Rael, Sofia

Abstract Background Isocitrate dehydrogenase (IDH)-mutant gliomas are infiltrative tumors with limited treatment options at recurrence. Early studies suggest IDH inhibition has therapeutic activity. We evaluated clinical outcomes associated with IDH-1 inhibitor ivosidenib in recurrent IDH-1-mutant gliomas and molecular predictors of response. Methods We retrospectively analyzed adults treated with ivosidenib from January 2021 to August 2025 with predominantly recurrent, pretreated CNS WHO grade 2-4 astrocytoma IDH-mutant or grade 2-3 oligodendroglioma, IDH-mutant and 1p/19q codeleted. Prior anticancer treatments, toxicities, enhancement status at ivosidenib initiation, and genomic alterations were collected. The primary endpoint was progression-free survival (PFS); secondary analyses evaluated associations between PFS, genomic complexity, and CDKN2A/B homozygous deletion. Results Ninety-two adults, median age 43, were included: 61 astrocytomas and 31 oligodendrogliomas, mostly grade 2. Before ivosidenib, 69 had surgery, 64 chemotherapy, and 64 radiation. Median time from diagnosis to ivosidenib was 4.8 years, with median of two prior progressions. Median treatment duration was 5.8 months. Median PFS was 15.2, 4.6, and 2.1 months for astrocytoma grades 2-4, 14.0 and 6.9 months for oligodendroglioma grades 2-3. Increasing genomic complexity was associated with shorter PFS in univariate analysis. Patients without CDKN2A/B homozygous deletion had median PFS of 19.2 months. Two patients with homozygous deletion had median PFS of 0.6 months. Conclusions In this retrospective analysis of predominantly recurrent IDH-1-mutant glioma, ivosidenib was associated with longer PFS in lower-grade, non-enhancing tumors that received little or no prior anticancer treatment and less complex genomic profiles. These findings support a context-dependent benefit of IDH inhibition in recurrent disease.

Abstract OBJECTIVE To demonstrate that Prostate-specific membrane antigen (PSMA) PET imaging, though primarily used in prostate cancer surveillance, can reveal PSMA uptake in non-prostatic tumors due to neovascular PSMA expression. BACKGROUND PSMA PET imaging is increasingly used for staging and monitoring prostate cancer. However, PSMA uptake is not exclusive to prostate carcinoma and may be observed in non-prostatic malignancies, including glioblastoma, due to neovascular expression. CASE REPORT We present a 67-year-old gentleman with metastatic prostate carcinoma, diagnosed in 2014 and treated with neoadjuvant Lupron, prostatectomy, and salvage radiation. In 2019, he developed nodal recurrence in retroperitoneal and bilateral iliac chain nodes, treated with lymphadenopathy, six cycles of Taxotere-based chemotherapy, and consolidative proton beam radiation (56.25 Gy/25 fractions). He later developed progression to the right proximal humerus and left coracoid process, treated with stereotactic body radiation therapy (25Gy/5 fractions). Follow-up PSMA PET/CT revealed no systemic abnormalities but showed a new PSMA-avid lesion in the right medial temporal lobe. Brain MRI confirmed a 3.5 x 1.7 x 2.5 cm ring-enhancing, intra-axial lesion with edema. The patient was asymptomatic. PSA was undetectable on abiraterone/prednisone and leuprolide. He underwent right frontotemporal craniotomy and resection. Pathology confirmed Glioblastoma, IDH-wildtype, CNS WHO Grade 4 with focal epithelioid features and positive MGMT promoter methylation. He received standard-of-care treatment with radiation, temozolomide, and TTF device. Surveillance PSMA PET and MRI showed no residual brain avidity or progression. Discussion: PSMA is a type II transmembrane glycoprotein expressed by prostatic and various non-prostatic tissues. In healthy brain parenchyma, PSMA expression is typically absent but is overexpressed in neovasculature of high-grade gliomas, including glioblastoma, IDH-wildtype, allowing for radiotracer uptake, as seen in this case. CONCLUSION This case illustrates the potential role of PSMA as a diagnostic tool, as it allows for easy identification of glioblastoma neovasculature, as demonstrated in our case report.

Abstract BACKGROUND Tumor Treating Field (TTF) therapy exerts antineoplastic effects through application of alternating electrical fields that disrupt mitotic machinery and induce DNA damage and activation of cell cycle checkpoints. However, despite extensive utilization in clinical practice for the management of glioblastoma, molecular markers for TTF sensitivity have proven elusive. METHODS To assess impact of molecular alterations on TTF response, we evaluated our institutional cohort of IDH wild type glioblastomas (n=449) for whom chromosomal microarray data was available. RESULTS A total of 142 patients were found to have undergone TTF treatment (31.6%) with improved overall survival (OS) (p=0.0049, univariate analysis). We assessed TTF treatment responses when stratified by alterations in the MDM2/4-TP53 axis, as well as the CDK4/6-RB1 axis, given well-described roles for these pathways on cellular responses to DNA damage and mitotic stressors. On univariate analysis, MDM2/4 amplified tumors treated with TTFs demonstrated significantly improved OS compared to untreated tumors (p=0.0012), and while MDM2/4-unaltered, TP53 intact tumors showed OS benefit from TTFs (p=0.0192), TP53-altered tumors did not demonstrate such benefit (p=0.6591). We confirmed these findings with multivariate Cox regression after adjusting for age and sex, where TTF therapy improved OS in MDM2/4 amplified tumors (HR 0.3881, p=0.0062) and a signal towards improved OS was seen in TP53 intact tumors (HR 0.7552, p=0.0509) but no such benefit was seen in TP53-altered tumors (HR 1.0025, p=0.9916). TTF therapy appeared to demonstrate improved OS in CDK4/6 amplified tumors (p=0.0116) on univariate analysis, with continued signal towards this effect on multivariate Cox regression (HR 0.5975, p=0.0870). CONCLUSIONS TP53 intact status and MDM2/4 amplification may represent previously unappreciated molecular markers for sensitivity to TTF therapy in IDH wild type glioblastoma. Confirmatory work with multi-institutional collaborations and evaluation of other potential prognostic factors are currently underway.