Citations

Abstract Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and anaplastic lymphoma kinase (ALK) status but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 patients with ALCL in the LLMPP (Lymphoma/Leukemia Molecular Profiling Project) and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple negative), and immunohistochemistry for phosphorylated STAT3Tyr705. RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression. Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non–tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27. Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK− ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials, and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.

Introduction Although Valsalva maneuvers and strenuous exercise are commonly discouraged in patients with intracranial aneurysms (IAs), the cerebrovascular stress they induce remains poorly characterized. To our knowledge, no prior review has systematically quantified their effects on hemodynamic surrogates of rupture risk. Objective To characterize the acute intracranial hemodynamic effects of strenuous physical activity and Valsalva maneuvers in individuals with and without IAs. Methods We searched PubMed, Embase, Scopus, Web of Science, and Cochrane (February 2025; PROSPERO ID: CRD42025637608) following PRISMA. Eligible studies reported acute changes in SBP, ICP, central venous pressure (CVP), cerebrovascular transmural pressure (CVTMP), middle cerebral artery (MCA) velocity, or CFD‐derived parameters (wall shear stress [WSS], oscillatory shear index [OSI], relative residence time [RRT]) in response to physical exertion or Valsalva. Populations included individuals with or without IAs. Acute neurological symptoms were also reviewed. Results From 2,859 records, 14 studies met inclusion criteria. Eight studies assessed real‐time hemodynamic responses during exercise (91 participants without IAs). Three studies (n=39) showed that resistance exercise increased SBP (mean Δ+21.8 mmHg). Two studies (n=22) showed significant MAP elevation (mean Δ+24.7 mmHg). When combined with a Valsalva maneuver, SBP increased further (mean Δ+26 mmHg; range 20–30). Three studies (n=38) evaluating isolated Valsalva identified significant ICP elevation (mean Δ+15 mmHg; range 5.7–24.3), primarily driven by CVP increases (mean Δ+52.0 mmHg; range 39–56). Breath‐holding during exertion reduced MCA velocity (mean Δ–11.6 cm/s), while continuous ventilation preserved more stable flow. In seven patients, resistance exercise without Valsalva increased CVTMP by 24.5%. In contrast, Valsalva alone raised ICP and CVP without increasing SBP, yielding a CVTMP 11% lower than during exercise alone. These paired observations suggest that Valsalva may transiently offset exercise‐induced transmural stress by raising ICP alongside SBP. However, this effect may be time‐limited and reverse during early recovery—when SBP remains elevated as ICP quickly normalizes—potentially producing a CVTMP rebound above exercise‐only levels. Six CFD studies (11 aneurysms; diameter 6.3–23 mm; 2 ruptured) reported exercise‐related increases in time‐averaged WSS (mean +21.7%, range –4.4% to +50%) and peak WSS (mean +382.3%, range +100% to +628%). Exercise‐induced changes in heart rate and flow pulsatility led to complex redistributions of intra‐aneurysmal WSS, potentially exposing the aneurysmal wall to focal mechanical stress. Conclusion Resistance exercise, especially with breath‐holding, provokes dynamic, time‐sensitive cerebrovascular stress. Valsalva maneuver may transiently lower CVTMP during effort, yet its release with lingering SBP elevation can precipitate delayed transmural pressure surges. The proposed biphasic effect of Valsalva offers a novel conceptual framework for prospective. Our findings underscore the need to define safe, individualized activity thresholds for patients with IAs with patient‐specific validation integrating concurrent physiology and CFD to reduce the risk of IA growth and rupture.

Introduction The risk of aneurysmal subarachnoid hemorrhage (aSAH) during exercise is not well quantified. We assessed temporal clustering of aSAH around physical exertion and around Valsalva‐like activities (defecation or urination). Objectives To estimate the proportion of aSAH cases temporally linked to strenuous activities using reported exposure‐to‐onset window uwing within‐person odds of rupture from case‐crossover studies. Methods We searched PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library from inception through January 2025, and hand‐searched reference lists (PRISMA‐aligned; PROSPERO CRD42025637608). Eligible studies reported the activity at aSAH onset or within a defined pre‐onset window. Exposures were analyzed separately (exertion; defecation/urination). Primary proportional estimates used each study's own exposure‐to‐onset window as reported. To improve comparability, subgroup analysis was performed with only a prespecified subset pooled consecutive case series that explicitly used a ≤2‐hour window between the index activity and aSAH. Within‐person odds ratios (ORs) were abstracted from case‐crossover studies. Risk of bias for observational exposure studies was assessed with ROBINS‐E by two independent reviewers. Results Sixteen studies (published 1980–2022) from 10 countries were included with 5,815 cases of aSAH (mean age 55 years; 60.6% female). Designs comprised 10 case series, 3 case reports, 2 case‐crossover studies, and 1 case‐control study. Activity‐at‐onset was recorded for 4,219/5,815 (72.6%); among these 4,219 patients, mean age was 52.7 years. Using each study's reported window, 308/4,219 (7.3%) aSAH occurred during or within the study‐defined window after physical exertion, and 387/4,219 (9.2%) during/within the window after defecation or urination 695/4,219 (16.5%) were temporally linked to either exposure. In the subset of 10 consecutive case series restricted to ≤2 hours, 275 (5.4%) were linked to exertion and 385 (7.6%) to defecation/urination (combined 660; 13.0%). Study‐specific proportions ranged from 0.8–21.3% for exertion and 2.0–15.4% for defecation/urination. Two case‐crossover studies reported higher within‐person odds of rupture after moderate‐to‐vigorous exertion (OR 2.4–2.7). Temporal clustering of aSAH around exertion or straining was observed in 13–17% of cases, depending on dataset and inclusion criteria. Conclusions Although this relatively high rate of temporal association between aSAH and exercise might suggest an increased risk of aneurysm rupture during strenuous activity, variable definitions and unstated exposure‐to‐onset windows do not permit causal inference. Prospective or registry‐embedded case‐crossover studies using standardized exposure definitions (intensity, duration) and objective exposure capture are needed to refine immediate‐risk estimates and identify patient‐level susceptibility modifiers.

PURPOSE STELLAR (ClinicalTrials.gov identifier: NCT02796261 ) was a phase III, randomized, open-label trial of eflornithine + lomustine versus lomustine monotherapy in patients with recurrent grade 3 astrocytoma. METHODS At trial initiation, eligibility criteria included: age ≥18 years, anaplastic astrocytoma (2016 WHO CNS Tumor classification [WHO CNS4]), first recurrence ≥6 months after radiation and temozolomide (TMZ), Karnofsky performance status ≥70, and no imaging findings consistent with grade 4 glioblastoma. Random assignment (1:1) was stratified by isocitrate dehydrogenase ( IDH ) mutation, age, resection extent, and geography. Patients received eflornithine (2.8 g/m 2 orally, every 8 hours [2 weeks on, 1 week off]) + lomustine (90 mg/m 2 orally, once every 6 weeks), or lomustine monotherapy (110 mg/m 2 once every 6 weeks). The primary end point was overall survival (OS). RESULTS Among 343 patients randomly assigned across 74 sites in eight countries, there was no difference in survival between eflornithine + lomustine and lomustine monotherapy (median OS 23.4 v 20.3 months, hazard ratio [HR], 0.94). Following changes in classification and grading in the 2021 WHO CNS5, a subset analysis of patients with IDH- mutant, grade 3 astrocytoma (n = 196), defined in 2024, before unblinding, showed clinically meaningful improvements in median OS with eflornithine + lomustine versus lomustine monotherapy (34.9 v 23.5 months, HR, 0.64) and median progression-free survival (PFS, 15.8 v 7.2 months, HR, 0.57). No differences were observed among patients with CNS grade 4 disease. Grade ≥3 treatment-emergent adverse events of relevance were related to reversible myelosuppression (eflornithine + lomustine 42% v lomustine monotherapy 29% of patients) and hearing impairment (24% v 0%). No new safety signals were identified. CONCLUSION Clinically meaningful improvements were observed; eflornithine + lomustine doubled PFS and improved OS in patients with recurrent IDH -mutant, grade 3 astrocytoma, but not grade 4 tumors, after prior radiotherapy and TMZ, consistent with its cytostatic mechanism of action.

ABSTRACT Introduction Hepatocellular carcinoma (HCC) development in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) is a growing health concern, but the underlying mechanisms are not fully understood. Epigenetic aging biomarkers, reflecting cellular and tissue aging, have been linked to various age‐related pathologies, but their association with MASLD‐HCC is unknown. We investigated associations between five epigenetic aging biomarkers and MASLD‐HCC risk. Methods We performed whole blood DNA methylation assay (Infinium 850k array) and calculated principal components‐based (PC) versions of HorvathAge, HannumAge, PhenoAge and GrimAge and the DunedinPACE aging rate. We further calculated relative age accelerations for PCHorvathAge, PCHannumAge, PCPhenoAge and PCGrimAge. The aging biomarkers were modelled as continuous variables and categorised into tertiles based on distributions among controls. Associations between each aging biomarker and MASLD‐HCC were examined using logistic regression, calculating odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for covariates. Results Data on 272 MASLD‐HCC cases and 316 cancer‐free MASLD controls recruited from six sites and matched on chronological age, sex and study site were analysed. Higher relative age accelerations of PCPhenoAge (OR T3 vs. T1 = 2.25, 95% CI: 1.45–3.50; OR continuous = 1.04, 95% CI: 1.02–1.07, p = 0.009), PCGrimAge (OR T3 vs. T1 = 3.97, 95% CI: 2.41–6.64; OR continuous = 1.16, 95% CI: 1.10–1.24, p = 8.76 × 10 −07 ) and DunedinPACE (OR T3 vs. T1 = 3.45, 95% CI: 2.17–5.55; OR continuous = 1.72, 95% CI: 1.43–2.10, p = 2.58 × 10 −08 ) were associated with MASLD‐HCC, but not PCHorvathAge or PCHannumAge. Conclusion Higher relative age accelerations of PCPhenoAge, PCGrimAge and DunedinPACE aging rate are associated with risk of MASLD‐HCC. These aging biomarkers could improve HCC risk assessment and facilitate risk stratification in patients with MASLD.

Abstract Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease linked to repetitive traumatic brain injury, but its prevalence and risk factors in the general population remain poorly defined. We investigated CTE neuropathological changes (CTE-NC) in an admixed, population-based clinicopathological cohort. Neuropathological evaluation was conducted on brain samples from 1151 individuals in the University of São Paulo Biobank for Aging Studies collected from 2004 to 2022. CTE-NC and aging-related tau astrogliopathy (ARTAG) were assessed across 14 963 histological slides using p-tau immunostaining. Clinical, cognitive, and neuropsychiatric data were obtained via informant interviews; information on sports exposure and traumatic brain injury history was limited. Seven cases (0.6%) met criteria for CTE-NC, mean age at death 73.4 ± 12.5 years; 1 was female. Dementia was present in 43% of CTE-NC cases; 57% exhibited neuropsychiatric symptoms. Most common co-pathologies were Alzheimer disease-type changes, ARTAG, and argyrophilic grain disease. Comprehensive exposure histories were unavailable for most cases; 2 had documented soccer involvement. These findings indicate that CTE-NC is rare in this population-based Brazilian cohort and predominantly affects males with frequent coexisting neuropathologies. Findings align with reports from high-income countries and support prioritizing primary prevention by reducing exposure to repetitive head impacts in sport and other settings.

Abstract Introduction This is the first International Consultation on Sexual Medicine (ICSM) position paper on sexual health in older adults. Physical, cognitive, and psychosocial factors create a unique set of challenges related to sexuality in older adults. Objectives This study explores the impact of the physiological aspects of aging, state of health, psychological, relationship-related, and sociocultural factors, on sexual health in older adults. The goal of this review is to provide recommendations for the comprehensive evaluation and treatment of this population. Methods A narrative review was conducted under the auspices of the ICSM, as part of its ongoing efforts to develop expert, evidence-based guidance in the field of sexual health. A multidisciplinary panel of international experts composed of specialists in urology, gynecology, psychiatry, sexual medicine, social work, and sex therapy was convened. A comprehensive literature review was conducted based on a search of psychological sources (PsycInfo), medical databases (PubMed, Medline), and Google Scholar. All retrieved articles were reviewed and critically assessed. Recommendations were then formulated using a modified Delphi method. Results Although there is extensive literature on the prevalence and risk of sexual challenges of adults over the age of 65, there is limited evidence regarding the quality of treatment modalities. In particular, there is scant data on women in this age group. This population faces specific and multifactorial challenges, which point to the need for a comprehensive approach to their care. Conclusion Any approach to sexual health in older adults needs to take all the factors that affect sexual health into account, while endorsing the full spectrum of sexual expression in a non-judgmental way. Individuals in a relationship should be offered a couple-centered approach. Special attention is needed for individuals in cognitive decline. Healthcare providers must be aware of ageist biases, which may prevent them from providing appropriate care.

Abstract This real-world retrospective cohort study evaluated utilization and comparative effectiveness of covalent Bruton tyrosine kinase inhibitor (cBTKi) monotherapies in relapsed/refractory mantle cell lymphoma (R/R MCL) from electronic health records in the United States. Adults with R/R MCL who received second- or third-line (2L/3L) zanubrutinib, acalabrutinib, or ibrutinib monotherapy, on or after 1 January 2018, were included. Inverse probability of treatment weighting was used in adjusted Cox models to compare real-world time-to-next treatment (rwTTNT) and overall survival (rwOS). Among 698 patients who received 2L/3L cBTKi monotherapy, 49%, 32%, and 19% received acalabrutinib, ibrutinib, and zanubrutinib, respectively. Unadjusted analyses showed median rwTTNT for 2L zanubrutinib, acalabrutinib, and ibrutinib was 14.5 (95% confidence interval [CI], 11.0-23.2), 12.8 (95% CI, 10.5-15.6), and 10.3 (95% CI, 7.6-13.7) months, and median rwOS was 26.4 (95% CI, 23.2 to not reached [NR]), 29.2 (95% CI, 22.9-38.1), and 29.3 (95% CI, 21.8-41.6) months, respectively. Median rwTTNT for 3L zanubrutinib, acalabrutinib, and ibrutinib was 21.1 (95% CI, 3.9 to NR), 9.2 (95% CI, 6.8-14.7), and 9.6 (95% CI, 4.8-18.0) months, and median rwOS was NR (95% CI, 27.3 to NR), 27.4 (95% CI, 15.1-42.2), and 27.0 (95% CI, 15.6 to NR) months, respectively. Adjusted models in the 2L/3L cohorts combined showed numerically longer rwTTNT and statistically significantly longer rwOS for zanubrutinib vs ibrutinib (hazard ratio, 0.63; 95% CI, 0.42-0.96), and trends for improved rwTTNT and rwOS for zanubrutinib over acalabrutinib. Toxicity was a frequent reason for changing to another cBTKi. These findings suggest potential improvements in rwTTNT and rwOS with the use of second- and next-generation cBTKis for R/R MCL from 2018 and beyond.

Abstract INTRODUCTION Apolipoprotein E allele 4 (APOE ε4) is the main genetic risk factor for late‐onset Alzheimer's disease (AD), but most evidence comes from White populations in high‐income countries. We investigated APOE and AD pathology in an ethnically diverse Brazilian autopsy cohort. METHODS This cross‐sectional study used Biobank for Aging Studies (BAS) data. AD pathology was evaluated with Braak, Consortium to Establish a Registry for Alzheimer's Disease, and Thal criteria. APOE genotypes were obtained from blood or brain tissue. Regression models were adjusted for age, sex, race, and education; interaction with race was tested. RESULTS Among 1391 participants (mean age 75.1 ± 12.4 years, 50% women, 64% White), APOE ε4showed a dose response with greater AD pathological burden and higher odds of AD diagnosis, while APOE ε2/X was protective. APOE ε4/ε4 did not show full penetrance across age groups. Associations were similar in White and Black individuals. DISCUSSION APOE ε4was strongly associated with AD pathology, with consistent associations across racial groups. Highlights APOE ε4 increased AD neuropathological burden in Brazilians. APOE ε2/εX was protective against AD pathology. APOE ε4/ε4did not show full penetrance across age groups. Associations between APOE and AD pathology were similar by race. Large multiethnic autopsy study expands evidence beyond high‐income country studies.