Citations

Purpose To evaluate the agreement between a simple magnetic resonance imaging‐based measurement method for determining the patellar tendon‐to‐lateral trochlear ridge (PT‐LTR) distance using an external adhesive marker and a previously validated conventional measurement technique. Methods Patients diagnosed with patellofemoral instability before undergoing primary patellar stabilization surgery at a single institution between 2020 and 2024 were eligible for inclusion. PT‐LTR distances were measured in a blinded fashion by 2 musculoskeletal‐trained radiologists using the conventional technique and by an orthopaedic group using the simple technique. Interrater reliability between the musculoskeletal‐trained radiologists and between the orthopaedic groups was calculated using intraclass correlation coefficients (ICCs) and concordance correlation coefficients (CCCs) and subsequently intermethod reliability between the 2 groups. The measurements were plotted on concordance correlation graphs. Results One hundred knees (38 right, 62 left) from 97 patients (37 men, 60 women; mean age 22 ± 9 years) were included. The average distance for PT‐LTR measured by the radiologists using the conventional technique was 10.9 ± 7.5 mm and by the orthopaedic group using the simple technique was 9.3 ± 6.8 mm. Excellent interobserver agreement was noted for the radiologist group (ICC 0.941, 95% confidence interval [CI], 0.914‐0.960; CCC 0.941, 95% CI, 0.915‐0.959) and orthopaedic group (ICC 0.976, 95% CI, 0.964‐0.985; CCC 0.976, 95% CI, 0.965‐0.984). Excellent intermethod agreement was noted between the 2 techniques (ICC 0.903, 95% CI, 0.775‐0.942; CCC 0.902, 95% CI, 0.861‐0.932). Conclusions There was excellent interobserver reliability for measuring PT‐LTR distance using both the conventional radiologist‐based technique and the external adhesive marker technique. Excellent intermethod agreement was also shown between the 2 techniques, with comparable mean measurements between groups; thus, the simple technique can be used as a reproducible alternative for PT‐LTR distance. Level of Evidence Level III, retrospective comparative study.

Abstract Background Regorafenib and anti-EGFR monoclonal antibodies are standard therapies for RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC) in the refractory setting, but the optimal sequencing remains unknown. Herein, we report results from REVERCE II, a randomized phase II trial evaluating the efficacy and safety of sequencing these therapies. Methods Patients with RAS WT mCRC previously treated with fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive (R-E) regorafenib followed by anti-EGFR therapy ± irinotecan or (E-R) anti-EGFR therapy ± irinotecan, followed by regorafenib sequentially. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) with initial (PFS1) and second treatment (PFS2), sequential treatment PFS (stPFS), objective response rate (ORR), and safety. Exploratory endpoints included serial biomarker analyses. Unfortunately, the trial was closed prematurely due to slow enrollment and lack of funding. Results Twenty-two patients were enrolled (R-E: n = 12; E-R: n = 10) with sequential treatment initiated in 33% (4/12) and 80% (8/10) of patients in R-E and E-R, respectively. Median OS for R-E and E-R was 21.9 and 13.3 months, respectively (one-sided P = .114). PFS1 was 2.5 (R-E) vs 5.6 months (E-R) (one-sided P = .998), while PFS2 was 3.7 vs 2.0 months (one-sided P = .086). stPFS was similar (9.3 vs 9.6 months; one-sided P = .358). ORR for initial treatment was 0% in R-E and 20% (2/8) in E-R. Sequential treatment ORR was 25% (n = 1/4) in R-E and 0% in E-R. No significant differences were observed adverse effects between arms. Conclusion While the study was closed prematurely prior to completion, the sequence of regorafenib before to anti-EGFR therapy suggested a possible survival benefit. Further studies may help better determine the optimal treatment sequencing strategy in refractory mCRC.

Abstract Cellular senescence is a central hallmark of aging, yet its measurement in humans remains invasive, low-throughput and tissue-specific, precluding population-scale study. We developed Methylation-associated Gene Expression (MaGE) predictors: whole-blood DNA methylation proxies of p14 ARF , p16 INK4A and p21 CIP1 expression, plus a composite score, providing the first scalable measure of senescence-marker expression. Deployed across Generation Scotland (n=18,859), MaGE yielded 45 Bonferroni-significant associations spanning 18 incident diseases and all-cause mortality. The two strongest associations recapitulated the established tissue specificity of p21 CIP1 and p16 INK4A activation, with MaGE-p21 associating with incident alcoholic liver disease and MaGE-p16 with pulmonary fibrosis. In a separate study, MaGE tracked disease severity and treatment response in Crohn’s disease. MaGE is a scalable, interpretable biomarker of senescence that enables its study at population scale and offers a route to patient stratification in senolytic trials.

Objective To evaluate the efficacy of cytokine‐directed therapies in VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory somatic) syndrome using previously proposed treatment response criteria. Methods All patients with genetically confirmed VEXAS syndrome who received targeted therapies with JAK inhibitors (JAKi), tumor necrosis factor α inhibitors (TNFαi), or interleukin‐1 (IL‐1) or IL‐6 inhibitors were identified. Clinical and biochemical data were recorded for patients at time of targeted therapy initiation, and at 3‐, 6‐, and 12‐month follow‐up time points. Treatment response was labeled as complete response (CR; normalization of C‐reactive protein [CRP], prednisone <10 mg/day, and resolution of disease activity), partial response (PR; >50% improvement in CRP, >50% prednisone dose reduction, improvement or resolution of disease features), treatment failure (TF; worsening CRP, increasing prednisone, worsening of disease features), or no response (not meeting criteria for CR, PR, or TF). Results Overall, 52 patients received an IL‐1i, IL‐6i, or JAKi therapy. At six‐month follow‐up, 3 of 19 IL‐6i patients experienced CR, 4 of 19 experienced PR, and 7 of 19 experienced TF. 2 of 17 patients receiving JAKi experienced CR, 3 of 17 experienced PR, and 6 of 17 experienced TF. No patients receiving IL‐1i or TNFαi experienced CR, and only 1 of 5 IL‐1i patients experienced PR. Among those still receiving biologic therapy at 12 months, only 1 of 11 receiving IL‐6i and 0 of 7 receiving JAKi experienced CR. Conclusion IL‐6i and JAKi therapies demonstrated limited, unsustained efficacy for management of VEXAS syndrome. IL‐1i and TNFαi therapies were not efficacious. Useful application of previously reported treatment response criteria was demonstrated, but future incorporation of hematologic parameters may be beneficial.

Antisense oligonucleotides (ASOs) represent a promising therapeutic modality for RNA-based disease mechanisms, but identifying high-efficacy candidates from large sequence spaces remains a major bottleneck in drug development. Here, we present ASOFormer, a novel Transformer-based neural network that predicts the inhibition efficiency of RNase H-mediated ASOs from sequence, predicted secondary structure, and chemical modification features. ASOFormer was trained on a knockdown efficacy dataset spanning over 170,000 ASO-target pairs compiled largely from published patents. Ablation analysis confirmed that the addition of chemical modification features to the primary sequence drove the largest performance gains, with predicted secondary structure providing complementary benefit when combined with modification information. Further analysis highlighted the importance of the wings of gapmer ASOs and other features. As independent validation, ASOFormer was applied to ASOs targeting seven genes that were not in the training dataset gene list. For four out of the seven genes, the ground truth ASO inhibition efficiency was obtained from a public dataset, whereas the others were measured in-house via qPCR. Compared to two published state-of-the-art methods, ASOFormer achieved the best overall accuracy and prioritized the strongest inhibitors. Crucially, only ASOFormer consistently exceeded random expectation for top-candidate recovery across all seven test genes.

Abstract Background: Sexual and gender minority (SGM) representation is growing in the United States. This study estimated the future SGM cancer burden amidst shifting cancer patterns. Methods: Age-specific incidence data for breast, prostate, colorectal, lung, and melanoma were obtained from the Surveillance, Epidemiology, and End Results Program’s 12-registry database. Nordpred age-period-cohort models projected incidence through 2040 to 2044. Rates were applied to US Census population estimates and generation- and sex-specific SGM identification proportions from Gallup’s 2023 to 2024 surveys. Prophet was used for sensitivity analysis. Results: At ages 55 to 59, breast cancer cases among Millennial SGMs were 3,672% higher than among Silent Generation SGMs (34,850 vs. 924 cases), melanoma cases were 1,061% higher (5,526 vs. 476 cases), and colorectal cancer cases were 2,206% higher (23,594 vs. 1,023 cases). Compared with Generation X, Millennial prostate cancer cases were 142% higher (8,100 vs. 3,344 cases), and lung cancer cases were 169% higher (5,451 vs. 2,029 cases). By 2040 to 2044, Millennials were projected to account for 68.4% of breast cancer cases and 59.7% of colorectal cancer cases among SGMs. Conclusions: At ages 55 to 59, the 5-year cancer burden was projected to be 15 times higher among Millennials than Silent Generation SGMs (77,521 vs. 5,134 cases), driven primarily by the larger SGM population in younger generations. Oncology systems will need to prepare for the increase in cancer care demand. Impact: These findings identify a substantial generational shift in the SGM cancer burden and may inform oncology workforce capacity, culturally responsive cancer care, and healthcare system preparation for this growing population.

BACKGROUND: The right ventricular (RV) response to pressure overload is a crucial determinant of outcomes in pulmonary arterial (PA) hypertension. Sotatercept improves clinical outcomes, but its effects on the right ventricle have been inconsistent. We evaluated the effects of sotatercept on load-independent measures of RV contractility, RV–PA coupling, and right heart deformation at rest and exertion in patients with PA hypertension. METHODS: In this prospective trial among participants with PA hypertension recruited between July 2024 and May 2025, we performed simultaneous echocardiography and invasive pressure measurements during rest and exercise to evaluate changes in RV contractility (end-systolic elastance [Ees]), afterload (PA elastance [Ea]), RV–PA coupling (ratio of arterial Ea to Ees), and right heart deformation, including RV and right atrial strain, before and after 24 weeks of sotatercept using mixed models. RESULTS: Among 30 participants (n=21; 70% female; mean age, 49.3 years [SD 13.5]), sotatercept decreased PA Ea. These changes were associated with reduced RV contractility, PA pulsatility index, and the maximal rate of RV pressure increase over time (dP/dt max ; P <0.001 for all). The decrease in Ees was associated with a decrease in PA Ea (r=+0.70 [95% CI, +0.44 to +0.85]; P <0.0001) with preserved RV–PA coupling (mean difference, +0.08 [95% CI, −0.11 to +0.26]; P =0.42). Although systolic indices measured at the base of the right ventricle (tricuspid annular plane systolic excursion and systolic velocity of the lateral tricuspid annulus) decreased after sotatercept use, there was an increase in RV free wall–dependent systolic indices, including resting and exercise RV free wall strain (mean difference, +6.2% [95% CI, +4.5 to +7.8]; P <0.0001) and fractional area change ( P =0.0001). Beyond the right ventricle, there was also improved right atrial filling and contractile performance across rest and exercise ( P <0.0001 for all). CONCLUSIONS: Sotatercept decreases RV contractility in proportion to reduced afterload, while preserving the RV–PA coupling relationship. Despite decreased RV contractility, global measures of right heart performance, such as RV free wall strain and RA strain, improve, alongside redistribution of RV deformation from annular motion to free wall shortening. These data suggest that sotatercept causes an energetically favorable reduction in resting RV contractility to match the lower afterload, which does not appear physiologically detrimental when considering the concurrent improvement in RV free wall contractile mechanics and exertional right heart reserve. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06409026.

Abstract Enfortumab vedotin (EV), pembrolizumab, and EV plus pembrolizumab (EV/P) have rapidly reshaped the treatment landscape of advanced urothelial carcinoma, but toxicity increasingly determines treatment delivery, treatment continuity, and real-world benefit. As EV/P moves into broader clinical use, clinicians must distinguish adverse events related to antibody-drug conjugate exposure from immune-mediated toxicities and recognize syndromes in which both mechanisms may contribute. In this practical, mechanism-informed review, we synthesize pivotal trials, mature follow-up reports, and representative real-world cohorts describing the safety of EV monotherapy, pembrolizumab monotherapy, and EV/P in urothelial carcinoma. Because adverse-event reporting and ascertainment are heterogeneous across studies, including differences in preferred terms, composite categories, grading frameworks, and treatment-related versus all-cause reporting, we emphasize clinically interpretable patterns rather than pooled estimates. EV monotherapy is characterized by cutaneous toxicity, peripheral neuropathy, hyperglycemia, dysgeusia, and ocular events, including early epithelial/metabolic events and cumulative neuropathy. Pembrolizumab monotherapy has a lower overall high-grade toxicity burden but is defined by immune-mediated endocrinopathies, pneumonitis, hepatitis, colitis, and nephritis. Combination therapy produces a predictable overlap of these toxicity domains, creating diagnostic and management challenges for syndromes such as skin toxicity, diarrhea, fatigue, and pulmonary symptoms. We provide comparative visual toxicity signatures, regimen-specific summary tables, temporal toxicity mapping, and a pragmatic attribution framework that classifies events as EV-predominant, immune-predominant, overlap/indeterminate, or high-risk requiring initial interruption of both agents. This review aims to support bedside recognition, provisional attribution, early management, and safer implementation of EV/P in contemporary urothelial carcinoma practice.