Citations

Abstract Background Women with a pathogenic variant in BRCA1 or BRCA2 are at high risk of developing ovarian cancer, and it is often recommended that they undergo bilateral salpingo-oophorectomy at an early age, resulting in surgical menopause. Menopausal hormone replacement therapy (HRT) is an effective way to mitigate the adverse outcomes of early menopause; however, the safety of menopausal HRT on breast cancer risk in this population has not been established. Methods We conducted a prospective matched analysis of HRT use following menopause and breast cancer risk in BRCA carriers. Women who initiated HRT were matched one-to-one with women who had not initiated menopausal HRT by gene, year of birth, and age at menopause, resulting in 676 matched pairs. Menopausal HRT use collected by questionnaire included formulation and mode of administration. Results After a mean of 5.6 years, there were 87 (12.9%) incident breast cancer cases in the 676 exposed women and 128 (18.9%) cases in the 676 unexposed women (P = .002). Compared with unexposed matched control individuals, women who used estrogen alone experienced a statistically significantly decreased risk of breast cancer (hazard ratio = 0.37, 95% CI = 0.24 to 0.57). No protective or adverse effect was associated with the use of estrogen plus progestogen (hazard ratio = 0.94, 95% CI = 0.54 to 1.63). Conclusions Our findings suggest no substantial increase in the risk of breast cancer in BRCA carriers with the use of HRT and that estrogen alone might be protective.

Abstract INTRODUCTION New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. METHODS Harmonized amyloid PET data from 4216 participants were used in genome‐wide survival, tissue‐specific gene expression, and genetic covariance analyses of EAOA. RESULTS Variants in apolipoprotein E ( APOE ), ABCA7 , and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7 , associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7 , which was associated with increased amyloid pathology at autopsy. Multiple immune‐related diseases shared genetic covariance with EAOA. DISCUSSION APOE , ABCA7 , and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue‐specific expression analyses, offering insights into intervenable targets at early stages of AD. Highlights Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E ( APOE ) , ABCA7 , and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue‐specific expression analyses.

Abstract Objective To compare the long‐term risk of subsequent abdominopelvic surgery in women who underwent hysterectomy with ovarian conservation (H‐OC) versus referent women, and in women who underwent abdominal H‐OC versus vaginal H‐OC. Methods We conducted a population‐based cohort study in Olmsted County, Minnesota, USA including 1573 women who underwent H‐OC for a benign indication at age 18–44 years between January 1, 1980, and December 31, 2002, and 1573 age‐matched (±1 year) referent women who had not undergone hysterectomy or any oophorectomy as of the matching date. For both the H‐OC women and the referent women, we defined the index date as the H‐OC or matching date plus 6 months. The index date served as the starting point for follow‐up. Results Overall, we found an increased risk of subsequent lysis of adhesions in women who underwent H‐OC compared to referent women (hazard ratio [HR], 1.57 [95% confidence interval [CI]: 1.09–2.27]). Women undergoing H‐OC also had an increased risk of subsequent gastrointestinal tract procedures (HR, 1.18 [95% CI: 1.05–1.31]) compared to referent women. When comparing surgical route of H‐OC, we identified an increased risk of subsequent adnexal surgeries in women undergoing abdominal compared with vaginal H‐OC (HR, 1.91 [95% CI: 1.40–2.61]). Conclusion Women who underwent H‐OC have an increased risk of subsequent abdominopelvic surgeries compared to referent women. In addition, women who underwent abdominal H‐OC have an increased risk of subsequent adnexal procedures compared to women who underwent vaginal H‐OC.

Objective The purpose of this study was to determine the cumulative incidence of diagnosis switching, drug‐free remission, and initiation of a biologic or targeted synthetic disease‐modifying antirheumatic drug (b/tsDMARD) in individuals with seronegative rheumatoid arthritis (RA). Methods Adult residents of Olmsted County, Minnesota, with incident seronegative (rheumatoid factor negative/anti–cyclic citrullinated peptide antibody negative) RA meeting the 1987 and/or 2010 American College of Rheumatology classification criteria were included. Data were collected from January 1, 2005, to December 31, 2023, through manual chart review. Drug‐free remission was defined as a period of at least six months where the individual was no longer taking treatment for RA and did not have evidence of active inflammatory arthritis upon evaluation by a rheumatologist. We calculated the 10‐year cumulative incidence of a change in diagnosis, adjusting for the competing risk of death, and of drug‐free remission and initiation of a b/tsDMARD, adjusting for the competing risks of death or change in diagnosis. Results A total of 176 individuals with seronegative RA (68% women) were included. The 10‐year cumulative incidence of a change in diagnosis was 12.8% (95% confidence interval [CI] 8.7%–18.9%). The most common change in diagnosis was to spondyloarthritis (4%). The 10‐year cumulative incidence of drug‐free remission and initiation of a b/tsDMARD was 26.6% (95% CI 20.7%–34.2%) and 19.9% (95% CI 14.7%–26.9%), respectively. Over a median follow‐up of 11.8 years, 49 individuals entered drug‐free remission. Conclusion After initial diagnosis of seronegative RA, about 13% of individuals had a change in diagnosis and a quarter experienced drug‐free remission within 10 years.

ABSTRACT Background Medial sural artery perforator (MSAP) flaps are favored in head and neck reconstruction for skin paddle pliability, pedicle length, and low donor site morbidity. We sought to characterize MSA vascular branching patterns based on the Dusseldorp et al. classification system using pre‐operative lower extremity computed tomography angiogram (CTA). Methods We conducted a retrospective review of 153 scans from 78 patients who underwent CTA prior to head and neck reconstruction at our institution. Primary data points included MSA branching pattern, branch dominance, and vessel depth. Results The type IIa branching type was most prevalent and the MSA lateral branch most frequently dominant, and they were significantly related to one another. There was no significant difference in depth between branching patterns. Conclusions Lower extremity CTA provides valuable insight to vascular anatomy for MSAP flap harvest. The type IIa and IIb types may be associated with lateral and medial MSA dominance, respectively.

PURPOSE Low-grade serous carcinoma (LGSOC) of the ovary, fallopian tube, or peritoneum is a hormonally driven, relatively chemoresistant malignancy with limited treatment options in the recurrent setting. Given frequent estrogen receptor (ER) expression and dysregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6)–p16–Rb pathway, features shared with hormone receptor–positive breast cancer, dual endocrine, and CDK4/6 inhibition is a biologically rational strategy. This phase II trial evaluated ribociclib plus letrozole in recurrent LGSOC. METHODS This open-label, single-arm, multicenter phase II study enrolled women with measurable, recurrent LGSOC. Patients received ribociclib (600 mg orally, once daily, days 1-21 of a 28-day cycle) and letrozole (2.5 mg orally, once daily). The primary end point was investigator-assessed objective response rate (ORR) per RECIST 1.1. Secondary end points included clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS Of 74 patients screened, 51 were enrolled and 49 treated. The confirmed ORR was 30.6% (90% CI, 19.9 to 43.2), including one complete and 14 partial responses. Among responders, the median duration of response was 21.2 months. The CBR was 84% (90% CI, 72.5 to 91.6). The median PFS was 14.5 months (90% CI, 10.1 to 28.8), and the median OS was 44.5 months (90% CI, 31.8 to not reached). The most common grade ≥3 adverse event (AE) was neutropenia (47%), managed with dose modifications. Three grade 5 events (6%) occurred but were unrelated to treatment. Treatment discontinuation because of AEs occurred in 4%. No dose-limiting toxicities were observed. CONCLUSION Ribociclib plus letrozole met the primary end point, achieving meaningful response rates and durable disease control in recurrent LGSOC. The safety profile was consistent with prior CDK4/6 inhibitor studies. This combination represents a therapeutic option in this rare and genomically distinct subtype.

Background. Long-term outcomes in kidney transplantation remain suboptimal, with subclinical acute rejection (subAR) frequently going undetected by conventional methods. We hypothesized that subAR represents a molecular precursor to clinical acute rejection (cAR). Leveraging a large National Institutes of Health-funded cohort with matched kidney tissue and peripheral blood samples, our primary objective was to determine whether subAR and cAR share molecular patterns, establishing subAR as an early stage of cAR. As a secondary aim, we compared biopsy and blood gene expression profiles to identify unique and shared pathways and to assess their diagnostic utility. Methods. This was a retrospective analysis of gene expression data from an observational clinical trial. We analyzed 578 blood and biopsy samples from 129 kidney transplant recipients enrolled in a multicenter observational study. Gene expression differences were analyzed using ANOVA with false discovery rate correction and molecular pathways analysis. Samples were matched and classified based on histologic findings and blood-based molecular diagnostics. Results. Gene expression and pathway analyses revealed that subAR exhibits a molecular profile consistent with a milder form of clinical rejection in both tissue and blood. Molecular signatures distinguished immune-mediated injury from nonimmune injury. Notably, tissue gene expression profiling in cases that were misclassified by peripheral blood diagnostics were like correctly classified cases, suggesting that histology alone may not reliably define true clinical phenotypes. Conclusions. Molecular profiling of tissue and blood reflects distinct but complementary aspects of transplant biology and confirms that subAR and cAR share overlapping molecular profiles, supporting the hypothesis that subAR represents an early stage in the progression toward clinical rejection. These findings highlight the limitations of relying solely on histological evaluation and support the use of molecular tissue profiling as an adjunct to histology, particularly in diagnostically ambiguous cases. Molecular profiling provides a supporting framework for identifying subclinical rejection and guiding personalized immunosuppression to improve long-term outcomes.