Pediatric neurosurgical medulloblastoma outcomes in La Paz, Bolivia: How a Lower Middle-Income Country (LMIC) institution in South America compares to the United States.

BACKGROUND: How pediatric medulloblastoma patients fare in Lower Middle-Income Country (LMICs) in South America is not well understood. Correspondingly, the aim of this study was to summarize the pediatric neurosurgical experience of an institution in La Paz, and compare outcomes to that of a generalized High Income Country (HIC) United States (US) experience. METHODS: A retrospective review of all pediatric neurosurgical medulloblastoma patients at the Children's Hospital of La Paz, Bolivia (Hospital del Niño "Dr. Ovidio Aliaga Uria") between 2014 and 2023 was conducted and compared to a generalized US experience abstracted from the US National Cancer Database (NCDB) and National Inpatient Sample (NIS) databases. Categorical, continuous and survival data were statistically summarized and compared. RESULTS: A total of 24 pediatric medulloblastoma patients underwent neurosurgical treatment at the Hospital del Niño. In this La Paz cohort, there were 15 (63%) males and 9 (38%) females, with a mean age of 5.6 years old at diagnosis. The majority of patients underwent subtotal resection (STR, 79%), while the remaining patients underwent biopsy only. Ten (42%) patients expired during their hospitalization, and mean length of stay overall was 39 days. Only 8 (33%) patients received adjuvant treatment after surgery. Median overall survival from diagnosis in the La Paz cohort was 1.9 months. Compared to the US databases, the La Paz cohort experienced significantly more emergency room admissions for surgery, less gross total resection, more STR, more return to operating room for ventriculoperitoneal shunting, more bacteremia, more tracheostomy procedures, more percutaneous gastrostomy placements, longer lengths of stay, less adjuvant chemotherapy, less radiation therapy, shorter follow-up, and ultimately, significantly shorter overall survival (all P < 0.050). CONCLUSIONS: Pediatric neurosurgical medulloblastoma outcomes at the Children's Hospital of La Paz, Bolivia are significantly inferior to that of a generalized US experience. Future research is required to identify institution- and country-specific initiatives to improve discrepancies between institutions in LMICs in South America compared to HICs.

Survival-Related Genes on Chromosomes 6 and 17 in Medulloblastoma.

Survival of Medulloblastoma (MB) depends on various factors, including the gene expression profiles of MB tumor tissues. In this study, we identified 967 MB survival-related genes (SRGs) using a gene expression dataset and the Cox proportional hazards regression model. Notably, the SRGs were over-represented on chromosomes 6 and 17, known for the abnormalities monosomy 6 and isochromosome 17 in MB. The most significant SRG was HMGA1 (high mobility group AT-hook 1) on chromosome 6, which is a known oncogene and a histone H1 competitor. High expression of HMGA1 was associated with worse survival, primarily in the Group 3γ subtype. The high expression of HMGA1 was unrelated to any known somatic copy number alteration. Most SRGs on chromosome 17p were associated with low expression in Group 4ß, the MB subtype, with 93% deletion of 17p and 98% copy gain of 17q. GO enrichment analysis showed that both chromosomes 6 and 17 included SRGs related to telomere maintenance and provided a rationale for testing telomerase inhibitors in Group 3 MBs. We conclude that HMGA1, along with other SRGs on chromosomes 6 and 17, warrant further investigation as potential therapeutic targets in selected subgroups or subtypes of MB.

Subgroup and subtype-specific outcomes in adult medulloblastoma.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.

Validated quantitative needs assessment differences in the management of children with central nervous system cancer between Brazil, an upper middle-income country, and the United States of America, a high income country.

BACKGROUND: Pediatric cancer cure rates differ among high-income countries (HIC) and upper middle-income countries (UMIC). We have compared individual capacities of two major referral pediatric centers from a HIC and an UMIC caring for children with central nervous system (CNS) cancer. METHODS: A quantitative needs assessment questionnaire and key informant interviews, distributed in March of 2017, were used to evaluate the treatment of children with CNS cancer at Grupo de Apoio ao Adolescente e à Criança com Câncer (GRAACC) children's cancer center in São Paulo, Brazil and Nationwide Children's Hospital (NCH) in Columbus, Ohio, United States of America (USA). RESULTS: Both hospitals had 24-hour pediatric oncology, nursing and intensivist coverage. Supportive care available at both institutions included social workers, psychologists, child life specialists, and physical/occupational/speech therapists. Differences included two part-time neuroradiologists and one pathologist specializing in neuropathology at IOP/GRAACC/UNIFESP, whereas eight full-time neuroradiologists and two neuropathologists at NCH/OSU. There were four pediatric neurosurgeons on staff at each hospital; however, there were only 2 operative days per week at IOP/GRAACC/UNIFESP, compared with 7 days at NCH/OSU. Additionally, time to initiation of radiation therapy at IOP/GRAACC/UNIFESP extended 2-4 weeks compared with less than 1 week at NCH/OSU. CONCLUSIONS: Center-specific differences in resources exist in highly specialized hospitals caring for children with CNS cancer in HIC and UMIC. This quantitative needs assessment may facilitate the development of targeted strategies for effective interventions to improve on the management of children with CNS cancers.

Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy.

Central nervous system (CNS) tumors are the most common solid tumor in pediatrics, accounting for approximately 25% of all childhood cancers, and the second most common pediatric malignancy after leukemia. CNS tumors can be associated with significant morbidity, even those classified as low grade. Mortality from CNS tumors is disproportionately high compared to other childhood malignancies, although surgery, radiation, and chemotherapy have improved outcomes in these patients over the last few decades. Current therapeutic strategies lead to a high risk of side effects, especially in young children. Pediatric brain tumor survivors have unique sequelae compared to age-matched patients who survived other malignancies. They are at greater risk of significant impairment in cognitive, neurological, endocrine, social, and emotional domains, depending on the location and type of the CNS tumor. Next-generation genomics have shed light on the broad molecular heterogeneity of pediatric brain tumors and have identified important genes and signaling pathways that serve to drive tumor proliferation. This insight has impacted the research field by providing potential therapeutic targets for these diseases. In this review, we highlight recent progress in understanding the molecular basis of common pediatric brain tumors, specifically low-grade glioma, high-grade glioma, ependymoma, embryonal tumors, and atypical teratoid/rhabdoid tumor (ATRT). © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Histologic Correlates of Molecular Group 4 Pediatric Medulloblastoma: A Retrospective Canadian Review.

INTRODUCTION: The World Health Organization currently classifies medulloblastoma (MB) into four molecular groups (WNT, SHH, Group 3 and Group 4) and four histologic subtypes (classic, desmoplastic nodular, MB with extensive nodularity, and large cell/anaplastic). "Classic" MB is the most frequent histology, but unfortunately it does not predict molecular group or patient outcome. While MB may exhibit additional histologic features outside of the traditional WHO subtypes, the clinical significance of such features, in a molecular context, is unclear. METHODS: The clinicopathologic features of 120 pediatric MB were reviewed in the context of NanoString molecular grouping. Each case was evaluated for five ancillary histologic features, including: nodularity without desmoplasia (i.e., "biphasic", B-MB), rhythmic palisades, and focal anaplasia. Molecular and histological features were statistically correlated to clinical outcome using Chi-square, log-rank, and multivariate Cox regression analysis. RESULTS: While B-MB (N = 32) and rhythmic palisades (N = 12) were enriched amongst non-WNT/SHH MB (especially Group 4), they were not statistically associated with outcome. In contrast, focal anaplasia (N = 12) was not associated with any molecular group, but did predict unfavorable outcome. CONCLUSION: These data nominate B-MB as a surrogate marker of Groups 3 and particularly 4 MB, which may earmark a clinically significant subset of cases.

Adjuvant chemotherapy in average-risk adult medulloblastoma patients improves survival: a long term study.

BACKGROUND: Medulloblastoma is extremely rare in adults. The role of chemotherapy for average-risk adult patients remains controversial. Surgery and radiotherapy provide a significant disease control and a good prognosis, but about 25% of average-risk patients have a relapse and die because of disease progression. No data in average-risk adult patients are available to compareradiotherapy alone and radiotherapyfollowed byadjuvant chemotherapy. METHODS: We analyzed 48 average-risk patients according to Chang classification diagnosed from 1988 to 2016. RESULTS: Median age was 29 years (range 16-61). Based on histological subtypes, 15 patients (31.3%) had classic, 15 patients (31.3%) had desmoplastic, 5 patients (10.4%) had extensive nodularity and 2 patients (4.2%) had large cells/anaplastic medulloblastoma. Twenty-four patients (50%) received adjuvant radiotherapy alone and 24 (50%) received radiotherapy and chemotherapy. After a median follow-up of 12.5 years, we found that chemotherapyincreases progression-free survival (PFS-15 82.3 ± 8.0% in patients treated with radiotherapy and chemotherapyvs. 38.5% ± 13.0% in patients treated with radiotherapy alone p = 0.05) and overall survival (OS-15 89.3% ± 7.2% vs. 52.0% ± 13.1%, p = 0.02). Among patients receiving chemotherapy, the reported grade ≥ 3 adverse events were: 9 cases of neutropenia (6 cases of G3 neutropenia [25%] and 3 cases of G4 neutropenia [13%]), 1 case of G3 thrombocytopenia (4%) and 2 cases of G3 nausea (8%). CONCLUSIONS: Our study with a long follow up period suggests that adding adjuvant chemotherapy to radiotherapy might improve PFS and OS in average-risk adult medulloblastoma patients.

Reduced-volume tumor-bed boost is not associated with inferior local control and survival outcomes in high-risk medulloblastoma.

BACKGROUND: Radiotherapy boost to the entire posterior fossa (PF) is standard of care for high-risk (H-R) medulloblastoma patients; the utility of tumor bed (TB)-only boost is unclear. The purpose of this study was to examine the impact of PF versus TB boost volume on tumor control and survival in the H-R medulloblastoma population. METHODS: Single-institution records for patients with H-R medulloblastoma were reviewed. The median craniospinal irradiation dose was 36 Gy (range, 23.4-45 Gy), and boost doses to either PF or TB were 54 to 55.8 Gy. PF (local) failures were scored as in-field, marginal (between 80% and 95% isodose lines), or distant. Kaplan-Meier methods and Cox proportional hazards were used to assess the impact of radiation boost technique on local control (LC) and survival endpoints. RESULTS: Thirty-two patients with H-R medulloblastoma were treated between 1990 and 2015, with a median follow-up length of 5.12 years. Twenty-two patients received PF boost, and 10 received TB boost. Patient and disease characteristic were comparable between groups. A total of 11 PF failures occurred, including 3 isolated LFs (2 in the PF and 1 in the TB group). Most PF failures were in-field: three of four in the TB group and six of seven in the PF group; the remainder were marginal failures. TB boost was not associated with inferior LC (hazard ratio [HR] 0.86, log-rank P = 0.81) or overall survival (HR 1.40, P = 0.56) compared with PF boost. CONCLUSION: Reduced-volume radiotherapy boost to the TB does not appear to compromise LC or survival in patients with H-R medulloblastoma; it may reduce the risk of ototoxicity.

Prolongation of radiotherapy duration is associated with inferior overall survival in patients with pediatric medulloblastoma and central nervous system primitive neuroectodermal tumors.

BACKGROUND: The importance of radiotherapy (RT) duration in medulloblastoma in the modern era of chemotherapy has not been well elucidated. The aim of this study was to determine the impact of RT treatment duration on overall survival (OS) in pediatric medulloblastoma and cenral nervous system neuroectodermal tumors (PNETs). METHODS: The National Cancer Database (NCDB) was queried to identify patients with newly diagnosed medulloblastoma and CNS PNETs diagnosed between 2004 and 2014. Patients were excluded if they had extraneural metastasis, did not receive standard craniospinal irradiation dose, had a nonstandard total dose outside of 54 or 55.8 Gy, did not receive adjuvant chemotherapy, or if the RT duration was outside of the expected range of 37 to 80 days. The Kaplan-Meier estimator was used to estimate the association between RT duration (≤45 days or >45 days) and OS. Multivariate Cox regression was used to assess other confounders of OS. RESULTS: Six-hundred twenty-five patients met inclusion criteria, of which 181 were assigned to the "RT long" (>45 days) cohort (29.0%) and 444 (71.0%) to the "RT short" group (≤45 days). The five-year OS for the "RT short" compared with "RT long" cohort was 82.2% versus 70.9%, respectively (log-rank, P < 0.0037). For average risk patients, the five-year OS was 84.6% versus 86.4% for "RT short" and "RT long," respectively (log-rank, P = 0.40). However, for high-risk patients, five-year OS was 77.7% versus 51.0% (log-rank, P < 0.0001) in the "RT short" and "RT long" cohorts. CONCLUSION: For patients with high-risk medulloblastoma and CNS PNETs, RT duration >45 days was associated with inferior OS.

Development of second primary tumors and outcomes in medulloblastoma by treatment modality: A Surveillance, Epidemiology, and End Results analysis.

BACKGROUND: As treatment modalities for medulloblastoma have developed and overall survival (OS) has improved, there are relatively limited data on the impact of long-term effects such as risk of second primary tumors (SPT). To address the knowledge gap, we analyzed factors associated with the risk of SPT and OS by treatment modality for medulloblastoma. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER)-18 database for patients diagnosed with medulloblastoma in 1973-2014. Patients were then grouped by age, gender, race, geographic region, histology, adjuvant treatment (no radiation [RT] and no chemotherapy [CT], RT and CT, RT alone, or CT alone), era of diagnosis (1973-1994 or 1995-2014), and survival time. Cumulative incidence, factors associated with SPT and OS were analyzed. RESULTS: Of 2271 patients, 146 developed SPT, of which 42 were benign. The incidence of SPT was 3.1% and 4.9% at 10 and 15 years, respectively. The incidence of SPT was 3.1% with RT + CT versus 3.7% with RT alone at 10 years. The most common site for an SPT was the central nervous system. Female gender (P = 0.01) and longer OS of ≥21 years (P < 0.01) were associated with higher risk of SPT. RT + CT led to better OS than RT only (66.1% and 61.4% vs 55.6% and 49.7% at 10 and 15 years) (P < 0.01). CONCLUSIONS: Medulloblastoma patients have a relatively low risk of SPT at 10 years with treatment. Use of RT + CT led to better OS with no statistical difference in SPT compared with the RT alone.

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics.

Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.

Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes.

In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I-VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.

Desmoplastic/nodular medulloblastomas (DNMB) and medulloblastomas with extensive nodularity (MBEN) disclose similar epigenetic signatures but different transcriptional profiles.

Desmoplastic/nodular medulloblastomas (DNMB) and medulloblastomas with extensive nodularity (MBEN) were outlined in the current WHO classification of tumors of the nervous system as two distinct histological MB variants. However, they are often considered as cognate SHH MB entities, and it is a reason why some clinical MB trials do not separate the patients with DNMB or MBEN histology. In the current study, we performed an integrated DNA/RNA-based molecular analysis of 83 DNMB and 36 MBEN to assess the etiopathogenetic relationship between these SHH MB variants. Methylation profiling revealed "infant" and "children" SHH MB clusters but neither DNMB nor MBEN composed separate epigenetic cohorts, and their profiles were intermixed within the "infant" cluster. In contrast, RNA-based transcriptional profiling disclosed that expression signatures of all MBEN were clustered separately from most of DNMB and a set of differentially expressed genes was identified. MBEN transcriptomes were enriched with genes associated with synaptic transmission, neuronal differentiation and metabolism, whereas DNMB profiling signatures included sets of genes involved in phototransduction and NOTCH signaling pathways. Thus, DNMB and MBEN are distinct tumor entities within the SHH MB family whose biology is determined by different transcriptional programs. Therefore, we recommend a transcriptome analysis as an optimal molecular tool to discriminate between DNMB and MBEN, which may be of benefit for patients' risk stratification in clinical trials. Molecular events identified in DNMB by RNA sequencing could be considered in the future as potent molecular targets for novel therapeutic interventions in treatment-resistant cases.

Outcomes of salvage re-irradiation in recurrent medulloblastoma correlate with age at initial diagnosis, primary risk-stratification, and molecular subgrouping.

PURPOSE: To report outcomes of salvage re-irradiation (re-RT) in recurrent/progressive medulloblastoma (MB). METHODS: Medical records of patients treated with curative-intent re-RT as multi-modality management for recurrent/progressive MB between 2008 and 2018 were analyzed retrospectively. RESULTS: A total of 28 patients (median age 18 years at index diagnosis) were included. Molecular subgrouping was done using real-time reverse transcriptase polymerase chain reaction (RT-PCR) based on the differential expression of select set of 12 protein coding genes and 9 microRNAs. Fifteen of 17 (88%) patients with sonic hedgehog (SHH)-MB developed isolated local recurrence within the index tumor-bed, while 5 of 7 (72%) patients with Group 4 MB developed localized relapse outside the posterior fossa. Diffuse neuraxial dissemination was seen in 2 patients with SHH-MB, and one each of Group 4 and wingless (WNT)-MB. Molecular subgrouping was not known in 3 patients. The dose and volume of re-RT was based on site and patterns of relapse, comprising unifocal in 18 (64%), multi-focal in 3 (11%), and repeat craniospinal irradiation (re-CSI) in 7 (25%) patients. Median interval from primary irradiation to re-RT was 49.5 months (range 24-98 months) with median cumulative biologically effective dose of 117 Gy (range 78-132 Gy). All patients received platinum-based salvage chemotherapy either before or after re-RT. One patient developed symptomatic radiation necrosis following re-CSI. At a median follow-up of 24 months (range 6-84 months), 2-year post-re-RT progression-free survival (PFS) and overall survival (OS) was 46% and 51% respectively. Younger age (< 18 years) at index diagnosis, primary risk stratification (standard-risk) and molecular subgrouping (Group 4) were associated with significantly better post-re-RT outcomes. CONCLUSION: Salvage re-RT provides good local control and encouraging survival outcomes with acceptable toxicity in selected patients with recurrent/progressive MB.

Children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor in Norway from 1974 through 2013: Unexplainable regional differences in survival.

BACKGROUND: A previous study based on Norwegian Cancer Registry data suggested regional differences in overall survival (OS) after treatment for medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET) in Norway. The purpose of the present study was to confirm in an extended cohort whether there were regional differences in outcome or not, and if so try to identify possible explanations. MATERIAL AND METHODS: Data from patients aged 0-20 years diagnosed with and treated for MB/CNS-PNET at all four university hospitals in Norway from 1974 to 2013 were collected and compared. RESULTS: Of 266 identified patients, 251 fulfilled inclusion criteria. MB was diagnosed in 200 and CNS-PNET in 51 patients. Five-year OS and event-free survival (EFS) were 59% and 52%, respectively. There was a significant difference in five-year OS and EFS between MB and CNS-PNET patients; 62% versus 47% (P =  0.007) and 57% versus 35% (P < 0.001). In multivariable analysis, two factors were found to significantly contribute to improved five-year OS and EFS, whereas one factor contributed to improved five-year OS only. Gross total resection (GTR) versus non-GTR (hazard ratio [HR] 0.53, P =  0.003; HR 0.46, P < 0.001) and cerebrospinal irradiation (CSI) versus non-CSI (HR 0.24, P < 0.001; HR 0.28, P < 0.001) for both, and treatment outside Oslo University Hospital for OS only (HR 0.64, P =  0.048). CONCLUSION: Survival was comparable with data from other population-based studies, and the importance of GTR and CSI was confirmed. The cause for regional survival differences could not be identified.

Updates on Management of Adult Medulloblastoma.

OPINION STATEMENT: Medulloblastoma (MB) is a malignant embryonal tumor of the posterior fossa and is the most common type of brain cancer in pediatric patients. In contrast, adult MB is very rare with an incidence of 0.6 per million per year and mostly affects young adults below the age of 40. Recent molecular analyses of pediatric and adult MB have classified these tumors into at least four individual molecular subgroups (SHH, WNT, group 3, and group 4) with distinct demographics, histology, and prognosis. The discrete biological composition of these tumors likely explains the marked heterogeneity in responses seen to conventional therapies such as radiation and cytotoxic chemotherapies. Given the low incidence of adult MB, prospective studies are challenging and scarce, and management guidelines are largely derived from the pediatric MB patient population and retrospective data. However, adult MB is clinically and molecularly distinct from pediatric MB and a comprehensive review of published literature on adult MB highlighting their differences is warranted. Here, we review the management of adult MB focusing on recent studies exploring the effectiveness of upfront chemotherapy, clinical trials in the context of molecular subgroup-specific therapies, and the potential role of immunotherapy in treating this disease.

Pediatric Patients With SHH Medulloblastoma Fail Differently as Compared With Adults: Possible Implications for Treatment Modifications.

PURPOSE: The purpose of this work was to study the diversity of sonic hedgehog (SHH) medulloblastoma across different age groups with an emphasis on patterns of relapse. METHODS: All data for the study were obtained through review of medical records, imaging, radiation charts, treatment planning, and chemotherapy details. RESULTS: Sixty-three patients with SHH medulloblastoma were identified from a prospectively maintained database and classified into 3 groups-infantile: ≤3 years (i-SHH, n=11); pediatric: >3 to <18 years (p-SHH, n=21); and adult: ≥18 years (a-SHH; n=31). Lateralized tumors were common with increasing age (81% a-SHH, 67% p-SHH, 27% i-SHH; P=0.01). Large cell anaplastic histology was relatively common for p-SHH (33%), while the nodular/desmoplastic variant was more frequent in i-SHH (64%) and adults (51%). Median follow-up was 38 months (range, 5 to 91 mo). Five-year event-free survival was 80%, 31%, and 52% for i-SHH, p-SHH, and a-SHH, respectively (P=0.001). Median time to failure for p-SHH and a-SHH were 12 and 36 months, respectively. For p-SHH, 83% were metastatic relapses compared with localized failure in 75% for a-SHH. Five-year overall survival for i-SHH, p-SHH, and a-SHH were 91%, 31%, and 70%, respectively (P=0.001). On univariate analysis, event-free survival was significantly worse for superiorly located tumors (P=0.01), nondesmoplastic histology (P=0.02), and histology alone for overall survival (P=0.04) (none on multivariate analysis). CONCLUSIONS: SHH medulloblastoma demonstrates varied outcomes depending on age, with p-SHH associated with early and metastatic relapses, while for a-SHH it tends to be delayed and localized.

Salvage Therapy for Childhood Medulloblastoma: A Single Center Experience.

INTRODUCTION: Children diagnosed with medulloblastoma (MB) who are refractory to upfront therapy or experience recurrence have very poor prognoses. Although phase I and phase II trials exist, these treatments bear significant treatment-related morbidity and mortality. METHODS: A retrospective review of children diagnosed with a recurrence of MB from 2002 to 2015 at McMaster University was undertaken. RESULTS: Recurrent disease in 10 patients involved leptomeningeal dissemination, with 3 experiencing local recurrence. In three recurrent patients the disease significantly progressed, and the children were palliated. The remaining 10 children underwent some form of salvage therapy, including surgical re-resection, radiation, and chemotherapy, either in isolation or in varying combinations. Of the 13 children experiencing treatment-refractory or recurrent disease, 4 are currently alive with a median follow-up of 38.5 months (75.5 months). Of the eight patients with molecular subgrouping data, none of the Wnt MB experienced recurrence. CONCLUSION: Recurrent MB carried a poor prognosis with a 5-year overall survival (OS) of 18.2% despite the administration of salvage therapy. The upfront therapy received, available treatment, and tolerability of the proposed salvage therapy resulted in significant heterogeneity in the treatment of our recurrent cohort.

Traitement de sauvetage dans le cas du médulloblastome chez l'enfant : une expérience menée au sein d'un établissement hospitalier. Introduction: Les enfants chez qui l'on a diagnostiqué un médulloblastome réfractaire à un traitement initial ou qui sont victimes d'une récidive présentent d'habitude des pronostics de guérison vraiment défavorables. Bien qu'il existe des traitements basés sur des essais cliniques de phases I et II, ces traitements ont tendance à produire des taux notables de morbidité et de mortalité. Méthodes: Nous avons ainsi mené à l'Université McMaster une analyse rétrospective des dossiers d'enfants chez qui l'on avait diagnostiqué entre 2002 et 2015 une récidive de médulloblastome. Résultats: La réapparition de cette maladie chez 10 patients a provoqué un phénomène de diffusion leptoméningée, trois d'entre eux étant victimes d'une récidive locale. Sur ces 10 jeunes patients, la maladie a progressé de façon importante : ces enfants ont alors été transférés aux soins palliatifs. Quant aux autres 10 enfants, ils ont subi un certain type de traitement de sauvetage (des résections chirurgicales, de la radiothérapie, de la chimiothérapie), que ce soit de façon exclusive ou en variant les combinaisons possibles. Sur les 13 enfants réfractaires à un traitement initial ou victimes d'une récidive, 4 sont toujours en vie, leur suivi médian ayant été de 38,5 mois (75,5 mois). Sur les 8 patients pour qui on a pu obtenir des données moléculaires, aucun de ceux qui étaient atteints d'un médulloblastome du sous-type Wnt n'a connu de récidive. Conclusion: Les médulloblastomes qui réapparaissent après une période de guérison complète présentent un pronostic de guérison défavorable. Leur taux de survie globale est en effet de 18,2 % au cours d'une période de 5 ans, et ce, même après avoir bénéficié d'un traitement de sauvetage. Ajoutons aussi que le type de traitement initial reçu, la disponibilité des traitements ainsi que la tolérance à l'égard des traitements de sauvetage proposés a entraîné une grande hétérogénéité dans le traitement de ces jeunes patients victimes d'une récidive.

Childhood medulloblastoma-a single institution's historical perspective on survival and functional morbidity.

PURPOSE: 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. METHODS: Review of neuro-oncology and imaging databases and previously published results. 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 risk < 3 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 risk < 3 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). CONCLUSIONS: 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.

Radiosurgery or hypofractionated stereotactic radiotherapy after craniospinal irradiation in children and adults with medulloblastoma and ependymoma.

PURPOSE: To assess the results and tolerance of radiosurgery/hypofractionated stereotactic radiotherapy performed after craniospinal irradiation for recurrent tumor. METHODS: Fourteen patients aged 3-46 years, diagnosed with medulloblastoma (10), anaplastic ependymoma (3), and primitive neuroectodermal tumor (1). All patients had craniospinal irradiation (CSI) with the total dose of 30.6-36 Gy and boost to 53.9-60 Gy either during primary or during second-line treatment. Twelve patients were irradiated with a single dose of 6-15 Gy (median 14.5 Gy). One received three fractions of 5 Gy and one six fractions of 5 Gy. In statistical analysis, the Kaplan-Meier method and log-rank test were used. The overall survival was calculated from the date of the end of stereotactic radiosurgery to the date of death or last contact. RESULTS: Recurrences were diagnosed after the median time of 16 months after the end of primary treatment. Eleven patients died during the follow-up. The follow-up for the 3 patients still alive was 6.7, 40.5, and 41.4 months, respectively. One- and 2-year overall survival (OS) was 70% and 39%. Patients who had ECOG performance status of 0 at the time of diagnosis of the disease trended to have better 2-year OS compared to those evaluated as ECOG 1 (p = 0.057). Treatment results were evaluable in 12 patients. Local control (stabilization or regression of the lesion) was achieved in 9 (75%). Overall disease progression was 67%. No patient developed radiation-induced necrosis. The treatment was well tolerated and no serious adverse effects were observed. Eleven patients were given steroids as a prevention of brain edema and four of them needed continuation of this treatment afterwards. In 7 patients, symptoms of brain edema were observed during the first weeks after reirradiation. CONCLUSIONS: Stereotactic radiosurgery or hypofractionated stereotactic radiotherapy is an effective treatment method of the local recurrence after CSI and can be performed safely in heavily pre-treated patients.