Sturm, Dominik

Abstract Embryonal tumors with multilayered rosettes (ETMR) are rare, highly aggressive tumors of infancy with extremely poor outcomes and no established standard of care therapy. ETMRs were recognized as a distinct molecular entity in 2016, however, the absence of prospective, biology-driven clinical trials has limited translation of these insights into standardized, risk-adapted treatment approaches for this vulnerable population. To address this gap, the Collaborative Network for Neuro-oncology Clinical Trials (CONNECT) developed CURE(Clinical trial advancing Understanding of Rare Embryonal Brain Tumors), an international, multi-institutional, molecularly guided umbrella trial. All patients enroll through the centralized CURE-Screening protocol, which provides rapid comprehensive molecular profiling with real-time central pathology, molecular, and radiographic review to confirm diagnosis, define molecular subtype, and determine eligibility and assignment to disease-specific treatment arms. CURE-ETMR represents the first disease-specific arm to open within this platform. Following centralized screening, children with newly diagnosed ETMR are assigned to clinically defined risk strata using integrated molecular, radiographic, and clinical criteria. Patients will be treated using a risk-adapted multimodal approach in which we prioritize maximal safe surgical resection with consideration of second-look surgery based on centralized imaging review; administer induction chemotherapy followed by consolidation with high-dose chemotherapy and autologous hematopoietic cell rescue or dose-intensified chemotherapy, selectively incorporate radiation sparing approach or early focal radiotherapy for patients with unresectable residual disease or brainstem involvement; deliver intrathecal chemotherapy for leptomeningeal prophylaxis; and include biologically informed maintenance therapy. In parallel, protocol-required longitudinal collection of tumor tissue, cerebrospinal fluid, blood, and advanced neuroimaging supports integrated molecular, liquid biopsy, and imaging biomarker analyses to identify predictors of treatment response, resistance, and relapse. Primary objectives include evaluation of feasibility, safety, progression-free survival, and overall survival compared with molecularly annotated historical cohorts. This centralized screening to assignment framework establishes a scalable model for prospective, biology-driven trials in rare embryonal brain tumors.

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 Astroblastomas are rare brain tumors predominantly affecting children and young adults, for which molecular subtypes and clinical management remain undefined. Methods We analyzed tumor samples, molecular profiles, and clinical data from 200 patients, classified as “Astroblastoma, MN1-altered” under WHO criteria, using DNA methylation profiling, DNA/RNA profiling/sequencing, and survival analyses. Results DNA methylation analyses identified 3 groups: Group A (n = 143, characterized by MN1::BEND2 fusions, predominantly supratentorial location, with striking female predominance and favorable survival); Group B (n = 37, epigenetically and transcriptionally closely related to Group A, but characterized by EWSR1::BEND2 fusions, with spinal and infratentorial locations and poor prognosis); and Group C (n = 20, epigenetically and transcriptionally distinct, characterized by MN1::CXXC5 fusions, exclusively supratentorially located, with favorable survival). Progression-free and overall survival were significantly shorter in Group B (5-year PFS 14%; 10-year OS 54%) compared to A (5-year PFS 47%; 10-year OS 89%) and C (5-year PFS 75%; 10-year OS 89%). Radiotherapy improved PFS in Group B (hazard ratio 0.25), while no clear benefit was identified for Groups A and C. Conclusions Astroblastoma, MN1-altered, comprises 3 molecularly and clinically distinct groups, characterized by different fusion genes, including those without MN1. These new insights, including the identification of potential predictive biomarkers like 14q/16q loss, provide a framework for the development of risk-stratified therapeutic approaches. Importantly, we identified a molecularly defined high-risk group that benefits from radiation therapy. Our findings redefine Astroblastoma as a molecularly diverse tumor type, propose a refined classification, support the development of risk-adapted therapeutic strategies and provide a rational standard of care.