Citations

Preserving Cognition and Reducing Dementia Risk in Focal Epilepsy Tai XY, Zhao S, Liem B, Galovic M, Husain M, Sen A, Manohar S. The Relationship Between Sleep, Cognition, and Dementia Risk in People With Focal Epilepsy. Neurology. 2026 May 26;106(10):e214985. doi: 10.1212/WNL.0000000000214985. Epub 2026 Apr 22. PMID: 42018962 Background and objectives: Sleep disruption and cognitive impairment are important comorbidities of focal epilepsy. However, the nature to which sleep affects cognition and long-term dementia risk in focal epilepsy, compared with other brain conditions, remains unclear. We examined the relationship between sleep, cognition, and dementia risk in patients with focal epilepsy compared with healthy controls and stroke patients. Methods: We conducted an analysis of the prospective UK Biobank cohort study, with baseline assessments performed between 2006 and 2010 and follow-up until 2021. Study groups were mutually exclusive participants with focal epilepsy and stroke at baseline assessment and healthy controls. Sleep characteristics included reports of sleep duration, obstructive sleep apnea, insomnia, napping, and dozing. Main outcomes were risk of incident all-cause dementia and Alzheimer’s disease from Cox proportional hazard modeling and comparison of executive function measures and brain total hippocampal and gray matter volumes using generalized linear modeling. Results: We examined a sample of 482,207 participants, aged between 38 and 72 years (mean [SD] 57.6 [8.1] years; 53.8% female), without dementia at baseline and a nested imaging subsample of 42,345 participants. Optimal sleep duration (6-8 h) was associated with better executive function in control, focal epilepsy, and stroke groups. The impact of optimal sleep was significantly higher in individuals with focal epilepsy compared with controls (interaction term, p = 0 . 009), but not in the stroke group (interaction term, p = 0 . 574). Nonoptimal sleep was associated with worse executive function up to 8 years before the diagnosis of focal epilepsy. A fivefold increased risk of developing dementia was seen in individuals with focal epilepsy and nonoptimal sleep (hazard ratio [HR] 5.15, 95% CI: 3.77–7.04, p < 0 . 001) compared with healthy controls with optimal sleep. This was greater than in stroke individuals with poor sleep (HR 3.48, 95% CI: 2.82–4.26, p < 0 . 001). Optimal sleep compared with nonoptimal sleep modified the dementia risk in individuals focal epilepsy, with a significantly greater improvement compared with healthy controls (interaction term p = 0 . 017), while no significant difference was seen in the stroke group (interaction term p = 0 . 991). Discussion: Optimal sleep modified both cognitive performance and dementia risk in individuals with focal epilepsy compared with stroke patients and healthy controls. Based on self-reported sleep data, these findings suggest that improving sleep may be an impactful intervention to improve cognition and reduce dementia risk particularly in focal epilepsy.

Radiation therapy is central to the management of gynecological cancers, including endometrial, cervical, ovarian, and vaginal malignancies. Despite advances in photon-based techniques, treatment-related toxicity remains significant owing to the anatomical proximity of pelvic targets to critical organs at risk (OARs), including the bowel, bladder, and bone marrow. Proton beam therapy exploits the Bragg peak to deliver a precise dose at depth with minimal exit dose, potentially reducing OAR exposure. This review develops the physical principles, dosimetric evidence, and early clinical data for proton therapy in gynecological malignancies, including cervical, endometrial, ovarian, vaginal, and vulvar cancers. Major focus is given to clinical conditions where conventional brachytherapy is not practical, and proton therapy may offer the greatest advantages, such as reirradiation for recurrent disease, post-operative pelvic irradiation, and extended field nodal treatment. This review also emphasizes current constraints that have slowed down wide clinical implementation, such as the lack of mature prospective data, cost, and accessibility. Finally, we emphasize future directions, including well-designed comparative trials, integration with systemic and immunotherapies, and adaptive treatment strategies. As the body of accumulated evidence evolves, the proton beam therapy potential for the treatment of gynecological malignancies has tremendously increased due to its role in safety and personalization of radiation treatment.

Abstract Purpose: The addition of MEK inhibition (MEKi) to programmed cell death ligand 1 (PD-L1) blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer. Although MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy. We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance antitumor immunity in this combination. Patients and Methods: We conducted a randomized, phase II trial evaluating atezolizumab (840 mg, intravenously, days 1 and 15) in combination with the CD27 costimulatory monoclonal antibody [CDX-1127/varlilumab (3 mg/kg, intravenously, days 1 and 15)], with/without the addition of an MEK inhibitor [cobimetinib (60 mg, orally, daily, days 1–21, off days 22–28)] in unresectable biliary tract cancer following at least one metastatic therapy. Overall response rate (ORR) and PFS were coprimary endpoints. Treatment-related changes in CD8+ tumor-infiltrating lymphocytes (TIL) were the primary correlative outcomes. Results: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled [n = 29 in the cobimetinib + atezolizumab + varlilumab (CAV) arm; n = 28 in the atezolizumab + varlilumab (AV) arm]. A majority (67%) had intrahepatic cholangiocarcinoma, and 32% were immunotherapy experienced. Both regimens were well tolerated without new safety signals. Objective responses were rare [0% (CAV); 3.8% (AV)]. The median PFS (mPFS) was 2.40 (CAV) and 1.84 (AV) months [hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.38–1.18]. Among immunotherapy-experienced patients, the mPFS was 3.62 (CAV) and 1.84 (AV) months (HR, 0.54; 95% CI, 0.18–1.62). Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV. Conclusions: The combinations of atezolizumab and varlilumab with/without cobimetinib were safe, but neither meaningfully improved outcomes in biliary tract cancer treated in the later lines. Correlative tissue studies validated preclinical work that MEKi increases CD8+ TILs.

Background: Adequate cam resection during hip arthroscopy for femoroacetabular impingement syndrome (FAIS) is necessary to restore femoral head-neck offset while avoiding under- or over-resection. The relationship between the extent of femoroplasty and postoperative patient-reported outcomes remains unclear. Purpose: We sought to answer the following questions: What is the association between the extent of cam femoroplasty resection and postoperative improvements? and is a 5% resection threshold associated with improved outcomes? Methods: We conducted a retrospective review of patients with adequate acetabular coverage who underwent primary hip arthroscopy with femoroplasty between January 2015 and December 2022 at our institution and had preoperative and 1- and/or 2-year postoperative modified Harris hip score (mHHS) and/or International Hip Outcome Tool (iHOT) scores. We included 400 patients (409 hips; ages 14–50 years). Outcomes included score changes and achievement of minimum clinically important difference (MCID) and substantial clinical benefit (SCB). Postoperative Dunn lateral radiographs quantified femoroplasty by resection depth percentage (resection depth/femoral head diameter), proximal resection angle, and postoperative α angle. Hips were classified as under-resection, neutral (0%–5%), or over-resection (>5%), and differences in outcomes were compared between resection groups. Multivariable regression analyses controlled for demographic, radiographic, and surgical variables. Results: Mean resection depth was 4.8%; mean proximal resection angle was 72.6°. No differences were observed in score improvements or MCID/SCB rates between groups with under-resection versus over-resection at 1 or 2 years. Greater resection depth was associated with larger 1-year mHHS and iHOT improvements and independently predicted 1-year iHOT MCID and SCB. Higher proximal resection angle predicted 2-year iHOT MCID. Conclusion: In this retrospective, single-institution cohort study, we found that in patients with FAIS, greater femoroplasty depth was associated with improved 1-year clinical outcomes. Level of Evidence: Level III, retrospective cohort study.

Squamous cell lung cancer (SqCLC) accounts for 20–30% of non-small cell lung cancer (NSCLC) and remains associated with a poorer prognosis compared with adenocarcinoma. Despite advances in treatment, 5-year overall survival for advanced (stage IV) disease remains below 10–15%. Unlike non-squamous NSCLC, SqCLC is characterized by a high tumor mutational burden and complex genomic landscape dominated by alterations in tumor suppressor genes and lineage survival pathways including TP53, CDKN2A, PIK3CA, FGFR1, SOX2, and the NFE2L2/KEAP1 oxidative stress pathway, as well as dysregulation of the NOTCH signaling pathway, but it harbors relatively few actionable oncogenic drivers, resulting in limited treatments for targeted therapy. HER2 alterations can occur by multiple mechanisms, including activating mutations, gene amplifications, and protein overexpression. They comprise a very small percentage of NSCLC, with HER2 mutations reported in approximately 1–3% and HER2 amplifications observed roughly in 2–4%. While HER2 alterations are well characterized in lung adenocarcinoma, the prevalence, genomic context, and clinical significance of HER2 alterations in SqCLC remain incompletely defined. Advances in next-generation sequencing have led to improved ability to detect HER2 alterations and facilitated the development of HER2 targeted therapies. Available treatments for advanced/metastatic SqCLC have been historically limited to platinum-doublet chemotherapy, with immune checkpoint inhibitors such as anti-PD-1/PD-L1 newly emerging in the past decade. Selective HER2 tyrosine kinase inhibitors and HER2 antibody/drug conjugates have shown improved efficacy in HER2-altered NSCLC as shown in DESTINY-LUNG02 and BEAMION LUNG-1 trials; however, most of the enrolled patients had non-squamous histology, with minimal or no SqCLC-specific efficacy data reported. Future progress in HER2-altered SqCLC will require inclusion of SqCLC in HER2 basket trials, incorporation of comprehensive molecular profiling and standardized HER2 testing in squamous histology. This review summarizes the current state of knowledge of HER2 biology in SqCLC and highlights areas for future directions for precision oncology in SqCLC.