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Abstract BACKGROUND While most meningiomas are classified as low-grade tumors with indolent behavior, a subset is characterized by a more aggressive clinical course and patients undergo repeated resections and courses of radiation. Once these therapies fail, prognosis is poor and progression-free survival (PFS) rates at 6 months (PFS-6) are estimated to only be 43.6% for WHO grade 1 and 38% for WHO grade 2/3 meningiomas. Effective medical therapies are limited. Somatostatin receptor 2 (SSTR2) is expressed in a majority of meningiomas and represents a suitable treatment target. [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) is an SSTR2-targeted radioligand therapy, established as standard of care in the treatment of certain neuroendocrine tumors. Two ongoing non-randomized studies of 177Lu-Dotatate in meningiomas have reported encouraging efficacy compared to historical benchmarks. METHODS/STUDY DESIGN The MOMENTUM-1 study (RTOG 3523, NCT#06955169) is a multicenter, randomized, open-label study of 177Lu-Dotatate in adult patients with progressive intracranial WHO grade 1-3 meningiomas. Up to 130 eligible subjects are randomized in a 2:1 fashion to 177Lu-Dotatate at 7.4 GBq (200 mCi) every 4 weeks for 4 (+2 optional) doses or standard of care (SOC) medical therapy as defined by the protocol and deemed appropriate by the local investigator. Treatment responses are assessed by gadolinium-enhanced MRI brain and [68Ga]Ga-DOTA-TATE (68Ga-Dotatate) PET imaging. At time of progression, cross-over from the SOC to the interventional treatment arm is allowed. The primary endpoint is PFS. Secondary endpoints include PFS-6, OS-12, OS, response assessments (ORR, DCR), safety/tolerability, and patient-reported outcomes. RESULTS/CONCLUSION MOMENTUM-1 is a multicenter, randomized, open-label, phase II study of 177Lu-Dotatate in adult patients with progressive WHO grade 1-3 meningioma. This clinical trial is expected to start enrolling patients in the United States in the third quarter of 2025. Details on study design, eligibility criteria for subject enrollment and study site eligibility criteria will be presented.

Abstract BACKGROUND The phase III ECOG-ACRIN E3F05 trial tested whether combined therapy with radiation and concomitant followed by adjuvant temozolomide is more effective than radiation alone in patients with grade II gliomas. The study incorporated 1p/19q analysis but predated assessment of IDH mutational status. We previously reported that the addition of temozolomide to radiotherapy significantly improved overall survival in grade II gliomas, with similar hazard ratios in co-deleted (0.56) and non-codeleted (0.53) tumors. Herein we incorporate the results of DNA methylation profiling to examine outcomes in IDHmt, non-codeleted subjects as well as co-deleted ones. METHODS All 172 subjects underwent 1p/19q co-deletion analysis as a stratification factor, 1p and 19q deletion analysis was performed on formalin-fixed paraffin-embedded (FFPE) gliomas by Fluorescent In Situ Hybridization (FISH) following standard methods, 97/172 (56.3%) had tissue with 60% or more tumor content available for DNA methylation profiling using Heidelberg classifier v12 and Bethesda Classifier 2.0 to ascertain classification as IDH mutant glioma and alternative evaluation of 1p/19q co-deletion status. RESULTS Of the 172 subjects, 74 (43.0%) had 1p/19q codeletion by FISH, 38 (22.1%) were IDHmt without codeletion, 14 (8.1%) were IDHwt, and 46 (26.7%) were non-codeleted with unknown IDH status (these include n=4 pts originally classified as 1p/19q undetermined). With a median follow-up of 130 months, the addition of TMZ to RT improved OS in patients with IDHmt, non-codeleted tumors (HR 0.15 (0.03-0.74)) and 10-year OS from 39% to 80%. In codeleted tumors, the addition of TMZ improved OS (HR 0.51 (0.19-1.42)) and 10-year OS from 68% to 90%. CONCLUSION The addition of temozolomide to radiation improves overall survival in both co-deleted and IDHmt, non-co-deleted grade II gliomas.

Abstract Glioma stem cells (GSCs) are key drivers of glioblastoma (GBM) progression, therapy resistance, and recurrence, making them critical therapeutic targets. While the lineage-defining transcription factor OLIG2 is critical for GSC maintenance, the molecular co-regulators and downstream pathways it engages remain poorly defined. Here, we identify a previously unrecognized, functionally significant interaction between OLIG2 and STAT5B, uncovering a novel regulatory axis in GSCs. Using proximity ligation assay (PLA), we demonstrate that OLIG2 interacts with STAT5 in human and mouse GSC models, particularly in EGFRvIII-mutant cells. We find that OLIG2 preferentially partners with STAT5B and not STAT5A. Knockdown studies in GSCs reveal that OLIG2 and STAT5B co-regulate critical oncogenes BIRC5 and NUSAP1, both of which are required for sphere formation and migration capacity of EGFRvIII positive GSCs. In orthotopic xenograft models, knockdown of either STAT5B or OLIG2 significantly prolongs survival reduces expression of stemness and invasion markers, SOX2, VIMENTIN, and NUSAP1. In contrast, STAT5A knockdown fails to recapitulate these phenotypes, underscoring the role of OLIG2-STAT5B signaling in GSCs. These findings reveal a novel OLIG2-STAT5B transcriptional circuit that plays a role in GSC stemness maintenance, invasion, and tumor growth, particularly in EGFRvIII-driven gliomas. Targeting this axis may offer a new avenue for GBM treatment.

Abstract PURPOSE Age over 40 years is commonly regarded as a “high risk” feature and potential indication for adjuvant chemoradiotherapy for patients with lower grade glioma in most clinical practice guidelines. However, these recommendations are based on retrospective observations and their subsequent incorporation into legacy clinical trials. It is unclear whether age remains a relevant prognostic factor in the molecular era. METHODS The Prospective Gliomas Research [PROGRES] Database contains individual patient-level data from 11 prospective clinical trials or observational registries, including seven international trials from the RTOG, EORTC, or Alliance cooperative groups. We determined the association of age with progression-free survival (PFS) in low grade or anaplastic glioma, stratified by isocitrate dehydrogenase (IDH1/2) status. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] Database). RESULTS We identified 1,619 and 1,271 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH-wildtype tumors were more common in patients >40 years (38% vs, 5%, odds ratio: 11.3 [95%CI 6.5 – 19.7]). Age was associated with PFS in IDH-wildtype (5-year PFS: 6% vs, 24%, P =.003) but not in IDH-mutant glioma (60% vs, 59%, P = 0.22, P value of interaction <.001). In IDH-wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% vs, 28%), EGFR amplification (41% vs, 15%), and chromosome +7/-10 alteration (57% vs, 25%). Age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone in IDH-mutant glioma. CONCLUSION Older age is a putative surrogate for IDH-wildtype status, but was not an independent predictor of progression in IDH-mutant lower grade glioma and did not predict benefit from chemoradiotherapy. In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

Objective: Vestibular schwannomas (VSs) treated with stereotactic radiosurgery (SRS) often show transient loss of central tumor enhancement. We hypothesized that this loss of enhancement may correlate with better tumor control on follow-up imaging. Methods: We evaluated 198 consecutive patients from a single center who met eligibility criteria. Tumor volumes on the pre-SRS and post-SRS scans were quantified along with regions of loss of enhancement on the first post-SRS study. The latter was correlated with tumor volumes at follow-up, radiation isocenter density, and loss of serviceable hearing. Results: For the entire cohort, the median loss of enhancement on the first post-SRS scan was 14% (IQR: 6 to 25) and median rate of change in tumor volume was −4.5% per year (IQR: −10.5 to 1.5). Percent loss of central enhancement showed significant negative correlation with tumor growth not only for the entire cohort (correlation coefficient: −0.18, P =0.01), but also for the subset of patients who had available imaging until at least 2 years (n=185) and 4 years (n=179) post-SRS. Loss of enhancement also strongly correlated positively with tumor volumes and number of radiation isocenters and negatively with isocenter density. Finally, patients with greater percent loss of enhancement had an increased likelihood of progression to non-serviceable hearing, although this association was not statistically significant. Conclusions: These findings suggest that loss of central tumor enhancement in VSs post-SRS may be associated with improved tumor control.

BACKGROUND: The association between breast cancer diagnosis, treatment, and the risk of incident ischemic stroke remains unclear. We aimed to investigate ischemic stroke risk among breast cancer survivors and evaluate the association by age, follow-up duration, and cancer treatments. METHODS: Using the Korean National Health Insurance Service database, we studied 113,232 women newly diagnosed with breast cancer (aged ≥18 years) without prior stroke history who underwent breast cancer surgery between January 2010 and December 2016. Each was matched 1:3 by birth year to a cancer-free female population (n=322,818). Subdistribution hazard ratios (sHRs) and 95% confidence intervals (CIs) were estimated, accounting for death as a competing risk and adjusting for sociodemographic factors and cardiovascular and noncardiovascular comorbidities. RESULTS: Over a mean follow-up of 7.2 years, ischemic stroke occurred in 1,155 (1.0%) breast cancer surgery survivors. Overall, breast cancer survivors had a slightly lower risk of stroke than cancer-free women (sHR 0.94; 95% CI 0.88–1.00). However, stroke risk was elevated in the short term following diagnosis (sHR 1.59, 95% CI 1.34–1.89 at 1 year; sHR 1.17, 95% CI 1.05–1.30 at 3 years) across all age groups, with stronger associations observed at 3 and 6 months post-diagnosis. A reduced risk was observed after 1 year in a landmark analysis that included only individuals event-free at the 1-year follow-up (sHR 0.87, 95% CI 0.81–0.93). Among breast cancer survivors, treatment with anthracycline (sHR 1.25) and the combination of tamoxifen and aromatase inhibitors (sHR 1.49) were associated with increased stroke risk, whereas radiation therapy was associated with decreased risk (sHR 0.84). These associations weakened and became nonsignificant after 1 year. Stroke risk was also higher in breast cancer survivors with low income, hypertension, diabetes, or current smoking. CONCLUSION: The association between breast cancer and ischemic stroke risk is time-dependent, with increased short-term risk post-diagnosis and treatment, followed by a decline over time. These findings highlight the importance of proactive stroke risk management, including baseline cardiovascular assessments and ongoing monitoring for thromboembolic events.

Abstract Background Although there are data describing the onset of neurocognitive toxicity following radiation for patients with brain metastases, less is known about the potential for functional cognitive recovery (CR). This study sought to evaluate CR following neurocognitive function failure (NCF) in patients treated with stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and hippocampal avoidance (HA)-WBRT. Methods A pooled analysis of 3 (NCCTG N107C/CEC.3, NCCTG N0574, and NRG CC001) clinical trials was performed. Patients with trial-defined NCF and longitudinal cognitive testing were included. The primary endpoint was time to CR, defined as patients no longer exhibiting a 1 or more standard deviation decline from baseline on any cognitive test. Results A total of 288 patients were included, with a median follow-up of 12.2 months. The cumulative incidence of CR was 38% (95% confidence interval [CI] = 32.5% to 43.9%) at 6 months after NCF. Incidence of CR was significantly improved with post-op SRS vs WBRT (hazard ratio [HR] = 2.68, 95% CI = 1.43 to 5.03, P = .002) and with SRS vs SRS+WBRT (HR = 2.35, 95% CI = 1.16 to 4.79, P = .008). On multivariable analysis, SRS was highly prognostic of CR compared with WBRT (HR = 2.42, 95% CI = 1.70 to 3.45, P < .0001). Meta-analysis demonstrated that conformal RT techniques (SRS or HA-WBRT) conferred a significantly higher rate of CR compared with WBRT (pooled HR = 2.12, 95% CI = 1.49 to 3.02, P < .001); 68% of patients had long-term sustained CR. Conclusions A sizeable proportion of patients who experience NCF following brain radiation eventually attain full and sustained CR, thereby highlighting that neurocognitive decline may not be permanent. The use of conformal radiation techniques results in greater rates of neurocognitive recovery.

Metastatic meningioma exhibits diverse dissemination patterns across organ systems (lungs, bone, liver, soft tissue, etc), with molecular imaging—particularly gallium 68 DOTA Tyr3-octreotide PET/CT—playing a pivotal role in detection, characterization, and guiding management.

ImportanceAlthough incarceration is associated with worse cancer outcomes, little is known about quality of cancer care among people with a history of incarceration.ObjectiveTo describe quality of cancer care among those diagnosed with cancer during or immediately after incarceration.Design, Setting, and ParticipantsThis longitudinal cohort study used Connecticut Tumor Registry data linked to Department of Correction rosters from 2005 through 2016. Patients diagnosed with cancer while incarcerated were matched to those diagnosed within 12 months after incarceration and to those with no history of incarceration. Analysis was performed between March 2024 and January 2025.ExposuresIncarceration status at time of cancer diagnosis.Main Outcomes and MeasuresThe main outcomes were treatment initiation within 60 days and receipt of recommended pretreatment and therapeutic care, ascertained from medical records and tumor registries. Logistic regression was used to evaluate odds of treatment initiation by 60 days. The proportion of recommended elements of pretreatment and therapeutic care received was calculated, and group differences were assessed using χ2 tests.ResultsThe sample included 690 individuals (233 diagnosed during incarceration, 221 diagnosed within 12 months after incarceration, and 236 with no incarceration history). The mean (SD) age was 49.7 (12.1) years, and 611 (88.6%) were male. Compared with those with no history of incarceration, those diagnosed with cancer during incarceration were less likely to initiate treatment within 60 days (169 of 209 [80.9%] vs 131 of 189 [69.3%]; OR, 0.49 [95% CI, 0.31-0.79]). Initiation of treatment within 60 days was not statistically different for those diagnosed after incarceration vs those with no history of incarceration (144 of 187 [77.0%]; OR, 0.81 [95% CI, 0.49-1.34]). Those diagnosed with local and regional cancers during incarceration received 49.2% of recommended treatment-related care (31 of 63 measures), while those diagnosed after incarceration received 45.3% (34 of 75 measures), compared with 66.7% (36 of 54 measures) among those with no history of incarceration (P < .001). People diagnosed with local and regional cancers during incarceration received 80.6% of recommended pretreatment evaluation (54 of 67 measures), and those diagnosed after received 96.8% (59 of 68 measures), compared with 78.1% (50 of 64 measures) among those with no history of incarceration (P = .01).Conclusions and RelevanceIn this cohort study of people with a history of incarceration, incarceration was associated with lower likelihood of receiving timely, high-quality cancer treatment. Along with other published literature, this work suggests that gaps in quality of care may contribute to observed disparities in outcomes.

Abstract Diffuse large B-cell lymphoma (DLBCL) poses a challenge in hematology given its varied symptoms, and the complex interplay between disease and treatment effects on health-related quality of life (HRQoL). The phase 3 POLARIX study demonstrated superior progression-free survival and a similar safety profile with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) vs R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with previously untreated DLBCL. Here, we evaluate HRQoL through patient-reported outcome (PRO) instruments to fully characterize the patient experience in the POLARIX study. Changes from baseline in HRQoL, lymphoma symptoms, and gastrointestinal (GI) symptoms were assessed, as well as incidence and severity of common symptoms by PROs vs clinician-reported adverse events (AEs). Baseline characteristics of PRO-evaluable patients (N = 874) were consistent. Comparison between PROs and clinician-reported AEs revealed a notable discordance; patients generally reported a higher incidence of symptoms than clinicians, emphasizing the need for patient-centric tools to accurately capture the patient experience. Both treatments exhibited rapid and sustained improvements in HRQoL and lymphoma symptoms, with the most substantial improvements seen in global health status/QoL, lymphoma symptoms, fatigue, role, emotional, and social functioning. GI symptoms (diarrhea, constipation, nausea, and vomiting) were generally similar between treatment arms and returned to baseline levels after treatment completion. These HRQoL data underscore the complementarity of PROs, as an adjunct to clinician-reported AEs, in evaluating the efficacy and tolerability of new treatments, including Pola-R-CHP, which may represent a new benchmark for patient-reported HRQoL in previously untreated DLBCL. This trial was registered at www.clinicaltrials.gov as NCT03274492.