Citations

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.

Importance: Chronic liver disease requires sustained engagement with the health system, which co-occurring social and functional risks may disrupt. Whether these risks form reproducible patterns with different mortality associations is uncertain. Objective: To identify social and functional risk patterns among US adults with chronic liver disease and evaluate their associations with all-cause mortality. Design, Setting, and Participants: Nationally representative cohort study of National Health Interview Survey sample adults interviewed from 2011 through 2018 and linked to the National Death Index through 31 December 2019. Participants were aged 18 years or older, eligible for mortality linkage, reported a chronic liver condition, and had no baseline liver cancer. Exposures: Latent class membership derived from 7 binary indicators: poverty, food insecurity, uninsurance, cost-related delayed care, no usual place of care, single-adult household status, and activity limitation. A complete 0- to 7-item count was a secondary exposure. Main Outcomes and Measures: All-cause mortality. Survey-weighted Cox models estimated hazard ratios (HRs) with sequential demographic, clinical, and liver-specific adjustment. Prespecified sensitivity analyses used 20 multiple imputed data sets, sampling-weighted pseudo-likelihood latent class models, complete-case re-estimation, a fixed 5-year horizon, and class-by-age interaction testing. Results: Among 3407 adults (weighted mean age, 54.0 years; 49.4% female), 529 deaths occurred over 17,297.6 person-years (median follow-up, 5.0 years [IQR, 3.0–7.0]). Four classes were retained: low social and access burden (weighted prevalence, 63.1%); functional limitation with financial strain (13.2%); poverty, single-adult household, and functional limitation (15.0%); and uninsurance with major access barriers (8.7%). Compared with the low-burden class, the functional-limitation/financial-strain class had higher adjusted mortality (HR, 1.95; 95% CI, 1.34–2.82; p < 0.001); the other 2 classes did not differ significantly. Sampling-weighted latent class analysis after multiple imputation reproduced 97.2% of modal assignments, and the association persisted with attenuation (HR, 1.55; 95% CI, 1.08–2.22; p = 0.02). Each additional risk was associated with higher mortality (exact count: HR, 1.24 [95% CI, 1.13–1.36]; imputed count: HR, 1.19 [95% CI, 1.10–1.29]). The class-by-age interaction was not significant (p = 0.41). Conclusions and Relevance: Among US adults with self-reported chronic liver disease, social and functional adversity was both cumulative and patterned. A profile combining functional limitation, food insecurity, and cost-related delayed care had the clearest independent mortality association despite largely retained insurance coverage. These profiles are not a validated clinical score, but the findings argue against reliance on any single indicator, particularly insurance status, as a marker of vulnerability.

ABSTRACT Background Long‐term health effects of thymectomy in adults remain uncertain. Previous reports suggested associations with increased mortality, cancer incidence, and autoimmune disease, although these findings may reflect differences in patient selection, surgical indication, or follow‐up duration. We aimed to examine long‐term outcomes following adult thymectomy. Methods We performed a propensity score‐matched retrospective study of patients who underwent thymectomy or comparator cardiothoracic procedures, with follow‐up extending to 10 years. Primary outcomes were all‐cause mortality, new‐onset malignancy, and autoimmune disease. Findings were compared with those reported in a recent study that has raised caution regarding thymic excision. Results We identified 425 patients who underwent thymectomy and 5401 controls who underwent coronary artery bypass or valve surgery. After matching, 398 patients remained in each group. Thymectomy was not associated with increased mortality at 5 years ( HR = 0.63; 95% CI , 0.38–1.04) or 10 years ( HR = 0.78; 95% CI , 0.54–1.13). Excluding reclassified thymic cancers, 5‐year extrathymic malignancy incidence was 2.3% versus 1.8% ( p = 0.54); no significant differences were observed in immune‐related disease. Mortality was higher among patients with thymic malignancy. Among MG patients, only one event occurred, precluding reliable estimation. Conclusions Thymectomy was not associated with excess mortality or malignancy at 10 years compared with matched cardiothoracic controls. Indication‐stratified analyses within the thymectomy cohort showed higher mortality for thymic malignancy, with insufficient events to assess outcomes in MG patients. These findings do not support a generalized survival penalty from thymectomy, though caution is warranted for incidental thymic removal.

Background Odontogenic sinusitis (ODS) is a common cause of unilateral infectious maxillary sinusitis but is frequently underdiagnosed due to nonspecific symptoms, subtle dental findings on imaging, and limitations of traditional bacterial cultures—particularly for anaerobic organisms. Next-generation DNA sequencing (NGS) may enhance detection of odontogenic bacteria. Objective This study compared bacterial detection between standard cultures versus NGS in patients with confirmed ODS. Methods Twenty consecutive adults with confirmed ODS were enrolled. Maxillary sinus purulence was collected endoscopically and submitted for routine aerobic and anaerobic bacterial cultures and for NGS-based microbial profiling using 16S rRNA gene sequencing. Detected organisms were categorized by aerotolerance and ODS relationship, and likely nasal colonizers were excluded from analyses. Alpha diversity, beta diversity, and compositional differences between methods were analyzed statistically. Results NGS detected significantly more bacterial species per specimen than culture (mean 4.9 vs 2.7; P = .0015). Compared to cultures, NGS identified more anaerobic bacteria (4.2 vs 0.9; P = .00004) and more ODS-related species (4.4 vs 1.0; P = .0001), while detection of aerobic species was similar between methods. Cultures also often yielded nonspeciated results, whereas NGS consistently revealed polymicrobial communities dominated by oral anaerobes. Microbial composition differed significantly between detection methods. Conclusion In confirmed ODS, NGS detected significantly more anaerobic and ODS-related species than culture from the same specimens. These findings suggest that culture alone may underestimate odontogenic contributions to purulent sinusitis. Future studies should explore he utility of NGS as an adjunctive tool to facilitate diagnosis and treatment in the setting of possible ODS.

Abstract Introduction Ovarian cancer (OvCa) remains the most lethal gynecologic malignancy, with older women experiencing the poorest outcomes. Aging profoundly remodels the ovarian tumor immune microenvironment (TME), promoting regulatory T cell (Treg) mediated immune evasion; however, the underlying metabolic mechanisms remain unclear. Methods Using young (3-month) and aged (22-month) female mice injected intraperitoneally with ID8p53⁻/⁻ OvCa cells, we investigated how age associated metabolic reprogramming influences tumor immunity Results Aged OvCa bearing mice exhibited accelerated tumor progression, reduced survival (median 54 vs. 72 days), decreased CD4+ and CD8+ T cells, and an expanded Treg population. Metabolomic profiling revealed increased succinate accumulation in ascites, tumor tissue, and serum of aged mice and elderly OvCa patients. Exogenous succinate enhanced CCR4+FOXP3+ Treg frequency and upregulated IL-10 and TGF-β secretion. Elevated levels of CCL22, a CCR4 ligand, were also detected in ascites from aged mice and patients, suggesting a chemokine-driven reinforcement of Treg recruitment. PBMCs from aged patients displayed an OXPHOS-reprogrammed CCR4+FOXP3+ Treg subset with heightened suppressive capacity, markedly inhibiting CD4+ and CD8+ effector cytotoxicity. Treatment with AA6, an α-ketoglutarate dehydrogenase inhibitor that blocks succinate synthesis, reduced CCR4+FOXP3+ Treg accumulation, restored effector T-cell function, and significantly prolonged survival in aged OvCa-bearing mice. Conclusion Together, these findings reveal a novel succinate—CCR4 metabolic—chemokine axis that drives Treg mediated immunosuppression in aged OvCa. Targeting this pathway offers a promising strategy to restore anti-tumor immunity and overcome age-related immunotherapy resistance in ovarian cancer. Funding Source N/A Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

ABSTRACT Objective Weight loss is frequently considered a cardinal presenting symptom for patients with Zenker diverticulum (ZD). We hypothesized that weight loss in patients with cricopharyngeal muscle dysfunction (CPMD), with or without diverticula, was associated with the length of symptoms and size of diverticulum. Methods Prospective, multicenter observational study of CPMD patients with and without diverticula reporting unintentional weight loss (+WL) or no weight loss (−WL) prior to enrollment in the Prospective Outcomes of Cricopharyngeal Hypertonicity (POuCH) database. Complications and symptom response using a patient reported outcome measure, the Eating Assessment Tool (EAT‐10), were compared. Results Of 427 patients, 101 (23.6%) were +WL. Median weight loss was 14 pounds (interquartile range [IQR] 10–25). +WL cohort had a mean age of 71.5 (standard deviation [SD] 11.5) vs. 67.9 in −WL (SD 11.6, p = 0.007). Mean preoperative EAT‐10 score was 24.7 in +WL (SD 9.7) and 14.8 in −WL (SD 8.8, p < 0.0001). Higher preoperative weight loss was associated with higher preoperative EAT‐10 ( p < 0.0001, Spearman's ρ = 0.43). Size of diverticulum was associated with WL ( p = 0.003), but weight loss was highest in both large diverticula and CP bars. Duration of symptoms was not associated with weight loss ( p = 0.30). Postoperative complications in +WL and −WL patients were similar ( p = 0.78). Conclusion Unintentional weight loss is common with ZD. Patients with worse dysphagia are more likely to have more weight loss. Weight loss does not increase with the size of the diverticulum or length of symptoms. Surgery has a similar safety profile with greater improvement in dysphagia in patients reporting weight loss. Level of Evidence 3.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

E-cigarette or vaping-associated lung injury (EVALI) was initially recognized as a public health problem in 2019, but pathologic changes from vaping (if any) outside the context of EVALI remain unknown. We aimed to further characterize the pathology of EVALI and vaping-associated changes in otherwise healthy patients without EVALI, including those presenting with spontaneous pneumothorax. Archives were searched for lung specimens from these patient groups (2019 to 2025). Previously reported cases were excluded. Clinical history and pathology slides were reviewed. Sixty-three patients (43 men; mean age: 36.0±15.2 y) were enrolled, including 47 wedge resections, 15 transbronchial biopsies, and 1 core biopsy. All reported current or recent vaping, and 24 reported prior or concurrent cigarette smoking. Thirty-six met criteria for EVALI and showed characteristic histologic features; novel findings included 12 (35%) with coarse lipid vacuolization and 6 (18%) with grungy proteinosis-like deposits. Eleven patients with prior suspected EVALI had chronic respiratory symptoms with airway-centered macrophages and variable airway-centered fibrosis. The remaining 16 patients presented with spontaneous pneumothoraces without EVALI and had rare foamy or lightly pigmented macrophages in airspaces but no other abnormalities beyond secondary changes from the pneumothorax. To our knowledge, this is the largest pathologic study of EVALI and the first to review histologic findings in the lungs of otherwise healthy vapers. EVALI is less common than in 2019 but is still encountered. Outside the context of EVALI, patients who vape and develop spontaneous pneumothorax have minimal histologic changes. The role (if any) of vaping in the development of pneumothorax remains unknown.

Abstract Background The expanding use of biologic and small-molecule therapies for ulcerative colitis (UC) has raised concerns regarding perioperative safety. We conducted a network meta-analysis to compare short-term postoperative complications associated with preoperative exposure to these agents in patients undergoing colorectal surgery. Methods We systematically searched PubMed, Web of Science, and the Cochrane Library through September 15, 2025, for cohort studies of adults with UC who were exposed to biologic or small-molecule therapy within 12 weeks prior to surgery. Interventions included biologic therapy, small-molecule therapy, and no biologic or small-molecule therapy (control). The primary outcome was overall postoperative complications at 30 and 90 days. Venous thromboembolism (VTE) was assessed as a key secondary outcome. Random-effects network meta-analysis was performed using risk ratios (RRs) with 95% confidence intervals (CIs). Results Sixteen retrospective cohort studies involving 3235 patients were included. At 30 days, ustekinumab and tofacitinib were associated with lower overall postoperative complication rates than control (RR: 0.29; 95% CI: 0.09-0.96; and RR: 0.66; 95% CI: 0.46-0.96, respectively). Anti-tumor necrosis factor (TNF) therapy was associated with higher complication rates compared with vedolizumab, ustekinumab, and tofacitinib at 30 days (RR: 1.27; 95% CI: 1.00-1.63; RR: 3.67; 95% CI: 1.12-12.03; and RR: 1.61; 95% CI: 1.14-2.27, respectively). At 90 days, anti-TNF therapy was associated with higher complication rates than control (RR 1.20, 95% CI 1.03-1.40), although the 90-day analysis was based on limited data. VTE rates were similar across treatments at both time points. Conclusion Preoperative ustekinumab and tofacitinib were associated with fewer 30-day postoperative complications than control or anti-TNF therapy, while vedolizumab was associated with fewer complications than anti-TNF therapy. At 90 days, anti-TNF therapy was associated with higher complication rates compared with control. These findings, particularly at 90 days based on limited data, should be interpreted with caution and require confirmation in well-designed prospective studies with rigorous adjustment for confounding factors.