Hansford, Jordan R

Abstract Purpose: Knowledge of prognostic factors and long-term survival in patients with diffuse hemispheric glioma, H3 G34–mutant (DHG, H3 G34), remains limited in this tumor with a poor prognosis. Experimental Design: This retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34, and their association with progression-free survival (PFS) and overall survival (OS). Uni- and multivariable Cox proportional hazard models were applied with multiple imputed datasets. Results: A total of 153 patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. The median age at diagnosis was 17 years (range, 2–45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation), and initial chemotherapy was given in 87% [70% temozolomide-based (TMZ), 25% TMZ/lomustine, 5% non-TMZ]. Median OS was 24 months [interquartile range (IQR), 22–28] with a median PFS of 14 months (IQR, 12–19). Twelve patients (8%) were found to be long-term survivors (≥5 years). Exploratory multivariable analysis showed that adjuvant radiotherapy [HR, 0.076; 95% confidence interval (CI), 0.033–0.17] and achieving GTR/NTR compared with < NTR (HR, 0.51; 95% CI, 0.33–0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR, 0.70; 95% CI, 0.57–0.87), initial radiotherapy (HR, 0.38; 95% CI, 0.15–0.96), and initial GTR/NTR compared with < NTR (HR, 0.60; 95% CI, 0.37–0.97). Conclusions: This cohort highlights prognostic factors for patients with DHG, H3 G34, and describes relapse patterns and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.

Abstract Background Pineoblastoma is a rare brain tumor usually diagnosed in children. Given its rarity, no pineoblastoma-specific trials have been conducted. Studies have included pineoblastoma accruing for other embryonal tumors over the past 30 years. These included only occasional children with pineoblastoma, making clinical features difficult to interpret and determinants of outcome difficult to ascertain. Patients and Methods Centrally or independently reviewed series with treatment and survival data from North American and Australian cases were pooled. To investigate associations between variables, Fisher’s exact tests, Wilcoxon-Mann-Whitney tests, and Spearman correlations were used. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analyses. Results We describe a pooled cohort of 178 pineoblastoma cases from Children’s Oncology Group (n = 82) and institutional series (n = 96) over 30 years. Children <3 years of age have significantly worse survival compared to older children, with 5-year progression-free survival (PFS) and overall survival (OS) estimates of 13.5 ± 5.1% and 16.2 ± 5.3%, respectively, compared with 60.8 ± 5.6% and 67.3 ± 5.0% for ≥3 years old (both P < .0001). Multivariable analysis showed male sex was associated with worse PFS in children <3 years of age (hazard ratio [HR] 3.93, 95% CI 1.80-8.55; P = .0006), suggestive of sex-specific risks needing future validation. For children ≥3 years of age, disseminated disease at diagnosis was significantly associated with an inferior 5-year PFS of 39.2 ± 9.7% (HR 2.88, 95% CI 1.52-5.45; P = .0012) and 5-year OS of 49.8 ± 9.1% (HR 2.87, 95% CI 1.49-5.53; P = .0016). Conclusion Given the rarity of this tumor, prospective, collaborative international studies will be vital to improving the long-term survival of these patients.

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.