ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance.

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and might aid to stratify patients within future clinical trials.

Clinical evidence for a biological effect of epigenetically active decitabine in relapsed or progressive rhabdoid tumors.

BACKGROUND: Refined therapy has helped to improve survival rates in rhabdoid tumors (RT). Prognosis for patients with chemoresistant, recurrent, or progressive RT remains dismal. Although decitabine, an epigenetically active agent, has mainly been evaluated in the management of hematologic malignancies in adults, safety in children has also been demonstrated repeatedly. MATERIALS AND METHODS: A retrospective series of patients who received decitabine upon relapse or progression following therapy according to the EU-RHAB regimen is presented. Due to the retrospective nature of analyses, response was defined as measurable regression of at least one lesion on imaging. 850k methylation profiling was done whenever tumor tissue was available. RESULTS: A total of 22 patients with RT of any anatomical localization were included. Most patients (19/22) presented with metastases. All received low-dose decitabine with or preceding conventional chemotherapy. Patients received a median of two (1-6) courses of decitabine; 27.3% (6/22) demonstrated a radiological response. Molecular analyses revealed increased methylation levels in tumors from responders. No excessive toxicity was observed. Clinical benefits for responders included eligibility for early phase trials or local therapy. Responders showed prolonged time to progression and overall survival. Due to small sample size, statistical correction for survivorship bias demonstrated no significant effect on survival for responders. CONCLUSIONS: Patients with RT demonstrate promising signs of antitumor activity after multiagent relapse therapy including decitabine. Analyses of methylation data suggest a specific effect on an epigenetic level. We propose to consider decitabine and other epigenetic drugs as candidates for further clinical investigations in RT.

Sickle cell disease in Germany: Results from a national registry.

BACKGROUND: Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the treatment modalities for patients with SCD in Germany. PROCEDURE: A nationwide German registry for patients with SCD documents basic data on diagnosis and patient history retrospectively at the time of registration. A prospective annual documentation provides more details on complications and treatment of SCD. For the current analyses, data of 439 patients were available. RESULTS: Most patients had homozygous SCD (HbSS 75.1%, HbS/ß-thalassemia 13.2%, and HbSC 11.3%). The median age at diagnosis was 1.9 years (interquartile range, 0.6-4.4 years), most patients were diagnosed when characteristic symptoms occurred. Sepsis and stroke had affected 3.2% and 4.2% of patients, respectively. During the first year of observation, 48.3% of patients were admitted to a hospital and 10.1% required intensive care. Prophylactic penicillin was prescribed to 95.6% of patients with homozygous SCD or HbS/ß thalassemia below the age of six and hydroxycarbamide to 90.4% of patients above the age of two years. At least one annual transcranial Doppler ultrasound was documented for 74.8% of patients between 2 and 18 years. CONCLUSION: With an estimated number of at least 2000, the prevalence of SCD in Germany remains low. Prospectively, we expect that the quality of care for children with SCD will be further improved by an earlier diagnosis after the anticipated introduction of a newborn screening program for SCD.

Favorable outcome of patients affected by rhabdoid tumors due to rhabdoid tumor predisposition syndrome (RTPS).

Rhabdoid tumor predisposition syndrome is usually associated with shorter survival in patients with malignant rhabdoid tumors regardless of anatomical origin. Here we present four children harboring truncating heterozygous SMARCB1/INI1 germline mutations with favorable outcome. All four patients received multi-modality treatment, three according to therapeutic recommendations by the EU-RHAB registry, two without radiotherapy, and mean event-free survival accounts for 7 years. In conclusion, intensive treatment with curative intent is justified for children with rhabdoid tumors even if an underlying rhabdoid predisposition syndrome is demonstrated.

Non-Syndromic and Syndromic Defects in Children with Extracranial Germ Cell Tumors: Data of 2610 Children Registered with the German MAKEI 96/MAHO 98 Registry Compared to the General Population.

GCTs are developmental tumors and are likely to reflect ontogenetic and teratogenetic determinants. The objective of this study was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were included. According to Teilum's holistic concept, malignant and benign teratomas were registered. We used a case-control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher's exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 16 isolated cases of eGCT with a wide range of syndromes. However, these were not found to be significantly associated following Bonferroni correction. Most of these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study, we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population.

Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors.

BACKGROUND: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses. METHODS: Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009-2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors. RESULTS: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ±â€…4.5% and 30.5 ±â€…4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P < 0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 y + non-TYR; 5-y OS = 0%), intermediate risk (<1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ±â€…8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ±â€…12.2%). CONCLUSIONS: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.

Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma.

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.

AlloHSCT in paediatric ALL and AML in complete remission: improvement over time impacted by accreditation?

Allogeneic hematopoietic stem cell transplantation (alloHSCT) has become a well-established treatment option for many patients suffering from malignant and non-malignant diseases. In the past decade, high-resolution HLA-typing, remission surveillance, pre-emptive immune intervention, and standardisation in supportive care measures have substantially improved transplant outcomes. This retrospective study evaluated transplant procedures in 162 paediatric patients with acute lymphoblastic leukaemia (n = 124) or acute myeloid leukaemia (n = 38) who received their first alloHSCT in our institution over an 11-year period. We observed a significant reduction in risk of non-relapse mortality (NRM) over time (HR = 0.34, 95% CI 0.12-0.98; P = 0.05), the 4-year NRM estimate decreased from 20% in 2005-2008 to 7% in 2012-2016 (P = 0.02) and an increase in survival after relapse. There was no significant difference in patients who received a graft from a sibling, haplo, or an unrelated donor with regard to their overall survival (P = 0.45), event-free survival (P = 0.61), and non-relapse mortality (P = 0.19). Our data suggest that a specific transplant infrastructure with a highly experienced team in an accredited transplant centre likely contributes to better transplant outcomes for acute leukaemia patients in complete remission regardless of donor type.

Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features.

Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1-MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow-up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.

Clinical and molecular characterisation of a prospectively collected cohort of children and adolescents with polycythemia vera.

The clinical, haematological, molecular and treatment data of eight paediatric patients with polycythemia vera (PV) were collected prospectively. One patient developed PV after treatment for large-cell anaplastic lymphoma. Budd-Chiari syndrome was diagnosed in two patients, necessitating orthotopic liver transplantation in one and transjugular portosystemic shunting in the other. The remaining patients presented with non-specific symptoms. Endogenous erythroid colonies were detected in all cases examined. The JAK2(V617F) mutation was found in six patients; two patients displayed JAK2 exon 12 mutations, including one novel mutation (JAK2(H538-K539delinsI)). CD177 (PRV-1) mRNA expression was increased in three of five patients tested.

Outcome of relapses of nephroblastoma in patients registered in the SIOP/GPOH trials and studies.

We registered 170 relapses in 1392 children with nephroblastoma in the SIOP/GPOH trials. The study aimed to evaluate prognostic factors for outcome in relapsed patients. Age, gender, initial stage, metastatic disease, local stage, histology, time to relapse and tumour volume were analysed for their prognostic relevance. Overall survival after relapse was 48% (median follow-up 5 years). Relapses were local in 28%, metastatic in 57% and combined in 15%. The median age of the cohort was 4.5 years whereas patients in complete continuous remission were significantly younger (3.1 years, p=0.001). Patients with initial stage I and II showed a significantly better prognosis than children with stage III (57 vs. 31%, p=0.008). Patients with high-risk tumours had a much poorer prognosis than those with intermediate and low-risk tumours (58 vs. 31%, p=0.003). Children with recurrence within 6 months after diagnosis had a poorer outcome than children relapsing later on (54 vs. 22%, p=0.0001). The tumour volume initially and after preoperative chemotherapy did not have any influence on outcome. Patients with isolated distant metastasis had a significantly better outcome than those with local and combined relapses (p=0.001). In conclusion, factors for poor prognosis after relapse are early relapse, local stage III, high-risk histology and combined relapse.

Rhabdoid tumors in children: prognostic factors in 70 patients diagnosed in Germany.

We retrospectively analysed the data of 70 patients (41 boys and 29 girls) with Rhabdoid tumors (RT) regardless of localisation, recorded in the German Childhood Cancer Registry (GCCR) from 1984 to 1999. The primary tumor was located in the kidney in 32 cases, in the central nervous system (CNS) in 13 cases and in the soft tissue in 25 cases. Variables examined were tumor stage, sex, age at diagnosis, surgical radicality, radiotherapy and chemotherapeutic regimens. Metastatic disease at diagnosis was observed in 18 of the 70 individuals. Outcome of this group was very poor with a 5-year overall survival of 11%. There were no differences in survival between males and females, or younger and older children. Chemotherapeutic regimens were mainly given according to the primary site of the tumor. Radiotherapy was given in 28 of the 70 patients with a mean dose of 35 Gray, though this did not improve the outcome. Overall survival of the whole cohort was 27% at 5 years and there was no significant difference in prognosis regarding the different locations of the tumor (kidney 24%, soft tissue 30%, CNS 29%). In conclusion, RT in infants and children has a dismal prognosis, independent from localisation. The presence of metastasis at diagnosis seems to be the only prognostic factor of outcome.

Stem cell transplantation for polycythemia vera.

Polycythemia vera (PV) is a rare disease in children. A 9-year-old male was diagnosed following laboratory results acquired because of an acute appendicitis. Regular phlebotomy was performed for over 2 years followed by alpha-interferon treatment. At the age of 12 years, HLA-matched unrelated stem cell transplantation including T-cell depletion was done. The conditioning regimen consisted of busulfan, cyclophosphamide, and ATG. Chimerism was monitored during the whole post-transplant period. A single dose of donor T-lymphocytes was given at month 3. One year after transplantation, chimerism was complete. The patient is in complete remission and shows no signs of transplant-related morbidity at month 78.

Hypothesis: Possible role of retinoic acid therapy in patients with biallelic mismatch repair gene defects.

A boy showing symptoms of a Turcot-like childhood cancer syndrome together with stigmata of neurofibromatosis type I is reported. His brother suffers from an infantile myofibromatosis, and a sister died of glioblastoma at age 7. Another 7-year-old brother is so far clinically unaffected. The parents are consanguineous. Molecular diagnosis in the index patient revealed a constitutional homozygous mutation of the mismatch repair gene PMS2. The patient was in remission of his glioblastoma (WHO grade IV) after multimodal treatment followed by retinoic acid chemoprevention for 7 years. After discontinuation of retinoic acid medication, he developed a relapse of his brain tumour together with the simultaneous occurrence of three other different HNPCC-related carcinomas. We think that retinoic acid might have provided an effective chemoprevention in this patient with homozygous mismatch repair gene defect. We propose to take a retinoic acid chemoprevention into account in children with proven biallelic PMS2 mismatch repair mutations being at highest risk concerning the development of a malignancy.

Spontaneous regression of Epstein-Barr virus-associated lymphoproliferative disorder in a juvenile idiopathic arthritis patient after the discontinuation of methotrexate and etanercept.

A case of a 16-year-old female with polyarticular juvenile idiopathic arthritis (JIA) since the age of 4 years is reported here. This patient also suffered from multiple congenital anomalies. On long-term treatment with oral methotrexate (MTX) and etanercept, multiple subcutaneous nodules were detected, which were accompanied by increased lactate dehydrogenase and uric acid levels. A biopsy of the largest nodule revealed Epstein-Barr (EB) virus-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified as clinical stage IIIA due to a mediastinal lesion. Immunosuppressive treatment was discontinued immediately, which led to regression of the remaining nodules and normalization of the lactate dehydrogenase levels. The patient was considered to have an iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" by the World health organization (WHO). To our knowledge, this is the first case report of a JIA patient with EBV-positive DLBCL following the administration of etanercept and methotrexate and spontaneous regression of lymphoproliferation after the discontinuation of antirheumatic treatment.

Intraindividual propofol dosage variability in children undergoing repetitive procedural sedations.

The authors prospectively assessed intraindividual variability in propofol dosage for induction of sedation in repetitive procedures in children with malignancies. A total of 80 procedures were performed in 24 children. Primary outcome measure was the intraindividual propofol dose required to achieve adequate sedation. Intraindividual variability in propofol dosage required to achieve adequate sedation was 0.0-2.2 mg.kg-1. Twenty-five percent of the patients had a dose range of 0.0-0.5 mg x kg-1; 37.5%, >0.5-1.0 mg x kg-1; and 37.5% >1.0-2.2 mg x kg-1. Due to remarkable intraindividual differences, propofol dosage should be titrated toward the desired level of sedation.

Wilms' tumor in adults: results of the Society of Pediatric Oncology (SIOP) 93-01/Society for Pediatric Oncology and Hematology (GPOH) Study.

PURPOSE: In the Society of Pediatric Oncology (SIOP) 93-01 study, 30 patients older than 16 years were found to have Wilms' tumor. They were treated according to the pediatric protocol and were analyzed for clinical presentation, stage distribution, and prognosis. PATIENTS AND METHODS: Patient age ranged from 16 to 62 years (median, 25.4 years). Tumor stages were defined according to SIOP, and treatment was risk-adapted according to SIOP 93-01/Society for Pediatric Oncology and Hematology (GPOH) protocol. The patients were evaluated with regard to response, toxicity, and prognosis. Specimens of all tumors were centrally reviewed. RESULTS: Ten patients (33%) had metastatic disease at the time of diagnosis (liver, four patients; lung, three patients; liver and lung, three patients). The local stage distribution showed a predominance of higher stages (stage I, eight patients; stage IIN-, three patients; stage IIN+, four patients; stage III, 15 patients). Histologic studies revealed intermediate-risk in 23 of 30 tumors; two tumors were classified as high-risk; and three tumors were clear-cell sarcomas. Two of 30 patients showed a nephroblastoma and a renal cell carcinoma simultaneously in the same kidney. A complete remission was achieved in 24 patients; four patients relapsed after complete remission; and three of them reached a second remission with further treatment. Event-free survival was 57%, with an overall survival of 83% (median observation time, 4 years). CONCLUSION: Adults can be cured in a high percentage by a multimodal treatment according to pediatric protocols. Toxicity is higher than in children, but acceptable in view of the high remission rate.