Citations

Abstract Skeletal muscle is a major determinant of functional status. The impact of advanced prostate cancer (aPC) systemic therapies on body composition is unknown. We identified aPC patients with serial PET-CTs receiving androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (ARPI), chemotherapy, and/or Lutetium-177. An artificial intelligence algorithm quantified body composition changes from PET-CT images. Linear mixed effects models examined body composition changes over time by treatment type. The algorithm examined 2,342 PET-CTs from 468 patients. On multivariable analysis, ADT was associated with a 9% reduction in muscle density (-1.91 Hounsfield units), ARPIs an additional 6% (-1.4 Hounsfield units), and Lutetium-177 a subsequent 6% (-1.3 Hounsfield units), demonstrating progressive reduction in muscle density across later stages of systemic therapy. This large longitudinal analysis of body composition in aPC patients supports the use of an automated PET-CT algorithm to identify aPC patients on systemic therapy at risk for muscle wasting.

ABSTRACT Background Prior studies in the pre‐MRI era suggest that patients with NCCN Intermediate and High Risk Grade Group 1 prostate cancer (GG1 PCa) on biopsy have increased risk for adverse oncologic outcomes. However, prostate MRI has altered patient selection for biopsy and improved prostate sampling. Herein, we examined factors associated with adverse pathologic features (APF) at radical prostatectomy (RP) and biochemical recurrence (BCR) among patients with GG1 in the MRI era. Methods A prospectively maintained institutional prostate cancer registry identified patients with GG1 PCa on biopsy who underwent RP from 2000 to 2023, stratified by MRI use. Multivariable logistic regression and Cox regression identified factors associated with APF at RP (GG3‐5, ≥ pT3a, or pN1) and BCR free survival (two consecutive PSA ≥ 0.2 ng/mL), respectively. Results Among patients without MRI ( n = 6732), NCCN risk group was associated with APF, BCR, and distant metastasis. Among 302 patients with GG1 and pre‐operative MRI, NCCN risk group was associated with neither APF nor BCR. Age (OR 1.07, 95% CI 1.01–1.14, p = 0.01), PIRADS ( p = 0.01), and % core positivity (OR 1.02, 95% CI 1.00–1.03, p = 0.04) were associated with APF. Age (HR 1.07, 95% CI 1.01–1.13, p = 0.03), APF (HR 4.36, 95% CI 2.14–8.86, p < 0.001), and positive margins (HR 4.88, 95% CI 2.39–9.98, p < 0.001) were associated with BCR. Conclusions Prior to prostate MRI, NCCN risk groups offered meaningful prognostication among patients with GG1 PCa. However, the utility of NCCN risk groups for GG1 in the MRI era appears limited. Contemporary risk stratification for GG1 should focus on biopsy and MRI characteristics rather than NCCN criteria.

Background/Objectives: A 12-week trial demonstrated that phenotype-tailored lifestyle intervention (PLI) was associated with greater weight loss than standard lifestyle intervention (SLI); however, differences in dietary patterns between groups were not examined. Methods: This secondary analysis evaluated caloric and macronutrient intake at 12 weeks in adults with obesity (BMI ≥ 30 kg/m2), classified into four energy-balance phenotypes (abnormal satiation, reduced postprandial satiety, low energy expenditure, emotional eating) (n = 77) who underwent PLI or SLI. Dietary intake was assessed by 24-h recalls and verified by a blinded registered dietitian. Results: Groups were compared at 12 weeks adjusting for baseline values. PLI was associated with lower total energy intake than SLI (1273 ± 182 vs. 1894 ± 176 kcal/day; p = 0.018), due to lower carbohydrate (464 ± 76 vs. 818 ± 73 kcal/day; p = 0.002) and fat intake (479 ± 76 vs. 697 ± 73 kcal/day; p = 0.036); absolute protein intake did not differ. However, protein comprised a greater proportion of energy intake in PLI (26.8 ± 1.6%) than SLI (19.8 ± 1.5%; p = 0.003), and dairy protein contributed more to total energy in PLI (6.8 ± 0.8% vs. 3.7 ± 0.7%; p = 0.004). Conclusions: PLI was associated with lower energy intake, mainly due to reduced carbohydrate and fat intake, and a higher relative contribution of protein, consistent with phenotype-based recommendations rather than macronutrient prescriptions. These findings suggest a potential role for personalized dietary approaches in obesity management. However, the non-randomized design does not allow causal inferences.

Abstract Objective To evaluate whether systemic hormone replacement therapy (HRT) influences recurrence outcomes in postmenopausal patients with idiopathic subglottic stenosis (iSGS). Study Design Retrospective cohort study. Setting Tertiary academic medical center. Methods Postmenopausal women (≥50 years) with iSGS who underwent laser‐wedge excision between 2002 and 2024 were included. Patients were categorized by systemic HRT exposure (oral estrogen, progesterone, combined estrogen‐progesterone, or transdermal estrogen) at or before their first surgery. Overdispersion was assessed for all Poisson models; given significant overdispersion, negative binomial regression with a log‐offset for follow‐up time was used as the primary model. Surgery‐free intervals were analyzed using linear mixed models, and time to first recurrence using Cox regression. Models were adjusted for age, body mass index (BMI), parity, oophorectomy, follow‐up length, surgery type, and serial intralesional steroid injections (SILSI) use. Results Among 125 patients, 96 had never used HRT (Never HRT) and 29 used HRT, including 19 actively using HRT at presentation (Current HRT), 5 past users, and 5 subsequent users. The HRT versus Never‐HRT recurrence rate comparison was not significant (adjusted incidence rate ratio [IRR] = 0.81, 95% CI: 0.48‐1.37, P = .422). However, Current HRT use was associated with a 53% lower adjusted recurrence rate versus Never‐HRT use (adjusted IRR = 0.47, 95% CI: 0.25, 0.89, P = .0203). Surgery‐free intervals and time to first recurrence trended longer in Current HRT users but were not statistically significant. Conclusion Current HRT use at presentation was associated with significantly fewer recurrences in postmenopausal iSGS patients. These findings may inform individualized, shared decision‐making regarding HRT use in this population. Level of Evidence 3.

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.

Purpose: The purpose of this study is to characterize the clinical features, management strategies, and outcomes of endophthalmitis cases following pars plana vitrectomy using data from the American Academy of Ophthalmology (Academy) IRIS ® Registry (Intelligent Research in Sight). Methods: This is a retrospective cohort study of eyes that developed endophthalmitis following pars plana vitrectomy between 2013 and 2022. Data was collected from the Academy IRIS Registry. This study analyzed differences in visual acuity, intraocular pressure, rates of evisceration and enucleation, and rates of rhegmatogenous retinal detachment following endophthalmitis diagnosis. Results: A total of 1,223,777 unique eyes underwent a PPV during the study period, with 1,275 eyes meeting the inclusion criteria. The median time from pars plana vitrectomy to endophthalmitis diagnosis was 10 days. The majority of eyes (80.9%) were managed with intravitreal antibiotics alone, without a repeat pars plana vitrectomy. Long-term visual acuity, intraocular pressure, cup-to-disc ratio, and rate of evisceration or enucleation did not differ significantly between treatment groups. However, eyes that underwent the initial pars plana vitrectomy for retinal detachment repair had poorer long-term vision and higher rates of retinal detachment following endophthalmitis. Overall, 16.1% of eyes required evisceration or enucleation in this cohort. Conclusions: Despite its rarity, post-pars plana vitrectomy endophthalmitis can cause significant morbidity and even globe loss. There were no significant differences observed between eyes that were treated with intravitreal tap and inject versus repeat pars plana vitrectomy.

Messenger RNA (mRNA) therapeutics have transformed vaccination and protein replacement strategies, yet efforts to improve their performance have focused largely on sequence engineering, nucleotide modification, and delivery vehicles. Here we show that mRNA function can be controlled by rational design of higher-order RNA architectures. We develop self-assembling mRNA origami (mRNA-OG), a class of unimolecular RNA nanostructures that encode protein-coding sequences within higher-order, programmable, and compact nucleic acid architectures. Using computational design and experimental validation, we demonstrate that mRNA-OG folds into well-defined nanostructures while remaining translationally competent in mammalian cells. Although folded mRNA-OG recruits ribosomes comparably to unfolded constructs, it produces lower protein output, indicating that RNA architecture can directly influence translational efficiency. The compact geometry of mRNA-OG also enhances encapsulation by cationic lipid delivery systems, suggesting a structural route to improved cargo packaging. Beyond its effects on translation, mRNA architecture modulates innate immune recognition. In primary human dendritic cells, folded and unfolded mRNA-OG elicit distinct cytokine programs and differential activation of stress-response pathways, including a modest induction of the integrated stress response that is not fully explained by canonical PKR signaling. Our results establish programmable structure as a new design parameter for mRNA therapeutics that can affect its functionality, delivery properties, and immune sensing.

Abstract BCMA-directed CAR T-cell and T-cell engager (TCE) therapies produce high response rates in relapsed multiple myeloma, yet most patients progress. Prior work identified TNFRSF17 alterations mediating antigen escape in up to 43% of TCE progressions. To evaluate the generalizability of these findings and examine antigen-loss-independent resistance, we performed whole-exome sequencing on 32 paired pre- and post-treatment progression bone marrow samples from 15 patients (5 CAR T, 10 TCE); two patients received both agents. TNFRSF17 alterations were infrequent and restricted to TCE recipients (one concurrent frameshift and missense mutation; two heterozygous copy-number losses); no biallelic loss or CAR T-associated events were observed. In contrast, deleterious/loss-of-function variants in NF-κB, PI3K-AKT-mTOR, and MAPK/ERK pathways were universal in pre-treatment samples and acquired or clonally enriched in 80% of patients at progression. Acquired events included loss-of-function alterations in CYLD , activating mutations in KRAS , NRAS and BRAF , and acquired TP53 mutations. In this series, antigen escape via TNFRSF17 /BCMA alteration was uncommon. Instead, pre-existing, acquired and clonally enriched pathogenic variants in NF-κB, PI3K-AKT-mTOR and MAPK cascades, together with TP53 mutation, emerged as a frequent finding. These alterations suggest that deregulation of BCMA-downstream survival signaling, enhanced proliferative fitness, and elevation of apoptotic threshold constitute antigen-loss-independent mechanisms of resistance.