Citations

Abstract Background: Perineural invasion (PNI) is a key prognostic factor in oral squamous cell carcinoma (OSCC). Recent studies have proposed the importance of subcategorizing PNI based on location in relation to the tumor. However, current gaps in definition of PNI subcategories limit its integration into staging system and treatment planning. This study evaluates the prognostic value of the presence of PNI and its location, in correlation with other tumor characteristics, and examines their relationship with survival and recurrence. Design: A total of 159 patients with histologically confirmed OSCC from February 2022–May 2025 were included in the study. PNI was subclassified into intratumoral, peripheral and extratumoral. Association of PNI metrics with other prognostic factors (margin status, lymph node metastasis [LN mets], and lymphovascular invasion [LVI]) were assessed using a Fisher’s exact test (categorical variables). Comparisons of disease-free survival (DFS) and overall survival (OS) between the PNI subgroups were made with a logrank test. Cox proportional hazards regression models were used to find univariate predictors of death and the composite outcome of recurrence or death. A p value <0.05 was considered statistically significant. Statistical analyses were performed using R Statistical Software (version 4.4.1; R Foundation for Statistical Computing, Vienna, Austria). Results: 49/159 cases were PNI positive. Median age: 69 years and male predominance (58.5%). Floor of mouth was the most common site. Presence of PNI correlated significantly with positive margins and positive LVI (p = 0.013 and 0.048 respectively). However, only peripheral PNI showed significant correlation with LN mets (p = 0.004). On univariate analysis, the strongest predictors of recurrence or death were larger tumor size (p <0.001); presence of PNI (p = 0.014), especially intratumoral (p = 0.003); positive LN mets (p = 0.024); and non-white race (p = 0.023). Both DFS and OS were significantly worse in patients with PNI compared with those without (DFS: p = 0.012, OS: p = 0.018). Subclassification of PNI showed a significantly poorer DFS and OS in cases with intratumoral PNI (DFS: p = 0.002, OS: p = 0.012), but not with extratumoral or peripheral PNI.

ABSTRACT Palliative care can be offered concurrently as a treatment option to patients with pulmonary arterial hypertension (PAH) to relieve symptoms and improve quality of life. However, it is infrequently used and is associated with misconceptions. Limited studies have reported patients' perspectives of palliative care as a treatment option for PAH. We conducted a web‐based survey, informed by a brief targeted literature review and input from patients and clinicians, which was completed by adults (≥ 18 years) in the United States (US) with self‐reported PAH. Patients reported demographic and disease variables and their perspectives and experiences with palliative care. Patients self‐reported their Pulmonary Hypertension Functional Class Self‐Report class, EmPHasis‐10, and 6‐min walk test. A total of 200 respondents (86.5% female; mean age 58.5 years) from 42 US states completed the survey between 19 September and 3 October 2023. Most respondents described palliative care as “end‐of‐life care” ( n = 43, 25.7%) and associated it with the need for extra support ( n = 111, 55.5%). Many respondents ( n = 171, 85.5%) had not discussed palliative care services, nor had a palliative care consultation with their healthcare provider (HCP); most had not been offered a consultation ( n = 109/171, 63.7%). Despite this low frequency of discussions, respondents reported feeling comfortable discussing palliative care with their HCPs ( n = 177, 88.5%). The survey results demonstrated that these patients with PAH had limited experiences with palliative care, where palliative care was frequently subject to misinterpretation. These findings emphasize the need for proactive engagement between patients and HCPs to ensure palliative care is optimally used and understood.

Abstract The impact of microglia antigen presentation on CNS infiltrating CD8 T cells responses during neurotropic virus infection remains undefined. Using Theiler’s murine encephalomyelitis virus (TMEV) infection of neurons as a model system, we generated H-2K b and H-2D b Tmem119 conditional knockout mice. During TMEV infection, we determined using Tmem119 K b cKO mice that microglia H-2K b contributes to antiviral CD8 T cell proliferation in the brain. Meanwhile, using Tmem119 D b cKO mice we determined that microglia H-2D b increased antiviral CD8 T cell perforin levels and the capacity to induce blood-brain barrier (BBB) disruption. Furthermore, microglial H-2D b was essential for antigen-specific reactivation of CD8 tissue resident memory (TRM) cell recall responses and BBB disruption long after virus had been cleared. These findings demonstrate discrete roles of individual MHC class I genes on microglia in CD8 T cell proliferation, effector functions, memory recall and neuropathology.

Abstract Aims Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events in diabetics. This study aimed to investigate the cardiac, cancer, and overall mortality effects of GLP-1 RAs in diabetics treated with anthracyclines. Methods and results We retrospectively identified 1384 diabetics treated with anthracyclines from 2013 to 2023; 56 received GLP-1 RAs between their first and last dose of anthracycline. These patients were propensity score matched 4:1 to 224 controls without concurrent GLP-1 RA use. Because stage was not available for 10 of the 56 patients, a repeat analysis was conducted with additional matching for cancer stage in 46 cases and 92 controls. Major endpoints were rate of all-cause and cancer-related and cardiovascular disease (CVD)–related mortality, no evidence of disease (NED), and hospitalization for CVD including heart failure (HF), over 5 years. Survival analyses were conducted using cause-specific hazards Cox regression. Patients on GLP-1 RAs had a significantly lower 5 year overall mortality (HR 0.46, CI 0.24–0.87, P = 0.007) and cancer-related mortality (HR 0.42, CI 0.19–0.91, P = 0.03). This mortality risk reduction remained significant even when accounting for covariates (HR 0.39, CI 0.20–0.75, P = 0.002). The percentage of patients with NED was higher in the GLP-1 RA than control group (60.9% vs. 38.0%, P = 0.007). A decline in left ventricular ejection fraction was seen in controls but not in patients on GLP-1 RAs. There was no significant difference in CVD hospitalization; the rate of HF-related hospitalization was very low overall. Conclusion GLP-1 RAs may offer survival benefits and better cancer- and cardiac function-related outcomes in diabetics undergoing anthracycline chemotherapy.

Chronic pelvic pain (CPP) represents a complex condition where peripheral nociceptive drivers and central nervous system processes produce symptoms that extend beyond the pelvis. Central sensitization (CS) is a state of heightened neuronal responsiveness with amplified pain signaling and diminished inhibitory control, in which patients experience multifocal pain, fatigue, sleep disturbance, cognitive difficulties, and hypersensitivity to sensory stimuli. Management of CS requires a multimodal and comprehensive approach, including pain neuroscience education, targeted pelvic physical therapy, and behavioral therapies. As the field advances, incorporating sensitization science offers a more accurate, patient-centered framework to reduce symptom burden and improve quality of life.

Stroke is the third leading cause of death in women and a major driver of disability. Menopause is a universal transition for midlife women, which is accompanied by menstrual cycle changes, hormonal fluctuations, and, for many women, the occurrence of menopausal symptoms. An accumulating body of research underscores the importance of menopause and its features to stroke risk in women, including the type and timing of menopause, endogenous hormone profiles, and menopausal symptoms, including vasomotor symptoms and sleep problems. In addition, menopausal hormone therapy, a leading approach to managing menopausal symptoms, has implications for stroke risk, which varies depending on the menopausal hormone therapy formulation, route of delivery, and the age and health of the recipient, with transdermal menopausal hormone therapy formulations administered to younger midlife women showing a more favorable profile. This review summarizes the data linking menopause and stroke, and offers suggestions to inform clinical decision-making. Knowledge gaps and directions for future research are highlighted.

Abstract Current advances in the treatment of melanoma brain metastases through immune checkpoint blockade and targeted therapy has significantly improved outcomes and patient survival. Yet, half of all patients continue to die from brain metastases despite use of these therapies and the addition of localized therapies like surgery and stereotactic radiosurgery. Novel treatments are needed to improve the morbidity and mortality associated with melanoma brain metastases. We have identified the inflammatory myddosomal pathway as a novel potential target of therapy in melanoma brain metastases, with gross upregulation in both tumor tissue and tumor-infiltrating immune cells. These cells display upregulation in MYD88, IRAK-1, IRAK-4, and downstream mediators of inflammatory activation at both the gene and protein level. We have previously shown the ability of the oral IRAK-4 inhibitor emavusertib (CA-4948) to penetrate the blood brain barrier and inhibit the myddosomal pathway in metastatic melanoma and primary CNS lymphoma. In this study we further show the capacity for IRAK-4 inhibition with emavusertib to improve the therapeutic efficacy of anti-PD-1 immune checkpoint blockade in melanoma brain metastases. Emavusertib in combination with anti-PD-1 therapy results in improved tumor-infiltrating lymphocyte recruitment, decreased myeloid derived suppressor cell function, and upregulation of interferon γ signaling resulting in improved survival in aggressive mouse models of melanoma brain metastases. This work supports the development of combination strategies of emavusertib with immune checkpoint blockade in melanoma brain metastases.

Abstract Embryonal tumors with multilayered rosettes (ETMR) are rare, highly aggressive tumors of infancy with extremely poor outcomes and no established standard of care therapy. ETMRs were recognized as a distinct molecular entity in 2016, however, the absence of prospective, biology-driven clinical trials has limited translation of these insights into standardized, risk-adapted treatment approaches for this vulnerable population. To address this gap, the Collaborative Network for Neuro-oncology Clinical Trials (CONNECT) developed CURE(Clinical trial advancing Understanding of Rare Embryonal Brain Tumors), an international, multi-institutional, molecularly guided umbrella trial. All patients enroll through the centralized CURE-Screening protocol, which provides rapid comprehensive molecular profiling with real-time central pathology, molecular, and radiographic review to confirm diagnosis, define molecular subtype, and determine eligibility and assignment to disease-specific treatment arms. CURE-ETMR represents the first disease-specific arm to open within this platform. Following centralized screening, children with newly diagnosed ETMR are assigned to clinically defined risk strata using integrated molecular, radiographic, and clinical criteria. Patients will be treated using a risk-adapted multimodal approach in which we prioritize maximal safe surgical resection with consideration of second-look surgery based on centralized imaging review; administer induction chemotherapy followed by consolidation with high-dose chemotherapy and autologous hematopoietic cell rescue or dose-intensified chemotherapy, selectively incorporate radiation sparing approach or early focal radiotherapy for patients with unresectable residual disease or brainstem involvement; deliver intrathecal chemotherapy for leptomeningeal prophylaxis; and include biologically informed maintenance therapy. In parallel, protocol-required longitudinal collection of tumor tissue, cerebrospinal fluid, blood, and advanced neuroimaging supports integrated molecular, liquid biopsy, and imaging biomarker analyses to identify predictors of treatment response, resistance, and relapse. Primary objectives include evaluation of feasibility, safety, progression-free survival, and overall survival compared with molecularly annotated historical cohorts. This centralized screening to assignment framework establishes a scalable model for prospective, biology-driven trials in rare embryonal brain tumors.

Abstract Background Rare pediatric and young adult brain tumors pose major diagnostic and therapeutic challenges due to limited evidence and scattered expertise. The International Rare Brain Tumor Board was established to enable multidisciplinary case review, shared learning, and collaborative decision support. Methods Launched in February 2025, the Rare Brain Tumor Board is a monthly collaborative initiative led by Children’s National Hospital and the National Institutes of Health (NIH). Close partnership with the European Pediatric Rare CNS Tumor Board enhances transatlantic exchange and alignment of diagnostic and treatment recommendations. De-identified cases are presented with clinical history, neuroimaging, histopathology, and molecular profiling, including DNA methylation classification, available for the majority of cases. Sessions are structured to support integrated diagnosis and evidence-informed management recommendations through multidisciplinary discussion (neuropathology, neuroradiology, neurosurgery, radiation oncology, and pediatric as well as adult neuro-oncology). Findings Since its inception, 12 sessions have been held averaging 138 participants per session, reviewing a total of 32 cases (mean 3 cases/session; range 1–4) from 7 different countries and 3 different continents. Entities reviewed include DICER1-intracranial sarcoma (n = 5), astroblastoma (n = 4), FOXR2-activated neuroblastoma (n = 4), CNS tumors with BCOR internal tandem duplication (n = 3) and, BCOR-fused tumors (n = 3), CIC-rearranged-sarcoma (n = 3), intracranial mesenchymal tumor FET::CREB fusion positive (n = 3), MN1::PATZ1 fusion tumors (n = 2), undifferentiated sarcoma (n = 2), PLAG1-fusion tumor (n = 1), medullomyoblastoma (n = 1), and EZHIP-altered diffuse midline glioma (DMG) (n = 1). Multidisciplinary review has supported diagnostic clarification, strengthened familiarity with ultra-rare entities, and informed real-world treatment discussions in settings where prospective data are limited. Discussions have also increased awareness of rare brain tumor registries and opportunities for systematic case capture. Conclusion An international multidisciplinary rare brain tumor board is a feasible, scalable model to advance integrated diagnosis and collaborative management of ultra-rare pediatric and young adult brain tumors, while building a shared knowledge base across institutions.