Citations

Abstract Introduction: The purpose of this study is to evaluate the effectiveness of opportunistic salpingectomy (OS), a procedure that aims to remove only the fallopian tubes of general population risk women, for the prevention of epithelial ovarian cancer. Currently, the method of prevention for individuals at high risk of ovarian cancer involves a bilateral salpingo-oophorectomy (BSO), a procedure that removes both the fallopian tubes and ovaries. However, this procedure is not recommended for individuals of the general population, who make up about 80% of ovarian cancers, due to negative health implications to the cardiovascular and skeletal systems because of surgically induced menopause. The effectiveness of the OS in preventing ovarian cancers and how the procedure impacts the histotype distribution of ovarian cancers remains unknown. Study Methods: This study uses a population-based approach and a case-based approach to determine the effectiveness of OS and its impact on histotype distribution, respectively. For the population-based analysis, we will search through clinical databases to acquire cases of individuals who have had an OS and a tumor. A control population who have their fallopian tubes in-tact will also be acquired. A cox-proportional hazard analysis will be performed to determine the effectiveness of the procedure. Using pathological records, the case-based ascertainment of tumors from individuals who have had an OS will be selected and reviewed for histotype confirmation. Fallopian tubes of these patients will also be reviewed for precursor lesions. This cohort will be compared to a historical histotype distribution of ovarian cancers. Results: For the population-based approach, we have to date, identified less than five serous ovarian cancers in individuals who have had an OS (n=40, 477). A comparator surgery was used as a control and showed 21 cancers. For the case-based approach, we have partnered with 23 collaborating institutions from around the world to identify tumors in individuals who have had an OS. We have identified 26 epithelial ovarian cancers, with the most lethal gynecological histotype, high grade serous carcinoma (HGSC), accounting for 23.1% of the total proportion of epithelial ovarian cancer cases (n=6/26). This is significantly less than the historical histotype distribution of HGSC, which is 69.3% (Fisher’s exact test, p<0.0001). One HGSC case had a precursor lesion called a serous tubal intraepithelial carcinoma (STIC) while reviewing fallopian tubes of this individual. TP53 mutation analysis on one HGSC tumor sample showed a frameshift mutation in TP53 (c229fs) with the tumor and the corresponding STIC staining negative for p53 protein expression by immunohistochemistry. Conclusion: This evidence demonstrates the effectiveness of opportunistic salpingectomy for the prevention of ovarian cancer and shows a histotype distribution shift, with the most lethal gynecological malignancy having a significant reduction in cases following the procedure. Citation Format: Ramlogan Sowamber, Alice J. Mei, Paramdeep Kaur, Julianne McLeod, Emily McKay, Alex Lukey, Jamie Bakkum-Gamez, Natalia Buza, Paul Cohen, Kyle Devins, Rhonda Farrell, Christine Garcia, Blake Gilks, Ellen Goode, Anjelica Hodgson, Brooke Howitt, Pei Hui, Jutta Huvila, Anthony Karnezis, Kianoosh Keyhanian, Mary Kinloch, Martin Köbel, Felix KF. Kommoss, Lawrence Kushi, Janice S. Kwon, Kara Long-Roche, Anais Malpica, Jessica N. McAlpine, Dianne Miller, Esther Oliva, Andrea Palicelli, Aleksandra Paliga, Carlos Parra-Herran, Celeste Leigh Pearce, Sharnel Perera, Jurgen M. Piek, Haiyan Qiu, Joseph Rabban, Robert Rome, Miranda Steenbeek, Rebecca Stone, Aline Talhouk, Kristin M. Tischer, Britton Trabert, Penelope M. Webb, John R. Zalcberg, Gillian E. Hanley, David G. Huntsman. Evaluating the effectiveness of opportunistic salpingectomy (OS) for the prevention of epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B045.

Technological innovations have improved many barriers in lung transplantation, but high rates of acute and chronic rejection still limit lung allograft survival. This may be explained by the unique environment of the lung. As a mucosal barrier organ, the lung is constantly exposed to the external environment, leading to unique immunological features that are not seen in other transplantable solid organ allografts such as hearts, kidneys, and livers. Thus, the higher rates of rejection and poor long-term survival of lung transplant recipients may stem from the global immunosuppression strategies that are indiscriminately used for all solid organ grafts. Data from our laboratory, and others, have demonstrated that the unique immunoregulatory pathways of the lung may require different strategies for long-term graft survival. For example, depletion of CD8 + T cells typically contributes to the acceptance of transplanted organs. However, these cells facilitate lung allograft acceptance through interferon gamma mediated nitric oxide production. Interestingly CD8 + T cells modify and polarize eosinophils to produce nitric oxide as a means of tolerance induction. Such eosinophils also function to maintain long-term lung allograft acceptance by interfering with humoral alloimmunity. For most other organs eosinophils are suspected to contribute to graft rejection. In this review, we aim to describe the cytokine pathways involved in lung allograft rejection or tolerance, contrast such pathways to those evident in other solid organs, and discuss the need for further studies that can be used to design rational methods for altering the cytokine environment to improve lung allograft survival.

Importance Cardiovascular (CV) disease is the leading cause of death globally for both men and women, yet women remain historically underrepresented in CV clinical trials, despite facing a disproportionately high burden of morbidity and mortality in many forms of CV disease. Objective To determine the representation of women across a broad range of CV trials. Evidence Review The participation of women in CV trials registered on ClinicalTrials.gov from 2017 to 2023 was systematically determined through the extraction of publicly available information. Data were extracted to identify the country of study, disease type, trial size, clinical intervention, and age of the participants. The proportion of women and the ratio of number of female to male participants (F:M ratio) were calculated for each trial. The women’s participation:prevalence ratio (PPR) was estimated for each trial based on the relative prevalence of the disease by sex in the specified region. Findings A total of 1079 registered CV trials were identified, including 1 396 104 participants, of whom 571 641 (41.0%) were women. The F:M ratio was significantly lower for studies on arrhythmia (median [IQR], 0.5), coronary heart disease (median [IQR], 0.39 [0.33-0.70]), acute coronary syndrome (median [IQR], 0.32 [0.24-0.51]), and heart failure (median [IQR], 0.51 [0.32-0.87]) but higher for obesity (median [IQR], 1.44 [1.08-4.50]) and pulmonary hypertension (median [IQR], 2.86 [1.50-3.97]) trials. The F:M ratio was higher for trials on lifestyle interventions (median [IQR], 1.51 [0.77-3.24]) than for drug trials. PPRs were low for clinical trials on coronary heart disease (median [IQR], 0.66 [0.50-0.86]), acute coronary syndrome (median [IQR], 0.79 [0.51-0.87]), and stroke (median [IQR], 0.74 [0.61-0.95]). Representation of women in CV trials varied by disease state, region, intervention, and sponsor type. Conclusions and Relevance These findings highlight both progress and persistent challenges in representation of women within CV trials. These gaps not only limit the generalizability of trial outcomes but also perpetuate inequities in evidence-based care for women with CV conditions.

ABSTRACT Hereditary hemorrhagic telangiectasia (HHT, Osler‐Weber‐Rendu disease) is the second most common inherited bleeding disorder worldwide, affecting approximately 1 in 5000 people. Development of disease‐modifying and efficacious hemostatic agents to treat HHT has finally begun after decades without such medical therapies. However, the lack of consensus on standardized severity definitions, outcome criteria, and terminology remains a major obstacle to clinical investigation and therapeutic development in HHT. Additionally, with the ongoing repurposing of antiangiogenic agents and emerging development of novel HHT‐specific therapies, comparative clinical trials are expected in the future. Therefore, to end the problematic heterogeneity hindering these efforts, the Global Research and Medical Advisory Board (GRMAB) of the Cure HHT Foundation, an international group of recognized HHT experts, convened a conference of expert HHT clinician‐investigators from within GRMAB as well as invited external experts in HHT and bleeding disorders generally, patients with HHT, and patient advocates to define standard terminology and definitions for outcomes and severity classification for bleeding and anemia in HHT. These criteria and definitions should be adopted by regulators, investigators, and the pharmaceutical industry in the development and performance of interventional clinical trials and cohort studies to allow improved comparability between clinical trials, facilitate communication between clinicians and investigators, improve therapeutic guideline development, and provide a standardized framework for regulatory agencies. Search Strategy and Selection Criteria Evidence for this report was systematically identified and evaluated utilizing two search strategies in Ovid MEDLINE, described in full detail in the Appendix, pp.4–13. The searches were conducted on January 7, 2025. The titles and abstracts of each record were reviewed, and the inclusion criteria were applied to all search results to identify full text articles to be retrieved for further review. All retrieved full texts were then reviewed to reach a final determination if a study met the inclusion criteria. Included references were then compiled into evidence tables, which were then utilized by the International Consensus Report Working Group throughout the development of report recommendations.

Background Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) is increasingly used to treat structural valve degeneration. Permanent pacemaker implantation (PPI) following TAVR is associated with increased morbidity and mortality, yet predictors specific to ViV-TAVR remain poorly defined. Objective To identify clinical and procedural predictors of PPI in patients undergoing ViV-TAVR. Methods We conducted a retrospective observational study of consecutive ViV-TAVR cases at the Mayo Clinic from 2012 to 2022. Clinical, ECG, procedural data and fluoroscopic measurements were analyzed, and propensity score matching was used to adjust for confounding. Predictors of PPI were identified using multivariable logistic regression. Results Among 261 patients, 24 (9.2%) required PPI. Balloon-expandable valves were used in 66.7% and self-expanding valves in 33.3%. Predictors of PPI included pre-procedural bifascicular block (OR 12.15, 95% CI: 2.52–68.89, p=0.003), greater septal implantation depth (OR 1.29, 95% CI: 1.04–1.65, p=0.019), and post-procedural new left (OR 23.56, 95% CI: 4.91–48.52, p=0.0004) and right bundle branch blocks (OR 24.4, 95% CI: 3.82–30.51, p=0.001). Aortic regurgitation as the mechanism of prosthetic valve failure was associated with reduced PPI odds (OR 0.28, 95% CI: 0.10–0.76, p=0.014). Pacing requirement—defined as >90% ventricular pacing—increased from 25% at 3 months to 56.25% at 12 months. At a median follow-up of 962.5 days (IQR 481.5–1555.3), adjusted mortality was significantly higher in the PPI group (aOR 9.4, 95% CI: 1.9–60.4, p=0.028). Conclusion Bifascicular block, greater septal depth, and new bundle branch blocks predict PPI post-ViV-TAVR, while aortic regurgitation appears protective. Risk stratification and procedural planning are critical.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Objectives: To analyze variations in patient characteristics, treatment patterns, clinical manifestations, clinical outcomes (i.e., response, flares and flare-free survival in HES; remission, relapses and relapse-free survival in EGPA; and overall survival), and healthcare resource utilization (HCRU) in patients with hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) across five European countries. Methods: In two parallel, retrospective, non-interventional, longitudinal chart review studies (GSK ID: 214661 [EGPA] and 214657 [HES]), physicians collected data of patients they treated in France, Germany, Italy, Spain, and the UK from January 2015 to December 2019, with follow-up until August 2021. Country-level results are presented for each study; HES and EGPA data were pooled in a post hoc exploratory analysis. Results: Per-country, 22–26 HES- and 38–45 EGPA-treating physicians collected data from 52–62 (total 280) patients with HES and 80–85 (total 407) with EGPA. Patient sex and age at diagnosis differed across countries. Pooled HES/EGPA data revealed high oral corticosteroid (OCS) use in all countries (94.9% of patients; median [IQR] duration 20.7 [9.0, 33.8] months); immunosuppressive treatments and biologics use varied between countries (43.7–61.5% and 25.6–59.8%, respectively). The most frequent clinical manifestations were constitutional (51.6–78.8%) and lung (43.5–55.8%) in HES, and lung (41.3–67.9) and ENT (43.8–61.2) in EGPA. Pooled HCRU data showed country-level variation; 70.7–91.2% of patients had disease-related outpatient visits and 36.1–52.6% had ER visits or hospitalizations. Conclusions: Results demonstrate substantial disease burden, including high HCRU and extensive OCS use among patients with HES and EGPA in five European countries. The findings highlight the need for improved treatment strategies such as optimizing use of biologics to mitigate the reliance on corticosteroids.

ABSTRACT Background Transvenous lead removal (TLR) is a Class I indication for patients with cardiac implantable electronic device (CIED) infections. However, disparities in the utilization of TLR have not been fully explored, particularly concerning demographic and socioeconomic factors. Objectives This study aims to examine whether disparities exist among patients hospitalized for CIED infections with respect to the utilization of TLR, focusing on sex, race, and income characteristics. Methods We utilized the 2019 National Inpatient Sample (NIS) to assess patients hospitalized with CIED infections and identify those who underwent TLR. Multiple logistic regression was used to examine risk factors for TLR utilization, including age, sex, race/ethnicity, and socioeconomic characteristics. Results A total of 56 709 patients were hospitalized for CIED infection in the United States in 2019, of which 9867 (17.4%) underwent TLR. On an adjusted analysis, females and Black patients were found to have lower odds of undergoing TLR compared to males and White patients (OR: 0.62; 95% CI: 0.59–0.78; p < 0.01; and OR: 0.47; 95% CI: 0.39–0.57; p < 0.01, respectively). Hispanic patients also had reduced odds of TLR (OR: 0.73; 95% CI: 0.58–0.93; p = 0.01). No significant associations were observed between income or insurance status and the likelihood of receiving TLR after adjustment. Conclusions This study identified significant disparities in the utilization of TLR among patients hospitalized for CIED infections. Female, Black, and Hispanic patients were significantly less likely to receive TLR.