vascular complications, and quality of survival are unknown for patients with childhood-onset craniopharyngioma.
vom Hoff, Katja	Therapieoptimierungsstudie SIOP-Ependymom II.	WIR - Zeitschrift der Deutschen Kinderkrebsstiftung und der Deutschen Leukämie-Forschungshilfe e.V 2/17
Hoffmann A, Azyurt J, Lohle K, Reichel J, Thiel CM, Mueller HL	First experiences with neuropsychological effects of oxytocin administration in childhood-onset craniopharyngioma.	Endocrine 2017, 56: 175
The hypothalamic hormone oxytocin plays a major role in regulation of behavior and body composition. Quality of survival is frequently impaired in childhood craniopharyngioma patients due to sequelae such as behavioral deficits and severe obesity caused by tumor or treatment-related hypothalamic lesions.
Hoffman LM, Veldhuijzen van Zanten SEM, Colditz N, Baugh J, Chaney B, Hoffmann M, Lane A, Fuller C, Miles L, Hawkins C, Bartels U, Bouffet E, Goldman S, Leary S, Foreman NK, Packer R, Warren KE, Broniscer A, Kieran MW, Minturn J, Comito M, Broxson E, Shih CS, Khatua S, Chintagumpala M, Carret AS, Escorza NY, Hassall T, Ziegler DS, Gottardo N, Dholaria H, Doughman R, Benesch M, Drissi R, Nazarian J, Jabado N, Boddaert N, Varlet P, Giraud G, Castel D, Puget S, Jones C, Hulleman E, Modena P, Giagnacovo M, Antonelli M, Pietsch T, Gielen GH, Jones DTW, Sturm D, Pfister SM, Gerber NU, Grotzer MA, Pfaff E, von Bueren AO, Hargrave D, Solanki GA, Jadrijevic Cvrlje F, Kaspers GJL, Vandertop WP, Grill J, Bailey S, Biassoni V, Massimino M, Calmon R, Sanchez E, Bison B, Warmuth-Metz M, Leach J, Jones B, van Vuurden DG, Kramm CM, Fouladi M	Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries.	Journal of clinical oncology 2018 Jul 1; 36: 1963
Abstract: urpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival Ã¢ÂÂ¥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.
Hoffman LM, Richardson EA, Ho B, Margol A, Reddy A, Lafay-Cousin L, Chi S, Slavc I, Judkins A, Hasselblatt M, Bourdeaut F, Frühwald MC, Vibhakar R, Bouffet E, Huang A	Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors.	Neuro-oncology 2020, 22: 944
Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable. Recent use of intensified therapies has modestly improved survival for ATRT; however, a majority of patients will still succumb to their disease. While ATRTs almost universally exhibit loss of SMARCB1 (BAF47/INI1/SNF5), recent whole genome, transcriptome, and epigenomic analyses of large cohorts reveal previously underappreciated molecular heterogeneity. These discoveries provide novel insights into how SMARCB1 loss drives oncogenesis and confer specific therapeutic vulnerabilities, raising exciting prospects for molecularly stratified treatment for patients with ATRT.
Hohlfeld Th	Hämostasestörungen durch Analgetika, Antiphlogistika und Antirheumatika.	Hämostasiologie 2001, 01, 22
Zusammenfassung Nichtsteroidale Antiphlogistika/Analgetika wie Azetylsalizylsäure (ASS), Indometazin, Diclofenac, Naproxen und Piroxicam hemmen die thrombozytäre Thromboxansynthese und damit die Thrombozytenfunktion. Auch in therapeutischer Dosierung können diese Verbindungen daher zu Blutungskomplikationen führen. Wohl am besten untersucht ist hier das Risiko gastrointestinaler Blutungen, welches bei Behandlung mit Metamizol, Propyphenazon und Paracetamol vergleichsweise gering, unter Indometazin, Diclofenac, Naproxen und Azetylsalizylsäure (ASS) höher und bei Piroxicam relativ gesehen am höchsten ist. Eine direkte Schädigung der Magen- und Duodenalschleimhaut trägt bei diesen Substanzen zum gastrointestinalen Blutungsrisiko bei. Selektive Inhibitoren der induzierbaren Zyklooxygenase (COX-2), wie Celecoxib und Rofecoxib, haben nach bisheriger Erfahrung nur selten zu gastrointestinalen Blutungen geführt. Glukokortikoide beeinflussen in mehrfacher Weise die Hämostase. Zunächst ist hier eine Stimulation der hepatischen Synthese verschiedener Gerinnungsfaktoren (I, II, V, VII, VIII, IX, XI, XII) bekannt. Darüber hinaus können Glukokortikoide auch eine Hypofibrinolyse bewirken, wahrscheinlich infolge erhöhter Aktivität von Inhibitoren der Fibrinolyse (PAI-1, 2 -Antiplasmin). Im Rahmen einer Behandlung mit antirheumatischen Basistherapeutika (darunter Goldsalze, Penicillamin, Methotrexat) ist vor allem auf nicht ganz seltene Thrombozytopenien immunologischer oder myelotoxischer Genese zu achten. Von praktischer Bedeutung sind auch Arzneimittelinteraktionen, wie z. B. eine Steigerung des Blutungsrisikos durch Antikoagulanzien (Warfarin-Derivate, Heparine) bei gleichzeitiger Behandlung mit nichtsteroidalen Antiphlogistika und Analgetika, wozu neben der synergistischen Wirkung auf Thrombozyten und das plasmatische Gerinnungssytem auch pharmakokinetische Mechanismen beitragen können.
Hohmann C, Borgmann A, Keil T	Re: Induced abortions in Danish cancer survivors: a population-based cohort study.	J Natl Cancer Inst 2011, 20; 103: 698
Hohmann C, Borgmann-Staudt A, Rendtorff R, Reinmuth S, Holzhausen S, Willich SN, Henze G, Goldbeck L, Keil T	Patient counselling on the risk of infertility and its impact on childhood cancer survivors: results from a national survey.	Journal of psychosocial oncology 2011, 29: 274
Fertility can be impaired by radiation and chemotherapy among childhood cancer survivors. Therefore, timely and adequate patient counselling about the risk of infertility and preservation methods is needed. The primary study objective was to assess remembered counselling among childhood cancer survivors. As a second objective, the impact of lacking patient counselling on offspring-related attitudes and behaviour was examined. Counselling regarding the late effects of gonadotoxicity that could be recalled by patients was assessed using a questionnaire sent by the German Childhood Cancer Registry. The questionnaire was answered by 2754 adult childhood cancer survivors (53.1% female, mean = 25.7 years). The proportion of patients who could not remember patient counselling about the late effects of chemo-/radiotherapy on fertility decreased significantly over time. In 1980 to 1984 67%, in 2000 to 2004 50% of the patients reported no memories of counselling (p < .001). Counselled patients feared significantly less that their children may have an increased cancer risk (4.4% vs. 6.7%, p = .03). They were also more likely to undergo fertility testing than patients who could not recall counselling (odds ratio = 2.91, 95% confidence interval [2.12, 3.99]). Patients reported an increased memory of patient counselling over the past 25 years. Still, a 50% rate of recalled counselling shows an ongoing need for adequate and especially sustainable counselling of paediatric cancer patients about infertility and other long-term adverse treatment effects. Those who reported a lack of counselling had offspring-related fears more frequently, which stopped them from having children.
Holter W, Ressmann G, Grois N, Lehner M, Parolini O, Gadner H	Normal monocyte-derived dendritic cell function in patients with Langerhans-cell-histiocytosis.	Medical and pediatric oncology 2002, 39: 181
BACKGROUND: Langerhans cell histiocytosis (LCH) is a histiocytic disease, characterized by the lesional accumulation of dendritic Langerhans cells together with T cells and eosinophils. The cause of this disease is unknown. Langerhans cells are bone marrow-derived dendritic cells (DCs), which can develop from CD34(+) hematopoietic progenitor cells as well as from monocytes. PROCEDURE: To test whether LCH patients have a general functional defect present in cells of their DC lineage, we generated immature DCs by culturing monocytes from nine patients with single- or multisystem LCH with GM-CSF and IL-4, and analyzed their phenotype and function before and after an in vitro maturation stimulus. Immature DCs were analyzed for their phenotype and cytokine production, DCs matured in response to TNF-alpha plus PGE(2) were analyzed for their phenotype, their stimulatory capacity in MLR, cell aggregation, and activation-induced apoptosis. RESULTS: In summary, no difference was found between both immature as well as mature DCs generated from patients and controls regarding the expression of CD1a, CD80, CD86, MHC class I, and MCH class II antigens. Similarly, no difference was found regarding IL-10, -12, and TNF-alpha production, as well as regarding cell aggregation and apoptosis in response to external stimuli. CONCLUSIONS: The absence of gross functional abnormalities in DCs generated from monocytes from patients with LCH makes the existence of a severe functional defect affecting all cells of the DC lineage in these patients unlikely.
Holleman A, Den Boer M, Kazemier K, Janka-Schaub G, Pieters R	Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia.	Blood 2003, 102: 4541
Holleman A, Cheok MH, den Boer ML, Yang W, Veerman AJ, Kazemier KM, Pei D, Cheng C, Pui CH, Relling MV, Janka-Schaub GE, Pieters R, Evans WE	Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.	The New England journal of medicine 2004, 351: 533
BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown. METHODS: We tested leukemia cells from 173 children for sensitivity in vitro to prednisolone, vincristine, asparaginase, and daunorubicin. The cells were then subjected to an assessment of gene expression with the use of 14,500 probe sets to identify differentially expressed genes in drug-sensitive and drug-resistant ALL. Gene-expression patterns that differed according to sensitivity or resistance to the four drugs were compared with treatment outcome in the original 173 patients and an independent cohort of 98 children treated with the same drugs at another institution. RESULTS: We identified sets of differentially expressed genes in B-lineage ALL that were sensitive or resistant to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes), or daunorubicin (20 genes). A combined gene-expression score of resistance to the four drugs, as compared with sensitivity to the four, was significantly and independently related to treatment outcome in a multivariate analysis (hazard ratio for relapse, 3.0; P=0.027). Results were confirmed in an independent population of patients treated with the same medications (hazard ratio for relapse, 11.85; P=0.019). Of the 124 genes identified, 121 have not previously been associated with resistance to the four drugs we tested. CONCLUSIONS: Differential expression of a relatively small number of genes is associated with drug resistance and treatment outcome in childhood ALL.
Holleman A, den Boer ML, Kazemier KM, Beverloo HB, von Bergh AR, Janka-Schaub GE, Pieters R	Decreased PARP and procaspase-2 protein levels are associated with cellular drug resistance in childhood acute lymphoblastic leukemia.	Blood 2005, 106: 1817
Drug resistance in childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is associated with impaired ability to induce apoptosis. To elucidate causes of apoptotic defects, we studied the protein expression of Apaf-1, procaspases-2, -3, -6, -7, -8, -10, and poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) in cells from children with acute lymphoblastic leukemia (ALL; n = 43) and acute myeloid leukemia (AML; n = 10). PARP expression was present in all B-lineage samples, but absent in 4 of 15 T-lineage ALL samples and 3 of 10 AML cases, which was not caused by genomic deletions. PARP expression was a median 7-fold lower in T-lineage ALL (P < .001) and 10-fold lower in AML (P < .001) compared with B-lineage ALL. PARP expression was 4-fold lower in prednisolone, vincristine and L-asparaginase (PVA)-resistant compared with PVA-sensitive ALL patients (P < .001). Procaspase-2 expression was 3-fold lower in T-lineage ALL (P = .022) and AML (P = .014) compared with B-lineage ALL. In addition, procaspase-2 expression was 2-fold lower in PVA-resistant compared to PVA-sensitive ALL patients (P = .042). No relation between apoptotic protease-activating factor 1 (Apaf-1), procaspases-3, -6, -7, -8, -10, and drug resistance was found. In conclusion, low baseline expression of PARP and procaspase-2 is related to cellular drug resistance in childhood acute lymphoblastic leukemia.
Hollink IH, Zwaan CM, Zimmermann M, Arentsen-Peters TC, Pieters R, Cloos J, Kaspers GJ, de Graaf SS, Harbott J, Creutzig U, Reinhardt D, van den Heuvel-Eibrink MM, Thiede C	Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML.	Leukemia 2009, 23: 262
Nucleophosmin (NPM1) mutations occur frequently in adult cytogenetically normal acute myeloid leukemia (CN-AML) and confer favorable outcome. We investigated the frequency and prognostic significance of NPM1 mutations in childhood AML (n=298), specifically focusing on the CN-AML subgroup (n=100). Mutations were found in 8.4%, and clustered significantly in the CN-AML subgroup (22%). No mutations were found in patients below the age of 3 years; in CN-AML, there was an increasing incidence above this age. In the overall group, NPM1 mutations conferred an independent favorable prognostic impact on event-free survival (5-year pEFS 66 vs 39%; P=0.02), which did not translate into a significantly better overall survival (5-year pOS 68 vs 56%; P=0.30). However, when the favorable cytogenetic subgroups [inv(16) and t(8;21)] were excluded from the NPM1 wild-type group, the difference in pOS was borderline statistically significant (68 vs 45%; P=0.07). In the CN-AML cohort, NPM1 mutations were an independent prognostic factor on pEFS (80 vs 39%; P=0.01), and pOS (85 vs 60%; P=0.06), which was not influenced by FLT3/ITD. However, in NPM1 wild-type CN-AML, FLT3/ITD-positive patients had a significantly worse outcome (pEFS 48 vs 18%; P<0.001). We conclude that NPM1 mutations confer a favorable prognosis in childhood AML and in CN-AML in particular.
Holzhauer S, Goldenberg NA, Junker R, Heller C, Stoll M, Manner D, Mesters R, Krümpel A, Stach M, Nowak-Göttl U	Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study.	Blood 2012, 120: 1510
Screening for inherited thrombophilia (IT) is controversial, individuals at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first and second degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (Hazard Ratio [HR] 7.6, 95% CI, 4.00-14.45]; P<0.001) and highest among carriers of antithrombin, protein C, or protein S deficiency (HR 25.7, 95% CI12.2-54.2]; P<0.001). Annual incidences of VTE were 2.82% (95% confidence interval [95%CI], 1.63-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12-0.53%) for factor II G202010A, 0.25% (0.12-0.53%) for factor V G1691A, and 0.10% (0.06-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S and antithrombin deficiency we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess if thromboembolism can be prevented in this high risk population.
Hol JA, van den Heuvel-Eibrink MM, Graf N, Pritchard-Jones K, Brok J, van Tinteren H, Howell L, Verschuur A, Bergeron C, Kager L, Catania S, Spreafico F, Mavinkurve-Groothuis AMC	Irinotecan for relapsed Wilms tumor in pediatric patients: SIOP experience and review of the literature-A report from the SIOP Renal Tumor Study Group.	Pediatric blood & cancer 2018, 65
While irinotecan has been studied in various pediatric solid tumors, its potential role in Wilms tumor (WT) is less clear. We evaluated response and outcome of irinotecan-containing regimens in relapsed WT and compared our results to the available literature. Among 14 evaluable patients, one complete response (CR) and two partial responses (PRs) were observed in patients with initial intermediate-risk (CR and PR) and blastemal-type histologies (PR). Two patients were alive at last follow-up showing no evidence of disease. Our results and the reviewed literature suggest some effectiveness of irinotecan in the setting of relapsed WT. © 2017 Wiley Periodicals, Inc.
Holsten T, Tsiakas K, Kordes U, Bison B, Pietsch T, Rutkowski S, Santer R, SchÃÂ¼ller U	Group 3 medulloblastoma in a patient with a GYS2 germline mutation and glycogen storage disease 0a.	ChNS 2018, 34: 581
Glycogen storage disease (GSD) 0a is a rare congenital metabolic disease with symptoms in infancy and childhood caused by biallelic GYS2 germline variants. A predisposition to cancer has not been described yet. We report here a boy with GSD 0a, who developed a malignant brain tumor at the age of 4.5ÃÂÃÂ years. The tumor was classified as a group 3 medulloblastoma, and the patient died from cancer 27ÃÂÃÂ months after initial tumor diagnosis. This case appears interesting as group 3 medulloblastoma is so far not known to arise in hereditary syndromes and the biology of sporadic group 3 medulloblastoma is largely unknown.
Holzapfel J, Kandels D, Schmidt R, Pietsch T, Warmuth-Metz M, Bison B, Krauss J, Kortmann RD, Timmermann B, Thomale UW, Albert MH, HernÃ¡iz Driever P, Witt O, Gnekow AK	Favorable prognosis in pediatric brainstem low-grade glioma: Report from the German SIOP-LGG 2004 cohort.	International journal of cancer 2020 Jun 15; 146: 3385
Reports on pediatric low-grade glioma (LGG) of the caudal brainstem are retrospective with heterogeneous cohorts, variable treatments and inconsistent outcome data. We analyzed their natural history and asked whether brainstem location proved unfavorable for survival within the framework of the comprehensive SIOP-LGG 2004 management strategy. Within the prospectively registered, population-based German SIOP-LGG 2004 cohort 116 patients (age 0.2-16.5Ã¢ÂÂyears, 10% Neurofibromatosis NF1) were diagnosed with LGG of the pons (27%) and medulla oblongata (73%). After biopsy (23%), variable resection (63%) or radiologic diagnosis only (14%), 59 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemo- (n = 39) or radiotherapy (n = 18). After further progression (28/57), salvage treatments included multiple treatment lines for 12/28 patients. Five-years event-free survival dropped to 0.40, while 5-years overall survival was 0.95 (median observation time 6.8Ã¢ÂÂyears). Higher extent of resection yielded lower progression rate (p = 0.001), but at a cost of 21/100 patients suffering from new postsurgical complications including respiratory insufficiency. Central review confirmed pilocytic astrocytoma (56%), diffuse astrocytoma (8%) or glioneuronal histology (16%) (others 4%, no histology 17%). Malignant evolution was documented in five patients associated with Histone3 mutation in 2/5. Our treatment algorithm conveyed high overall survival for pediatric brainstem LGG. Extensive neurosurgical resection did increase additional postoperative neurologic deficits but not overall survival in this often-chronic disease. More than half of all patients can be safely followed by observation, while multimodal adjuvant treatment can control progressive tumors. Molecular assessment should confirm low-grade diagnosis and may detect patterns prognostic for malignant evolution.
Holdhof D, Johann PD, Spohn M, Bockmayr M, Safaei S, Joshi P, Masliah-Planchon J, Ho B, Andrianteranagna M, Bourdeaut F, Huang A, Kool M, Upadhyaya SA, Bendel AE, Indenbirken D, Foulkes WD, Bush JW, Creytens D, Kordes U, Frühwald MC, Hasselblatt M, Schüller U	Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases.	Acta neuropathologica 2021, 141: 291
Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.
Hol JA, Jewell R, Chowdhury T, Duncan C, Nakata K, Oue T, Gauthier-Villars M, Littooij AS, Kaneko Y, Graf N, Bourdeaut F, van den Heuvel-Eibrink MM, Pritchard-Jones K, Maher ER, Kratz CP, Jongmans MCJ	Wilms tumour surveillance in at-risk children: Literature review and recommendations from the SIOP-Europe Host Genome Working Group and SIOP Renal Tumour Study Group.	European journal of cancer (Oxford, England : 1990) 2021, 153: 51
Since previous consensus-based Wilms tumour (WT) surveillance guidelines were published, novel genes and syndromes associated with WT risk have been identified, and diagnostic molecular tests for previously known syndromes have improved. In view of this, the International Society of Pediatric Oncology (SIOP)-Europe Host Genome Working Group and SIOP Renal Tumour Study Group hereby present updated WT surveillance guidelines after an extensive literature review and international consensus meetings. These guidelines are for use by clinical geneticists, pediatricians, pediatric oncologists and radiologists involved in the care of children at risk of WT. Additionally, we emphasise the need to register all patients with a cancer predisposition syndrome in national or international databases, to enable the development of better tumour risk estimates and tumour surveillance programs in the future.
Hongo T, Yajima S, Sakurai M, Horikoshi Y, Hanada R	In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia.	Blood 1997, 89: 2959−2965
Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC	Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.	Nature genetics 1999, 23: 433
Human cyclic haematopoiesis (cyclic neutropenia, MIM 162800) is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency. Here we use a genome-wide screen and positional cloning to map the locus to chromosome 19p13.3. We identified 7 different single-base substitutions in the gene (ELA2) encoding neutrophil elastase (EC 3. 4.21.37, also known as leukocyte elastase, elastase 2 and medullasin), a serine protease of neutrophil and monocyte granules, on unique haplotypes in 13 of 13 families as well as a new mutation in a sporadic case. Neutrophil elastase (a 240-aa mature protein predominantly found in neutrophil granules) is the target for protease inhibition by alpha1-antitrypsin, and its unopposed release destroys tissue at sites of inflammation. We hypothesize that a perturbed interaction between neutrophil elastase and serpins or other substrates may regulate mechanisms governing the clock-like timing of haematopoiesis.
von Hornstein S, Kortmann RD, Pietsch T, Emser A, Warmuth-Metz M, Soerensen N, Straeter R, Graf N, Thieme B, Gnekow AK	Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: report from the HIT-LGG 1996 trial.	Pediatric blood & cancer 2011 Jul 1; 56: 1046
We describe demographic data of disseminated childhood low-grade glioma (DLGG) prospectively recruited in the HIT-LGG 1996 study and evaluate the impact of primary chemotherapy (CT) on the outcome of these tumors, which have previously only been described in small and retrospective series.
Zur, Hoser G, Reiter A, Welte K, Sykora K	Application of long PCR to detect t(8;14)(q24;q32) translocations in childhood Burkitt's lymphoma and B-ALL.	Ann Oncol 1997, 8 Suppl 1: 31-5: 31
Hotfilder M, Lanvers C, Jürgens H, Boos J, Vormoor J	c-KIT-expressing Ewing tumour cells are insensitive to imatinib mesylate (STI571).	Cancer Chemother Pharmacol 2002, 50: 167
Hotfilder M, Sondermann P, Senss A, van Valen F, Jürgens H, Vormoor J	PI3K/AKT is involved in mediating survival signals that rescue Ewing tumour cells from fibroblast growth factor 2-induced cell death.	British journal of cancer 2005, 92: 705
While in vitro studies had shown that fibroblast growth factor 2 (FGF2) can induce cell death in Ewing tumours, it remained unclear how Ewing tumour cells survive in vivo within a FGF2-rich microenvironment. Serum- and integrin-mediated survival signals were, therefore, studied in adherent monolayer and anchorage-independent colony cell cultures. In a panel of Ewing tumour cell lines, either adhesion to collagen or exposure to serum alone only had a minor protective effect against FGF2. However, both combined led to complete resistance to 5 ng ml(-1) FGF2 in three of four FGF2-sensitive cell lines (RD-ES, RM-82 and WE-68), and to an increased survival as compared to other culture conditions in TC-71 cells. Inhibition studies with LY294002 demonstrated that the serum signal is mediated via the phosphoinositide 3-OH kinase/AKT pathway. Thus, Ewing tumour cells escape FGF2-induced cell death by modulating FGF2 signalling. The tumour microenvironment provides the necessary survival signals by integrin-mediated adhesion and soluble serum factor(s). These survival signals warrant further investigation as a potential resistance mechanism to other apoptosis-inducing agents in vivo.
Houston SK, Murray TG, Wolfe SQ, Fernandes CE	Current update on retinoblastoma.	International ophthalmology clinics 2011, 51: 77
Howe GR, Burch JD, Chiarelli AM, Risch HA, Choi BC	An exploratory case-control study of brain tumors in children.	Cancer Res 1989, 49: 4349
Howell SJ, Shalet SM	Effect of cancer therapy on pituitary-testicular axis.	International journal of andrology 2002, 25: 269
Treatment with cytotoxic chemotherapy and radiotherapy is associated with significant gonadal damage in men. Alkylating agents, such as cyclophosphamide and procarbazine, are the most common agents implicated. The vast majority of men receiving procarbazine-containing regimens for the treatment of lymphomas are rendered permanently infertile. Treatment with adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) appears to have a significant advantage in terms of testicular function, with a return to normal fertility in the vast majority of patients. Cisplatin-based chemotherapy for testicular cancer results in temporary azoospermia in most men with a recovery of spermatogenesis in about 50% after 2 years and 80% after 5 years. There is also evidence of chemotherapy-induced Leydig cell impairment in a proportion of these men, although this appears to be of no clinical significance in the majority of patients. The germinal epithelium is very sensitive to radiation-induced damage with changes to spermatogonia following as little as 0.1 Gy, and permanent infertility after fractionated doses of 2 Gy and above, whereas clinically significant Leydig cell impairment occurs rarely with doses of less than 20 Gy.
Hsieh MM, Fitzhugh CD, Weitzel RP, Link ME, Coles WA, Zhao X, Rodgers GP, Powell JD, Tisdale JF	Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype.	JAMA 2014, 312: 48
Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be prohibitive for adults. Nonmyeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and graft-vs-host disease remain significant.
Hsu JL, Glaser SL	Epstein-Barr virus-associated malignancies: epidemiologic patterns and etiologic implications.	Crit Rev Oncol Hematol 2000, 34: 27
Hua C, Bass JK, Khan R, Kun LE, Merchant TE	Hearing loss after radiotherapy for pediatric brain tumors: effect of cochlear dose.	International journal of radiation oncology, biology, physics 2008 Nov 1; 72: 892
To determine the effect of cochlear dose on sensorineural hearing loss in pediatric patients with brain tumor treated by using conformal radiation therapy (CRT).
Hua C, Bass JK, Khan R, Kun LE, Merchant TE	Hearing loss after radiotherapy for pediatric brain tumors: effect of cochlear dose.	International journal of radiation oncology, biology, physics 2008 Nov 1; 72: 892
To determine the effect of cochlear dose on sensorineural hearing loss in pediatric patients with brain tumor treated by using conformal radiation therapy (CRT).
Hubner S, Cazzaniga G, Flohr T, van der, Konrad M, Potschger U, Basso G, Schrappe M, van Dongen J, Bartram C, Biondi A, Panzer-Grumayer E	High incidence and unique features of antigen receptor gene rearrangements in TEL-AML1-positive leukemias.	Leukemia 2004, 18: 84
Hubeek I, Peters GJ, Broekhuizen AJ, Talianidis I, Sigmond J, Gibson BE, Creutzig U, Giaccone G, Kaspers GJ	Immunocytochemical detection of deoxycytidine kinase in haematological malignancies and solid tumours.	Journal of clinical pathology 2005, 58: 695
BACKGROUND: Deoxycytidine kinase (dCK) is responsible for the activation of several clinically important deoxynucleoside analogues used for the treatment of haematological and solid malignancies. AIM: To measure dCK expression in tumour cells from different origins. METHOD: A rabbit antihuman dCK antibody was used for the immunocytochemical detection of dCK expression in three leukaemic cell lines (HL60, U937, and CCRF-CEM) and 97 patient samples (paediatric acute myeloid leukaemia (AML) and lymphoid leukaemia (ALL), retinoblastoma, paediatric brain tumours, and adult non-small cell lung cancer (NSCLC)). RESULTS: CCRF-CEM, U937, and HL60 cells stained positively for dCK and the degree of expression correlated with dCK activity. dCK expression varied between tumour types and between individual patients within one tumour type. dCK was located predominantly in the cytoplasm. The staining intensity was scored as negative (0), low (1+), intermediate (2+), or high (3+). Expression of dCK was high in AML blasts. In contrast, brain tumour samples expressed low amounts of dCK. dCK staining ranged from low (1+) to high (3+) in ALL blasts, retinoblastoma, and NSCLC tissue samples. Staining was consistent (interobserver variability, 88%; kappa = 0.83) and specific. Western blotting detected the dCK protein appropriately at 30 kDa, without additional bands. CONCLUSIONS: Immunocytochemistry is an effective and reliable method for determining the expression of dCK in patient samples and requires little tumour material. This method enables large scale screening of dCK expression in tumour samples.
Hubertus J, Boxberger N, Redlich A, von Schweinitz D, Vorwerk P	Surgical aspects in the treatment of adrenocortical carcinomas in children: data of the GPOH-MET 97 trial.	Klinische Padiatrie 2012, 224: 143
Adrenocortical carcinomas (ACCs) are a rare entity, with an incidence of 1.5 per million population per year. The prognosis of ACC is poor. Complete surgical resection is essential for a curative approach and significantly determines overall prognosis. Tumor resection is sophisticated and complicated by the vulnerability of the tumor and its invasive growth. Chemotherapy and Mitotane are additional therapeutic approaches that are combined with surgery in an interdisciplinary strategy. In this study, 59 patients between 2 months and 18 years of age with histologically verified ACC were analyzed retrospectively with respect to oncosurgical aspects. Patients were registered in the GPOH-MET 97 trial of the Society of Pediatric Oncology and Haematology. Preoperative management, factors influencing surgical severity, and operative complications were assessed.The gender ratio was 1:2 (m:f). A total of 58 patients showed increased hormonal activity and associated clinical signs of hormonal excess. Tumor volume was ≥ 300 mL in 25 patients. These patients showed an increased rate of operative complications and a poorer overall survival (OS) rate (p<0.01). A total of 14 patients showed metastatic spread, particularly to the lungs and lymph nodes. Biopsy of the tumor was performed in 12 patients. Tumor rupture occurred in 11 patients. Preoperative biopsy and/or experienced tumor rupture were associated with poorer OS rate. R2 resection only was achievable in 5 patients, and surgery was not feasible in 3 patients.In conclusion, since most of the pediatric ACC are hormone active and can be diagnosed clinically, the need of a tumor biopsy has to be discussed critically. Thorough pre- and perioperative management is essential for oncosurgical success.
Hudson MM, Poquette CA, Lee J, Greenwald CA, Shah A, Luo X, Thompson EI, Wilimas JA, Kun LE, Crist WM	Increased mortality after successful treatment for Hodgkin's disease.	J Clin Oncol 1998, 16: 3592
Hughes M, Marsden HB, Palmer MK	Histologic patterns of neuroblastoma related to prognosis and clinical staging.	Cancer 1974, 34: 1706
Hug K, Grize L, Seidler A, Kaatsch P, Schüz J	Parental occupational exposure to extremely low frequency magnetic fields and childhood cancer: a German case-control study.	American journal of epidemiology 2010, 171: 27
Extremely low frequency magnetic fields (ELF-MFs) have been classified as possibly carcinogenic to humans by the International Agency for Research on Cancer. The authors investigated, in a population-based case-control study in Germany, if children whose parents were exposed preconceptionally at work to ELF-MFs had an increased risk of developing cancer. Cases aged 0-14 years were ascertained from the German Childhood Cancer Registry. Controls were selected from local resident registration offices. The parental occupational history was recorded in questionnaires and telephone interviews, and preconceptional magnetic field exposure was estimated according to a job-exposure matrix. The analysis included 2,382 controls and 2,049 cases (846 children with acute leukemia, 159 children with non-Hodgkin's lymphoma, 444 children with central nervous system tumors, and 600 children with other solid tumors). Frequency-matched conditional logistic regression models revealed no increased cancer risks in children whose fathers were occupationally exposed to magnetic fields above 0.2 microT. Additionally, there was no evidence for a risk increase at magnetic field levels exceeding 1 microT. Based on much smaller numbers, maternal occupational exposure was also not related to increased cancer risks. In this large case-control study, the risk of childhood cancer was not linked to preconceptional parental ELF-MF exposure.
Humpl T	Neuroblastome, in: Gutjahr P (Hrsg.): Krebs bei Kindern und Jugendlichen.	Deutscher Ärzte-Verlag Köln 5. Aufl. 2004, 347
Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jürgens H	Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors.	Pediatric blood & cancer 2006, 47: 795
Hundsdoerfer P, Dietrich I, Schmelz K, Eckert C, Henze G	XIAP expression is post-transcriptionally upregulated in childhood ALL and is associated with glucocorticoid response in T-cell ALL.	Pediatric blood & cancer 2010, 55: 260
BACKGROUND: Resistance to glucocorticoid induced apoptosis is one of the major risk factors for relapse and poor outcome in childhood acute lymphoblastic leukemia (ALL). Overexpression of X-linked inhibitor of apoptosis protein (XIAP) has been shown to be associated with chemotherapy resistance in several malignancies. PROCEDURE: XIAP protein and mRNA expression were determined in leukemic blasts of 51 childhood ALL patients and normal bone marrow mononuclear cells. XIAP expression was correlated with glucocorticoid response and outcome. RESULTS: XIAP protein but not mRNA expression was found to be highly increased in childhood ALL compared to control bone marrow mononuclear cells (MNC) (median: 3.5 vs. 0.14 ng/10(5) MNC, P < 0.0001) indicating a post-transcriptional regulation of XIAP expression. In patients with T-cell ALL, poor prednisone response was associated with increased XIAP expression (median: 2.8 in good vs. 5.8 in poor responders; P = 0.005). Similarly, T-cell ALL patients suffering adverse events showed higher initial XIAP levels than patients in continuous complete remission (CCR) (median: 2.7 in patients in CCR vs. 5.6 in patients suffering adverse events; P = 0.007). XIAP inhibition using the low-molecular-weight SMAC mimetic LBW242 resulted in a significant increase of prednisone-induced apoptosis in vitro. CONCLUSION: In childhood ALL compared to control bone marrow, the expression of the apoptosis inhibitor XIAP is highly increased by post-transcriptional regulation. The association with poor in vivo glucocorticoid response and outcome in T-cell ALL suggests XIAP inhibition as a promising novel approach for the treatment of resistant ALL.
Hupp M, Falkenstein F, Bison B, Mirow C, Krauß J, Gnekow A, Solymosi L, Warmuth-Metz M	Infarction following chiasmatic low grade glioma resection.	Child's nervous system 2011,Epub ahead of print
INTRODUCTION: The current SIOP (International Society for Paediatric Oncology)-LGG (low grade glioma) study protocol allows chiasmatic tumours identified as LGG on the basis of neuroradiological characteristics to be treated without histological verification. As some tumours do not respond well to treatment, the search for molecular tissue markers will gain importance for future studies. Anecdotal observations of infarctions after surgery for chiasmatic tumours during central reviewing initiated this study. MATERIALS AND METHODS: In 84 patients, histology was obtained during 102 interventions in the years 1992-2009 by 33 biopsies, 67 partial/subtotal and 2 total resections. Median age at the time of operation was 5 years (mean 5 years 11 months). We could identify 17 infarctions following partial resection of chiasmatic LGG. Biopsies were not complicated by infarction. Children developing infarction were considerably younger (median 3 years; mean 4 years 5 months) than the patients without infarction (median 5 years 4 months; mean 6 years 2 months). A total of 51 patients with cerebellar LGG (median 7 years; mean 7 years 4 months) served as a control group, with 65 surgical procedures (2 biopsies, 22 partial/subtotal resections and 41 total resections) performed in the years 2004-2009. Only one total resection (1.5%) in this group was followed by infarction. CONCLUSION: Partial/subtotal resections of chiasmatic LGG in our study population bear a considerable risk for infarction especially in young children. As there is currently no evidence for a better outcome after tumour resection, we suggest that the sampling of tumour tissue should be performed via biopsies whenever possible.
Häberle H	Stationäre familienorientierte Nachsorge, in Schwarz R, Zettl S: Praxis der psychosozialen Onkologie.	Verlag für Medizin Fischer 1993
Häberle H, Schwarz R, Mathes L	Familienorientierte Betreuung bei krebskranken Kindern und Jugendlichen.	Prax Kinderpsych 1997, 46: 406
Häberle B, Hero B, Berthold F, von Schweinitz D	Characteristics and outcome of thoracic neuroblastoma.	Eur J Pediatr Surg 2002, 12: 145
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