Citations

Summary Asthma genetic architecture varies according to age at onset and biological sex. Medication‐defined severity showed limited common variant genetic heterogeneity compared with age at onset and sex.

Abstract Objective In 2024, the US News and World Report (USNWR)'s Best Hospitals began reporting complications following elective outpatient otolaryngology procedures in its ears, nose, and throat (ENT) ranking. However, this methodology has not been clinically adjudicated in a peer‐reviewed domain. We aimed to conduct manual health record adjudication to assess whether the USNWR methodology accurately attributes complications following elective outpatient otolaryngology procedures. Study Design Case‐cohort. Setting A case‐cohort of n = 80 elective, outpatient otolaryngology procedure/complication pairings from January 2019 to October 2023 across four academic medical centers using the 2024 USNWR otolaryngology procedure subgroups and Solventum Ambulatory Potentially Preventable Complications (AM‐PPC) software. Methods We used the AM‐PPC‐defined complication types as our standard of comparison for our clinical adjudication. Using the electronic health record, we adjudicated: (1) Was there agreement (yes/no) on complication type between our clinical adjudication and the Solventum AM‐PPC software? (2) Was the complication clinically related to, or a sequela of, the index otolaryngology procedure (yes/no)? Results The clinical adjudication agreed on complication type in 59/80 (74%) of patients, and 63/80 (79%) were judged to be clinically related to the index otolaryngology procedure. In total, 50/80 (63%) complications were adjudicated to be in agreement on both the complication type and clinical relatedness to the index procedure, while 9/80 (11%) complications did not agree with the complication type nor were clinically related to the index procedure. Conclusion Outpatient complications reported in the USNWR ENT rating lack the specificity to exclude patients whose complications are sequelae of chronic underlying conditions or related to concurrent, non‐otolaryngology procedures.

Objective To characterize regional brain atrophy patterns, evaluate their association with regional leucine‐rich glioma‐inactivated‐1 ( LGI1 ) gene expression, and identify clinical predictors of hippocampal atrophy in LGI1 autoimmune encephalitis (AE). Methods This study compared regional brain volumes in LGI1‐AE patients versus age‐ and sex‐matched healthy controls (HC) and Alzheimer's disease (AD) patients. LGI1 gene expression was derived from the Allen Human Brain Atlas. Multivariable linear regression and generalized linear models were utilized. Results A total of 55 LGI1‐AE patients were included. Median age was 68 years (IQR 62.5–74.2 years) at volumetric analysis, after 19 months (IQR 11–45 months) from symptom onset. Compared with HC ( n = 55) and AD patients ( n = 55), LGI1‐AE patients had greater regional atrophy of the hippocampus, insula, caudate, and putamen ( p < 0.002). Longitudinal analyses demonstrated hippocampal and pallidal atrophy after covariate adjustment. Among those who did not fulfill limbic encephalitis criteria and/or had non‐lesional magnetic resonance imaging, limbic and striatal atrophy were identified compared with HC ( p < 0.01). Regions with the greatest differential atrophy corresponded to higher LGI1 gene expression (Spearman ρ = 0.7, p = 0.005). Severe cognitive deficits at diagnosis ( β = −0.56; p = 0.002) and longer disease duration ( β = −0.01; p = 0.001) independently predicted total hippocampal volume ( R 2 = 0.31). Interpretation LGI1‐AE demonstrates a distinct pattern of limbic and striatal atrophy that differs from AD and aligns with regional LGI1 expression, supporting a model of selective network vulnerability. Greater baseline cognitive impairment and longer disease duration independently associated with hippocampal atrophy, underscoring the potential importance of early diagnosis and treatment to limit structural brain injury. ANN NEUROL 2026

This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix I and Appendix II). Updates are published regularly and can be found on the ASCO Publications website .

BACKGROUND: Degenerative mitral regurgitation (DMR) due to valve prolapse predominates in men, but sex-specific differences are poorly understood due to a lack of quantitative and sex-stratified studies. METHODS: The international MIDA-Q (Mitral Regurgitation International Database-Quantitative) registry enrolled 3274 men and 2331 women with greater than or equal to mild DMR prospectively quantified, comprehensively characterized, and long-term follow-up. RESULTS: Women were more symptomatic despite lower effective regurgitant orifice (ERO, 27±18 versus 38±22 mm 2 , standardized mean difference 0.54; P <0.0001) and regurgitant volume (46±26 versus 61±31 mL/beat, standardized mean difference 0.52; P <0.0001), even for similar mitral lesions. With increasing ERO, women showed lower regurgitant volume, higher heart rate, lower blood pressure, but left ventricular size response in women was smaller in absolute measures while larger when body surface area normalized, with higher ejection fraction and cardiac index (all P <0.0001). Incidence of mitral valve surgery was similar in symptomatic women and men, but lower in asymptomatic women versus men (adjusted hazard ratio, 0.80 [0.69–0.94]; P =0.008) for similar ERO, linked to smaller left ventricular diastolic absolute diameter ( P <0.0001). Excess mortality under medical management (of severe versus mild ERO) was similar in women (adjusted hazard ratio, 1.67 [1.24–2.24]; P =0.0007) and men (adjusted hazard ratio, 1.63 [1.27–2.09]; P <0.0001) and versus expected survival (2.12 [1.51–2.98] in women and 2.27 [1.75–2.94] in men). However, moderate ERO (20–39 mm 2 ) was associated with significant excess mortality in women (1.47 [1.19–1.77] versus mild). In men, the corresponding hazard ratio did not reach statistical significance. Postoperative survival was similar in men and women. CONCLUSIONS: Women with DMR present with lower ERO and regurgitant volume than men and with considerable adaptive differences to increasing DMR severity versus men. Asymptomatic women are less referred to surgery than men of similar DMR severity, linked to smaller absolute left ventricular size. Severe DMR by similar quantitative thresholds causes similar excess mortality in men and women; moderate quantitative DMR shows a trend for higher excess mortality versus expected in women than men, requiring further confirmation. These data emphasize the importance of quantitative DMR and left ventricular remodeling assessment in men and women for appropriate clinical management.

Abstract Introduction Quantitative interpretation of pediatric brain [ 18 F]-FDG PET is limited by the lack of age-matched normative reference databases, despite substantial developmental variation in cerebral glucose metabolism. This study aimed to construct a large-scale normative pediatric [ 18 F]-FDG PET database and develop an age-specific z-score mapping framework for quantitative evaluation of pediatric epilepsy. Method Pediatric brain PET data were retrospectively derived from clinically acquired whole-body or dedicated [ 18 F]-FDG PET examinations in participants 0–19 years of age without neurologic disease or visible brain abnormalities. A total of 417 PET scans from 341 participants were stratified into five developmental age groups: infancy, early childhood, middle childhood/school age, adolescence, and late adolescence. SUVR maps were generated using whole-brain atlas and brainstem reference regions. Voxel-wise t-test analyses were performed to characterize age- and sex-related metabolic differences. Age-specific voxel-wise mean and standard deviation maps were generated from the normative cohort and used to calculate age-matched hypometabolic z-score maps in 14 pediatric patients with epilepsy. The resulting abnormalities were qualitatively evaluated for concordance with epileptogenic findings identified on clinical MRI and/or PET by expert image review. Results Voxel-wise analyses demonstrated prominent age-dependent SUVR differences, particularly between infancy and older age groups. With whole-brain atlas normalization, older children showed progressively higher relative SUVR in cortical and cerebellar gray matter regions, whereas infancy showed relatively higher SUVR in the occipital cortex, white matter, thalamus, and brainstem. Brainstem normalization produced distinct developmental patterns, emphasizing higher white matter SUVR in infancy and broader gray matter differences in older groups. Sex-related differences were limited and regionally specific. Whole-brain atlas normalization showed lower variability than brainstem normalization and was selected for z-score mapping. In representative epilepsy cases, age-matched z-score maps identified focal or regional hypometabolism corresponding to malformations of cortical development, focal cortical dysplasia, mesial temporal sclerosis, nonlesional MRI cases, remote insult, tumor-related abnormalities, and Sturge-Weber syndrome. Discussion A large-scale normative pediatric [18F]-FDG PET database can support developmentally appropriate quantitative interpretation of pediatric brain PET. Age-matched z-score mapping may complement visual assessment by highlighting abnormal cerebral glucose metabolism in pediatric epilepsy, although findings should be interpreted with MRI, EEG, seizure semiology, and other presurgical data.

Importance Lichen planus is a chronic, highly pruritic, inflammatory disease that affects the skin and other tissues. Objective To evaluate the efficacy and safety of ruxolitinib, 1.5%, cream in patients with cutaneous lichen planus. Design, Setting, and Participants This phase 2, 16-week, randomized, double-blind, vehicle-controlled trial with a 16-week open-label extension was conducted from November 2022 to February 2024. Patients were enrolled from 19 sites in the US and Canada. The trial included adults with predominantly cutaneous lichen planus, an Investigator’s Global Assessment (IGA) score of 3 or 4, an Itch Numerical Rating Scale score of 4 or greater, and an affected body surface area of 20% or less were enrolled. Data were analyzed from February to August 2024. Interventions Patients were randomized 1:1 to ruxolitinib, 1.5%, twice daily cream or vehicle cream for 16 weeks, after which eligible patients applied ruxolitinib cream twice daily as needed in a 16-week, open-label extension. Main Outcomes and Measures The primary end point was IGA treatment success (IGA score of 0 or 1 [clear/almost clear skin] with a ≥2-grade improvement from baseline) at week 16. Results Among 64 randomized patients, 46 (72%) were female, 18 (28%) were male, 18 (28%) were African American/Black, 4 (6%) were Asian, 40 (63%) were White, and the median (range) age was 57.0 (18-78) years. Significantly more patients who applied ruxolitinib, 1.5%, cream vs vehicle achieved IGA treatment success (50.0% [95% CI, 31.9%-68.1%] vs 21.9% [95% CI, 9.3%-40.0%], respectively; response rate difference, 29.4% [95% CI, 7.6%-51.3%]; P = .01; primary end point) at week 16, with further improvement to week 32. Similar results were observed in the proportion of patients who achieved a 4 or greater–point improvement from baseline in Itch Numerical Rating Scale score (week 16, 48.4% [95% CI, 30.2%-66.9%] vs 16.1% [95% CI, 5.5%-33.7%]; response rate difference, 33.5%; 95% CI, 12.2%-54.9%; P = .004; secondary end point). No serious treatment-emergent adverse events or discontinuations due to an adverse event were observed with ruxolitinib cream. Conclusions and Relevance The results of this randomized clinical trial suggest that ruxolitinib cream significantly reduced lesions and itch in patients with lichen planus. Therefore, ruxolitinib cream represents a potential treatment option for patients with cutaneous lichen planus. Trial Registration ClinicalTrials.gov Identifier: NCT05593432

Abstract The paradigm in the field of oncolytic virotherapy proposes that tumor cell killing by an oncolytic virus (OV) culminates in the priming of antitumor CD8+ T cells. However, this ignores the impact a highly immunodominant antiviral response against the OV has on the subdominant antitumor response, particularly with regard to the naturally low affinity of tumor antigens to their cognate T-cell receptors. To investigate this experimentally, we first studied the interaction between the two responses in B16 and MC38 tumor models, both expressing ovalbumin (OVA). Contrary to the accepted paradigm, the inflammatory vesicular stomatitis virus (VSV) failed to expand OVA-specific T cells in vivo unless armed with tumor-associated antigen (TAA). In fact, treatment with the control VSV led to the ablation of antitumor T cells and a shift toward dysfunction as determined by the upregulation of markers, including LAG3 and CD39, correlating with lower rates of survival. Combination with anti–PD-1 immune checkpoint blockade therapy significantly improved survival only when VSV expressed TAA. VSV-expressing altered peptide ligand variants of tumor antigens, which evade mechanisms of central tolerance, expanded near self-antigen–specific T cells with the ability to cross-react with tolerized tumor antigens, thus providing an antitumor effector population capable of proliferating in the presence of a potent antiviral response. Taken together, these findings offer a rational approach to OV design which preserves acute antitumor therapy provided by antiviral innate and T-cell responses while promoting the induction of tumor-specific T cells. Significance: Oncolytic viruses can induce an antiviral T-cell response that occludes an antitumor response, challenging the paradigm in the field and elucidating strategies to optimize the efficacy of oncolytic viroimmunotherapy.

Abstract The development of biocompatible and biologically responsive scaffolds remains a key challenge for bone tissue engineering. Here, we report an enzyme-degradable, metal-free click-cross-linked organic–inorganic nanohybrid (Enz-Deg-Click-ON) scaffold with high biocompatibility for bone repair. The formulation was synthesized using a cyclooctyne-functionalized poly(propylene fumarate) polyphosphoester (PPF-poly(PE-BCN)) and azide-terminated dendritic polycaprolactone (PCL) with a polyhedral oligomeric silsesquioxane core (POSS-PCL-N3) via strain-promoted alkyne-azide cycloaddition (SPAAC) bioorthogonal click chemistry. The incorporation of phosphate-containing linkages enabled alkaline phosphatase (ALP)-responsive degradation. The scaffold exhibited rapid catalyst-free crosslinking, tunable swelling, and suitable mechanical properties. In vitro studies demonstrated excellent cytocompatibility, robust stem cell proliferation, and enhanced osteogenic differentiation with an elevated level of ALP and Runx2 expression. Enzyme-triggered degradation was confirmed in the presence of ALP. In the in vivo rat calvarial defect model, the scaffold significantly improved bone regeneration, as shown by an increased bone volume, mineral density, and defect coverage. Histological and immunofluorescence analyses revealed enhanced collagen deposition, angiogenesis, and osteogenesis. These results indicate that the Enz-Deg-Click-ON system provides a dynamic, bioresponsive platform for bone repair.