Neuro-oncology最新文献

Background: This study explored MRI characteristics at the time of tumor progression to study pathologically confirmed MT in IDHm 1p/19q-intact astrocytomas (IDHm-A) and IDHm 1p/19q-co-deleted oligodendrogliomas (IDHm-O).

Methods: N = 64 patients with initial pathological grade 2 IDH-mutant glioma diagnosis who underwent repeated tissue sampling and were classified as pathologically confirmed MT (n = 35) or non-MT (n = 29) with available presurgical anatomical (n = 64), diffusion-weighted (n = 61), and dynamic susceptibility contrast perfusion MRI (n = 53) were retrospectively studied. Measurable contrast enhancement (> 1000 mm3), tumor volume, tumor growth rate, sphericity, median apparent diffusion coefficient (ADC), and normalized relative cerebral blood volume (nrCBV) were compared between MT vs non-MT IDHm-A and IDHm-O.

Results: 81% of contrast-enhancing IDHm-A and 100% of contrast-enhancing IDHm-O demonstrated MT, while 41% of IDHm-A and 62% IDHm-O exhibited both nonenhancing tumor progression and MT. Tumor volumes were significantly larger in patients with MT compared to non-MT groups for IDHm-A (P = .02) and IDHm-O (P = .04). T2/FLAIR tumor volume growth rate was significantly higher (P = .003), nrCBV was significantly higher (P = .002), and ADC trended lower (P = .06) in MT vs non-MT IDHm-A. There were no significant differences in growth rate, ADC, nrCBV, or sphericity when comparing MT vs non-MT IDHm-O (P > .05).

Conclusions: Many MT IDHm gliomas remain nonenhancing. Growth rate, diffusion, and perfusion MRI show differences between MT and non-MT in IDHm-A but not IDHm-O, which may reflect the different tumor biology of these IDHm molecular subtypes and their need for separate imaging biomarkers. Tumor volumes can help determine MT for both IDHm-A and IDHm-O.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive sarcomas, with 40% associated with neurofibromatosis type 1 (NF1). Surgical excision is the main treatment for localized disease; however, local recurrence (LR) remains high. Radiotherapy (RTx) is increasingly used to enhance local control in STS, but its use remains controversial due to the potential for increased major wound complications and an increased risk of secondary malignancies in NF1 patients. This study investigated the use and impact of RTx on local control in MPNSTs, particularly in the NF1 setting.

Methods: Surgically treated primary MPNSTs from 1988 to 2019 in the MONACO multicenter cohort were included. Differences in demographics, treatment, and RTx use between NF1 and non-NF1 cases were examined. Factors influencing RTx administration and LR were assessed via multivariable analyses.

Results: Among 499 patients (33.1% NF1), 143 (28.7%) experienced LRs. Radiotherapy was administered to 56.3% of patients (57.0% in the NF1 group), with 27.3% receiving neoadjuvant and 72.7% adjuvant RTx. RTx was administered significantly more often to high-grade and extremity tumors. While RTx did not affect overall survival, it reduced LR risk in sporadic cases (hazard ratio [HR] 0.530; 95% confidence interval [CI], 0.354-0.793) but not in the NF1 subgroup (HR 1.00; 95% CI, 0.545-1.85). In NF1 patients, a microscopically positive margin (R1) was the only risk factor for LR development (HR 2.1; 95% CI, 1.19-3.79).

Conclusions: RTx is frequently used in the treatment of MPNSTs, regardless of NF1 status. While it may affect the LR rate in sporadic cases, its impact on NF1 patients is less clear.

Background: Glycoprotein A-repetitions predominant (GARP) is a cell surface non-signaling receptor for docking and activating latent transforming growth factor beta (LTGFβ) expressed by regulatory T cells, platelets, and tumor cells. In lung and breast cancers, its expression correlates with advanced stage and poor prognosis-suggesting that GARP could act as a therapeutic target. This study examines the therapeutic impact of targeting GARP in glioblastoma (GBM) via a novel anti-GARP chimeric antigen receptor-expressing T cell (CAR-T) modality in murine models of GBM.

Methods: We examined multiple human glioma databases to correlate the expression of GARP with clinical outcomes. We then performed multi-plex imaging of human GBM samples to understand the impact of GARP expression on the tumor microenvironment (TME). Importantly, we developed a novel anti-GARP CAR-T cell strategy to treat GBM. We examine if this therapy is efficacious against orthotopic models of GBM, in both immunocompetent syngeneic and immunodeficient mice.

Results: We demonstrate that elevated GARP expression in human GBM correlates with poor overall survival, mesenchymal subtype, and gene signatures associated with angiogenesis and immune exclusion in the TME. Our novel anti-GARP CAR-T is efficacious in vitro and in vivo, against multiple preclinical models of GBM, including patient-derived xenograft (PDX) models without significant toxicity.

Conclusions: GARP-LTGFβ plays a key role in the development and prognostics of GBM, and GARP-targeted CAR-T therapy shows promising efficacy and safety in murine orthotopic GBM models. A first-in-human phase I clinical trial for patients with recurrent GBM began to enroll patients in May 2025 (NCT06964737).

Background: Brain metastasis (BM) in colorectal cancer (CRC) is a rare event that undermines longevity and neurocognitive function. However, the molecular basis of BM in CRC is poorly understood. We analyzed next-generation sequencing (NGS) from patients with CRC to identify genomic features associated with BM and intracranial progression (IP).

Methods: Patients with CRC who had NGS between 2014 and 2024 were included. Sequenced tumor specimens were classified by the anatomic site of biopsy as primary tumors (PT), extracranial metastases (EM), or BM. Sequenced PT specimens were compared to identify genomic differences between patients who did and did not develop BM. Among patients with BM, sequenced tumor specimens were compared to identify genomic differences by anatomic site. Sequenced BM samples were compared to identify genomic differences between patients who did and did not experience IP after BM-directed local therapy.

Results: This analysis included 5526 patients with NGS of CRC, including 269 patients with BM. PT of patients who developed BM more frequently contained alterations in the KRAS, BRAF, and SMAD4, compared with PT of patients without BM. Among patients with BM, resected BM specimens had greater tumor mutation burden, fraction of genome altered, and frequency of TP53, SMAD4, and MYC alterations, compared with extracranial tumor specimens. Patients with BM carrying SMAD4 or PI3K pathway alterations showed a trend toward earlier IP after BM-directed therapy.

Conclusions: This study identifies novel genomic associations with intracranial metastasis and progression in CRC, suggesting a potential basis for personalized clinical management.

Background: The 5th edition of the World Health Organization Classification of Tumors of the CNS introduced a subclassification of tumors based on key molecular markers. In adult-type diffuse gliomas, isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase (TERT) promoter mutations play pivotal roles in the molecular classification. This study developed a rapid genotyping system using GeneSoC, a real-time PCR platform with microfluidic thermal cycling capable of completing 50 cycles of PCR within 20 min.

Methods: To establish optimal analytical conditions, frozen tumor tissues from 67 patients and artificial DNA vectors were analyzed using this system. This system demonstrated a detection limit of at least 5% variant allele frequency for the IDH1 R132H and TERT promoter C228T/C250T mutations. Subsequently, intraoperative testing was performed in 120 cases using this system.

Results: The sensitivity and specificity of IDH1 R132H mutation were 0.985 and 0.982, respectively, whereas those of TERT promoter C228T/C250T mutation were 1.000 and 1.000, respectively. These mutations were detected intraoperatively within approximately 25 min after tumor tissue collection. Furthermore, this assay identified tumor boundaries in an IDH-mutated glioma case, where IDH1 R132H mutations could not be detected.

Conclusions: The GeneSoC®︎-based rapid genotyping system may be effective not only for intraoperative diagnosis of diffuse glioma but also for detecting tumor boundaries.

Background: Central nervous system (CNS) tumors are associated with considerable morbidity and high mortality. Cyclin-dependent kinases (CDKs) regulate cell division in cancer, and CDK4/6 inhibitors are used for the treatment of breast cancer, representing an attractive therapy for different tumor types.

Methods: Here, we report mature results of a multicenter basket trial exploring the CDK4/6 inhibitor abemaciclib in patients with recurrent CNS tumors, including patients with glioma, primary CNS lymphoma, meningioma, and ependymoma. We expanded our cohort of meningioma patients based on preliminary evidence for activity. Patients were treated with 200 mg oral abemaciclib twice daily for days 1-28, following FDA recommendations for breast cancer. Primary outcomes included radiographic response rates and progression-free survival (PFS) at 6 months post-treatment. We also evaluated overall survival (OS) and toxicity. Exploratory outcomes included next-generation sequencing of tumor biopsies.

Results: Most cohorts did not demonstrate activity with the exception of the cohort of patients with recurrent meningioma, including patients with grade 2 or 3 disease (19/22 meningioma patients). In that group, the median PFS was 15 months (95% CI: 6.5, not reached) and median OS was 32.9 months (95% CI: 10.7, not reached); the 6-month PFS was 68.2% (95% CI: 51.3%, 90.7%). All 22 patients were evaluable for radiographic response, showing stable disease in 16/22 (73%) and progressive disease in 6/22 patients (27%).

Conclusion: Our data suggest that abemaciclib improves PFS and OS in patients with advanced meningioma. The 6-month PFS with abemaciclib in this study (68.2%) exceeded RANO proposed benchmarks for activity (49%).

Trial registration: NCT03220646.