Citations

ABSTRACT Background Primary Biliary Cholangitis (PBC) is an autoimmune cholangiopathy with polygenic architecture and unknown aetiology. Evidence links Neanderthal‐derived genetic variants to autoimmune conditions; however, their contribution to PBC susceptibility remains unexplored. Objective We investigate whether archaic alleles influence PBC risk. Design Genotype data from four PBC cohorts were analysed: CANUK (4615 cases, 9233 controls), OLD IT (444 cases, 901 controls), NEW IT (255 cases, 579 controls) and MAYO (891 cases, 621 controls). Association testing with 235 592 Neanderthal Informative Markers (NIMs) was performed, adjusting for population stratification. Heritability was estimated using RHE‐mc and temporal haplotype dynamics were assessed using ancient DNA data from Europe and Asia. Results A Neanderthal‐derived variant in TNPO3 (rs12531711), previously reported by Cordell et al. showed strong association in CANUK ( p = 2.04 × 10 −26 ) and replicated across all validation cohorts. This variant functions as an eQTL, upregulating IRF5 and downregulating TNPO3 in blood. It is rare in African populations but common both in Europeans and Asians. Temporal analysis of the haplotype carrying rs12531711 revealed frequency increased substantially during the Bronze Age (5000–3000 BP), rising from 2.0% to 7.7% in Europe and 3.4% to 17.4% in Asia, before stabilizing. Despite this strong single‐variant association, the heritability explained by NIMs was not significantly different from that of non‐NIM variants. Conclusion A Neanderthal‐derived variant contributes to PBC risk and its frequency increased in the Bronze Age, possibly due to pathogen‐driven selection. Archaic introgression overall has limited influence on PBC heritability. Functional studies are needed to elucidate the role of rs12531711.

Abstract Treatment resistance and metastases occur in 10–20% of patients with invasive lobular carcinoma (ILC), the most common special histological subtype of breast cancer. ILC metastasizes to the ovary more frequently than no special type (NST) tumors, also known as invasive ductal carcinoma (IDC). To characterize the genomic landscape of breast cancer ovarian metastases, we analyzed 15,613 local breast cancers, 22,010 non-ovarian metastases, and 246 ovarian metastases sequenced using FoundationOne®CDx or FoundationOne® assays. Ovarian metastases had enriched CDH1 , PIK3CA , and TBX3 mutations and depleted TP53 and MYC alterations relative to local breast cancers, with additional depletion of ESR1 mutations compared to non-ovarian metastases. CDH1 mutations were less frequent in ovarian metastases (47%) than local ILC (81.3%), with reduced 16q loss (64% vs 84%), indicating that ovarian metastases also arise from non-ILC tumors. We extended these findings to a UPMC cohort of 27 ovarian metastases (13 ILC, 8 IDC, 6 mixed ductal-lobular carcinoma) with patient-matched primary tumors in most cases. In both cohorts, patients with ovarian metastases were significantly younger than those with other metastatic sites. In the UPMC cohort, the most frequent mutations were in PIK3CA , CDH1 , KMT2C , FOXA1 , and RUNX1 . Transcriptomic analysis identified upregulated G protein-coupled receptor (GPCR) pathways, including metabotropic glutamate receptor signaling. Functional studies showed that calcium-sensing receptor (CaSR), a GPCR overexpressed in ovarian metastases, drives MEK/ERK-dependent migration and F-actin reorganization in ILC cell lines, enhanced by estrogen and blocked by calcilytic, MEK, or anti- estrogen treatment. Our findings inform future therapeutic targeting of ovarian metastasis.

Importance Anhydramnios from fetal kidney failure causes lethal pulmonary hypoplasia. Serial amnioinfusions have shown promise in mitigating pulmonary disease from bilateral renal agenesis, but efficacy and safety for other causes of fetal kidney failure are unproven. Objective To assess the efficacy of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia in cases of anhydramnios due to fetal kidney failure. Design, Setting, and Participants Prospective, nonrandomized clinical trial conducted at 13 US fetal therapy centers from December 2018 to February 2025. Outcomes for maternal-fetal pairs with anhydramnios before 22 weeks’ gestation due to fetal kidney failure without bilateral renal agenesis are reported; data collection for surviving infants continued until February 13, 2026. Exposure Thirty-two participants underwent serial amnioinfusions with isotonic fluid beginning before 26 weeks’ gestation. Main Outcomes and Measures The primary end point was neonatal survival for 14 days or longer with dialysis access placement. Secondary outcome measures of survival to discharge home and kidney transplant are reported. Results Twenty-nine of 32 participants (91%) had a live birth, with a median (IQR) gestational age at delivery of 34 weeks 1 day (31 weeks 5 days to 34 weeks 6 days). All participants delivered before 37 weeks’ gestation. No unexpected serious maternal adverse events occurred, and the most common maternal complications were preterm prelabor rupture of membranes in 19 participants (56%) and chorioamniotic separation in 10 (29%). The primary outcome occurred in 19 (65.5%) of 29 live-born neonates (95% CI, 45.7%-82.1%). Factors associated with survival to the primary outcome included receiving more amnioinfusions (median [IQR], 14 [9-18] in survivors vs 7 [4-11] in nonsurvivors; P = .01), longer time interval from first amnioinfusion to preterm prelabor rupture of membranes (63.5 [60.5-74.5] days in survivors vs 29.0 [22.0-56.0] days in nonsurvivors; P = .01), gestational age greater than 32 weeks (79% of survivors vs 38% of nonsurvivors; P = .03), and higher birth weight (2029 [1770-2250] g in survivors vs 1635 [1185-1915] g in nonsurvivors; P = .01). Fourteen live-born infants (48%) survived to hospital discharge at a median (IQR) age of 4.7 (3.4-5.7) months. Of the 11 infants surviving to date, 7 (64%) have undergone kidney transplant between ages 2 years to 5 years. Conclusions and Relevance Serial amnioinfusions mitigated lethal pulmonary hypoplasia in neonates with anhydramnios due to fetal kidney failure. Significant neonatal morbidity and mortality independent of early lung function was noted. Factors associated with survival were consistent with the Renal Anhydramnios Fetal Therapy trial’s bilateral renal agenesis cohort, suggesting common mechanistic pathways for mitigating pulmonary hypoplasia. Trial Registration ClinicalTrials.gov Identifier: NCT03101891

Abstract Rationale This Registry was designed to prospectively evaluate the efficacy of extracorporeal photopheresis (ECP) to arrest the rate of FEV1 decline (FEV1 decline) and prolong survival in lung allograft recipients with Bronchiolitis Obliterans refractory to standard of care therapy. Methods After IRB approval, 258 lung transplant recipients were enrolled from 20 US lung transplant centers. Subjects were assigned to ECP treatment (ECPRx) (i.e., 24 procedures over 6 months) at or a few months after enrollment based on spirometric criteria. Maintenance ECPRx (mECP) was at the discretion of managing clinicians. Rate of FEV1 decline in mL/month (FEV1 decline) was compared between 6 months prior to and 6 & 12 months after ECPRx initiation using linear mixed effects models. Time 0 for survival was set as the start of ECPRx for generation of Kaplan-Meier curves. Hazard Ratios (HR) with 95% confidence intervals (lower-upper) were generated using Cox Proportional Hazards Regression to characterize significant (p < 0.05) independent associations of mECP and/or any other covariates (i.e., demographic, operative, enrollment site, spirometric ) and survival. Results An 89% (78%-96%) decrease in the FEV1 decline was observed 12 months after ECPRx initiation in 191 participants assigned to ECPRx. FEV1 decline (-164 mL/month: 144-185) was greater (p < 0.001) in participants who expired within six months of Time 0 (n = 28) vs participants (-111 mL/month: 101-120) who died six months after Time 0 (n = 77). Of 159 participants who survived for at least six months after ECPRx initiation, 40 participants without mECP, who had up to 24 ECPRx (ECPRx: n = 19), had a lower survival HR: 2.43(1.75-3.4) (p < 0.001) relative to 119 participants who received mECP (ECPRx: n = 86)(see Figure). The response to ECPRx (% Change in FEV1 decline prior to and 6 months after 1st ECP) was similar between subcohorts (No mECP: -81 decrease vs mECP: -85%, p = 0.3). The association of mECP persisted after multivariate adjustment HR 1.8 (1.8-2.7)(p = 0.002) using significant covariates: FEV1 HR 0.37 (0.3-0.5), FEV1 decline HR 0.001 (0.001-0.04), Male Gender HR 2.4 (1.7-3.4); Reflux Disease HR 1.8 (1.2-2.8); Coronary Disease HR 1.8 (1.2-2.7). Conclusions This analysis indicates that mECP is independently associated with enhanced survival most likely due to attenuation of relapse six months after ECP initiation based on similar initial response to ECPRx. A risk-adjusted, control cohort is being pursued to facilitate submission of a scientifically rigorous petition to CMS to expand the ECP National Coverage Decision to include BOS predicated on CMS 2024 scientific guidelines. This abstract is funded by: Therakos Inc

Abstract Introduction Penile implant (PI) surgery is a well-recognized strategy for erectile dysfunction (ED) with excellent functional/satisfaction outcomes. To date, little attention has been paid to the attitudes and satisfaction outcomes of female partners of such patients. Objective To qualitatively assess how female partners feel about PI surgery to inform the development of a female partner specific questionnaire. Methods Female partners of men who had undergone PI surgery (3-piece inflatable) underwent concept elicitation interviews. Prior to this, a panel of experts in female sexual health and PI surgery was convened to define potential domains of interest. Women were interviewed by one of two female sexual medicine clinicians to elicit concepts. As part of the spontaneous item generation phase, participants were asked about their attitudes, hopes and concerns prior to PI surgery, as well as changes in partner post-surgery. Participants were then asked whether they identified domains raised by the expert panel that were not mentioned during the spontaneous phase. Additional open-ended questions were asked about experiences before and after PI surgery. Interviews were transcribed verbatim for subsequent qualitative analysis by 2 trained members of the study team. Results 12 women have been interviewed. Mean partner age = 60 years, relationship duration = 20years. Interviews were held <12 months post-PI for 17% of partners, 12-24 months for 25%,>24 months for 58%. Partner communication and involvement in decision to get the implant were uniquely raised as pre-surgical concerns, whereas PI attributes were uniquely mentioned as post-surgical concerns. How the PI has impacted the man’s self-esteem, whether impacts to self-esteem have affected the partner, and overall satisfaction with sex were most common concepts raised across pre- and post-surgery Conclusions Using rigorous qualitative methodology, we have identified concepts that are unique to pre-surgery, post-surgery, and common across the surgical experience among partners of men who have undergone penile implant surgery. These data will facilitate development of a tool to assess female partner attitudes, beliefs and satisfaction prior to and after PI surgery. Disclosure Yes, this is sponsored by industry/sponsor: Coloplast Clarification: Industry funding only - investigator initiated and executed study

Abstract Context Limited data are available on quality of life (QoL) and adrenal crises in patients with immune checkpoint inhibitor–induced secondary adrenal insufficiency (ICI-SAI). Objective To (1) characterize the presentation, management, and outcomes of patients with ICI-SAI; (2) compare outcomes of ICI-SAI with other etiologies of secondary adrenal insufficiency (oSAI); and (3) identify variables associated with QoL and adrenal crisis. Methods In this single-center cross-sectional study, adults with ICI-SAI or oSAI (2018-2025) completed questionnaires assessing symptoms, management, adrenal crises, and the Addison’s Disease–Specific QoL survey (AddiQoL); outcomes included AddiQoL score and adrenal crisis events. Results Patients with ICI-SAI (n = 109) were older (median age 66 vs 60 years), more often women (59% vs 43%), and more frequently diagnosed within 1 year of symptom onset (88% vs 42%, P < .001), compared to patients with oSAI (n = 139). Patients with ICI-SAI had higher AddiQoL scores (median 87 vs 85, P = .020). In a multivariable analysis of age, sex, glucocorticoid dose and type, insurance support, and duration of SAI, ICI-SAI remained independently associated with higher AddiQoL (estimate 5.4, P = .010). The prevalence of reported adrenal crises within the prior year was similar between groups (15% vs 14%, P = .782). In a multivariable analysis, higher AddiQoL scores were independently associated with lower odds of adrenal crisis (OR 0.57; 95% CI 0.42-0.76). Conclusion Patients with ICI-SAI report better QoL compared with patients with other causes of SAI, despite similar adrenal crisis rates. These differences may be related to earlier diagnosis and differing clinical contexts, underscoring the importance of timeline recognition and patient-centered management.

Abstract Context The clinical relevance of etiologic concordance and temporal presentation in bilateral adrenal masses remains poorly defined, creating uncertainty in diagnostic evaluation and management. Objective To characterize the etiologic spectrum of bilateral adrenal masses, evaluate patterns by concordance and synchronicity, and identify predictors of discordance and malignant or pheochromocytoma contralateral lesions. Design Retrospective cohort study (2010-2025). Setting Tertiary referral center. Participants Adults with bilateral adrenal masses. Main Outcome Measures Etiology, concordance, synchronicity, interval to contralateral lesion, and factors associated with discordance and malignant or pheochromocytoma contralateral lesions. Results Among 1035 patients (median age 59.6 years; 51% women), 85% had concordant and 15% discordant etiologies. Concordant cases were predominantly bilateral benign cortical lesions (76%), whereas discordant cases were heterogeneous (benign 35%, malignant 31%, and indeterminate 34%). Presentation was synchronous in 84% and asynchronous in 16%, with a median interval of 45 months (interquartile range 15-87). Asynchronous disease was associated with higher discordance (23% vs 13%, P = .001) and greater prevalence of malignant lesions (bilateral malignant: 17% vs 7%; discordant malignant: 8% vs 4%; overall P < .001). Among asynchronous cases, shorter interval to contralateral lesion (<2 vs ≥5 years) was independently associated with malignant or pheochromocytoma etiology (adjusted odds ratio [OR] 2.63, 95% CI 1.01-6.85), as was larger tumor size (adjusted OR 1.06 per mm, 95% CI 1.02-1.09). Conclusion Most bilateral adrenal masses are benign and concordant; however, discordant or asynchronous disease identifies a higher-risk subgroup enriched for malignancy. Early contralateral lesion development and larger tumor size are key risk factors.

Abstract Context Bilateral adrenalectomy (BLA) and autoimmune adrenal insufficiency (AAI) are 2 major causes of primary adrenal insufficiency (PAI). Comparative data between etiologies are limited. Objective To compare management, quality of life (QoL), and frequency of adrenal crises between participants post-BLA vs AAI. Methods We conducted a dual-center, cross-sectional study of adults with AAI or BLA between 2018 and 2025. All participants completed questionnaires on management, adrenal crises, and the Addison Disease-specific QoL Questionnaire (AddiQoL). Results Of 343 participants, 203 had AAI (median age 54 years, 72% women) and 139 had BLA (median age 57 years, 76% women). AddiQoL scores were similar between participants with AAI and BLA (median 84 vs 83, P = .947), but better in participants post-BLA for pheochromocytoma versus hypercortisolism (median 88 vs 81, P = .031). Participants with AAI reported a higher number of adrenal crises within the past year than those post-BLA (25% vs 13%, P = .022). In multivariable analyses of age, sex, glucocorticoid dose and type, PAI type, AddiQoL score, and autoimmune comorbidities, only PAI type was associated with higher number of reported adrenal crisis within the last year (AAI vs BLA: odds ratios of 2.1-2.2, P < .05 for all models). Conclusion QoL was comparable between participants with AAI and BLA, though patients post-BLA for pheochromocytoma reported better QoL than patients post-BLA for hypercortisolism. Adrenal crises were more common in participants with AAI than those post-BLA, a finding that was not explained by patients’ glucocorticoid management, underscoring the need for tailored crisis prevention strategies.