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Medulloblastoma (MB) is the first primary central nervous system cancer of infancy. During the last thirty years, there has been an evolution of its treatment: although chemotherapy and radiotherapy have improved the prognosis, surgery remains a determinant key-factor for therapeutic outcome. The search of an effective adjuvant treatment along with a reduced toxicity is difficult. Following treatment with surgery, chemotherapy and radiotherapy, the prognosis for infants and young children with MB is still unfavourable and burdened by an high risk of neurocognitive deficits. The biological features of MB are not fully characterized, but now there are important directions for research. Clinical and molecular prognostic markers can be used to create a disease risk classification. In our review we resume the main features of MB, including clinical, histopathologic and molecular aspects and discuss on the therapeutic options for its treatment.

BackgroundLittle is known about risks associated with germlineSUFUpathogenic variants (PVs) known as a cancer predisposition syndrome.MethodsTo study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germlineSUFUPV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives withSUFUPV (89 patients) using the Nelson-Aalen estimator.ResultsOverall, 117/172 (68%)SUFUPV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entireSUFUgene and inherited in 73% of cases in which inheritance could be evaluated.ConclusionGermlineSUFUPV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.

Given the very poor prognosis for children with recurrent medulloblastoma, we aimed to identify prognostic factors for survival post-relapse in children with childhood medulloblastoma. We retrospectively collected clinico-biological data at diagnosis and main clinical characteristics at relapse of children newly diagnosed with a medulloblastoma between 2007 and 2017 at Gustave Roussy and Necker Hospital. At a median follow-up of 6.6 years (range, 0.4&ndash, 12.3 years), relapse occurred in 48 out 155 patients (31%). The median time from diagnosis to relapse was 14.3 months (range, 1.2&ndash, 87.2 months). Relapse was local in 9, metastatic in 22 and combined (local and metastatic) in 17 patients. Second-line treatment consisted of chemotherapy in 31 cases, radiotherapy in 9, SHH-inhibitor in four and no treatment in the remaining four. The 1-year overall survival rate post-relapse was 44.8% (CI 95%, 31.5% to 59.0%). While molecular subgrouping at diagnosis was significantly associated with survival post-relapse, the use of radiotherapy at relapse and time to first relapse (&gt, 12 months) might also have a potential impact on post-relapse survival.

Medulloblastoma is a highly aggressive brain tumor that typically affects children, while in adults it represents ~1% of all brain tumors. Little is known about microRNA expression profile of the rare adult medulloblastoma. The main aim of this study was to identify peculiar differences in microRNA expression between childhood and adult medulloblastoma. Medulloblastomas were profiled for microRNA expression using the Exiqon Human miRNome panel (I + II) analyzing 752 microRNAs in a training set of six adult and six childhood cases. Then, the most differentially expressed microRNAs were validated in a total of 21 adult and 19 childhood cases. Eight microRNAs (miR-196b-5p, miR-183-5p, miR-200b-3p, miR-196a-5p, miR-193a-3p, miR-29c-3p, miR-33b-5p, and miR-200a-3p) were differentially expressed in medulloblastoma of adults and children. Analysis of the validation set confirmed that miR-196b-5p and miR-200b-3p were significantly overexpressed in medulloblastoma of adults as compared with those of children. We followed an in silico approach to investigate direct targets and the pathways involved for the two microRNAs (miR-196b and miR-200b) differently expressed between adult and childhood medulloblastoma. Adult and childhood medulloblastoma have different miRNA expression profiles. In particular, the differential dysregulation of miR-196b-5p and miR-200b-3p characterizes the miRNA profile of adult medulloblastoma and suggests potential targets for novel diagnostic, prognostic, or therapeutic strategies.

Childhood medulloblastoma (MB) is the most common embryo brain tumor and an area that needs utmost attention, as clinical diagnosis can be very difficult in case of infants and children. The rate of survival can increase with prompt diagnosis. Till date, there is no computer aided methodology for identification of childhood medulloblastoma and its subtypes. The diagnosis depends on qualitative visual inspection of the histological slides of the biopsy samples by clinical experts. We convert this qualitative judgment to quantitative features after digitization of the images. The feature set obtained from digital analysis from these biopsy tissues is very large and is computationally expensive. In this study, we examine whether the features are statistically significant for analysis towards classifying childhood MB from normal samples and its various subtypes, using MANOVA. Further, this technique is used as a feature reduction technique, which proves that it can be effectively used as such. Infact, the simplicity of the technique makes it a better choice when considering a sizeably high number of features.

OBJECTIVE: To examine the contribution of anesthesia exposure during treatment for childhood medulloblastoma to neurocognitive outcomes 3 years after tumor diagnosis. STUDY DESIGN: In this retrospective study, anesthesia data were abstracted from medical records for 111 patients treated with risk-adapted protocol therapy at St. Jude Children’s Research Hospital. Neurocognitive testing data were obtained for 90.9% of patients. RESULTS: For the 101 patients (62.4% male) who completed testing, mean age at diagnosis was 10.1 years and 74.3% were staged to have average-risk disease. Anesthesia exposure during treatment ranged from 1–52 events (mean = 19.9); mean cumulative duration per patient was 21.1 hours (range 0.7–59.7). Compared with normative expectations (16%), the group had a significantly higher frequency of at-risk scores (

BACKGROUND Salvage therapy for recurrent medulloblastoma (MB) is not standardized. Factors associated with survival after recurrence have not been reported. MATERIAL AND METHODS Medical records were reviewed for 155 consecutive patients with newly diagnosed MB between 2007 and 2017, treated at Gustave Roussy and Hospital Necker. The following variables were collected for all patients: age at diagnosis, stage, histology (central review according to WHO 2016 classification), molecular subgrouping (DNA methylation), first-line treatment modalities, time to relapse, pattern of recurrence and current status. RESULTS A disease recurrence was observed in 47 patients (30%) at a median time of 15 months (range, 1–88 months). The 1-year survival after recurrence was 44% (CI 95%,29.6 to 58.8). The pattern of recurrence was local in 9 patients, metastatic in 21 and combined local and metastatic in 17 patients. The time to first recurrence, less or more than 12 months from diagnosis, was a predictor of post-recurrence overall survival (p < 0.0001) after adjustment for age, treatment, MYC amplification and molecular subgroups. Twenty-seven patients (57%) experiencing recurrent or progressive disease more than 12 months after diagnosis, had an estimated 1-year survival after recurrence of 100% (CI 95%, 100.0 to 100.0) vs 30% (CI 95%, 12.2 to 50.1) with an earlier recurrence. Early relapse was more frequent in children younger than 5 years of age at diagnosis (75% vs 37%, p =0.009), anaplastic/large cell MB (30% vs 3.7%, p=0.046) and Group 3 tumours (76.5% vs 20.8%, p=0.003). Other factors influencing post-relapse survival were metastatic disease and treatment modalities at diagnosis. Multivariable analyses will be presented. CONCLUSION The overall prognosis after relapse remains poor. Time to relapse is a significant prognostic factor for postrelapse survival and may help in the design of clinical trials evaluating new agents.

To compare results from a third (1995-2010) cohort of children with medulloblastoma with two previous series (J Neurosurg 86:13-21, 1997; Arch Dis Child 54:200-203, 1979) to analyse the effects of management changes aimed at improving both overall and event-free survivals (OS and EFS) and functional outcomes.Review of neuro-oncology and imaging databases and previously published results.There was no statistically significant improvement in the 5-year OS for 104 children diagnosed 1995-2010, 61.5% (95% CI, 52.9, 71.6), compared with 50% of the 80 children presenting 1980-1990 (J Neurosurg 86:13-21, 1997) (difference 11.5%; 95% CI, 2.8, 25.4). Five-year OS for 96 children suitable for risk-stratification was overall 66% (95% CI, 57.9, 75.8); standard risk 77.8% (95% CI, 67.4, 89.7); high risk3 years 50.0% (95% CI, 32.3, 77.5); high risk ≥ 3 years 54.5% (95% CI, 37.2, 79.9); 5-year EFS were standard risk 68.5% (95% CI, 57.2, 82.1); high risk3 years 40.0% (95% CI, 23.4, 68.4); and high risk ≥ 3 years 36.4% (95% CI, 20.9, 63.2); overall 55.2% (95% CI, 46.1, 66.1). Of 62/63 ≥ 5-year survivor, 9 died later from tumour relapse and 4 from second malignancy. Functional outcomes of 62 of the 63 ≥ 5-year survivors: 67.7% had educational issues requiring remedial input; 18% restricted mobility indoors and outdoors; 59.7% hearing impairment (42% prescribed aids).1. Comparison of this single-institution series with its predecessor found that revised chemotherapy and RT protocols and greater accuracy of risk stratification did not result in statistically significant improvements in either survival or treatment-related functional disability. 2. Extended (5-year) follow-up is essential if 20% of late deaths from relapse and second malignancies are not to be overlooked.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Group 3 MB patients face the highest incidence of metastasis and poor overall survival. The early onset and aggressive nature of MB suggest a stem cell origin, where a highly self-renewing transformed cell of the postnatal cerebellum drives MB tumorigenesis. In this work, we explore the therapeutic value of activating WNT signaling and targeting other essential drivers of self-renewal, BMI1 and MSI1. A small molecule BMI1 inhibitor, PTC-028, induced a remarkable decrease in self-renewal, while reducing local and spinal metastatic disease in recurrent MB, which is striking as no prior drug has shown efficacy against recurrent Group 3 MB. Although mouse and human neural stem cells (NSCs) express BMI1 and are mildly sensitive to BMI1 inhibitors, no significant toxicity was observed in NSCs upon PTC-028 treatment, at doses that effectively kill MB cells. Another novel therapeutic paradigm includes activating Wnt signaling in otherwise non-Wnt MB, which abrogates self-renewal and tumorigenicity of these aggressive tumors. For safe and non-toxic activation of Wnt in preclinical models, we identified L807mts, a novel inhibitor that functions through a substrate-to-inhibitor conversion mechanism within the catalytic site of GSK. A final therapeutic strategy lies in the discovery of the targetable MB-specific interactome of the RNA binding protein (RBP) Musashi1. shRNA knockdown of Msi1 decreased the self-renewal capacity of MB stem cells, significantly decreased tumor burden and increased survival in our PDX model. Comparative eCLIP (enhanced cross-linking and immunoprecipitation) of MB stem cells and normal NSCs, combined with mass spectrometry and RNA-sequencing of shMSI1 MB cells has elucidated novel therapeutic targets in interactome of MSI1. Characterization and therapeutic targeting of self-renewal mechanisms may provide an opportunity to limit treatment-resistant stem cell populations from driving patient relapse in Group 3 MB, a disease currently lacking any targeted therapies.

Treatment for medulloblastoma (MB) — the most common malignant pediatric brain tumor — includes prophylactic radiation administered to the entire brain and spine due to the high incidence of metastasis to the central nervous system. However, the majority of long-term survivors are left with permanent and debilitating neurocognitive impairments as a result of this therapy, while the remaining 30–40% of patients relapse with terminal metastatic disease. Development of more effective targeted therapies has been hindered by our lack of understanding of the underlying mechanisms regulating the metastatic process in this disease. To understand the mechanism by which MB metastasis occurs, three-dimensional matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) experiments were performed on whole brains from a mouse model of human medulloblastoma. Analyzing the tumor and surrounding normal brain in its entirety enabled the detection of low abundance, spatially-heterogeneous lipids associated with tumor development. Boundaries of metastasizing and non-metastasizing primary tumors were readily defined, leading to the identification of lipids associated with medulloblastoma metastasis, including phosphatidic acids, phosphatidylethanolamines, phosphatidylserines, and phosphoinositides. These lipids provide a greater insight into the metastatic process and may ultimately lead to the discovery of biomarkers and novel targets for the diagnosis and treatment of metastasizing MB in humans.

BACKGROUND In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). Part of our aim was to explore the clinical application for drug target identification and finding clues to genetic predisposition. METHODS In total, 52 frozen tumor tissues of childhood MBs were collected. RNA-Seq and DNA methylation array data were generated. Molecular subgrouping was performed. We selected 51 clinically relevant genes for somatic variant calling using RNA-Seq data. Correlated clinical findings to genetic predisposition were defined. Potential drug targets and genetic predispositions were explored. RESULTS Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Potential drug targets were detected in the pathways of DNA damage response. Five patients with relevant clinical findings to genetic predisposition clustered in SHH MBs. The corresponding somatic driver mutations involved TP53, MSH6, PTEN, PTCH1, and TERT promoter (suspicious). For validation, whole exome sequencing (WES) of blood and tumor tissue was used in 10 patients with SHH MBs in the cohort series. This study included the five patients with potential genetic predispositions. Four patients exhibited relevant germline mutations named as TP53, MSH6, PTEN, and SUFU. CONCLUSION The findings of this study provide valuable information for personalized care of childhood MB in our cohort series and in Taiwan.

Purpose Pediatric medulloblastoma (MB) treatment has evolved over the past few decades; however, treating children in countries with limited resources remains challenging. Until now, the literature regarding childhood MB in Malaysia has been nonexistent. Our objectives were to review the demographics and outcome of pediatric MB treated at the University Malaya Medical Center between January 1994 and December 2013 and describe the challenges encountered. Methods Fifty-one patients with childhood MB were seen at University Malaya Medical Center. Data from 43 patients were analyzed; eight patients were excluded because their families refused treatment after surgery. Results Headache and vomiting were the most common presenting symptoms, and the mean interval between symptom onset and diagnosis was 4 weeks. Fourteen patients presented with metastatic disease. Five-year progression-free survival (± SE) for patients ≥ 3 years old was 41.7% ± 14.2% (95% CI, 21.3% to 81.4%) in the high-risk group and 68.6% ± 18.6% (95% CI, 40.3% to 100%) in the average-risk group, and 5-year overall survival (± SE) in these two groups was 41.7% ± 14.2% (95% CI, 21.3% to 81.4%) and 58.3% ± 18.6% (95% CI, 31.3% to 100%), respectively. Children younger than 3 years old had 5-year progression-free and overall survival rates (± SE) of 47.6% ± 12.1% (95% CI, 28.9% to 78.4%) and 45.6% ± 11.7% (95% CI, 27.6% to 75.5%), respectively. Time to relapse ranged from 4 to 132 months. Most patients who experienced relapse died within 1 year. Febrile neutropenia, hearing loss, and endocrinopathy were the most common treatment-related complications. Conclusion The survival rate of childhood MB in Malaysia is inferior to that usually reported in the literature. We postulate that the following factors contribute to this difference: lack of a multidisciplinary neuro-oncology team, limited health care facilities, inconsistent risk assessment, insufficient data in the National Cancer Registry and pathology reports, inadequate long-term follow-up, and cultural beliefs leading to treatment abandonment.

Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and in some instances individual genetic aberrations such as MYC and MYCN amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including MYC and MYCN gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3–17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75–90 % survival), high risk (50–75 % survival) and very high risk (

Currently medulloblastoma is treated with a uniform therapeutic approach based on histopathology and clinico-radiological risk stratification, resulting in unpredictable treatment failure and relapses. Improved understanding of the biological, molecular and genetic make-up of these tumors now clearly identifies it as a compendium of four distinct subtypes (WNT, SHH, group 3 and 4). Advances in utilization of the genomic and epigenomic machinery have now delineated genetic aberrations and epigenetic perturbations in each subgroup as potential druggable targets. This has resulted in endeavors to profile targeted therapy. The challenge and future of medulloblastoma therapeutics will be to keep pace with the evolving novel biological insights and translating them into optimal targeted treatment regimens.

To investigate intellectual and situation-based social outcome and educational achievement in adult survivors of childhood medulloblastoma and analyse factors influencing outcome Methods: We collected demographic, medical and cognitive data, and social and educational outcome at a mean time since the end of treatments of 14.9 years in 58 adults, aged 19-35 years, consecutively treated in a single cancer center between 1989 and 2005.Ten survivors had severe intellectual disability, 12 were still studying, 23 had a regular employment and 13 were unemployed. Full Scale Intellectual Quotient, assessed 6.6 years after the end of treatments, ranged from 46 to 131. It was strongly associated with educational achievement and significantly lower in patients who experienced postoperative cerebellar mutism, and when parental education level was low.These factors should be systematically considered at diagnosis in order to offer adequate and timely assessments and interventions.

Summary Introduction. Dental implant therapy has become a popular method of replacing one or more missing teeth. Osseointegrated dental implants have been studied from histological, microbiologic and biomechanical point of view, but the neurophysiologic integration of the implants and the supported prostheses has received less attention. The sensory mechanism of dental implants is qualitatively different from that of natural teeth. Psychophysiological tests are used to determine the tactile sensibility perceived with the implants and teeth. Aim of the study. The purpose of this study was to compare tactile sensibility of natural teeth and osseointegrated dental implants. Material and methods. Forty-three patients were included in the study. Natural teeth were divided into two groups: non endodontically treated teeth (NETT) and endodontically treated teeth (ETT). Load tests were done by a computer-controlled pressure sensitive device („Power Lab“ Data Acquisition System - model 4/25T, sensor - model MLT003/D; ADInstruments), specially modified for intraoral use. Pushing forces were applied parallel to the vertical axis of teeth and implants. The patient held a signal button which he/she activated as soon as touch was sensed. At this moment the computer registered passive absolute tactile threshold - measured in Newtons. The mean values of passive absolute tactile threshold for natural teeth and dental implants were calculated. Comparison of the mean values was performed by the means of t-test. Results. Passive absolute tactile threshold for osseointegrated dental implants was 2.39 N (SD=1.92), and for teeth - 0.67 N (SD=0.72), for non endodontically treated teeth it was 0.63 N (SD=0.72) and for endodontically treated teeth - 0.73 N (SD=0.69). The differences in mean values were statistically significant (p Conclusion. This study shows that patients with osseointegrated implants subjectively feel “touch” sensation when greater force is applied compared with natural teeth.

BACKGROUND: International consensus recognises four medulloblastoma molecular subgroups - WNT (MBWNT), SHH (MBSHH), Group 3 (MBGrp3) and Group 4 (MBGrp4) - each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. Subgroups harbor distinct clinico-pathological and molecular features, underpin current disease sub-classification and initial subgroup-directed therapies are underway in clinical trials (i.e. reduced risk-adapted treatments for favorable-risk MBWNT patients; SMO inhibitors for MBSHH patients). However, significant biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. METHODS: We undertook comprehensive molecular profiling and unsupervised class discovery (non-negative matrix factorization, t-SNE) of test and validation cohorts (n=704 in total), to identify consensus primary molecular subgroups within childhood medulloblastoma (3.0 years). FINDINGS: Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified, characterized by distinct biological/clinical features. For instance, MBSHH comprised two age-dependent subgroups, while MBGrp3 and MBGrp4 each split into two subgroups with significantly different survival rates. Survival analysis identified secondary features predictive of outcome. Cross-validated subgroup-dependent models incorporating these novel subgroups along with secondary features and established disease risk-factors, outperformed current disease risk-stratification schemes. These schema stratified patients into four clinical risk-groups - favorable-risk (91% 5-year survival, 25% of patients), standard-risk (81%, 23%), high-risk (42%, 38%) and very high-risk (28%, 13%) - to be considered for treatment reduction, intensification or novel therapies respectively. INTERPRETATION: The discovery of seven novel, clinically-significant, subgroups significantly improves disease risk-stratification and provides a new foundation for future research and clinical investigations.

Purpose Medulloblastoma is the most common primary malignant central nervous system tumour in children. These last decades, treatment modalities have largely evolved resulting in better survival rates. Nevertheless, long-term toxicity is a major concern in this setting. The purpose of this study was to analyse the clinical results and medical outcomes of a cohort of paediatric patients treated for medulloblastoma in Xhinhua Hospital in Shanghai. These results are compared with those from other centres reported in literature. Patients and methods This was a retrospective study conducted at Xhinhua Hospital in Shanghai, China. It included 121 patients treated for medulloblastoma from 1993 to December 2013. Results Mean age at diagnosis was 6.7 years (range: 1–14.3 years). Total surgical resection was achieved in 60% of the cases. Classic medulloblastoma was found in 59% of the cases. Adjuvant radiotherapy was delivered in all cases and chemotherapy concerned 70.2% of the studied cohort. The median follow-up time of the study was 84 months (range: 24–120 months). Five- and 10 years progression-free survival rates were 83.2%, and 69.5% and 5 years and 10 years. Overall survival rates were 82.5%, and 72.5%. Patient's age significantly influenced survival: patients under 3 years old had the worse outcomes (P = 0.01). T and M stages also significantly impacted survival rates: advanced stages were associated with lower rates (P = 0.08 and 0.05 respectively). Finally, patients receiving temezolomide had bad outcomes when compared to the new standard protocol used in the department (P = 0.03). The most commonly reported late toxicity was growth suppression in 35 patients (52.2%). Hypothyroidism requiring hormone replacement was recorded in 29% of the cases. Hearing loss, and problems including poor concentration, poor memory and learning difficulties were reported in 19% and 25% of the cases respectively. Second cancers were noted in three cases. Conclusion Overall, our results are comparable to those reported in literature. Nevertheless, efforts should be made to ensure longer follow-ups and correctly assess treatment-related toxicity.

Background Medulloblastoma is the most common malignant brain tumor in children, currently treated uniformly based on histopathology and clinico-radiological risk stratification leading to unpredictable relapses and therapeutic failures. Identification of molecular subgroups have thrown light on the reasons for these and now reveals clues to profile molecularly based personalized therapy against these tumors. Methods Research and online contents were evaluated for pediatric medulloblastoma which included latest information on the molecular subgroups and their clinical relevance and update on efforts to translate them into clinics. Results Scientific endeavors over the last decade have clearly identified four molecular variants (WNT, SHH, Group 3, and Group 4) and their demographic, genomic, and epigenetic profile. Latest revelations include significant heterogeneity within these subgroups and 12 different subtypes of MB are now identified with disparate outcomes and biology. These findings have important implications for stratification and profiling future clinical trials against these formidable tumors. Conclusion With the continued outpouring of genomic/epigenomic data of these molecular subgroups and evolution of further subtypes in each subgroup, the challenge lies in comprehensive evaluation of these informations. Current and future endeavors are now needed to profile personalized therapy for each child based on the molecular risk stratification of medulloblastoma, with a hope to improve survival outcome and reduce relapses.

Introdução: meduloblastoma é o tumor maligno cerebral mais comum em crianças. Nas últimas décadas, a sobrevida geral e a sobrevida livre de doença melhoraram, no entanto, um terço dos pacientes ainda permanece sem cura. Novas evidências sugerem que o meduloblastoma compreende quatro entidades moleculares distintas com características epidemiológicas próprias. Um novo sistema de estratificação e o des-escalonamento do tratamento são necessário. O objetivo deste artigo é avaliar dados epidemiológicos de pacientes tratados em nossa instituição. O objetivo principal é analisar a sobrevida geral e a sobrevida livre de doença. O objetivo secundário é identificar o fator prognóstico nesta coorte. Métodos: Analisamos retrospectivamente 69 pacientes submetidos à ressecção cirúrgica de meduloblastoma entre 423 crianças do banco de registro de tumores do Hospital da Criança Santo Antônio entre 1995 e 2016. Através do método de Kaplan-Meier e a regressão de Cox, identificamos índices de sobrevida geral (SG) e sobrevida livre de doença (SLD) bem como fatores prognósticos. Resultados: valores encontrados para SG e SLD foram 44,5% e 36,4% respectivamente. A extensão da ressecção cirúrgica e radioterapia foram correlacionadas positivamente com o desfecho clínico. A presença de doença metastática no momento do diagnóstico correlacionase negativamente à sobrevida. Idade inferior a 3 anos não foi associada a pior prognóstico em nossa coorte. Conclusão: Os resultados que encontramos são semelhantes aos estudos populacionais, mas ainda enfrentamos dificuldades devido às limitações de um país em desenvolvimento. Futuramente, a aplicação de técnicas de diagnóstico que classificam os meduloblastomas de acordo com subgrupos moleculares permitirá aplicar os avanços da terapêutica. Background: Medulloblastoma is the most commo mnalignant brain tumor in pediatric population. Despite prognosis improvement in the last two decades, one third of the patients still remain uncurable. New evidence suggests that medulloblastoma comprises four distict entities therefore treatment de-escalation is required. The aim of this article is to evaluate epidemiological data from patients treated at our institution. Primary objective is to analyze overall survival (OS), event free survival (EFS) and secondary objective is to identify prognostic factor from this cohort. Methods: We retrospectvely analyzed 69 patients who underwent surgical resection for medulloblastoma among 423 children from the tumor registry data bank of Hospital da Criança Santo Antônio from 1995 to 2016. Kaplan-Meier method and Cox regression analysis were used to identify OS, EFS and prognostic factors. Results: The OS and EFS rates found were 44,5% and 36,4% respectively. Extent of resection and radiotherapy as adjuvant treatment were positively correlated to outcome while metastatic disease at diagnosis were negatively related to OS. Age younger than 3 years old did not have worse outcome in our cohort. Conclusion: Similar resulte population-based studies were found, but we still face difficulties due to live in a developing country. In the near future, we look forward to new diagnostic techniques which will enable us to classify medulloblastomas according to molecular subgroups.

Background Children presenting with medulloblastoma have a wide range of initial presenting symptoms. However, the influence of underlying tumor biology on the initial presentation of medulloblastoma is currently unknown. In light of the recent discovery of distinct medulloblastoma subgroups, we sought to define the initial presentation of childhood medulloblastoma in a subgroup specific manner. Procedure We assembled a cohort of 126 medulloblastoma cases at the Hospital for Sick Children between 1994 and 2012 and determined subgroup affiliation using nanoString. Clinical details pertaining to the initial presentation were determined through a retrospective chart review. Results The median pre-diagnostic interval across all medulloblastoma cases was 4 weeks (IQR: 4–12 weeks). Strikingly, when the pre-diagnostic interval was then determined in a subgroup specific manner, cases with WNT and Group 4 tumors showed significantly longer median pre-diagnostic intervals of 8 weeks compared to 2 weeks for SHH and 4 weeks for Group 3 (P = 0.0001). Younger age was significantly associated with a prolonged pre-diagnostic interval (P = 0.02 for all). When stratifying by subgroup the association with age was only significant in Group 4 (P = 0.04 for Group 4). Improved survival was significantly associated with a longer pre-diagnostic interval (P = 0.02), however is no longer significant when controlling for subgroup (P = 0.07). Conclusions The duration of the pre-diagnostic interval in childhood medulloblastoma is highly subgroup dependent, further highlighting the clinical heterogeneity and biological relevance of the four principle subgroups of medulloblastoma. Pediatr Blood Cancer 2014;61:1190–1194. © 2014 Wiley Periodicals, Inc.

Medulloblastoma is the most common malignant childhood brain tumor, although long-term risks for chronic neurologic health and psychosocial functioning in aging adult survivors are incompletely characterized.The Childhood Cancer Survivor Study (CCSS) includes 380 five-year survivors of medulloblastoma/primitive neuroectodermal tumor (PNET; median age at follow-up: 30 y, interquartile range 24-36) and sibling comparison (n = 4031). Cumulative incidence of neurologic health conditions was reported. Cox regression models provided hazard ratios (HRs) and 95% CIs. Cross-sectional outcomes were assessed using generalized linear models.Compared with siblings, survivors were at increased risk of late-onset hearing loss (HR: 36.0, 95% CI: 23.6-54.9), stroke (HR: 33.9, 95% CI: 17.8-64.7), seizure (HR: 12.8, 95% CI: 9.0-18.1), poor balance (HR: 10.4, 95% CI: 6.7-15.9), tinnitus (HR: 4.8, 95% CI: 3.5-6.8), and cataracts (HR: 31.8, 95% CI: 16.7-60.5). Temporal/frontal lobe radiotherapy of 50 Gy or more increased risk for hearing loss (HR: 1.9, 95% CI: 1.1-1.3), seizure (HR: 2.1, 95% CI: 1.1-3.9), stroke (HR: 3.5, 95% CI: 1.3-9.1), and tinnitus (HR: 2.0, 95% CI: 1.0-3.9). Survivors were less likely than siblings to earn a college degree (relative risk [RR]: 0.49, 95% CI: 0.39-0.60), marry (RR: 0.35, 95% CI: 0.29-0.42), and live independently (RR: 0.58, 95% CI: 0.52-0.66).Adult survivors of childhood medulloblastoma/PNET demonstrate pronounced risk for hearing impairment, stroke, lower educational attainment, and social independence. Interventions to support survivors should be a high priority.

Background: Medulloblastoma is the most common malignant brain tumor in the pediatric population. Despite prognosis improvement in the past two decades, one-third of the patients still remain incurable. New evidence suggests that medulloblastoma comprises four distinct entities; therefore, treatment de-escalation is required. The aim of this article is to evaluate epidemiological data from patients treated at our institution. The primary objective is to analyze overall survival (OS) and event-free survival (EFS) and the secondary objective is to identify prognostic factor from this cohort. Methods: We retrospectively analyzed 69 patients who underwent surgical resection for medulloblastoma among 423 children from the tumor registry data bank of Santo Antônio Children’s Hospital from 1995 to 2016. Kaplan–Meier method and Cox regression analysis were used to identify OS, EFS, and prognostic factors. Results: The 5-year OS and EFS rates found were 44.5% and 36.4%, respectively. The extent of resection and radiotherapy as adjuvant treatments was positively correlated to outcome while metastatic disease at diagnosis was negatively related to OS. Age younger than 3 years old did not have a worse outcome in our cohort. Conclusion: Similar results to population-based studies were found, but we still face difficulties due to living in a developing country. In the near future, we look forward to new diagnostic techniques that will enable us to classify medulloblastomas according to molecular subgroups.

The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 +/- 2 % and 78 +/- 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. > 5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 +/- 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour. Funding for this work was provided by: The Swedish Children's Cancer Foundation, The German Children's Cancer Foundation, Cancer Research UK, The French Ministry of Health, The French National Cancer Institute (INCa) and Associazione Bianca Garavaglia onlus (B. Arsizio, Milano).

Due to the lacking specificity of symptoms making a correct diagnosis can be a challenge in children with medulloblastoma. This can lead to prediagnostic symptomatic intervals (PSIs) of several weeks to months. It is unknown whether the length of the PSI is associated with an inferior survival outcome in this population.To study the association of PSI with disease stage at diagnosis, tumour control and survival in children with medulloblastoma, prospectively collected data on PSI, clinical, and biological features were analysed in 224 patients diagnosed at the age of 3-18 years and treated within the prospective randomised multicentre trial HIT'91.Patients with lower-stage disease tended towards a longer median PSI than those with higher-stage disease (M0 stage, 2.0 months; M1 stage, 2.0 months; M2/M3 stage, 1 month; p = 0.094. M0/1 stage versus M2/3 stage; p = 0.025). The patient group with the longest PSI had the best survival outcome (PSI ≥ 4.0 months: 10-year overall survival rate (OS), 71%; PSI4.0 months, 10-year OS, 61%; p = 0.056). Age at diagnosis was positively correlated with PSI (p = 0.027). No associations were found between PSI and sex histological subtype, presence of postoperative residual tumour, or c-myc and TrkC mRNA expression.Contrary to a common belief that a longer PSI may adversely affect prognosis, a longer PSI was associated with a trend towards lower metastatic stage and better survival probabilities. Nevertheless these findings do not obviate the importance of a timely diagnosis in paediatric patients with medulloblastoma.