Faculty Bibliography

Glioblastoma (GBM) patients have dismal survival due to resistance to initial ionizing radiation therapy (RT). Clonal evolution analysis reveals no dominant RT-resistant clones, prompting a genome-wide CRISPR screen to identify radiosensitizing targets. The screening highlights DNA damage response genes, validating the effectiveness of our approach. N-acylneuraminate-9-phosphatase (NANP), a critical enzyme in the sialic acid synthetic pathway, is top-ranked in the screening and associated with patient outcomes. After radiation, NANP-deficient cells exhibit more DNA damage, G2/M arrest and apoptosis, and impaired DNA repair by favoring non-homologous end-joining over homologous recombination. Mechanistically, NANP influences NF-κB signaling and the mesenchymal state by modulating sialylation and internalization of tumor necrosis factor receptor 1 (TNFR1), thereby affecting RT sensitivity. Intracranial orthotopic xenograft experiments validate the function of NANP in vivo. Here, we identify NANP as a radiosensitizing target dependent on TNFR1 sialylation and mesenchymal shift, providing a basis for developing RT sensitizers for GBM.

BACKGROUND:F-fluciclovine PET. METHODS:). RESULTS:threshold=4.8). Dynamic measures provided no further diagnostic value. Additional reads showed visual-only interpretation was optimal at 15-25-minutes (sensitivity: 60-90%, specificity: 77-100%). SUVR-based interpretation using a threshold of 1.1 provided 70-80% sensitivity and 85% specificity. CONCLUSION/CONCLUSIONS:F-fluciclovine PET in future studies.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Only a minority of renal oncocytic tumors are aggressive. These tumors' behavior is difficult to predict by histopathological evaluation; consequently, many patients experience anxiety upon diagnosis and may undergo unnecessary treatment. Our aim was to derive genomic and epigenomic signatures to distinguish clinically indolent renal oncocytic tumors from aggressive chromophobe renal cell carcinoma (ChRCC). METHODS:We performed molecular profiling of nephrectomies from 68 patients: 44 with indolent renal oncocytic tumors (19 renal oncocytoma, two oncocytic renal neoplasm of low malignant potential, and 23 indolent ChRCC) and 24 with aggressive ChRCC. We performed targeted exome sequencing, gene expression profiling, and whole-genome methylation sequencing of formalin-fixed, paraffin-embedded (FFPE) samples. We also analyzed The Cancer Genome Atlas Kidney Chromophobe data from 66 ChRCC patients in silico. Genomic and epigenomic signatures linked to aggressive ChRCC-obtained from sampling morphologically nonsarcomatoid foci-from both cohorts were derived using the least absolute shrinkage and selection operator method. KEY FINDINGS AND LIMITATIONS/UNASSIGNED:Aggressive ChRCC was distinguished from indolent ChRCC and other indolent renal oncocytic tumors using a focused seven- to 11-gene expression signature (ten-fold cross-validation [CV] area under the curve [AUC] = 0.77-0.85) with an external validation AUC of 0.88, and an eight-CpG methylation signature (ten-fold CV AUC = 0.86) with an external validation AUC of 0.91. TP53 and PTEN mutations substantially increased the probability of aggressive ChRCC. Limitations include the small sample size. CONCLUSIONS AND CLINICAL IMPLICATIONS/CONCLUSIONS:Focused genomic and epigenomic signatures from routinely processed FFPE tumor tissues can help distinguish aggressive ChRCC from indolent renal oncocytic tumors, including indolent ChRCC. This forms the basis for replication studies to inform appropriate patient management, provide reassurance, and guide follow-up.

Multimodality therapy, including surgery, radiotherapy, and systemic therapy, has significantly improved overall survival for patients with brain metastases. However, treatment-related neurocognitive sequelae remain a major challenge in survivorship. Although advances in radiotherapy delivery techniques have reduced toxicity, the potential interaction with chemotherapy, targeted therapy, and immunotherapy, and the consequent effect on neurocognitive outcomes is poorly characterised. We conducted a systematic review of clinical trials reporting neurocognitive endpoints in patients with brain metastases receiving radiotherapy with or without other concurrent systemic therapies. Neurocognitive outcomes were manually extracted from published reports. 39 studies from 1997 to 2024 involving 6617 patients met inclusion criteria (n=27 whole-brain radiotherapy; n=12 radiosurgery), including six studies evaluating combined-modality therapy. Baseline neurocognitive disability was frequently observed, and the majority of randomised trials evaluating advanced radiotherapy delivery techniques (hippocampal avoidance and radiosurgery) compared with whole-brain radiotherapy reported reduced cognitive decline and improved quality of life. There was no signal for increased toxicity with combined-modality therapy, including radiotherapy with concurrent systemic therapy, although evaluable trials were few in number. Given improvements in survival for patients with brain metastases, characterisation of long-term neurocognitive outcomes is growing in importance. There is an urgent need for targeted research to resolve evidence gaps around modality-specific neurocognitive toxicity and optimal sequencing of therapies. Systemic issues, such as integration of routine neuropsychological screening or assessment and incorporation of rehabilitation strategies into neuro-oncology care pathways, warrant evaluation. Exploration of emerging strategies, ranging from neuroprotectants to dose-sparing radiotherapy techniques, could further mitigate long-term adverse effects.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Hypofractionated Gamma Knife radiosurgery (hfGKRS) is increasingly considered for treating large or near-critical structure meningiomas because of potential safety advantages. However, data on optimal fractionation and long-term outcomes remain limited. This study evaluated the longer-term tumor control and toxicity after hfGKRS for intracranial meningiomas at 2 large centers, supplemented by a systematic review and meta-analysis of existing literature. METHODS:The analysis included 34 patients (site 1 = 25, site 2 = 9, median age 62.6 years) with 40 tumors (median volume 11.2 cm3). 62% was low-grade (World Health Organization grade 0-1) and 38% was high-grade (World Health Organization grade 2-3). The most common fractionation schemes were 20 Gy in 5 fractions for low-grade and 21 Gy in 3 fractions for high-grade tumors. The mean follow-up was 28.8 months. RESULTS:Only 6 of 34 patients did not have any previous treatment including surgery and/or radiotherapy. 82% of patient patients had neurological deficits before stereotactic radiosurgery. The estimated rate of 5-year tumor progression for low-grade and high-grade tumors was 7.7% (95% CI 0.41%-30%) and 36% (95% CI 12%-62%). Symptoms improved in 12 patients (35%) and worsened in 6 patients (16%), with 1 case attributed to tumor progression and no significant visual deterioration in 16 tumors within 3 mm of the optic apparatus. There was no statistically significant association between fractionation (3 vs 5) scheme and tumor control (P = .07) or survival (P = .12). Karnofsky Performance Status performance was a significant predictor of death (HR 0.89, P = .012) and tumor progression (HR 0.93, P = .048). The combined meta-analysis revealed a 5-year tumor control rate of 91.6% for low-grade and 37.9% for high-grade meningiomas. CONCLUSION/CONCLUSIONS:hfGKRS demonstrates durable control and acceptable safety for low-grade intracranial meningiomas. High-grade tumors showed less favorable outcomes comparable with single-session Gamma Knife radiosurgery historical data. Further prospective data are needed to confirm these findings and optimize fractionation strategies.

PURPOSE/OBJECTIVE:) disease. NRG Oncology BN002 (phase I) demonstrated safety and suggested efficacy of ipilimumab (ipi) with nivolumab (nivo) in newly diagnosed glioblastoma, leading to this phase II/III trial. METHODS:) of .15, superior PFS with immunotherapy in phase II would lead to phase III overall survival (OS) testing. Corticosteroids were disallowed when starting immunotherapy. Diagnosis, biomarkers, and PFS were centrally assessed. RESULTS:= .36). CONCLUSION/CONCLUSIONS:glioblastoma versus TMZ. Accrual closed permanently; the trial will not proceed to phase III. No new safety signals were identified. Molecular correlative analyses and survival follow-up are ongoing.

PURPOSE/OBJECTIVE:Immune checkpoint inhibition (ICI) has revolutionized the treatment of melanoma care. Stereotactic radiosurgery combined with ICI has shown promise to improve clinical outcomes in prior studies in patients who have metastatic melanoma with brain metastases. However, others have suggested that concurrent ICI with stereotactic radiosurgery can increase the risk of complications. METHODS:We present a retrospective, single-institution analysis of 98 patients with a median follow up of 17.1 months managed with immune checkpoint inhibition and stereotactic radiosurgery concurrently and non-concurrently. A total of 55 patients were included in the concurrent group and 43 patients in the non-concurrent treatment group. Cox proportional hazards models were used to assess the relation between concurrent or non-concurrent treatment and overall survival or local progression-free survival. The Wald test was used to assess significance. Significant differences between patients in both groups experiencing adverse events including adverse radiation effects, perilesional edema, and neurological deficits were tested for using the Chi-square or Fisher's exact test. RESULTS:Patients receiving concurrent versus non-concurrent ICI showed a significant increase in overall survival (median 37.1 months, 95% CI: 18.9 months - NA versus median 11.4 months, 95% CI: 6.4-33.2 months, p = 0.0056) but not local progression-free survival. There were no significant differences between groups with regards to adverse radiation effects (2% versus 3%), perilesional edema (20% versus 9%), neurological deficits (3% versus 20%). CONCLUSION/CONCLUSIONS:These results suggest that the timing of ICI does not increase risk of neurological complications when delivered within 4 weeks of SRS.