Gui, Chloe

Abstract Background Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response. Methods Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death within 3 years. Results Modern grading criteria, including brain invasion, TERT mutation, CDKN2A/B deletion, and 1p/1q status, would reclassify 10% of tumors and alter treatment group assignment in 7%. Non-responders to RT exhibited more frequent 1p and 14q loss, and more copy number alterations. Transcriptomic and epigenetic profiling revealed immune-related signatures in responders and cell cycle–related pathways in non-responders, several of which overlapped with targets of vorinostat, a histone deacetylase inhibitor previously validated in aggressive meningioma models. The Proliferative Molecular Group was an independent predictor of post-RT recurrence in multivariable analysis, outperforming WHO grade. Conclusion Multi-omic analysis of the NRG/RTOG-0539 cohort shows that updated WHO grading criteria, incorporating molecular and cytogenetic features, improve risk stratification. However, molecular classification, particularly the Proliferative group, remains an independent and stronger predictor of RT response. These findings support integrating molecular biomarkers alongside modern grading frameworks to guide treatment and trial design in meningioma. Clinical Trial Information NCT00895622.

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas arising from Schwann cells and characterized by marked cellular and molecular heterogeneity. Although bulk multi-omic studies have provided valuable insights into MPNST biology, recent advances in single-cell profiling have deepened our understanding of the tumor microenvironment and molecular mechanisms underlying malignant transformation. Single cell analyses have revealed distinct Schwann cell-like, malignant neural crest-like, immune, and stromal cellular subpopulations within MPNSTs and their precursor lesions. Comparative profiling of MPNSTs, neurofibromas, and atypical neurofibromatous neoplasms of uncertain biologic potential, suggest that MPNST progression involves Schwann cell dedifferentiation into a more primitive, stem-like state. In this review, we summarize key discoveries from single-cell characterization studies, and discuss how these findings illuminate MPNST tumorigenesis, cellular plasticity, and potential therapeutic vulnerabilities.

Abstract Background DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed. Methods We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade. Results We first demonstrated that all risk groups benefit from gross total resection. All “high-risk, RT sensitive” tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). “Low-risk, RT sensitive cases” (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither “low-risk RT resistant” (n = 84, 4.3%) nor “high-risk RT resistant” (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes. Conclusions We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas predominantly associated with neurofibromatosis type 1 (NF1). However, their occurrence within NF type 2 (NF2)–related and SMARCB1-related schwannomatosis remains rare and poorly characterized. Accurate and timely diagnosis is challenging due to clinical and radiological similarities with benign schwannomas, potentially delaying appropriate management and impacting outcomes. This study presents an institutional case series aiming to better characterize the clinical presentations specifically for MPNSTs arising in patients with NF2- and SMARCB1-related schwannomatosis. METHODS This retrospective case series included patients diagnosed with schwannomatosis who subsequently developed histopathologically confirmed MPNSTs. Conducted at Mayo Clinic (Rochester, Minnesota) and University Health Network (Toronto, Canada), the study spanned January 1, 2003, to November 1, 2024. Patients were selected based on clinical or genetic diagnoses of schwannomatosis using International Consensus Group on Neurofibromatosis Diagnostic Criteria. Comprehensive clinical, radiological, and pathological data, including demographics, presenting symptoms, tumor features (size, location, immunohistochemistry, genetics), treatments (resection, chemotherapy, radiotherapy), and follow-up outcomes were extracted from electronic medical records. RESULTS The authors identified 8 patients with a mean age of 36 years, half of whom had NF2-related schwannomatosis. The most common presenting symptom was pain (71%). The mean tumor size was 8.2 ± 7.0 cm, with gross-total resection being the most common surgical treatment (67%), typically supplemented with radiation therapy (78%). More than half of the patients (56%) exhibited metastatic disease, and all tumors with reported grading were Fédération Nationale des Centres de Lutte Contre le Cancer grade 3. No tumors were associated with LZTR1 mutations. One notable case involved a 39-year-old male with SMARCB1-related schwannomatosis who had a femoral MPNST resected 13 years prior and subsequently developed a sciatic nerve MPNST that was managed successfully with neoadjuvant chemotherapy, radiation therapy, and negative margin resection. Of note, the second lesion arose from a hybrid neurofibroma/schwannoma. Another case, a 33-year-old male with SMARCB1-related schwannomatosis, had an incidental finding of epithelioid MPNST in a minimally symptomatic small palmar lesion. CONCLUSIONS This case series highlights that MPNSTs, although uncommon, can arise in NF2- and SMARCB1-related schwannomatosis without prior radiation exposure, presenting significant diagnostic challenges due to their similarity to benign schwannomas. The findings underscore the importance of maintaining clinical vigilance and employing individualized management strategies, balancing thorough resection with the preservation of function and patient quality of life.