大場 茂生

BRAF p.V600E-mutant gliomas and glioneuronal tumors comprise a wide clinicopathological spectrum, yet the relationship between genomic alteration burden and histological grade remains incompletely defined. We analyzed 15 BRAF p.V600E-mutant gliomas and glioneuronal tumors across histological grades using the PleSSision Rapid sequencing platform. Single-nucleotide variants (SNVs) and copy-number alterations were assessed in parallel to characterize genomic alteration profiles. Low-grade tumors generally exhibited limited genomic alterations; however, a subset of low-grade tumors showed increased numbers of SNVs. High-grade tumors demonstrated more extensive genomic alterations, characterized predominantly by copy-number gains. A trend toward increased copy-number gains with higher WHO grade was observed. Homozygous deletion of CDKN2A was observed in pleomorphic xanthoastrocytoma, including both CNS WHO grade 2 and grade 3 tumors, and epithelioid glioblastoma. These findings indicate substantial genomic heterogeneity among BRAF p.V600E-mutant gliomas and glioneuronal tumors. While low-grade tumors are generally genomically quiet, a subset shows increased alterations, and high-grade tumors tend to acquire copy-number changes, highlighting the limitations of genomic event counts alone as a surrogate for malignant potential.

OBJECTIVE: Central nervous system (CNS) solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms with a high propensity for local recurrence and extracranial metastasis. Although surgery and radiotherapy are the mainstays of treatment, systemic therapeutic options for recurrent disease remain limited. Pazopanib, a multitargeted tyrosine kinase inhibitor, has demonstrated clinical activity in extracranial SFTs; however, evidence in CNS SFTs is scarce. METHODS: We conducted a retrospective, single-institution study of patients with recurrent CNS SFTs treated with pazopanib. Clinical data, including prior treatments, imaging responses, treatment duration, and adverse events, were collected from medical records. Exploratory next-generation sequencing-based cancer panel testing was performed in two patients. RESULTS: Four patients with recurrent CNS SFTs were included. All had undergone prior surgical resection and radiotherapy. Pazopanib achieved partial response in one patient and stable disease in three patients, with treatment durations ranging from 7 months to over 2 years. One patient experienced disease progression after an initial period of response. Adverse events, including fatigue, gastrointestinal symptoms, and hypertension, were observed in all patients but were generally manageable with supportive care or dose adjustment. Exploratory molecular profiling identified various genomic alterations in two patients. CONCLUSIONS: In this single-institution retrospective series, pazopanib provided durable disease control with acceptable tolerability in selected patients with recurrent CNS SFTs. These findings support considering pazopanib as a systemic treatment option when further local therapies are not feasible, while highlighting the need for larger multicenter studies.

Abstract Differentiating pseudoprogression (PsP) from recurrence in cases of glioblastoma (GBM) after chemoradiotherapy is challenging, with neuroimaging as the only non-invasive method. In this study, we aimed to identify a blood biomarker for precise disease monitoring and investigated the role of Ataxin-2 (ATXN2). Blood samples (n = 45) from patients with suspected recurrence, including eight with PSP, were analyzed. In addition, tumor tissue samples (n = 22), including those from seven patients who also provided blood samples, were examined. Protein levels were assessed using quantitative proteomics and ELISA. ATXN2 levels were measured via western blotting, and localization was determined through immunohistochemistry and immunocytochemistry. ATXN2 knockdown was performed in glioma cell lines to assess its effects on proliferation, migration, and invasion. Proteomics identified ATXN2 as a potential biomarker. ELISA showed significantly higher serum ATXN2 levels in recurrence than in PsP (p = 0.028). ATXN2 ≥ 11.0 ng/mL and ≥ 8 months post-chemoradiotherapy distinguished recurrence from PsP (AUC = 0.82, sensitivity = 67.6%, specificity = 87.5%). ATXN2 was highly expressed in GBM tissues, localized in neurons and glioma cells, and its knockdown enhanced proliferation, migration, and invasion via ERK phosphorylation. ATXN2, highly expressed in GBM, may serve as a potential blood biomarker for distinguishing PsP from recurrence.

Compared to oligodendrogliomas, astrocytomas may have a relatively higher frequency of intracranial remote recurrence, despite generally favorable prognoses. Previous studies identified 8q gain, particularly in the terminal region, as a poor prognostic factor. This study evaluated MYC expression and its relationship with copy number gain at 8q24.21, in relation to recurrence patterns in astrocytomas, with a particular focus on intracranial remote recurrence. A retrospective analysis was conducted on 27 patients treated between 2006 and 2019. MYC expression was assessed by immunohistochemistry (IHC), and copy number status by metaphase comparative genomic hybridization and next-generation sequencing. Recurrence patterns were categorized as local or remote.Among 43 specimens analyzed by IHC, MYC expression was observed in 72%, with higher positivity in recurrent (80%) than initial (61%) specimens, though the difference was not statistically significant (p = 0.30). Copy number analysis showed a significant increase in 8q24.21 copy number in specimens from cases with remote recurrence compared to those with local recurrence (p = 0.033). However, no significant correlation was found between MYC copy number and protein expression (p = 0.055). These findings suggest that MYC is frequently expressed in astrocytomas, but its expression does not significantly reflect 8q gain or recurrence pattern.

Karnofsky Performance Status (KPS) is a widely used scale to assess performance status. KPS ≥ 50% implies that patients can live at home. Therefore, maintaining KPS ≥ 50% is important to improve the quality of life of patients with glioblastoma, whose median survival is less than 2 years. This study aimed to identify the factors associated with survival time with maintenance of KPS ≥ 50% (survival with KPS ≥ 50%) in patients with glioblastoma, IDH-wildtype. Ninety-eight patients with glioblastomas, IDH-wildtype, who were treated with concomitant radiotherapy (RT) and temozolomide (TMZ) followed by maintenance TMZ therapy, and whose KPS at the start of RT was ≥ 50%, were included. The median survival with KPS ≥ 50% was 13.3 months. In univariate analysis, preoperative KPS (≥ 80%), KPS at the start of RT (≥ 80%), residual tumor size (< 2 cm3), methylated MGMT promotor, and implantation of BCNU wafer were associated with survival with KPS ≥ 50%. In multivariate analysis, KPS at the start of RT (≥ 80%), methylated MGMT promotor, and residual tumor size (< 2 cm3) were significantly associated with increased survival with KPS ≥ 50%. A strategy of maximum possible tumor resection without compromising KPS is desirable to prolong the survival time with KPS ≥ 50%.