| Autor(en) |
Titel |
Quelle |
Links |
| Machatschek JN, Paulussen M, Bielack S |
Chemotherapie bei malignen Knochentumoren. |
Buchbeitrag 2005 |
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| MacDonald TJ, Aguilera D, Kramm CM |
Treatment of high-grade glioma in children and adolescents. [+] |
Neuro Oncol 2011, [Epub ahead of print] |
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| Pediatric high-grade gliomas (HGGs)-including glioblastoma multiforme, anaplastic astrocytoma, and diffuse intrinsic pontine glioma-are difficult to treat and are associated with an extremely poor prognosis. There are no effective chemotherapeutic regimens for the treatment of pediatric HGG, but many new treatment options are in active investigation. There are crucial molecular differences between adult and pediatric HGG such that results from adult clinical trials cannot simply be extrapolated to children. Molecular markers overexpressed in pediatric HGG include PDGFRα and P53. Amplification of EGFR is observed, but to a lesser degree than in adult HGG. Potential molecular targets and new therapies in development for pediatric HGG are described in this review. Research into bevacizumab in pediatric HGG indicates that its activity is less than that observed in adult HGG. Similarly, tipifarnib was found to have minimal activity in pediatric HGG, whereas gefitinib has shown greater effects. After promising phase I findings in children with primary CNS tumors, the integrin inhibitor cilengitide is being investigated in a phase II trial in pediatric HGG. Studies are also ongoing in pediatric HGG with 2 EGFR inhibitors: cetuximab and nimotuzumab. Other novel treatment modalities under investigation include dendritic cell-based vaccinations, boron neutron capture therapy, and telomerase inhibition. While the results of these trials are keenly awaited, the current belief is that multimodal therapy holds the greatest promise. Research efforts should be directed toward building multitherapeutic regimens that are well tolerated and that offer the greatest antitumor activity in the setting of pediatric HGG. |
| Magrath IT |
African Burkitt's lymphoma: History, biology, clinical features, and treatment. |
Am J Pediatr Hematol Oncol 1991, 13: 222 |
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| Mann G, Reinhardt D, Ritter J, Hermann J, Schmitt K, Gadner H, Creutzig U |
Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children. |
Annals Hematology 2001, 80: 417 |
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| Manzke O, Russello O, Leenen C, Diehl V, Bohlen H, Berthold F |
Immunotherapeutic strategies in neuroblastoma. |
Med Pediatr Oncol 2001, 36: 185 |
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| Mann G, Cazzaniga G, van der Velden VH, Flohr T, Csinady E, Paganin M, Schrauder A, Dohnal AM, Schrappe M, Biondi A, Gadner H, van Dongen JJ, Panzer-Grümayer ER |
Acute lymphoblastic leukemia with t(4;11) in children 1 year and older: The 'big sister' of the infant disease? [+] |
Leukemia 2007, 21: 642 |
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| The t(4;11)-positive acute lymphoblastic leukemia (ALL) is a rare disease in children above the age of 1 year. We studied the clinical and biological characteristics in 32 consecutively diagnosed childhood cases (median age 10.0 years, range 1.0-17.1 years). Immunophenotyping revealed a pro-B and a pre-B stage in 24 and eight cases, respectively. IGH genes were rearranged in 84% of leukemias with a predominance of incomplete DJ(H) joints. Whereas IGK-Kde and TCRD rearrangements were rare, TCRG rearrangements were present in 50% of cases and involved mainly Vgamma11 or Vgamma9 together with a Jgamma1.3./2.3 gene segment, an unusual combination among t(4;11)-negative B-cell precursor ALL. Oligoclonality was found in about 30% as assessed by heterogeneous IGH and TCRG rearrangements. Our data are in line with transformation of a precursor cell at an early stage of B-cell development but retaining the potential to differentiate to the pre-B cell stage in vivo. Although a distinct difference between infant and older childhood cases with t(4;11) became evident, no age-related biological features were found within the childhood age group. In contrast to infants with t(4;11)-positive ALL, childhood cases had a relatively low cumulative incidence of relapse of 25% at 3.5 years with BFM-based high-risk protocols. |
| Mann G, Attarbaschi A, Burkhardt B, Niggli F, Klapper W, Ludwig WD, Schrappe M, Zimmermann M, Gadner H, Reiter A, Berlin-Frankfurt-Münster Group |
Clinical characteristics and treatment outcome of infants with non-Hodgkin lymphoma. [+] |
British journal of haematology 2007, 139: 443 |
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| Non-Hodgkin lymphoma (NHL) is rarely observed during infancy and data on its incidence, characteristics and outcome are scarce. The present study aimed to assess the prevalence, clinical presentation and treatment results of all infants who were diagnosed with NHL between October 1986 and December 2002 among 2084 patients treated according to the NHL-BFM (Berlin-Frankfurt-Münster) multicentre trials 86, 90 and 95. We identified 20 (1%) infants with NHL including five with T-cell lymphoblastic lymphoma (T-cell LBL), seven with precursor B-cell LBL (pB-cell LBL), two with a mature Burkitt neoplasm, five with anaplastic large cell lymphoma (ALCL) and one with peripheral T-cell lymphoma (PTCL). The PTCL patient, 3/7 pB-cell LBL and 1/5 ALCL patients relapsed. One patient each from the T-cell LBL and Burkitt lymphoma groups suffered from a second malignancy and one patient each with ALCL and Burkitt leukaemia died from treatment-related toxicity. The 5-year event-free survival rate was 53 +/- 12% for the 20 cases. This study has provided preliminary evidence that infants with NHL have a dismal prognosis and showed that infant NHL differed to lymphomas in older patients with respect to the distribution of gender, histopathologic subtypes as well as the ratio of T- to pB-cell LBL and the frequency of relapses of pB-cell LBL. |
| Manola KN |
Cytogenetics of pediatric acute myeloid leukemia. [+] |
European journal of haematology 2009, 83: 391 |
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| Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease accounting for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. This article focuses on the significance of cytogenetic analysis in pediatric AML supporting the importance of cytogenetic analysis in the pathogenesis, diagnosis, prognosis, follow-up and treatment selection in childhood AML. It reviews in detail the types and frequencies of most common chromosomal aberrations, their molecular background, their correlation with French American British (FAB) subtypes and age distribution and their prognostic relevance. It also summarizes some less frequent or rare chromosome aberrations in which the prognostic classification has not been determined yet owning to the small number of patients and the variable treatment modalities used in different study groups. Furthermore, it discusses the association of specific chromosome rearrangements with prenatal exposure to carcinogenic agents or therapeutic agents and highlights the ongoing and future research on pediatric AML in the evolving field of Cytogenetics. |
| Mann G, Attarbaschi A, Schrappe M, De Lorenzo P, Peters C, Hann I, De Rossi G, Felice M, Lausen B, Leblanc T, Szczepanski T, Ferster A, Janka-Schaub G, Rubnitz J, Silverman LB, Stary J, Campbell M, Li CK, Suppiah R, Biondi A, Vora A, Valsecchi MG, Pieters R |
Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukaemia: results from the Interfant-99 Study. [+] |
Blood 2010 Jun 30; [Epub ahead of print] |
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| To define a role for hematopoietic stem cell transplantation (HSCT) in infants with acute lymphoblastic leukemia (ALL) and rearrangements of the mixed-lineage-leukemia gene (MLL+) we compared the outcome of MLL+ patients from trial Interfant-99 who either received chemotherapy only or HSCT. Of 376 patients with a known MLL status in the trial, 297 (79%) were MLL+. Among the 277/297 MLL+ patients (93%) in first remission (CR), there appeared to be a significant difference in disease-free survival (adjusted by waiting time to HSCT) between the 37 (13%) who received HSCT and the 240 (87%) who received chemotherapy only (P=0.03). However, the advantage was restricted to a subgroup with two additional unfavourable prognostic features: age <6 months and either poor response to steroids at day 8 or leukocytes >/=300 G/L. Ninety-seven/297 MLL+ patients (33%) had such high-risk criteria, with 87 achieving CR. In this group HSCT was associated with a 64% reduction in the risk of failure due to relapse or death in CR (HR=0.36, 95% CI: 0.15-0.86). In the remaining patients, there was no advantage for HSCT over chemotherapy only. In summary, HSCT seems to be a valuable option for a subgroup of infant MLL+ ALL carrying further poor prognostic factors. The trial was registered with http://ClinicalTrials.gov (NCT 00015873) and at http://controlled-trials.com (ISRCTN24251487). |
| Martinez-Climent JA, Lane NJ, Rubin CM, Morgan E, Johnstone HS, Mick R, Murphy SB, Vardiman JW, Larson RA, Le Beau MM et al. |
Clinical and prognostic significance of chromosomal abnormalities in childhood acute myeloid leukemia. |
Leukemia 1995, 9: 95 |
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| Marymont MH, Geohas J, Tomita T, Strauss L, Brand WN, Mittal BB |
Hyperfractionated craniospinal radiation in medulloblastoma. [+] |
Pediatric neurosurgery 1996, 24: 178 |
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| From 1986 to 1991, 13 patients at Northwestern Memorial Hospital were entered onto a pilot study designed to test the feasibility of treating children with medulloblastoma (11 patients) or primitive neuroectodermal tumors of the cerebral hemispheres (2 patients) with hyperfractionated craniospinal radiotherapy (HFxRT). Follow-up times ranged from 10 to 96 months with a median of 53 months. The patients were prospectively divided among three treatment arms depending on prior treatment history, if any, and degree of surgical resection. The 3 patients in group I had undergone gross total resection of the primary site, receiving 64.8 Gy to the primary site and 31.2 Gy directed to the craniospinal axis (CSA). Of these 3 patients, patient 1 had residual disease in the thoracic spine at T-10. The 8 patients in group II, who had gross residual disease remaining at the primary site, received 72 Gy to the primary site and 34 Gy to the CSA. Five of these eight patients in group II also received 8-in-1 chemotherapy. The 2 patients in group III had already failed chemotherapy and were then treated with 60 Gy to the primary site and 26 Gy to the CSA. Of the 11 patients in groups I and II, 7 of the 11 (64%) have never recurred. Two of the three group-I patients have not recurred, and 5 of the 7 group-II patients have not recurred. In addition, patient 7 (group II) remains alive after salvage with bone marrow transplant, following a local failure bordering the tentorium. Unfortunately, neither of the group-III patients could be salvaged with HFxRT. Acute/subacute toxicities included 7 cases of external auditory canal or skin desquamation, 2 cases of postradiation somnolence, and 1 case each of poor wound healing and neutropenia. Chronic toxicities included hypothyroidism in 2 patients and growth problems in 2 patients. Neuropsychologic complications affected only the 3 youngest patients in the study. Three patients developed neurologic sequelae attributed to radiation, including 1 with progressive urinary incontinence, 1 who developed a transient ischemic attack, and 1 who became progressively ataxic. Our research, although based on a small number of patients, suggests that hyperfractionated radiation therapy to craniospinal access is feasible and that the survival results are favorable. This treatment strategy should be further explored in a phase-III randomized trial. |
| Marx M, Langer T, Beck J, Dörr H |
Disorders of endocrine function after brain tumor therapy in childhood. |
Strahlenther Onkol 1999, 175: 305 |
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| Marx M, Schoof E, Grabenbauer G, Beck J, Dörr H |
Effects of puberty on bone age maturation in a girl after medulloblastoma therapy. |
J Pediatr Adolesc Gynecol 1999, 12: 62 |
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| Marx M, Beck J, Müller H, Kühl J, Langer T, Dörr H |
Endocrine late-effects of brain tumour therapy in childhood and adolescence. |
Klin Pädiatr 2000, 212: 224 |
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| Marx M, Beck J, Grabenbauer G, Dörr H |
Spontaneous nocturnal growth hormone secretion in children after medulloblastoma therapy. |
Med Pediatr Oncol 2001, 36: 494 |
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| Marx M, Langer T, Graf N, Hausdorf G, Stohr W, Ludwig R, Beck J |
Multicentre analysis of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No. 9/GPOH and SIOP 93-01/GPOH. |
Med Pediatr Oncol 2002, 39: 18 |
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| Marx M, Langer T, Graf N, Hausdorf G, Stohr W, Ludwig R, Beck J |
Multicentre analysis of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No. 9/GPOH and SIOP 93-01/GPOH*. |
Med Pediatr Oncol 2002, 39: 18 |
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| Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Fernández-Viña M, Geraghty DE, Holdsworth R, Hurley CK, Lau M, Lee KW, Mach B, Maiers M, Mayr WR, Müller CR, Parham P, Petersdorf EW, Sasazuki T, Strominger JL, Svejgaard A, Terasaki PI, Tiercy JM, Trowsdale J |
An update to HLA Nomenclature, 2010. [+] |
Bone marrow transplantation 2010, 45: 846 |
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| The WHO Nomenclature Committee for Factors of the HLA System met during the 15th International Histocompatibility and Immunogenetics Workshop in Buzios, Brazil in September 2008. This update is an extract of the main report that documents the additions and revisions to the nomenclature of human leukocyte antigen (HLA) specificities following the principles established in previous reports.Bone Marrow Transplantation advance online publication, 29 March 2010; doi:10.1038/bmt.2010.79. |
| Massimino M, Spreafico F, Cefalo G, Riccardi R, Tesoro-Tess JD, Gandola L, Riva D, Ruggiero A, Valentini L, Mazza E, Genitori L, Di Rocco C, Navarria P, Casanova M, Ferrari A, Luksch R, Terenziani M, Balestrini MR, Colosimo C, Fossati-Bellani F |
High response rate to cisplatin/etoposide regimen in childhood low-grade glioma. [+] |
J Clin Oncol 2002, 20: 4209 |
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| PURPOSE: The aim of this study was to avoid radiotherapy and to induce an objective response in children with low-grade glioma (LGG) using a simple chemotherapy regimen based on cisplatin and etoposide. PATIENTS AND METHODS: Thirty-four children (median age, 45 months) with unresectable LGG were treated with 10 monthly cycles of cisplatin (30 mg/m(2)/d on days 1 to 3) and etoposide (150 mg/m(2)/d on days 1 to 3). Tumor originated in the visual pathway in 29 patients, in the temporal lobe in two, in the frontal lobe in two, and in the spine in one. Eight children were affected by neurofibromatosis type 1. Objective tumor response and toxicity were evaluated by magnetic resonance imaging and neurologic and functional tests at 3-month intervals. RESULTS: An objective response was obtained in 24 (70%) of 34 patients, whereas the others had stable disease. None of the children were electively irradiated. In 31 previously untreated children, overall survival was 100% and progression-free survival was 78% at 3 years, with a median follow-up of 44 months. Acute toxicity was unremarkable; 28% patients evaluated for acoustic neurotoxicity revealed a loss of perception of high frequencies. CONCLUSION: Cisplatin and etoposide combined treatment is one of the most active regimens for LGG in children and allows avoidance of radiotherapy in the vast majority of patients. |
| Masera G, Eden T, Schrappe M, Nachman J, Gadner H, Gaynon P, Evans W, Pui C |
Statement by members of the Ponte di Legno Group on the right of children to have full access to essential treatment for acute lymphoblastic leukemia. |
Pediatr Blood Cancer 2004, 43: 103 |
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| Masjosthusmann K, Bielack SS, Kohler G, Florax A, Schiborr M, Bruch J, Reinhardt D, Kuhn N, Paulussen M, Jürgens H |
Concomitant Ewing sarcoma and acute lymphoblastic leukemia in a 5-year-old girl. [+] |
Pediatric blood & cancer 2005, 45: 846 |
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| Malignancies from the Ewing family of tumors and acute lymphoblastic leukemia (ALL) are not known to be associated with each other. A 5-year-old girl was incidentally found to suffer from acute lymphoblastic leukemia during bone marrow staging for Ewing sarcoma of the radius. The simultaneous presence of two distinct neoplasms was confirmed by RT-PCR, with EWS/FLI1 type 1 rearrangement in the bone tumor and TEL/AML1 rearrangement in the marrow. She was treated with chemotherapy, radiotherapy, and surgery and was in remission of both diseases 31 months after diagnosis. |
| Masoudi A, Elopre M, Amini E, Nagel ME, Ater JL, Gopalakrishnan V, Wolff JE |
Influence of valproic acid on outcome of high-grade gliomas in children. [+] |
Anticancer Res 2008, 28: 2437 |
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| BACKGROUND: Chemotherapy has limited effects in the treatment of high-grade gliomas (HGGs). Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, may sensitize HGGs to radiochemotherapy. As the drug has been given frequently as an antiepileptic drug, a retrospective analysis was conducted to ensure relevant information was not missed before a prospective study was launched.
MATERIALS AND METHODS: An analysis of 66 pediatric patients (range, 1-19 years of age) with glioblastoma multiforme (GBM) (n=40) or anaplastic astrocytoma (AA) (n=26) was retrospectively conducted for predictors of survival and response and for effects of VPA on outcome or toxicity.
RESULTS: The overall survival (OS) was better for AA (p=0.0114) and complete resection (p<0.00005) and event-free survival (EFS) was better for complete resection (p=0.0049). Nine patients received VPA (for seizure) plus further oncological treatment. The most severe adverse effect was a pulmonary embolism (n=1); no other severe side-effects were noted. The response to nonsurgical treatment after 8 weeks was: complete response (CR): 0, partial response (PR): 3, stable disease (SD): 4, progressive disease (PD): 2. Some of the patients with SD responded later resulting in best response: CR:0, PR:5, SD:2, PD:2.
CONCLUSION: Treatment with VPA plus radiochemotherapy is well tolerated with an encouraging response rate. |
| Massimino M, Giangaspero F, Garrè ML, Gandola L, Poggi G, Biassoni V, Gatta G, Rutkowski S |
Childhood medulloblastoma. [+] |
Crit Rev Oncol Hematol 2010, Epub ahead of print |
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| Among all the childhood central nervous system tumours, medulloblastoma and other neuroectodermal tumours account for 16-25% of cases. The causative factors of medulloblastoma/PNET have not been well established. It is more frequent in boys than in girl and in children than in adults. There was a significant improvement of survival for children diagnosed in 2000-2002 compared to those diagnosed in 1995-1999. The risk of dying was reduced by 30%. Patients are generally divided into risk-stratified schemes on the basis of age, the extent of residual disease, and dissemination. Sixty to 70% of patients older than 3 years are assigned to the average-risk group. High-risk patients include those in the disseminated category, and in North American trials those that have less than a gross or near-total resection, which is arbitrarily defined as 1.5cm(2) of post-operative residual disease. Current and currently planned clinical trials will:define molecular and biological markers that improve outcome prediction in patients with medulloblastoma and which can be incorporated for front-line stratification of newly defined risk subgroups. |
| Masqué-Soler N, Szczepanowski M, Leuschner I, Vokuhl C, Haag J, Calaminus G, Klapper W |
Absence of BRAF mutation in pediatric and adolescent germ cell tumors indicate biological differences to adult tumors. [+] |
Pediatric blood & cancer 2012, 59: 732 |
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| The V600E mutation of the BRAF gene has been reported to be associated with poor prognosis of germ cell tumors in adult patients. We analyzed the mutational status of the BRAF and KRAS gene as well as MLH1 and MSH6 expression as surrogate markers for microsatellite instability in 70 pediatric germ cell tumors. Neither BRAF and KRAS mutations nor loss of MLH1 and MSH6 expression were found. Our data provide further evidence for patient age related biological differences in germ cell tumors and demonstrate that prognostic biomarkers cannot necessarily be transferred from one age group to the other. |
| Matthes-Martin S, Lion T, Aberle SW, Fritsch G, Lawitschka A, Bittner B, Frommlet F, Gadner H, Peters C |
Pre-emptive treatment of CMV DNAemia in paediatric stem cell transplantation: the impact of recipient and donor CMV serostatus on the incidence of CMV disease and CMV-related mortality. [+] |
Bone marrow transplantation 2003, 31: 803 |
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| Cytomegalovirus (CMV) DNAemia was detected by PCR in 30/125 (24%) consecutive paediatric patients undergoing allogeneic stem cell transplantation. All patients with CMV DNAemia received pre-emptive ganciclovir until two consecutive negative results were obtained. CMV-IgG-positive patients (R+) had a significantly increased risk of DNAemia as compared to CMV-IgG-negative (R-) patients (62% vs 8%) P<0.0001. The incidence of DNAemia was 71% (10/14) in R+ transplanted from seronegative donors (D-) compared to 54% (13/32) in those transplanted from seropositive donors (D+). Of 30 (40%) children with DNAemia, 12 developed CMV disease despite pre-emptive treatment. The overall incidence of disease was 0% (0/59) for R-/D-, 9% (3/23) for R+/D+, 7% (2/29) for R-/D+ and 57% (8/14) for R+/D-. In patients with DNAemia, 4/20 (20%) patients with D+ and 8/10 (80%) with D- became symptomatic. In the multivariate analysis of both groups, patients at risk (R+ and/or D+) and patients with DNAemia, a negative donor serostatus was the only factor associated with a significantly increased incidence of disease. Seven of 9 patients with lethal CMV disease had received CMV-IgG-negative grafts. The data suggest that in CMV seropositive recipients donor CMV seropositivity is associated with a reduced incidence of CMV disease and a favourable outcome following pre-emptive treatment. |
| Mattke AC, Bailey EJ, Schuck A, Dantonello T, Leuschner I, Klingebiel T, Treuner J, Koscielniak E |
Does the time-point of relapse influence outcome in pediatric rhabdomyosarcomas? [+] |
Pediatric blood & cancer 2009, 52: 772 |
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| BACKGROUND: Childhood rhabdomyosarcoma (RMS), a soft tissue malignant tumor of skeletal muscle origin, accounts for approximately 3.5% of the cases of cancer among children 0-14 years and 2% of the cases among adolescents and young adults 15-19 years of age. PROCEDURE: We evaluated survival (SUR) after first relapse depending on the time to relapse (TTR) in RMSs of childhood and adolescence. Early, intermediate, and late relapsing patients were evaluated for prognostic risk factors. RESULTS: Two hundred thirty-four patients with RMS enrolled in the German sarcoma trial CWS-81, CWS-86, CWS-91, and CWS-96 met selection criteria. Of the 234 patients, 35%, 32%, and 33% relapsed within 6 (early), 6-12 (intermediate), and more than 12 (late) months respectively after the end of primary therapy. Four-year SUR was 12%, 21%, and 41% for early, intermediate, and late relapse respectively (P < 0.001). Four-year SUR after local relapse was 18% (early), 38% (intermediate), and 49% (late). Embryonal RMS showed four year SUR of 16%, 30%, and 46% (P < 0.001) whereas alveolar histology showed four year SUR of 8%, 6%, and 23% (P < 0.01) for early, intermediate, and late relapse respectively. CONCLUSION: TTR has significant influence on prognosis in relapsed RMS. It influences SUR independent of other features such as type of relapse, histology, tumor site, primary treatment time or irradiation in primary treatment. |
| Mauz-Körholz C, Harms D, Calaminus G, Göbel U |
Primary chemotherapy and conservative surgery for vaginal yolk-sac tumour. Maligne Keimzelltumoren Study Group [letter]. |
Lancet 2000, 355 |
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| Mauz-Körholz C, Gorde-Grosjean S, Hasenclever D, Shankar A, Dörffel W, Wallace WH, Schellong G, Robert A, Körholz D, Oberlin O, Hall GW, Landman-Parker J |
Resection alone in 58 children with limited stage, lymphocyte-predominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma. [+] |
Cancer 2007, 110: 179 |
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| BACKGROUND: Lymphocyte-predominant Hodgkin lymphoma (LPHL) is a rare, CD20-positive, good prognostic lymphoma in children. Patients with early-stage LPHL who underwent successful surgical lymph node resection alone have been reported. To clarify the optimum treatment strategy in children, European study groups were asked to report their experience of surgery alone used in the treatment of pediatric LPHL. METHODS: Data from 58 patients were collected by the French Society for Pediatric Cancers, the German-Austrian Pediatric Study Group/German Society of Pediatric Oncology and Hematology (Germany), and the Children's Cancer and Leukaemia Group (United Kingdom). In total, there were 50 boys and 8 girls, and the median age was 11 years (age range, 4-17 years). Fifty-four patients had stage IA disease, 2 patients had stage IIA disease, and 2 patients had stage IIIA disease. RESULTS: With a median follow-up of 43 months (range, 2-202 months), the overall survival rate was 100%, and the progression-free survival (PFS) rate was 57%. Fifty-one of 58 patients achieved complete remission (CR) after surgery. In the CR group, the overall PFS rate was 67% (95% confidence interval, 51-82%). All seven patients who had residual disease after initial surgery developed recurrences (P = .003). Among 18 patients with stage IA LPHL who developed recurrent disease, 11 patients had local recurrences, and 7 patients recurred in stage IIA. One patient with stage IIIA disease presented with high-grade B-cell non-Hodgkin lymphoma at 10 years of follow-up. CONCLUSIONS: When complete resection was achieved, a substantial proportion of patients with surgically treated, early-stage LPHL experienced long-term remission and actually may have been cured. |
| Mauz-Körholz C, Hasenclever D, Dörffel W, Ruschke K, Pelz T, Voigt A, Stiefel M, Winkler M, Vilser C, Dieckmann K, Karlén J, Bergsträsser E, Fosså A, Mann G, Hummel M, Klapper W, Stein H, Vordermark D, Kluge R, Körholz D |
Procarbazine-Free OEPA-COPDAC Chemotherapy in Boys and Standard OPPA-COPP in Girls Have Comparable Effectiveness in Pediatric Hodgkin's Lymphoma: The GPOH-HD-2002 Study. [+] |
Journal of clinical oncology 2010, |
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| PURPOSE Vincristine, etoposide, prednisone, and doxorubicin (OEPA)-cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDAC) is derived from standard vincristine, procarbazine, prednisone, and doxorubicin (OPPA)-cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) chemotherapy by replacing procarbazine with etoposide and dacarbazine for a potentially less gonadotoxic regimen for boys with Hodgkin's lymphoma (HL). PATIENTS AND METHODS Five hundred seventy-three pediatric patients with classical HL were enrolled onto the German Society of Pediatric Oncology and Hematology-Hodgkin's Disease (GPOH-HD) -2002 study between November 2002 and December 2005. Boys received two courses of OEPA and girls received two courses of OPPA for induction. Treatment group (TG) -2 (intermediate stages) and TG-3 (advanced stages) patients received further two or four cycles COPP (girls) or COPDAC (boys), respectively. After chemotherapy all patients received involved-field irradiation with 19.8 Gy, except for patients with early-stage disease (TG-1) in complete remission. Results Five hundred seventy-three patients (287 males and 286 females) were less than 18 years old and fulfilled all inclusion criteria; 195 patients (34.0%) were allocated to TG-1, 139 (24.3%) were allocated to TG-2, and 239 (41.7%) were allocated to TG-3. Toxicity of OEPA-COPDAC was tolerable overall. Hematotoxicity was more pronounced with OEPA than OPPA, whereas it was less pronounced with COPDAC compared with COPP. The median observation time was 58.6 months. Overall survival and event-free survival (EFS) rates (+/- SE) at 5 years were 97.4% +/- 0.7% and 89.0% +/- 1.4%, respectively. In TG-1, overall EFS was 92.0% +/- 2.0%. EFS of patients without irradiation (93.2% +/- 3.3%) was similar to that of irradiated patients (91.7% +/- 2.5%), confirming results of the previous GPOH-HD-95 study. In TG-2+3, EFS did not significantly differ between boys and girls (90.2% +/- 2.3 v 84.7% +/- 2.7, respectively; P = .12). CONCLUSION In TG-2+3, results in boys and girls are superimposable. OPPA-COPP and OEPA-COPDAC seem to be exchangeable regimens in intermediate- and advanced-stage classical HL in pediatric patients. |
| Mazloom A, Wolff JE, Paulino AC |
The impact of radiotherapy fields in the treatment of patients with choroid plexus carcinoma. [+] |
Int J Radiat Oncol Biol Phys 2010, 78: 79 |
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| PURPOSE: To perform a comprehensive literature review and analysis of cases dealing with choroid plexus carcinoma (CPC) to determine the optimal radiotherapy (RT) treatment field.
METHODS AND MATERIALS: A PubMed search of English language articles from 1979 to 2008 was performed, yielding 33 articles with 56 patients who had available data regarding RT treatment field. The median age at diagnosis was 2.7 years (range, 1 month-53 years). Of 54 patients with data regarding type of surgery, 21 (38.9%) had complete resection. Chemotherapy was delivered to 27 (48%) as part of initial therapy. The RT treatment volume was the craniospinal axis in 38 (68%), whole brain in 9 (16%), and tumor/tumor bed in 9 (16%). Median follow-up for surviving patients was 40 months.
RESULTS: The 5-year overall survival and progression-free survival (PFS) rates were 59.5% and 37.2%, respectively. Complete resection (p = 0.035) and use of craniospinal irradiation (CSI; p = 0.025) were found to positively affect PFS. The 5-year PFS for patients who had CSI vs. whole brain and tumor/tumor bed RT were 44.2% and 15.3%. For the 19 patients who relapsed, 9 (47%) had a recurrence in the RT field, 6 (32%) had a recurrence outside the RT field, and 4 (21%) had a recurrence inside and outside the irradiated field.
CONCLUSION: Patients with CPC who received CSI had better PFS compared with those receiving less than CSI. This study supports the use of CSI in the multimodality management of patients with CPC. |
| McIntosh N |
Medulloblastoma--a changing prognosis? [+] |
Arch Dis Child 1979, 200 |
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| 87 of 90 consecutive cases of medulloblastoma diagnosed at The Hospital for Sick Children, London, in the 10-year period 1965-74 were followed-up until death or until 1 January 1978. Only one patient survived in the 1st 5-year period and is a cure. In the 2nd 5-year period 17 (41%) of 41 patients presenting are alive and, of these, 11 are 5-year survivors (=39% of possible 5-year survivors). Reasons for this improvement are discussed; it is thought likely that the main contribution is improved radiotherapeutic techniques. |
| Meadows AT, Obringer AC, Marrero O, Oberlin O, Robison L, Fossati-Bellani F, Green D, Voûte PA, Morris-Jones P, Greenberg M |
Second malignant neoplasms following childhood Hodgkin's disease: treatment and splenectomy as risk factors. [+] |
Medical and pediatric oncology 1989, 17: 477 |
|
| The risk of second malignant neoplasm (SMN) was evaluated in 979 children with Hodgkin's disease. This cohort was diagnosed between 1955 and 1979 at one of the institutions of the Late Effects Study Group. Solid tumors, non-lymphocytic leukemia, and non-Hodgkin's lymphoma (NHL) developed in 18, 17, and 3 patients, respectively. The estimated cumulative probability of developing any SMN was 2% at 5 years from diagnosis, 5% at 10 years, and 9% at 15 years. The incidence is ninefold greater than the risk of acquiring cancer in 19 year-olds, the median age at which the diagnosis of SMN was made in this study population. For leukemia and NHL the corresponding probabilities were 1%, 3%, and 4% for the group as a whole but were increased (2%, 6%, and 8%) in patients who had suffered one or more recurrences. In order to analyze the risk of leukemia and NHL associated with alkylating agent chemotherapy, each patient was assigned a score of one for each alkylating agent administered for a 6-month period. Scores of 2, 4, 6, and 8 were associated with probabilities of leukemia or NHL of 2%, 3%, 6%, and 10%, respectively. In a multivariate analysis for leukemia/lymphoma that included AAD score, stage, and splenectomy, the effect of AAD score and splenectomy did not change substantially compared to the univariate results. AAD score remained statistically significant (P = .0001), and splenectomy was of borderline significance (P = .09). Of the 18 solid tumor SMNs, 15 developed within the field of radiation, and one other developed in tissue irradiated 34 years earlier for hemangioma. This study of a large and unselected group of children with Hodgkin's disease who received a variety of therapies demonstrates that children are as likely as adults to develop acute leukemia after alkylating agents and solid tumors in the field of radiation therapy. |
| Mehes G, Lorch T, Ambros P |
Quantitative analysis of disseminated tumor cells in the bone marrow by automated fluorescence image analysis. |
Cytometry 2000, 42: 357 |
|
| Mehes G, Luegmayr A, Ambros I, Ladenstein R, Ambros P |
Combined automatic immunological and molecular cytogenetic analysis allows exact identification and quantification of tumor cells in the bone marrow. |
Clin Cancer Res 2001, 7: 1969 |
|
| Mehes G, Luegmayr A, Hattinger C, Lorch T, Ambros I, Gadner H, Ambros P |
Automatic detection and genetic profiling of disseminated neuroblastoma cells. |
Med Pediatr Oncol 2001, 36: 205 |
|
| Meinert R, Kaatsch P, Kaletsch U, Krummenauer F, Miesner A, Michaelis J |
Childhood leukaemia and exposure to pesticides. |
Eur J Cancer 1996, 32A: 1943 |
|
| Meinert R, Kaletsch U, Kaatsch P, Schuz J, Michaelis J |
Associations between childhood cancer and ionizing radiation. |
Cancer Epidemiol Biomarkers Prev 1999, 8: 793 |
|
| Meinert R, Schuz J, Kaletsch U, Kaatsch P, Michaelis J |
Leukemia and non-Hodgkin's lymphoma in childhood and exposure to pesticides. |
Am J Epidemiol 2000, 151: 639 |
|
| Meissner B, Stanulla M, Ludwig W, Harbott J, Moricke A, Welte K, Schrappe M |
The GSTT1 deletion polymorphism is associated with initial response to glucocorticoids in childhood acute lymphoblastic leukemia. |
Leukemia 2004 |
|
| Meissner B, Borkhardt A, Dilloo D, Fuchs D, Friedrich W, Handgretinger R, Peters C, Schrauder A, Schuster FR, Vormoor J, Maecker B, Sykora KW, Zintl F, Welte K, Sauer M |
Relapse, not regimen-related toxicity, was the major cause of treatment failure in 11 children with Down syndrome undergoing haematopoietic stem cell transplantation for acute leukaemia. [+] |
Bone marrow transplantation 2007, 40: 945 |
|
| We report a retrospective analysis of 11 children with Down syndrome (DS) treated by SCT in eight German/Austrian SCT centres. Indications for transplantation were acute lymphoblastic leukaemia (N=8) and acute myeloid leukaemia (N=3). A reduced intensity conditioning (RIC) containing 2 Gy TBI was given to two patients, another five received a myeloablative regimen with 12 Gy TBI. Treosulphan or busulphan was used in the remaining four children. Four of eleven (36%) patients are alive. All of them were treated with a myeloablative regimen. One of the four surviving children relapsed 9 months after SCT and is currently receiving palliative outpatient treatment. The main cause of death was relapse (5/11). Two children died of regimen-related toxicity (RRT), one from severe exfoliative dermatitis and multiorgan failure after a treosulphan-containing regimen, the other from GvHD-related infections after RIC. Acute GvHD of the skin was observed in 10 of 10 evaluable patients, and chronic GvHD in 4 of 8. Our data show that DS patients can tolerate commonly used, fully myeloablative preparative regimens. The major cause of death is relapse rather than RRT resulting in an event-free survival of 18% and over all survival of 36%. |
| Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Müller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, Hanenberg H |
Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. [+] |
Nature genetics 2010, 42: 410 |
|
| Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis. |
| Meinhardt A, Burkhardt B, Zimmermann M, Borkhardt A, Kontny U, Klingebiel T, Berthold F, Janka-Schaub G, Klein C, Kabickova E, Klapper W, Attarbaschi A, Schrappe M, Reiter A, Berlin-Frankfurt-Münster group |
Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin's lymphoma and Burkitt leukemia. [+] |
Journal of clinical oncology 2010, 28: 3115 |
|
| PURPOSE: The activity of rituximab in pediatric B-cell non-Hodgkin's lymphoma (B-NHL) has not yet been determined. We conducted a phase II window study to examine activity and tolerability of rituximab in newly diagnosed pediatric B-NHL. PATIENTS AND METHODS: Patients younger than age 19 years with CD20(+) B-NHL with at least one measurable site were eligible. Treatment consisted of rituximab at 375 mg/m(2) administered intravenously on day 1; concomitant therapy consisted of rasburicase, intrathecally (IT) triple drug (methotrexate, cytarabine, and prednisolone) on days 1 and 3 for CNS-positive patients and steroids only for anaphylaxis. Response criterion was the product of the two largest perpendicular diameters of one to three lesions and/or the percentage of blasts in bone marrow (BM) or peripheral blood (PB) within 24 hours before rituximab and on day 5. Responders had > or = 25% decrease of at least one lesion or BM or PB blasts and no disease progress at other sites. Response rate (RR) was set at 45% for unfavorable activity or at 65% for favorable activity. RESULTS: From April 2004 to August 2008, 136 patients were enrolled. National Cancer Institute Common Toxicity Criteria 3/4 toxicities attributable to rituximab were general condition, 15%; fatigue, 13%; anaphylaxis, 7%; infection, 3%; glutamic-oxaloacetic transaminase/glutamic-pyruvic transaminase, 8%; no capillary leakage; and no toxic death. Forty-nine patients were not evaluable for response because of withdrawal from the study (n = 16), IT therapy in CNS-negative patients (n = 8), corticosteroid treatment (n = 3), technical inadequacy of response evaluation (n = 21), or no evaluable lesion (n = 1). Of 87 evaluable patients, 36 were responders (RR, 41.4%; 95% CI, 31% to 52%); among them, 27 of 67 with Burkitt lymphoma and seven of 15 with diffuse large B-cell lymphoma. A response was more frequently observed in BM (12 of 18) compared with solid tumor lesions (36 of 108; P = .007). CONCLUSION: Rituximab is active as a single-agent in pediatric B-NHL even though the RR was lower than requested in the phase II plan. |
| Meier, Emily Riem, Miller, Jeffery L |
Sickle Cell Disease in Children. [+] |
Drugs 2012, 72 : 895 |
|
| Early identification of infants with sickle cell disease (SCD) by newborn
screening, now universal in all 50 states in the US, has improved survival,
mainly by preventing overwhelming sepsis with the early use of prophylactic
penicillin. Routine transcranial Doppler screening with the institution of
chronic transfusion decreases the risk of stroke from 10% to 1% in paediatric
SCD patients. Hydroxyurea decreases the number and frequency of painful
crises, acute chest syndromes and number of blood transfusions in children
with SCD. Genetic research continues to be driven toward the prevention and
ultimate cure of SCD before adulthood. This review focuses on clinical
manifestations and therapeutic strategies for paediatric SCD as well as the
evolving topic of gene-focused prevention and therapy. |
| Menke-Moellers I, Berthold F |
In Vitro Sensitivity of Human Neuroblastoma Cells to Antineoplastic Drugs. |
Am J Pediatr Hematol Oncol 1993, 15: 47 |
|
| Merchant TE, Haida T, Wang MH, Finlay JL, Leibel SA |
Anaplastic ependymoma: treatment of pediatric patients with or without craniospinal radiation therapy. [+] |
J Neurosurg 1997, 86: 943 |
|
| The authors conducted a retrospective review of the clinical and treatment characteristics and outcomes in 28 pediatric patients with anaplastic ependymoma treated with radiation therapy since the advent of computerized tomography (CT) (1978-1994). Twelve patients received craniospinal irradiation followed by a boost to the primary site, two received whole-brain radiation therapy followed by a boost to the primary site, and the remaining 14 were treated with focal radiation therapy. The mean dose to the primary site was 5486 cGy. With a median follow-up period of 86 months for the 14 surviving patients (range 31-201 months), the median disease-free survival, measured from the date of diagnosis to the time of recurrence after radiation therapy, was 40 months. The median disease-free survival measured from the start of radiation therapy was 32 months. The median overall survival rate has not been reached and the actuarial estimates of overall survival rates at 5 and 10 years were 56% and 38%, respectively. According to univariate analysis, the disease-free survival rate was significantly improved (p < 0.01) in patients who underwent a gross-total resection at diagnosis. Overall survival rates were negatively influenced by treatment with craniospinal and whole-brain irradiation. As calculated by multivariate analysis, increasing dosage to the primary site (p < 0.05), infratentorial location (p < 0.01), and gross-total resections (p < 0.02) resulted in the longest disease-free survival times. All 19 patients in whom treatment failed after radiation therapy suffered a recurrence at the primary site. In addition, one of these patients experienced subarachnoid dissemination. Radiation treatment recommendations for patients with ependymoma have been based on the tumor's location, perceived risk for dissemination, and malignant propensity. The significance of anaplastic histological classification is controversial. Differences in the disease-free and overall survival rates have been demonstrated between ependymomas and anaplastic ependymomas treated in the pre-CT era. The results of this study show that there is no benefit from craniospinal irradiation in this group of patients |
| Merchant TE, Fouladi M |
Ependymoma: new therapeutic approaches including radiation and chemotherapy. [+] |
Journal of neuro-oncology 2005, 75: 287 |
|
| Recent advances in neuroimaging, neurosurgery and radiation therapy have improved disease control and functional outcomes for children with ependymoma, including children under the age of 3 years. The rate of gross-total resection has been increased to 85% in some series and 3 year progression-free survival after radiation therapy as high as 75% has been reported along with significant reductions in neurologic, endocrine and cognitive deficits. Based on these advances and renewed interest in radiation therapy as a frontline treatment modality, attention has been refocused on disease control instead of radiotherapy avoidance. Future research in the treatment of this tumor, that afflicts fewer than 200 children in the US each year, will focus on molecular biology, clarifying risk factors for tumor control and late effects, and testing novel agents. |
| Metayer C, Lynch CF, Clarke EA, Glimelius B, Storm H, Pukkala E, Joensuu T, van Leeuwen FE, van't Veer MB, Curtis RE, Holowaty EJ, Andersson M, Wiklund T, Gospodarowicz M, Travis LB |
Second cancers among long-term survivors of Hodgkin's disease diagnosed in childhood and adolescence. |
J Clin Oncol 2000, 18: 2435 |
|
| Metzler M, Brehm U, Langer T, Viehmann S, Borkhardt A, Stanulla M, Schrappe M, Harbott J, Beck J, Rascher W, Repp R |
Asymmetric multiplex-polymerase chain reaction - a high throughput method for detection and sequencing genomic fusion sites in t(4;11). |
Br J Haematol 2004, 124: 47 |
|
| Metzler M, Strissel P, Strick R, Niemeyer C, Roettgers S, Borkhardt A, Harbott J, Ludwig W, Stanulla M, Schrappe M, Reinhardt D, Creutzig U, Beck J, Rascher W, Repp R, Langer T |
Emergence of translocation t(9;11)-positive leukemia during treatment of childhood acute lymphoblastic leukemia. |
Genes Chromosomes Cancer 2004, 41: 291 |
|
| Meyer LH, Queudeville M, Eckhoff SM, Creutzig U, Reinhardt D, Karawajew L, Ludwig WD, Stahnke K, Debatin KM |
Intact apoptosis signaling in myeloid leukemia cells determines treatment outcome in childhood AML. [+] |
Blood 2008, 111: 2899 |
|
| Recently we reported that intact apoptosis signaling is indicative of favorable outcome in childhood acute lymphoblastic leukemia. Here we addressed this issue in 45 pediatric acute myeloid leukemia patients analyzing 2 core apoptogenic events: cytochrome c release and caspase-3 activation. In patients with good prognosis cytochrome c release was clearly found to be caspasedependent and correlated with activated caspase-3, indicating that activation of initiator or amplifier caspases such as caspase-8 together with an intact apoptosome function are elementary for favorable outcome. The functional integrity of this apoptogenic checkpoint is reflected by the parameter caspase-dependent cytochrome c-related activation of caspase-3 (CRAC(dep)). Patients with positive CRAC(dep) values (intact signaling) exhibited superior survival compared with CRAC(dep) negative patients (deficient signaling). Thus, the propensity to undergo apoptosis of leukemia cells is an important feature for favorable treatment outcome and may serve as an additional stratification tool for pediatric AML patients. This trial was registered at www.ClinicalTrials.gov as #NCT00111345. |
| Meyer C, Kowarz E, Hofmann J, Renneville A, Zuna J, Trka J, Ben Abdelali R, Macintyre E, De Braekeleer E, De Braekeleer M, Delabesse E, de Oliveira MP, Cavé H, Clappier E, van Dongen JJ, Balgobind BV, van den Heuvel-Eibrink MM, Beverloo HB, Panzer-Grümayer R, Teigler-Schlegel A, Harbott J, Kjeldsen E, Schnittger S, Koehl U, Gruhn B, Heidenreich O, Chan LC, Yip SF, Krzywinski M, Eckert C, Möricke A, Schrappe M, Alonso CN, Schäfer BW, Krauter J, Lee DA, Zur Stadt U, Te Kronnie G, Sutton R, Izraeli S, Trakhtenbrot L, Lo Nigro L, Tsaur G, Fechina L, Szczepanski T, Strehl S, Ilencikova D, Molkentin M, Burmeister T, Dingermann T, Klingebiel T, Marschalek R |
New insights to the MLL recombinome of acute leukemias. [+] |
Leukemia 2009, 23: 1490 |
|
| Chromosomal rearrangements of the human MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemias. These patients need to be identified, treated appropriately and minimal residual disease was monitored by quantitative PCR techniques. Genomic DNA was isolated from individual acute leukemia patients to identify and characterize chromosomal rearrangements involving the human MLL gene. A total of 760 MLL-rearranged biopsy samples obtained from 384 pediatric and 376 adult leukemia patients were characterized at the molecular level. The distribution of MLL breakpoints for clinical subtypes (acute lymphoblastic leukemia, acute myeloid leukemia, pediatric and adult) and fused translocation partner genes (TPGs) will be presented, including novel MLL fusion genes. Combined data of our study and recently published data revealed 104 different MLL rearrangements of which 64 TPGs are now characterized on the molecular level. Nine TPGs seem to be predominantly involved in genetic recombinations of MLL: AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, MLLT4/AF6, ELL, EPS15/AF1P, MLLT6/AF17 and SEPT6, respectively. Moreover, we describe for the first time the genetic network of reciprocal MLL gene fusions deriving from complex rearrangements. |
| Meyer LH, Eckhoff SM, Queudeville M, Kraus JM, Giordan M, Stursberg J, Zangrando A, Vendramini E, Möricke A, Zimmermann M, Schrauder A, Lahr G, Holzmann K, Schrappe M, Basso G, Stahnke K, Kestler HA, Te Kronnie G, Debatin KM |
Early relapse in all is identified by time to leukemia in NOD/SCID mice and is characterized by a gene signature involving survival pathways. [+] |
Cancer Cell 2011, 19: 206 |
|
| We investigated the engraftment properties and impact on patient outcome of 50 pediatric acute lymphoblastic leukemia (ALL) samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. Short TTL was strongly associated with high risk for early relapse, identifying an independent prognostic factor. This high-risk phenotype is reflected by a gene signature that upon validation in an independent patient cohort (n = 197) identified a high-risk cluster of patients with early relapse. Furthermore, the signature points to independent pathways, including mTOR, involved in cell growth and apoptosis. The pathways identified can directly be targeted, thereby offering additional treatment approaches for these high-risk patients. |
| Miano M, Labopin M, Hartmann O, Angelucci E, Cornish J, Gluckman E, Locatelli F, Fischer A, Egeler RM, Or R, Peters C, Ortega J, Veys P, Bordigoni P, Iori AP, Niethammer D, Rocha V, Dini G, Paediatric Diseases Working Party of the European Group for Blood and Marrow Transplantation |
Haematopoietic stem cell transplantation trends in children over the last three decades: a survey by the paediatric diseases working party of the European Group for Blood and Marrow Transplantation. [+] |
Bone marrow transplantation 2007, 39: 89 |
|
| This paper describes the trends in haematopoietic stem cell transplantation (HSCT) activity for children in Europe over the last three decades. We analysed 31,713 consecutive paediatric HSCTs reported by the European Group for Blood and Marrow Transplantation (EBMT) centres between 1970 and 2002. Data were taken from the EBMT registry and were compared according to period and centre category (paediatric or combined). Since 1996, there has been a significant increase in the number of HSCTs performed exclusively by paediatric centres, as well as in the number of alternative donor HSCTs, and in the use of peripheral blood stem cells (P<0.0001). The number of allogeneic HSCTs (allo-HSCTs) for acute lymphoblastic leukaemia, acute myeloblastic leukaemia and chronic myeloid leukaemia remained stable, whereas it increased for myelodysplastic syndromes and lymphomas, and decreased significantly for non-malignant diseases (P<0.0001). Multivariate analysis showed that younger age, human leukocyte antigen genoidentical donors, HSCT performed after 1996 and transplant centres performing more than 10 allo-HSCT/year were all associated with decreased transplant-related mortality (TRM) (P<0.0001). The number of autologus HSCTs (auto-HSCTs) for acute leukaemia decreased significantly, whereas it increased for solid tumours (P<0.0001). Multivariate analysis showed that both auto-HSCT performed before 1996 and paediatric solid tumours (P<0.0001) had higher TRM. Indications for paediatric HSCT have changed considerably during the last seven years. These changes provide tools for decision making in health-care planning and counselling. |
| Michaelis J, Kaatsch P |
Use of information from clinical trials for an integrated cancer registry. |
Methods Inf Med 1990, 29: 92 |
|
| Michaelis J, Haaf G, Kaatsch P, Keller B |
Krebserkrankungen im Kindesalter in der Umgebung westdeutscher kerntechnischer Anlagen. |
Deutsches Ärzteblatt 1992, 2538 |
|
| Michaelis J, Keller B, Haaf G, Kaatsch P |
Incidence of childhood malignancies in the vicinity of west German nuclear power plants. |
Cancer Causes Control 1992, 3: 255 |
|
| Michaelis J, Kaatsch P, Zöllner J |
Querschnittsuntersuchung zur Häufigkeit von Krebserkrankungen bei Kindern von beruflich strahlenexponierten Beschäftigten in westdeutschen kerntechnischen Anlagen. |
Arbeitsmed Sozialmed Umweltmed 1995, 29 und 30: 29 30 -29 |
|
| Michaelis J, Haaf H, Zollner J, Kaatsch P, Krummenauer F, Berthold F |
Case control study of neuroblastoma in west-Germany after the Chernobyl accident. |
Klin Pädiatr 1996, 208: 172 |
|
| Michaelis J, Kaatsch P |
Krebs bei Kindern - Das Deutsche Kinderkrebsregister als Instrument der Krebsbekämpfung. |
Zeitschrift des Deutschen Krebsforschungszentrums 1996, 8 |
|
| Michaelis J, Kaletsch U, Burkart W, Grosche B |
Infant leukaemia after the Chernobyl accident. |
Nature 1997, 387 |
|
| Michaelis J, Schuz J, Meinert R, Menger M, Grigat J, Kaatsch P, Kaletsch U, Miesner A, Stamm A, Brinkmann K, Karner H |
Childhood leukemia and electromagnetic fields. |
Cancer Causes Control 1997, 8: 167 |
|
| Michaelis J |
Recent epidemiological studies on ionizing radiation and childhood cancer in Germany. |
Int J Radiat Biol 1998, 73: 377 |
|
| Michaelis J, Schuz J, Meinert R, Zemann E, Grigat J, Kaatsch P, Kaletsch U, Miesner A, Brinkmann K, Kalkner W, Karner H |
Combined risk estimates for two German population-based case-control studies on residential magnetic fields and childhood acute leukemia. |
Epidemiology 1998, 9: 92 |
|
| Michaelis J, Kaatsch P, Kaletsch U |
Leukämien im Kindesalter-Epidemiologische Untersuchungen des Deutschen Kinderkrebsregisters. |
Deutsches Ärzteblatt 1999, 918 |
|
| Michaelis J, Kaletsch U, Kaatsch P |
Epidemiology of childhood brain tumors. |
Zentralbl Neurochir 2000, 61: 80 |
|
| Mielcarek M, Sperling C, Schrappe M, Meyer U, Riehm H, Ludwig W |
Expression of intercellular adhesion molecule 1 (ICAM-1) in childhood acute lymphoblastic leukaemia. |
Br J Haematol 1997, 96: 301 |
|
| Miller DR |
Hematologic malignancies: leukemia and lymphoma. |
Mosby Company, St. Louis, Philadelphia, Washington DC, Toronto 6th edition, 1990, 604 |
|
| Mild G, Schmahl G, Shayan P, Niemeyer C |
Expression of interferon regulatory factor 1 and 2 in hematopoietic cells of children with juvenile myelomonocytic leukemia. |
Leuk Lymphoma 1999, 35: 507 |
|
| Mildenberger H, Schweinitz D |
Lebertumore im Kindesalter. |
Monatsschr Kinderheilkunde 2000, 143: 644 |
|
| Milman N |
Anemia--still a major health problem in many parts of the world!. [+] |
Ann Hematol 2011, 90: 369 |
|
| Anemia is a major global health problem, especially in developing countries. This fundamental health issue still has not been solved and continues to exist affecting the health, quality of life, and working capacity in billions of people all over the world. This paper gives a review on the prevalence and major causes of anemia seen on a global scale. Most cases of anemia are due to iron deficiency, which often work in symphony with folate deficiency and/or vitamin B12 deficiency as well as with infections. More efforts should be dedicated to tackle this massive problem--we have the tools, and we know the ways. Iron fortification of appropriate food items combined with iron supplements in specific population groups has proven to be efficient. Initially, the efforts should be centered on the specific risk groups for iron deficiency anemia, i.e., young children, adolescent females, women of reproductive age, as well as pregnant women and postpartum lactating mothers. |
| Minkov M, Grois N, Broadbent V, Ceci A, Jakobson A, Ladisch S |
Cyclosporine A therapy for multisystem langerhans cell histiocytosis. |
Med Pediatr Oncol 1999, 33: 482 |
|
| Minkov M, Grois N, Heitger A, Potschger U, Westermeier T, Gadner H |
Treatment of multisystem Langerhans cell histiocytosis. Results of the DAL-HX 83 and DAL-HX 90 studies In Process Citation. |
Klin Pädiatr 2000, 212: 139 |
|
| Minkov M, Grois N, Heitger A, Pötschger U, Westermeier T, Gadner H, DAL-HX Study Group |
Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator. [+] |
Medical and pediatric oncology 2002, 39: 581 |
|
| BACKGROUND: Reliable prediction of prognosis allowing risk-adapted therapy remains a major issue in the management of multisystem Langerhans cell histiocytosis (LCH). In a recent publication of the International LCH Study Group, response to initial therapy appears to be a reliable outcome predictor. The aim of this study is to test this observation in a cohort of patients treated with more intensive initial therapy. Furthermore, we compare the predictive value of response to initial therapy to some other well-established stratification systems. PROCEDURE: Response to initial combination chemotherapy (prednisolone, vinblastine, and etoposide) at 6 weeks and its prognostic value was evaluated retrospectively in 63 patients with multisystem LCH from the DAL-HX 83 and 90 Studies, and correlated to some established scoring systems from the literature. RESULTS: After 6 weeks of therapy, 50/63 (79%) patients qualified as responders, 4/63 (7%) patients showed intermediate response, and 9/63 (14%) patients did not respond. Probability of survival at 5 years was 0.94 +/- 0.03 for responders, 0.75 +/- 0.22 for patients with intermediate response, and only 0.11 +/- 0.10 for non-responders. CONCLUSIONS: Response to initial therapy appears to be a reliable prognostic predictor. Compared to the published international LCH-I Study, our results suggest that more intensive initial treatment allows a better discrimination between responders and non-responders. This allows to identify a subgroup of patients with extremely poor prognosis (mortality rate 90%) relatively early in the disease course. |
| Minkov M, Prosch H, Steiner M, Grois N, Pötschger U, Kaatsch P, Janka-Schaub G, Gadner H |
Langerhans cell histiocytosis in neonates. [+] |
Pediatric blood & cancer 2005, 45: 802 |
|
| BACKGROUND: To study the incidence, clinical patterns, course, and outcome of neonatal Langerhans cell histiocytosis (LCH). PROCEDURE: Retrospective analysis of the data of the Austrian/German/Swiss/Netherlands LCH Study Group. The incidence of neonatal LCH was estimated with the data from the population-based German Childhood Cancer Registry. RESULTS: The estimated incidence of neonatal LCH (LCH diagnosed within 28 days after birth) in the population-based registry was 1-2/1,000,000. In 61/1,069 trial patients (6%), the first disease manifestations were observed in the neonatal period. However, in only 20 of them, the diagnosis was established within this period. There was a preponderance of multisystem (MS)-LCH 36/61 (59%). Cutaneous changes were the most common initial manifestation in both, single-system (SS)-LCH (92%), and MS-LCH (86%). In 72% of the MS-LCH patients, risk organs (ROs) were involved at diagnosis as well. The probability of survival at 5 years was 94% in SS-LCH and 57% in MS-LCH, which is significantly lower than in older age groups. CONCLUSIONS: In contrast to the available literature, neonatal LCH is characterized by a clear predominance of MS-LCH. Cutaneous changes are the most common initial manifestation in neonates with both SS-LCH and MS-LCH. Prompt evaluation of disease extent upon diagnosis is mandatory for risk-adapted treatment. The disease course is unpredictable upon diagnosis. Close monitoring for disease progression is mandatory if isolated cutaneous LCH is managed by the |
| Minkov M, Pötschger U, Grois N, Gadner H, Dworzak MN |
Bone marrow assessment in Langerhans cell histiocytosis. [+] |
Pediatric blood & cancer 2007, 49: 694 |
|
| BACKGROUND: Bone marrow changes and their relation to blood cytopenia in patients with Langerhans cell histiocytosis (LCH) have not been extensively studied to date. The aim of the present study was to characterize the bone marrow changes in LCH patients and to ascertain their relation to disease severity. METHODS: Fifty-seven marrow samples of LCH patients were studied by conventional cytology, immunocytochemistry (ICC) and flow cytometry (FCM). RESULTS: On conventional cytology there was no significant difference between LCH cases and controls with respect to cellularity, number of monocytes and progenitor cells, and presence of histiocytes and hemophagocytosis. The numbers of nucleated cells, CD34(pos) cells, and CD14(pos) cells on FCM did not differ, either. The CD1a staining by ICC was positive in 14/41 LCH samples, and was consistently negative in controls. FCM staining for CD1a was positive in 12/54 samples, but also in 5/35 controls. The number of the CD1a(pos) cells in LCH marrows was usually very low (<10-20 cells/slide by ICC, or <0.5% of the leukocytes by FCM). The CD1a staining was more frequently positive and more pronounced in patients with severe disease. CONCLUSIONS: The combination of conventional aspirate cytology with ICC (CD1a staining) appears to be the most reliable tool for bone marrow assessment in LCH. |
| Minkov M, Steiner M, Pötschger U, Aricò M, Braier J, Donadieu J, Grois N, Henter JI, Janka G, McClain K, Weitzman S, Windebank K, Ladisch S, Gadner H, International LCH Study Group |
Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry. [+] |
The Journal of pediatrics 2008, 153: 700-5, 705.e1 |
|
| OBJECTIVE: To assess multisystem Langerhans cell histiocytosis reactivation and its impact on morbidity and mortality. STUDY DESIGN: Retrospective analysis of 335 patients with MS-LCH and documented complete disease resolution (NAD1). RESULTS: The probability of a reactivation within 5 years of NAD1 was 46%. The first reactivation occurred within 2 years after NAD1 in most of the patients. Of 134 events, 35% were confined to skeleton, 24% were single-system nonbony lesions, 24% were multisystem reactivations without risk-organ involvement, and 10% with risk-organ involvement. In 7%, the location was unspecified. Only 3 deaths (2.2%) were documented within the context of a first reactivation. Second disease resolution (NAD2) was achieved in 85% of the cases. The probability of a second reactivation within 5 years of NAD2 was 44%. The risk for permanent consequences in patients with reactivations was higher, compared with patients without reactivation (RHR 2.2, P = .046). CONCLUSIONS: Reactivation is a frequent and early event in MS-LCH, but involvement of risk organs at reactivation is rare and mortality is minimal. However, reactivations increase the risk for permanent consequences by about 2-fold. Prospective trials targeting reduction of acute morbidity and permanent disabilities through nontoxic treatment of the reactivations are warranted. |
| Mittheisz E, Seidl R, Prayer D, Waldenmair M, Neophytou B, Pötschger U, Minkov M, Steiner M, Prosch H, Wnorowski M, Gadner H, Grois N |
Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis. [+] |
Pediatric blood & cancer 2007, 48: 50 |
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| BACKGROUND: Permanent consequences in Langerhans cell histiocytosis (LCH) are irreversible late sequelae related to the disease that may severely impair the quality of life of survivors. The frequency and pattern of permanent consequences affecting the central nervous system (CNS) remains to be determined. PROCEDURE: In this single center study, 25 LCH patients observed for a median time of 10 years 3 months underwent a uniform thorough follow-up program including neuropsychological testing and electrophysiological evaluation. RESULTS: Overall permanent consequences were seen in 9 of 25 patients. Intracranial abnormalities were the most frequent including diabetes insipidus (DI) in seven patients, anterior pituitary deficiencies in five patients, and neurodegenerative CNS disease in five patients. No patient had overt neurological symptoms upon neurological evaluation, but psychological testing revealed subtle deficits in short-term auditory memory (STAM) in 14 patients. Brain stem evoked potentials showed abnormalities in four of nine tested patients, all of these four had neurodegeneration on MRI. CONCLUSION: Psychoneuroendocrine sequelae were found in an unexpectedly high number of patients in this single center study. Long-term follow-up focusing on such sequelae are important in LCH survivors, in order to detect early deficits, to monitor the evolution of the disease, and to provide specific support. |
| Mitchell L, Lambers M, Flege S, Kenet G, Li-Thiao-Te V, Holzhauer S, Bidlingmaier C, Frühwald MC, Heller C, Schmidt W, Pautard B, Nowak-Göttl U |
Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study. [+] |
Blood 2010, 115: 4999 |
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| Among risk factors for developing thromboembolism (VTE) in children with acute lymphoblastic leukemia were Escherichia coli asparaginase, concomitant steroid use, presence of central venous lines, and thrombophilic abnormalities. Developing a predictive model for determining children at increased risk would be beneficial in targeting interventional studies to high-risk groups (HRGs). Predictive variables were incorporated into a risk assessment model, which was evaluated in 456 children and then validated in 339 patients. VTE risk by score was no greater than 2.5 for low-risk group (LRG) and greater than 2.5 for HRG. VTE rates at 3.5 months (validation cohorts) were 2.5% in LRG and 64.7% in HRG. In multivariate analysis adjusted for age, duration of asparaginase administration, enoxaparin prophylaxis, and T-immunophenotype, the HRG was significantly associated with VTE compared with the LRG (hazard/95% confidence interval [CI], 8.22/1.85-36.53). Model specificity was 96.2% and sensitivity was 63.2%. As secondary objective we investigated the use of enoxaparin for VTE prophylaxis in the HRG. HRG patients without enoxaparin prophylaxis showed a significantly reduced thrombosis-free survival compared with children on low-molecular-weight heparin (LMWH). On the basis of the high specificity, the model may identify children with leukemia at risk of VTE. LMWH may help prevent VTE in the HRG; this warrants assessment in larger cooperative clinical trials. |
| Modritz D, Ladenstein R, Potschger U, Amman G, Dieckmann K, Horcher E, Urban C, Meister B, Schmitt K, Jones R, Kaulfersch W, Haas H, Moser R, Stollinger O, Peham M, Gadner H, Koscielniak E, Treuner J |
Treatment for soft tissue sarcoma in childhood and adolescence. Austrian results within the CWS 96 study. [+] |
Wiener klinische Wochenschrift 2005, 117(5-6): 196 |
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| OBJECTIVE: The aim of the CWS 96 Study was to achieve an optimal treatment in children and adolescents with soft tissue sarcoma (STS) implementing a further refinement of risk-adapted allocation to chemotherapy, surgery and radiotherapy. METHODS: Treatment stratification was based on tumour histology, TNM status, postsurgical stage, localisation and age. Local tumour control was ensured by surgery and risk-adapted radiotherapy. RESULTS: From 1995 to 2002, 89 patients were registered in Austria. The 3-year event-free survival (EFS) and overall survival rates (OS) were 63% +/- 6% and 71% +/- 6%, respectively. 59/89 patients had localised RMS-like (rhabdomayosarcoma) STS (EFS 73% +/- 7%), 14 had localised NON-RMS STS (EFS 54% +/- 16%) and 15 patients had metastatic disease at diagnosis (EFS 33% +/- 12%), 1 patient had fibromatosis. The EFS rates at 3 years in patients with localised RMS-like tumours according to risk group were 92% +/- 8% for low and standard risk (12 patients) and 67% +/- 8% for high risk (47 patients). Favourable primary tumour sites of nonmetastatic RMS-like STS i.e. orbit, head/neck nonparameningeal or genitourinary non-bladder/prostate were diagnosed in 15 patients (1/15 patients died). In 44 patients with unfavourable localisation such as parameningeal, genitourinary bladder/prostate, extremity and others, 7 deceased. The 3 year EFS according to histology in patients with RMS-like STS was 61% +/- 11% for RME (embryonal RMS ) (28 patients) and 71% +/- 15% for RMA (alveolar RMS) (10 patients). The most common treatment failure was local relapse occurring in 21% of patients in the high-risk group. CONCLUSION: Risk-adapted individualisation of treatment led to a reduction of chemotherapy in the low and standard risk group without compromising survival. The outcome of RME and RMA was similar in this cohort of patients. These preliminary results after a median observation time of 2.5 years confirm the CWS 96 strategy. |
| Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, Löning L, Beier R, Ludwig WD, Ratei R, Harbott J, Boos J, Mann G, Niggli F, Feldges A, Henze G, Welte K, Beck JD, Klingebiel T, Niemeyer C, Zintl F, Bode U, Urban C, Wehinger H, Niethammer D, Riehm H, Schrappe M, German-Austrian-Swiss ALL-BFM Study Group |
Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. |
Blood 2008, 111: 4477 |
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| Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, Ludwig WD, Ritter J, Harbott J, Mann G, Klingebiel T, Zintl F, Niemeyer C, Kremens B, Niggli F, Niethammer D, Welte K, Stanulla M, Odenwald E, Riehm H, Schrappe M |
Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. [+] |
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 2010, 24: 265 |
|
| Between 1981 and 2000, 6609 children (<18 years of age) were treated in five consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria and Switzerland. Probability of 10-year event-free survival (EFS) (survival) improved from 65% (77%) in study ALL-BFM 81 to 78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: (1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk (HR) ALL patients, and eliminated in non- HR non-T-ALL patients, if it was replaced by high-dose and intrathecal (IT) MTX; (2) omission of delayed re-intensification severely impaired outcome of low-risk patients; (3) 6-month-less maintenance therapy caused an increase in systemic relapses; (4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; (5) condensed induction therapy resulted in significant improvement of outcome; (6) the daunorubicin dose in induction could be safely reduced in low-risk patients and (7) intensification of consolidation/re-intensification treatment led to considerable improvement of outcome in HR patients. |
| Möricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H, Ludwig WD, Ritter J, Harbott J, Mann G, Klingebiel T, Zintl F, Niemeyer C, Kremens B, Niggli F, Niethammer D, Welte K, Stanulla M, Odenwald E, Riehm H, Schrappe M |
Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. [+] |
Leukemia : 2010, 24: 265 |
|
| Between 1981 and 2000, 6609 children (<18 years of age) were treated in five consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria and Switzerland. Probability of 10-year event-free survival (EFS) (survival) improved from 65% (77%) in study ALL-BFM 81 to 78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: (1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk (HR) ALL patients, and eliminated in non- HR non-T-ALL patients, if it was replaced by high-dose and intrathecal (IT) MTX; (2) omission of delayed re-intensification severely impaired outcome of low-risk patients; (3) 6-month-less maintenance therapy caused an increase in systemic relapses; (4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; (5) condensed induction therapy resulted in significant improvement of outcome; (6) the daunorubicin dose in induction could be safely reduced in low-risk patients and (7) intensification of consolidation/re-intensification treatment led to considerable improvement of outcome in HR patients. |
| Moll AC, Imhof SM, Schouten-Van Meeteren AY, Kuik DJ, Hofman P, Boers M |
Second primary tumors in hereditary retinoblastoma: a register-based study, 1945-1997: is there an age effect on radiation-related risk? [+] |
Ophthalmology 2001, 108: 1109 |
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| OBJECTIVE: The aim of this study is to evaluate the influence of age at external beam irradiation (EBRT) on the occurrence of second primary tumors (SPTs) inside and outside the irradiation field in hereditary retinoblastoma patients. DESIGN: Cross-sectional study. PARTICIPANTS: The study included 263 hereditary retinoblastoma patients born in The Netherlands between 1945 and 1997. METHODS: A national register-based follow-up cohort study was performed on hereditary retinoblastoma patients. Information on therapy, age at irradiation, and location of SPT was obtained from the register. The Kaplan-Meier method calculated cumulative incidences of SPT in three subgroups: irradiation before (early EBRT) and after 12 months of age (late EBRT), and no irradiation. The Mantel-Cox method determined the statistical significance of differences between the cumulative incidence curves. MAIN OUTCOME MEASURES: Development of SPT inside and outside a precisely defined irradiation field in relation to age at irradiation. Our definition excluded pineoblastoma as SPT, because they constitute part of a trilateral retinoblastoma; in addition, they lie outside the field of irradiation. RESULTS: The cumulative incidence of SPT at the age of 25 years was 22% (95% confidence intervals 13%-34%) in the early EBRT group, 3% (0%-14%) in the late EBRT group, and 5% (1%-16%) in the nonirradiated group (Mantel-Cox overall: P = 0.001; between early and late EBRT, P = 0.04). However, in early irradiated patients, the incidence of SPTs inside and outside the irradiation field was similar (11%), and the difference between early and late EBRT in incidence of SPT inside the field of irradiation was less prominent than overall (11% vs. 3%: P = 0.37). Sensitivity analysis showed the results depended on the way SPT, irradiation field, and, especially, pineoblastomas are defined. CONCLUSIONS: Hereditary retinoblastoma confers an increased risk for the development of SPT, especially in patients treated with EBRT before the age of 12 months. However, the presence of similar numbers of SPTs inside and outside the irradiation field suggests that irradiation is not the cause. In other words, this study does not show an age effect on radiation-related risk. Rather, early EBRT is probably a marker for other risk factors of SPT. |
| Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, Kaneko M, London WB, Matthay KK, Nuchtern JG, von Schweinitz D, Simon T, Cohn SL, Pearson AD, INRG Task Force |
The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. [+] |
Journal of clinical oncology 2009, 27: 298 |
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| PURPOSE: The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. Because the International Neuroblastoma Staging System (INSS) is a postsurgical staging system, a new clinical staging system was required for the INRG pretreatment risk classification system. METHODS: To stage patients before any treatment, the INRG Task Force, consisting of neuroblastoma experts from Australia/New Zealand, China, Europe, Japan, and North America, developed a new INRG staging system (INRGSS) based on clinical criteria and image-defined risk factors (IDRFs). To investigate the impact of IDRFs on outcome, survival analyses were performed on 661 European patients with INSS stages 1, 2, or 3 disease for whom IDRFs were known. RESULTS: In the INGRSS, locoregional tumors are staged L1 or L2 based on the absence or presence of one or more of 20 IDRFs, respectively. Metastatic tumors are defined as stage M, except for stage MS, in which metastases are confined to the skin, liver, and/or bone marrow in children younger than 18 months of age. Within the 661-patient cohort, IDRFs were present (ie, stage L2) in 21% of patients with stage 1, 45% of patients with stage 2, and 94% of patients with stage 3 disease. Patients with INRGSS stage L2 disease had significantly lower 5-year event-free survival than those with INRGSS stage L1 disease (78% +/- 4% v 90% +/- 3%; P = .0010). CONCLUSION: Use of the new staging (INRGSS) and risk classification (INRG) of neuroblastoma will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world. |
| Morrell D, Cromartie E, Swift M |
Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. |
J Natl Cancer Inst 1986, 77: 89 |
|
| Moricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dordelmann M, Loning L, Beier R, Ludwig WD, Ratei R, Harbott J, Boos J, Mann G, Niggli F, Feldges A, Henze G, Welte K, Beck JD, Klingebiel T, Niemeyer C, Zintl F, Bode U, Urban C, Wehinger H, Niethammer D, Riehm H, Schrappe M |
Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. [+] |
Blood 2008, 111: 4477 |
|
| The trial ALL-BFM 95 for treatment of childhood acute lymphoblastic leukemia was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in poor-risk groups by treatment intensification. The basis for these aims was set by a stratification strategy using white blood cell count, age, immunophenotype, treatment response and unfavorable genetic aberrations providing an excellent discrimination of distinct risk groups. Estimated 6-year event-free survival (6y-pEFS) for all 2169 patients was 79.6+/-0.9%. The large standard-risk (SR) group (35% of patients) achieved excellent 6y-EFS of 89.5+/-1.1% despite significant reduction of the daunorubicin dose. In the medium-risk (MR) group (53% of patients), 6y-pEFS was 79.7+/-1.2%; no improvement was accomplished by the randomized use of additional intermediate-dose cytarabine after consolidation. Omission of preventive cranial irradiation in Non-T-ALL MR patients was possible without significant reduction of EFS though the incidence of CNS relapses increased. In the small high-risk (HR) group (12% of patients), intensification of consolidation/reinduction treatment led to considerable improvement over the previous ALL-BFM trials yielding a 6y-pEFS of 49.2+/-3.2%. Compared with the previous trial ALL-BFM 90, consistently favorable results in non-HR patients were achieved with significant treatment reduction in the majority of these patients. |
| Müller H |
Warum brauchen manche Hirntumorpatienten Hormone, obwohl ihre Drüsen gesund sind? |
WIR Informationsschrift der Aktion für krebskranke Kinder e.V. (Bonn) 2006, 2: 12 |
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| Müller HL, Gebhardt U, Pohl F, Flentje M, Emser A, Warmuth-Metz M, Kolb R, Calaminus G, Sörensen N |
Relapse pattern after complete resection and early progression after incomplete resection of childhood craniopharyngioma. [+] |
Klin Pädiatr 2006, 218: 315-20. |
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| In HIT Endo data on therapy and prognosis of 306 patients with childhood craniopharyngioma (CP) were analyzed. The 5 years-overall survival rate was 94 +/- 4 % in irradiated patients and 93 +/- 5 % in non-irradiated patients. Aims of the prospective study KRANIOPHARYNGEOM 2000 were to collect data on the incidence and time course of relapses after complete surgery and tumour progressions after incomplete resection. Furthermore, the impact of irradiation therapy (XRT) on tumour relapse and recurrence rates was analyzed. Since 2001 ninety-eight patients with CP were recruited at a median age at diagnosis of 9.9 years ranging from 1.8 to 18.0 years. Complete resection was achieved in 44 %, incomplete resection in 54 %. XRT was performed in 24 of 98 CP patients; in 10 early after incomplete resection, in 14 of 24 after progression of residual tumour or relapse, in 3 of 14 after second surgery of relapse. XRT was performed at a median age of 12.0 years ranging from 5.0 to 18.9 years and in median after an interval of 9 months after first diagnosis. The analysis of event-free survival rates (EFS) in patients with CP showed a high rate of early events in terms of tumour progression after incomplete resection (3y-EFS: 0.22 +/- 0.09) and relapses after complete resection (3y-EFS: 0.60 +/- 0.10) during the first three years of follow-up. A high rate of early events (1y-EFS: 0.78 +/- 0.10; 2y-EFS: 0.57 +/- 0.15) was also found for patients after XRT (3 cystic progressions, 3 progressions of solid tumour; in 24 patients after XRT). We conclude that tumour progression and relapse are frequent and early events even in irradiated patients. Monitoring of cerebral imaging and clinical status is recommended in follow-up of patients with childhood CP. In order to analyze the appropriate time point of XRT after incomplete resection, QoL, EFS and overall survival in patients (age > or = 5 years) will be analyzed in KRANIOPHARYNGEOM 2007 after stratified randomization of the time point of irradiation after incomplete resection (early irradiation versus irradiation at progression of residual tumour). |
| Müller HL, Albanese A, Calaminus G, Hargrave D, Garré ML, Gebhardt U, Saran F, Sörensen N, Spoudeas HA |
Consensus and perspectives on treatment strategies in childhood craniopharyngioma: results of a meeting of the Craniopharyngioma Study Group (SIOP), Genova, 2004. |
J Pediatr Endocrinol Metab 2006, 19 Suppl 1: 453 |
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| Müller HL, Gebhardt U, Wessel V, Schröder S, Kolb R, Sörensen N, Maroske J, Hanisch E |
First experiences with laparoscopic adjustable gastric banding (LAGB) in the treatment of patients with childhood craniopharyngioma and morbid obesity. [+] |
Klin padiatr 2007, 219: 323-5. |
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| Craniopharyngiomas are embryogenic malformations which lead to eating disorders and morbid obesity due to hypothalamic involvement in about 50% of all patients with pediatric craniopharyngioma. The experience with laparoscopic adjustable gastric banding (LAGB) in obese craniopharyngioma patients is limited. We are reporting on four patients with childhood craniopharyngioma diagnosed at age 2, 11, 12, and 21 years. BMI-SDS at diagnosis was +0.9, +4.5, +4.7 and -0.1 SD. During follow-up, all patients developed morbid obesity (BMI-SDS: +13.9, +10.3, +11.4, +7.3) so that 11, 6, 9 and 3 years after diagnosis LAGB were performed. After a follow-up of 4.5, 1.5, 3.0 and 2.5 years BMI decreased or stabilized continuously in all patients (BMI-SDS at latest visit: +9.9, +9.7, +9.5, +5.9 SD). The eating behavior changed in all patients profoundly. The addiction to food and especially sweets significantly improved based on self-assessment. In two patients a dislocation of the LAGB occurred and resulted in weight gain. We conclude that LAGB could be effective in weight reduction of obese craniopharyngioma patients with hypothalamic syndrome. Close follow-up is necessary in order to analyze long-term effects and complications of LAGB in patients with childhood craniopharyngioma and morbid obesity. |
| Müller HL |
Childhood craniopharyngioma. Recent advances in diagnosis, treatment and follow-up. [+] |
Horm Res 2008, 69: 193 |
|
| BACKGROUND:
Craniopharyngioma are embryogenic malformations of the sellar area. With an overall incidence of 0.5-2 new cases per million population per year, 30-50% of all cases occur in childhood. Overall survival rates are high. However, quality of life (QoL) is substantially reduced in many survivors due to sequelae such as extreme obesity caused by hypothalamic lesions.
METHODS:
Based on retrospective analysis of 306 patients with childhood craniopharyngioma (HIT ENDO), we found that QoL was negatively related to hypothalamic involvement, tumor size and the number of neurosurgical interventions.
RESULTS:
Irradiation had no significant impact on long-term QoL. The prospective surveillance of 98 patients in KRANIOPHARYNGEOM 2000 revealed frequent and early events in terms of tumor relapse after apparently complete resection (EFS: 0.60 +/- 0.09 at 3 years) and tumor progression after incomplete resection (EFS: 0.22 +/- 0.09).
CONCLUSION:
We conclude that radical surgery in patients with hypothalamic involvement has a major negative impact on long-term QoL. Innovative treatment strategies are warranted to improve QoL in these patients at risk. Accordingly, the appropriate time point of irradiation after incomplete resection will be analyzed in KRANIOPHARYNGEOM 2007. |
| Müller HL, Sörensen N |
Kraniopharyngiom im Kindes- und Jugendalter. |
Interdisziplinäre Leitlinie der Deutschen Krebsgesellschaft und der Gesellschaft für Pädiatrische Onkologie und Hämatologie AWMF online 2008 |
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| Müller HL |
Increased daytime sleepiness in patients with childhood craniopharyngioma and hypothalamic tumor involvement: review of the literature and perspectives. [+] |
nt J Endocrinol 2010, 2010, 519607 |
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| Childhood craniopharyngiomas are rare embryogenic malformations of the sellar region, presumably derived from Rathke cleft epithelium. The overall survival rates after neurosurgical intervention and/or irradiation are high (92%). However, the quality of survival is frequently impaired due to endocrine deficiencies, sleep disturbances, daytime sleepiness, and severe obesity caused by hypothalamic lesions. Based on self-assessment using nutritional diaries, caloric intake was similar in patients and BMI-matched controls. Analyses of physical activity by accelerometric measurements showed a markedly lower level of physical activity. Significant daytime sleepiness and disturbances of circadian rhythms have been demonstrated in obese childhood craniopharyngioma patients. Daytime sleepiness and obesity in these patients were both correlated with low nocturnal and early morning melatonin levels. Polysomnographic studies in patients with severe daytime sleepiness revealed sleeping patterns typical for secondary narcolepsy. Reports on a beneficial effect of treatment with central stimulating agents supported the hypothesis that secondary narcolepsy should be considered as a rare cause for severe daytime sleepiness in patients with childhood craniopharyngioma. |
| Müller HL |
Childhood craniopharyngioma: current controversies on management in diagnostics, treatment and follow-up. [+] |
Expert Rev Neurother 2010, 10: 515 |
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| Craniopharyngiomas are embryogenic malformations of the sellar region of low histological malignancy, thought to be derived from Rathke's pouch epithelium. With an overall incidence of 0.5-2.0 new cases per million of the population per year, 30-50% of all cases occur in childhood. Overall survival rates are high. However, quality of survival is substantially reduced in many survivors, owing to long-term sequelae, such as extreme obesity caused by hypothalamic tumor involvement, which occurs in up to 40% of all cases. The treatment of craniopharyngioma remains controversial. Radical surgical strategies are associated with poor outcome in craniopharyngioma with hypothalamic involvement. |
| Müller HL, Gebhardt U, Schröder S, Pohl F, Kortmann RD, Faldum A, Zwiener I, Warmuth-Metz M, Pietsch T, Calaminus G, Kolb R, Wiegand C, Sörensen N, study committee of KRANIOPHARYNGEOM 2000/2007 |
Analyses of treatment variables for patients with childhood craniopharyngioma--results of the multicenter prospective trial KRANIOPHARYNGEOM 2000 after three years of follow-up. [+] |
Horm Res Paediatr 2010, 73: 175 |
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| BACKGROUND:
Controversies surround various treatment variables for patients with childhood craniopharyngioma such as growth hormone (GH) replacement, which some believe can exacerbate recurrence/progression. We prospectively assessed the risk of tumor recurrence/progression in survivors of childhood craniopharyngioma.
METHODS:
Multivariable analyses of risk factors (age at diagnosis, degree of resection, irradiation, GH treatment and gender) and descriptive analyses of overall survival (OS) and event-free survival (EFS) rates were performed in 117 patients, recruited prospectively and evaluated after 3 years of follow-up in the German, Austrian and Swiss multicenter trial KRANIOPHARYNGEOM 2000.
RESULTS:
We observed a 3-year OS of 0.97 and a 3-year EFS of 0.46, indicating high recurrence rates after complete resection (CR) (n = 47; 3-year-EFS: 0.64) and high progression rates after incomplete resection (IR) (n = 64; 3-year EFS: 0.31). The risk of an event decreased by 80% after CR compared to IR (hazard ratio = 0.20; p < 0.001). Irradiation had protective effects on EFS: irradiated patients had an 88% lower risk of recurrence/progression compared to patients without/before irradiation (hazard ratio = 0.12; p < 0.001). GH treatment had no impact on 3-year EFS rates.
CONCLUSIONS:
Tumor recurrences/progressions are frequent and occur early after initial treatment of childhood craniopharyngioma. A radical resection preserving the integrity of hypothalamic structures appears optimal at original diagnosis. Irradiation was efficient in preventing recurrences/progressions. GH treatment had no impact on the low 3-year EFS observed in our study. However, further conclusions on the influence of GH on recurrence rates have to be refined to long-term follow-up studies of patients with childhood craniopharyngioma. |
| Müller HL, Gebhardt U, Teske C, Faldum A, Zwiener I, Warmuth-Metz M, Pietsch T, Pohl F, Sörensen N, Calaminus G, the study committee of KRANIOPHARYNGEOM 2000 |
Post-operative hypothalamic lesions and obesity in childhood craniopharyngioma: results of the multinational prospective trial KRANIOPHARYNGEOM 2000 after 3-year follow-up. [+] |
Eur J Endocrinol 2011, 165: 17 |
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| Background Hypothalamic obesity has major impact on prognosis and quality of life (QoL) in childhood craniopharyngioma. Patients and methods For this study, 120 patients were prospectively recruited during 2001 and 2007 and evaluated after 3 years of follow-up (KRANIOPHARYNGEOM 2000). Body mass index (BMI) and QoL at diagnosis and 36 months after diagnosis were analysed based on the reference assessment of tumour localisation and post-surgical hypothalamic lesions. Treatment was analysed based on the neurosurgical strategy of 50 participating neurosurgical centres, the centre size based on the patient load. Results BMI SDS at diagnosis was similar in patients with or without hypothalamic involvement. Surgical lesions of anterior and posterior hypothalamic areas were associated with higher increase in BMI SDS during 36 months post-diagnosis compared with patients without or only anterior lesion (+1.8 BMISD, P=0.033, +2.1 BMISD; P=0.011), negative impact on QoL in patients with posterior hypothalamic lesions. Surgical strategies varied among the 50 neurosurgical centres (three large-sized, 24 middle-sized and 23 small-sized centres). Patients treated in small-sized centres presented with a higher rate of hypothalamic involvement compared with those treated in the middle- and large-sized centres. Treatment in large-sized centres was less radical, and the rates of complete resection and hypothalamic surgical lesions were lower in large-sized centres than those of the middle- and small-sized centres. However, a multivariable analysis showed that pre-operative hypothalamic involvement was the only independent risk factor for severe obesity (P=0.002). Conclusions Radical neurosurgical strategies leading to posterior hypothalamic lesions are not recommended due to the potential to exacerbate hypothalamic obesity and impaired QoL. Treatment should be confined to experienced multidisciplinary teams. |
| Müller HL |
Consequences of craniopharyngioma surgery in children. [+] |
J Clin Endocrinol Metab 2011, 96: 1981 |
|
| Context: Childhood craniopharyngioma, a rare embryogenic tumorous malformation of the sellar region, is characterized by survival rates ranging from 91 to 98%. However, quality of survival is frequently impaired due to proximity to optical, pituitary, and hypothalamic structures. Long-term sequelae substantially reduce the quality of life of approximately 50% of long-term survivors, notably extreme obesity owing to hypothalamic involvement and/or surgical- or radiation-induced lesions. Evidence Acquisition and Synthesis: This report reviews the current understanding of diagnostic and treatment options and their consequences on the prognosis and quality of life in patients with childhood craniopharyngioma based on publications from PubMed, Science Citation Index Expanded, EMBASE, and Scopus from the year 1980 onward. Conclusions: Total resection is the treatment of choice in patients with favorable tumor localization, with extreme care taken to preserve hypothalamic-pituitary and optical nerve functions. When tumor localization is unfavorable, i.e. involvement of hypothalamic or optic structures, a limited resection followed by local irradiation is recommended. Optimal timing of recurrence-inhibiting irradiation after incomplete resection is currently under investigation in an international trial. The rarity of the disease, coupled with limited surgical options, dictates that treatment and long-term monitoring of consequences should be confined to experienced multidisciplinary teams. |
| Müller K, Zwiener I, Welker H, Maaß E, Bongartz R, Berthold F, Pietsch T, Warmuth-Metz M, von Bueren A, Rutkowski S |
Curative treatment for central nervous system medulloepithelioma despite residual disease after resection : Report of two cases treated according to the GPHO protocol HIT 2000 and review of the literature. [+] |
Strahlentherapie und Onkologie 2011,Epub ahead of print |
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| Medulloepithelioma of the central nervous system (CNS) is an uncommon primitive neuroectodermal tumor (PNET) usually occurring in early childhood. It is characterized by highly malignant behavior with a propensity for progression, recurrence, and dissemination despite intensive therapy. Due to its rarity, the optimal management is still unknown. However, gross total resection (GTR) has been considered crucial to achieve cure.In this article, the authors report on 2 cases of CNS medulloepithelioma in which long-term survival (more than 6 years) could be achieved despite evidence of, or suspected postoperative residual disease with an otherwise dismal prognosis.The patients were treated according to different strata of the protocol for primitive neuroectodermal tumors (PNET) of the German-Austrian multicenter trial of the German Society for Pediatric Oncology and Hematology (GPOH) for childhood brain tumors (HIT 2000). Treatment included postoperative hyperfractionated radiotherapy of the craniospinal axis followed by a boost to the tumor site in combination with chemotherapy.A review of the 2 reported and 37 previously published cases confirmed GTR and older age as positive prognostic factors. |
| Muller J, Diallo R, Schaefer K, Lanvers C, Schuck A, Ahrens S, Willich N, Jürgens H, Poremba C |
Prognostic factors in Ewing tumors assessed by tissue microarray technology. |
Klin Pädiatr 2002, 214 |
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| Murphy SB |
Classification, staging and end results of treatment of childhood non-Hodgkins-lymphomas: dissimilarities from lymphomas in adults. |
Semin Oncol 1980, 7: 332 |
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| Linn Murphree A |
Intraocular retinoblastoma: the case for a new group classification. [+] |
Ophthalmology clinics of North America 2005, 18: 41-53, viii |
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| This article argues the case for the creation of a new group classification of intraocular retinoblastoma. The current Reese-Ellsworth group classification has not been updated since it was published 35 years ago. The proposed classification is based on the natural history of intraocular retinoblastoma and on the risk of loss of the eye following primary therapy. |
| Myers K, Davies SM, Harris RE, Spunt SL, Smolarek T, Zimmerman S, McMasters R, Wagner L, Mueller R, Auerbach AD, Mehta PA |
The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations. [+] |
Pediatric blood & cancer 2012, 58: 462 |
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| Fanconi anemia (FA) is characterized by progressive marrow failure, congenital anomalies, and predisposition to malignancy. Biallelic FANCD1/BRCA2 mutations are the genetic basis of disease in a small proportion of children with FA with earlier onset and increased incidence of leukemia and solid tumors. Patients with FA have increased sensitivity to chemotherapy and radiation, and upon development of a solid tumor, require modification of these therapies. We report clinical and molecular features of three patients with FA associated with FANCD1/BRCA2 mutations, including two novel mutations, and discuss treatment of malignancy and associated side effects in this particularly vulnerable group. Pediatr Blood Cancer 2012; 58: 462-465. © 2011 Wiley Periodicals, Inc. |
| Müller HL |
Childhood craniopharyngioma--current concepts in diagnosis, therapy and follow-up. [+] |
Nat Rev Endocrinol 2010, 6: 609 |
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| Craniopharyngiomas have an overall incidence of 0.5-2.0 new cases per million of the population per year, and ∼30-50% of all cases represent childhood craniopharyngioma. These partly cystic embryogenic malformations of the sellar region are presumably derived from Rathke cleft epithelium. Many of the typical manifestations at primary diagnosis are nonspecific and include headache, visual impairment, polyuria and/or polydypsia, growth retardation and weight gain. Total resection is the treatment of choice in patients with favorable tumor localization, with the intention to maintain hypothalamic-pituitary and optical nerve functions. When the tumor localization is unfavorable, a limited resection followed by local irradiation is recommended. The overall survival rates are high (91-98%). High recurrence rates after complete resection and high progression rates after incomplete resection have been observed, although the risk of recurrence or progression is less after complete resection than partial resection. Irradiation of the tumor is protective and the appropriate time point of irradiation after incomplete resection is currently under investigation in a randomized trial. Long-term sequelae substantially reduce the quality of life of ∼50% of long-term survivors, notably extreme obesity owing to hypothalamic involvement. |
| Müller H, Fruhwald M, Scheubeck M, Rendl J, Warmuth-Metz M, Sörensen N, Kühl J, Reubi J |
A possible role for somatostatin receptor scintigraphy in the diagnosis and follow-up of children with medulloblastoma. |
J Neurooncol 1998, 38: 27 |
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| Müller-Berghaus J, Kurowski C, Gharib M, Engelskirchen R, Roth B, Berthold F |
Artificial abdominal hernia for the treatment of hepatomegaly in a neonate with stage 4S neuroblastoma. |
Pediatr Hematol Oncol 1999, 16: 453 |
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| Müller H, Loning L, Horn A, Schwabe D, Gunkel M, Schrappe M, von Schutz V, Henze G, Casimiro da, Ritter J, Pinheiro J, Winkelhorst M, Boos J |
Pegylated asparaginase (Oncaspar) in children with ALL. |
Br J Haematol 2000, 110: 379 |
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| Müller-Berghaus J, Berthold F |
Neuroblastom in Poliwoda H, Link H (Hrsg.) |
Kompendium der Hämatologie / Onkologie 2000 |
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| Müller H, Beier R, Loning L, Blutters-Sawatzki R, Dörffel W, Maass E, Muller-Weihrich S, Scheel-Walter H, Scherer F, Stahnke K, Schrappe M, Horn A, Lumkemann K, Boos J |
Pharmacokinetics of native Escherichia coli asparaginase (Asparaginase medac) and hypersensitivity reactions in ALL-BFM 95 reinduction treatment. |
Br J Haematol 2001, 114: 794 |
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| Müller H, Beier R, da Palma J, Lanvers C, Ahlke E, von Schutz V, Gunkel M, Horn A, Schrappe M, Henze G, Kranz K, Boos J |
PEG-asparaginase (Oncaspar) 2500 U/m2 BSA in reinduction and relapse treatment in the ALL/NHL-BFM protocols. |
Cancer Chemother Pharmacol 2002, 49: 149 |
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