| Autor(en) |
Titel |
Quelle |
Links |
| Machatschek JN, Paulussen M, Bielack S |
Chemotherapie bei malignen Knochentumoren. |
Buchbeitrag 2005 |
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| Mack JW, Hilden JM, Watterson J, Moore C, Turner B, Grier HE, Weeks JC, Wolfe J |
Parent and physician perspectives on quality of care at the end of life in children with cancer. |
Journal of clinical oncology 2005, 23: 9155 |
|
| To ascertain parents' and physicians' assessments of quality of end-of-life care for children with cancer and to determine factors associated with high-quality care as perceived by parents and physicians. |
| MacDonald TJ, Aguilera D, Kramm CM |
Treatment of high-grade glioma in children and adolescents. |
Neuro Oncol 2011, [Epub ahead of print] |
|
| 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. |
| Maccari ME, Schneider P, Smulski CR, Meinhardt A, Pinto F, Gonzalez-Granado LI, Schuetz C, Sica MP, Gross M, Fuchs I, Kury P, Heeg M, Vocat T, Willen L, Thomas C, Hühn R, Magerus A, Lorenz M, Schwarz K, Rieux-Laucat F, Ehl S, Rensing-Ehl A |
Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations. |
The Journal of allergy and clinical immunology 2023, 151: 1391-1401.e7 |
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| Fas ligand (FasL) is expressed by activated T cells and induces death in target cells upon binding to Fas. Loss-of-function FAS or FASLG mutations cause autoimmune-lymphoproliferative syndrome (ALPS) characterized by expanded double-negative T cells (DNT) and elevated serum biomarkers. While most ALPS patients carry heterozygous FAS mutations, FASLG mutations are rare and usually biallelic. Only 2 heterozygous variants were reported, associated with an atypical clinical phenotype. |
| Maennlin S, Chaika M, Gassenmaier S, Grimm R, Sparber-Sauer M, Fuchs J, Schmidt A, Ebinger M, Hettmer S, Gatidids S, Dittmann H, Schäfer JF |
Evaluation of functional and metabolic tumor volume using voxel-wise analysis in childhood rhabdomyosarcoma. |
Pediatric radiology 2023, 53: 438 |
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| Cross-sectional imaging-based morphological characteristics of pediatric rhabdomyosarcoma have failed to predict outcomes. |
| Magrath IT |
African Burkitt's lymphoma: History, biology, clinical features, and treatment. |
Am J Pediatr Hematol Oncol 1991, 13: 222 |
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| Magerus A, Rensing-Ehl A, Rao VK, Teachey D, Rieux-Laucat F, Ehl S |
Autoimmune-lymphoproliferative immunodeficiencies (ALPID) A proposed approach to redefining ALPS and other lymphoproliferative immune disorders. |
The Journal of allergy and clinical immunology 2023 Nov 15; |
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| Chronic nonmalignant lymphoproliferation and autoimmune cytopenia are relevant manifestations of immunohematological diseases of childhood. Their diagnostic classification is challenging, but important for therapy. Autoimmune-lymphoproliferative syndrome (ALPS) is a genetically defined inborn error of immunity combining these manifestations, but can only explain a small proportion of cases. Diagnostic categories such as "ALPS-like" disease, common variable immunodeficiency (CVID), or Evans syndrome have therefore been used. Advances in genetics and increasing availablity of targeted therapies call for more therapy-oriented disease classification. Moreover, recent discoveries in the (re-) analysis of genetic conditions affecting FAS signaling ask for a more precise definition of ALPS. In this review, we propose the term autoimmune-lymphoproliferative immunodeficiencies (ALPID) for a disease phenotype that is enriched for patients with genetic diseases for which targeted therapies are available. For patients without a current molecular diagnosis it defines a subgroup of immune dysregulatory disorders for further studies. Within the concept of ALPID, we propose a revision of the ALPS classification, restricting the use of this term to conditions with clear evidence of perturbation of FAS signaling and resulting specific biological and clinical consequences. This proposed approach to redefining ALPS and other lymphoproliferative conditions provides a framework for disease classification and diagnosis relevant for the many specialists confronted with these diseases. |
| McMahon AD, Conway DI, Macdonald TM, McInnes GT |
The unintended consequences of clinical trials regulations. |
PLoS medicine 2009, 3:e1000131 |
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| Mahmood L |
The metabolic processes of folic acid and Vitamin B12 deficiency. |
J Health Res Rev 2014, 1: 5 - 9 |
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| Maigne G, Ferlicot S, Galacteros F, Belenfant X, Ulinski T, Niaudet P, Ronco P, Godeau B, Durrbach A, Sahali S, Lang P, Lambotte O, Audard V |
Glomerular lesions in patients with sickle cell disease. |
Medicine 2010, 89: 18 |
|
| Sickle cell disease (SCD) is an increasing cause of chronic kidney disease, but the spectrum of glomerular lesions and their underlying mechanisms remain poorly described. We reviewed 18 renal biopsies from patients with SCD and glomerular involvement and studied the expression of hypoxic markers in the biopsy specimens. Four histopathologic variants were distinguished: focal segmental glomerulosclerosis (FSGS) (39%), membranoproliferative glomerulonephritis (28%), thrombotic microangiopathy glomerulopathy (17%), and specific sickle cell disease glomerulopathy (17%). Chronic organ damage and history of acute chest syndrome were associated with the occurrence of SCD glomerulopathy. All patients exhibited macroalbuminuria but only 6 patients displayed impaired renal function. SCD was not associated with a specific FSGS histologic variant. Long-term follow-up analysis revealed that 50% of patients exhibited chronic kidney disease. Regardless of the histologic variants, immunohistochemistry did not reveal a specific induction of hypoxic markers (inducible nitric oxide synthase [iNOS], nitrotyrosine, hypoxia-inducible factor [HIF]-1 alpha) at the time of renal biopsy. This large study shows that a wide spectrum of glomerular lesions is associated with SCD. Whatever lesions are observed, the renal prognosis is poor, and early renoprotective treatment is necessary. Hypoxic state does not seem to play a key role in the progression of glomerular lesions, but its potential role at an early stage of glomerular injury requires further investigation. |
| Majumdar S, Thompson W, Ahmad N, Gordon C, Addison C |
The use and effectiveness of complementary and alternative medicine for pain in sickle cell anemia. |
Complementary therapies in clinical practice 2013, 19: 184 |
|
| Pain is the clinical hallmark for sickle cell disease (SCD). The objective of this study was to survey the extent and effectiveness of complementary and alternative medicine (CAM) use for pain control among adults with SCD. Of a total of 227 African-American adults with SCD, 208 (92%) admitted to using at least one type of CAM. The three most common types of CAM were prayer (61%), relaxation technique (44%), and massage (35%). Multiple logistic regression showed that marital status was associated with use of relaxation techniques (p = 0.044), and age between 18 and 24 years and at least a high school level of education were associated with use of prayer (p = 0.008 and p = 0.004 respectively). Our study showed that CAM use is common among adult patients with SCD. Further well designed prospective studies are needed to help develop best practices that emphasize an optimized balance of conventional and evidence based CAM therapies. |
| Makarova O, Oschlies I, Mueller S, Ruf S, Zimmermann M, Niggli F, Attarbaschi A, Kabickova E, Klapper W, Woessmann W, Burkhardt B |
Excellent outcome with limited treatment in paediatric patients with marginal zone lymphoma. |
British journal of haematology 2018, 182: 735 |
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| Makis A, Voskaridou E, Papassotiriou I, Hatzimichael E |
Novel Therapeutic Advances in β-Thalassemia. |
Biology 2021, 10 |
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| The main characteristic of the pathophysiology of β-thalassemia is reduced β-globin chain production. The inevitable imbalance in the α/β-globin ratio and α-globin accumulation lead to oxidative stress in the erythroid lineage, apoptosis, and ineffective erythropoiesis. The result is compensatory hematopoietic expansion and impaired hepcidin production that causes increased intestinal iron absorption and progressive iron overload. Chronic hemolysis and red blood cell transfusions also contribute to iron tissue deposition. A better understanding of the underlying mechanisms led to the detection of new curative or "disease-modifying" therapeutic options. Substantial evolvement has been made in allogeneic hematopoietic stem cell transplantation with current clinical trials investigating new condition regimens as well as different donors and stem cell source options. Gene therapy has also moved forward, and phase 2 clinical trials with the use of β-globin insertion techniques have recently been successfully completed leading to approval for use in transfusion-dependent patients. Genetic and epigenetic manipulation of the γ- or β-globin gene have entered the clinical trial setting. Agents such as TGF-β ligand traps and pyruvate kinase activators, which reduce the ineffective erythropoiesis, have been tested in clinical trials with favorable results. One TGF-β ligand trap, luspatercept, has been approved for use in adults with transfusion-dependent β-thalassemia. The induction of HbF with the phosphodiesterase 9 inhibitor IMR-687, which increase cyclic guanosine monophosphate, is currently being tested. Another therapeutic approach is to target the dysregulation of iron homeostasis, using, for example, hepcidin agonists (inhibitors of TMPRSS6 and minihepcidins) or ferroportin inhibitors (VIT-2763). This review provides an update on the novel therapeutic options that are presently in development at the clinical level in β-thalassemia. |
| Makowska A, Lelabi N, Nothbaum C, Shen L, Busson P, Tran TTB, Eble M, Kontny U |
Radiotherapy Combined with PD-1 Inhibition Increases NK Cell Cytotoxicity towards Nasopharyngeal Carcinoma Cells. |
Cells 2021, 10 |
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| Nasopharyngeal carcinoma (NPC) in endemic regions and younger patients is characterized by a prominent lymphomononuclear infiltration. Radiation is the principal therapeutic modality for patients with NPC. Recent data suggest that the efficacy of radiotherapy in various cancers can be augmented when combined with immune checkpoint blockade. Here, we investigate the effect of radiotherapy on the killing of NPC cells by Natural Killer (NK) cells. |
| Mallick AA, Ganesan V, Kirkham FJ, Fallon P, Hedderly T, McShane T, Parker AP, Wassmer E, Wraige E, Amin S, Edwards HB, Tilling K, O'Callaghan FJ |
Childhood arterial ischaemic stroke incidence, presenting features, and risk factors: a prospective population-based study. |
Lancet Neurol. 2014, 13: 35 |
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| van Maldegem AM, Benson C, Rutkowski P, Blay JY, van den Berg H, Placzke J, Rasper M, Judson I, Jürgens H, Dirksen U, Gelderblom H |
Etoposide and carbo-or cisplatin combination therapy in refractory or relapsed Ewing sarcoma: a large retrospective study. |
Pediatric blood & cancer 2015, 62: 40 |
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| Mamrak NE, Shimamura A, Howlett NG |
Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia. |
Blood reviews 2017, 31: 93 |
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| Fanconi anemia (FA) is a rare autosomal and X-linked genetic disease characterized by congenital abnormalities, progressive bone marrow failure (BMF), and increased cancer risk during early adulthood. The median lifespan for FA patients is approximately 33years. The proteins encoded by the FA genes function together in the FA-BRCA pathway to repair DNA damage and to maintain genome stability. Within the past two years, five new FA genes have been identified-RAD51/FANCR, BRCA1/FANCS, UBE2T/FANCT, XRCC2/FANCU, and REV7/FANCV-bringing the total number of disease-causing genes to 21. This review summarizes the discovery of these new FA genes and describes how these proteins integrate into the FA-BRCA pathway to maintain genome stability and critically prevent early-onset BMF and cancer. |
| 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. |
| Mannhalter Ch |
Molekularbiologie und Hämostase. |
Hämostaseologie 2008, 28: 272 |
|
| Für die Diagnostik von Erkrankungen spielen molekularbiologische Methoden bei schweren angeborenen Krankheiten (z. B. Hämophilie A oder B) eine wichtige Rolle. Auch zur Diagnostik polygenetischer Erkrankungen (z. B. venöse und arterielle Thrombosen) sind sie unentbehrlich. Neben der Analyse der zwei häufigsten genetischen Defekte (Inversion im Intron 22 und Intron 1) im Faktor-VIII-Gen als Ursache der schweren Hämophilie A wurde in den vergangenen Jahren die Sequenzierung des Faktor-VIII-Gens in mehreren Zentren eingeführt und wird nun in der Hämophilie- und Überträgerinnen- Diagnostik eingesetzt. Bei Patienten mit Thrombophilie trägt der Nachweis von Mutationen im Protein-C- und Protein-S-Gen zur Verbesserung der Diagnostik bei bekanntem familiären Protein-C- bzw. -S-Mangel bei. Die Analysen der Arg506Gln-Mutation im Faktor-V-Gen (Faktor-V-Leiden) und die 20210G>A-Mutation im Prothrombin-Gen, die das Risiko für venöse Thrombose beeinflussen, können potenziell helfen, das individuelle Risiko für eine Thrombose bzw. Rezidivthrombose besser einzuschätzen. Allerdings führt die unkritische Untersuchung genetischer Ursachen der Thrombose zu keinem wesentlichen Informationsgewinn hinsichtlich Behandlung und Beratung der Patienten und kostet Zeit und Geld. Daher sollen immer nur jene Tests durchgeführt werden, die medizinische bzw. therapeutische Konsequenzen nach sich ziehen. Trotz der Bedeutung der molekulargenetischen Diagnostik sind die Einsatzmöglichkeiten der Mutationsdiagnostik im klinischen Alltag eines Gerinnungslabors begrenzt. Große Studien haben gezeigt, dass eine Mutation nicht bei jedem Menschen die gleiche Auswirkung hat, da endogene und exogene modulierende Faktoren den Phänotyp beeinflussen. Da sehr wenig über modulierende Faktoren bekannt ist, ist es häufig schwierig, die Auswirkung einer Mutation in ihrer Tragweite zu bewerten. Es ist daher von außerordentlicher Wichtigkeit, die Forschung voranzutreiben, um Gen- Gen- und Gen-Umwelt-Interaktionen zu verstehen, damit in Zukunft eine zuverlässige Interpretation der Mutationsergebnisse möglich wird. |
| Manola KN |
Cytogenetics of pediatric acute myeloid leukemia. |
European journal of haematology 2009, 83: 391 |
|
| 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] |
|
| 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). |
| Manwani D, Frenette PS |
Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. |
Blood 2013, 122: 3892 |
|
| Recurrent and unpredictable episodes of vaso-occlusion are the hallmark of sickle cell disease. Symptomatic management and prevention of these events using the fetal hemoglobin-reactivating agent hydroxyurea are currently the mainstay of treatment. Discoveries over the past 2 decades have highlighted the important contributions of various cellular and soluble participants in the vaso-occlusive cascade. The role of these elements and the opportunities for therapeutic intervention are summarized in this review. |
| 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. |
| Maris JM, Kyemba SM, Rebbeck TR, White PS, Sulman EP, Jensen SJ, Allen C, Biegel JA, Brodeur GM |
Molecular genetic analysis of familial neuroblastoma. |
European journal of cancer (Oxford, England : 1990) 1997, 33: 1923 |
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| Neuroblastoma has several clinical and molecular genetic parallels with the other paediatric embryonal tumours, such as retinoblastoma, including a hereditary form of the disease. We hypothesised that neuroblastoma susceptibility is due to germline mutations in a tumour suppressor gene and that this predisposition gene may be involved in sporadic neuroblastoma tumorigenesis as well. We therefore aimed to localise the familial neuroblastoma predisposition gene by linkage analysis in neuroblastoma kindreds. Eighteen families segregating for neuroblastoma were ascertained for candidate locus linkage analysis. Although many of the 49 affected individuals in these families were diagnosed as infants with multifocal primary tumours, there was marked clinical heterogeneity. We originally hypothesised that familial neuroblastoma predisposition would map to the telomeric portion of chromosome band 1p36, a genomic region likely to contain a sporadic neuroblastoma suppressor gene. However, neuroblastoma predisposition did not map to any of eight polymorphic markers spanning 1p36.2-.3 in three large kindreds. In addition, there was strong evidence against linkage to two Hirschsprung disease susceptibility genes (RET and EDNRB), a condition that can cosegregate with neuroblastoma as in one of the kindreds tested here. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 neuroblastoma suppressor and two of the currently identified Hirschsprung disease susceptibility genes. |
| 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. |
| Maris JM |
Recent advances in neuroblastoma. |
The New England journal of medicine 2010 Jun 10; 362: 2202 |
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| Maroz A, Stachorski L, Emmrich S, Reinhardt K, Xu J, Shao Z, Käbler S, Dertmann T, Hitzler J, Roberts I, Vyas P, Juban G, Hennig C, Hansen G, Li Z, Orkin S, Reinhardt D, Klusmann JH |
GATA1s induces hyperproliferation of eosinophil precursors in Down syndrome transient leukemia. |
Leukemia 2014, 28: 1259 |
|
| Transient leukemia (TL) is evident in 5-10% of all neonates with Down syndrome (DS) and associated with N-terminal truncating GATA1 mutations (GATA1s). Here we report that TL-cell clones generate abundant eosinophils in a substantial fraction of patients. Sorted eosinophils from patients with TL and eosinophilia carried the same GATA1s mutations as sorted TL blasts, consistent with their clonal origin. TL blasts exhibited a genetic program characteristic of eosinophils and differentiated along the eosinophil lineage in vitro. Similarly, ectopic expression of Gata1s, but not Gata1, in wild-type CD34(+)-hematopoietic stem and progenitor cells induced hyperproliferation of eosinophil promyelocytes in vitro. Although GATA1s retained the function of GATA1 to induce eosinophil genes by occupying their promoter regions, GATA1s was impaired in its ability to repress oncogenic MYC and the pro-proliferative E2F transcription network. Chromatin Immunoprecipitation Sequencing (ChIP-seq) indicated reduced GATA1s occupancy at the MYC promoter. Knockdown of MYC, or the obligate E2F-cooperation partner DP1, rescued the GATA1s-induced hyperproliferative phenotype. In agreement, terminal eosinophil maturation was blocked in Gata1(Δe2) knockin mice, exclusively expressing Gata1s, leading to accumulation of eosinophil precursors in blood and bone marrow. These data suggest a direct relationship between the N-terminal truncating mutations of GATA1 and clonal eosinophilia in DS patients. |
| Marina N, Smeland S, Bielack S, Bernstein M, Jovic G, Krailo M, Hook J, Arndt C, van den Berg H, Brennan B, Brichard B, Brown K, Butterfass-Bahloul T, Calaminus G, Daldrup-Link H, Erksson M, Gebhardt M, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale J, Hall K, Hardes J, Hawkins D, Helmke K, Hogendoorn P, Isakoff M, Janeway K, Jürgens H, Kager L, Kühne T, Lau C, Leavey P, Lessnick S, Mascarenhas L, Meyers P, Mottl H, Nathrath M, Papai Z, Randall R, Reichardt P, Renard M, Safwat A, Schwartz C, Stevens M, Strauss S, Teot L, Werner M, Sydes M, Whelan J |
Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial . |
Lancet Oncol 2016, 17: 1396 |
|
| Maricic N, Schwermer M, Schramm A, Morosan-Puopolo G, Ketteler P, Brand-Saberi B |
Zebrafish as an Orthotopic Tumor Model for Retinoblastoma Mimicking Routes of Human Metastasis. |
Cancers 2022, 14 |
|
| Retinoblastoma (RB) is the most common eye cancer in children that has a high mortality rate when left untreated. Mouse models for retinoblastoma have been established but are time- and cost-intensive. The aim of this work was to evaluate an orthotopic transplantation model of retinoblastoma in zebrafish that also allows for tracking migratory routes and to explore advantages and disadvantages with respect to drug testing. |
| 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 |
|
| 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 |
|
| 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 |
|
| 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 |
|
| 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. |
| Mashhadi MA, Heidari Z, Sepehri Z, Bakhshipour AR, Karimkoshte A |
The selenium status in thalassemia patients in South East of iran. |
Int J Hematol Oncol Stem Cell Res 2014 Oct 1; 8: 1 |
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| There are limited reports about selenium status in major thalassemia patients. The aim of this study is evaluation of selenium status in patients with major thalassemia south east of Iran with large sample size and wide range of age. This study compared selenium status with other sites of the world. |
| 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. |
| Matthyssens LE, Nuchtern JG, Van De Ven CP, Gabra HOS, Bjornland K, Irtan S, Stenman J, Pio L, Cross KM, Avanzini S, Inserra A, Chacon JG, Dall'igna P, Von Schweinitz D, Holmes K, Fuchs J, Squire R, Valteau-Couanet D, Park JR, Eggert A, Losty PD, La Quaglia MP, Sarnacki S, Surgical and Medical Committees of SIOPEN*, COG** and GPOH*** |
A Novel Standard for Systematic Reporting of Neuroblastoma Surgery: The International Neuroblastoma Surgical Report Form (INSRF): A Joint Initiative by the Pediatric Oncological Cooperative Groups SIOPEN*, COG**, and GPOH**. |
Annals of surgery 2020, |
|
| To create the first structured surgical report form for NBL with international consensus, to permit standardized documentation of all NBL-related surgical procedures and their outcomes. |
| Matthyssens LE, Nuchtern JG, Van De Ven CP, Gabra HOS, Bjornland K, Irtan S, Stenman J, Pio L, Cross KM, Avanzini S, Inserra A, Chacon JG, Dall'igna P, Von Schweinitz D, Holmes K, Fuchs J, Squire R, Valteau-Couanet D, Park JR, Eggert A, Losty PD, La Quaglia MP, Sarnacki S, Surgical and Medical Committees of SIOPEN*, COG** and GPOH*** |
A Novel Standard for Systematic Reporting of Neuroblastoma Surgery: The International Neuroblastoma Surgical Report Form (INSRF): A Joint Initiative by the Pediatric Oncological Cooperative Groups SIOPEN*, COG**, and GPOH**. |
Annals of surgery 2020 Jul 7; online ahaed of print |
|
| To create the first structured surgical report form for NBL with international consensus, to permit standardized documentation of all NBL-related surgical procedures and their outcomes. |
| Matzdorff A, Alesci SR, Gebhart J, Holzhauer S, Hütter-Krönke ML, Kühne T, Meyer O, Ostermann H, Pabinger I, Rummel M, Sachs UJ, Stauch T, Trautmann-Grill K, Wörmann B |
Expert Report on Immune Thrombocytopenia: Current Diagnostics and Treatment - Recommendations from an Expert Group from Austria, Germany, and Switzerland. |
Oncology research and treatment 2023, 46 Suppl 2: 5 |
|
| 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 |
|
| 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, |
|
| 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. |
| Mauz-Körholz C, Hasenclever D, Holzendorf V, Bernstädt M, Jürgens H, Burdach S, Eggert A, Berthold F, Müller HL, Frühwald MC, Klingebiel T, Metzler M, Körholz D |
Feasibility of VECOPA, a dose-intensive chemotherapy regimen for children and adolescents with intermediate and advanced stage Hodgkin lymphoma: results of the GPOH-HD-2002/VECOPA pilot trial. |
Leukemia & lymphoma 2014, 1 |
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| The GPOH-HD (Gesellschaft für Pädiatrische Onkologie und Hämatologie-Hodgkin Disease) strategy for children and adolescents with intermediate and advanced stage Hodgkin lymphoma is based on two induction cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin) followed by COPP (cyclophosphamide, vincristine, procarbazine, prednisone) or COPDAC (cyclophosphamide, vincristine, prednisone, dacarbazine) consolidation. The feasibility and efficacy of an intensified procarbazine-free consolidation regimen VECOPA (vinblastine, etoposide, cyclophosphamide, vincristine, prednisone, doxorubicin) were investigated. Following two OEPA and one or two VECOPA cycles, involved field radiotherapy was applied. The main endpoint was feasibility. Secondary endpoints were toxicity, proportion of delayed cycles, granulocyte-colony stimulating factor use, and event-free and overall survival. The regimen was well tolerated with mostly hematotoxicity exceeding Common Toxicity Criteria grade 2. In most patients with advanced stage the second VECOPA cycle was delayed despite hematopoietic recovery and absence of serious adverse events. Event-free survival at 36 months was 0.86 (95% confidence interval 0.70-1). The VECOPA regimen is effective and tolerable. However, its time-intensification was not fully exploited within this trial. |
| Mauz-Körholz C, Lange T, Hasenclever D, Burkhardt B, Feller AC, Dörffel W, Kluge R, Vordermark D, Körholz D |
Pediatric Nodular Lymphocyte-predominant Hodgkin Lymphoma: Treatment Recommendations of the GPOH-HD Study Group. |
Klinische Padiatrie 2015, 227(6-7): 314 |
|
| Nodular lymphocyte-predominant Hodgkin lymphoma (nLPHL) is a very rare disease in childhood and adolescence. In Germany, about 15 newly diagnosed patients present with this disease annually; this number comprises less than 10% of all pediatric Hodgkin lymphoma cases. Since the EuroNet-PHL-LP1 trial for early stage nLPHL patients stopped recruiting in Germany in October 2014, the GPOH-HD writing committee reviewed the literature and decided to deliver treatment recommendations for childhood and adolescent nLPHL patients. These guidelines shall be applicable to young nLPHL patients in European countries that will no longer be able to participate in nLPHL trials for young patients. Therefore, the EuroNet-PHL-nLPHL-registry will be installed to provide quality assured central review of staging and response assessment for registered patients by the Central Review Board of EuroNet-PHL in Halle/Leipzig, Germany. |
| Mauz-Körholz C, Metzger ML, Kelly KM, Schwartz CL, Castellanos ME, Dieckmann K, Kluge R, Körholz D |
Pediatric Hodgkin Lymphoma. |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2015 Sep 20; 33: 2975 |
|
| Hodgkin lymphoma (HL) is one of the most curable pediatric and adult cancers, with long-term survival rates now exceeding 90% after treatment with chemotherapy alone or combined with radiotherapy (RT). Of note, global collaboration in clinical trials within cooperative pediatric HL study groups has resulted in continued progress; however, survivors of pediatric HL are at high risk of potentially life-limiting second cancers and treatment-associated cardiovascular disease. Over the last three decades, all major pediatric and several adult HL study groups have followed the paradigm of response-based treatment adaptation and toxicity sparing through the reduction or elimination of RT and tailoring of chemotherapy. High treatment efficacy is achieved using dose-dense chemotherapy. Refinement and reduction of RT have been implemented on the basis of results from collaborative group studies, such that radiation has been completely eliminated for certain subgroups of patients. Because pediatric staging and response criteria are not uniform, comparing the results of trial series among different pediatric and adult study groups remains difficult; thus, initiatives to harmonize criteria are desperately needed. A dynamic harmonization process is of utmost importance to standardize therapeutic risk stratification and response definitions as well as improve the care of children with HL in resource-restricted environments. |
| Mauz-Körholz C, Landman-Parker J, Balwierz W, Ammann RA, Anderson RA, Attarbaschi A, Bartelt JM, Beishuizen A, Boudjemaa S, Cepelova M, Claviez A, Daw S, Dieckmann K, Fernández-Teijeiro A, Fosså A, Gattenlöhner S, Georgi T, Hjalgrim LL, Hraskova A, Karlén J, Kluge R, Kurch L, Leblanc T, Mann G, Montravers F, Pears J, Pelz T, Rajić V, Ramsay AD, Stoevesandt D, Uyttebroeck A, Vordermark D, Körholz D, Hasenclever D, Wallace WH |
Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial. |
The Lancet. Oncology 2022, 23: 125 |
|
| Background: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity.
Findings: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. |
| Mauz-Körholz C, Landman-Parker J, Fernández-Teijeiro A, Attarbaschi A, Balwierz W, Bartelt JM, Beishuizen A, Boudjemaa S, Cepelova M, Ceppi F, Claviez A, Daw S, Dieckmann K, Fosså A, Gattenlöhner S, Georgi T, Hjalgrim LL, Hraskova A, Karlén J, Kurch L, Leblanc T, Mann G, Montravers F, Pears J, Pelz T, Rajić V, Ramsay AD, Stoevesandt D, Uyttebroeck A, Vordermark D, Körholz D, Hasenclever D, Wallace WH, Kluge R |
Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (EuroNet-PHL-C1): a titration study. |
The Lancet. Oncology 2023, 24: 252 |
|
| Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. |
| Mavinkurve-Groothuis AM, van den Heuvel-Eibrink MM, Tytgat GA, van Tinteren H, Vujanic G, Pritchard-Jones KL, Howell L, Graf N, Bergeron C, Acha T, Catania S, Spreafico F |
Treatment of relapsed Wilms tumour (WT) patients: Experience with topotecan. A report from the SIOP Renal Tumour Study Group (RTSG). |
Pediatric blood & cancer 2014, epub ahead of print |
|
| Topotecan has been variably incorporated in the treatment of patients with relapsed Wilms tumour (WT) who failed initial treatment with three or more effective drugs. Our objective was to describe outcome and to retrospectively investigate the potential role of topotecan in relapsed WT patients. |
| Mayer B, Salama A |
Successful treatment of bleeding with tranexamic acid in a series of 12 patients with immune thrombocytopenia. |
Vox sanguinis 2017, 112: 767 |
|
| BACKGROUND AND OBJECTIVES:
The clinical significance of immune thrombocytopenia (ITP) is mainly reflected by bleeding and/or bleeding risks, which, in some cases, cannot be adequately controlled by standard therapy. Tranexamic acid (TA) is increasingly used in preventing and reducing bleeding in several medical settings. There is little information on whether TA may also be useful in the management of ITP.
MATERIALS AND METHODS:
Twelve patients with ITP were treated with TA (0·5-3 g/day) due to recognizable bleeding. Ten of the 12 patients were under regular treatment for ITP. The remaining two patients did not require additional therapy.
RESULTS:
Cessation or, at least, significant improvement of bleeding was achieved shortly after the initiation of TA in all cases. TA was well tolerated and discontinued after cessation of bleeding.
CONCLUSIONS:
We recommend the use of TA in ITP patients with bleeding and/or an increased bleeding risk. Ultimately, cessation of bleeding plays a key role in the management of such affected patients. However, future studies are required to optimize dose and administration routes (intravenous or oral). |
| Mayerhofer C, Niemeyer CM, Flotho C |
Current Treatment of Juvenile Myelomonocytic Leukemia. |
Journal of clinical medicine 2021 Jul 13; 10 |
|
| 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 |
|
| 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. |
| Mazereeuw-Hautier J, Hoeger PH, Benlahrech S, Ammour A, Broue P, Vial J, Ohanessian G, Léauté-Labrèze C, Labenne M, Vabres P, Rössler J, Bodemer C |
Efficacy of propranolol in hepatic infantile hemangiomas with diffuse neonatal hemangiomatosis. |
The Journal of pediatrics 2010, 157: 340 |
|
| We report the rapid and dramatic efficacy of propranolol in 8 infants with infantile hepatic hemangiomas. The degree of response varied from a significant improvement to a complete resolution of hepatic lesions. Heart failure and hypothyroidism resolved, and hepatomegaly decreased. No side-effects of the drug were noted. |
| McCune CA, Al-Jader LN, May A, Hayes SL, Jackson HA, Worwood M |
Hereditary haemochromatosis: only 1% of adult HFEC282Y homozygotes in South Wales have a clinical diagnosis of iron overload. |
Human genetics 2002, 111: 538 |
|
| In northern Europe, about 90% of patients with hereditary haemochromatosis (HH) are homozygous for a single mutation (C282Y) of the HFEgene and approximately 1 in 150 people in the general population carries this genotype. However, the clinical significance of HFE mutations remains uncertain, as is the proportion of people homozygous for C282Y who will develop clinical symptoms leading to a diagnosis of HH. A systematic review of patients with HH over a 2-year period within a defined UK region has revealed that only 1.2% of adult C282Y homozygotes have been diagnosed with iron overload and received treatment. In those in whom body iron load could be estimated, only 51% has more than 4 g iron (the diagnostic threshold for iron overload). |
| McGann PT, Nero AC, Ware RE |
Current management of sickle cell anemia. |
Cold Spring Harbor perspectives in medicine 2013, 3 |
|
| Proper management of sickle cell anemia (SCA) begins with establishing the correct diagnosis early in life, ideally during the newborn period. The identification of affected infants by neonatal screening programs allows early initiation of prophylactic penicillin and pneumococcal immunizations, which help prevent overwhelming sepsis. Ongoing education of families promotes the early recognition of disease-released complications, which allows prompt and appropriate medical evaluation and therapeutic intervention. Periodic evaluation by trained specialists helps provide comprehensive care, including transcranial Doppler examinations to identify children at risk for primary stroke, plus assessments for other parenchymal organ damage as patients become teens and adults. Treatment approaches that previously highlighted acute vaso-occlusive events are now evolving to the concept of preventive therapy. Liberalized use of blood transfusions and early consideration of hydroxyurea treatment represent a new treatment paradigm for SCA management. |
| McIntosh N |
Medulloblastoma--a changing prognosis? |
Arch Dis Child 1979, 200 |
|
| 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. |
| Meany HJ, London WB, Ambros PF, Matthay KK, Monclair T, Simon T, Garaventa A, Berthold F, Nakagawara A, Cohn SL, Pearson AD, Park JR |
Significance of clinical and biologic features in Stage 3 neuroblastoma: A report from the International Neuroblastoma Risk Group project. |
Pediatric blood & cancer 2014, |
|
| International Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome. |
| Meerpohl JJ, Schell LK, Rücker G, Motschall E, Fleeman N, Niemeyer CM, Bassler D |
Deferasirox for managing transfusional iron overload in people with sickle cell disease. |
The Cochrane database of systematic reviews 2014, 5:CD007477 |
|
| Sickle cell disease (SCD) is a group of genetic haemoglobin disorders, that occurs in about 2.2 per 1000 births worldwide. Increasingly, some people with SCD develop secondary iron overload due to occasional red blood cell transfusions or are on long-term transfusion programmes for e.g. secondary stroke prevention. Iron chelation therapy can prevent long-term complications.Deferoxamine and deferiprone have been found to be efficacious. However, questions exist about the effectiveness and safety of the newer oral chelator deferasirox. |
| Meeser A, Bartenhagen C, Werr L, Hellmann AM, Kahlert Y, Hemstedt N, Nürnberg P, Altmüller J, Ackermann S, Hero B, Simon T, Peifer M, Fischer M, Rosswog C |
Reliable assessment of telomere maintenance mechanisms in neuroblastoma. |
Cell & bioscience 2022, 12: 160 |
|
| Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved. |
| 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 |
|
| Mehren A, Azyurt J, Zu Klampen P, Boekhoff S, Thiel CM, Müller HL |
Self- and informant-rated apathy in patients with childhood-onset craniopharyngioma. |
Journal of neuro-oncology 2018, 140: 27 |
|
| The current study aimed to assess whether childhood-onset craniopharyngioma patients suffer from symptoms of apathy, as assessed by patients themselves and their close others. We further analyzed whether apathy scores are related to symptoms of depression. |
| 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 |
|
| Meisel R, Enczmann J, Balzer S, Bernbeck B, Kramm C, Schönberger S, Sinha K, Tröger A, Wernet P, Göbel U, Laws HJ, Dilloo D |
Similar survival following HLA-identical sibling transplantation for standard indication in children with haematologic malignancies: a single center comparison of mobilized peripheral blood stem cell with bone marrow transplantation. |
Klinische Padiatrie 2005 May-Jun; 217: 135 |
|
| Peripheral blood stem cell (PBSC) grafts are increasingly used for autologous and allogeneic haematopoietic stem cell transplantation (alloHSCT) with the aim to hasten neutrophil and platelet engraftment and thereby to reduce transplant-related complications due to infections, bleeding and graft failure. Based on the paucity of data on PBSC transplantation in children we performed a retrospective single-center analysis comparing the outcome of children receiving mobilized PBSC from human leukocyte antigen (HLA)-identical sibling donors to bone marrow (BM) transplant recipients. |
| 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%. |
| Meisel R, Dilloo D |
Pneumococcal vaccination of children after hematopoietic stem cell transplantation: timing is crucial. |
Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2007 Aug 1; 45: 397-8; author reply 398 |
|
| 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. |
| Meister MT, Scheer M, Hallmen E, Stegmaier S, Vokuhl C, von Kalle T, Fuchs J, Münter M, Niggli F, Ladenstein R, Kazanowska B, Ljungman G, Bielack S, Koscielniak E, Klingebiel T, Cooperative Weichteilsarkom Studiengruppe [CWS] |
Malignant peripheral nerve sheath tumors in children, adolescents, and young adults: Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. |
Journal of surgical oncology 2020, 122: 1337 |
|
| Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that present as large, invasive tumors. Our aim was to assess outcomes, identify prognostic factors, and analyze treatment strategies in a prospectively collected pediatric cohort. |
| Meier CM, Furtwängler R, von Schweinitz D, Stein R, Welter N, Wagenpfeil S, Kager L, Schenk JP, Vokuhl C, Melchior P, Fuchs J, Graf N |
Vena Cava Thrombus in Patients with Wilms Tumor. |
Cancers 2022, 14 |
|
| (1) Background: Vena cava thrombus (VCT) is rare in Wilms tumor (WT) (4−10%). The aim of this study is to identify factors for an outcome to improve treatment for better survival. (2) Methods: 148/3015 patients with WT (aged < 18 years) and VCT, prospectively enrolled over a period of 32 years (1989−2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH), are retrospectively analyzed to describe clinical features, response to preoperative chemotherapy (PC) (142 patients) and surgical interventions and to evaluate risk factors for overall survival (OS). (3) Results: 14 VCT regressed completely with PC and another 12 in parts. The thrombus was completely removed in 111 (85.4%), incompletely in 16 (12.3%), and not removed in 3 (2.3%). The type of removal is unknown in four patients. Patients without VCT have a significantly (p < 0.001) better OS (97.8%) than those with VCT (90.1%). OS after complete resection is (89.9%), after incomplete (93.8%) and with no resection (100%). Patients with anaplasia or stage IV without complete remission (CR) after PC had a significantly worse OS compared to the remaining patients with VCT (77.1% vs. 94.4%; p = 0.002). (4) Conclusions: As a result of our study, two risk factors for poor outcomes in WT patients with VCT emerge: diffuse anaplasia and metastatic disease, especially those with non-CR after PC. |
| Meier CM, Furtwängler R, Mergen M, Welter N, Melchior P, Schenk JP, Vokuhl C, Kager L, Kroiss-Benninger S, Wagenpfeil S, Graf N |
Impact of Time to Surgery on Outcome in Wilms Tumor Treated with Preoperative Chemotherapy. |
Cancers 2023, 15 |
|
| (1) Background: Wilms tumor (WT) treated preoperatively is cured in over 90% of cases. However, how long preoperative chemotherapy can be given is unknown. (2) Methods: 2561/3030 patients with WT (age < 18 years) treated between 1989 and 2022 according to SIOP-9/GPOH, SIOP-93-01/GPOH, and SIOP-2001/GPOH are retrospectively analyzed to assess the risk of time to surgery (TTS) for relapse-free survival (RFS) and overall survival (OS). (3) Results: TTS was calculated for all surgeries, with the mean being 39 days (38.5 ± 12.5) for unilateral tumors (UWT) and 70 days (69.9 ± 32.7) for bilateral disease (BWT). Relapse occurred in 347 patients, of which 63 (2.5%) were local, 199 (7.8%) were metastatic, and 85 (3.3%) were combined. Moreover, 184 patients (7.2%) died, 152 (5.9%) due to tumor progression. In UWT, recurrences and mortality are independent of TTS. For BWT without metastases at diagnosis, the incidence of recurrence is less than 18% up to 120 days and increases to 29% after 120 days, and to 60% after 150 days. The risk of relapse (Hazard Ratio) adjusted for age, local stage, and histological risk group increases to 2.87 after 120 days (CI 1.19-7.95, = 0.022) and to 4.62 after 150 days (CI 1.17-18.26, = 0.029). In metastatic BWT, no influence of TTS is detected. (4) Conclusions: The length of preoperative chemotherapy has no negative impact on RFS or OS in UWT. In BWT without metastatic disease, surgery should be performed before day 120, as the risk of recurrence increases significantly thereafter. |
| Meier CM, Fuchs J, von Schweinitz D, Stein R, Wagenpfeil S, Kager L, Schenk JP, Vokuhl C, Melchior P, Welter N, Furtwängler R, Graf N |
Surgical Factors Influencing Local Relapse and Outcome in the Treatment of Unilateral Nephroblastoma. |
Annals of surgery 2023, 278:e360-e367 |
|
| This study aims to identify factors associated with the occurrence of local relapse (LR) after treatment for unilateral nephroblastoma. |
| Mejstríková E, Hrusak O, Borowitz MJ, Whitlock JA, Brethon B, Trippett TM, Zugmaier G, Gore L, von Stackelberg A, Locatelli F |
CD19-negative relapse of pediatric B-cell precursor acute lymphoblastic leukemia following blinatumomab treatment. |
Blood cancer journal 2017, 7: 659 |
|
| No abstract available |
| Melcher V, Graf M, Interlandi M, Moreno N, de Faria FW, Kim SN, Kastrati D, Korbanka S, Alfert A, Gerß J, Meyer Zu Hörste G, Hartmann W, Frühwald MC, Dugas M, Schüller U, Hasselblatt M, Albert TK, Kerl K |
Macrophage-tumor cell interaction promotes ATRT progression and chemoresistance. |
Acta neuropathologica 2020, 139: 913 |
|
| Atypical teratoid/rhabdoid tumors (ATRT) are known for their heterogeneity concerning pathophysiology and outcome. However, predictive factors within distinct subgroups still need to be uncovered. Using multiplex immunofluorescent staining and single-cell RNA sequencing we unraveled distinct compositions of the immunological tumor microenvironment (TME) across ATRT subgroups. CD68 cells predominantly infiltrate ATRT-SHH and ATRT-MYC and are a negative prognostic factor for patients' survival. Within the murine ATRT-MYC and ATRT-SHH TME, Cd68 macrophages are core to intercellular communication with tumor cells. In ATRT-MYC distinct tumor cell phenotypes express macrophage marker genes. These cells are involved in the acquisition of chemotherapy resistance in our relapse xenograft mouse model. In conclusion, the tumor cell-macrophage interaction contributes to ATRT-MYC heterogeneity and potentially to tumor recurrence. |
| Menke-Moellers I, Berthold F |
In Vitro Sensitivity of Human Neuroblastoma Cells to Antineoplastic Drugs. |
Am J Pediatr Hematol Oncol 1993, 15: 47 |
|
| Mertens R, Lassay L, Heimann G |
Combined treatment of nasopharyngeal cancer in children and adolescents--concept of a study. |
Klinische Padiatrie 1993, 205: 241 |
|
| Nasopharyngeal carcinomas (NPCs) are malignant tumors which exhibit a wide disparity in their age, racial, and geographic incidence. In parts of Africa NPCs account for 10% to 20% of childhood malignancies. In USA and Europe, the NCP is an uncommon tumor (0.2% of all malignancies) and amounts to only 1% to 2% of childhood malignancies. Etiology and pathogenesis are closely related to an infection with Epstein-Barr Virus (EBV) and the EBV genome was detected in tumor tissues. Children with NPC differ from their adult counterparts in having a closer association with Epstein-Barr-Virus-Infections. The classical lymphoepithelial carcinomas (Cologne type II-type III) have been found in young patients. Clinically, the disease is aggressive, characterised by frequent metastases in bone and lung. These carcinomas are associated with significantly elevated anti-EBV-titers. The prognosis of children with advanced NPC is poor with a 5-year survival rate between 20-30%. Radiotherapy is the treatment of choice in NPC which has provided an improvement in local tumor control in recent years. Human fibroblast interferon is an active agent in recurrent NPC. Seven children have been treated with IFN-beta, (6 with human und 1 with recombinant IFN-beta) as an adjuvant therapy in doses of 10(5) U/kg body weight three times a week for half a year. All patients received radiotherapy to primary site and had advanced stages (III-IV) at presentation. The patients' age ranged from 14-19 years at diagnosis. Six are still in CR (RFS are 10, 8, 8, 7, 6 and 1.5 years) and one patient relapsed after 18 months.(ABSTRACT TRUNCATED AT 250 WORDS) |
| 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 |
| Mertens R, Granzen B, Lassay L, Gademann G, Hess CF, Heimann G |
Nasopharyngeal carcinoma in childhood and adolescence: concept and preliminary results of the cooperative GPOH study NPC-91. Gesellschaft für Pädiatrische Onkologie und Hämatologie. |
Cancer 1997, 80: 951 |
|
| The increasing use of chemotherapy has improved the prognosis of patients with nasopharyngeal carcinoma (NPC), and the authors demonstrated the beneficial effect of adjuvant interferon (IFN)-beta in a previous pilot study of children with advanced stage NPC. The current multi-institutional, cooperative GPOH (Gesellschaft für Pädiatrische Onkologie und Hämatologie) study NPC-91 was begun in 1992 to determine the efficacy of preradiation chemotherapy, radiotherapy, and adjuvant IFN-beta, in the treatment of advanced stage NPC. |
| Merchant TE, Mulhern RK, Krasin MJ, Kun LE, Williams T, Li C, Xiong X, Khan RB, Lustig RH, Boop FA, Sanford RA |
Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. |
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2004 Aug 1; 22: 3156 |
|
| We conducted a phase II trial of conformal radiation therapy (CRT) for localized childhood ependymoma to determine whether the irradiated volume could be reduced to decrease CNS-related side effects without diminishing the rate of disease control. |
| 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. |
| Mertens R, Granzen B, Lassay L, Bucsky P, Hundgen M, Stetter G, Heimann G, Weiss C, Hess CF, Gademann G |
Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH). |
Cancer 2005, 104: 1083 |
|
| Preliminary results of combined neoadjuvant chemotherapy, radiotherapy, and postradiation interferon beta (IFN-beta) in children and adolescents with nasopharyngeal carcinoma, especially in high-risk patients, have been promising. |
| Mertens R, Lassay L |
Seltene Tumoren, In: Gadner H, Gaedicke G, Niemeyer CH, Ritter J (Hrsg.): Pädiatrische Hämatologie und Onkologie. |
Springer-Verlag 2006, 950 |
|
| Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA |
Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. |
The Lancet. Oncology 2009, 10: 258 |
|
| Merker M, Wagner J, Kreyenberg H, Heim C, Moser LM, Wels WS, Bonig H, Ivics Z, Ullrich E, Klingebiel T, Bader P, Rettinger E |
ERBB2-CAR-Engineered Cytokine-Induced Killer Cells Exhibit Both CAR-Mediated and Innate Immunity Against High-Risk Rhabdomyosarcoma. |
Frontiers in immunology 2020, 11: 581468 |
|
| High-risk rhabdomyosarcoma (RMS) occurring in childhood to young adulthood is associated with a poor prognosis; especially children above the age of 10 with advanced stage alveolar RMS still succumb to the disease within a median of 2 years. The advent of chimeric antigen receptor (CAR)-engineered T cells marked significant progress in the treatment of refractory B cell malignancies, but experience for solid tumors has proven challenging. We speculate that this is at least in part due to the poor quality of the patient's own T cells and therefore propose using CAR-modified cytokine-induced killer (CIK) cells as effector cells. CIK cells are a heterogeneous population of polyclonal T cells that acquire phenotypic and cytotoxic properties of natural killer (NK) cells through the cultivation process, becoming so-called T-NK cells. CIK cells can be genetically modified to express CARs. They are minimally alloreactive and can therefore be acquired from haploidentical first-degree relatives. Here, we explored the potential of ERBB2-CAR-modified random-donor CIK cells as a treatment for RMS in xenotolerant mice bearing disseminated high-risk RMS tumors. In otherwise untreated mice, RMS tumors engrafted 13-35 days after intravenous tumor cell injection, as shown by bioluminescence imaging, immunohistochemistry, and polymerase chain reaction for human gDNA, and mice died shortly thereafter (median/range: 62/56-66 days, = 5). Wild-type (WT) CIK cells given at an early stage delayed and eliminated RMS engraftment in 4 of 6 (67%) mice, while ERBB2-CAR CIK cells inhibited initial tumor load in 8 of 8 (100%) mice. WT CIK cells were detectable but not as active as CAR CIK cells at distant tumor sites. CIK cell therapies during advanced RMS delayed but did not inhibit tumor progression compared to untreated controls. ERBB2-CAR CIK cell therapy also supported innate immunity as evidenced by selective accumulation of NK and T-NK cell subpopulations in disseminated RMS tumors, which was not observed for WT CIK cells. Our data underscore the power of heterogenous immune cell populations (T, NK, and T-NK cells) to control solid tumors, which can be further enhanced with CARs, suggesting ERBB2-CAR CIK cells as a potential treatment for high-risk RMS. |
| 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 |
|
| Metry D, Heyer G, Hess C, Garzon M, Haggstrom A, Frommelt P, Adams D, Siegel D, Hall K, Powell J, Frieden I, Drolet B, PHACE Syndrome Research Conference |
Consensus Statement on Diagnostic Criteria for PHACE Syndrome. |
Pediatrics 2009, 124: 1447 |
|
| Mettmann VL, Baumhoer D, Bielack SS, Blattmann C, Friedel G, von Kalle T, Kager L, Kevric M, Nathrath M, Sorg B, Dürken M, Hecker-Nolting S |
Solitary pulmonary metastases at first recurrence of osteosarcoma: Presentation, treatment, and survival of 219 patients of the Cooperative Osteosarcoma Study Group. |
Cancer medicine 2023, 12: 18219 |
|
| To evaluate patient and tumour characteristics, treatment and their impact on survival in patients with a solitary pulmonary metastasis at first relapse of high-grade osteosarcoma. |
| 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. |
| Meyer C, Hofmann J, Burmeister T, Gröger D, Park TS, Emerenciano M, Pombo de Oliveira M, Renneville A, Villarese P, Macintyre E, Cavé H, Clappier E, Mass-Malo K, Zuna J, Trka J, De Braekeleer E, De Braekeleer M, Oh SH, Tsaur G, Fechina L, van der Velden VH, van Dongen JJ, Delabesse E, Binato R, Silva ML, Kustanovich A, Aleinikova O, Harris MH, Lund-Aho T, Juvonen V, Heidenreich O, Vormoor J, Choi WW, Jarosova M, Kolenova A, Bueno C, Menendez P, Wehner S, Eckert C, Talmant P, Tondeur S, Lippert E, Launay E, Henry C, Ballerini P, Lapillone H, Callanan MB, Cayuela JM, Herbaux C, Cazzaniga G, Kakadiya PM, Bohlander S, Ahlmann M, Choi JR, Gameiro P, Lee DS, Krauter J, Cornillet-Lefebvre P, Te Kronnie G, Schäfer BW, Kubetzko S, Alonso CN, Zur Stadt U, Sutton R, Venn NC, Izraeli S, Trakhtenbrot L, Madsen HO, Archer P, Hancock J, Cerveira N, Teixeira MR, Lo Nigro L, Möricke A, Stanulla M, Schrappe M, Sedék L, Szczepański T, Zwaan CM, Coenen EA, van den Heuvel-Eibrink MM, Strehl S, Dworzak M, Panzer-Grümayer R, Dingermann T, Klingebiel T, Marschalek R |
The MLL recombinome of acute leukemias in 2013. |
Leukemia 2013, Epub ahead of print |
|
| Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (∼90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.Leukemia advance online publication, 17 May 2013; doi:10.1038/leu.2013.135. |
| Meyr F, Escherich G, Mann G, Klingebiel T, Kulozik A, Rossig C, Schrappe M, Henze G, von Stackelberg A, Hitzler J |
Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with Down syndrome. |
British journal of haematology 2013, Epub ahead of print |
|
| Children with Down syndrome (DS) have a greater risk for developing both acute lymphoblastic leukaemia (ALL) and significant adverse effects of chemotherapy. We investigated their outcome with, and tolerance of, treatment protocols for relapsed ALL optimized in the paediatric population without DS. Probability of survival and causes of treatment failure were determined for 49 children with DS and a matched cohort of 98 children without DS among 2160 children treated for relapsed ALL in clinical trials conducted by the Berlin-Frankfurt-Münster ALL Relapse Study Group between 1983 and 2012. Despite more favourable ALL relapse characteristics, children with DS experienced lower event-free (EFS) and overall survival (OS) than the control group without DS (EFS 17 ± 08% vs. non-DS 41 ± 06%, P = 0·006; OS 17 ± 09% vs. non-DS 51 ± 06%, P < 0·001). Children with DS developed more frequently fatal complications of treatment (34 ± 07% vs. non-DS 10 ± 04%, P < 0·001). During the last decade, EFS and OS were no longer significantly different in children with and without DS (EFS 31 ± 09% vs. 36 ± 09%, P = 0·399; OS 31 ± 12% vs. 53 ± 09%, P = 0·151). DS proved an independent prognostic factor of outcome after ALL relapse. Induction deaths and treatment-related mortality but not subsequent relapse were the main barrier to successful outcomes of relapse therapy in children with DS. |
| Meyers RL, Maibach R, Hiyama E, Häberle B, Krailo M, Rangaswami A, Aronson DC, Malogolowkin MH, Perilongo G, von Schweinitz D, Ansari M, Lopez-Terrada D, Tanaka Y, Alaggio R, Leuschner I, Hishiki T, Schmid I, Watanabe K, Yoshimura K, Feng Y, Rinaldi E, Saraceno D, Derosa M, Czauderna P |
Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration. |
The Lancet 2017, 18: 122 |
|
| Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the four major trial groups. To address this challenge, we formed a global coalition, the Children's Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer. |
| Mezger K, Ebert S, Muhle HE, Stadt UZ, Borkhardt A, Dilloo D, Faber J, Feuchtinger T, Imschweiler T, Jorch N, Pekrun A, Schmid I, Schramm F, Zimmermann M, Horstmann MA, Escherich G |
Amsacrine combined with etoposide and methylprednisolone is a feasible and safe component in first-line intensified treatment of pediatric patients with high-risk acute lymphoblastic leukemia in CoALL08-09 trial. |
Pediatric blood & cancer 2022, 69:e29997 |
|
| The prognosis of children with acute lymphoblastic leukemia (ALL) has improved considerably over the past five decades. However, to achieve cure in patients with refractory or relapsed disease, novel treatment options are necessary. |
| 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. |
| Miano M, Eikema DJ, de la Fuente J, Bosman P, Ghavamzadeh A, Smiers F, Sengeløv H, Yesilipek A, Formankova R, Bader P, Díaz Pérez MÁ, Bertrand Y, Niemeyer C, Diallo S, Ansari M, Bykova TA, Faraci M, Bonanomi S, Gozdzik J, Satti TM, Bodova I, Wölfl M, Rocha VG, Mellgren K, Rascon J, Holter W, Lange A, Meisel R, Beguin Y, Mozo Y, Kriván G, Sirvent A, Bruno B, Dalle JH, Onofrillo D, Giardino S, Risitano AM, de Latour RP, Dufour C |
Stem Cell Transplantation for Diamond-Blackfan Anemia. A Retrospective Study on Behalf of the Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplantation Group (EBMT). |
Transplantation and cellular therapy 2021, 27: 274.e1-274.e5 |
|
| Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients. |
| 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 I |
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 |
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| 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 |
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| 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 |
|
| Miesbach W, Oldenburg J, Klamroth R, Eichler H, Koscielny J, Holzhauer S, Holstein K, Hovinga JAK, Alberio L, Olivieri M, Knöfler R, Male C, Tiede A |
Erratum: Gentherapie der Hämophilie: Empfehlung der Gesellschaft für Thrombose- und Hämostaseforschung (GTH). |
Hamostaseologie 2022 |
|
| mophilie entwickelt. Unter Berücksichtigung der verfügbaren Literatur und der persönlichen Erfahrungen aus klinischen Studien diskutieren wir hier wesentliche Aspekte der Gentherapie der Hämophilie A und B mit Vektoren auf Basis des Adeno-assoziierten Virus (AAV) einschließlich zu erwartender Ergebnisse, Risiken, Nebenwirkungen und Auswirkungen auf patientenrelevante Endpunkte. Überlegungen zur Auswahl von Patienten, zum Aufklärungs- und Einwilligungsprozess, zur ambulanten Durchführung und Überwachung der Gentherapie sowie zur Erfassung von Daten werden dargestellt. Die Notwendigkeit interdisziplinärer Zusammenarbeit mit der Hepatologie und anderen Fachgruppen wird dargelegt. Besondere Berücksichtigung finden strukturelle und organisatorische Voraussetzungen der Zentren, die Gentherapie durchführen (Dosierungszentren oder „Hub“), und der heimatnahen Zentren, die Patienten der Gentherapie zuführen und die Nachsorge übernehmen („Spoke“). Wir geben eine Empfehlung zur Nutzung einer elektronischen Plattform zum sicheren und verzögerungsfreien Datenaustausch zwischen diesen Zentren und den Patienten. Diese elektronische Plattform wird auch die Primärdatenquelle sein für Pharmakovigilanz, Studien, nationale und internationale Register sowie für die frühe Nutzenbewertung dieser neuen Therapieform. Überlegungen zur Finanzierung der Gentherapie sowie zur möglichen zukünftigen Nutzung bei Jugendlichen und Kindern werden diskutiert. In einem sich rasch entwickelnden wissenschaftlichen Umfeld sollen diese Empfehlungen den betreuenden Einrichtungen und Kostenträgern erste Orientierung in Vorbereitung auf die Anwendung der Gentherapie nach ihrer Zulassung geben. |
| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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. |
| Minniti CP, Kato GJ |
Critical Reviews: How we treat sickle cell patients with leg ulcers. |
American journal of hematology 2015, |
|
| Minkov M, Rodriguez-Galindo C |
Treatment of Langerhans cell histiocytosis: it is time to learn from the past. |
Br J Haematol 2015, 171: 148 |
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| Minkov M, Pötschger U, Thacker N, Astigarraga I, Braier J, Donadieu J, Henter JI, Lehrnbecher T, Rodriguez-Galindo C, Sieni E, Nanduri V, van den Bos C, Abla O, LCH Study Group of the Histiocyte Society |
Additive Prognostic Impact of Gastrointestinal Involvement in Severe Multisystem Langerhans Cell Histiocytosis. |
The Journal of pediatrics 2021, 237: 65-70.e3 |
|
| To evaluate the prognostic impact of gastrointestinal involvement on the survival of children with Langerhans cell histiocytosis (GI-LCH) registered with the international clinical trials of the Histiocyte Society. |
| Mirow C, Pietsch T, Berkefeld S, Kwiecien R, Warmuth-Metz M, Falkenstein F, Diehl B, von Hornstein S, Gnekow AK |
Children <1 year show an inferior outcome when treated according to the traditional LGG treatment strategy: a report from the German multicenter trial HIT-LGG 1996 for children with low grade glioma (LGG). |
Pediatric blood & cancer 2014, 61: 457 |
|
| Children diagnosed with LGG at an age <1 year are reported to have an impaired prognosis in comparison to older patients. Analysis of this subgroup could reveal the necessity to develop risk-adapted treatment approaches. |
| Mir P, Klimiankou M, Findik B, Hähnel K, Mellor-Heineke S, Zeidler C, Skokowa J, Welte K |
New insights into the pathomechanism of cyclic neutropenia. |
Annals of the New York Academy of Sciences 2020, 1466, 83 |
|
| Cyclic neutropenia (CyN) is a hematologic disorder in which peripheral blood absolute neutrophil counts (ANCs) show cycles of approximately 21-day intervals. The majority of CyN patients harbor ELANE mutations, but the mechanism of ANC cycling is unclear. We performed analysis of bone marrow (BM) subpopulations in CyN patients at the peak and the nadir of the ANC cycle and detected high proportions of BM hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) at the nadir of the ANC cycle, as compared with the peak. BM HSPCs produced fewer granulocyte colony-forming unit colonies at the ANC peak. To investigate the mechanism of cycling, we found that mRNA expression levels of ELANE and unfolded protein response (UPR)-related genes (ATF6, BiP (HSPA5), CHOP (DDIT3), and PERK (EIF2AK3)) were elevated, but antiapoptotic genes (Bcl-2 (BCL2) and bcl-xL (BCL2L1)) were reduced in CD34 cells tested at the ANC nadir. Moreover, HSPCs revealed increased levels of reactive oxygen species and gH2AX at the ANC nadir. We suggest that in CyN patients, some HSPCs escape the UPR-induced endoplasmic reticulum (ER) stress and proliferate in response to granulocyte colony-stimulating factor (G-CSF) to a certain threshold at which UPR again affects the majority of HSPCs. There is a cyclic balance between ER stress-induced apoptosis of HSPCs and compensatory G-CSF-stimulated HSPC proliferation followed by granulocytic differentiation. |
| Mifsud W, Furtwängler R, Vokuhl C, D'Hooghe E, Pritchard-Jones K, Graf N, Vujanić GM |
Treatment of patients with stage I focal anaplastic and diffuse anaplastic Wilms tumour: A report from the SIOP-WT-2001 GPOH and UK-CCLG studies. |
European journal of cancer 2022, 166: 1 |
|
| Anaplasia is an unfavourable prognostic histological feature in Wilms tumour (WT). Patients with stage I anaplastic WT (AWT) typically achieve good outcomes, albeit with more treatment than for stage I non-AWT. Since the SIOP-WT-2001 study, patients with focal AWT (FAWT) have been classified as intermediate risk and received less intense treatment than patients with diffuse AWT (DAWT). The aim of the study was to analyse outcomes in these patients. |
| 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 |
|
| 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 |
|
| 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. |
| Möricke A, Lauten M, Beier R, Odenwald E, Stanulla M, Zimmermann M, Attarbaschi A, Niggli F, Schrappe M |
Prediction of Outcome by Early Response in Childhood Acute Lymphoblastic Leukemia. |
Klinische Padiatrie 2013, 225(S 01):S50-S56 |
|
| In the ALL-BFM studies for treatment of acute lymphoblastic leukemia, reduction of leukemic blasts in peripheral blood after a one-week prednisone pre-phase - the so-called prednisone response - has been used for risk stratification since the 1980s and has been one of the most relevant factors for identification of high-risk patients. In the trial ALL-BFM 95, early cytomorphological marrow response on day 15 of induction therapy was prospectively evaluated and its prognostic value was analyzed in comparison to the prednisone response and other established prognostic factors.Compared to prednisone response, day 15 marrow response was superior in outcome prediction - yet with differential effect depending on blast lineage. Outcome was poor in T cell leukemia patients with prednisone poor-response independent of day 15 marrow response, whereas among patients with prednisone good-response different risk groups could be identified by day 15 marrow response. In contrast, prednisone response lost prognostic significance in precursor B cell leukemia when stratified by day 15 marrow response.Selective addition of day 15 marrow response to conventional stratification criteria applied on ALL-BFM 95 may significantly improve risk-adapted treatment delivery. Even though cutting-edge trial risk stratification is meanwhile dominated by minimal residual disease evaluation, an improved conventional risk assessment, as presented here, could be of great importance to countries lacking the technical and/or financial resources associated with the application of minimal residual disease analysis. |
| Möricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Aricò M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rössig C, Conter V, Schrappe M |
Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. |
Blood 2016, 127: 2101 |
|
| Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457). |
| Moenen FCJI, Vries MJA, Nelemans PJ, van Rooy KJM, Vranken JRRA, Verhezen PWM, Wetzels RJH, Ten Cate H, Schouten HC, Beckers EAM, Henskens YMC |
Screening for platelet function disorders with Multiplate and platelet function analyzer. |
Platelets 2019, 30: 81 |
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| Möker P, Zur Stadt U, Zimmermann M, Alawi M, Mueller S, Finger J, Knörr F, Riquelme A, Oschlies I, Klapper W, Bradtke J, Burkhardt B, Woessmann W, Damm-Welk C |
Characterization of IG-MYC-breakpoints and their application for quantitative minimal disease monitoring in high-risk pediatric Burkitt-lymphoma and -leukemia. |
Leukemia 2022, 36: 2343 |
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| Möricke A, Rizzari C, Alten J, Attarbaschi A, Beier R, Biondi A, Burkhardt B, Bodmer N, Boos J, Cario G, Conter V, Flotho C, Kulozik A, Lanvers-Kaminsky C, Mann G, Niggli F, Silvestri D, von Stackelberg A, Stanulla M, Valsecchi MG, Schrappe M, Zimmermann M |
Hypersensitivity Reactions to Native E. coli L-asparaginase in Children With Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction. |
HemaSphere 2023, 7:e888 |
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| 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. |
| Molenaar JJ, Domingo-Fernández R, Ebus ME, Lindner S, Koster J, Drabek K, Mestdagh P, van Sluis P, Valentijn LJ, van Nes J, Broekmans M, Haneveld F, Volckmann R, Bray I, Heukamp L, Sprüssel A, Thor T, Kieckbusch K, Klein-Hitpass L, Fischer M, Vandesompele J, Schramm A, van Noesel MM, Varesio L, Speleman F, Eggert A, Stallings RL, Caron HN, Versteeg R, Schulte JH |
LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. |
Nat Genet 2012, 44: 1199 |
|
| LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-let-7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives. |
| 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 |
|
| 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. |
| Monje M, Fisher PG |
Neurological complications following treatment of children with brain tumors. |
Journal of pediatric rehabilitation medicine 2011, 4: 31 |
|
| Brain tumors and their treatments in children result in a range of neurological complications that can affect daily function and rehabilitation potential, including neurocognitive sequelae, ototoxicity, seizure disorders, stroke, and peripheral neuropathy. Deficits in cognitive function, particularly learning and memory, attention and speed of information processing, can be debilitating. With new insights to the cellular and molecular etiology of these deficits, new therapies for cognitive decline after therapy are emerging. Management strategies for other neurological complications are also emerging. |
| Morrell D, Cromartie E, Swift M |
Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. |
J Natl Cancer Inst 1986, 77: 89 |
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| 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. |
| Morris B, Partap S, Yeom K, Gibbs IC, Fisher PG, King AA |
Cerebrovascular disease in childhood cancer survivors: A Children's Oncology Group Report. |
Neurology 2009 Dec 1; 73: 1906 |
|
| Curative therapy for childhood cancer has dramatically improved over past decades. Therapeutic radiation has been instrumental in this success. Unfortunately, irradiation is associated with untoward effects, including stroke and other cerebrovascular disease (CVD). The Children's Oncology Group (COG) has developed guidelines for screening survivors at risk for persistent or late sequelae of cancer therapy. |
| Moratto D, Giliani S, Bonfim C, Mazzolari E, Fischer A, Ochs HD, Cant AJ, Thrasher AJ, Cowan MJ, Albert MH, Small T, Pai SY, Haddad E, Lisa A, Hambleton S, Slatter M, Cavazzana-Calvo M, Mahlaoui N, Picard C, Torgerson TR, Burroughs L, Koliski A, Neto JZ, Porta F, Qasim W, Veys P, Kavanau K, Hönig M, Schulz A, Friedrich W, Notarangelo LD |
Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. |
Blood 2011 Aug 11; 118: 1675 |
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| In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980- 2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications. |
| Morgenstern DA, London WB, Stephens D, Volchenboum SL, Simon T, Nakagawara A, Shimada H, Schleiermacher G, Matthay KK, Cohn SL, Pearson AD, Irwin MS |
Prognostic significance of pattern and burden of metastatic disease in patients with stage 4 neuroblastoma: A study from the International Neuroblastoma Risk Group database. |
European journal of cancer (Oxford, England : 1990) 2016, 65: 1 |
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| Neuroblastoma is a childhood cancer with remarkably divergent tumour behaviour and the presence of metastatic disease is a powerful predictor of adverse outcome. However, the importance of the involvement of specific metastatic sites or overall metastatic burden in determining outcome has not been fully explored. We analysed data from the International Neuroblastoma Risk Group database for 2250 patients with stage 4 disease treated from 1990 to 2002. Metastatic burden was assessed using a 'metastatic site index' (MSI), a score based on the number of metastatic systems involved. Overall, involvement of bone marrow, bone, lung, central nervous system, or other sites was associated with worse outcome. For patients aged â¥18 months, involvement of liver had the greatest impact on outcome and was associated with tumour MYCN amplification and adrenal primary and lung metastases. Increased MSI was associated with worse outcome and higher baseline ferritin/lactate dehydrogenase. We explored the impact of initial treatment approach on these associations. Limiting the analysis to patients allocated to protocols including stem cell transplant (SCT), there was no longer an association of outcome with metastatic involvement of any individual system or increasing MSI. Thus, treatment escalation with SCT (and the addition of differentiating agents to maintenance therapy) appears to have provided maximal benefit to patients with greatest metastatic disease burden. These findings underscore the importance of examining prognostic factors in the context of specific treatments since the addition of new therapies may change or even negate the predictive impact of a particular variable. |
| Moreno L, Caron H, Geoerger B, Eggert A, Schleiermacher G, Brock P, Valteau-Couanet D, Chesler L, Schulte JH, De Preter K, Molenaar J, Schramm A, Eilers M, Van Maerken T, Johnsen JI, Garrett M, George SL, Tweddle DA, Kogner P, Berthold F, Koster J, Barone G, Tucker ER, Marshall L, Herold R, Sterba J, Norga K, Vassal G, Pearson AD |
Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project. |
Expert opinion on drug discovery 2017, 12: 801 |
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| Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies. |
| Morales JS, Valenzuela PL, Rincón-Castanedo C, Takken T, Fiuza-Luces C, Santos-Lozano A, Lucia A |
Exercise training in childhood cancer: A systematic review and meta-analysis of randomized controlled trials. |
Cancer treatment reviews 2018, 70: 154 |
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| Physical capacity and quality of life (QoL) are typically impaired in children/adolescents with cancer. Our primary objective was to examine the effects of exercise training performed after diagnosis of any type of pediatric cancer on physical capacity-related endpoints, survival, disease relapse and adverse effects. |
| Moreno L, Barone G, DuBois SG, Molenaar J, Fischer M, Schulte J, Eggert A, Schleiermacher G, Speleman F, Chesler L, Geoerger B, Hogarty MD, Irwin MS, Bird N, Blanchard GB, Buckland S, Caron H, Davis S, De Wilde B, Deubzer HE, Dolman E, Eilers M, George RE, George S, Jaroslav Š, Maris JM, Marshall L, Merchant M, Mortimer P, Owens C, Philpott A, Poon E, Shay JW, Tonelli R, Valteau-Couanet D, Vassal G, Park JR, Pearson ADJ |
Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma. |
European journal of cancer (Oxford, England : 1990) 2020, 136: 52 |
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| Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy. |
| Moroz V, Machin D, Hero B, Ladenstein R, Berthold F, Kao P, Obeng Y, Pearson ADJ, Cohn SL, London WB |
The prognostic strength of serum LDH and serum ferritin in children with neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project. |
Pediatric blood & cancer 2020, 67:e28359 |
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| Age, MYCN status, stage, and histology have been used as neuroblastoma (NB) risk factors for decades. Serum lactate dehydrogenase (LDH) and serum ferritin are reproducible, easily obtained, and prognostic, though never used in risk stratification, except one German trial. We analyzed the prognostic strength of LDH and ferritin, overall, within high-risk NB, and by era, using the International Neuroblastoma Risk Group Data Commons. |
| Morris CD, Tunn PU, Rodeberg DA, Terwisscha van Scheltinga S, Binitie O, Godzinski J, Dall'Igna P, Million L, Hawkins DS, Koscielniak E, Bisogno G, Rogers TN |
Surgical management of extremity rhabdomyosarcoma: A consensus opinion from the Children's Oncology Group, the European Pediatric Soft-Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe. |
Pediatric blood & cancer 2020,e28608 |
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| The treatment of extremity rhabdomyosarcoma remains a challenge due to several adverse prognostic factors frequently associated with this tumor site. The International Soft-Tissue Sarcoma Database Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group Soft-Tissue Sarcoma Committee, the European Pediatric Soft-Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe. The INSTRuCT surgical committee developed an internationally applicable consensus opinion document for the surgical treatment of extremity rhabdomyosarcoma. This document addresses surgical management, including biopsy, nodal staging, timing of therapy, resection and reexcision, reconstruction, and surgical approach at relapse. |
| Morana G, Shaw D, MacDonald SM, Alapetite C, Ajithkumar T, Bhatia A, Brisse H, Jaimes C, Czech T, Dhall G, Fangusaro J, Faure-Conter C, Fouladi M, Hargrave D, Harreld JH, Mitra D, Nicholson JC, Souweidane M, Timmermann B, Calaminus G, Bartels U, Bison B, Murray MJ |
Imaging response assessment for CNS germ cell tumours: consensus recommendations from the European Society for Paediatric Oncology Brain Tumour Group and North American Children's Oncology Group. |
The Lancet. Oncology 2022, 23:e218-e228 |
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| Homogeneous and common objective disease assessments and standardised response criteria are important for better international clinical trials for CNS germ cell tumours. Currently, European protocols differ from those of North America (the USA and Canada) in terms of criteria to assess radiological disease response. An international working group of the European Society for Paediatric Oncology Brain Tumour Group and North American Children's Oncology Group was therefore established to review existing literature and current practices, identify major challenges regarding imaging assessment, and develop consensus recommendations for imaging response assessment for patients with CNS germ cell tumours. New clinical imaging standards were defined for the most common sites of CNS germ cell tumour and for the definition of locoregional extension. These new standards will allow the evaluation of response to therapy in patients with CNS germ cell tumours to be more consistent, and facilitate direct comparison of treatment outcomes across international studies. |
| Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, Chen AI, Stiff P, Gianni AM, Carella A, Osmanov D, Bachanova V, Sweetenham J, Sureda A, Huebner D, Sievers EL, Chi A, Larsen EK, Hunder NN, Walewski J, AETHERA Study Group |
Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. |
Lancet (London, England) 2015 May 9; 385: 1853 |
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| Moser O, Zimmermann M, Meyer U, Klapper W, Oschlies I, Schrappe M, Attarbaschi A, Mann G, Niggli F, Spix C, Kontny U, Klingebiel T, Reiter A, Burkhardt B, Woessmann W |
Second malignancies after treatment of childhood non-Hodgkin lymphoma: a report of the Berlin-Frankfurt-Muenster study group. |
Haematologica 2021, 106: 1390 |
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| Second malignant neoplasms pose a concern for survivors of childhood cancer. We evaluated incidence, type and risk factors for second malignant neoplasms in patients included in Berlin-Frankfurt-Muenster protocols for childhood non-Hodgkin lymphoma. 3590 patients <15 years of age at diagnosis registered between 01/1981 and 06/2010 were analyzed. Second malignant neoplasms were reported by the treating institutions and the German Childhood Cancer Registry. After median follow-up of 9.4 years (Quartile, Q1 6.7 and Q3 12.1) 95 second malignant neoplasms were registered (26 carcinomas including 9 basal cell carcinomas, 21 acute myeloid leukemias/myelodysplastic syndromes, 20 lymphoid malignancies, 12 CNS-tumors, and 16 other). Cumulative incidence at 20 years was 5.7±0.7%, standard incidence ratio excluding basal cell carcinomas was 19.8 (95% CI 14.5-26.5). Median time from initial diagnosis to second malignancy was 8.7 years (range: 0.2-30.3). Acute-lymphoblastic-leukemia-type therapy, cumulative anthracycline dose, and cranial radiotherapy for brain tumor-development were significant risk factors in univariate analysis only. In multivariate analysis including risk factors significant in univariate analysis, female sex (HR 1.87, 95% CI 1.23-2.86, p=0.004), CNS-involvement (HR 2.24, 95% CI 1.03-4.88, p=0.042), lymphoblastic lymphoma (HR 2.60, 95% CI 1.69-3.97, p<0.001), and cancer-predisposing condition (HR 11.2, 95% CI 5.52-22.75, p<0.001) retained an independent risk. Carcinomas were the most frequent second malignant neoplasms after non-Hodgkin lymphoma in childhood followed by acute myeloid leukemia and lymphoid malignancies. Female sex, lymphoblastic lymphoma, CNS-involvement, or/and known cancer-predisposing condition were risk factors for second malignant neoplasm-development. Our findings set the basis for individualized long-term follow-up and risk assessment of new therapies. |
| Muckenthaler MU, Rivella S, Hentze MW, Galy B |
A Red Carpet for Iron Metabolism. |
Cell 2017 Jan 26; 168: 344 |
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| 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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| Mühlisch J, Schwering A, Grotzer M, Vince GH, Roggendorf W, Hagemann C, Sörensen N, Rickert CH, Osada N, Jürgens H, Früwald MC |
Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood. |
Oncogene 2006, 25: 1111 |
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| Supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of the CNS represent a biological and clinical enigma, despite advances in both molecular techniques and clinical management for these two rare embryonal brain tumors of childhood. Epigenetic changes hold great potential as possible disease mechanisms and may be manipulated therapeutically. We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT-PCR. In all, 17 samples of autopsy-derived normal appearing brain served as controls. Opposed to control tissues 19/24 sPNET and 4/6 AT/RT demonstrated aberrant methylation for the RASSF1A promoter region. Treatment of cell lines using 5-Aza-2'-deoxycytidine (5AZA) alone or in combination with trichostatin A (TSA) succeeded in re-establishing expression of RASSF1A in cell lines derived from a renal rhabdoid, an AT/RT and a medulloblastoma. A 5' CpG-rich region of CASP8 was methylated in normal tissues and in tumors. However, CASP8 showed inconsistent expression patterns in normal and tumor tissues. Our results indicate that aberrant methylation of the RASSF1A promoter region may be of importance in the origin and progression of sPNET and AT/RT while the analysed 5'-CpG rich region of the CASP8 gene does not seem to play an important role in these tumors. Further studies of epigenetic changes in these rare tumors are warranted as their biology remains obscure and treatment efforts have been rather unsuccessfull. |
| 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 |
|
| 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 |
|
| 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. |
| Müller HL, Gebhardt U, Faldum A, Warmuth-Metz M, Pietsch T, Pohl F, Calaminus G, Sörensen N, Kraniopharyngeom 2000 Study Committee |
Xanthogranuloma, Rathke's cyst, and childhood craniopharyngioma: results of prospective multinational studies of children and adolescents with rare sellar malformations. |
The Journal of clinical endocrinology and metabolism 2012, 97: 3935 |
|
| Craniopharyngioma (CP), Rathke's cyst (RC), and xanthogranuloma (XG) are closely related rare sellar masses. Treatment strategies in children lack consensus. |
| Müller K, Gnekow A, Falkenstein F, Scheiderbauer J, Zwiener I, Pietsch T, Warmuth-Metz M, Voges J, Nikkhah G, Flentje M, Combs SE, Vordermark D, Kocher M, Kortmann RD |
Radiotherapy in pediatric pilocytic astrocytomas : A subgroup analysis within the prospective multicenter study HIT-LGG 1996 by the German Society of Pediatric Oncology and Hematology (GPOH). |
Strahlentherapie und Onkologie 2013, 189: 647 |
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| We evaluated clinical outcomes in the subset of patients who underwent radiotherapy (RT) due to progressive pilocytic astrocytoma within the Multicenter Treatment Study for Children and Adolescents with a Low Grade Glioma HIT-LGG 1996. |
| Müller K, Schlamann A, Seidel C, Warmuth-Metz M, Christiansen H, Vordermark D, Kortmann RD, Kramm CM, von Bueren AO |
Craniospinal irradiation with concurrent temozolomide and nimotuzumab in a child with primary metastatic diffuse intrinsic pontine glioma : A compassionate use treatment. |
Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al] 2013, 189: 693 |
|
| Primary metastatic diffuse intrinsic pontine glioma (DIPG) is relatively rare and associated with a dismal prognosis. Combining craniospinal irradiation (CSI) with concurrent temozolomide and nimotuzumab therapy may slightly improve tumor control and overall survival. However, little is known about the feasibility and toxicity of this treatment approach. Here, we describe the case of an 8-year-old girl with primary metastatic DIPG who received craniospinal radiotherapy, a local boost, and concurrent temozolomide and nimotuzumab treatment based on an individual therapy recommendation. Radiotherapy could be completed without any interruption. However, concurrent temozolomide had to be disrupted several times due to considerable acute myelotoxicity (grade III-IV).Maintenance immunochemotherapy could be started with a delay of 5 days and was performed according to treatment schedule. The disease could be stabilized for a few months. A routine MRI scan finally depicted disease progression 5.7 months after the start of irradiation. The patient died 1.9 months later. |
| Müller HL |
Paediatrics: Surgical strategy and quality of life in craniopharyngioma. |
Nature reviews. Endocrinology 2013, 9: 447 |
|
| Mueller S, Fullerton HJ, Stratton K, Leisenring W, Weathers RE, Stovall M, Armstrong GT, Goldsby RE, Packer RJ, Sklar CA, Bowers DC, Robison LL, Krull KR |
Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. |
International journal of radiation oncology, biology, physics 2013 Jul 15; 86: 649 |
|
| To test the hypotheses that (1) the increased risk of stroke conferred by childhood cranial radiation therapy (CRT) persists into adulthood; and (2) atherosclerotic risk factors further increase the stroke risk in cancer survivors. |
| Müller CR, Mytilineos J, Ottinger H, Arnold R, Bader P et al. |
Deutscher Konsensus 2013 zur immungenetischen Spenderauswahl für die allogene Stammzelltransplantation. |
Empfehlungen der Deutschen Gesellschaft für Immungenetik DGI 2013 |
|
| Müller K, Schlamann A, Guckenberger M, Warmuth-Metz M, Glück A, Pietschmann S, Wawer A, Kortmann RD, Kramm C, von Bueren AO |
Craniospinal irradiation with concurrent temozolomide for primary metastatic pediatric high-grade or diffuse intrinsic pontine gliomas. A first report from the GPOH-HIT-HGG Study Group. |
Strahlentherapie und Onkologie 2014, 190: 377 |
|
| Müller K, Scheithauer H, Pietschmann S, Hoffmann M, Rössler J, Graf N, Baumert BG, Christiansen H, Kortmann RD, Kramm CM, von Bueren AO |
Reirradiation as part of a salvage treatment approach for progressive non-pontine pediatric high-grade gliomas: preliminary experiences from the German HIT-HGG study group. |
Radiation oncology 2014, 9: 177 |
|
| Background and purpose: The aim of the present analysis was to assess the feasibility, toxicity, and the tumor control of reirradiation as a salvage treatment for progressive pediatric non-pontine high-grade gliomas (HGG).Patients and methods: The database of the Reference Center for Radiation Oncology of the German HIT (HIT = German acronym for brain tumor) treatment network for childhood brain tumors was screened for children who were reirradiated for progressive non-pontine HGG. |
| Mueller HL |
Preoperative staging in childhood craniopharyngioma: standardization as a first step towards improved outcome. |
Endocrine 2016, 51: 1 |
|
| Mueller HL |
Craniopharyngioma: long-term consequences of a chronic disease. |
Expert review of neurotherapeutics 2015, 15: 1241 |
|
| Childhood-onset craniopharyngiomas (CP) are rare embryonal malformations of low-grade histological malignancy. Hypothalamic involvement and/or treatment-related lesions result in impaired physical and social functionality and severe neuroendocrine sequelae. Quality of life in CP with hypothalamic involvement is impaired by severe obesity, physical fatigue, reduced motivation, dyspnea, diarrhea, and non-optimal psychosocial development. 567 CI patients have been recruited between 1998 and 2010 in the German Craniopharyngioma Registry. Only 5 of 567 patients (<1%) presented without confirmed signs of relapse/progression, visual impairment, and endocrine deficiencies during longitudinal follow-up of more than 5 years. Hypothalamic obesity in CP is associated with a severe increase in BMI during the early post-operative period. Patients with CP involving hypothalamic structures show reduced 10-years overall survival, whereas overall and progression-free survival rates are not related to the degree of surgical resection. Accordingly, gross-total resection should be avoided in cases of hypothalamic involvement to prevent further hypothalamic damage. As surgical expertise has been shown to have impact on postoperative morbidity, medical societies should establish criteria of adequate professional expertise for the treatment of CP. Based on these criteria, health authorities should organize the certification of centers of excellence authorized for treatment and care of patients with this chronic disease. |
| Mueller HL |
Risk-adapted treatment and follow-up management in childhood-onset craniopharyngioma. |
Expert review of neurotherapeutics 2016, 16: 535 |
|
| Craniopharyngiomas are rare embryonic malformations of the sellar/parasellar region with low histological grade. Here, we review findings on the diagnosis, treatment, clinical course, follow-up, and prognosis of craniopharyngioma patients. Clinical manifestations develop from increased intracranial pressure, anterior visual pathway damage, and hypothalamic/pituitary deficiencies. If the tumor is favorably localized (no anatomical involvement with the hypothalamic and optical structures) therapy of choice is complete resection, meticulously performed to preserve hypothalamic and optic functions. In patients with unfavorable tumor involvement, optimal therapy is limited hypothalamus-sparing surgical strategy, followed by judicious irradiation dosage to minimize recurrences and progression. Surgical lesions and/or anatomical involvement of posterior hypothalamic areas result in serious sequelae, mainly hypothalamic syndrome. Craniopharyngioma is a chronic disease and must be managed as such, providing ongoing care of pediatric and adult patients by experienced multidisciplinary teams in the context of multicenter trials. |
| Mueller HL |
Craniopharyngioma and hypothalamic injury: latest insights into consequent eating disorders and obesity. |
Current opinion in endocrinology, diabetes, and obesity 2016, 23: 81 |
|
| Hypothalamic alterations, pathological or treatment induced, have major impact on prognosis in craniopharyngioma patients mainly because of consequent hypothalamic obesity. Recent insight in molecular genetics, treatment strategies, risk factors and outcomes associated with hypothalamic obesity provide novel therapeutic perspectives. This review includes relevant publications since 2013. |
| Mueller HL |
Diagnosis, treatment, clinical course, and prognosis of childhood-onset craniopharyngioma patients. |
Minerva endocrinologica 2017, 42: 356 |
|
| For decades gross-total resection was the preferred treatment option in childhood-onset craniopharyngioma, assuming that radical strategies at the time of initial diagnosis and treatment would result in cure. Recent reports on long-term prognosis, novel treatment approaches, and molecular genetics provide new insights into more risk-adapted treatment strategies in order to prevent sequelae such as hypothalamic syndrome. A search for original articles published between 2000 and 2016 was performed in PubMed, Science Citation Index Expanded, EMBASE and Scopus. The search terms used were |
| Mueller HL, Merchant TE, Puget S, Martinez-Barbera JP |
New outlook on the diagnosis, treatment and follow-up of childhood-onset craniopharyngioma. |
Nature reviews. Endocrinology 2017, 13: 299 |
|
| Childhood-onset craniopharyngiomas are rare embryonic tumours of low-grade histological malignancy. Novel insights into the molecular pathogenesis of human adamantinomatous craniopharyngioma have started to unveil the possibility of testing novel treatments targeting pathogenic pathways. Hypothalamic involvement and/or treatment-related lesions result in impaired physical and social functionality and in severe neuroendocrine sequelae. Quality of survival in patients with craniopharyngioma with hypothalamic involvement is impaired by severe obesity, physical fatigue and non-optimal psychosocial development. Patients with craniopharyngioma involving hypothalamic structures have reduced 20-year overall survival, but overall and progression-free survival are not related to the degree of surgical resection. Irradiation is effective in the prevention of tumour progression and recurrence. For favourably localized craniopharyngiomas, the preferred treatment of choice is to attempt complete resection with preservation of visual, hypothalamic and pituitary function. For unfavourably localized tumours in close proximity to optic and/or hypothalamic structures, a radical neurosurgical strategy attempting complete resection is not recommended owing to potential severe sequelae. As expertise has been shown to have an impact on post-treatment morbidity, medical societies should establish criteria for adequate professional expertise for the treatment of craniopharyngioma. On the basis of these criteria, health authorities should organize the certification of centres of excellence that are authorized to treat and care for patients with this chronic disease. |
| Mueller HL |
Risk-adapted, long-term management in childhood-onset craniopharyngioma. |
Pituitary 2017, 20: 267 |
|
| This report is a review of findings on the diagnosis, treatment, clinical course, follow-up, and prognosis of craniopharyngioma patients with special regard to clinical trials and long-term management. |
| Mueller I, Ehlert K, Endres S, Pill L, Siebert N, Kietz S, Brock P, Garaventa A, Valteau-Couanet D, Janzek E, Hosten N, Zinke A, Barthlen W, Varol E, Loibner H, Ladenstein R, Lode HN |
Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14. 18/CHO. |
mAbs 2018, 10: 55 |
|
| Immunotherapy with short term infusion (STI) of monoclonal anti-GD2 antibody (mAb) ch14.18 (4 × 25 mg/m2/d; 8-20 h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10 mg/m2; 24 h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival. Fifty-three high-risk NB patients received up to 6 cycles of 100 mg/m2 ch14.18/CHO (d8-17) as LTI combined with 6 × 106 IU/m2 s.c. IL-2 (d1-5; 8-12) and 160 mg/m2 oral RA (d19-32). Pain toxicity was documented with validated pain scores and intravenous (i.v.) morphine usage. Response was assessed in 37/53 evaluable patients following International Neuroblastoma Risk Group criteria. Progression-free (PFS) and overall survival (OS) was analyzed by the Kaplan-Meier method and compared to a matched historical control group from the database of AIEOP, the "Italian Pediatric Ematology and Oncology Association". LTI of ch14.18/CHO showed acceptable toxicity profile indicated by low pain scores, reduced i.v. morphine usage and low frequency of Grade ≥3 adverse events that allowed outpatient treatment. We observed a best response rate of 40.5% (15/37; 5 CR, 10 PR), 4-year (4 y) PFS of 33.1% (observation 0.1- 4.9 y, mean: 2.2 y) and a 4 y OS of 47.7% (observation 0.27 - 5.20 y, mean: 3.6 y). Survival of the entire cohort (53/53) and the relapsed patients (29/53) was significantly improved compared to historical controls. LTI of ch14.18/CHO thus shows an acceptable toxicity profile, objective clinical responses and a strong signal of clinical efficacy in NB patients. |
| Müller HL, Merks JHM, Geoerger B, Grill J, Hargrave D, Glade Bender J, Gururangan S, Navid F, Johnston M, Bachir J, Elze MC, Fürst-Recktenwald S |
Integrated analysis of long-term growth and bone development in pediatric and adolescent patients receiving bevacizumab. |
Pediatric blood & cancer 2019, 66:e27487 |
|
| We conducted an integrated analysis of clinical data to describe long-term effects of bevacizumab on growth and bone development in pediatric and adolescent patients with solid tumors. |
| Müller HL, Reichel J, Boekhoff S, Warmuth-Metz M, Eveslage M, Peng J, Flitsch J |
Low concordance between surgical and radiological assessment of degree of resection and treatment-related hypothalamic damage: results of KRANIOPHARYNGEOM 2007. |
Pituitary 2018, 21: 371 |
|
| Assessment of presurgical hypothalamic involvement (psHI) and treatment-related hypothalamic damage (trHD) is relevant for the decision on risk-adapted treatment and rehabilitation strategies in craniopharyngioma. |
| Müller HL |
Hypothalamic involvement in craniopharyngioma-Implications for surgical, radiooncological, and molecularly targeted treatment strategies. |
Pediatric blood & cancer 2018, 65:e26936 |
|
| Müller HL, Merchant TE, Warmuth-Metz M, Martinez-Barbera JP, Puget S |
Craniopharyngioma. |
Nature reviews. Disease primers 2019, 5: 75 |
|
| Craniopharyngiomas are rare malformational tumours of low histological malignancy arising along the craniopharyngeal duct. The two histological subtypes, adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP), differ in genesis and age distribution. ACPs are diagnosed with a bimodal peak of incidence (5-15 years and 45-60 years), whereas PCPs are restricted to adults mainly in the fifth and sixth decades of life. ACPs are driven by somatic mutations in CTNNB1 (encoding ò-catenin) that affect ò-catenin stability and are predominantly cystic in appearance. PCPs frequently harbour somatic BRAF mutations and are typically solid tumours. Clinical manifestations due to increased intracranial pressure, visual impairment and endocrine deficiencies should prompt imaging investigations, preferentially MRI. Treatment comprises neurosurgery and radiotherapy; intracystic chemotherapy is used in monocystic ACP. Although long-term survival is high, quality of life and neuropsychological function are frequently impaired due to the close anatomical proximity to the optic chiasm, hypothalamus and pituitary gland. Indeed, hypothalamic involvement and treatment-related hypothalamic lesions frequently result in hypothalamic obesity, physical fatigue and psychosocial deficits. Given the rarity of these tumours, efforts to optimize infrastructure and international collaboration should be research priorities. |
| Müller HL |
The Diagnosis and Treatment of Craniopharyngiomas. |
Neuroendocrinology 2019,Epub ahead of print |
|
| Craniopharyngiomas (CP) are rare embryonic malformations of the sellar/parasellar region with low histological grade. Clinical manifestations are related to hypothalamic/pituitary deficiencies, visual impairment, and increased intracranial pressure. Recent insight in molecular pathogenesis of CP opens new perspectives on targeted therapy in papillary CP harboring BRAF-V600E mutations. Further research to elucidate pathogenic mechanisms and hopefully prevent hypothalamic involvement of CP is warranted. If the tumor is favorably localized, therapy of choice is complete resection, with care taken to preserve optical and hypothalamic functions. In patients with unfavorable tumor localization (i.e., hypothalamic involvement), recommended therapy is limited hypothalamus-sparing surgical strategy followed by local irradiation. Surgical treatment strategies should be based on a multidisciplinary approach involving experienced teams. Centralizing treatment of CP in experienced |
| Müller HL |
MANAGEMENT OF ENDOCRINE DISEASE: Childhood-onset craniopharyngioma: state of the art of care in 2018. |
European journal of endocrinology 2019, 180:R159-R174 |
|
| This review presents an update on current concepts of pathogenesis, diagnostics, multidisciplinary treatment and follow-up care, with special focus on neuropsychological sequelae of childhood-onset craniopharyngioma (CP) based on most recent publications on these topics. Recent insight in molecular pathogenesis of CP opens new perspectives on targeted therapy. Further research to elucidate pathogenic mechanisms and to prevent hypothalamic involvement of CP is warranted. Surgical treatment strategies should be based on a multidisciplinary approach involving experienced teams aiming at posterior hypothalamus-sparing treatment for prevention of quality of life impairments. Centralization of CP treatment in experienced 'centers of excellence' is recommended. However, such centralization includes high thresholds concerning infrastructure not achievable in all health systems. Alternatives such as multicenter-based networks used for reference assessments should be considered to assure high standards of treatment quality. Irradiation is efficient in preventing further growth or recurrence in CP patients with residual tumor. Proton beam therapy - available on a wider range in the near future - will help to avoid radiooncological side effects. Novel insights into neuropsychological sequelae after CP should be the basis for the development of future therapeutic neuropsychological interventions. Due to the rareness of the disease, common international efforts in research and treatment are recommended and should lead to an international registry for childhood-onset CP, as a first step toward efficient coordination of scientific and clinical initiatives. |
| Müller HL |
Reply to: Understanding treatment options in craniopharyngioma better. |
Nature reviews. Disease primers 2020, 6: 27 |
|
| Müller HL |
Management of Hypothalamic Obesity. |
Endocrinology and metabolism clinics of North America 2020, 49: 533 |
|
| Energy homeostasis, appetite, and satiety are modulated by a complex neuroendocrine system regulated by the hypothalamus. Dysregulation of this system resulting in hypothalamic obesity (HO) is caused by brain tumors, neurosurgery, and/or cranial irradiation. Craniopharyngioma (CP) is a paradigmatic disease with regard to the development of HO. Initial hypothalamic involvement of CP and/or treatment-related damage to hypothalamic-pituitary axes result in HO. Attempts to control HO with lifestyle interventions have not been satisfactory. No generally accepted pharmacologic or bariatric therapy for HO in CP has been effective in randomized controlled trials. Accordingly, prevention of HO is recommended. |
| Müller HL |
The Diagnosis and Treatment of Craniopharyngioma. |
Neuroendocrinology 2020, 110(9-10): 753 |
|
| Craniopharyngioma (CP) is a rare embryonic malformation of the sellar/parasellar region with a low histological grade. Clinical manifestations are related to hypothalamic/pituitary deficiencies, visual impairment, and increased intracranial pressure. Recent insight into the molecular pathogenesis of CP opens new perspectives on targeted therapy in papillary CP harboring BRAF-V600E mutations. Further research to elucidate pathogenic mechanisms and hopefully prevent hypothalamic involvement of CP is warranted. If the tumor is favorably localized, the therapy of choice is complete resection, with care taken to preserve the optical and hypothalamic functions. In patients with unfavorable tumor localization (i.e., hypothalamic involvement), the recommended therapy is a limited hypothalamus-sparing surgical strategy followed by local irradiation. Surgical treatment strategies should be based on a multidisciplinary approach involving experienced teams. Centralizing the treatment of CP in experienced "centers of excellence" and multicenter-based networks for reference assessments should be considered to assure a high standard of treatment quality. CP recurrence and progression are frequent. Irradiation has proven effective in reducing recurrences and progression. Proton beam therapy, available in a wider range in the near future, will help to avoid radio-oncological side effects. Anatomical involvement and/or surgical lesions of posterior hypothalamic areas can result in serious sequelae that compromise quality of life (QoL), such as hypothalamic obesity and psychopathological symptoms. Novel insights into neuropsychological sequelae after CP occurrence should be the basis for the development of therapeutic neuropsychological interventions. CP should be managed as a frequently chronic disease, providing ongoing care of pediatric and adult patients' clinical and QoL consequences by experienced multidisciplinary teams. |
| Müller HL |
Bariatric Interventions in Craniopharyngioma Patients-Best Choice or Last Option for Treatment of Hypothalamic Obesity? |
The Journal of clinical endocrinology and metabolism 2022 Jan ; 107:e426-e428 |
|
| Mulliken JB, Glowacki J |
Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. |
Plastic and reconstructive surgery 1982, 69: 412 |
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| 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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| Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE |
Late neurocognitive sequelae in survivors of brain tumours in childhood. |
The Lancet. Oncology 2004, 5: 399 |
|
| As survival among children treated for cancer continues to improve, more attention is being focussed on the late effects of cancer treatment. In children treated for brain tumours, chronic neurocognitive effects are especially challenging. Deficits in cognitive development have been described most thoroughly among children treated for posterior-fossa tumours, specifically medulloblastomas and ependymomas, which account for about 30% of all newly diagnosed cases of brain tumours in children. Most children who have survived brain tumours have required surgical resection and focal or craniospinal radiotherapy (irradiation of the entire subarachnoid volume of the brain and spine), with or without systemic chemotherapy. Historically, intelligence quotient (IQ) scores have provided a benchmark against which to measure changes in cognitive development after treatment. Observed declines in IQ are most likely a result of failure to learn at a rate that is appropriate for the age of the child, rather than from a loss of previously acquired knowledge. The rate of IQ decline is associated with a several risk factors, including younger age at time of treatment, longer time since treatment, female sex, as well as clinical variables such as hydrocephalus, use of radiotherapy and radiotherapy dose, and the volume of the brain that received treatment. Loss of cerebral white matter and failure to develop white matter at a rate appropriate to the developmental stage of the child could partly account for changes in IQ score. Technical advances in radiotherapy hold promise for lowering the frequency of neurocognitive sequelae. Further efforts to limit neurocognitive sequelae have included design of clinical trials to test the effectiveness of cognitive, behavioural, and pharmacological interventions. |
| Mulla H, Buck H, Price L, Parry A, Bell G, Skinner R |
Acceptability of a new oral suspension formulation of mercaptopurine in children with acute lymphoblastic leukaemia. |
J Oncol Pharm Practice 0 1 |
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| The aim of this questionnaire-based survey was to determine the 'acceptability' of Xaluprine®, a new oral liquid formulation of mercaptopurine, when administered chronically to children during the maintenance treatment phase of acute lymphoblastic leukaemia. |
| Mul J, Melchior P, Seravalli E, Saunders D, Bolle S, Cameron AL, Gurtner K, Harrabi S, Lassen-Ramshad Y, Lavan N, Magelssen H, Mandeville H, Boterberg T, Kroon PS, Kotte ANTJ, Hoeben BAW, van Rossum PSN, van Grotel M, Graf N, van den Heuvel-Eibrink MM, Rübe C, Janssens GO |
Inter-clinician delineation variation for a new highly-conformal flank target volume in children with renal tumors: A SIOP-Renal Tumor Study Group international multicenter exercise. |
Clinical and translational radiation oncology 2021, 28: 39 |
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| Recently, the SIOP-RTSG developed a highly-conformal flank target volume definition for children with renal tumors. The aims of this study were to evaluate the inter-clinician delineation variation of this new target volume definition in an international multicenter setting and to explore the necessity of quality assurance. |
| Munden A, Butschek R, Tom WL, Marshall JS, Poeltler DM, Krohne SE, Alió AB, Ritter M, Friedlander DF, Catanzarite V, Mendoza A, Smith L, Friedlander M, Friedlander SF |
Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies. |
The British journal of dermatology 2014, 170: 907 |
|
| 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. |
| Murray MJ, Bailey S, Heinemann K, Mann J, Göbel UK, Saran F, Hale JP, Calaminus G, Nicholson JC |
Treatment and outcomes of UK and German patients with relapsed intracranial germ cell tumors following uniform first-line therapy. |
International journal of cancer 2017, 141: 621 |
|
| We aimed to retrospectively assess treatments/outcomes, including the value of high-dose-chemotherapy and autologous-stem-cell-rescue (HDC + AuSCR) and re-irradiation, in a large, European patient-cohort with relapsed intracranial germ-cell-tumors (GCTs) receiving uniform first-line therapy, including radiotherapy as standard-of-care. Fifty-eight UK/German patients (48 male/10 female) with relapsed intracranial-GCTs [13 germinoma/45 non-germinomatous GCT (NGGCT)] treated 1996-2010 as per the SIOP-CNS-GCT-96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five-year overall-survival (OS) for the whole-group (n = 11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard-dose-chemotherapy (SDC) and re-irradiation or HDC + AuSCR with/without re-irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (three non-protocol adherence, five teratoma, five palliation). Five-year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9% (95%CI: 2-26%). By treatment received, 5-year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC + AuSCR was 0% (0-0%) and 14% (3-36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5-year OS than those with relapsed NGGCT (55 vs. 9%; p = 0.007). Patients with relapsed germinoma were salvaged both with SDC and re-irradiation or HDC + AuSCR with/without re-irradiation; both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa-based HDC + AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible. |
| Murawski M, Scheer M, Leuschner I, Stefanowicz J, Bonar J, Dembowska-Bagińska B, Kaliciński P, Koscielniak E, Czauderna P, Fuchs J |
Undifferentiated sarcoma of the liver: Multicenter international experience of the Cooperative Soft-Tissue Sarcoma Group and Polish Paediatric Solid Tumor Group. |
Pediatric blood & cancer 2020, 67:e28598 |
|
| Undifferentiated embryonal sarcomas of the liver (UESL) are extremely rare and continue to pose a diagnostic and therapeutic challenge. The aim of the study was to present a multicenter experience of the German CWS and Polish PPSTG groups in the treatment of UESL in children. |
| Musial-Bright L, Fengler R, Henze G, Hernáiz Driever P |
Carboplatin and ototoxicity: hearing loss rates among survivors of childhood medulloblastoma. |
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 2011, 27: 407 |
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| 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. |
| Myers KC, Furutani E, Weller E, Siegele B, Galvin A, Arsenault V, Alter BP, Boulad F, Bueso-Ramos C, Burroughs L, Castillo P, Connelly J, Davies SM, DiNardo CD, Hanif I, Ho RH, Karras N, Manalang M, McReynolds LJ, Nakano TA, Nalepa G, Norkin M, Oberley MJ, Orgel E, Pastore YD, Rosenthal J, Walkovich K, Larson J, Malsch M, Elghetany MT, Fleming MD, Shimamura A |
Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study. |
The Lancet. Haematology 2020, 7:e238-e246 |
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| Mynarek M, Bettoni da Cunha Riehm C, Brinkmann F, Weißenborn K, Tell-Lüersen M, Heuft HG, Maecker-Kolhoff B, Sykora KW |
Normalized Transcranial Doppler Velocities, Stroke Prevention and Improved Pulmonary Function after Stem Cell Transplantation in Children with Sickle Cell Anemia. |
Klinische Padiatrie 2013, 225: 127 |
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| Abnormal transcranial Doppler velocities (TCD) indicate an increased risk of stroke in patients with sickle cell anemia (SCA) and require regular blood transfusions. Hematopoietic stem cell transplantation (HSCT) is under discussion as an alternative to chronic transfusion in these patients.This retrospective analysis includes 9 patients with SCA undergoing HSCT at a single center in Germany. Special focus was given to the neurologic follow-up and to the results of TCD studies.High risk of stroke or previous stroke was an HSCT-indication in 8 of 9 patients, although most patients had more than one indication for HSCT. TCD was normalized in all 5 patients after HSCT in whom this test was available. None of the patients developed a stroke after HSCT. No further strokes occurred even in patients that experienced recurrent strokes during chronic transfusion before HSCT. 2 of the 9 patients received a 10/10 HLA-matched unrelated donor graft, the others matched related grafts.All patients were alive, free of SCA symptoms and transfusion-independent with stable chimerism 3-11 years after HSCT. Pulmonary function tests normalized in 1 patient with severe sickle cell lung disease.HSCT is able to prevent stroke in patients with SCA. Its perspectives and limitations should be discussed early during the treatment of a patient with complicated SCA. |
| Mynarek M, Pizer B, Dufour C, van Vuurden D, Garami M, Massimino M, Fangusaro J, Davidson T, Gil-da-Costa MJ, Sterba J, Benesch M, Gerber N, Juhnke BO, Kwiecien R, Pietsch T, Kool M, Clifford S, Ellison DW, Giangaspero F, Wesseling P, Gilles F, Gottardo N, Finlay JL, Rutkowski S, von Hoff K |
Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data. |
Neuro-oncology 2017 Apr 1; 19: 576 |
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| Mynarek M, von Hoff K, Pietsch T, Ottensmeier H, Warmuth-Metz M, Bison B, Pfister S, Korshunov A, Sharma T, Jaeger N, Ryzhova M, Zheludkova O, Golanov A, Rushing EJ, Hasselblatt M, Koch A, Schüller U, von Deimling A, Sahm F, Sill M, Riemenschneider MJ, Dohmen H, Monoranu CM, Sommer C, Staszewski O, Mawrin C, Schittenhelm J, Brück W, Filipski K, Hartmann C, Meinhardt M, Pietschmann K, Haberler C, Slavc I, Gerber NU, Grotzer M, Benesch M, Schlegel PG, Deinlein F, von Bueren AO, Friedrich C, Juhnke BO, Obrecht D, Fleischhack G, Kwiecien R, Faldum A, Kortmann RD, Kool M, Rutkowski S |
Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort. |
Journal of clinical oncology 2020, JCO1903057 |
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| The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. |
| Mynarek M, Rutkowski S |
Young children with medulloblastoma: important open questions and the high-risk dilemma. |
Neuro-oncology 2020, 22: 1723 |
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| Hill RM, Plasschaert SLA, Timmermann B, Dufour C, Aquilina K, Avula S, Donovan L, Lequin M, Pietsch T, Thomale U, Tippelt S, Wesseling P, Rutkowski S, Clifford SC, Pfister SM, Bailey S, Fleischhack G |
Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment. |
Cancers 2021, 14 |
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| Relapsed medulloblastoma (rMB) accounts for a considerable, and disproportionate amount of childhood cancer deaths. Recent advances have gone someway to characterising disease biology at relapse including second malignancies that often cannot be distinguished from relapse on imaging alone. Furthermore, there are now multiple international early-phase trials exploring drug-target matches across a range of high-risk/relapsed paediatric tumours. Despite these advances, treatment at relapse in pre-irradiated patients is typically non-curative and focuses on providing life-prolonging and symptom-modifying care that is tailored to the needs and wishes of the individual and their family. Here, we describe the current understanding of prognostic factors at disease relapse such as principal molecular group, adverse molecular biology, and timing of relapse. We provide an overview of the clinical diagnostic process including signs and symptoms, staging investigations, and molecular pathology, followed by a summary of treatment modalities and considerations. Finally, we summarise future directions to progress understanding of treatment resistance and the biological mechanisms underpinning early therapy-refractory and relapsed disease. These initiatives include development of comprehensive and collaborative molecular profiling approaches at relapse, liquid biopsies such as cerebrospinal fluid (CSF) as a biomarker of minimal residual disease (MRD), modelling strategies, and the use of primary tumour material for real-time drug screening approaches. |
| Mynarek M, Obrecht D, Sill M, Sturm D, Kloth-Stachnau K, Selt F, Ecker J, von Hoff K, Juhnke BO, Goschzik T, Pietsch T, Bockmayr M, Kool M, von Deimling A, Witt O, Schüller U, Benesch M, Gerber NU, Sahm F, Jones DTW, Korshunov A, Pfister SM, Rutkowski S, Milde T |
Identification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts. |
Acta neuropathologica 2023, 145: 97 |
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| Molecular groups of medulloblastoma (MB) are well established. Novel risk stratification parameters include Group 3/4 (non-WNT/non-SHH) methylation subgroups I-VIII or whole-chromosomal aberration (WCA) phenotypes. This study investigates the integration of clinical and molecular parameters to improve risk stratification of non-WNT/non-SHH MB. Non-WNT/non-SHH MB from the HIT2000 study and the HIT-MED registries were selected based on availability of DNA-methylation profiling data. MYC or MYCN amplification and WCA of chromosomes 7, 8, and 11 were inferred from methylation array-based copy number profiles. In total, 403 non-WNT/non-SHH MB were identified, 346/403 (86%) had a methylation class family Group 3/4 methylation score (classifier v11b6) ≥ 0.9, and 294/346 (73%) were included in the risk stratification modeling based on Group 3 or 4 score (v11b6) ≥ 0.8 and subgroup I-VIII score (mb_g34) ≥ 0.8. Group 3 MB (5y-PFS, survival estimation ± standard deviation: 41.4 ± 4.6%; 5y-OS: 48.8 ± 5.0%) showed poorer survival compared to Group 4 (5y-PFS: 68.2 ± 3.7%; 5y-OS: 84.8 ± 2.8%). Subgroups II (5y-PFS: 27.6 ± 8.2%) and III (5y-PFS: 37.5 ± 7.9%) showed the poorest and subgroup VI (5y-PFS: 76.6 ± 7.9%), VII (5y-PFS: 75.9 ± 7.2%), and VIII (5y-PFS: 66.6 ± 5.8%) the best survival. Multivariate analysis revealed subgroup in combination with WCA phenotype to best predict risk of progression and death. The integration of clinical (age, M and R status) and molecular (MYC/N, subgroup, WCA phenotype) variables identified a low-risk stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk stratum with a 5y-PFS of 29 ± 6.1%. Validation in an international MB cohort confirmed the combined stratification scheme with 82.1 ± 6.0% 5y-PFS in the low and 47.5 ± 4.1% in very high-risk groups, and outperformed the clinical model. These newly identified clinico-molecular low-risk and very high-risk strata, accounting for 6%, and 21% of non-WNT/non-SHH MB patients, respectively, may improve future treatment stratification. |
| 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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