Nodular Medulloblastoma Research Articles

Molecular Subgrouping Based on Immunohistochemistry in Medulloblastoma: A Single-Center Experience.

To investigate the efficacy of immunohistochemical methods to determine molecular subgroups and prognostic predictions of medulloblastomas (MBs). β-catenin, GAB1, YAP1, filamin A and p53 were immunohistochemically stained, and MYC and MYCN fluorescent in situ hybridization (FISH) procedures were applied to 218 cases in our series. Based on the histomorphological characteristics of the cases, 67.9% were deemed classic MB; 15.6% as desmoplastic/ nodular medulloblastoma (DNMB); 12.8% as large cell/anaplastic (LC/A) MB; 3.7% as medulloblastoma with extensive nodularity (MBEN). Molecular characteristics revealed that 50.5% had non-WNT/non-SHH; 33.9% had SHH-activated and TP53-wildtype; 8.7% had WNT-activated; 6.9% had SHH-activated and TP53-mutant. According to the survival curves, LC/A MBs or non-WNT/ non-SHH tumors showed the worst prognosis, whereas DNMBs and WNT-activated tumors showed the best prognosis. Classic MBs or SHH-activated tumors showed a moderate course. MYCN amplification was found to act as an independent poor prognostic factor in the study. The distribution of histological subtypes and molecular subgroups, amplification rates, and prognostic data obtained through immunohistochemical methods in our study were consistent with those reported in the literature. It was therefore hypothesized that the determination of molecular subgroups by immunohistochemical methods can be useful in daily diagnostic practice, especially in centers with limited access to molecular techniques.

Concurrent medulloblastoma and cardiac fibroma: a rare presentation of Gorlin-Goltz syndrome.

Gorlin-Goltz syndrome is a rare autosomal dominant disorder resulting from PTCH1 gene mutation and presents with variable clinical manifestations. The co-occurrence of medulloblastoma and cardiac fibroma in Gorlin-Goltz syndrome is extremely rare. The present article discusses a patient diagnosed with Gorlin-Goltz syndrome and concurrent medulloblastoma and cardiac fibroma. A 19-month-old boy transferred to our hospital after a radiological finding of posterior fossa lesion and hydrocephalus. A pericardial mass was noted after persistent arrhythmias. Both tumors were excised for definitive management. The histopathological sections were diagnostic of desmoplastic nodular medulloblastoma, WHO grade 4 and cardiac fibroma. Molecular and genetic investigations confirmed a pathogenic variant of PTCH1 gene, suggestive of autosomal dominant Gorlin-Goltz syndrome. Co-occurrence of medulloblastoma and cardiac fibroma is extremely rare and poses a management dilemma. Genetic counseling and antenatal screening are of utmost importance to early detect and manage patients with Gorlin-Goltz syndrome.

Survival Study in Pediatric Patients with Medulloblastoma in a General Hospital in Tehran, Iran

Abstract Brain tumours are the most common solid tumours that afflict the pediatric population. Me-dulloblastoma (MB) is the most common malignant brain tumour in children, constituting nearly 20% of all pediatric brain tumours. This study is an evaluation of overall survival rate of pediatric MB tumour patients after one year, three years, five years, and ten years according to case studies. From 22 June 2009 to 19 December 2019, a total of 22 patients ranging in age from 1 to 14 years old underwent tumour removal. These patients were followed to determine survival rate. Tumours were classified into three pathological subtypes: The first was classic MB, the second was desmoplastic nodular MB and MB with extensive nodularity, and the third was large cell and anaplastic MB. Patients who were 3 years old or older had a better survival rate than younger patients (log-rank test; p = 0.01). The survival probability in the older children group (55%) was significant compared to the group of younger children (29%). The Kaplan–Meier survival curves of the patients were significantly different. The ten-year survival rates in the average- and high-risk groups were 64.4% and 86.0%, respectively. After a follow-up of 120 months (median range = 60 months), recurrence or progression was observed in 22 patients and 15 patients were still alive. The estimated 10-year overall survival rates for all patients were 49.36 ± 38.33. MB patients’ survival rate was quite good in our hospital. More than half of the patients, most of whom had large cell anaplastic and classic type MB, survived the 10-year follow-up period without any problems.

Chemotherapy strategies for young children newly diagnosed with desmoplastic/extensive nodular medulloblastoma up to the era of molecular profiling – a comparative outcomes analysis of prospective multi-center European and North American trials.

Abstract Aims Survival has been poor in several multi-center/national trials since the 1980s, either delaying, avoiding or minimizing brain irradiation in young children with medulloblastoma. The introduction of German regimens supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these differing strategies for young children with desmoplastic/extensive nodular medulloblastoma. Method Data from 12 trials reported between 2005 and 2020 for children <six-years-old with desmoplastic/extensive nodular medulloblastoma were reviewed; event-free (EFS) survival+/-standard errors were compared. Results The German HIT-SKK’92 and HIT-SKK’00 trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/-5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HIT-SKK therapy but without IVENT-MTX reported only 49+/-10% EFS. Three trials (Head Start I and II combined and CCG-99703) employing induction chemotherapy without HD-MTX, followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing induction chemotherapy (Head Start III and ACNS0334), followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR (UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5 year EFS of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9% respectively. Conclusion A trend towards better EFS for young children with desmoplastic/extensive nodular medulloblastoma is observed in trials including eitherHD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

MBCL-19. CHEMOTHERAPY STRATEGIES FOR YOUNG CHILDREN NEWLY DIAGNOSED WITH DESMOPLASTIC/EXTENSIVE NODULAR MEDULLOBLASTOMA UP TO THE ERA OF MOLECULAR PROFILING – A COMPARATIVE OUTCOMES ANALYSIS OF PROSPECTIVE MULTI-CENTER EUROPEAN AND NORTH AMERICAN TRIALS

BACKGROUND/OBJECTIVESurvival has been poor in several multi-center/national trials since the 1980s, either delaying, avoiding or minimizing brain irradiation in young children with medulloblastoma. The introduction of German regimens incorporating both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens utilizing marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these strategies for young children with desmoplastic/extensive nodular medulloblastoma (D/ENMB).DESIGN/METHODSData from 12 trials reported between 2005 and 2019 for children <six-years-old with D/ENMB were reviewed; event-free (EFS) with standard errors were compared.RESULTSThe German HIT-SKK’92 and HIT-SKK’00 trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/-5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HIT-SKK therapy but without IVENT-MTX reported 49+/-10% EFS. Three trials (Head Start I/II combined and CCG-99703) employing induction chemotherapy without HD-MTX, followed by 1/3 HDCx+AuHCR cycles, reported 3-5-year EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing induction chemotherapy (Head Start III and ACNS0334), followed by 1/3 HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR (UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5-year EFS of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9%.CONCLUSIONSA trend towards better EFS for young children with D/ENMB is observed in trials including either HD-MTX as well as IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.

MBCL-27. ASSOCIATION OF MEDULLOBLASTOMA WITH CHARCOT-MARIE-TOOTH DISEASE

Charcot-Marie-Tooth disease (CMT) is one of the most common hereditary neurological disorders and damages peripheral nerves that results in motor and sensory disturbance. Association of medulloblastoma (MBL) with CMT has been rarely reported. A one-year-old male was referred to our hospital because of cerebellar mass. He had partial resection of the tumor, and was pathologically diagnosed as having desmoplastic nodular medulloblastoma. He received chemotherapy according to the HIT protocol, however, developed severe peripheral neurotoxicity in the initial stage of the treatment. Reinvestigation of family history revealed his mother, grandmother, and aunt had muscle weakness. We suspected he had an inherited neurological disease including CMT, and discontinued administration of vincristine. Fluorescence in situ hybridization analysis detected duplication of PMP22 gene located on 17p11.2, confirming the diagnosis of CMT1A. He completed the rest of chemotherapy without vincristine, and remained in complete remission for four years from the end of treatment. In the literature, there are reports of patients with CMT who developed MBL and were complicated with severe peripheral neurotoxicity due to the use of vincristine. The present case, along with previous reports, suggests that medulloblastoma can develop in patients with CMT and reminds the importance of recalling the possibility of CMT when patients develop severe chemotherapy-induced peripheral neurotoxicity upon use of vincristine. Desmoplastic nodular medulloblastoma may be successfully treated by chemotherapy without vincristine.

MAGNETIC RESONANCE IMAGING FEATURES OF PEDIATRIC MEDULLOBLASTOMA IN RELATION TO PATHOLOGICAL SUBTYPES

Medulloblastma (MB) is a highly malignant (WHO grade IV), primitive cerebellar tumor of neuroectodermal origin. Medulloblastomas have been classified, based on histopathological, biological, and clinical characteristics, into classic medulloblastoma (CMB), desmoplastic nodular medulloblastoma (DNMB), medulloblastoma with extensive nodularity and anaplastic/large cell medulloblastoma.Medulloblastoma shows heterogenous tumor features in each subtype. Based on these heterogeneity, magnetic resonance imaging (MRI) could differentiate pathological subtypes according to each imaging features. This study aimed to assess the relation between Magnetic Resonance imaging features of pediatric medulloblastoma and pathological subtypes to improve treatment outcomes of the disease.All patients were subjected to the following:o History taking.o Thorough clinical examination.o Conventional MRI study of the brain.o Susceptibility-weighted imaging of the brain with post processing phase image. The study was applied on a 1.5 Tesla Magnetom Avanto Siemens (left handed system) machine using conventional MRI sequences in addition to DWI. Imaging evaluation depended on tumor location, tumor enhancement and degree of tumor restriction on DWI. Histo-pathology remains the gold standard in differentiating subtypes, however we can use MRI in early prediction of the subtypes and early planning for their management, regardless MRI very important role in post-surgical assessment and follow up.

A Retrospective Analysis of the Demographics, Treatment, and Survival Outcomes of Patients with Desmoplastic Nodular Medulloblastoma Using the Surveillance, Epidemiology, and End Results (SEER) Database.

ObjectiveMedulloblastoma is the most common malignant brain tumor in children younger than four years of age. Children diagnosed with desmoplastic nodular medulloblastoma (DNMB) have more favorable survival outcomes when compared to other subtypes of this disease and, to date, the demographics of DNMB have only been characterized by a few small clinical case series. Additionally, the current effort is being made at reducing radiotherapeutic modalities in this patient population to avoid the adverse effects associated with radiotherapy in children. Therefore, the goal of this study was to characterize the demographics, treatments, and survival outcomes of patients with DNMB using a large federal database.MethodsThe Surveillance, Epidemiology, and End Results database was queried to retrieve demographical, treatment, and survival data for patients diagnosed with DNMB. Statistical testing was performed with the R software stats package (R Foundation for Statistical Computing, Vienna, Austria). Student’s t tests and analysis of variance tests were used to measure differences among survival rates.ResultsData from 360 patients with DNMB were retrieved from 1975-2016. There was a higher prevalence of DNMB in children younger than four years of age (33% of all cases). Males had a higher prevalence than females (57%). There was a preponderance of diagnoses in white individuals (82% of all cases) and more diagnoses in the Pacific Coast region (49% of all cases). Distant metastases were present at initial diagnosis in 8.7%. Surgery was performed in almost all patients, and gross total resection was achieved in 77%. The overall rate of survival was 77.8% at five years; age, sex, race, and geographical region of diagnosis were not associated with differences in survival outcomes. Patients with no radiotherapy had a lower rate of survival compared to patients with postoperative radiotherapy (mean difference = 19.7%; [95% CI 1.4%-38.0%], p = 0.0314). However, radiotherapy did not improve survival outcomes in patients undergoing chemotherapeutic treatment to a degree with any statistical significance. There was no statistically significant improvement in survival for patients undergoing radiotherapy prior to procedure when compared to patients with no radiotherapy.ConclusionsIn patients undergoing chemotherapeutic treatment for the DNMB subtype of medulloblastoma specifically, additional radiotherapy may offer only minimal benefit to the survival outcome. It is essential continued clinical trials be performed for the purpose of devising alternate treatments to radiotherapy.

Survival in adult and pediatric patients with medulloblastoma: A 2018 SEER-based analysis.

e14529 Background: Medulloblastoma (MB) is a malignant neuroectodermal tumor accounting for 30% of pediatric and only 1% of adult brain tumors. In previous studies comparing survival in pediatric and adult MB from the National Cancer Institute Surveillance Epidemiology and End Results (SEER) database no difference has been found. However, diagnostic subgroup analyses have been limited. Methods: We examined survival in children (age 0-19) and adults (20-79) coded as MB in the 2018 SEER database (2000-2016). We used Kaplan Meier analysis, log-rank test and Cox proportional hazard ratios (HR) with 95% confidence intervals (CI). MB in SEER-18 is defined as ICD-O-3 histology codes 9470–9474 (n = 1,728). ICD 9473, supratentorial PNET (sPNET, n = 97) is biologically distinct and therefore it was analyzed separately. Results: We found that 5-year survival for MB, excluding sPNET, was similar in children (n = 1,091, 75.3%) and adults (n = 488, 79.1%) (HR = 0.97, CI: 0.79 – 1.17, p = 0.50). Furthermore, subtype analyses showed no survival difference comparing adults and children with desmoplastic nodular MB (n = 222, p = 0.09), large cell MB (n = 73, p = 0.46), or MB NOS (n = 1330, p = 0.10). Yet, children with sPNET had improved 5-year survival (n = 65, 72.3%) compared to adults (n = 29, 51.7%) (HR = 2.0, CI: 1.10 – 3.92; p = 0.02,). These findings indicate that while survival in patients with MB is similar across age groups, children with sPNET have improved outcomes. Conclusions: In summary, 2018 SEER data for MB continue to show no survival difference between adults and children, suggesting adult patients could appropriately be entered on pediatric MB treatment protocols. Further analyses of the 2018 data are ongoing adjusting for sex, race, and treatment (chemotherapy or radiation). For sPNET, the apparent improved outcomes for children merit further detailed investigation and will be re-evaluated using the new 2016 World Health Organization classification.

Histopathological Patterns of Intracranial Tumours at a Tertiary Health Facility in Sokoto, North-West Nigeria

Brain tumours are diverse group of primary CNS tumours and secondary neoplasm arising either from the scalp or from haematogenous spread from distant sites with few biologically aggressive tumours in both adult and paediatric age groups. Brain tumours have been classified based on their presumed cell of origin and degree of differentiation as determined by light microscopy and immunohistochemical studies with tumours distinctive tumour biology, treatment and prognosis. A retrospective study of all cases of intracranial tumours seen over a period of 10 years from January 2008 to December 2017 at Department of Pathology, Usmanu Danfodiyo University Teaching Hospital. This is a regional neurosurgical centre situated at Sokoto North-West Nigeria receiving surgical specimens from Birnin Kebbi, Zamfara, Sokoto, and Katsina state. The age, sex, histologic diagnosis, and histologic grading system using the 2007 WHO grading system were retrieved and recorded. This study reviewed 151 patients managed with histology confirmed intracranial tumour (ICTs). Mean age was 28.17 ±17.26 years. The male-to-female ratio was 1.6:1.0. Peak age range was the third decade (21-30years) and accounted for (20.5%). Primary ICTs accounted for 95.4% of the cases and metastatic adenocarcinomas accounted for 4.6% of the diagnoses and all the cases were seen in adults. Meningioma was the most commonly diagnosed intracranial tumours (39.7%), followed by astrocytoma (23.2%), pituitary adenomas (7.3%), craniopharyngioma (11.9%) and nodular medulloblastoma accounted for 4.0%. The most common histologic subtype of meningioma was psammomatous accounted for 75.5%, followed by meningotheliomatous 18.5% and the least was transitional 1.3%. The mean age of meningioma was 32±11.9 years with age range from 3 – 58years and male to female ratio of 1.4:1 and WHO classification of meningioma are stratified into 3; 95% are in grade 1 and 5% are in grade 11. Meningioma was the most commonly diagnosed intracranial tumours (39.7%), followed by astrocytoma (23.2%), pituitary adenomas (7.3%), craniopharyngioma (11.9%) and nodular medulloblastoma accounted for 4.0%. The most common histologic subtype of meningioma was psammomatous accounted for 75.5%, followed by meningotheliomatous 18.5% and the least was transitional 1.3% with WHO classification of meningioma are stratified into 3; 95% are in grade 1 and 5% are in grade 11.

Desmoplastic nodular medulloblastoma in young children: a management dilemma.

Children with desmoplastic nodular medulloblastoma (DNMB) have excellent survival, leading multiple groups globally to attempt reduction of treatment-related morbidity. In 2013, the Children's Oncology Group began a clinical trial (ACNS1221) eliminating both radiation therapy (RT) and intraventricular methotrexate for children under 3 years of age with localized DNMB, aiming to build upon the excellent outcomes of the German HIT trials. ACNS1221 has recently closed due to increased incidence of recurrences noted at the 2-year interim analysis, raising important questions regarding optimal therapy for DNMB. A review of major clinical trials that included children with DNMB was performed through July 2017. One hundred and eighty-eight DNMB patients enrolled on 11 prospective clinical trials were identified. The use of marrow-ablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) or treatment with intraventricular methotrexate has been associated with excellent outcomes. RT was usually required for patients with evidence of disease at the end of therapy. The minimal intensity and duration of chemotherapy required to maximally cure children with DNMB without need of RT remains unknown. Further trials are required to better identify a subset of DNMB patients who can be cured without marrow-ablative chemotherapy or intraventricular methotrexate.

SHP2, SOCS3 and PIAS3 Expression Patterns in Medulloblastomas: Relevance to STAT3 Activation and Resveratrol-Suppressed STAT3 Signaling.

Background: Activated STAT3 signaling is critical for human medulloblastoma cells. SHP2, SOCS3 and PIAS3 are known as the negative regulators of STAT3 signaling, while their relevance to frequent STAT3 activation in medulloblastomas remains unknown. Methods: Tissue microarrays were constructed with 17 tumor-surrounding noncancerous brain tissues and 61 cases of the classic medulloblastomas, 44 the large-cell medulloblastomas, and 15 nodular medulloblastomas, which were used for immunohistochemical profiling of STAT3, SHP2, SOCS3 and PIAS3 expression patterns and the frequencies of STAT3 nuclear translocation. Three human medulloblastoma cell lines (Daoy, UW228-2 and UW228-3) were cultured with and without 100 μM resveratrol supplementation. The influences of resveratrol in SHP2, SOCS3 and PIAS3 expression and SOCS3 knockdown in STAT3 activation were analyzed using multiple experimental approaches. Results: SHP2, SOCS3 and PIAS3 levels are reduced in medulloblastomas in vivo and in vitro, of which PIAS3 downregulation is more reversely correlated with STAT3 activation. In resveratrol-suppressed medulloblastoma cells with STAT3 downregulation and decreased incidence of STAT3 nuclear translocation, PIAS3 is upregulated, the SHP2 level remains unchanged and SOCS3 is downregulated. SOCS3 proteins are accumulated in the distal ends of axon-like processes of resveratrol-differentiated medulloblastoma cells. Knockdown of SOCS3 expression by siRNA neither influences cell proliferation nor STAT3 activation or resveratrol sensitivity but inhibits resveratrol-induced axon-like process formation. Conclusion: Our results suggest that (1) the overall reduction of SHP2, SOCS3 and PIAS3 in medulloblastoma tissues and cell lines; (2) the more inverse relevance of PIAS3 expression with STAT3 activation; (3) the favorable prognostic values of PIAS3 for medulloblastomas and (4) the involvement of SOCS3 in resveratrol-promoted axon regeneration of medulloblastoma cells.

Inhibition of SIRT1 Transcription in Resveratrol-differentiated Medulloblastoma Cells

Backgrounds: Medulloblastoma (MB) is the commonest brain malignancy in childhood with poor prognosis, because of its rapid aggressive growth and frequent occurrence. The current chemotherapeutic regimens for medulloblastoma patients involve a combination of lomustine, cisplatin, carboplatin, vincristine or cyclophosphamide, which have distinct short- and long-term side-effects. It is therefore in urgent need to explore safer and more effective adjuvant approach(s). Resveratrol, a polyphenol rich in numerous plants, has multiple biological activities including anticancer effects. Our previous data confirmed that resveratrol inhibited proliferation and induced differentiation and apoptosis of medulloblastoma cells. SIRT1 is a deacetylase of class III HDACs and the supposed molecular effecter of resveratrol. SIRT1 involves in aging prevention and cancer formation in a cell-context specific manner. Nevertheless, the datum concerning the role(s) of SIRT1 in formation and prognosis of medulloblastoma is still missing.Objective: The present study aimed to address the expression patterna of SIRT1 in medulloblastoma tissues and non-cancerous counterparts and to explore whether resveratrol exerts its anti-medulloblastoma effects via regulating SIRT1 expression and bioactivity.Methods: The expression of SIRT1 in medulloblastoma and non-cancerous counterparts was elucidated by immunohistochemical ataining (IHC). To clarify the function of SIRT1 in medulloblastomas, SIRT1 expression in UW228-3 medulloblastoma cells were suppressed by RNA interference (RNAi). The influence of resveratrol in SIRT1 expressions in UW228-3 cells was analyzed by reverse transcription-polymerase chain reaction (RT-PCR), immunocytochemistry (ICC) and Western blotting (WB). The catalytic activity of deacetylase SIRT1 was examined by measuring the acetylation of the main substrate p53.Results: IHC staining revealed that SIRT1 was expressed in 64.17% of MB tissues, which was higher than that in noncancerous cerebellum tissues (14.29%). The frequencies of SIRT1 expression in the nodular MB (22.22%) with better prognosis is lower than that in anaplastic MB (79.07% ) and classic MB (60.29 %; P&lt;0.05). The proliferation of UW228-3 cells was remarkably suppressed after being transfected with SIRT1 siRNA, accompanied with extensive cell death. The results of RT-PCR and WB showed that after 48 hours 100 M resveratrol treatment, SIRT1 expression in UW228-3 cells was down-regulated at both transcriptional and translational levels. However, resveratrol has no effect on the deacetylase activity of SIRT1.Conclusion: The above findings suggested that SIRT1 expression is corrected with the formation and prognosis of human MB. Resveratrol influences SIRT1 functioning in human MB cells through inhibiting SIRT1 expression rather than modulating its acetylation activity.Keywords: resveratrol, SIRT1, RNA interference, deacetylase, medulloblastoma

Medulloblastoma

The mainstay of medulloblastoma treatment is high-quality interdisciplinary collaboration in diagnosis, treatment, and aftercare by all involved disciplines. The first step in treatment of medulloblastoma is a maximal safe surgery, followed by thorough staging. Surgery should only be performed in experienced neurosurgical centers, with age-appropriate postoperative care. As optimal risk stratification is based on histopathological and neuroradiological assessments, these should be performed or confirmed by experienced specialists. Central review of histopathological subtype, as well as review of staging evaluations is highly desirable. For young children with desmoplastic/nodular (DMB), or extensive nodular medulloblastoma, craniospinal or any radiotherapy should be avoided. For young children with classic medulloblastoma (CMB), large cell, or anaplastic medulloblastoma (LC/A MB) optimized strategies with high-dose chemotherapy and autologous stem cell rescue with or without local radiotherapy are under investigation. For older clinical standard risk patients (without metastases, without postoperative residual tumor >1.5cm(2)) with CMB or DMB, craniospinal radiotherapy with 23.4Gy and boost to the posterior fossa to 54Gy, followed by maintenance chemotherapy can be regarded as a standard therapy besides other currently applied regimen, such as the use of intensified chemotherapy after irradiation. Older children with LC/A MB, metastatic medulloblastoma, and/or large residual tumor can be regarded as high-risk patients and should receive intensified treatment: intensified chemotherapeutic regimen before or after radiotherapy with increased dose (36-Gy CSI normofractionated, or 40-Gy hyperfractionated) is used. For treatment to be effective, quality control of radiotherapy is of high relevance. Information on long-term sequelae is essential and appropriate multidisciplinary follow-up and support, including rehabilitation and help for reintegration, is necessary. Whenever possible, patients should be included in prospective studies, and tumor material should be sampled to facilitate further research on medulloblastoma biology, which will significantly influence the stratification criteria and the introduction of targeted therapies in standard treatment recommendations in the future.

Abstract 3463: Treatment of young children with localized medulloblastoma by chemotherapy alone: Final results of the prospective multicenter trial HIT 2000 confirming the prognostic impact of histology

Abstract Background: This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with non-metastatic medulloblastoma (MB) treated by postoperative chemotherapy alone. Methods: Patients diagnosed between January 2001 and December 2005 and younger than 4 years received three cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In case of complete remission, treatment was terminated after two additional cycles of chemotherapy. Otherwise secondary surgery, radiotherapy and consolidation chemotherapy were recommended. Results: The 5-year event-free survival (EFS) and overall survival (OS) (±SE) rates of 45 patients were 57 ± 8% and 80 ± 6% (median follow-up: 4.5 years, median age: 2.5 years). Nineteen patients with desmoplastic / nodular MB variants had better EFS and OS (5-year rates: 90 ± 7% and 100 ± 0%) compared to 23 patients with classic MB (30 ± 11% and 68 ± 10%; p&amp;lt; 0.001 for EFS, p=0.008 for OS). Five-year EFS and OS rates of 3 children with anaplastic MB were 33 ± 27%. Desmoplastic / nodular histology was an independent prognostic factor for EFS. Twenty-nine of 30 (97%) patients without postoperative residual tumor remained in continuous complete remission. Conclusions: Our results confirm histology of MB variants as a strong prognostic factor in this age-group. Sustained tumor control and favorable survival rates can be achieved by this chemotherapy regimen in young children with desmoplastic / nodular MB variants. For children with non-desmoplastic / non-nodular MB variants, where predominantly local relapses lead to less favorable survival rates, local radiotherapy has been introduced after chemotherapy since 2006. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3463. doi:10.1158/1538-7445.AM2011-3463

Hepatocyte Growth Factor and Sonic Hedgehog Expression in Cerebellar Neural Progenitor Cells Costimulate Medulloblastoma Initiation and Growth

Medulloblastomas are malignant brain tumors that arise by transformation of neural progenitor cells in the cerebellum in children. Treatment-related neurotoxicity has created a critical need to identify signaling molecules that can be targeted therapeutically to maximize tumor growth suppression and minimize collateral neurologic injury. In genetically engineered mice, activation of Sonic Hedgehog (Shh) signaling in neural stem cells in the developing cerebellum induces medulloblastomas. Hepatocyte growth factor (HGF) and its cell surface receptor c-Met are highly expressed in human medulloblastomas, and elevated levels of c-Met and HGF mRNA predict an unfavorable prognosis for patients. HGF is neuroprotective for cerebellar granule cells and promotes growth of human medulloblastoma cells in culture and in murine xenografts. We modeled the ability of HGF to induce medulloblastomas in mice using a version of the RCAS/tv-a system that allows gene transfer to cerebellar neural progenitors during their postnatal expansion phase when these cells are highly susceptible to transformation. Here, we report a high frequency of medulloblastoma formation in mice after postnatal expression of HGF in cooperation with Shh. Some tumors showed neurocytic differentiation similar to that in human nodular medulloblastomas with activated Shh signaling. Systemic administration of a monoclonal antibody against HGF prolonged survival of mice bearing Shh + HGF-induced medulloblastomas by stimulating apoptosis. These findings indicate a role for HGF in medulloblastoma initiation and growth and show efficacy of HGF-targeted therapy in a mouse model of endogenously arising tumors.

Histologic Features and Prognosis in Pediatric Medulloblastoma

Because individual histologic features in childhood medulloblastoma alter survival likelihood, the recent 4th edition of the World Health Organization (WHO) Classification of Brain Tumors recognizes desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity, large cell medulloblastoma, and anaplastic medulloblastoma, in addition to medulloblastoma with no other distinguishing features. To identify features affecting survival likelihood, we investigated 33 histologic features in 556 childhood tumors diagnosed as medulloblastoma in the Childhood Brain Tumor Consortium (CBTC) database; all features have CBTC verified read-reread reliability and those features important in the classification of medulloblastoma and its WHO variants regardless of their measured reliability. Nineteen features had no effect on survival likelihood, and 8 features were too prevalent or too rare to measure their effect on survival. Nodules, balls, high cell density, and fine fibrillary stroma improved survival likelihood; necrosis and prominent nucleoli worsened survival likelihood. Of note, the presence of desmoplasia, currently a defining feature (along with nodules) for desmoplastic/nodular medulloblastoma, had no effect on survival likelihood. We conclude that the presence of nodularity in medulloblastoma is important to improved survival likelihood, particularly when combined with balls and fine fibrillary stroma. Given the "overlap" of desmoplastic/nodular medulloblastoma and nodular medulloblastoma, we suggest they be combined into a diagnosis of nodular medulloblastoma, with nodules, balls, and fine fibrillary stroma as defining criteria. We also suggest that because of the considerable overlap of anaplastic medulloblastoma and large cell medulloblastoma they be combined into 1 diagnosis of anaplastic/large cell medulloblastoma, with necrosis and prominent nucleoli among the defining criteria.

Hedgehog Signaling Promotes Medulloblastoma Survival via BclII

Activation of the Hedgehog (Hh) pathway has been identified in several cancers, including medulloblastoma, but the mechanisms by which this pathway affects tumor survival and growth are incompletely understood. We investigated whether Hedgehog might promote survival of medulloblastoma cells via up-regulation of BclII. We found that mRNA levels of the Hedgehog pathway effector Gli1 were significantly associated with BclII expression in medulloblastoma and that Gli1 and BclII are both present in regions of decreased apoptosis in nodular medulloblastoma. Transient overexpression of Gli1 and Gli2 in medulloblastoma cultures induced a BclII transcriptional reporter and increased BclII protein levels, whereas stable overexpression of Gli1 was associated with increased BclII mRNA. The Hedgehog antagonist cyclopamine blocked expression of the Hh pathway targets PTCH1 and Gli1, lowered BclII levels, and increased apoptosis in DAOY and UW228 medulloblastoma cells. Apoptotic induction caused by cyclopamine could be rescued in part by enforced expression of Gli1 or BclII. Hh pathway blockade also sensitized medulloblastoma to the effects of the proapoptotic agent lovastatin. These data demonstrate that BclII is an important mediator of Hh activity in medulloblastoma and suggest new strategies for combined chemotherapeutic regimens.

Subtype-specific expression and genetic alterations of the chemokinereceptor geneCXCR4 in medulloblastomas

Recent findings indicate that the chemokine receptor Cxcr4 is essential for normal development of the cerebellar cortex. As medulloblastomas (MBs), the most common malignant brain tumors of childhood, are believed to arise from neuronal cerebellar precursors, we asked whether there is a potential role for Cxcr4 in the pathogenesis of MB. RT-PCR and immunohistochemistry revealed expression of Cxcr4 in different variants of MBs. Whereas 18/20 classic MBs showed very low levels of CXCR4 mRNA, high amounts were expressed in 17/18 desmoplastic and 6/7 extensively nodular MBs. In addition, a significant correlation of high CXCR4 mRNA levels and presence of the neurotrophin receptor p75NTR or expression of ATOH1 and GLI1 suggests that CXCR4 is a reliable marker for tumors derived from the cerebellar external granular layer. Because Cxcr4 is important for migration and cell cycle control of granular precursors, we screened for mutations in the coding region by SSCP and gene sequencing. In a series of 90 MBs and 8 MB cell lines, we found one germline and one somatic mutation resulting in amino acid substitutions in the first (Ile53Leu) and second (Asp97Asn) transmembrane regions, respectively. These data suggest that Cxcr4 may be involved in the pathogenesis of MBs.

Apoptosis, Neuronal Maturation, and Neurotrophin Expression Within Medulloblastoma Nodules

Nodular/desmoplastic medulloblastomas are a well-established histopathological subtype containing reticulin-free nodules or "pale islands' that are comprised of cells with round "neurocytic" nuclei and abundant cytoplasm. Significant neuronal maturation occurs within nodules. We used immunohistochemistry to evaluate neuronal differentiation in the nodules of 6 of these tumors. The neuronal markers NeuN, synaptophysin, and MAP-2 were identified in the "pale islands" of all 6 nodular medulloblastomas examined, and high and medium molecular weight nonphosphorylated neurofilaments were detected in 2 of the 6 cases. We also observed collections of apoptotic cells within nodules. Given the known role of neurotrophin signaling in neuronal maturation and apoptosis, we analyzed immunohistochemically the distribution of neurotrophin receptors TrkA and TrkC and their primary ligands NGF and NT3 in 14 nodular medulloblastomas. TrkA and TrkC were detected in 13 and 10 cases, respectively, and were predominantly localized within nodules. NGF and NT3 were distributed diffusely with some nodular accentuation. The localized expression of Trk receptors within nodules of desmoplastic medulloblastomas suggests neurotrophin signaling is involved in the apoptosis and neuronal differentiation in medulloblastomas. We also examined expression of p53 and BCL-2 in these tumors; both were prominent in internodular regions but only weakly expressed within nodules. Trk receptors, p53, and BCL-2 are all expressed during development of the normal cerebellum. Interestingly, the immunohistochemical expression profile of these proteins in the differentiating nodules of medulloblastomas is in many ways similar to their expression in the developing cerebellum. Thus similar signaling pathways may be operational in cerebellar development and medulloblastoma tumor differentiation.