| Autor(en) |
Titel |
Quelle |
Links |
| Labarque V, Van Geet C |
Clinical practice: immune thrombocytopenia in paediatrics. |
European journal of pediatrics 2014, 173: 163 |
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| Immune thrombocytopenia (ITP) is a disease affecting both children and adults. It is defined as acquired isolated thrombocytopenia caused by the autoimmune production of anti-platelet antibodies. Childhood ITP most frequently occurs in young children who have been previously well, although a viral respiratory tract infection often precedes thrombocytopenia. A benign and self-limiting course is common, but major bleeding complications such as intracranial haemorrhage may occur. Yet one cannot predict which child will have a prolonged course of thrombocytopenia and who will develop an intracranial haemorrhage. In children without atypical characteristics, only minimal diagnostic investigations are needed, and most paediatric ITP patients do not need platelet-enhancing therapy even though various treatment options are available. A |
| Ladenstein R, Treuner J, Koscielniak E, d'Oleire F, Keim M, Gadner H, Jürgens H, Niethammer D, Ritter J, Schmidt D |
Synovial sarcoma of childhood and adolescence. Report of the German CWS-81 study. |
Cancer 1993, 71: 3647 |
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| Ladisch S, Gadner H |
Treatment of Langerhans cell histiocytosis--evolution and current approaches. |
Br J Cancer Suppl 1994, 23: 41 |
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| Ladisch S, Gadner H, Arico M, Broadbent V, Grois N, Jacobson A, Komp D, Nicholson H |
LCH-I |
Med Pediatr Oncol 1994, 23: 107 |
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| Ladisch S, Gadner H, Elinder G |
Langerhans cell granulomatosis. |
Am J Surg Pathol 1997, 21: 1523 |
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| Ladenstein R, Matthay K, Berthold F, Kogner P, Pearsan A, Frappaz D, De Bernardi B, Yamamoto K, Hartmann O |
What can we expect from neuroblastoma screening? |
Med Pediatr Oncol 1998, 31: 408 |
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| Ladenstein R, Ambros I, Potschger U, Amann G, Urban C, Fink F, Schmitt K, Jones R, Slociak M, Schilling F, Ritter J, Berthold F, Gadner H, Ambros P |
Prognostic significance of DNA di-tetraploidy in neuroblastoma. |
Med Pediatr Oncol 2001, 36: 83 |
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| Ladenstein R, Berthold F, Ambros I, Ambros P |
Neuroblastome. |
In: Gadner H, Gaedicke G, Niemeyer R, Ritter J (Hrsg.). Pädiatrische Hämatologie und Onkologie Springer Verlag, 2006 |
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| Ladenstein R, Poetschger U, Hartman O, Jürgens H, Koscielniak E, Dallorso G, Doz F, Dini, G |
Megatherapy/SCT activity in paediatric solid tumours in Europe. |
Bone Marrow Transplant 2006, 37 Suppl.; 149 |
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| Ladenstein R, Whelan J, Oberlin O, Weston C, Juergens, H |
A prospective multicentre evaluation of intensive treatment including high-dose chemotherapy and PSCR for Ewing's tumours with extra-pulmonary metastatic disease. Results from the Euro-Ewing 99 Study. |
Bone Marrow Transplant 2006, 37 Suppl.; 16 |
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| Ladenstein R, Pötschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin O, van den Berg H, Dirksen U, Hjorth L, Michon J, Lewis I, Craft A, Jürgens H |
Primary Disseminated Multifocal Ewing Sarcoma: Results of the Euro-EWING 99 Trial. |
Journal of clinical oncology 2010, 28: 3284 |
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| PURPOSE To improve the poor prognosis of patients with primary disseminated multifocal Ewing sarcomas (PDMES) with a dose-intense treatment concept. PATIENTS AND METHODS From 1999 to 2005, 281 patients with PDMES were enrolled onto the Euro-EWING 99 R3 study. Median age was 16.2 years (range, 0.4 to 49 years). Recommended treatment consisted of six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), one cycle of vincristine, dactinomycin, and ifosfamide (VAI), local treatment (surgery and/or radiotherapy), and high-dose busulfan-melphalan followed by autologous stem-cell transplantation (HDT/SCT). Results After a median follow-up of 3.8 years, event-free survival (EFS) and overall survival (OS) at 3 years for all 281 patients were 27% +/- 3% and 34% +/- 4% respectively. Six VIDE cycles were completed by 250 patients (89%); 169 patients (60%) received HDT/SCT. The estimated 3-year EFS from the start of HDT/SCT was 45% for 46 children younger than 14 years. Cox regression analyses demonstrated increased risk at diagnosis for patients older than 14 years (hazard ratio [HR] = 1.6), a primary tumor volume more than 200 mL (HR = 1.8), more than one bone metastatic site (HR = 2.0), bone marrow metastases (HR = 1.6), and additional lung metastases (HR = 1.5). An up-front risk score based on these HR factors identified three groups with EFS rates of 50% for score /= 5 (70 patients; P < .0001). CONCLUSION PDMES patients may survive with intensive multimodal therapy. Age, tumor volume, and extent of metastatic spread are relevant risk factors. A score based on these factors may facilitate risk-adapted treatment approaches. |
| Ladenstein R, Pötschger U, Pearson ADJ, Brock P, Luksch R, Castel V, Yaniv I, Papadakis V, Laureys G, Malis J, Balwierz W, Ruud E, Kogner P, Schroeder H, de Lacerda AF, Beck-Popovic M, Bician P, Garami M, Trahair T, Canete A, Ambros PF, Holmes K, Gaze M, Schreier G, Garaventa A, Vassal G, Michon J, Valteau-Couanet D, SIOP Europe Neuroblastoma Group (SIOPEN) |
Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. |
The Lancet. Oncology 2017, 18: 500 |
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| High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. |
| Ladenstein R, Pötschger U, Valteau-Couanet D, Luksch R, Castel V, Yaniv I, Laureys G, Brock P, Michon JM, Owens C, Trahair T, Chan GCF, Ruud E, Schroeder H, Beck Popovic M, Schreier G, Loibner H, Ambros P, Holmes K, Castellani MR, Gaze MN, Garaventa A, Pearson ADJ, Lode HN |
Interleukin 2 with anti-GD2 antibody ch14. 18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. |
The Lancet. Oncology 2018, 19: 1617 |
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| Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma. |
| Längler A, Spix C, Jung I, Kaatsch P |
Comlementary and alternative medicine (CAM) in Pediatric oncology- results of a nationwide parents-questionnaire on frequency of CAM-use. |
37th SIOP Congress, Vancouver, Canada 2005 |
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| Längler A, Herold R, Kaatsch P, Souchon R, Tautz C |
Kinder sind keine kleine Erwachsenen (Teil 1: Allgemeine Grundlagen der pädiatrischen Onkologie). |
Klinikarzt 34: 159-64, 2005 |
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| Längler A, Spix C, Gottschling S, Graf N, Kaatsch P |
Parents-interview on use of complementary and alternative medicine in pediatric oncology in Germany. |
Klinische Pädiatrie 2005, 217: 357 |
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| BACKGROUND: There are no published data on the use of complementary and alternative medicine (CAM) in pediatric oncology in Germany. PATIENTS/METHOD: All parents of children, who where diagnosed a disease registered in the German Childhood Registry in 2001 were sent a questionnaire to evaluate possible CAM-use. RESULTS: 1 602 questionnaires were sent to the families, from whom 1 063 sent the questionnaire back to us. They reported a 35 % CAM-use-rate. The probability to use CAM was positively influenced by preexisting experience with CAM, higher social level and poor prognosis. 71 % of the users discussed the CAM-use with a physician. The reason for CAM-use seldom was missing trust in conventional medicine. 89 % of the CAM-users would recommend CAM-use to other parents in a comparable situation. CONCLUSIONS: The reported CAM-use rate of 35 % in pediatric oncology in Germany is as reported in the international literature for other European countries. Essential parts of CAM-advise and -prescription are done by non-professionals, so that there is a need to get competence in CAM in pediatric oncology in Germany. |
| Laengler A, Spix C, Seifert G, Gottschling S, Graf N, Kaatsch P |
Complementary and alternative treatment methods in children with cancer: A population-based retrospective survey on the prevalence of use in Germany. |
European journal of cancer 2008, 44: 2233 |
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| INTRODUCTION: Few studies have been conducted to date on the prevalence of use of complementary and alternative treatment methods (CAMs) in paediatric oncology, and those that have been conducted are often not representative. We therefore decided to study a representative sample of children with cancer in the German population. PATIENTS AND METHODS: The study took the form of a retrospective survey amongst all parents whose children were first diagnosed with a disease covered by the German Childhood Cancer Registry in 2001. The primary objectives of the survey were to establish the prevalence of use of CAM and the factors related to its use. RESULTS: Of the 1595 questionnaires sent out, 1063 (67%) could be evaluated. 35% of the responders had used CAM. The most frequently used methods were homeopathy, dietary supplements and anthroposophic medicine including mistletoe therapy. Factors which increased the probability of using CAM were the previous use of CAM, higher social status and poor prognosis of the child's disease. The most frequently named reasons for use of CAM were physical stabilisation, strengthening the immune system and improving the chance of cure. Whilst the sources of information about CAM were in most cases not doctors, 71% of users had nevertheless spoken to a doctor about using CAM. The effects of the CAM perceived by the parents were for the most part positive. 89% of the users reported that they would recommend CAM to other parents. CONCLUSIONS: CAMs are administered alongside standard therapy to 35% of children with cancer in Germany, usually by the parents. Prospective studies on the effects and side-effects of the most frequently used methods are urgently needed, and paediatric oncologists should have sufficient knowledge of CAM to enable them to advise parents professionally and competently about these treatments, too. |
| Laithier V, Grill J, Le Deley MC, Ruchoux MM, Couanet D, Doz F, Pichon F, Rubie H, Frappaz D, Vannier JP, Babin-Boilletot A, Sariban E, Chastagner P, Zerah M, Raquin MA, Hartmann O, Kalifa C, French Society of Pediatric Oncology |
Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy--results of the first French prospective study for the French Society of Pediatric Oncology. |
J Clin Oncol 2003, 21: 4572 |
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| PURPOSE: To evaluate a strategy aimed at avoiding radiotherapy during first-line treatment of children with progressive optic pathway tumors (OPT), by exclusively administering multiagent chemotherapy during 16 months. PATIENTS AND METHODS: Between 1990 and 1998, 85 children with progressive OPT were enrolled onto this multicenter nationwide trial. Chemotherapy alternating procarbazine plus carboplatin, etoposide plus cisplatin, and vincristine plus cyclophosphamide was given every 3 weeks. At the time of relapse or progression, second-line chemotherapy was authorized before recourse to radiotherapy. RESULTS: Objective response rate (partial response [PR] + complete response [CR]) to chemotherapy was 42%. Five-year progression-free survival (PFS) and overall survival rates were 34% and 89%, respectively. The 5-year radiotherapy-free survival rate was 61%. In the multivariate analysis of the 85 patients that entered onto the study, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P =.047) and absence of neurofibromatosis type 1 (P =.035). In the multivariate analysis of the 74 patients that remained on study after the first cycle of chemotherapy, factors associated with the risk of disease progression were age younger than 1 year at diagnosis (P =.0053) and no objective response to chemotherapy (P =.0029). Three-year PFS was 44% in infants < or = 1 year versus 66% in children older than 1 year. Three-year PFS was 53% in the absence of an objective response to chemotherapy versus 68% after a PR or CR. CONCLUSION: A significant proportion of children with OPT can avoid radiotherapy after prolonged chemotherapy. Deferring irradiation with chemotherapy protocols did not compromise overall survival of the entire population or visual function. |
| Lakatos K, Sterlich K, Pötschger U, Thiem E, Hutter C, Prosch H, Minkov M |
Langerhans Cell Histiocytosis of the Orbit: Spectrum of Clinical and Imaging Findings. |
The Journal of pediatrics 2021, 230: 174-181.e1 |
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| To evaluate the clinical and imaging characteristics of orbital lesions of pediatric Langerhans cell histiocytosis (LCH). |
| Lampert F, Harbott J, Ludwig W, Bartram C, Ritter J, Gerein V, Neidhardt M, Mertens R, Graf N, Riehm H |
Acute leukemia with chromosome translocation (4;11). |
Blut 1987, 54: 325 |
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| Lampert F, Harbott J, Ritterbach J, Schellong G, Ritter J, Creutzig U, Riehm H, Reiter A |
Karyotypes in acute childhood leukemias may lose prognostic significance with more intensive and specific chemotherapy. |
Cancer Genet Cytogenet 1991, 54: 277 |
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| Lampert F, Christiansen H, Berner F, Terpe H, Berthold F |
Disseminated neuroblastomas under 1 year of age. |
J Neurooncol 1997, 31: 181 |
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| Lampert F |
Langerhans cell histiocytosis. Historical perspectives. |
Hematol Oncol Clin North Am 1998, 12: 213 |
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| Lanvers C, Wagner A, Dübbers A, Krümpelmann S, Würthwein G, Ritter J, Creutzig U, Blaschke G, Jürgens H, Boos J |
Pharmakokinetics and metabolism of low-dose ATRA in children - first observations. |
Haematology and Blood Transfusion 1997, 39: 565 |
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| Langer T, Huk W, Hertzberg H, Überall M, Meier W, Korinthenberg R, Beck J |
Akute lymphoblastische Leukämie im Kindesalter. |
Dt Ärzteblatt 1998, 3058 |
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| Langer T, Hertzberg H, Dörr H, Greil J, Beck J |
Prinzipien zur Erfassung von Spätfolgen. |
Leitlinien Kinderheilkunde und Jugendmedizin 1999,L16-L22 |
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| Langer T, Henze G, Beck J |
Basic methods and the developing structure of a late effects surveillance system (LESS) in the long-term follow-up of pediatric cancer patients in Germany. For the German Late Effects Study Group in the German Society Pediatric Oncology and Hematology (GPOH). |
Med Pediatr Oncol 2000, 34: 348 |
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| Langer T, Krappmann P, Kochendörfer S, Kusch M, Göbel U, Huk W, Martus P, Beck J |
The late effects of prophylactic CNS treatment. Prognsotic factors and treatment strategies. |
Acute leukemias 2001,VIII: 370 |
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| Langebrake C, Reinhardt D, Ritter J |
Minimising the long-term adverse effects of childhood leukaemia therapy. |
Drug Saf 2002, 25: 1057 |
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| Langer T, Führer M, Stöhr W, Dörffel W, Dörr H, Bielack S, Rossi R, Kaatsch P, Beck J |
Die Überlebenden einer Krebserkrankung im Kindesalter. |
Monatsschr Kinderheilkd 2002, 150: 942 |
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| Langer T, Martus P, Ottensmeier H, Hertzberg H, Beck J, Meier W |
CNS late-effects after ALL therapy in childhood. Part III. |
Med Pediatr Oncol 2002, 38: 320 |
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| Langler A, Christaras A, Abshagen K, Krauth K, Hero B, Berthold F |
Topotecan in the treatment of refractory neuroblastoma and other malignant tumors in childhood - a phase-II-study. |
Klin Pädiatr 2002, 214: 153 |
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| Langer T, Beck J, Gravou-Apostulatou C, Lang P, Handgretinger R, Greil J |
Successful treatment of primary refractory acute myeloid leukemia with megadose stem cell transplantation, bone marrow boost and reduced intensity conditioning avoiding chronic graft vs. host disease and severe late toxicity. |
Pediatr Transplant 2003, 7: 494 |
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| Langer T, Metzler M, Reinhardt D, Viehmann S, Borkhardt A, Reichel M, Stanulla M, Schrappe M, Creutzig U, Ritter J, Leis T, Jacobs U, Harbott J, Beck J, Rascher W, Repp R |
Analysis of t(9;11) chromosomal breakpoint sequences in childhood acute leukemia. |
Genes Chromosomes Cancer 2003, 36: 393 |
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| Lanvers C, Reinhardt D, Dubbers A, Wagner-Bohn A, Creutzig U, Ritter J, Boos J |
Pharmacology of all-trans-retinoic acid in children with acute promyelocytic leukemia. |
Med Pediatr Oncol 2003, 40: 293 |
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| Langer T, Führer M, Stöhr W, Dörffel W, Dörr H, Bielack S, Rossi R, Kaatsch P, Beck J |
Die Überlebenden einer Krebserkrankung im Kindesalter. |
Monatsschr Kinderheilkd 2004, 150: 942 |
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| Langer T, Stohr W, Bielack S, Paulussen M, Treuner J, Beck J |
Late effects surveillance system for sarcoma patients. |
Pediatr Blood Cancer 2004, 42: 373 |
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| Langebrake C, Brinkmann I, Teigler-Schlegel A, Creutzig U, Griesinger F, Puhlmann U, Reinhardt D |
Immunophenotypic differences between diagnosis and relapse in childhood AML: Implications for MRD monitoring. |
Cytometry. Part B, Clinical cytometry 2005, 63: 1 |
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| BACKGROUND: Determination of antigen expression patterns is, in addition to morphologic analysis, essential to the diagnosis of acute myeloid leukemia (AML). The present study was performed to determine (a) the degree of changes in immunophenotype and their consequences on the monitoring of minimal residual disease (MRD) in childhood AML and (b) whether certain clusters of changes in antigen expression patterns exist between diagnosis and relapse. METHODS: Bone marrow specimens of 48 children enrolled in the German AML-BFM-93/98 (Acute Myeloid Leukemia-Berlin-Frankfurt-Munster) studies were analyzed immunologically, morphologically, and genetically at diagnosis and at first relapse. RESULTS: The immunophenotypes by flow cytometry differed by at least one antigen between samples at presentation and relapse in 42 of 48 children (88%). More children displayed an immature phenotype at relapse (43 of 47, 91.5%, vs. 37 of 48, 77%; P = 0.05) with expression of CD34 and/or CD117. This was reflected by a gain of markers that are associated with lineage immaturity in 18 of 25 (72%) of cases, whereas the loss of such antigens was observed in 6 of 25 (24%) patients. We did not observe significant changes for lineage specific markers, with comparable occurrences of loss or gain of myeloid and lymphoid antigens in the sample pairs. Only minimal changes were seen for morphologic and genetic features. CONCLUSION: An antigenic shift was observed in 88% of cases in this study. The antibody panels used for MRD monitoring in childhood AML should therefore not be restricted to the immunophenotype detected at presentation but should include in particular markers of lineage immaturity. The clinical observation of a shift toward a more immature phenotype of the myeloblasts is consistent with the model of a clonal evolution of a leukemic stem cell. |
| Langebrake C, Creutzig U, Reinhardt D |
Immunophenotype of Down syndrome acute myeloid leukemia and transient myeloproliferative disease differs significantly from other diseases with morphologically identical or similar blasts. |
Klinische Padiatrie 2005, 217: 126 |
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| BACKGROUND AND OBJECTIVES: Children with Down Syndrome (DS) have a 20-40 fold increased risk of developing acute myeloid leukemia (AML), mainly of the megakaryoblastic subtype (AMKL). Approximately 10 % of newborns with DS show transient myeloproliferative disease (TMD) which normally resolves spontaneously. The blast cells of both entities show megakaryoblastic/erythroblastic features (M7/M6) and cannot be distinguished by morphological characteristics. DESIGN AND METHODS: Blast cells of 62 children were analyzed by four-color flow cytometry and dual color fluorescence microscopy. RESULTS: The immunophenotype of blast cells from children with TMD and DS-AMKL is characterized by the expression of CD33 (+)/CD13 (+/-)/CD38 (+)/CD117 (+)/CD34 (+/-)/CD7 (+)/CD56 (+/-)/CD36 (+)/CD71 (+)/CD42b (+)/CD4dim (+)/TPO-R (+)/EPO-R (-)/IL-3-Ralpha (+)/IL-6-Ralpha (-). Non-DS children with morphologically related diseases, i. e. myelodysplastic syndrome (MDS), juvenile myelomonocytic leukemia (JMML), or AML-M6 and AML-M7, did not show this expression profile. CD34 expression was observed in 93 % of TMD, but only 50 % of DS-AMKL patients. The blast cells of all TMD and DS-AMKL cases were positive for TPO-R and IL-3R, whereas EPO-R and IL-6R were absent. CONCLUSIONS: Immunophenotyping by the use of surface antigens and growth factor receptors is a useful tool to discriminate TMD and DS-AMKL from diseases with morphologically similar or identical blasts. The absence of EPO-R on the blast cells might be a sign of the high expression of the mutated -- and less active -- GATA1 in DS. The higher amount of CD34 co-expression in TMD may be interpreted to indicate that TMD is a slightly more immature disease than DS-AMKL. |
| Langer T, Dörr HG, Bielack S, Jürgens H, Göbel U, Willich N and Beck JD |
Spätfolgen in der Nachsorge von krebskranken Kindern und Jugendlichen. |
Der Onkologe 2005, 11: 1101 |
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| Langer T, Stöhr W, Paulides M, Kremers A, Dorr HG, Göbel U, Beck JD |
Prospective multicenter registration of major late sequelae in sarcoma patients using the Late Effects Surveillance System (LESS). |
Klinische Pädiatrie 2005, 217: 176 |
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| BACKGROUND: Late effects become progressively more important for the evaluation of therapeutic success in paediatric oncology. Thus, in 1998, the Late Effects Surveillance System (LESS) started to register and assess multicentrally, prospectively and longitudinally late effects of treatment for the group of Ewing's, soft tissue- and osteosarcoma patients. PATIENTS AND METHODS: The yearly results of the follow-up examinations of 785 Ewing's, soft tissue- and osteosarcoma patients, who were treated from 1.1.1998 until 31.12.2001, were prompted and assessed conforming to the guidelines developed by the LESS-study. RESULTS: 136/181 (75 %) of follow-up institutions take part in the LESS-study. Only 8 % of patients eligible for the LESS-study were cared for in non-cooperating facilities. Questionnaire return could be raised to 73-78 % and data completeness could also be significantly improved in the course of the study. Departments of internal medicine had a lower questionnaire return percentage than departments of paediatrics. Data availability for the nephrologic after-care was not satisfactory. CONCLUSIONS: The LESS project has been well established. Thus, the basis has been set for the development of risk-oriented strategies for intervention and for the further improvement of the follow-up of major late effects in sarcoma patients. |
| Lanvers-Kaminsky C, Winter B, Koling S, Frodermann B, Braun Y, Schaefer KL, Diallo R, Koenemann S, Wai D, Willich N, Poremba C, Schuck A |
Doxorubicin modulates telomerase activity in Ewing's sarcoma in vitro and in vivo. |
Oncology reports 2005, 14: 751 |
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| Since most tumours escape replicative senescence by re-activation of the enzyme telomerase, telomerase is a promising target in the treatment of cancer and a promising marker for diagnosis and therapeutic response. We evaluated the effects of doxorubicin, one of the most active drugs in the treatment of Ewing's sarcoma, on telomerase in the human Ewing's sarcoma cell line STA-ET-1 in vitro and in STA-ET-1 xenografts in vivo. Telomerase activity (TA) was examined by TRAP-assay and real-time PCR. Real-time PCR was also used to quantify the mRNA expression of the catalytic subunit of telomerase (hTERT). In vitro growth inhibition was determined by the MTT-assay. Tumour xenografts were analyzed for tumour volume, apoptosis, necrosis, and proliferation. Doxorubicin concentrations that inhibited in vitro growth of STA-ET-1 by 50% compared to untreated controls ranged between 0.14 microM after 24 h and 0.01 microM after 72 h. Compared to untreated controls doxorubicin reduced TA in STA-ET-1 at toxic concentrations, but increased TA at non-toxic concentrations. In comparison with untreated xenografts, TA was reduced to 65% and hTERT expression dropped to 25% within 72 h in xenografts treated with 17.5 mg/kg doxorubicin i.p.; both recovered to initial values after 264 h. The rate of proliferating cells dropped to 70% within 96 h and increased thereafter. The highest rates of necrosis and apoptosis were seen after 96 h. hTERT expression co-varied significantly with proliferation but not with TA, apoptosis, and necrosis. No correlation was observed between TA, proliferation, apoptosis and necrosis. The results suggest doxorubicin induces down-regulation of hTERT gene expression that at least in part modulates TA in these tumours. |
| Langebrake C, Creutzig U, Dworzak M, Hrusak O, Mejstrikova E, Griesinger F, Zimmermann M, Reinhardt D |
Residual disease monitoring in childhood acute myeloid leukemia by multiparameter flow cytometry: the MRD-AML-BFM Study Group. |
Journal of clinical oncology 2006, 24: 3686 |
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| PURPOSE: Monitoring of residual disease (RD) by flow cytometry in childhood acute myeloid leukemia (AML) may predict outcome. However, the optimal time points for investigation, the best antibody combinations, and most importantly, the clinical impact of RD analysis remain unclear. PATIENTS AND METHODS: Five hundred forty-two specimens of 150 children enrolled in the AML-Berlin-Frankfurt-Muenster (BFM) 98 study were analyzed by four-color immunophenotyping at up to four predefined time points during treatment. For each of the 12 leukemia-associated immunophenotypes and time points, a threshold level based on a previous retrospective analysis of another cohort of children with AML and on control bone marrows was determined. RESULTS: Regarding all four time points, there is a statistically significant difference in the 3-year event-free survival (EFS) in those children presenting with immunologically detectable blasts at 3 or more time points. The levels at bone marrow puncture (BMP) 1 and BMP2 turned out to have the most significant predictive value for 3-year-EFS: 71% +/- 6% versus 48% +/- 9%, P(Log-Rank) = .029 and 70% +/- 6% versus 50% +/- 7%, P(Log-Rank) = .033), resulting in a more than two-fold risk of relapse. In a multivariate analysis, using a combined risk classification based on morphologically determined blasts at BMP1 and BMP2, French-American-British classification, and cytogenetics, the influence of immunologically determined RD was no longer statistically significant. CONCLUSION: RD monitoring before second induction has the same predictive value as examining levels at four different time points during intensive chemotherapy. Compared with commonly defined risk factors in the AML-BFM studies, flow cytometry does not provide additional information for outcome prediction, but may be helpful to evaluate the remission status at day 28. |
| Lanvers-Kaminsky C, Nolting DM, Koster J, Schroder A, Sandkotter J, Boos J |
In-vitro toxicity of Ukrain against human Ewing tumor cell lines. |
Anti-cancer drugs 2006, 17: 1025 |
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| Ukrain is advertised by the manufacturer as a drug for alternative cancer cures with high activity against progressive Ewing tumors. Using the MTT assay, we compared the cytotoxicity of Ukrain with the cytotoxicity of N,N',N''-triethylenethiophosphoramide (thioTEPA), Chelidonium majus L. alkaloids, doxorubicin, cyclophosphamide and etoposide against four human Ewing tumor cell lines. In addition, we studied the cytotoxicity of thioTEPA combined with C. majus L. alkaloids after 48, 72 and 96 h. All compounds reduced the growth of Ewing tumor cell lines in a dose-dependent manner. The concentrations that reduced cell growth by 50% ranged between 6.2 and 31.1 micromol/l for Ukrain, 1.9 and 26.1 micromol/l for C. majus L. extract, and 1.7 and 448 micromol/l for thioTEPA. The sensitivity profile of Ukrain was comparable to that of the C. majus L. alkaloids, and different from that of thioTEPA, cyclophosphamide, etoposide and doxorubicin. Overall, doxorubicin was the most cytotoxic drug followed by cyclophosphamide. Ukrain and the C. majus L. alkaloids were slightly more cytotoxic than etoposide, while thioTEPA showed the lowest cytotoxicity. Co-exposure of thioTEPA with C. majus L. alkaloids resulted in additive but not in synergistic cytotoxicity. The in-vitro results indicate that the cytotoxicity of Ukrain against Ewing tumors is comparable to that of etoposide. While the latter can be used on the basis of broad clinical experience and known risk-benefit ratio, Ukrain for the present might be considered as a candidate for subsequent drug development by xenograft studies followed by systematic clinical trials. |
| Lanvers-Kaminsky C, Bremer A, Dirksen U, Jürgens H, Boos J |
Cytotoxicity of treosulfan and busulfan on pediatric tumor cell lines. |
Anti-cancer drugs 2006, 17: 657 |
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| High-dose chemotherapy of solid tumors aims at eliminating residual or metastatic tumor cells, which remained after conventional treatment. Thus, anticancer drugs used for high-dose chemotherapy should display significant cytotoxicity against the respective tumors. As little data are available about the in-vitro toxicity of busulfan and treosulfan especially on pediatric tumor cell lines, we compared the cytotoxicity of treosulfan and busulfan on four Ewing tumor, four neuroblastoma, two osteosarcoma and two leukemia cell lines in vitro. Growth inhibition of tumor cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide test after 24, 48, 72 and 96 h. Treosulfan and busulfan reduced the growth of all tumor cell lines in a time-dependent and dose-dependent manner. In vitro treosulfan was consistently more cytotoxic than busulfan. Fifty percent growth inhibitions of 608-0.73 micromol/l were determined for treosulfan and of above 5,000-2.81 micromol/l for busulfan. Both drugs exhibited similar cytotoxicity profiles. Busulfan-sensitive/resistant cell lines were also sensitive/resistant to treosulfan. Overall, the leukemia cell lines were most sensitive to busulfan and treosulfan. The Ewing tumor cell lines were the second most sensitive followed by the neuroblastoma cell lines. The osteosarcoma cell lines were the most resistant cell lines. Although the in-vitro stability of both drugs makes direct comparison of their in-vitro toxicity difficult and does not allow any estimation of dosages needed clinically, the in-vitro results indicate substantial cytotoxicity of both drugs on leukemias, Ewing tumors and neuroblastomas. These data suggest further evaluation of treosulfan for high-dose chemotherapy of advanced Ewing tumors, neuroblastomas and high-risk leukemias. |
| Langer T, Dörr H-G, Beck J-D |
Spätfolgen der Erkrankung und Therapie. |
In: Gadner H, Gaedicke G, Niemeyer C, Ritter J, editors. Pädiatrische Hämatologie und Onkologie Berlin, Heidelberg, New York: Springer Verlag, 2006, 1085 |
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| |
| Langer T, Paulides M |
Nachsorge von krebskranken Kindern, Jugendlichen und jungen Erwachsenen - Erkennen, Vermeiden und Behandeln von Spätfolgen. |
Leitlinien für die Diagnostik und Therapie in der Pädiatrischen Onkologie und Hämatologie AWMF online 2007 |
|
| Lanino E, Sacchi N, Peters C, Giardino S, Rocha V, Dini G, EBMT Paediatric, Acute Leukemia Working Parties, Eurocord |
Strategies of the donor search for children with second CR ALL lacking a matched sibling donor. |
Bone marrow transplantation 2008, 41 Suppl 2:S75 |
|
| During the last 10 years, the number of alternative Haematopoietic stem cell transplantations (HSCTs) performed on children in Europe has increased significantly and has reached 61% of the allografts. In this paper, we provide practical guidelines to help define an algorithm for the treatment of children relapsing during or after first-line chemotherapy for ALL and lacking a matched sibling donor. A simultaneous search for an unrelated donor and for a cord blood unit should be started. This study focuses mainly on the effects of some factors on survival in an effort to highlight the influence that these factors have on our choices. Matching the patient for HLA-A, -B, -C and -DRB1 alleles remains the top priority: a single HLA class I or II allele mismatch has no influence on survival, while multiple mismatching for more than one class I allele and simultaneous disparities in class I and II alleles increase mortality. The impact of additional mismatches for HLA-DQ and -DP loci on survival is still controversial. Young donor age is the most important factor that has a significant effect on better survival from among several other factors, including CMV sero-status, gender and ABO. An 18- to 30-year-old, 8/8 allele-matched donor (excluding allele matching at DQB1) or for many teams 10/10 allele-matched donor; or a 4 out of 6 (considering Ag HLA-A, -B and allelic typing of DRB1) CB unit containing more than 3.0 x 10(7) nuclear cells is considered by most institutions. The choice should be made on the basis of urgency. If a donor or a CB unit is not found within an appropriate time frame, generally less than 3 months after obtention of remission, haploidentical HSCT should be offered. Some institutions consider haploidentical HSCT the second therapeutic option when a matched donor is not available. |
| Landmann E, Oschlies I, Zimmermann M, Moser O, Graf N, Suttorp M, Greiner J, Reiter A, Berlin-Frankfurt-Münster group |
Secondary non-Hodgkin lymphoma (NHL) in children and adolescents after childhood cancer other than NHL. |
British journal of haematology 2008, 143: 387 |
|
| The emergence of non-Hodgkin lymphoma (NHL) during childhood and adolescence as a secondary neoplasm (SN) after previous cancer other than NHL is rare. To describe the characteristics and outcome of NHL following previous cancer other than NHL in children and adolescents, this study analysed the data of patients reported to the NHL-Berlin-Frankfurt-Münster study centre from 1986 to 2005. Out of the total of 2968 NHL-patients registered, 11 patients were assessed as having suffered from NHL as a proven SN. Four additional children had most likely suffered from NHL as an SN, but a late relapse of the first neoplasm could not be ruled out unequivocally. In the patients with proven SN, median age at diagnosis of the primary malignancy was 3.9 years (range 2-11.7). The median age at diagnosis of NHL was 7.6 years (range 4.7-18). Only lymphoblastic (n = 7) and diffuse large B-cell (n = 4) lymphomas were diagnosed as SN. The estimated 5-year event-free survival from time of diagnosis of NHL was 91% [95% confidence interval (CI) 74-100%] in patients with proven SNs and 84% (95% CI 63-100%) when the patients with probable SNs were included in the analysis. We concluded that secondary NHL in children and adolescents confers a favourable prognosis. |
| Langer T, Meitert J, Dörr H-G, Beck J-D, Paulides M |
Langzeitfolgen von onkologischen Erkrankungen bei Kindern - Erkennen, Vermeiden und Behandeln von Spätfolgen. |
Im Focus Onkologie 7-8, 2011 |
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| Lannering B, Rutkowski S, Doz F, Pizer B, Gustafsson G, Navajas A, Massimino M, Reddingius R, Benesch M, Carrie C, Taylor R, Gandola L, Björk-Eriksson T, Giralt J, Oldenburger F, Pietsch T, Figarella-Branger D, Robson K, Forni M, Clifford SC, Warmuth-Metz M, von Hoff K, Faldum A, Mosseri V, Kortmann R |
Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial. |
Journal of clinical oncology 2012 Sep 10; 30: 3187 |
|
| To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy. |
| Langer T, Am Zehnhoff-Dinnesen A, Radtke S, Meitert J, Zolk O |
Understanding platinum-induced ototoxicity. |
Trends in pharmacological sciences 2013, 34: 458 |
|
| Childhood cancer survival rates are now nearly 80% in more developed European countries because of improved therapies and better supportive care. Platinum chemotherapy drugs, such as cisplatin and carboplatin, are the cornerstone of many effective therapeutic protocols for childhood cancer. However, the antitumor efficacy of cisplatin and carboplatin comes at the cost of ototoxicity, which affects at least 60% of pediatric patients. Although ototoxicity is not life threatening, it can have debilitating effects on patients' quality of life. Recently, many initiatives have been launched with the ultimate goal of reducing cisplatin and high-dose carboplatin ototoxicity without compromising antitumor efficacy. This review addresses the incidence of platinum ototoxicity and its clinical presentation, time course, and early diagnostic evaluation. Genetic and non-genetic risk factors for platinum-associated ototoxicity, and their predictive value, are discussed. Recent developments in the prevention of platinum ototoxicity are also summarized. |
| Lange J, Lenz G, Burkhardt B |
Mature aggressive B-cell lymphoma across age groups - molecular advances and therapeutic implications. |
Expert review of hematology 2017, 10: 123 |
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| Landmann E, Burkhardt B, Zimmermann M, Meyer U, Woessmann W, Klapper W, Wrobel G, Rosolen A, Pillon M, Escherich G, Attarbaschi A, Beishuizen A, Mellgren K, Wynn R, Ratei R, Plesa A, Schrappe M, Reiter A, Bergeron C, Patte C, Bertrand Y |
Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma. |
Haematologica 2017, 102: 2086 |
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| Langer T, Grabow D, Steinmann D, Wörmann B, Calaminus G |
Late Effects and Long-Term Follow-Up after Cancer in Childhood. |
Oncology research and treatment 2017, 40: 746 |
|
| Today, 80% of children and adolescents with cancer survive their disease. From the results of aftercare research arises the question: Are the survivors also healthy? Many late effects depend on the type of cancer and its treatment. Patients with brain tumors and with malignant sarcomas are very often affected by secondary diseases. Data from the USA report that around 2/3 of all patients still living 30 years after their cancer treatment in childhood suffer from late complications. Equivalent figures for Germany were previously unavailable. In accordance with the guidelines, regular follow-ups to diagnose a relapse or possible late effects have mostly been carried out in the primary children's hospitals. In adolescence and in young adulthood, this regimen does no longer serve the patients' mental and physical needs. To ensure appropriate care for this maturing patient group, interdisciplinary approaches (e.g., aftercare consultations) are required in which pediatric oncologists collaborate with colleagues from the field of internal medicine and other disciplines. Individual, risk-adapted (depending on the cancer treatment) aftercare plans based on pre-existing aftercare recommendations must be drawn up for every patient and to secure the early diagnosis of possible late effects. The conservation of health and quality of life after cancer treatment (in all age groups) will in the future not only represent a social but also an economic consideration. |
| Langer et al. |
Langzeitbeobachtung ehemaliger krebskranker Kinder und Jugendlicher. |
Klin Pädiatr 2018 230: 291 |
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| Lauten M, Stanulla M, Zimmermann M, Welte K, Riehm H, Schrappe M |
Clinical outcome of patients with childhood acute lymphoblastic leukaemia and an initial leukaemic blood blast count of less than 1000 per microliter. |
Klin Pädiatr 2001, 213: 169 |
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| Lauten M, Matthias T, Stanulla M, Beger C, Welte K, Schrappe M |
Association of initial response to prednisone treatment in childhood acute lymphoblastic leukaemia and polymorphisms within the tumour necrosis factor and the interleukin-10 genes. |
Leukemia 2002, 16: 1437 |
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| Laupert A, Bodenmüller-Kroll R, Böttcher M, Overkamp F, Wiedemann GJ |
Fortbildung für Arzthelferinnen in onkologischen Schwerpunktpraxen - eine Bilanz. |
In|Fo|Onkologie 2003, 2: 82 |
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| Lauten M, Asgedom G, Welte K, Schrappe M, Stanulla M |
Thymidylate synthase gene polymorphism and its association with relapse in childhood B-cell precursor acute lymphoblastic leukemia. |
haematologica 2003, 88: 353 |
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| Lauten M, Beger C, Gerdes K, Asgedom G, Kardinal C, Welte K, Schrappe M |
Expression of heat-shock protein 90 in glucocorticoid-sensitive and -resistant childhood acute lymphoblastic leukaemia. |
Leukemia 2003, 17: 1551 |
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| Lauten M, Cario G, Asgedom G, Welte K, Schrappe M |
Protein expression of the glucocorticoid receptor in childhood acute lymphoblastic leukemia. |
haematologica 2003, 88: 1253 |
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| Lauten M, Möricke A, Beier R, Zimmermann M, Stanulla M, Meissner B, Odenwald E, Attarbaschi A, Niemeyer C, Niggli F, Riehm H, Schrappe M |
Prediction of outcome by early bone marrow response in childhood acute lymphoblastic leukemia treated in the trial ALL-BFM 95. Differential effects in precursor B-cell and T-cell leukemia. |
Haematologica 2012, Epub ahead of print |
|
| Background. In the trial ALL-BFM 95 for treatment of acute lymphoblastic leukemia, response to a prednisone pre-phase (prednisone response) was used for risk stratification in combination with age and white blood cell count at diagnosis, response to induction therapy, and specific genetic high-risk features. Design and Methods. Cytomorphologic marrow response was prospectively assessed on day 15 during induction, and its prognostic value was analyzed in 1431 patients treated on ALL-BFM 95.Results. The 8-year probabilities of event-free survival were 86.1%, 74.5%, and 46.4% for patients with M1, M2, and M3 day 15 marrows, respectively. Compared to prednisone response, day 15 marrow response was superior in outcome prediction in precursor B cell and T cell leukemia - yet with differential effect depending on blast lineage. Outcome was poor in T cell leukemia patients with prednisone poor-response independent of day 15 marrow response, whereas among patients with prednisone good-response different risk groups could be identified by day 15 marrow response. In contrast, prednisone response lost prognostic significance in precursor B cell leukemia when stratified by day 15 marrow response. Age and white blood cell count retained their independent prognostic effect.Conclusions. Selective addition of day 15 marrow response to conventional stratification criteria applied on ALL-BFM 95, currently in use as regular chemotherapy protocol for childhood acute lymphoblastic leukemia in several countries, may significantly improve risk-adapted treatment delivery. Even though cutting-edge trial risk stratification is meanwhile dominated by minimal residual disease evaluation, an improved conventional risk assessment, as presented here, could be of great importance to countries lacking the technical and/or financial resources associated with the application of minimal residual disease analysis. |
| Lautz TB, Martelli H, Fuchs J, Chargari C, Smeulders N, Granberg CF, Wolden SL, Sparber-Sauer M, Hawkins DS, Bisogno G, Koscielniak E, Rodeberg DA, Seitz G, INSTRuCT group |
Local treatment of rhabdomyosarcoma of the female genital tract: Expert consensus from the Children's Oncology Group, the European Soft-Tissue Sarcoma Group, and the Cooperative Weichteilsarkom Studiengruppe. |
Pediatric blood & cancer 2020,:e28601 |
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| The International Soft-Tissue Sarcoma Consortium (INSTRuCT) was founded as an international collaboration between different pediatric soft-tissue sarcoma cooperative groups (Children's Oncology Group, European Pediatric Soft-Tissue Sarcoma Group, and Cooperative Weichteilsarkom Studiengruppe). Besides other tasks, a major goal of INSTRuCT is to develop consensus expert opinions for best clinical treatment. This consensus paper for patients with rhabdomyosarcoma of the female genital tract (FGU-RMS) provides treatment recommendations for local treatment, long-term follow-up, and fertility preservation. Therefore, a review of the current literature was combined with recommendations of the treatment protocols of the appropriate clinical trials. Additionally, opinions of international FGU-RMS experts were incorporated into recommendations. Results were that the prognosis of FGU-RMS is favorable with an excellent response to chemotherapy. Initial complete surgical resection is not indicated, but diagnosis should be established properly. In patients with tumors localized at the vagina or cervix demonstrating incomplete response after induction chemotherapy, local radiotherapy (brachytherapy) should be carried out. In patients with persistent tumors at the corpus uteri, hysterectomy should be performed. Fertility preservation should be considered in all patients. In conclusion, for the first time, an international consensus for the treatment of FGU-RMS patients could be achieved, which will help to harmonize the treatment of these patients in different study groups. |
| Launspach M, Seif M, Thole TM, Jesse P, Schulz J, Schulte JH, Bischoff S, Eggert A, Deubzer HE |
Clinical Presentation and Management of a Dinutuximab Beta Extravasation in a Patient with Neuroblastoma. |
Children (Basel, Switzerland) 2021, 8 |
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| Extravasation can present serious accidental complication of intravenous drug application. While monoclonal antibodies do not show the necrotic potential of cytotoxic chemotherapy drugs, considerable inflammatory toxicity can occur, necessitating standardized operating procedures for the management of their extravasation. Here, we report the clinical course and management of dinutuximab beta extravasation in a 3-year-old child. Dinutuximab beta is a chimeric monoclonal antibody targeting the GD2 disialoganglioside on the surface of neuroblastoma cells that has in recent years gained significant importance in the treatment of high-risk neuroblastoma, now contributing to both first- and second-line therapy protocols. The dinutuximab beta extravasation reported here occurred when the patient received the antibody cycle as a continuous infusion over a 10-day period after haploidentical stem cell transplantation for relapsed high-risk neuroblastoma. The extravasated dinutuximab beta caused local pain, swelling, and hyperemia accompanied by fever and an overall deterioration in the general condition. Laboratory diagnostics demonstrated an increase in C-reactive protein level and total white blood cell count. Clinical complication management consisted of intravenous fluid therapy, local dabbing with dimethyl sulfoxide (DMSO), analgesia with dipyrone, as well as application of intravenous antibiotics to prevent bacterial superinfection in the severely immunocompromised host. The patient considerably improved after six days with this treatment regimen and fully recovered by day 20. |
| Launspach M, Temel D, Ohlendorf E, Zirngibl F, Materne B, Oevermann L, Deubzer HE, Henssen AG, Künkele A, Hundsdörfer P, Bernuth HV, Pruß A, Eggert A, Stackelberg AV, Lang P, Schulte JH |
Rituximab therapy after pediatric hematopoietic stem cell transplantation can cause prolonged B-cell impairment and increases the risk for infections - a retrospective matched cohort study. |
Haematologica 2023, 108: 267 |
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| Lawrenz-Wolf B, Wolfrom C, Frickel C, Fengler R, Wehinger H, Henze G |
Severe renal impairment of methotrexate elimination after high dose therapy. |
Klin Pädiatr 1994, 206: 319 |
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| Laws H, Burdach S, van Kaick B, Engel B, Dirksen U, Körholz D, Pape H, Kahn T, Merck H, Schmitz M, Heyll A, Jürgens H, Göbel U |
Multimodality diagnostics and megatherapy in poor prognosis Ewing's tumor patients. A single-center report. |
Strahlenther Onkol 1999, 175: 488 |
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| Laws HJ, Lehrnbecher T |
Therapie von Infektionen in der Kinderonkologie. |
Klin Pädiatr 2005, 217 Suppl 1: 1 |
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| Laws HJ, Lehrnbecher T, Meisel R |
Wer soll wann, wogegen und womit geimpft werden? Impfstrategien bei Kindern nach onkologischer Therapie. |
WIR 2005, 3 |
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| Laws HJ, Ammann RA, Lehrnbecher T |
Diagnostic procedures and management of fever in pediatric cancer patients. |
Klin Pädiatr 2005, 217 Suppl 1:S9 |
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| Laws HJ, Janssen G, Borkhardt A |
Reassessment of treatment modalities for paediatric patients with chronic immune thrombocytopenia. |
Hamostaseologie 2009, 29: 171 |
|
| Approximately 70% of children have the acute form of immune thrombocytopenia (ITP), which is defined by recovery within six months of presentation with or without treatment. Chronic ITP is to be reserved for patients with platelets < 100000/microl for more than twelve months and exclusion of other diagnosis like systemic lupus erythematosus or bone marrow failures. In children, the chance of spontaneous recovery is 52% after diagnosis of chronic ITP. The Intercontinental Childhood ITP Study group recommends that children without bleeding may not require therapy regardless of their platelet count. Whereas in patients with bleeding symptoms first line therapy is defined and includes steroids or immunoglobuline, second line therapy in refractory patients with significant hemorrhagic problems is unclear. Guidelines recommend splenectomy, but for more than 50 years patients and physicians look for pharmacological alternatives. It may be that rituximab is a promising option which has been proven to be effective with few adverse effects. Till now the treatment has focused on immunomodulation. Research has now focused on stimulating platelet production. In this review we discuss old and new therapy modalities for children with cITP. |
| Lawitschka A, Ball L, Peters C |
Nonpharmacologic treatment of chronic graft-versus-host disease in children and adolescents. |
Biology of blood and marrow transplantation 2012, 18(1 Suppl):S74-81. |
|
| Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many children with life-threatening diseases. One of the most significant long-term complications of transplantation is chronic graft-versus-host disease (cGVHD). Although the rates of cGVHD after HSCT are lower in the pediatric population than in adults, cGVHD remains a significant cause of morbidity and mortality. Medicines used to prevent and treat cGVHD remain unsatisfactory, with protracted use of immune suppression necessary and high rates of first-line treatment failure. Efforts to improve salvage treatment are urgently required. Nonpharmacologic strategies attempt to modulate the cellular inflammation response and possibly allow reduction or cessation of immunosuppressive drugs. Mesenchymal stromal cells (MSC) have been shown in vitro to mediate a wide variety of immune responses. MSC have been used in the prophylaxis of acute GVHD (aGVHD) and for the treatment of established steroid refractory aGVHD and, more recently, in the management of cGVHD. Extracorporeal photochemotherapy (ECP) has shown promising efficacy in graft-versus-host disease, and may allow a significant reduction in the use of systemic steroids and other immunosuppressants, reducing long-term morbidity and mortality. The accumulated experience shows ECP to be well tolerated, with no clinically significant side effects. |
| Law N, Greenberg M, Bouffet E, Taylor MD, Laughlin S, Strother D, Fryer C, McConnell D, Hukin J, Kaise C, Wang F, Mabbott DJ |
Clinical and neuroanatomical predictors of cerebellar mutism syndrome. |
Neuro-oncology 2012, 14: 1294 |
|
| Cerebellar mutism syndrome (CMS) is an important medical challenge in the management of pediatric posterior fossa brain tumors, because it occurs in a subset of children following tumor resection. A definitive clinical profile and neuroanatomical substrate associated with CMS remains unclear. We investigated the relationship between presurgical and clinical variables and the incidence of CMS, along with diffusion tensor imaging, to characterize the integrity of cerebello-thalamo-cerebral white matter pathways. Seventeen children with posterior fossa tumors and CMS, 34 children with posterior fossa tumors without CMS, and 28 healthy children were enrolled in this study. Bilateral cerebello-thalamo-cerebral pathways were delineated and segmented into anatomical regions. Mean integrity measures for each region were compared among children with CMS, children without CMS, and healthy children. Left-handedness, medulloblastoma histology, and larger tumor size distinguished between patients with CMS and patients without CMS (P < .04). Right cerebellar white matter within the cerebello-thalamo-cerebral pathway was compromised in children with CMS relative to children without CMS and healthy children (P < .02). We provide a potential schema for CMS risk among children treated for posterior fossa tumors. Left-handed children treated for medulloblastoma may be the most at risk for CMS, and unilateral, localized damage within the cerebello-thalamo-cerebral pathway at the level of the right cerebellum is implicated in the presentation of CMS. This disruption in communication between the right cerebellum and left frontal cortex may contribute to speech-language problems observed in children with CMS. Our findings may be relevant for surgical planning and speech-language therapy to mitigate symptoms of CMS. |
| Lawitschka A, Faraci M, Yaniv I, Veys P, Bader P, Wachowiak J, Socie G, Aljurf MD, Arat M, Boelens JJ, Duarte R, Tichelli A, Peters C |
Paediatric reduced intensity conditioning: analysis of centre strategies on regimens and definitions by the EBMT Paediatric Diseases and Complications and Quality of Life WP. |
Bone marrow transplantation 2015, epub ahead of print |
|
| The aim of this analysis was to explore the diversity of reduced intensity conditioning (RIC) in paediatric allo-SCT in daily practice across Europe. Data from the European Group for Blood and Marrow Transplantation (EBMT) Promise database from 1994 to 2008 were supplemented by a survey of EBMT centres performing paediatric allo-SCT on the current policy asking for the underlying diseases and for the drug combinations. Records from 161 centres from 30 countries were analysed and 139 various RIC regimens were reported. More centres applied RIC for malignant rather than for non-malignant diseases. In general, fludarabine (FLU)-based regimens predominated except for BU-based regimens in myeloid malignancies and haemoglobinopathies. Treosulfan (TREO) was mainly applied for unspecified malignant diseases and for haemophagocytic diseases. FLU-based regimens revealed the greatest number of different combinations. Correlating the number of regimens with the number of treating centres revealed the lowest variety in FLU and the highest variety in TBI and TREO. FLU/melphalane and FLU/CY were the most frequent combinations. This extreme heterogeneity in RIC may influence both the efficacy and the safety of the procedures, which requires further investigation. Optimization and standardization of RIC is the final goal to provide a platform for future prospective studies.Bone Marrow Transplantation advance online publication, 26 January 2015; doi:10.1038/bmt.2014.306. |
| Lawitschka A, Lucchini G, Strahm B, Dalle JH, Balduzzi A, Gibson B, Diaz De Heredia C, Wachowiak J, Dalissier A, Vettenranta K, Yaniv I, Bordon V, Bauer D, Bader P, Meisel R, Peters C, Corbacioglu S, European Society for Blood, Marrow Transplantation (EBMT) Pediatric Diseases Working Party |
Pediatric acute graft-versus-host disease prophylaxis and treatment: surveyed real-life approach reveals dissimilarities compared to published recommendations. |
Transplant international 2020, Epup ahead of print |
|
| Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with âÂÂ¥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases. |
| Laws HJ, Baumann U, Bogdan C, Burchard G, Christopeit M, Hecht J, Heininger U, Hilgendorf I, Kern W, Kling K, Kobbe G, Külper W, Lehrnbecher T, Meisel R, Simon A, Ullmann A, de Wit M, Zepp F |
Impfen bei Immundefizienz : Anwendungshinweise zu den von der Ständigen Impfkommission empfohlenen Impfungen. (III) Impfen bei hämatologischen und onkologischen Erkrankungen (antineoplastische Therapie, Stammzelltransplantation), Organtransplantation und Asplenie. |
Bundesgesundheitsblatt 2020, 63: 588 |
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| Laws H, Baumann U, Bogdan C et al. |
Impfen bei Immundefizienz. |
Bundesgesundheitsbl 2020, 63, 588 |
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| Leahey AM, Teunissen H, Friedman DL, Moshang T, Lange BJ, Meadows AT |
Late effects of chemotherapy compared to bone marrow transplantation in the treatment of pediatric acute myeloid leukemia and myelodysplasia. |
Med Pediatr Oncol 1999, 32: 163 |
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| Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A |
Propranolol for severe hemangiomas of infancy. |
The New England journal of medicine 2008, 358: 2649 |
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| Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, Guibaud L, Baselga E, Posiunas G, Phillips RJ, Caceres H, Lopez Gutierrez JC, Ballona R, Friedlander SF, Powell J, Perek D, Metz B, Barbarot S, Maruani A, Szalai ZZ, Krol A, Boccara O, Foelster-Holst R, Febrer Bosch MI, Su J, Buckova H, Torrelo A, Cambazard F, Grantzow R, Wargon O, Wyrzykowski D, Roessler J, Bernabeu-Wittel J, Valencia AM, Przewratil P, Glick S, Pope E, Birchall N, Benjamin L, Mancini AJ, Vabres P, Souteyrand P, Frieden IJ, Berul CI, Mehta CR, Prey S, Boralevi F, Morgan CC, Heritier S, Delarue A, Voisard JJ |
A randomized, controlled trial of oral propranolol in infantile hemangioma. |
The New England journal of medicine 2015, 372: 735 |
|
| Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited. |
| Léauté-Labrèze C, Harper JI, Hoeger PH |
Infantile haemangioma. |
Lancet (London, England) 2017 Jul 1; 390: 85 |
|
| Léauté-Labrèze C, Baselga Torres E, Weibel L, Boon LM, El Hachem M, van der Vleuten C, Roessler J, Troilius Rubin A |
The Infantile Hemangioma Referral Score: A Validated Tool for Physicians. |
Pediatrics 2020, 145 |
|
| Le Deley MC, Rosolen A, Williams DM, Horibe K, Wrobel G, Attarbaschi A, Zsiros J, Uyttebroeck A, Marky IM, Lamant L, Woessmann W, Pillon M, Hobson R, Mauguen A, Reiter A, Brugières L |
Vinblastine in children and adolescents with high-risk anaplastic large-cell lymphoma: results of the randomized ALCL99-vinblastine trial. |
Journal of clinical oncology 2010, 28: 3987 |
|
| PURPOSE: The impact of adding vinblastine to a 4-month chemotherapy regimen, based on the Non-Hodgkin's Lymphoma Berlin-Frankfurt-Münster 90 protocol, in childhood high-risk anaplastic large-cell lymphoma (ALCL) was assessed. PATIENTS AND METHODS: Children and adolescents with high-risk ALCL, defined by mediastinal, lung, liver, spleen, or skin involvement, were eligible for the trial. After a prephase and one chemotherapy course, patients were randomly assigned to receive either five further chemotherapy courses without vinblastine or the same regimen with one vinblastine injection (6 mg/m(2)) during each course followed by weekly vinblastine to complete a total of 1 year of treatment. The primary end point was event-free survival (EFS), analyzed on the intent-to-treat population. RESULTS: Between November 1999 and June 2006, 110 patients were randomly assigned to receive vinblastine, and 107 were randomly assigned not to receive vinblastine. Median follow-up was 4.8 years. Patients in the vinblastine arm had a significantly reduced risk of events during the first year (hazard ratio [HR] = 0.31; 95% CI, 0.15 to 0.67; P = .002) followed by an increased risk thereafter (HR = 4.98; 95% CI, 1.65 to 15.0; P = .003). Consequently, EFS at 1 year differed significantly (91% in the vinblastine group v 74% in the no-vinblastine group), with no difference at 2 years (73% and 70%, respectively). Overall EFS curves did not differ significantly (HR = 0.91; 95% CI, 0.55 to 1.5; P = .71). Thirty-one percent of weekly doses of vinblastine were reduced as a result of hematologic toxicity, although vinblastine was discontinued for toxicity in only three patients. CONCLUSION: Adding vinblastine during induction and as maintenance for a total treatment duration of 1 year significantly delayed the occurrence of relapses but did not reduce the risk of failure. |
| Lefkowitz IB, Packer RJ, Siegel KR, Sutton LN, Schut L, Evans AE |
Results of treatment of children with recurrent medulloblastoma/primitive neuroectodermal tumors with lomustine, cisplatin, and vincristine. |
Cancer 1990 Feb 1; 65: 412 |
|
| Primitive neuroectodermal tumors/medulloblastoma (PNET/MB) are the most common posterior fossa tumors in childhood. Despite surgery and radiation therapy, 40% to 50% of children with PNET/MB will have recurrent disease. Various chemotherapeutic agents are transiently effective in recurrent PNET/MB, but long-lasting responses are rarely attainable. To increase the rate and duration of response in children with recurrent PNET/MB, the authors treated seven patients (ages 2-18 years; median, 10 years) with lomustine (CCNU) (100 mg/m2), cisplatin (CPDD) (90 mg/m2) and vincristine (VCR) (1.5 mg/m2; maximum, 2 mg) in a 6-week cycle for a maximum of eight cycles. Six of six evaluable patients responded to chemotherapy. Four patients had a complete response; three with complete disappearance of tumor by imaging studies; and one with eradication of extraneural disease for a median of 24 months from relapse (13-29 months). Overall disease-free survival was 18.5 months. All six patients have subsequently died of recurrent tumor. Major toxicities consisted of reversible bone marrow suppression (six of six), high frequency hearing loss (six of six) and decreased renal function (three of six). All patients required dosage modification for toxicity. A regimen of CCNU, VCR, and CPDD is effective therapy in children with relapsed PNET/MB and can produce relatively long-term disease control with good quality of life. Further investigation into the efficacy of this combination as adjuvant chemotherapy in newly diagnosed high-risk PNET/MB is now being performed. |
| Lehrnbecher T, Varwig D, Kaiser J, Reinhardt D, Groll A, Klingebiel T |
Infectious Complications in Children with AML. |
Blood 2002, 100: 244b-244b |
|
| Lehrnbecher T, Varwig D, Kaiser J, Reinhardt D, Klingebiel T, Creutzig U |
Infectious complications in pediatric acute myeloid leukemia. |
Leukemia 2004, 18: 72 |
|
| Lehrnbecher T, Laws HJ |
Infektionen in der pädiatrischen Hämatologie und Onkologie, in Laws HJ, Lehrnbecher T: Therapie von Infektionen in der Kinderonkologie. |
Klin Pädiatr 2005, 217 [S1]: 3 |
|
| Lehrnbecher T, Bernig T, Hanisch M, Koehl U, Behl M, Reinhardt D, Creutzig U, Klingebiel T, Chanock SJ, Schwabe D |
Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia. |
Leukemia 2005, 19: 1745 |
|
| Infectious complications represent a substantial cause of morbidity and mortality in children undergoing therapy for acute myeloid leukemia (AML). Since it has been shown that alterations in innate immune pathways contribute to the risk for serious infections, we analyzed well-characterized variants in innate immune genes (TNF, IL6, IL8, MPO, CHIT, FCGR2A, TLR2, and TLR4) to determine their possible contribution to infectious complications during therapy for pediatric AML. The study population consisted of 168 North European Caucasian children enrolled on the clinical trial AML-BFM 93. We found an association between Gram-negative bacterial infection and common, functional variants in two genes, IL6 and CHIT. The risk for infection was significantly higher in children with the G allele in the IL6 promoter at -174 bp (P=0.026) and in patients with the H allele of CHIT (P=0.033). The promoter variant in IL6 has been shown to increase expression while the H allele disrupts both function and circulating levels. Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Follow-up studies, namely replication association studies and in vitro investigation of these common polymorphisms, are warranted to confirm these observations. |
| Lehrnbecher T, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Creutzig U |
Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia. |
Blood 2007, 109: 936 |
|
| Children with acute myelogenous leukemia (AML) have a high risk of infectious complications that might be reduced by prophylactic granulocyte colony-stimulating factor (G-CSF). However, G-CSF could induce AML blast proliferation. The prospective randomized trial AML-BFM 98 investigated the impact of G-CSF on hematopoetic recovery and infectious complications (primary endpoints) and on outcome (secondary endpoint) in children (aged 0-18 years) with de novo AML. Patients with more than 5% blasts in day-15 bone marrow or with FAB M3 were not included. Between 1998 and 2003, 161 children with AML were randomized to receive G-CSF after inductions 1 and 2, whereas 156 patients were assigned to the control group. Time of neutropenia after inductions 1 and 2 was significantly shorter in the G-CSF group (23 vs 18 days and 16 vs 11 days; P=.02 and=.001, respectively). G-CSF did not decrease the incidence of febrile neutropenia (72 and 36 patients vs 78 and 37 patients, respectively), microbiologically documented infections (27 and 25 patients vs 36 and 19 patients, respectively) and infection-associated mortality (5 vs 2 patients). Both groups had similar 5-year event-free survival (EFS; 59%+/-4% vs 58%+/-4%). Since G-CSF does not influence the risk of infectious complications or outcome in children undergoing therapy for AML, one cannot advocate the routine use of G-CSF in this patient group. |
| Lehrnbecher T, Salzmann-Manrique E, Soerensen J, Beutel K, Janka G, Gadner H, Minkov M |
Variant alleles of cytokine genes influence risk and clinical course of Langerhans cell histiocytosis. |
British journal of haematology 2011,Epub ahead of print |
|
| Lehrnbecher T, Phillips R, Alexander S, Alvaro F, Carlesse F, Fisher B, Hakim H, Santolaya M, Castagnola E, Davis BL, Dupuis LL, Gibson F, Groll AH, Gaur A, Gupta A, Kebudi R, Petrilli S, Steinbach WJ, Villarroel M, Zaoutis T, Sung L, International Pediatric Fever and Neutropenia Guideline Panel |
Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012, 30: 4427 |
|
| To develop an evidence-based guideline for the empiric management of pediatric fever and neutropenia (FN). |
| Lehmberg K, Grosse R, Muckenthaler MU, Altamura S, Nielsen P, Schmid H, Graubner U, Oyen F, Zeller W, Schneppenheim R, Janka GE |
Administration of recombinant erythropoietin alone does not improve the phenotype in iron refractory iron deficiency anemia patients. |
Annals of hematology 2013, 92: 387 |
|
| Mutations in transmembrane protease, serine 6 (TMPRSS6) cause iron refractory iron deficiency anemia (IRIDA). Parenteral iron administration may slightly improve hemoglobin level but is troublesome for patients. Optimal treatment has yet to be determined. We identified five patients from four independent families displaying the IRIDA picture with truncating biallelic mutations in TMPRSS6, one of which is novel. Liver iron determined by superconducting quantum interference device biosusceptometry ranged from 390 to 720 µg Fe/g wet weight (normal range 100-500; n = 3). Intestinal iron absorption (12 and 32 %, normal range 10-50; n = 2) and 59Fe erythrocyte incorporation after ingestion of 59Fe (57 and 38 %, normal range 70-90; n = 2) were inadequately low for iron-deficient anemic individuals. Baseline serum erythropoietin was elevated or borderline high in four patients. Administration of recombinant human erythropoietin (rhEPO) at up to 273 and 188 U/kg body weight/week alone did not improve anemia or result in a decrease of urinary hepcidin in two individuals. In conclusion, the ability of exogenous rhEPO to increase hemoglobin level appears to be impaired in IRIDA. |
| Lehmberg K, Ehl S |
Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. |
British journal of haematology 2013, 160: 275 |
|
| Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by severely disturbed immune homeostasis. It can affect all age groups. Diagnostic evaluation of the patient with suspected HLH has to address three main questions: (i) does the patient have HLH? There is no simple diagnostic test, but a number of clinical and laboratory criteria define this clinical syndrome. (ii) Can a trigger be identified? A variety of infections, malignant or autoimmune diseases can contribute to the disturbed immune homeostasis with important consequences for treatment. (iii) Does the patient suffer from a genetic disease predisposing to HLH? Recent advances in the understanding of the genetic and pathophysiological basis of HLH have enabled a better and more rapid answer to this question, which is relevant for prognosis and the decision to perform haematopoietic stem cell transplantation. This review summarizes the current diagnostic approach to the patient with HLH. |
| Lehmberg K, Sprekels B, Nichols KE, Woessmann W, Müller I, Suttorp M, Bernig T, Beutel K, Bode SF, Kentouche K, Kolb R, Längler A, Minkov M, Schilling FH, Schmid I, Vieth S, Ehl S, Zur Stadt U, Janka GE |
Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. |
Br J Haematol 2015, 170: 539 |
|
| Haemophagocytic lymphohistiocytosis (HLH) in the context of malignancy is mainly considered a challenge of adult haematology. While this association is also observed in children, little is known regarding inciting factors, appropriate treatment and prognosis. We retrospectively analysed 29 paediatric and adolescent patients for presenting features, type of neoplasm or preceding chemotherapy, treatment and outcome. Haemophagocytic lymphohistiocytosis was considered triggered by the malignancy (M-HLH) in 21 patients, most of whom had T- (n = 12) or B-cell neoplasms (n = 7), with Epstein-Barr virus as a co-trigger in five patients. In eight patients, HLH occurred during chemotherapy (Ch-HLH) for malignancy, mainly acute leukaemias (n = 7); an infectious trigger was found in seven. In M- and Ch-HLH, median overall survival was 1·2 and 0·9 years, and the 6 month survival rates were 67% and 63%, respectively. Seven of 11 deceased M-HLH patients exhibited active malignancy and HLH at the time of death, while only two out of five deceased Ch-HLH patients had evidence of active HLH. To overcome HLH, malignancy- and HLH-directed treatments were administered in the M-HLH cohort; however, it was not possible to determine superiority of one approach over the other. For Ch-HLH, treatment ranged from postponement of chemotherapy to the use of etoposide-containing regimens. |
| Lehmberg K, Nichols KE, Henter JI, Girschikofsky M, Greenwood T, Jordan M, Kumar A, Minkov M, La Rosée P, Weitzman S |
Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. |
Haematologica 2015, 100: 997 |
|
| The hyperinflammatory syndrome hemophagocytic lymphohistiocytosis can occur in the context of malignancies. Malignancy-triggered hemophagocytic lymphohistiocytosis should be regarded separately from hemophagocytic lymphohistiocytosis during chemotherapeutic treatment, which is frequently associated with an infectious trigger. The substantial overlap between the features of hemophagocytic lymphohistiocytosis with features of neoplasms makes its identification difficult when it occurs in malignant conditions. To facilitate recognition and diagnostic workup, and provide guidance regarding the treatment of malignancy-associated hemophagocytic lymphohistiocytosis, consensus recommendations were developed by the Study Group on Hemophagocytic Lymphohistiocytosis Subtypes of the Histiocyte Society, an interdisciplinary group consisting of pediatric and adult hemato-oncologists and immunologists. |
| Lehmberg K, Ehl S |
Hämophagozytische Lymphohistiozytose. |
Pädiatrische Hämatologie und Onkologie, Hrsg: A. Eggert, C. Niemeyer, Springer Verlag 2. Auflage 2018 |
|
| Lehrnbecher T, Minkov M |
Histiozytosen inkl. Langerhans-Zell-Histiozytose. |
In: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie, Springer-Verlag GmbH Deutschland, 2. vollständig überarbeitete Auflage 2018, 94 |
|
| Lehrnbecher T, Groll AH, Cesaro S, Alten J, Attarbaschi A, Barbaric D, Bodmer N, Conter V, Izraeli S, Mann G, Möricke A, Niggli F, Schrappe M, Stary J, Zapotocka E, Zimmermann M, Elitzur S |
Invasive fungal diseases impact on outcome of childhood ALL - an analysis of the international trial AIEOP-BFM ALL 2009. |
Leukemia 2023, 37: 72 |
|
| In children with acute lymphoblastic leukemia (ALL), risk groups for invasive fungal disease (IFD) with need for antifungal prophylaxis are not well characterized, and with the advent of new antifungal compounds, current data on outcome are scarce. Prospectively captured serious adverse event reports of children enrolled in the international, multi-center clinical trial AIEOP-BFM ALL2009 were screened for proven/probable IFD, defined according to the updated EORTC/MSG consensus definitions. In a total of 6136 children (median age 5.2 years), 224 proven/probable IFDs (65 yeast and 159 mold) were reported. By logistic regression, the risk for proven/probable IFDs was significantly increased in children ≥12 years and those with a blast count ≥10% in the bone marrow on day 15 (P < 0.0001 each). Proven/probable IFDs had a 6-week and 12-week mortality of 10.7% and 11.2%, respectively. In the multivariate analysis, the hazard ratio for event-free and overall survival was significantly increased for proven/probable IFD, age ≥12 years, and insufficient response to therapy (P < 0.001, each). Our data define older children with ALL and those with insufficient treatment-response at high risk for IFD. As we show that IFD is an independent risk factor for event-free and overall survival, these patients may benefit from targeted antifungal prophylaxis. |
| Lehrnbecher T, Minkov M |
Leitlinie 025/015 - Langerhanszell-Histiozytose (LCH) im Kindes- und Jugendalter. |
S1-Leitlinie (Handlungsempfehlung) der Gesellschaft für Pädiatrische Onkologie und Hämatologie und der Deutschen Gesellschaft für Kinder- und Jugendmedizin AWMF online 2023 |
|
| Leidig E, Maier S (Hrsg) |
Positionspapier zur familienorientierten Rehabilitation bei krebskranken Kindern. |
2001 |
|
| Leiper A |
Non-endocrine late complications of bone marrow transplantation in childhood. |
British J Haemato 2002, 118: 3 |
|
| Leidinger B, Bielack S, Koehler G, Vieth V, Winkelmann W, Gosheger G |
High level of beta-hCG simulating pregnancy in recurrent osteosarcoma: case report and review of literature. |
Journal of cancer research and clinical oncology 2004, 130: 357 |
|
| PURPOSE: A high serum level of beta human chorionic gonadotropin (hCG) normally indicates pregnancy in healthy women. We were confused by this finding in one of our patients. This 18-year-old girl presented with amenorrhoea of 1-month duration, a positive pregnancy test and a high beta-hCG serum level although taking contraceptives. Pregnancy was excluded by ultrasound. Three years previously, she had had an osteosarcoma of the humerus. The tumour initially had been wide resected and had shown a good response to neoadjuvant chemotherapy with COSS-96-protocol. METHODS: We reviewed the original histological result and the literature about possible similar findings. We analysed therapeutic options and the value of beta-hCG levels as a therapy monitor. RESULTS: During examination we detected a recurrent osteosarcoma of the left humerus. The local relapse evidently expressed beta-hCG which, retrospectively, could only sparsely be shown in the primary resectate. After intralesional surgery, chemotherapy and radiotherapy levels of beta-hCG normalised. CONCLUSION: Osteosarcoma very rarely is able to produce a paraneoplastic syndrome by high levels of beta-hCG. This may well be of diagnostic value and offer an additional monitoring tool. It can indicate tumour recurrence and dedifferentiation. |
| Leidig E |
Rehabilitation in der pädiatrischen Onkologie (Kurzversion). |
Leitlinien der Fachgesellschaft Rehabilitation in der Kinder- und Jugendmedizin. AWMF online 2008 |
|
| Deutsche Gesellschaft für Palliativmedizin |
S3-Leitlinie Palliativmedizin für Patienten mit einer nicht heilbaren Krebserkrankung. |
AWMF |
|
| Leiss U et al. |
Psychosoziale Basisversorgung in der pädiatrischen Onkologie und Hämatologie 2. 0. |
2022 |
|
| Lennert K, Feller AC |
Histopathologie der Non-Hodgkin-Lymphome. |
Springer-Verlag 2. Aufl. 1990 |
|
| Lengfelder E, Baerlocher GM, Döhner K, Ernst T, Gisslinger H, Grießhammer M, Koschmieder S, Petrides PE |
Polycythaemia vera. |
Oncopedia Leitlinie https://www.onkopedia.com/de/onkopedia/guidelines/polycythaemia-vera-pv/@@guideline/html/index.html |
|
| Leonard A, Wolff JE |
Etoposide Improves Survival in High-grade Glioma: A Meta-Analysis. |
Anticancer research 2013, 33: 3307 |
|
| The purpose of this meta-analysis was to evaluate the therapeutic efficacy of topoisomerase inhibitors in the treatment of high-grade gliomas (HGGs). |
| Lerner LB |
Megaloblastic Anemias. |
In: Nelson Textbook of Pediatrics, 19th Edition - ed. by Kliegman RM, St. Geme J 2011, 448: 1655 |
|
| Leung W, Hudson MM, Strickland DK, Phipps S, Srivastava DK, Ribeiro RC, Rubnitz JE, Sandlund JT, Kun LE, Bowman LC, Razzouk BI, Mathew P, Shearer P, Evans WE, Pui CH |
Late effects of treatment in survivors of childhood acute myeloid leukemia. |
J Clin Oncol 2000 Sep 15; 18: 3273 |
|
| Leuschner I, Harms D, Mattke A, Koscielniak E, Treuner J |
Rhabdomyosarcoma of the urinary bladder and vagina. |
Am J Surg Pathol 2001, 25: 856 |
|
| Leung W, Sandlund JT, Hudson MM, Zhou Y, Hancock ML, Zhu Y, Ribeiro RC, Rubnitz JE, Kun LE, Razzouk B, Evans WE, Pui CH |
Second malignancy after treatment of childhood non-Hodgkin lymphoma. |
Cancer 2001, 92: 1959 |
|
| Leuschner I, Langhans I, Schmitz R, Harms D, Mattke A, Treuner J |
p53 and mdm-2 expression in Rhabdomyosarcoma of childhood and adolescence. |
Pediatr Dev Pathol 2003, 6: 128 |
|
| Leuchte K, Altvater B, Hoffschlag S, Potratz J, Meltzer J, Clemens D, Luecke A, Hardes J, Dirksen U, Jürgens H, Kailayangiri S, Rossig C |
Anchorage-independent growth of Ewing sarcoma cells under serum-free conditions is not associated with stem-cell like phenotype and function. |
Oncology reports 2014, 32: 845 |
|
| Novel treatment strategies for Ewing sarcoma aim to eliminate residual tumor cells that have maintained the capacity to reinitiate tumor growth after intensive conventional therapy. Preclinical models that more closely mimic in vivo tumor growth than standard monolayer cultures are needed. Sphere formation under anchorage-independent, serum-free conditions has been proposed to enrich for cells with tumor-initiating, stem cell-like properties in various solid cancers. In the present study, we assessed the phenotype and functional stem cell characteristics of Ewing sarcoma spheres. Spheres were generated under serum-free culture conditions from four Ewing sarcoma cell lines and four relapse tumor biopsies. Standard monolayer cultures were established as controls. Median levels of surface expression of the Ewing sarcoma marker CD99 as well as the supposed stem cell marker CD133 and the neural crest marker CD57 were comparable between spheres and monolayers. Ewing sarcoma spheres from individual tumors failed to continuously self-renew by secondary sphere formation. They contained variable proportions of side populations (SPs). Sphere culture did not enhance the in vivo tumorigenicity of Ewing sarcoma cells in a murine xenograft model. We conclude that sphere formation under serum-free conditions is not a reliable tool to enrich for cells with stem cell characteristics in Ewing sarcoma. By mimicking the anchorage-independent, multicellular growth of Ewing sarcoma micrometastases, in vitro sphere growth may still add value as a preclinical tool to evaluate the efficacy of novel therapeutics. |
| Lie SO, Jonmundsson G, Mellander L, Siimes MA, Yssing M, Gustafsson G |
A population-based study of 272 children with acute myeloid leukaemia treated on two consecutive protocols with different intensity: best outcome in girls, infants, and children with Down's syndrome. Nordic Society of Paediatric Haematology and Oncology (NOPHO). |
Br J Haematol 1996, 94: 82 |
|
| Liebmann A, Admard J, Armeanu-Ebinger S, Wild H, Abele M, Gschwind A, Seibel-Kelemen O, Seitz C, Bonzheim I, Riess O, Demidov G, Sturm M, Schadeck M, Pogoda M, Bien E, Krawczyk M, Jüttner E, Mentzel T, Cesen M, Pfaff E, Kunc M, Forchhammer S, Forschner A, Leiter-Stöppke U, Eigentler TK, Schneider DT, Schroeder C, Ossowski S, Brecht IB |
UV-radiation and MC1R germline mutations are risk factors for the development of conventional and spitzoid melanomas in children and adolescents. |
EBioMedicine 2023, 96: 104797 |
|
| Genomic characterisation has led to an improved understanding of adult melanoma. However, the aetiology of melanoma in children is still unclear and identifying the correct diagnosis and therapeutic strategies remains challenging. |
| Lilleyman JS |
Management of childhood idiopathic thrombocytopenic purpura. |
British journal of haematology 1999, 105: 871 |
|
| Limperger V, Klostermeier UC, Kenet G, Holzhauer S, Alhenc Gelas M, Finckh U, Junker R, Heller C, Zieger B, Kurnik K, Knöfler R, Mesters R, Halimeh S, Nowak-Göttl U |
Clinical and laboratory characteristics of children with venous thromboembolism and protein C-deficiency: an observational Israeli-German cohort study. |
British journal of haematology 2014, 167: 385 |
|
| Venous thromboembolism [TE] is a multifactorial disease and protein C deficiency [PCD] constitutes a major risk factor. In the present study the prevalence of PCD and the clinical presentation at TE onset, including neonatal purpura fulminans, in a cohort of children are reported. In 367 unselected children (0·1-19 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Twenty-five of 338 children (7·4%) had PCD. Mean age at first TE onset was 10 years (range 0·1-18). Leading thromboembolic manifestations were neonatal purpura fulminans (n = 5), TE of cerebral veins (n = 3), stroke (n = 2) deep veinthrombosis (DVT) of the leg (n = 10), DVT & pulmonary embolism (n = 2) and DVT & pelvic veins (n = 3). Concomitant risk factors for TE were identified in 12 patients, whereas 13 children spontaneously developed TE. A positive family history of DVT was found in 10 children. In this unselected cohort of paediatric patients with symptomatic TE the overall prevalence of PCD was 7·4%; 1·5% presented with neonatal purpura fulminans. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high-risk population. |
| Limond JA, Bull KS, Calaminus G, Kennedy CR, Spoudeas HA, Chevignard MP, Brain Tumour Quality of Survival Group, International Society of Paediatric Oncology (Europe) (SIOP-E) |
Quality of survival assessment in European childhood brain tumour trials, for children aged 5 years and over. |
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 2015, 19: 202 |
|
| There is increasing recognition of the long-term sequelae of brain tumours treated in childhood. Five year survival rates now exceed 75% and assessing the quality of survival (QoS) in multiple domains is essential to any comparison of the benefits and harms of treatment regimens. |
| Limond J, Thomas S, Bull KS, Calaminus G, Lemiere J, Traunwieser T, van Santen HM, Weiler L, Spoudeas HA, Chevignard M |
Quality of survival assessment in European childhood brain tumour trials, for children below the age of 5 years. |
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 2020, 25: 59 |
|
| The highest incidence rate of childhood brain tumours is in children below the age of five years, who are particularly vulnerable to the effects of treatments. The assessment of quality of survival (QoS) in multiple domains is essential to compare the outcomes for different tumour types and treatment regimens. The aim of this position statement is to present the domains of health and functioning to be assessed in children from birth to five years, to advance the collection of a common QoS data set in European brain tumour trials. The QoS group of the European Society of Paediatric Oncology (SIOP-E) Brain Tumour group conducted consensus discussions over a period of six years to establish domains of QoS that should be prioritised in clinical trials involving children under 5 years. The domains of health and functioning that were agreed to affect QoS included: medical outcomes (e.g. vision, hearing, mobility, endocrine), emotion, behaviour, adaptive behaviour, and cognitive functioning. As for children aged five years and older, a 'core plus' approach is suggested in which core assessments are recommended for all clinical trials. The core component for children from birth to three years includes indirect assessment which, in this age-group, requires proxy assessment by a parent, of cognitive, emotional and behaviour variables and both direct and indirect endocrine measures. For children from four years of age direct cognitive assessment is also recommended as 'core'. The 'plus' components enable the addition of assessments which can be selected by individual countries and/or by, age-, treatment-, tumour type- and tumour location-specific trials. |
| Linet MS, Pottern LM |
Familial aggregation of hematopoietic malignancies and risk of non-Hodgkin's lymphoma. |
Cancer Res 1992, 52 : 5468 |
|
| Linden T, Oommen PT, Ueck B, Bucsky P |
Paediatric adrenocortical carcinoma: preliminary results of the multicentre therapy study on malignant endocrine tumours GPOH-MET 97. |
Pediatric Blood & Cancer 2005, 482 P. D. 112 |
|
| Link DC, Kunter G, Kasai Y, Zhao Y, Miner T, McLellan MD, Ries RE, Kapur D, Nagarajan R, Dale DC, Bolyard AA, Boxer LA, Welte K, Zeidler C, Donadieu J, Bellanné-Chantelot C, Vardiman JW, Caligiuri MA, Bloomfield CD, DiPersio JF, Tomasson MH, Graubert TA, Westervelt P, Watson M, Shannon W, Baty J, Mardis ER, Wilson RK, Ley TJ |
Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia. |
Blood 2007, 110: 1648 |
|
| Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the |
| Linabery AM, Erhardt EB, Fonstad RK, Ambinder RF, Bunin GR, Ross JA, Spector LG, Grufferman S |
Infectious, autoimmune and allergic diseases and risk of Hodgkin lymphoma in children and adolescents: a Children's Oncology Group study. |
International journal of cancer 2014 Sep 15; 135: 1454 |
|
| An infectious origin for pediatric Hodgkin lymphoma (HL) has long been suspected and Epstein-Barr virus (EBV) has been implicated in a subset of cases. Increased HL incidence in children with congenital and acquired immunodeficiencies, consistent associations between autoimmune diseases and adult HL and genome-wide association and other genetic studies together suggest immune dysregulation is involved in lymphomagenesis. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL diagnosed in 1989-2003 at 0-14 years at Children's Oncology Group institutions. Parents of 517 cases and 784 controls completed telephone interviews, including items regarding medical histories. Tumor EBV status was determined for 355 cases. Using conditional logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for risk of HL. Cases were more likely to have had an infection>1 year prior to HL diagnosis (OR=1.69, 95% CI: 0.98-2.91); case siblings were also more likely to have had a prior infection (OR=2.04, 95% CI: 1.01-4.14). Parental history of autoimmunity associated with increased EBV+ HL risk (OR=2.97, 95% CI: 1.34-6.58), while having a parent (OR=1.47, 95% CI: 1.01-2.14) or sibling (OR=1.62, 95% CI: 1.11-2.36) with an allergy was associated with EBVâ-âHL. These results may indicate true increased risk for infections and increased risk with family history of autoimmune and allergic conditions that varies by tumor EBV status, or they may be attributable to inaccurate recall. In addition to employing biomarkers to confirm the role of immune-modulating conditions in pediatric HL, future studies should focus on family based designs. |
| Lin SH, Sampson JN, Grünewald TGP, Surdez D, Reynaud S, Mirabeau O, Karlins E, Rubio RA, Zaidi S, Grossetête-Lalami S, Ballet S, Lapouble E, Laurence V, Michon J, Pierron G, Kovar H, Kontny U, González-Neira A, Alonso J, Patino-Garcia A, Corradini N, Bérard PM, Miller J, Freedman ND, Rothman N, Carter BD, Dagnall CL, Burdett L, Jones K, Manning M, Wyatt K, Zhou W, Yeager M, Cox DG, Hoover RN, Khan J, Armstrong GT, Leisenring WM, Bhatia S, Robison LL, Kulozik AE, Kriebel J, Meitinger T, Metzler M, Krumbholz M, Hartmann W, Strauch K, Kirchner T, Dirksen U, Mirabello L, Tucker MA, Tirode F, Morton LM, Chanock SJ, Delattre O, Machiela MJ |
Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma. |
PloS one 2020, 15:e0237792 |
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| Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. |
| Lion T, Haas O, Harbott J, Bannier E, Ritterbach J, Jankovic M, Fink F, Stojimirovic A, Hermann J, Riehm H, Lampert F, Ritter J, Koch H, Gadner H |
The translocation t(1;22)(p13;q13) is a nonrandom marker specifically associated with acute megakaryocytic leukemia in young children. |
Blood 1992, 79: 3325 |
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| Lion TH, Kovar H |
Tumorgenetik, in Gutjahr P: Krebs bei Kindern und Jugendlichen. |
Deutscher Ärzte-Verlag Köln 5. Aufl. 2004, 10 |
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| Li Q, Demir S, Del Río-Álvarez Á, Maxwell R, Wagner A, Carrillo-Reixach J, Armengol C, Vokuhl C, Häberle B, von Schweinitz D, Schmid I, Cairo S, Kappler R |
Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma. |
Cancers 2022, 14 |
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| Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin, the current treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony and tumor spheroid formation capabilities, cell cycle arrest, and induction of apoptosis of hepatoblastoma cells. Mechanistically, mebendazole causes blockage of microtubule formation and transcriptional downregulation of genes encoding the unwindosome, which are highly expressed in chemoresistant tumors. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model without side effects. In conclusion, our results strongly support the clinical use of mebendazole in the treatment of chemoresistant hepatoblastoma and highlight the potential theranostic value of unwindosome-associated genes. |
| Listernick R, Louis DN, Packer RJ, Gutmann DH |
Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. |
Ann Neurol 1997, 41: 143 |
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| Lissat A, van Schewick C, Steffen IG, Arakawa A, Bourquin JP, Burkhardt B, Henze G, Mann G, Peters C, Sramkova L, Eckert C, von Stackelberg A, Chen-Santel C |
Other (Non-CNS/Testicular) Extramedullary Localizations of Childhood Relapsed Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma-A Report from the ALL-REZ Study Group. |
Journal of clinical medicine 2021, 10 |
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| Children with other extramedullary relapse of acute lymphoblastic leukemia are currently poorly characterized. We aim to assess the prevalence and the clinical, therapeutic and prognostic features of extramedullary localizations other than central nervous system or testis in children with relapse of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treated on a relapsed ALL protocol. |
| Liu C, Rueten-Budde AJ, Ranft A, Dirksen U, Gelderblom H, Fiocco M |
Dynamic prediction of overall survival: a retrospective analysis on 979 patients with Ewing sarcoma from the German registry. |
BMJ open 2020, 10:e036376 |
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| This study aimed at developing a dynamic prediction model for patients with Ewing sarcoma (ES) to provide predictions at different follow-up times. During follow-up, disease-related information becomes available, which has an impact on a patient's prognosis. Many prediction models include predictors available at baseline and do not consider the evolution of disease over time. |
| Liu T, Zhao T, Shi C, Chen L |
Pancreatoblastoma in children: Clinical management and literature review. |
Transl Oncol 2022, 18: 101359 |
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| Purpose: The aim of this study is to analyze the clinical and pathological features of pancreatoblastoma (PB) and to obtain better management for patients with relapsed or metastatic disease.
Methods: Four cases treated in our institution and 59 cases reported previously in the literature from the PubMed biomedical database (2000-2020) were reviewed and analyzed.
Results: Four cases with PB presented with abdominal pain and palpable abdominal masses, with the tumor size ranging from 5.2 to 18 cm in diameter. The invasion of the splenic vein and superior mesenteric artery, duodenum, and lymph nodes were risk factors for PB. Three cases were treated with combination therapy and showed favorable outcomes, while one case was treated with chemotherapy alone due to tumor progression and died of the disease. Squamous corpuscles were revealed in the tumor samples and considered a defining component for histological diagnosis.
Conclusions: Multidisciplinary diagnosis plays an important role in clinical management. The risk factors should be considered in the therapeutic stratification of PB before surgery. |
| Liu Y, Karlsson S |
Perspectives of current understanding and therapeutics of Diamond-Blackan anemia. |
Leukemia 2023, |
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| Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure disorder characterized by erythroid hypoplasia. It primarily affects infants and is often caused by heterozygous allelic variations in ribosomal protein (RP) genes. Recent studies also indicated that non-RP genes like GATA1, TSR2, are associated with DBA. P53 activation, translational dysfunction, inflammation, imbalanced globin/heme synthesis, and autophagy dysregulation were shown to contribute to disrupted erythropoiesis and impaired red blood cell production. The main therapeutic option for DBA patients is corticosteroids. However, half of these patients become non-responsive to corticosteroid therapy over prolonged treatment and have to be given blood transfusions. Hematopoietic stem cell transplantation is currently the sole curative option, however, the treatment is limited by the availability of suitable donors and the potential for serious immunological complications. Recent advances in gene therapy using lentiviral vectors have shown promise in treating RPS19-deficient DBA by promoting normal hematopoiesis. With deepening insights into the molecular framework of DBA, emerging therapies like gene therapy hold promise for providing curative solutions and advancing comprehension of the underlying disease mechanisms. |
| Ljungman P, Bregni M, Brune M, Cornelissen J, de Witte T, Dini G, Einsele H, Gaspar HB, Gratwohl A, Passweg J, Peters C, Rocha V, Saccardi R, Schouten H, Sureda A, Tichelli A, Velardi A, Niederwieser D, European Group for Blood and Marrow Transplantation |
Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe 2009. |
Bone marrow transplantation 2010, 45: 219 |
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| The European Group for Blood and Marrow Transplantation regularly publishes special reports on the current practice of haematopoietic SCT for haematological diseases, solid tumours and immune disorders in Europe. Major changes have occurred since the first report was published. HSCT today includes grafting with allogeneic and autologous stem cells derived from BM, peripheral blood and cord blood. With reduced-intensity conditioning regimens in allogeneic transplantation, the age limit has increased, permitting the inclusion of older patients. New indications have emerged, such as autoimmune disorders and AL amyloidosis for autologous HSCT and solid tumours, myeloproliferative syndromes and specific subgroups of lymphomas for allogeneic transplants. The introduction of alternative therapies, such as imatinib for CML, has challenged well-established indications. An updated report with revised tables and operating definitions is presented. |
| Lobitz S, Frömmel C, Brose A, Klein J, Blankenstein O |
Incidence of sickle cell disease in an unselected cohort of neonates born in Berlin, Germany. |
European journal of human genetics 2014, 22: 1051 |
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| Sickle cell disease (SCD) does not occur in the indigenous German population. However, with the increasing numbers of immigrants its prevalence is steadily rising. Nevertheless, robust epidemiological data is not available for Germany and, consequently, the German newborn screening (NBS) program does not include SCD. Between 1 September 2011 and 30 November 2012, an unselected cohort of 34,084 Berlin newborns was tested for SCD. The results of 14 newborns were consistent with SCD and 265 babies were identified as hemoglobin S (Hb S) carriers. These data indicate a 95% probability that the incidence of SCD in Berlin is at least 2.5/10,000. |
| Lobitz S, Telfer P, Cela E, Allaf B, Angastiniotis M, Backman Johansson C, Badens C, Bento C, Bouva MJ, Canatan D, Charlton M, Coppinger C, Daniel Y, de Montalembert M, Ducoroy P, Dulin E, Fingerhut R, Froemmel C, Garcia-Morin M, Gulbis B, Holtkamp U, Inusa B, James J, Kleanthous M, Klein J, Kunz JB, Langabeer L, Lapoumeoulie C, Marcao A, Marin Soria JL, McMahon C, Ohene-Frempong K, Perini JM, Piel FB, Russo G, Sainati L, Schmugge M, Streetly A, Tshilolo L, Turner C, Venturelli D, Vilarinho L, Yahyaoui R, Elion J, Colombatti R, with the endorsement of EuroBloodNet, the European Reference Network in Rare Haematological Diseases |
Newborn screening for sickle cell disease in Europe: recommendations from a Pan-European Consensus Conference. |
British journal of haematology 2018, 183: 648 |
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| Lobitz S, Kunz JB, Cario H, Hakimeh D, Jarisch A, Kulozik AE, Oevermann L, Grosse R |
Introduction of Universal Newborn Screening for Sickle Cell Disease in Germany-A Brief Narrative Review. |
International journal of neonatal screening 2021, 7 |
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| Sickle cell disease (SCD) is a severe non-malignant disorder of hemoglobin and is inherited in an autosomal-recessive manner [...]. |
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| Lobitz S, Frömmel C, Brose A, Blankenstein O, Turner C, Dalton RN, Daniel Y, Klein J |
Simultaneous newborn screening for sickle cell disease, biotinidase deficiency, and hereditary tyrosinemia type 1 with an optimized tandem mass spectrometry protocol. |
Annals of hematology 2022, 101: 1859 |
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| Locatelli F, Zecca M, Niemeyer C, Angelucci E, Arcese G, Bender-Götze C, Bonetti F, Burdach S, Dini G, Ebell W, Friedrich W, Hasle H, Hermann J, Jacobsen N, Klingebiel T, Kremens B, Mann G, Miniero R, Pession A, Peters C, Paolucci P, Rossetti F, Schmid H, Stary J, Zimmermann M |
Role of allogeneic bone marrow transplantation for the treatment of myelodysplastic syndromes in childhood. The European Working Group on Childhood Myelodysplastic Syndrome (EWOG-MDS) and the Austria-Germany-Italy (AGI) Bone Marrow Transplantation Registry. |
Bone Marrow Transplant 1996, 18 Suppl 2: 63-8: 63 |
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| Locatelli F, Niemeyer C, Angelucci E, Bender-Götze C, Burdach S, Ebell W, Friedrich W, Hasle H, Hermann J, Jacobsen N, Klingebiel T, Kremens B, Mann G, Pession A, Peters C, Schmid H, Stary J, Suttorp M, Uderzo C, van't Veer-Korthof E, Vossen J, Zecca M, Zimmermann M |
Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood. |
J Clin Oncol 1997, 15: 566 |
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| Locatelli F, Nollke P, Zecca M, Korthof E, Lanino E, Peters C, Pession A, Kabisch H, Uderzo C, Bonfim CS, Bader P, Dilloo D, Stary J, Fischer A, Revesz T, Fuhrer M, Hasle H, Trebo M, van den Heuvel-Eibrink MM, Fenu S, Strahm B, Giorgiani G, Bonora MR, Duffner U, Niemeyer CM, European Working Group on Childhood MDS, European Blood and Marrow Transplantation Group |
Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. |
Blood 2005, 105: 410 |
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| Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative therapy for juvenile myelomonocytic leukemia (JMML). We, the European Working Group on Childhood MDS (EWOG-MDS) and the European Blood and Marrow Transplantation (EBMT) Group, report the outcome of 100 children (67 boys and 33 girls) with JMML given unmanipulated HSCT after a preparative regimen including busulfan, cyclophosphamide, and melphalan. Forty-eight and 52 children received transplants from an HLA-identical relative or an unrelated donor (UD), respectively. The source of hematopoietic stem cells was bone marrow, peripheral blood, and cord blood in 79, 14, and 7 children, respectively. Splenectomy had been performed before HSCT in 24 children. The 5-year cumulative incidence of transplantation-related mortality and leukemia recurrence was 13% and 35%, respectively. Age older than 4 years predicted an increased risk of disease recurrence. The 5-year probability of event-free survival for children given HSCT from either a relative or a UD was 55% and 49%, respectively (P = NS), with median observation time of patients alive being 40 months (range, 6 to 144). In multivariate analysis, age older than 4 years and female sex predicted poorer outcome. Results of this study compare favorably with previously published reports. Disease recurrence remains the major cause of treatment failure. Outcome of UD-HSCT recipients is comparable to that of children receiving transplants from an HLA-identical sibling. |
| Locatelli F, Pagliara D |
Allogeneic hematopoietic stem cell transplantation in children with sickle cell disease. |
Pediatric blood & cancer 2012, 59: 372 |
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| Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment for sickle cell disease (SCD), being successful in around 85-90% of patients. Mortality and long-term morbidity (including infertility, gonadal failure, and chronic graft-vs.-host disease) associated with conventional approaches curtail the number of patients who undergo allo-HSCT. Recently, it has been demonstrated that cord blood is as effective as and possibly safer than bone marrow in pediatric patients with SCD. Likewise, transplant strategies based on the use of reduced-intensity regimens and the induction of mixed chimerism have been explored to decrease allo-HSCT short- and long-term complications. Pediatr Blood Cancer 2012;59:372-376. © 2012 Wiley Periodicals, Inc. |
| Locatelli F, Strahm B |
How I treat myelodysplastic syndromes of childhood. |
Blood 2018 Mar 29; 131: 1406 |
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| Pediatric myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal disorders with an annual incidence of 1 to 4 cases per million, accounting for less than 5% of childhood hematologic malignancies. MDSs in children often occur in the context of inherited bone marrow failure syndromes, which represent a peculiarity of myelodysplasia diagnosed in pediatric patients. Moreover, germ line syndromes predisposing individuals to develop MDS or acute myeloid leukemia have recently been identified, such as those caused by mutations in , , , and Refractory cytopenia of childhood (RCC) is the most frequent pediatric MDS variant, and it has specific histopathologic features. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many children with MDSs and is routinely offered to all patients with MDS with excess of blasts, to those with MDS secondary to previously administered chemoradiotherapy, and to those with RCC associated with monosomy 7, complex karyotype, severe neutropenia, or transfusion dependence. Immune-suppressive therapy may be a treatment option for RCC patients with hypocellular bone marrow and the absence of monosomy 7 or a complex karyotype, although the response rate is lower than that observed in severe aplastic anemia, and a relevant proportion of these patients will subsequently need HSCT for either nonresponse or relapse. |
| Locatelli F, Zugmaier G, Mergen N, Bader P, Jeha S, Schlegel PG, Bourquin JP, Handgretinger R, Brethon B, Rossig C, Chen-Santel C |
Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the RIALTO trial, an expanded access study. |
Blood cancer journal 2020, 10: 77 |
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| Locatelli F, Whitlock JA, Peters C, Chen-Santel C, Chia V, Dennis RM, Heym KM, Katz AJ, Kelsh MA, Sposto R, Tu H, Tuglus CA, Verma A, Vinti L, Wilkes JJ, Zubarovskaja N, Zugmaier G, von Stackelberg A, Sun W |
Blinatumomab versus historical standard therapy in pediatric patients with relapsed/refractory Ph-negative B-cell precursor acute lymphoblastic leukemia. |
Leukemia 2020, 34: 2473 |
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| No abstract available |
| Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, Möricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A |
Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. |
JAMA 2021, 325: 843 |
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| Importance: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).
Objective: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant.
Design, setting, and participants: In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥5% and <25%) at randomization.
Intervention: Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m2/d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation.
Main outcomes and measures: The primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events.
Results: A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group.
Conclusions and relevance: Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up. |
| Locatelli F, Eckert C, Hrusak O, Buldini B, Sartor M, Zugmaier G, Zeng Y, Pilankar D, Morris J, von Stackelberg A |
Blinatumomab overcomes poor prognostic impact of measurable residual disease in pediatric high-risk first relapse B-cell precursor acute lymphoblastic leukemia. |
Pediatric blood & cancer 2022, 69:e29715 |
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| Blinatumomab, a CD3/CD19 BiTE (bispecific T cell engager) molecule, was superior to high-risk third course consolidation chemotherapy (HC3) in prolonging event-free survival (EFS) in children with high-risk first relapse B-cell precursor acute lymphoblastic leukemia (B-ALL). Here, we report results from a post hoc measurable residual disease (MRD) analysis of this phase 3 study (NCT02393859). |
| Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Zeng Y, Desai R, Kormany WN, Eckert C, Möricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A |
Improved survival and MRD remission with blinatumomab vs. chemotherapy in children with first high-risk relapse B-ALL. |
Leukemia 2023, 37: 222 |
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| Lode H, Reisfeld R, Handgretinger R, Nicolaou K, Gaedicke G, Wrasidlo W |
Targeted therapy with a novel enediyene antibiotic calicheamicin theta(I)1 effectively suppresses growth and dissemination of liver metastases in a syngeneic model of murine neuroblastoma. |
Cancer Res 1998, 58: 2925 |
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| Lodrini M, Sprüssel A, Astrahantseff K, Tiburtius D, Konschak R, Lode HN, Fischer M, Keilholz U, Eggert A, Deubzer HE |
Using droplet digital PCR to analyze MYCN and ALK copy number in plasma from patients with neuroblastoma. |
Oncotarget 2017 Oct 17; 8: 85234 |
|
| The invasive nature of surgical biopsies deters sequential application, and single biopsies often fail to reflect tumor dynamics, intratumor heterogeneity and drug sensitivities likely to change during tumor evolution and treatment. Implementing molecular characterization of cell-free neuroblastoma-derived DNA isolated from blood plasma could improve disease assessment for treatment selection and monitoring of patients with high-risk neuroblastoma. We established droplet digital PCR (ddPCR) protocols for and copy number status in plasma from neuroblastoma patients. Our ddPCR protocol accurately discriminated between and amplification, gain and normal diploid status in a large panel of neuroblastoma cell lines, and discrepancies with reported and status were detected, including a high-level amplification in NB-1, a gain in SH-SY5Y, a high-level amplification in IMR-32 and gains in BE(2)-C, Kelly, SH-SY5Y and LAN-6. and status were also reliably determined from cell-free DNA derived from medium conditioned by the cell lines. and copy numbers of subcutaneous neuroblastoma xenograft tumors were accurately determined from cell-free DNA in the mouse blood plasma. In a final validation step, we accurately distinguished and copy numbers of the corresponding primary tumors using retrospectively collected blood plasma samples from 10 neuroblastoma patients. Our data justify the further development of molecular disease characterization using cell-free DNA in blood plasma from patients with neuroblastoma. This expanded molecular diagnostic palette may improve monitoring of disease progression including relapse and metastatic events as well as therapy success or failure in high-risk neuroblastoma patients. |
| Lodrini M, Sprüssel A, Astrahantseff K, Tiburtius D, Konschak R, Lode HN, Fischer M, Keilholz U, Eggert A, Deubzer HE |
Using droplet digital PCR to analyze MYCN and ALK copy number in plasma from patients with neuroblastoma. |
Oncotarget 2017 Oct 17; 8: 85234 |
|
| The invasive nature of surgical biopsies deters sequential application, and single biopsies often fail to reflect tumor dynamics, intratumor heterogeneity and drug sensitivities likely to change during tumor evolution and treatment. Implementing molecular characterization of cell-free neuroblastoma-derived DNA isolated from blood plasma could improve disease assessment for treatment selection and monitoring of patients with high-risk neuroblastoma. We established droplet digital PCR (ddPCR) protocols for and copy number status in plasma from neuroblastoma patients. Our ddPCR protocol accurately discriminated between and amplification, gain and normal diploid status in a large panel of neuroblastoma cell lines, and discrepancies with reported and status were detected, including a high-level amplification in NB-1, a gain in SH-SY5Y, a high-level amplification in IMR-32 and gains in BE(2)-C, Kelly, SH-SY5Y and LAN-6. and status were also reliably determined from cell-free DNA derived from medium conditioned by the cell lines. and copy numbers of subcutaneous neuroblastoma xenograft tumors were accurately determined from cell-free DNA in the mouse blood plasma. In a final validation step, we accurately distinguished and copy numbers of the corresponding primary tumors using retrospectively collected blood plasma samples from 10 neuroblastoma patients. Our data justify the further development of molecular disease characterization using cell-free DNA in blood plasma from patients with neuroblastoma. This expanded molecular diagnostic palette may improve monitoring of disease progression including relapse and metastatic events as well as therapy success or failure in high-risk neuroblastoma patients. |
| Lodrini M, Wünschel J, Thole-Kliesch TM, Grimaldi M, Sprüssel A, Linke RB, Hollander JF, Tiburtius D, Künkele A, Schulte JH, Lankes E, Elgeti T, Hundsdörfer P, Astrahantseff K, Simon T, Eggert A, Deubzer HE |
Circulating Cell-Free DNA Assessment in Biofluids from Children with Neuroblastoma Demonstrates Feasibility and Potential for Minimally Invasive Molecular Diagnostics. |
Cancers 2022, 14 |
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| Liquid biopsy strategies in pediatric patients are challenging due to low body weight. This study investigated cfDNA size distribution and concentration in blood, bone marrow, cerebrospinal fluid, and urine from 84 patients with neuroblastoma classified as low ( = 28), intermediate ( = 6), or high risk ( = 50) to provide key data for liquid biopsy biobanking strategies. The average volume of blood and bone marrow plasma provided ranged between 1 and 2 mL. Analysis of 637 DNA electropherograms obtained by Agilent TapeStation measurement revealed five different major profiles and characteristic DNA size distribution patterns for each of the biofluids. The proportion of samples containing primarily cfDNA was, at 85.5%, the highest for blood plasma. The median cfDNA concentration amounted to 6.28 ng/mL (blood plasma), 58.2 ng/mL (bone marrow plasma), 0.08 ng/mL (cerebrospinal fluid), and 0.49 ng/mL (urine) in samples. Meta-analysis of the dataset demonstrated that multiple cfDNA-based assays employing the same biofluid sample optimally require sampling volumes of 1 mL for blood and bone marrow plasma, 2 mL for cerebrospinal fluid, and as large as possible for urine samples. A favorable response to treatment was associated with a rapid decrease in blood-based cfDNA concentration in patients with high-risk neuroblastoma. Blood-based cfDNA concentration was not sufficient as a single parameter to indicate high-risk disease recurrence. We provide proof of concept that monitoring neuroblastoma-specific markers in very small blood volumes from infants is feasible. |
| Lode HN, Ladenstein R, Troschke-Meurer S, Struppe L, Siebert N, Zumpe M, Ehlert K, Huber S, Glogova E, Hundsdoerfer P, Eggert A, Zaniewska-Tekieli A, Balwierz W, Wieczorek A |
Effect and Tolerance of N5 and N6 Chemotherapy Cycles in Combination with Dinutuximab Beta in Relapsed High-Risk Neuroblastoma Patients Who Failed at Least One Second-Line Therapy. |
Cancers 2023, 15 |
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| The anti-disialoganglioside (GD2) monoclonal antibody dinutuximab beta is approved for the maintenance treatment of high-risk neuroblastoma. Dinutuximab beta combined with different chemotherapy regimens is being investigated in various clinical settings. We conducted a retrospective clinical chart review of 25 patients with relapsed/refractory neuroblastoma who had failed ≥1 second-line therapy and received compassionate use treatment with dinutuximab beta long-term infusion combined with the induction chemotherapy regimens N5 (cisplatin, etoposide, vindesine) and N6 (vincristine, dacarbazine, ifosfamide, doxorubicin) recommended by the German Pediatric Oncology and Hematology Group [GPOH] guidelines. The treatment did not result in any unexpected severe toxicities or in any major treatment delays. Grade 3/4 pain was reported by 4/25 patients in cycle 1, decreasing to 0/9 patients in cycles 3 and 4. The median follow-up was 0.6 years. The best response in this group was 48% (12/25 patients), which included three patients with minor responses. At 1 year, the estimated event-free survival was 27% (95% confidence interval [CI] 8-47) and overall survival was 44% (95% CI 24-65). Combining long-term infusion of dinutuximab beta with N5 and N6 chemotherapy demonstrated an acceptable safety profile and encouraging objective response rates in heavily pretreated patients with high-risk neuroblastoma, warranting further evaluation in clinical trials. |
| Löning L, Zimmermann M, Reiter A, Kaatsch P, Henze G, Riehm H, Schrappe M |
Secondary neoplasms subsequent to Berlin-Frankfurt-Münster therapy of acute lymphoblastic leukemia in childhood. |
Blood 2000, 95: 2770 |
|
| Löbel U, Trah J, Escherich G |
Severe neurotoxicity following intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia. |
Pediatr Blood Cancer 2015, 62: 539 |
|
| Systemic and intrathecal methotrexate is widely used in treatment protocols for childhood acute lymphoblastic leukemia. Its side effects vary in characteristics, intensity and time of onset, and depend on the administration route. Interactions with several drugs are known. Side effects of nitrous oxide sedation, often used for moderately painful procedures, typically occur after long time use and include neurological symptoms. We present a child who experienced a severe and long-lasting neurotoxicity after the third intrathecal application of methotrexate with short sedation by nitrous oxide during induction therapy for acute lymphoblastic leukemia. Symptoms completely resolved after 12 months. |
| Lohmann DR, Brandt B, Passarge E, Horsthemke B |
[Molecular genetics and diagnosis of retinoblastoma. Significance for ophthalmologic practice]. |
Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft 1997, 94: 263 |
|
| Retinoblastoma (RB) is initiated by loss of function of both copies of the retinoblastoma susceptibility gene (RB 1). Hereditary predisposition to RB is caused by germline mutations in the RB 1 gene. Tumor formation is initiated by the somatic loss of the second allele. Most patients with hereditary RB develop multiple tumors that usually affect both eyes. In nonhereditary disease, however, both RB 1 mutations are somatic events that cause the formation of a single tumor focus. Knowledge of the germline mutation is often essential for accurate risk prediction. Applying strategies for efficient mutation detection, germline mutations can be identified in most individuals with hereditary RB. The vast majority of mutant alleles cause premature termination of translation owing to frameshift or nonsense mutations. In patients carrying these mutant alleles, penetrance is almost complete (> 95%) and numerous tumor foci are observed. However, some 5% of the mutations result in comparatively mild alterations at the protein level. Patients with mutations of this kind often show a lower mean number of tumor foci (reduced expressivity) or no tumor at all (incomplete penetrance). Reduced expressivity and incomplete penetrance are also observed in patients with large cytogenetic deletions. By mutation analysis in DNA from fresh frozen tumor samples and peripheral blood, we have detected RB 1 germline mutations in some 20% of patients with unilateral RB. These results emphasize the importance of molecular analysis in patients with isolated unilateral RB. |
| Lohmann DR, Gallie BL, Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K |
Retinoblastoma. |
1993, |
|
| Loh ML, Rubnitz JE |
TEL/AML1-positive pediatric leukemia: prognostic significance and therapeutic approaches. |
Curr Opin Hematol 2002, 9: 345 |
|
| Lohmann D |
Die Genetik des Retinoblastoms. |
WIR Informationsschrift der Aktion für krebskranke Kinder e.V. (Bonn) 2007, 1: 31 |
|
| Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S, Mullighan CG, Chen L, Bergstraesser E, Bueso-Ramos CE, Emanuel PD, Hasle H, Issa JP, van den Heuvel-Eibrink MM, Locatelli F, Stary J, Trebo M, Wlodarski M, Zecca M, Shannon KM, Niemeyer CM |
Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. |
Blood 2009, 114: 1859 |
|
| Juvenile myelomonocytic leukemia is an aggressive myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Seventy-five percent of patients harbor mutations in the NF1, NRAS, KRAS, or PTPN11 genes, which encode components of Ras signaling networks. Using single nucleotide polymorphism arrays, we identified a region of 11q isodisomy that contains the CBL gene in several JMML samples, and subsequently identified CBL mutations in 27 of 159 JMML samples. Thirteen of these mutations alter codon Y371. In this report, we also demonstrate that CBL and RAS/PTPN11 mutations were mutually exclusive in these patients. Moreover, the exclusivity of CBL mutations with respect to other Ras pathway-associated mutations indicates that CBL may have a role in deregulating this key pathway in JMML. |
| Lohse J, Schweigel J, Naeke A, Lee-Kirsch MA, Siegert G, Bergmann S, Kuhlisch E, Suttorp M, Knöfler R |
Platelet function in obese children and adolescents. |
Hamostaseologie 2010, 30 Suppl 1:S126 |
|
| Platelet hyperaggregability contributes to thromboembolic events of obesity in adulthood. In obese children hyperaggregability was described in platelet rich plasma. We investigated platelet aggregation in children with obesity and lipometabolic disorders in whole blood. |
| Longoni D, D'Amico G, Gaipa G, Bernasconi S, Vulcano M, Onnis P, Niemeyer C, Allavena P, Biondi A |
Commitment of juvenile myelo-monocytic (JMML) leukemic cells to spontaneously differentiate into dendritic cells. |
Hematol J 2002, 3: 302 |
|
| Lones MA, Perkins SL, Sposto R, Tedeschi N, Kadin ME, Kjeldsberg CR, Wilson JF, Zwick DL, Cairo MS |
Non-Hodgkin's lymphoma arising in bone in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report. |
J Clin Oncol 2002, 20: 2293 |
|
| Loncarevic IF, Hering A, Posorski N, Linden T, Hoyer H, Bucsky P |
Number of genomic imbalances correlates with the overall survival for adrenocortical cancer in childhood. |
Pediatr Blood Cancer 2008, 51: 356-62. |
|
| BACKGROUND: Adrenocortical tumours (ACT) in children are rare and, if malignant, often associated with poor prognosis. Relevant cytogenetic factors for prognosis are hardly available.
PROCEDURES: We analysed 14 adrenocortical cancers (ACC) of children by comparative genomic hybridisation (CGH).
RESULTS: The total number of genomic imbalances ranged from 1 to 17 in individual tumour samples. The most common imbalances were +1q (57%), +12p (50%), +12q (50%), +1p (43%), +7q (42%), +9q (42%), +15q (42%), and -4q (57%), -11q (57%), -4p (42%), and -16q (42%). The median number of genomic changes was 5.5 (n = 8) in pT1-pT2 and 15.5 (n = 6) in pT3-pT4 tumours. The median number was 4 in the eight patients, who remain in remission more than 51 months and 15.5 in the six patients, who have died from the disease within 44 months. Moreover, all seven patients with less than 10 individual imbalances were in remission (median follow-up 72 months), while all but one patient with 10 and more individual imbalances (n = 7) have died from the disease (median survival time 30 months). Comparison of the data from children and adults revealed characteristic differences. Gain of 1p and loss of 4p, 4q and 16q are frequent in childhood and rare in adults. Inversely, loss of 1p is rare in childhood but frequent in adult ACT.
CONCLUSION: The number of CGH imbalances appeared to have a predictive value for overall survival in paediatric ACC.
(c) 2008 Wiley-Liss, Inc. |
| London WB, Castel V, Monclair T, Ambros PF, Pearson AD, Cohn SL, Berthold F, Nakagawara A, Ladenstein RL, Iehara T, Matthay KK |
Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the international neuroblastoma risk group project. |
J Clin Oncol 2011 29: 3286 |
|
| PURPOSE Survival after neuroblastoma relapse is poor. Understanding the relationship between clinical and biologic features and outcome after relapse may help in selection of optimal therapy. Our aim was to determine which factors were significantly predictive of postrelapse overall survival (OS) in patients with recurrent neuroblastoma-particularly whether time from diagnosis to first relapse (TTFR) was a significant predictor of OS. PATIENTS AND METHODS Patients with first relapse/progression were identified in the International Neuroblastoma Risk Group (INRG) database. Time from study enrollment until first event and OS time starting from first event were calculated. Cox regression models were used to calculate the hazard ratio of increased death risk and perform survival tree regression. TTFR was tested in a multivariable Cox model with other factors. Results In the INRG database (N = 8,800), 2,266 patients experienced first progression/relapse. Median time to relapse was 13.2 months (range, 1 day to 11.4 years). Five-year OS from time of first event was 20% (SE, ± 1%). TTFR was statistically significantly associated with OS time in a nonlinear relationship; patients with TTFR of 36 months or longer had the lowest risk of death, followed by patients who relapsed in the period of 0 to less than 6 months or 18 to 36 months. Patients who relapsed between 6 and 18 months after diagnosis had the highest risk of death. TTFR, age, International Neuroblastoma Staging System stage, and MYCN copy number status were independently predictive of postrelapse OS in multivariable analysis. CONCLUSION Age, stage, MYCN status, and TTFR are significant prognostic factors for postrelapse survival and may help in the design of clinical trials evaluating novel agents. |
| Longhi A, Bielack SS, Grimer R, Whelan J, Windhager R, Leithner A, Gronchi A, Biau D, Jutte P, Krieg AH, Klenke FM, Grignani G, Donati DM, Capanna R, Casanova J, Gerrand C, Bisogno G, Hecker-Nolting S, De Lisa M, D'Ambrosio L, Willegger M, Scoccianti G, Ferrari S |
Extraskeletal osteosarcoma: A European Musculoskeletal Oncology Society study on 266 patients. |
European journal of cancer (Oxford, England : 1990) 2017, 74: 9 |
|
| PURPOSE: Prognosis of extraskeletal osteosarcoma (ESOS) is reported to be poorer than that of skeletal osteosarcoma. This multicenter retrospective study aimed to evaluate factors influencing ESOS prognosis.
PATIENTS AND METHODS: Members of the European Musculoskeletal Oncology Society (EMSOS) submitted institutional data on patients with ESOS.
RESULTS: Data from 274 patients treated from 1981 to 2014 were collected from 16 EMSOS centres; 266 patients were eligible. Fifty (18.7%) had metastases at diagnosis. Of 216 patients with localised disease, 211 (98%) underwent surgery (R0 = 70.6%, R1 = 27%). Five-year overall survival (OS) for all 266 patients was 47% (95% CI 40-54%). Five-year OS for metastatic patients was 27% (95% CI 13-41%). In the analysis restricted to the 211 localised patients who achieved complete remission after surgery 5-year OS was 51.4% (95% CI 44-59%) and 5-year disease-free survival (DFS) was 43% (95% CI 35-51%). One hundred twenty-one patients (57.3%) received adjuvant or neoadjuvant chemotherapy and 80 patients (37.9%) received radiotherapy. A favourable trend was seen for osteosarcoma-type chemotherapy versus soft tissue sarcoma-type (doxorubicin ± ifosfamide) regimens. For the 211 patients in complete remission after surgery, patient age, tumour size, margins and chemotherapy were positive prognostic factors for DFS and OS by univariate analysis. At multivariate analysis, patient age (≤40 years versus >40 years) (P = 0.05), tumour size (P = 0.0001) and receipt of chemotherapy (P = 0.006) were statistically significant prognostic factors for survival.
CONCLUSION: Patient age and tumour size are factors influencing ESOS prognosis. Higher survival was observed in patients who received perioperative chemotherapy with a trend in favour of multiagent osteosarcoma-type regimen which included doxorubicin, ifosfamide and cisplatin.
Copyright © 2017 Elsevier Ltd. All rights reserved.
|
| Lorenzana A, Armin S, Sharma A, Allarakhia I, Witkowski A |
Cerebral Infarctions After Intravenous Immunoglobulin Therapy for ITP in a Child. |
Pediatric neurology 2014, 50: 188 |
|
| Intravenous immunoglobulin is the favored therapy in childhood immune thrombocytopenic purpura. It is usually well tolerated with manageable side effects, but venous and arterial thrombosis following its administration have been described, mostly in adults. |
| Lo SS, Fakiris AJ, Abdulrahman R, Henderson MA, Chang EL, Suh JH, Timmerman RD |
Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy in pediatric brain tumors. |
Expert review of neurotherapeutics 2008, 8: 121 |
|
| Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P |
The 2007 WHO classification of tumours of the central nervous system. |
Acta neuropathologica 2007, 114: 97 |
|
| Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW |
The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. |
Acta neuropathologica 2016, 131: 803 |
|
| Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW |
The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. |
Neuro-oncology 2021 Aug 2; 23: 1231 |
|
| Lucarelli G, Isgro`, A, Sodani P, Gaziev, J |
Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Anemia. |
Cold Spring Harb Perspect Med 2012, 2: a011825 |
|
| The globally widespread single-gene disorders β-thalassemia and sickle cell anemia (SCA) can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). HSCT treatment of thalassemia has substantially improved over the last two decades, with advancements in preventive strategies, control of transplant-related complications, and preparative regimens. A risk class–based transplantation approach results in disease-free survival probabilities of 90%, 84%, and 78% for class 1, 2, and 3 thalassemia patients, respectively. Because of disease advancement, adult thalassemia patients have a higher risk for transplant-related toxicity and a 65% cure rate. Patients without matched donors could benefit from haploidentical mother-to-child transplantation. There is a high cure rate for children with SCA who receive HSCT following myeloablative conditioning protocols. Novel non-myeloablative transplantation protocols could make HSCT available to adult SCA patients who were previously excluded from allogeneic stem cell transplantation. |
| Ludwig W, Herrmann F, Gatzke A, Budde M, Creutzig U, Ritter J, Schellong G |
Surface marker analysis by monoclonal antibodies. |
Haematology and Blood Transfusion 1987, 30: 418 |
|
| Ludwig W, Bartram C, Ritter J, Raghavachar A, Hiddemann W, Heil G, Harbott J, Seibt-Jung H, Teichmann J, Riehm H |
Ambiguous phenotypes and genotypes in 16 children with acute leukemia as characterized by multiparameter analysis. |
Blood 1988, 71: 1518 |
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| Ludwig W, Köller U, Bartram C, Harbott J, Haas O, Ritter J, Creutzig U, Gadner H, Riehm H |
Phenotypic and genotypic heterogeneity in infant acute leukemia. |
Contrib Oncol 1990, 41: 46 |
|
| Ludwig W, Thiel E, Köller U, Bartram C, Harbott J, Teichmann J, Seibt Jung H, Creutzig U, Ritter J, Riehm H |
Incidence and clinical implications of acute hybrid leukemia in childhood. |
Haematology and Blood Transfusion 1990, 33: 516 |
|
| Ludwig R, Weirich A, Potter R, Harms D, Burger D, Michaelis J, Erttmann R, Weinel P, Haas R, Ritter J, |
Preoperative chemotherapy of nephroblastoma. Preliminary results of the SIOP-9/GPO therapy study. |
Klin Pädiatr 1992, 204: 204 |
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| Ludwig W, Harbott J, Bartram C, Komischke B, Sperling C, Teichmann J, Seibt-Jung H, Notter M, Odenwald E, Nehmer A, |
Incidence and prognostic significance of immunophenotypic subgroups in childhood acute lymphoblastic leukemia. |
Recent Results Cancer Res 1993, 131: 269 |
|
| Ludwig R, Weirich A, Bürger D, Graf N, Harms D, Kaatsch P |
Duchführung eines neuen Therapiekonzepts für Nephroblastome (SIOP 9/GPOH) im Bereich der Gesellschaft für Pädiatrische Onkologie und Hämatologie. |
Monatsschr Kinderheilkd 1997, 145: 128 |
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| Ludwig R, Weirich A, Abel U, Hofmann W, Graf N, Tournade M |
Hepatotoxicity in patients treated according to the nephroblastoma trial and study SIOP-9/GPOH. |
Med Pediatr Oncol 1999, 33: 462 |
|
| Ludwig JA, Meyers PA, Dirksen U |
Ewing's Sarcoma. |
The New England journal of medicine 2021, 384: 1476 |
|
| Lünenbürger H, Lanvers-Kaminsky C, Lechtape B, Frühwald MC |
Systematic analysis of the antiproliferative effects of novel and standard anticancer agents in rhabdoid tumor cell lines. |
Anti-cancer drugs 2010, 21: 514 |
|
| Rhabdoid tumors are highly aggressive pediatric malignancies. Although the prognosis of children with rhabdoid tumors has improved, it still remains dismal and long-term survivors suffer from severe side effects of current therapeutic approaches. The objective of our study was to explore the toxicity of standard and novel anticancer drugs against rhabdoid tumors in vitro and to prioritize them for future preclinical and clinical studies. Antitumor activity of 10 standard anticancer drugs (doxorubicin, idarubicin, mitoxantrone, actinomycin D, temozolomide, carmustine, oxaliplatin, vinorelbine, methotrexate, thiotepa), five target-specific drugs (sorafenib, imatinib, roscovitine, rapamycin, ciglitazone) and two herbal compounds (curcumin and apigenin) was assessed by a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) cell proliferation assay on three rhabdoid tumor cell lines, A204, G401, and BT16, derived from different anatomical sites. Comparable with their high clinical activity, anthracyclines inhibited tumor cell proliferation by 50% (GI50) in the nanomolar range. Actinomycin D exhibited the lowest GI50 values overall ranging from 2.8x10(-6) nmol/l for G401 to 3.8 nmol/l for A204 cells while thiotepa was the only alkylating drug that inhibited tumor cell growth in clinically relevant concentrations. Target-specific drugs, such as sorafenib, roscovitine, and rapamycin, showed promising results as well. In this report, we show for the first time that apigenin and curcumin effectively inhibit rhabdoid tumor cell growth. Supporting earlier reports we conclude that cyclin D1 seems to be an excellent target in the treatment of rhabdoid tumors. Idarubicin or mitoxantrone represent potent alternatives to doxorubicin, and vinorelbine may substitute vincristine in future clinical trials. |
| Lueth M, Stein H, Spors B, Henze G, Driever PH |
First case report of a peripheral T-cell lymphoma, not otherwise specified, of the central nervous system in a child. |
Journal of pediatric hematology/oncology 2012, 34:e66 |
|
| We report on the first pediatric patient with a localized primary peripheral T-cell lymphoma, not otherwise specified, of the central nervous system (CNS). The solid lesion that was enhanced in magnetic resonance images of the left precentral region was totally resected. The histopathology revealed a peripheral T-cell lymphoma, not otherwise specified. Staging procedures showed that the lesion was confined to the CNS. Without any further therapy, the patient still remains in complete remission 6 years after diagnosis. Thus, we conclude that a peripheral T-cell lymphoma, not otherwise specified, of the CNS can occur in children. In the case presented here, complete resection sufficed. |
| von Lützau P, Otto M, Hechler T, Metzing S, Wolfe J, Zernikow B |
Children dying from cancer: parents' perspectives on symptoms, quality of life, characteristics of death, and end-of-life decisions. |
Journal of palliative care 2012, 28: 274 |
|
| In this study, we investigated the experience of children who died of cancer, as perceived by their parents. All the pediatric oncology departments in one German federal state were contacted and asked to invite parents who had lost a child to cancer in the period 2005-2006 to participate. Those parents who accepted were interviewed by means of a semi-structured questionnaire. In the participating 16 departments, 158 children died in 2005-2006. Parents of 48 children (38.3 percent) agreed to participate and were interviewed. Nearly all of the children had suffered from at least one distressing symptom. Pain and fatigue occurred most frequently. Symptoms were successfully treated over 65 percent of the time. In all, 64 percent of the children received home care services; 50 percent died at home, and only 10 percent in the ICU. Results suggest that some progress has been made in pediatric palliative care. To further improve end-of-life care for children with cancer, it is also necessary to evaluate parents' perspectives on structures for pediatric palliative care delivery. |
| Lugthart S, Cheok MH, den Boer ML, Yang W, Holleman A, Cheng C, Pui CH, Relling MV, Janka-Schaub GE, Pieters R, Evans WE |
Identification of genes associated with chemotherapy crossresistance and treatment response in childhood acute lymphoblastic leukemia. |
Cancer cell 2005, 7: 375 |
|
| Acute lymphoblastic leukemia (ALL) can be cured with combination chemotherapy in over 75% of children, but the cause of treatment failure in the remaining patients is unknown. We determined the sensitivity of ALL cells to individual antileukemic agents in 441 patients and used a genome-wide approach to identify 45 genes differentially expressed in ALL exhibiting crossresistance to prednisolone, vincristine, asparaginase, and daunorubicin. We also identified a distinct phenotype of discordant resistance to asparaginase and vincristine and 139 genes whose expression was associated with this novel phenotype. The expression of these genes discriminated treatment outcome in two independent patient populations, identifying a subset of patients with a markedly inferior outcome (37% +/- 13% 5 year DFS). |
| Luzzatto L, Arese P |
Favism and Glucose-6-Phosphate Dehydrogenase Deficiency. |
The New England journal of medicine 2018, 378: 60 |
|
| Lönnerholm G, Valsecchi MG, De Lorenzo P, Schrappe M, Hovi L, Campbell M, Mann G, Janka-Schaub G, Li CK, Stary J, Hann I, Pieters R, Interfant-99 study group |
Pharmacokinetics of high-dose methotrexate in infants treated for acute lymphoblastic leukemia. |
Pediatric blood & cancer 2009, 52: 596 |
|
| BACKGROUND: Interfant-99 was an international collaborative treatment protocol for infants with acute lymphoblastic leukemia (ALL). PROCEDURE: We collected data on 103 infants at the time of their first treatment with high-dose methotrexate (HD MTX), 5 g/m(2). Children <6 months of age received two-third of the calculated dose based on body surface area (BSA), children 6-12 months three-fourth of the calculated dose, and children >12 months full dose. RESULTS: The median steady-state MTX concentration at the end of the 24-hr infusion was 57.8 microM (range 9.5-313). The median systemic clearance was 6.22 L/hr/m(2) BSA, and tended to increase with age (P = 0.099). Boys had higher clearance than girls, 6.77 and 5.28 L/hr/m(2) (P = 0.030), and tended to have lower median MTX concentration at 24 hr. Eight infants had MTX levels below 20 microM, a level judged to be sufficient in B-lineage ALL in children >1 year of age. All infants tolerated the dose well enough to receive a second dose of HD MTX without dose reduction. We found no significant effect on disease-free survival for MTX steady-state concentration, MTX clearance, or time to MTX below 0.2 microM. CONCLUSIONS: Our data provide no support for a change in the dosing rules for MTX used in Interfant-99. However, in view of the poor treatment results for infants, one might consider increase in the dose for patients who reach plasma levels below median after the first MTX dose. |
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