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PURPOSE Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH -wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH -wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH -mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], P interaction < .001). In IDH -wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/–10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH -mutant glioma. CONCLUSION In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

Abstract Glioblastoma (GBM) remains the most aggressive primary adult brain cancer with limited therapeutic options. Our prior research demonstrated that androgen receptor antagonists (ARAs) enhance survival in GBM mouse models by preferentially suppressing glioma stem cells. This study investigates the potential of ARAs as radiosensitizers in combination with radiotherapy (RT). Combined effects of ARAs and RT were evaluated using an orthotopic GBM mouse model. RNA-Seq and TCGA analyses delineated AR-associated regulatory networks, while integrated cellular and molecular approaches utilizing human and mouse GBM cell lines, as well as in patient-derived primary high-grade glioma cultures, interrogated signaling and immune paradigms. ARA treatment induced G2/M cell cycle arrest, apoptosis, and downregulated DNA repair genes, with AR expression correlating with the DNA repair and TGF-β pathway. In both immortalized GBM cell lines and primary high-grade glioma cultured cells, ARAs in combination with RT showed only a modest enhancement of radiosensitivity. However, in an orthotopic GBM mouse model, ARA + RT demonstrated a strong synergy, achieving 100% long-term survival, compared to less than 50% with ARA alone and 0% with RT alone. Mechanistically, ARA modulated the TGF-β pathway, durably switching from Smad3 linker to c-terminal phosphorylation (pSmad3C) and inhibiting LIF/STAT3 axis. Distinct TGF-βs ligand expression patterns were observed in ARA-treated GBM cells. A protein–protein interaction noted between AR and Smad3, which was disrupted following ARA treatment, leading to elevated protein levels and nuclear localization of pSmad3C (S423/425), indicating normalization/activation of the TGF-β/pSmad3C-dependent anti-tumorigenic cascade. Comprehensive analyses in GBM cell lines and mouse model tissues demonstrated pathway reprogramming characterized by elevated TGF-β2 and increased pSmad3C. Tissue analysis revealed immune activation in the tumor microenvironment, while peripheral blood and spleen showed systemic immune responses following ARA + RT. Our study provides novel insights into how ARAs enhance RT efficacy through immunomodulation involving TGF-β/pSmad3C cascade, offering therapeutic implications in GBM.

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 &gt;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 &lt;.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.

PURPOSE Survival for patients with melanoma has recently improved. The propensity of melanoma to metastasize to the brain remains a common and serious feature of this disease. The purposes of this study were to evaluate prognostic factors for patients with newly diagnosed melanoma brain metastases (MBMs) in a large cohort treated with modern multimodal therapies, compare those results with those in prior eras, and update the Melanoma Graded Prognostic Assessment (GPA). METHODS Univariable and multivariable (MVA) analyses of prognostic factors and treatments associated with survival were performed on 1,796 patients with newly diagnosed MBM treated between January 01, 2015, and December 31, 2021, using a multi-institutional retrospective database. Multiple imputation was used to address missingness of potential predictors. Significant variables in combined MVA were used to update the Melanoma GPA. Comparisons were made with legacy cohorts. RESULTS Median survivals for cohorts A (1985-2007, n = 481), B (2006-2015, n = 823), and C (2015-2021, n = 1,796) were 6.7, 9.8, and 16.6 months and median follow-up times were 40.1, 43.6, and 48.8 months, respectively. In combined MVA, significant prognostic factors for survival were higher Karnofsky Performance Status, fewer MBMs, absence of extracranial metastases, lower serum lactate dehydrogenase, and no immunotherapy before MBM. These factors were incorporated into the updated Melanoma GPA. The combined median and 3-year survivals for patients with GPA 0-1, 1.5-2, and 2.5-4.0 were 5.4, 13.2, and 43.2 months and 12.4%, 28.8%, and 51.6%, respectively. CONCLUSION Prognostic factors have changed and survival has improved for patients with MBM but varies widely by GPA. The updated Melanoma GPA calculator (BrainMetGPA), available free online, can be used to estimate survival, individualize treatment, stratify clinical trials, guide surveillance, and augment clinical trial eligibility. Multidisciplinary treatment is essential. Trials are needed to elucidate the optimal sequencing of various therapeutic modalities.

AbstractGastroenteropancreatic neuroendocrine tumours (GEP‐NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non‐secreting (also known as non‐functioning NETs) are associated with severe morbidity and have a median overall survival of 75–124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP‐NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled‐receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP‐NET subtypes. Using RNA‐Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non‐functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP‐NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC‐seq analyses in the pancreatic NET cell line QGP‐1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP‐1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP‐NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type.

Abstract Background IDH-wild type (-wt) status is a prerequisite for the diagnosis of glioblastoma (GBM); however, IDH-wt gliomas with low-grade or anaplastic morphology have historically been excluded from GBM trials and may represent a distinct prognostic entity. While alkylating agent chemotherapy improves overall survival (OS) and progression-free survival (PFS) for IDH-wt GBM and also IDH-mutant gliomas, irrespective of grade, the benefit for IDH-wt diffuse histologic lower-grade gliomas is unclear. Methods We performed a meta-analysis of randomized clinical trials for World Health Organization (WHO) grades 2–3 gliomas (2009 to present) to determine the effect of alkylating chemotherapy on IDH-wt and -mutant gliomas using a random-effects model with inverse-variance pooling. Results We identified 6 trials with 1204 patients (430 IDH-wt, 774 IDH-mutant) that evaluated alkylating chemoradiotherapy versus radiotherapy alone, allowing us to perform an analysis focused on the value of adding alkylating chemotherapy to radiotherapy. For patients with IDH-wt tumors, alkylating chemotherapy added to radiotherapy was associated with improved PFS (HR:0.77 [95% CI: 0.62–0.97], P = .03) but not OS (HR:0.87 [95% CI: 0.64–1.18], P = .17). For patients with IDH-mutant tumors, alkylating chemotherapy added to radiotherapy improved both OS (HR:0.52 [95% CI: 0.42–0.64], P &lt; .001) and PFS (HR = 0.47 [95% CI: 0.39–0.57], P &lt; .001) compared to radiotherapy alone. The magnitude of benefit was similar for IDH-mutant gliomas with or without 1p19q-codeletion. Conclusions Alkylating chemotherapy reduces mortality by 48% and progression by 53% for patients with IDH-mutant gliomas. Optimal management of IDH-wt diffuse histologic lower-grade gliomas remains to be determined, as there is little evidence supporting an OS benefit from alkylating chemotherapy.

Background and importance Neurointervention is a very competitive specialty in the United States due to the limited number of training spots and the larger pool of applicants. The training standards are continuously updated to ensure solid training experiences. Factors affecting candidate(s) selection have not been fully established yet. Our study aims to investigate the factors influencing the selection process. Methods A 52-question survey was distributed to 93 program directors (PDs). The survey consisted of six categories: (a) Program characteristics, (b) Candidate demographics, (c) Educational credentials, (d) Personal traits, (e) Research and extracurricular activities, and (f) Overall final set of characteristics. The response rate was 59.1%. As per the programs’ characteristics, neurosurgery was the most involved specialty in running the training programs (69%). Regarding demographics, the need for visa sponsorship held the greatest prominence with a mean score of 5.9 [standard deviation (SD) 2.9]. For the educational credentials, being a graduate from a neurosurgical residency and the institution where the candidate's residency training is/was scored the highest [5.4 (SD = 2.9), 5.4 (SD = 2.5), respectively]. Regarding the personal traits, assessment by faculty members achieved the highest score [8.9 (SD = 1)]. In terms of research/extracurricular activities, fluency in English had the highest score [7.2 (SD = 1.9)] followed by peer-reviewed/PubMed-indexed publications [6.4 (SD = 2.2)]. Conclusion Our survey investigated the factors influencing the final decision when choosing the future neurointerventional trainee, including demographic, educational, research, and extracurricular activities, which might serve as valuable guidance for both applicants and programs to refine the selection process.

PURPOSE Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non–small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

Abstract Background Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). Methods A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. Results The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors—nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17–28 mo, P = 0.12; HER2, 15–19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27–18 mo, P = 0.02; HER2, 30–18 mo, P = 0.08). Conclusions Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. Key Points 1. Receptor discordance alters subtype in 32% of BCBM patients. 2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively. 3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.