Citations

Abstract Oncogenic BRAF alterations occur in a subset of diffuse gliomas across WHO grades and are increasingly identified through modern molecular diagnostics. In addition to standard glioma therapies, targeted treatments are available for patients with BRAF-altered glioma supported by variable evidence spanning randomized trials, single-arm studies, and real-world evidence. This joint consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO) synthesizes current knowledge on the diagnosis and management of BRAF-altered gliomas across age groups, tumor grades, and lines of therapy. Particular emphasis is placed on expert consensus in clinical scenarios where high-quality trial evidence remains limited. The review addresses rationale testing for BRAF alterations, selection, and monitoring of targeted therapies, management of treatment-related toxicities, approaches to resistance, and priorities for future research. It aims to provide practical, evidence-based guidance for clinicians while highlighting gaps to inform prospective studies.

Objectives: Consensus clinical criteria for refractory septic shock were recently developed, but the incidence and outcomes with these criteria are unknown. There were two aims: 1) to describe the incidence of refractory septic shock and 2) to assess outcomes of patients with septic shock meeting refractory septic shock criteria compared with those who did not. Design: Multicohort, retrospective study. For aim 1, a descriptive epidemiologic study was designed to ascertain the cumulative incidence of refractory septic shock in patients with septic shock. For aim 2, a cohort study was conducted to compare hospital mortality between patients meeting refractory septic shock clinical criteria compared with those who did not. Setting: Large U.S. health system from 2012 to 2024. Patients: Adults (age ≥ 18 yr) meeting both Centers for Disease Control and Prevention Adult Sepsis Event and Sepsis-3 clinical criteria for septic shock. Patients with missing hospital discharge disposition and incomplete vasopressor dosage information were excluded. Interventions: None. Measurements and Main Results: Clinical criteria for refractory septic shock were operationalized as concomitant occurrence of norepinephrine (base) equivalent greater than 0.5 µg/kg/min and lactate greater than 2 mmol/L. Risk-adjusted hospital mortality was assessed with a generalized linear mixed-effects model with a random effect for hospital and fixed effects for age, sex, Elixhauser Comorbidity Index, and Sequential Organ Failure Assessment (original description, without cardiovascular component). Of 35,914 patients assessed, 15,732 patients with septic shock were included. Refractory septic shock occurred in 3423 patients (21.8%), with a cumulative incidence of 218 cases (95% CI, 211–224) per 1000 patients with septic shock. Hospital mortality with refractory septic shock was 64.4%, and risk-adjusted hospital mortality odds were 4.87-fold higher (95% CI, 4.46–5.31) compared with patients without refractory septic shock. Conclusions: Clinical criteria for refractory septic shock were fulfilled in about one in five patients with septic shock and associated with substantially higher mortality.

Objectives: The electroconvulsive therapy for the acute management of severe agitation in dementia (ECT-AD) trial is a multisite study evaluating the effectiveness of ECT for severe agitation in individuals with advanced dementia. Given that participants lack decisional capacity because of advanced cognitive impairment, the trial required a structured and ethically sound approach to obtaining informed consent and assent across jurisdictions with differing legal requirements, including Massachusetts, New York, Georgia, Minnesota, and Michigan. This paper describes the approach used in the study. Methods: We describe the consent framework developed for the ECT-AD trial, including procedures for identifying legally authorized representatives, complying with state-specific laws for ECT consent, obtaining surrogate consent for research participation, and assessing patient assent and dissent using a standardized tool. Conclusions: The approach used in this study may serve as a practical model for future research involving individuals without decision-making capacity and legally complex interventions such as ECT.

INTRODUCTION: Alcohol-associated hepatitis (AH) is a severe condition with high short-term mortality. Identifying key predictors of poor outcomes is critical for guiding therapeutic strategies. Mean arterial pressure (MAP), a key determinant of tissue perfusion and systemic hemodynamics, may play a pivotal role in prognosis. METHODS: We analyzed a multicenter, prospective cohort of 323 patients hospitalized with AH, with validation in an independent cohort of 290 patients. Survival was evaluated using Kaplan-Meier curves and compared with the log-rank (Mantel-Cox) test. Cox proportional hazards models were used to estimate hazard ratios for mortality, adjusted for Model for end stage liver disease score. Mechanistic insights were explored through assessment of cardiovascular biomarkers. RESULTS: A baseline MAP <80 mm Hg was associated with significantly higher mortality at both 28 days (27.3% vs 8.0%) and 90 days (40.3% vs 15.6%; P < 0.001 for both). This association persisted after adjusting for Model for end stage liver disease score, age, and baseline hepatic encephalopathy. The incidence of infections during follow-up was similar across MAP groups (27.6% vs 22.8%), but acute kidney injury occurred more frequently in the MAP <80 mm Hg group (62% vs 38%, P < 0.001). In the validation cohort, patients with MAP <80 mm Hg also demonstrated significantly lower 28-day transplant-free survival. Although B-type natriuretic peptide and plasma renin levels were altered in patients with AH, they did not correlate with MAP values. DISCUSSION: A baseline MAP <80 mm Hg is an independent predictor of short-term and mid-term mortality in patients with AH. Strategies aimed at restoring hemodynamic stability may improve outcomes in this high-risk population.

Abstract Objective This study was undertaken to evaluate the safety and effectiveness of responsive thalamic stimulation as adjunctive therapy for drug‐resistant idiopathic generalized epilepsy (IGE) with generalized tonic–clonic seizures (GTCSs). Methods NAUTILUS is a prospective, multicenter, single‐blind, randomized sham‐controlled pivotal trial. Patients were ≥12 years of age with drug‐resistant IGE and ≥2 GTCSs over a 3‐month baseline. Bilateral depth leads were targeted to the centromedian thalamus. One month later, patients were randomized to Active (responsive stimulation, n = 44) or Sham (no stimulation, n = 43). The effectiveness evaluation period (EEP) began 3 months postimplant through 1 year. After a second GTCS in the EEP, patients transitioned to open‐label active stimulation. The primary safety endpoint was the serious adverse device‐related event (SADE) rate at 84 days postimplant. The primary effectiveness endpoint was time‐to‐second‐GTCS during the EEP. Additional endpoints included median percent change in days with any generalized seizure, GTCS frequency, and responder rate (RR). Results Eighty‐seven patients were implanted across 23 US centers. The SADE rate was significantly below the performance goal (6.9%, p < .0001), with no adverse effects on cognition, mood, or sleep. The prespecified primary effectiveness endpoint was not significant. However, a post hoc mixed‐effects model considering all EEP days demonstrated greater GTCS reduction in the originally randomized Active group (61%) compared to patients originally randomized to Sham (49%, p = .030). Eighteen‐month outcomes included 76.8% median GTCS reduction, 62.5% RR, 40% GTCS‐free at that timepoint, and 77.8% median reduction in days with any generalized seizure. More than 90% of patients and 86% of physicians reported improvement on Global Impression of Change scales. Significance NAUTILUS is the first randomized controlled neuromodulation trial in IGE. Responsive thalamic stimulation provided a clinically meaningful and durable reduction in seizures with an acceptable safety profile, offering a much‐needed option for drug‐resistant IGE.

Lung cancer remains the leading cause of cancer-related mortality worldwide. Although small cell lung cancer (SCLC) accounts for a smaller percentage of lung cancer cases, it has remained a significant contributor to the overall mortality burden because of its inherently aggressive nature. Over several years, and until recently, there have been no major breakthroughs in the management of SCLC. Concurrent chemoradiation with platinum doublet chemotherapy has remained the mainstay of treatment in limited-stage disease, with chemotherapy being the main and only treatment in extensive stage. Despite having an initial good response to those treatments in most patients, progression of cancer has been nearly inevitable, with no additional effective therapeutic options, and the majority of patients with SCLC dying of their disease. Fortunately, the last decade has witnessed some major scientific advances addressing the huge unmet needs in the realm of SCLC management and ushered in renewed hope in the lung cancer community. From approval of immune checkpoint inhibitors and lurbinectedin, a newer chemotherapy agent, to novel immunotherapies such as tarlatamab, a DLL3-CD3 bispecific T-cell engager, and other upcoming promising drugs, the therapeutic armamentarium for SCLC is steadily expanding. In this study, we review the current landscape of both systemic therapy as well as radiation therapy for SCLC, with a focus on major developments over the past decade, current standards of care, and novel therapeutics that are expected to revolutionize the treatment of this aggressive malignancy.

ABSTRACT Background and Objectives Occult intra‐abdominal metastases are identified in approximately 20% of patients with radiographically localized pancreatic ductal adenocarcinoma (PDAC) through staging laparoscopy, as peritoneal cytology is limited in sensitivity. Methylated DNA markers (MDMs) have demonstrated high diagnostic accuracy for PDAC in tumor tissue, blood, and pancreatic secretions. This study assesses the feasibility and diagnostic performance of MDMs in peritoneal lavage fluid collected during staging laparoscopy, comparing their performance to mutant KRAS (m KRAS ) detection. Methods DNA from peritoneal lavage fluid of PDAC patients was analyzed for m KRAS mutations (codons 12, 13, and 61) using droplet‐digital PCR and for 13 MDMs and a reference gene (B3GALT6) using quantitative methylation‐specific PCR. An MDM score was generated from the average signal of the 13 MDMs and evaluated for its ability to detect intra‐abdominal metastases via receiver operator characteristic (ROC) analysis. Results Among 48 patients, 15 (31%) had intra‐abdominal metastases. The MDM score showed 87% sensitivity and 90% specificity (AUC = 0.98), outperforming m KRAS , which showed 40% sensitivity and 85% specificity (AUC = 0.62; p < 0.0001). Conclusions MDMs in peritoneal lavage fluid may enable highly accurate molecular staging of PDAC and warrant validation in larger studies.

Abstract Repetitive head impacts sustained during American football have been associated with neuropathological changes such as white matter shear injuries. However, the impact of specific factors, such as age of first exposure and cumulative head impact burden, on white matter integrity remains unclear. This study investigated in vivo white matter microstructural changes using diffusion tensor imaging and tract-based spatial statistics in 165 male former American football players (mean age 57.3 years, range 45–74) and 52 unexposed asymptomatic male controls (mean age 59.4 years, range 45–74) in the DIAGNOSE CTE Research Project. Compared to controls, former football players exhibited significantly higher fractional anisotropy (FA) in 1.97% of the white matter skeleton (1552 voxels; Cohen’s d = 0.587) and higher tissue-corrected FA (FAt) in 1.48% of the white matter skeleton (1004 voxels; Cohen’s d = 0.616). No significant differences were observed for mean diffusivity, axial diffusivity, radial diffusivity, or free water between football players and controls. Among football players, there were no significant differences in the white matter microstructure between players diagnosed with traumatic encephalopathy syndrome and those without the diagnosis. Lower FA was significantly associated with older age (P &lt; 0.00001) and an earlier age of first exposure to tackle football (P &lt; 0.01), while lower FAt was associated with greater cumulative head impact burden, specifically higher linear acceleration (P &lt; 0.04) and rotational force (P &lt; 0.02). This study highlights the influential role of exposure factors on white matter microstructure in former American football players, as well as the utility of diffusion tensor imaging to aid in characterizing the long-term effects of repetitive head impacts in contact sport athletes.

TPS6126 Background: Oral cavity cancers (OCC) are a rare subtype of head and neck cancer (HNC) with poor outcomes and limited second-line treatment options in the recurrent or metastatic (R/M) setting. Treatment-related morbidity and repeated local recurrences in OCC result in significant impairment of function and quality of life. Rural OCC patients comprise a sizable portion (50%) of our practice and are usually of lower socioeconomic status with lack of access to specialist care. They also have multiple barriers to treatment access and ancillary services, translating to poorer clinical outcomes. There is a critical need for effective and accessible therapies for R/M OCC in rural patients. Triple oral metronomic chemotherapy (TOMC) with Methotrexate, Erlotinib and Celecoxib (MEC) suppresses angiogenesis and activates antitumor microenvironment in HNC. Studies using TOMC in R/M OCC outside the US show reasonable efficacy (6-month OS 52.9%), better safety and lower cost compared to standard second line options. We hypothesize that a decentralized clinical trial with TOMC in R/M OCC is feasible, safe and effective in addition to being economical and accessible for rural patients. Methods: MC240701 is a single institution, open label, decentralized, single arm pilot study of MEC in patients with R/M OCC. Eligible pts must be ≥18 years old, have pathologically confirmed R/M OCC not amenable to curative-intent therapy, ECOG 0-2 and adequate organ function. At least 1 measurable lesion by RECIST 1.1 OR non-measurable disease (evident mucosal lesions, CNS/bone disease, lesions not meeting RECIST criteria) is permitted. Patients must have received standard first line immunotherapy with or without chemotherapy OR should be unable/unwilling to receive first line treatment. Key exclusion criteria include patients unable to take pills by mouth, serious medical co-morbidity or autoimmune disease, immunocompromised patients and other active malignancy. Primary endpoint is to demonstrate feasibility of decentralized clinical trials, secondary outcomes include overall response rate, progression free and overall survival and toxicity. Additional goals are to evaluate patient impact of decentralized treatment through surveys and interviews After initial screening and evaluation, patients are remotely consented and will receive study drugs by mail. All patients will receive the same treatment of Methotrexate 9mg/m 2 PO weekly, Erlotinib 150 mg PO daily, and Celecoxib 200 mg PO BID, each cycle will be 28 days. Treatment will continue until disease progression or treatment tolerance, study duration is for 2 years. All subsequent clinical and laboratory monitoring and response assessments (every 3 cycles) will be remotely performed or have an option for local testing. Enrollment began July 2025 and 4 out of planned 25 patients have been accrued. FDA IND:174540. Clinical trial information: NCT06997068 .