To evaluate the utility of plasma-derived cell-free DNA (cfDNA) using targeted next-generation sequencing (NGS) for molecular profiling of diffuse gliomas (DG) by assessing concordance with matched tumor tissue DNA, mutation profiles, variant allele frequencies, therapeutically actionable alterations, and survival associations. A total of 30 DG cases were included and 10 healthy control were included. Paired plasma cfDNA and formalin-fixed paraffin-embedded tumor tissue DNA were analyzed using targeted next-generation sequencing (NGS). Plasma cfDNA concentrations were higher in patients with DG (n = 30) than in healthy controls (P = .0002), though this comparison was limited by the small, unmatched control cohort (n = 10). Targeted sequencing predominantly identified single nucleotide variants (81%). Gene-level concordance between plasma cfDNA and tumor tissue DNA was 90.0%, whereas ≥1 matched variant was identified in 76.7% of cases. Plasma cfDNA detectability and concordance varied across diffuse glioma subtypes, and multiple therapeutically actionable alterations involving receptor tyrosine kinase, MAPK, PI3K/AKT/mTOR, and mismatch repair pathways were identified. Higher plasma cfDNA concentrations were associated with shorter survival, whereas cases with matched plasma and tissue variants demonstrated longer survival; however, these associations were not statistically significant. Plasma cfDNA-based liquid biopsy may serve as a minimally invasive approach for molecular profiling of diffuse gliomas, demonstrating high gene-level concordance with tumor tissue DNA and detection of clinically relevant, potentially actionable genomic alterations. Although variant-level concordance and detectability varied across glioma subtypes, these findings support a complementary role for plasma cfDNA analysis in diffuse gliomas. Further prospective studies, including serial sampling and matched leukocyte controls, are needed to improve analytical sensitivity and define its clinical utility.
Purpose: To evaluate prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) kinetics following PSMA-positron emission tomography (PET) and magnetic resonance (MR) guided stereotactic body radiation therapy (SBRT) and short-term androgen deprivation therapy with dominant intraprostatic lesion (DIL) boost in localized prostate cancer. Methods and Materials: This prespecified analysis from the phase 2 PROBE trial (IRB approval: IEC 900917) included patients with intermediate- or high-risk prostate cancer treated with 5-fraction SBRT (36.25 Gy to prostate; 40 to 42.5 Gy to PSMA/MRI-defined DIL) and 6 months of androgen deprivation therapy. PSA kinetics relied on 3-monthly PSA levels. Longitudinal metabolic response, based on the adapted PET Response Criteria in Solid Tumors, was assessed using 68Ga-PSMA-PET/computed tomography done at SBRT completion, 3 to 6 months, and 9 to 12 months after SBRT completion. Cumulative genitourinary/gastrointestinal toxicities were reported per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Results: Thirty enrolled patients (54% intermediate risk, 46% high risk) were included. A PSA <0.1 ng/mL was achieved in 79% of patients at 6 months and 50% at 12 months. The mean maximum standardized uptake value (SUVmax) decreased from 12.2 (range, 4.0-39.6) pretreatment to 3.2 at 3 to 6 months and 1.8 at 9 to 12 months. Complete response (CR) rates increased from 17% at SBRT completion to 48% at 3 to 6 months and 65% at 9 to 12 months. Patients achieving CR at 3 to 6 months reached a lower mean PSA (0.04 vs 0.3 ng/mL, P = .009). Those with PSA <0.1 ng/mL at 6 months were more likely to attain CR at 12 months (76% vs 28%, P = .003). An early standardized uptake value (SUV) "flare" was observed in 4 (14%) patients, resolving by 9 to 12 months. No National Cancer Institute Common Terminology Criteria for Adverse Events grade >= 3 genitourinary/gastrointestinal toxicity was seen. Conclusions: PSMA-PET and MR guided prostate SBRT with DIL boost achieved deep PSA nadirs, gradual PSMA kinetics, and a favorable safety profile. About 80% of patients achieved a PSA <0.1 ng/mL at 6 months, with two-thirds achieving CR by 12 months post-SBRT. Achieving a PSA <0.1 ng/mL could potentially predict PSMA-CR. Early PSMA-CR at 3 to 6 months may predict durable PSA response and warrants further evaluation as a biomarker for risk-adapted strategies in localized prostate cancer. (c) 2026 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Purpose: Differentiating recurrent brain metastases (BM) from treatment-related changes after radiation therapy remains challenging. PURSUE (NCT04410367) evaluated various lesion uptake metrics to establish image interpretation criteria to detect recurrent BM with F-18-fluciclovine positron emission tomography (PET). Methods and materials: Patients with BM were enrolled if they had a previously irradiated MRI-equivocal "reference" lesion and were planned for craniotomy. PET with F-18-fluciclovine (185 MBq) was performed <42 days post-MRI and 1-21 days precraniotomy. Performance of different qualitative thresholds of lesion F-18-fluciclovine uptake on static PET images (10-20 minutes postinjection) versus histopathological standard of truth was assessed by 3 blinded readers, as were semiquantitative (standardized uptake value [SUV]) and dynamic uptake measures, to establish F-18-fluciclovine interpretation criteria. A separate committee reviewed all data to establish interpretation criteria. Following initial review, additional blinded reads were conducted at three timepoints (10-20, 15-25, and 20-30 minutes) to explore visual-only reads (uptake >= parotid/pituitary as reference) and SUV ratio (SUVR)-based criteria (SUVpeak(lesion-to-pituitary)). Results: Twenty-three reference lesions from 23 subjects underwent histopathological analysis; 10 (43%) were confirmed as recurrence. At 10-20 minutes postinjection, the highest performing qualitative measure was "uptake higher than parotid" (specificity: 92%-100%; sensitivity: 40%-80% across readers). SUVmax was a high-performing metric on receiver operating characteristic analysis (area under the curve: 0.87, sensitivity: 80%, specificity: 85% for SUVmax threshold = 4.8). Dynamic measures provided no further diagnostic value. Additional reads showed visual-only interpretation was optimal at 15 to 25 minutes (sensitivity: 60%-90%; specificity: 77%-100%). SUVR-based interpretation using a threshold of 1.1 provided 70% to 80% sensitivity and 85% specificity. Conclusions: PURSUE established effective, histopathologically verified F-18-fluciclovine interpretation criteria for diagnosing recurrent BM after radiation therapy that will help evaluate F-18-fluciclovine PET in future studies.
Abstract One of the most frequent genetic alterations in high-grade gliomas is the homozygous deletion of the 9p21.3 chromosomal region, affecting 20-50% of tumors. The 9p21.3 locus encodes key tumor suppressor genes (CDKN2A and CDKN2B), MTAP, and a cluster of type I interferon (IFN) genes. The loss of CDKN2A and CDKN2B deregulates the Rb and p53 pathways, driving uncontrolled proliferation and creating a replication-permissive state that oncolytic viruses can exploit. The simultaneous deletion of MTAP and type I IFN genes impairs innate immune surveillance, thereby enhancing viral replication but limiting the host’s capacity for adaptive immune priming. Hence, current evidence suggests that 9p21.3 deletions eliminate a proliferative block and promote immune evasion, contributing to tumorigenesis. Despite the high frequency of 9p21.3 loss in malignant gliomas, the extent to which this deletion affects the therapeutic efficacy of oncolytic viruses remains unclear. In this review, we discuss the potential of using 9p21.3 status as a biomarker of therapeutic response, the challenges of modeling 9p21.3 loss in preclinical glioma models, and future strategies to exploit oncolytic viral permissiveness while stimulating antitumor immunity in patients with high-grade gliomas and 9p21.3 loss.
Abstract Mismatch repair-deficient glioblastomas represent a rare molecular subset with important hereditary and therapeutic implications. We report a 58-year-old man with adult-onset giant cell glioblastoma showing isolated PMS2 loss, MSI-H status, ultra-high tumor mutational burden, and confirmed biallelic PMS2 inactivation from a likely pathogenic germline PMS2 splice-site variant and somatic PMS2 nonsense mutation, revealing previously unrecognized Lynch syndrome. DNA methylation profiling classified the tumor as high-grade glioma with mismatch repair deficiency, with a methylation match to diffuse high-grade glioma, IDH-wildtype, subtype E. Given MGMT promoter unmethylation and mismatch repair deficiency, temozolomide was omitted, and the patient received adjuvant radiation therapy with concurrent and maintenance pembrolizumab. Surveillance MRI at five months after gross total resection showed no evidence of recurrence. This case highlights giant cell morphology and ultra-high tumor mutational burden as potential clues to underlying mismatch repair deficiency and supports consideration of reflex MMR immunohistochemistry, germline evaluation, and immune checkpoint inhibition in selected dMMR/MSI-H glioblastomas.
