Citations

Abstract Background Metabolic dysfunction–associated steatotic liver disease (MASLD) is increasingly recognized among people with human immunodeficiency virus (PWH), which is likely related to metabolic alterations and fat redistribution. Anthropometric measures such as body mass index (BMI) and waist circumference (WC) are commonly used for assessing metabolic risk. However, their predictive accuracy for MASLD in this population remains uncertain. Method This multicenter cross-sectional study enrolled adults with HIV who underwent transient elastography with controlled attenuation parameter (CAP) measurement. Anthropometric and metabolic indices, including BMI, WC, hip circumference, waist-to-hip ratio (WHR), and visceral adiposity index (VAI), were collected from the study participants. Receiver operating characteristic (ROC) curve analyses were performed to determine the diagnostic performance of these indices for detecting hepatic steatosis, defined as CAP value of ≥248 dB/m. Analyses were stratified by sex assigned at birth. Results Altogether, 256 participants were included. WC demonstrated the numerically highest discrimination for CAP-defined steatosis (area under the ROC curve 0.769), followed by BMI and hip circumference, whereas WHR and VAI showed weaker performance. In sex-stratified analyses, WC remained the numerically highest-performing measure among males, whereas BMI, WC, hip circumference, and VAI showed similar discrimination among females. Conclusions Simple anthropometric measures, particularly WC, show fair ability to discriminate CAP-defined hepatic steatosis in PWH and may facilitate targeted fatty liver screening in routine HIV care.

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

Biological heterogeneity among different breast cancer (BC) subtypes results in markedly varying clinical outcomes. Identification and analysis of key gene biomarkers that are differentially regulated during radiation therapy (RT) may pose multiple clinical challenges for BC treatment. The purpose of the study is to identify and analyze the expression of key gene biomarkers and their networks that are differentially regulated after hypofractionated RT. Patients with BC (cT0-T2, N0, M0) were treated with hypofractionated whole breast RT 25 Gy in five fractions, 4 to 8 weeks before breast conservation surgery (BCS). Biopsy (pre-RT; n = 5) and surgical (post-RT; n = 14 or 15) BC tumor samples were used for NanoString targeted sequencing. We identified 165 and 244 differentially expressed genes (DEGs; p < 0.05) in BC tumor samples from BC patients post-RT using the nCounter BC360 and IO360 panels, respectively. Gene networks and pathway analysis revealed that RT increases the gene signature of tumor inflammation (TIS), cytotoxicity, and apoptosis, while downregulating the gene signatures of tumor cell proliferation, differentiation, and cell adhesion, and increases the claudin-low gene score. RT-induced mammary stemness and enhanced infiltration of stroma, mast, and macrophage cells in the BC tumor microenvironment (TME). Further, the nCounter IO360 (immuno-oncology) panel analysis validated the findings of BC360 and demonstrated that RT increased the myeloid inflammation signature and chemokine expression, modulated B, T, NK, and DC cell activities, and enhanced residual cancer burden (RCB) in BC tumors, thus creating an immunosuppressive TME. Collectively, RT sensitized BC tumors by increasing the gene signature of TIS, cytotoxicity, apoptosis, and mammary stemness. RT facilitated an immunosuppressive environment and increased RCB, suggesting that the therapeutic potential of RT is highly individualized for each patient based on their unique tumor biology, genetic makeup, and TME.

Due to systemic barriers, policymakers in the United States may be unaware of immigrants’ health-related priorities. In response, Rochester Healthy Community Partnership, a 22-year community-engaged partnership, collaborated with 14 Hispanic/Latino and Somali immigrant health promoters in fall 2023 using Photovoice to document their health-related assets and needs. After taking photos, the health promoters reflected, discussed the issues revealed in their images, and developed policy recommendations. Guided by Public Health Critical Race Praxis, we used thematic analysis to analyze health promoters’ reflections. Three themes emerged: healthy choices, inclusion of people and cultural celebrations, and access to opportunity. Health promoters want to expand healthy choices in Southeast Minnesota by growing community garden programming, protecting the environment, making healthy options accessible, and opening an affordable gym. They highlighted the importance of integrating culture and community into youth education, access to culturally appropriate foods, and the need to address Islamophobia. Health promoters wanted increased access to job opportunities, affordable housing, and health care. They saw these opportunities as vehicles for self-improvement but emphasized time management as essential in the United States. Ensuring that immigrants have a meaningful voice in shaping policies that affect health is critical. Policymakers can leverage these findings by demonstrating responsiveness to community-identified priorities and acting on health promoters’ policy recommendations. We encourage future Photovoice researchers to apply explicitly anti-racist frameworks, such as Public Health Critical Race Praxis, to document and challenge systemic oppression.

Abstract Background The van Herk margin formula, derived for 3‐D conformal radiotherapy with a uniform 3.2 mm dose penumbra and no intrinsic dose buffer, remains widely used to design CTV‐to‐PTV expansions in contemporary image‐guided prostate radiotherapy. However, coplanar VMAT techniques often feature broader penumbrae and explicit PTV–isodose clearances, potentially violating the assumptions underlying the original formulation and leading to overly conservative margins. Purpose We investigated whether the widely adopted van Herk margin formula overestimates clinical target volume (CTV)‐to‐planning target volume (PTV) expansions for contemporary coplanar volumetric modulated arc therapy (VMAT) prostate treatments. Methods Fifty consecutive intact‐prostate VMAT radiotherapy plans (two coplanar arcs; clinical margins 3 mm, except for 2 mm posterior) were exported. Direction‐specific 90% isodose–to‐PTV gaps and penumbra widths were measured. Candidate anisotropic margins were tested by eroding the PTV to create CTV_eval. Monte‐Carlo simulations combined systematic (Σ) shifts with Gaussian random (σ′) blurring kernels of 0–2 mm were performed. Acceptability criteria of (i) CTV Dmin0.03 cc ≥ 90% Rx in ≥ 90% of simulated scenarios or (ii) population tumor‐control probability (TCP) loss < 1 % were used. Results VMAT plans exhibited intrinsic 90% isodose clearances of 3–5 mm laterally/anteriorly and 1–2 mm superior–inferiorly, while axial‐plane penumbras were up to fivefold broader than van Herk's assumption. With a [0, 0, 2] mm (LR/AP/SI) margin, ≥ 90% of patients maintained Dmin0.03 cc ≥ 90% Rx provided Σ lay within an ellipsoid of [2.0, 1.5, 1.8] mm and σ′ ≤ [1.5, 2.0, 1.5] mm. Under TCP criteria the safe Σ ellipsoid for high‐risk disease was [2.5, 1.9, 2.2] mm, while low‐intermediate risk was even less sensitive. Conclusions For image‐guided coplanar VMAT prostate radiotherapy, an anisotropic [0, 0, 2] mm CTV‐to‐PTV margin is sufficient for target coverage. A modified margin expression that subtracts the measured isodose–to‐PTV gap and uses reduced random‐error coefficients better reflects modern practice.

Background Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), is a rare subset of primary cutaneous lymphoma known for its aggressive behavior, poor prognosis, and limited treatment options, particularly in the relapsed or refractory setting. We report a case of a patient diagnosed with PCDLBCL-LT who achieved a clinically significant response and sustained remission for seven months with acalabrutinib, a covalent inhibitor of Bruton’s tyrosine kinase (BTK), before disease progression. Case presentation An 88-year-old woman presented with a rapidly enlarging ulcerated lesion on the left lower leg. Histopathological and immunohistochemical analyses confirmed the diagnosis of PCDLBCL-LT. She was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemoimmunotherapy, followed by external beam radiation therapy (RT). These interventions resulted in only a partial response, and the disease progressed within several months. The patient was receiving direct oral anticoagulant (DOAC) therapy for left lower limb deep vein thrombosis, and she also had a history of hypertension. Considering the increased risk of major bleeding associated with DOAC use and the elevated risk of cardiovascular adverse events previously reported with ibrutinib, an alternative BTK inhibitor was considered. Accordingly, she was initiated on acalabrutinib at a dose of 100 mg orally twice daily. The patient exhibited a rapid and robust clinical response, with complete resolution of cutaneous lesions and sustained remission lasting seven months. Ultimately, the disease progressed, and given her advanced age and overall poor performance status, she was transitioned to hospice care. She subsequently died 14 months after initiating acalabrutinib. Conclusion This report documents the first known case of successful treatment of relapsed/refractory PCDLBCL-LT with acalabrutinib. Despite advanced age and poor performance status, the patient experienced rapid symptom resolution and durable remission without treatment-related adverse events. These findings suggest that BTK inhibitors may represent a promising therapeutic approach for PCDLBCL-LT, either as monotherapy or in combination with anti-CD20 antibodies. Further investigation into novel targeted therapies is urgently needed for this rare and aggressive lymphoma subtype.

Abstract Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the CLPTM1L signal marked by rs465498) with CRISPRi revealed opposing effects on TERT expression in pancreatic versus lung cancer cells, consistent with the antagonistic pleiotropy observed for this signal. Furthermore, CRISPRi nominated an intronic CLPTM1L variable number tandem repeat (VNTR) as a potent enhancer. Long-read sequencing established VNTR polymorphisms as potential causal variants for the rs465498 signal. We showed that Hippo-pathway transcription factors mediate VNTR enhancer activity in lung and pancreatic cancer cells. Together, these findings indicate that cancer susceptibility at 5p15.33 may be mediated by both SNPs and VNTRs and provide an integrated framework for resolving complex pleiotropic loci.

TPS283 Background: Emerging evidence suggests that metastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) can delay systemic therapy in oligometastatic castration-sensitive prostate cancer (omCSPC). However, the optimal timing of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (ARPI) initiation in this setting remains undefined. While deferred ADT following MDT may preserve quality of life, early short-course ADT/ARPI may eradicate micrometastatic disease and extend progression-free survival. Extracellular vesicles (EVs) carrying PSMA-positive prostate cancer (PC) signals and circulating tumor DNA (ctDNA) may serve as real-time biomarkers of MRD and treatment response. Methods: DIVINE [NCT06378866] is an open-label, phase II, randomized trial enrolling men with omCSPC defined by 1–5 metastases (≥1 extrapelvic) on conventional imaging (CT/MRI and bone scan) and testosterone >100 ng/dL. PSMA PET may be obtained for correlative purposes but does not determine eligibility. Participants (N = 220) are randomized 1:1 to: Arm A (Early systemic): SBRT plus 6 months of ADT + ARPI. Arm B (Deferred systemic): SBRT alone with observation, reserving systemic therapy until radiographic progression not amenable to further SBRT (mrPD). SBRT is delivered per institutional standard; repeat SBRT is allowed until lesions become non-addressable. The primary endpoint, modified radiographic progression-free survival (mrPFS), is the time from randomization to death or radiographic progression not amenable to further MDT, defined by PCWG3 (bone) and modified RECIST 1.1 (soft tissue) criteria on conventional imaging. Soft-tissue progression requires ≥ 20% increase in measurable disease or a new lesion; bone progression requires ≥ 2 new confirmed lesions. Secondary endpoints include OS, biochemical PFS, time to local and distant progression, and grade 3–5 adverse events during systemic therapy. Exploratory endpoints evaluate EV and ctDNA kinetics as MRD markers, correlation of PSMA-positive EV burden with outcomes, and duration of response after short-course ADT/ARPI. Correlative analyses will longitudinally quantify PSMA-positive EVs and ctDNA at baseline, on treatment, and at progression to define MRD dynamics and resistance patterns. The trial uses Pocock–Simon dynamic allocation by EV strata and metastatic burden to ensure balance across arms. The trial is open and actively enrolling across all Mayo Clinic sites; as of October 2025, 35 of the planned 220 patients have been accrued. Clinical trial information: NCT06378866 .