Citations

Abstract BACKGROUND Understanding long-term sequelae of cancer care is critical. Cognitive impairment is a common and disabling survivorship issue. Because sex influences tumor biology, therapy exposure, and dementia risk, we examined whether cancer care for a prior malignancy alters late-life cognitive outcomes differently in males and females. METHODS We assessed adults ≥50 years, cognitively normal at study entry, from a longitudinal, population-based cohort (Mayo Clinic Study of Aging). Participants were linked to our institutional cancer registry (excluding non-melanoma skin cancers). Mild cognitive impairment (MCI) and dementia were adjudicated by consensus. We fitted multivariable Cox proportional-hazards models to estimate how prevalent cancer diagnosis influenced the risk of developing MCI/dementia. Sex-specific effects were determined by incorporating a cancer×sex interaction term and by generating separate hazard ratios. Analyses were controlled for age, APOE4 status, education, and presence of vascular/metabolic conditions. RESULTS 5793 MCSA participants (female: 49.4%, APOE4 positive: 27.5%) were included in the study, with a mean age of 73 years at study entry. Incident MCI was recorded in 866 participants, and 737 were diagnosed with incident dementia. About 20% (n=1176) of the cohort had a cancer diagnosis, most commonly prostate (n=423) and breast (n=277). There was no independent relationship between history of cancer and risk for MCI or dementia. We found that males with cancer had an increased risk for MCI (HR 1.28, 95% CI 1.04-1.57, p=0.003) and dementia (HR 1.29, 95% CI 1.04-1.6, p=0.053). Conversely, females with cancer had a lower risk for MCI (HR 0.79, 95% CI 0.61-1.01, p=0.063), although this was not statistically significant. CONCLUSIONS Our data suggests male cancer survivors may be more susceptible to cognitive impairment, independent of age, APOE4 status, education, and vascular/metabolic burden. Elucidating the hormonal, treatment-related, and systemic pathways driving this should be a priority for future mechanistic studies.

Abstract PURPOSE Age over 40 years is commonly regarded as a “high risk” feature and potential indication for adjuvant chemoradiotherapy for patients with lower grade glioma in most clinical practice guidelines. However, these recommendations are based on retrospective observations and their subsequent incorporation into legacy clinical trials. It is unclear whether age remains a relevant prognostic factor in the molecular era. METHODS The Prospective Gliomas Research [PROGRES] Database contains individual patient-level data from 11 prospective clinical trials or observational registries, including seven international trials from the RTOG, EORTC, or Alliance cooperative groups. We determined the association of age with progression-free survival (PFS) in low grade or anaplastic glioma, stratified by isocitrate dehydrogenase (IDH1/2) status. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] Database). RESULTS We identified 1,619 and 1,271 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH-wildtype tumors were more common in patients >40 years (38% vs, 5%, odds ratio: 11.3 [95%CI 6.5 – 19.7]). Age was associated with PFS in IDH-wildtype (5-year PFS: 6% vs, 24%, P =.003) but not in IDH-mutant glioma (60% vs, 59%, P = 0.22, P value of interaction <.001). In IDH-wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% vs, 28%), EGFR amplification (41% vs, 15%), and chromosome +7/-10 alteration (57% vs, 25%). Age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone in IDH-mutant glioma. CONCLUSION Older age is a putative surrogate for IDH-wildtype status, but was not an independent predictor of progression in IDH-mutant lower grade glioma and did not predict benefit from chemoradiotherapy. In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

Recent studies highlight transcriptionally distinct fibroblast subpopulations in human lungs. We observed the loss of these native transcriptional programs as fresh isolated cells are maintained in traditional culture conditions. Identifying the signals defining native fibroblast identities will be pivotal to creating culture models that preserve unique subpopulations. The screening system developed here will allow the investigation of a broad selection of cues, leading to better culture models for studying human lung fibroblast function and plasticity.

Background: Orthopaedic sports medicine fellowships are highly competitive, yet objective data defining characteristics of successful applicants remain limited. Hypothesis: It was hypothesized that greater academic productivity, top-tier residency training, and certain demographic factors would be associated with matching into a top-ranked orthopaedic sports medicine fellowship. Study Design: Cross-sectional study. Methods: We retrospectively reviewed applicants who matched into one of the top 10 orthopaedic sports medicine fellowships from 2020 to 2025, as identified by previous applicant preference rankings. Applicant data were obtained from publicly available sources and verified by 2 independent reviewers. Variables included sex, degree type, residency program ranking, geographic region, and research productivity (total publications, primary publication count, H-index, and sports-related publications). Multivariate logistic regression assessed predictors of matching into top 5 versus 6th- to 10th-ranked programs. Results: Among 226 matched applicants, 87.7% were male and 99.1% held a doctorate in medicine degree. The mean total publication count was 12.4, mean H-index was 8.2, and 30.5% trained at a top 20 orthopaedic residency. Applicants matching into top 5 programs had significantly higher research metrics than those in the 6th- to 10th-ranked programs: total publications (20.1 vs 4.7), primary publication count (6.2 vs 1.6), and sports-related publications (11.4 vs 1.9). On regression analysis, total publications, H-index, and residency ranking were independent predictors of matching into a top 5 program. Conclusion: Matching into a top orthopaedic sports medicine fellowship is associated with higher academic productivity and training at a top-tier residency program.

Objective Lewy body disease (LBD) is a complex neurodegenerative disorder characterized by the accumulation of misfolded α‐synuclein in the brain. Neuroinflammation has long been implicated in LBD pathogenesis, and recent genetic studies in Parkinson's disease (a clinical manifestation of LBD) have shown consistent association with the human leukocyte antigen (HLA) gene complex. Here, we assessed whether variation in HLA alleles influences neuropathological burden in a neuropathologically‐defined series of LBD cases. Methods We conducted a comprehensive analysis of HLA allelic variants in a cohort of 539 LBD cases of European descent from the Mayo Clinic brain bank. High‐resolution whole‐genome sequencing was used, and the HLA alleles of each sample were called using the HLA*LA tool and assessed for association with neuropathological outcomes. Results Our analysis identified 1 significant ( P < 3.43 × 10 −5 ) and 4 suggestive ( P < 0.001) associations between certain HLA alleles and specific neuropathological outcomes in LBD, suggesting a potential role for HLA‐mediated immune mechanisms in disease progression and subtype differentiation. Specifically, HLA‐DPB1*06:01 was significantly associated with lower Lewy body counts in the parahippocampal gyrus ( P = 3.30 × 10 −5 ), with weaker and suggestive associations observed in the middle frontal ( P = 1.80 × 10 −4 ) and inferior parietal gyrus ( P = 6.33 × 10 −4 ). Additionally, although only suggestive, HLA‐DRB1*11:01 correlated with a lower Thal amyloid phase ( P = 1.56 x 10 −4 ), and HLA‐B*15:01 correlated with an increased risk of diffuse LBD ( P = 7.58 x 10 −4 ). Interpretation This study provides a detailed evaluation of the relationship between HLA alleles and LBD pathology, highlighting the importance of immune‐related genetic factors in the etiology of LBD. ANN NEUROL 2026;99:492–501

Bone surface lesions include a variety of benign and malignant tumors and nonneoplastic entities, and knowledge of the different cell types and cortical bone surface anatomy equips radiologists to provide a useful differential diagnosis for these lesions.

Decades of research on biomarker identification and integration in Alzheimer’s disease (AD) have helped to advance biologically driven disease models, disease subtypes, and disease-modifying treatments. Key lessons learned from AD biomarker development include the need for integration of new biological insights, investment in large cross-sectional and longitudinal studies, a multicomponent biomarker approach, and recruitment of clinical trial cohorts and biosamples that are representative of the target population. We describe how these lessons are being applied in Parkinson’s disease, Huntington’s disease, multiple sclerosis, and psychotic disorders as use cases to inform biomarker-based approaches across central nervous system disorders.

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.