Saya Hideyuki

The clinical significance of comprehensive genomic profiling (CGP) has been established in metastatic castration-resistant prostate cancer (PC). However, the role of genomic profiling in localized PC remains unclear. In this exploratory study, we evaluated somatic genomic alterations in localized PC using an in-house CGP platform to examine their associations with biochemical recurrence (BCR) and recurrence-free survival (RFS) after radical prostatectomy. DNA extracted from surgical specimens of 314 patients with localized PC was analyzed for alterations in 164 cancer-related genes. Six genes (PTEN, BRCA2, POLD1, ERBB3, MYC, and SETD2) were more frequently altered in patients who developed BCR in exploratory analyses. Patients harboring alterations in any of these genes (n = 96) showed higher pathological T stage, increased BCR rates (27.1% vs. 6.4%), and inferior RFS compared with alteration-negative patients (n = 218; p < 0.001). In multivariate analysis, the presence of these alterations was independently associated with worse RFS. Among individual genes, BRCA2 alteration, and particularly BRCA2-SETD2 co-alteration, were associated with unfavorable outcomes, although the latter finding was based on a limited number of cases. In patients who developed BCR, alterations were associated with shorter PSA doubling time and poorer outcomes after salvage radiotherapy, particularly in margin-negative cases; however, these subgroup analyses were based on small numbers and should be interpreted as hypothesis-generating. These findings suggest that somatic genomic alterations identified at prostatectomy are associated with early recurrence in localized PC. Further validation in independent cohorts is required to determine whether genomic profiling may contribute to future risk stratification and management strategies.

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.

Pancreatic cancer is a highly intractable malignancy that necessitates personalized treatment strategies. Conventional patient-derived models, such as three-dimensional organoids, are often limited by intellectual property constraints and high costs. In this study, we developed an affordable adherent culture system for patient-derived pancreatic cancer cells using a proprietary medium and laminin-coated dishes. Primary cultures were successfully established from 28 patients with pancreatic ductal adenocarcinoma, exceeding a 90% success rate. Validation of eight samples confirmed maintenance of epithelial cell adhesion molecule expression and preservation of oncogenic KRAS mutations. Transcriptomic profiling revealed consistent upregulation of a six-gene signature (FAP, IGFBP5, PRRX1, SPARC, WNT5A, and ADAMTS12), which is associated with malignancy. In vitro drug sensitivity assays revealed interpatient heterogeneity with preliminary clinical associations. In conclusion, this simplified platform provides high-purity cancer cells and serves as a functional precision medicine tool. Beyond conventional chemotherapy, this platform has the potential to support applications ranging from biomarker validation and exploratory preclinical testing of novel therapeutics, including immune checkpoint inhibitors and antibody–drug conjugates. This optimization can lead to personalized therapeutic strategies for pancreatic cancer.

Lower grade gliomas frequently harbor mutations in isocitrate dehydrogenase (IDH), which define biologically distinct tumor subtypes. Although IDH-mutant and IDH-wildtype gliomas share similar histological morphology, they display markedly different metabolic profiles that may be exploited for targeted therapy. In this study, we investigated therapeutic approaches tailored to these metabolic differences. Using capillary electrophoresis-mass spectrometry, we compared the metabolomes of engineered IDH-wildtype and IDH-mutant glioma cell models. IDH-mutant cells exhibited elevated asparagine levels and reduced glutamine and glutamate levels compared with IDH-wildtype cells. These differences were corroborated in vivo by proton magnetic resonance spectroscopy of 130 patients with diffuse gliomas, showing lower glutamine and glutamate in IDH-mutant tumors. Pharmacological depletion of asparagine with L-asparaginase, which converts asparagine to aspartate, preferentially inhibited the growth of IDH-wildtype glioma cells, and this effect was potentiated by inhibition of asparagine synthetase. In contrast, inhibition of glutamate dehydrogenase 1 (GLUD1), the enzyme catalyzing the conversion of glutamate to α-ketoglutarate, selectively suppressed proliferation of IDH-mutant glioma cells by inducing reactive oxygen species accumulation and apoptosis. In vivo, L-asparaginase suppressed tumor growth in xenografted IDH-wildtype gliomas, whereas GLUD1 inhibition significantly reduced tumor growth in IDH-mutant glioma xenografts. These findings reveal distinct amino acid metabolic vulnerabilities defined by IDH mutation status and identify L-asparaginase and GLUD1 inhibition (via R162) as promising, mutation-specific therapeutic strategies. L-asparaginase demonstrated potent antitumor activity against IDH-wildtype gliomas, while GLUD1 inhibition selectively suppressed IDH-mutant gliomas both in vitro and in vivo. These results highlight the clinical potential of targeting amino acid metabolism in gliomas and provide a strong rationale for translating these mutation-specific approaches into future clinical trials.