Faculty Bibliography

BACKGROUND:Although radiation therapy (RT) remains one of the most effective treatments for patients with the lethal brain tumor glioblastoma (GBM), quite a number of patients show resistance or relapse shortly after RT. There is an urgent need to uncover the temporal and spatial dynamics of RT resistance during tumor progression and treatment. METHODS:The radio-resistance signature score (RRSS) was calculated by utilizing glioma sphere-forming cells (GSCs) which recapitulate the transcriptomic landscape of GBM. RESULTS:RRSS can assess the RT response on both cell lines and GBM patients. Both transdifferentiated and irradiated glioma cells show increased radiation resistance, demonstrating that the recurrent GBM may acquire resistance along with cell differentiation and selective advantage during treatment. Moreover, RRSS of the marginal tumors is found to be higher than that of core tumors (Wilcoxon's rank-sum test, p-value<0.01). The infiltration of macrophages was significantly associated with radiation resistance (p-value<0.01), which was further validated by single-cell RNAseq based experiments and clonogenic assays. Moreover, we demonstrated that IL1B, a pro-inflammatory cytokine secreted by macrophages, could enhance the radiation resistance of tumor cells. CONCLUSIONS:Our study revealed the spatiotemporal evolution of radiation resistance of GBM, and shed light on the development of novel adjuvant therapeutic strategies.

Sexual dysfunction after female genital mutilation/cutting (FGM/C) is poorly characterized, limiting targeted clinical intervention. In a concentrated FGM/C referral population, we aimed to characterize patterns of sexual dysfunction and evaluate associations with organ-specific genital anatomy, trauma history, and psychiatric comorbidities among women with FGM/C. We conducted a retrospective cross-sectional study of adults with FGM/C evaluated between 2014 and 2025 in an obstetrics and gynecology clinic specializing in sexual trauma. Using standardized abstraction tools, we obtained sexual symptoms, genital examination findings, demographics, and trauma-related and psychiatric variables from the electronic medical record. Associations between these variables and three primary outcomes (loss of libido, loss of sexual pleasure, dyspareunia) were assessed using univariate logistic regression. A composite arousal-pleasure dysfunction outcome was evaluated in secondary analyses adjusted for age and organ-specific genital anatomy. Among 135 women with FGM/C, approximately two-thirds reported sexual dysfunction, most commonly dyspareunia (45.9%), loss of sexual pleasure (28.9%), and loss of libido (25.9%). Absence or attenuation of the clitoris, labia minora, or labia majora was not associated with these outcomes. In contrast, depression (odds ratio [OR] 2.80), post-traumatic stress disorder (PTSD) (OR 3.86), and intact memory of the FGM/C event (OR 2.82) were associated with loss of libido. Depression was also associated with loss of sexual pleasure (OR 4.67). After adjustment for age and genital anatomy, depression (adjusted OR 3.87) and PTSD (adjusted OR 3.67) remained associated with composite arousal-pleasure dysfunction. In this well-documented cohort with FGM/C, sexual dysfunction was more closely associated with trauma-related and psychiatric factors than with genital tissue loss. These findings support prioritizing mental health and trauma-focused interventions for sexual health after FGM/C and underscore the need for prospective multicenter studies.

OBJECTIVE/UNASSIGNED:The objective of this study is to determine the optimal first trimester reticulocyte hemoglobin cutoff to predict iron deficiency anemia at 24 to 28 weeks' gestation and to compare its performance to first trimester ferritin. STUDY DESIGN/UNASSIGNED:weeks. Patients with first trimester anemia or blood transfusion 3 months prior to pregnancy were excluded. Iron deficiency anemia was defined as hemoglobin < 10.5 g/dL and ferritin < 30 µg/L. Optimal cutoffs were calculated using the receiver operating characteristic curve and the sensitivity/specificity pairs with the largest Youden index. RESULTS/UNASSIGNED:Of 600 nonanemic, pregnant participants enrolled, 499 participants were eligible for analysis at 24 to 28 weeks' gestation; 40 (8%) had iron deficiency anemia. The area under the curve of reticulocyte hemoglobin was 0.69 (95% confidence interval [CI]: 0.61-0.78) compared with 0.73 (95% CI: 0.65-0.81) for ferritin. The optimal first trimester cutoff was 32.6 pg for reticulocyte hemoglobin (sensitivity 42.5%, specificity 86.9%) and 29 µg/L for ferritin (sensitivity 47.5, specificity 87.6%). CONCLUSION/UNASSIGNED:First trimester reticulocyte hemoglobin did not outperform ferritin in predicting iron deficiency anemia at 24 to 28 weeks' gestation. Both reticulocyte hemoglobin and ferritin were weak predictors of iron deficiency anemia at 24 to 28 weeks and were more effective in identifying patients at low risk of iron deficiency anemia at 24 to 28 weeks.

OBJECTIVE:Dostarlimab+carboplatin-paclitaxel (CP) demonstrated significant improvement in progression-free survival (PFS) and clinically meaningful improvement in overall survival (OS) vs CP alone among patients with dMMR/MSI-H primary advanced/recurrent endometrial cancer (EC) in Part 1 of the randomized phase 3 RUBY trial (NCT03981796). We report updated efficacy and safety data with approximately 4 years of follow-up. METHODS:Patients were randomized 1:1 to receive dostarlimab+CP or placebo+CP followed by dostarlimab or placebo up to 3 years or until disease progression. Descriptive analyses of OS and PFS were conducted in the dMMR/MSI-H population (median follow-up, 55.6 months). Post hoc conditional survival analyses and a mixture cure model (MCM) fitted to PFS data to estimate the proportion of patients who had curative potential are presented to provide prognostic insights into long-term survival. RESULTS:Dostarlimab+CP demonstrated sustained OS and PFS benefits. Median PFS and OS were not reached with a 66% reduction in risk of death vs placebo+CP. PFS curve plateauing (only 4 progression events with additional 2.5 years follow-up since the previous PFS analysis at interim analysis 1) demonstrated durable disease control. Patients alive at the 1- and 2-year landmarks had >80% probability of remaining alive an additional 3 and 2 years, respectively. At 4 years, the MCM analysis estimated a cure rate with dostarlimab of 54% (95% CI 35%-72%). No new safety signals were observed. CONCLUSIONS:At 4 years, RUBY demonstrated sustained remission and long-term survival benefit, suggesting the potential for curative intent with dostarlimab+CP in patients with dMMR/MSI-H primary advanced or recurrent EC.

Women are increasingly utilizing assisted reproductive technologies when pursuing pregnancy, particularly in vitro fertilization (IVF), which requires supraphysiologic hormonal exposures and intensive pharmacotherapy. As IVF use continues to rise, recognition of associated cutaneous adverse events has become increasingly important, with dermatologic manifestations reported in up to one-quarter of patients. These manifestations encompass a broad clinical spectrum, including progestogen hypersensitivity, alopecia, acneiform eruptions, injection-related cutaneous complications, urticaria and other hypersensitivity reactions, and, in rare cases, severe cutaneous adverse reactions. The pathogenesis of these reactions is multifactorial and may reflect underlying infertility-related conditions, hormonally mediated effects on skin physiology, drug-specific immune responses, or complications related to the route of medication delivery. Although most cutaneous manifestations are mild and self-limited, they may significantly impact quality of life, treatment adherence, and patient anxiety during an already physically and emotionally demanding process. In this review, we summarize the existing literature to characterize the array, mechanisms, and clinical implications of cutaneous manifestations associated with IVF, highlighting the importance of multidisciplinary collaboration to ensure high-quality patient care.

INTRODUCTION/BACKGROUND:We describe bleeding and cramping patterns during the first 90 days after intrauterine device (IUD) placement. METHODS:This was a planned sub-analysis of a prospective cohort study of IUD users in the United States who initiated the copper T380A (Cu-IUD) or the levonorgestrel 52 mg intrauterine device (LNG IUD) at any time in the menstrual cycle. Participants rated bleeding and cramping from 1 (no bleeding or cramping) to 4 (heavy bleeding or severe cramping). We included participants providing ≥ 60 days of continuous responses and described overall bleeding/cramping. RESULTS:Of 230 participants enrolled, 137 (60%) met inclusion criteria (Cu-IUD n = 69, 50% and LNG IUD n = 68, 50%). Cu-IUD users reported fewer days with any bleeding (26 days, IQR 18-31) compared with LNG IUD users (38 days, IQR 27-55, p < 0.001). LNG IUD users reported more spotting days (median 31 [IQR 17-41] vs. 13 [IQR 10-20], p < 0.01). Total bleeding/spotting days were similar for each IUD type regardless of placement timing or prior contraceptive method. Median reported cramping days were similar for both IUDs (Cu-IUD 18, IQR 7-29 and LNG IUD 18, IQR 10-38, p = 0.18). Cramping was most common in the week following placement for both IUD types, decreased over the 90-day period, and did not vary by IUD type. CONCLUSION/CONCLUSIONS:LNG IUD users reported more days with any bleeding in the first 90 days after placement overall compared with Cu-IUD users, largely driven by more than twice the number of spotting days. Cramping was most common in the first week following IUD placement and decreased over time. TRIAL REGISTRATION/BACKGROUND:Clinicaltrials.Gov Identifier: NCT01730911.

OBJECTIVE/UNASSIGNED:To examine the effect of DT56a (Femarelle®), a non-hormonal oral treatment for the management of menopause, on symptoms of vulvovaginal atrophy (VVA)/genitourinary syndrome of menopause (GSM) in postmenopausal women. METHODS/UNASSIGNED: = 12) postmenopausal women with severe VVA (100% parabasal cells on cervical cytology) and at least one severe VVA symptom were recruited for a 12-week open-label pilot study. At baseline and week 12, participants underwent physical examination, Pap smear, vaginal ultrasound, vaginal cultures, vaginal pH assessment, and vaginal maturation index evaluation. Subjects also completed questionnaires assessing atrophy symptoms and quality of life using the Utian Quality of Life (UQoL) scale. Follow-up at 24 months was available for several participants. RESULTS/UNASSIGNED:After 12 weeks of treatment, all patients showed a significant reduction in vaginal pH. In addition, 11 of the 12 women demonstrated significant improvement in the vaginal maturation index and UQoL questionnaire scores. CONCLUSIONS/UNASSIGNED:DT56a significantly improved subjective and objective parameters of VVA/GSM, including vaginal pH, vaginal maturation index, and quality of life. These findings support its potential role as a non-hormonal systemic treatment option for women with VVA/GSM.

OBJECTIVE:Mood disturbances-including depressed mood, irritability, anxiety, and mental exhaustion-are common during the menopause transition, affecting up to 68% of women. While menopausal hormone therapy (HT) is FDA-approved for vasomotor and genitourinary symptoms, its role in managing mood symptoms remains less well understood. This retrospective, comparative study evaluated the impact of systemic HT on mood in a cohort of HT-naive individuals. METHODS:We included 260 patients presenting to an urban, academic menopause center between 2023 and 2025 who completed the Menopause Rating Scale (MRS) before and after initiating systemic HT for FDA-approved indications. MRS psychological subdomain scores covering depressive mood, irritability, anxiety, and mental exhaustion were analyzed. Most patients (96.5%) received transdermal estradiol, had an average age of 52.1 years, and a mean follow-up of 4.5 months. Notably, 51% had a history of anxiety or depression, and 24% were on antidepressant therapy at baseline. RESULTS:Results showed a significant reduction in MRS psychological subdomain scores from baseline to follow-up (P<0.001). The proportion of patients with severe mood symptoms (score ≥7) decreased from 62.3% to 24.6%. Improvement was greatest in those with severe baseline symptoms (mean change: -3.85, SE: 0.223). Treatment response did not differ by psychiatric history, age, menopausal stage, or antidepressant use. CONCLUSIONS:These findings suggest systemic HT may improve mood symptoms in midlife, especially among those with elevated baseline severity, independent of prior mental health diagnosis, antidepressant use, or menopause stage. These findings support further investigation of HT's impact on mood in midlife women.

OBJECTIVE:To evaluate the clinical outcome potential of embryos classified by preimplantation genetic testing for aneuploidy (PGT-A) as non-mosaic whole chromosome aneuploid (WCA) or segmental aneuploid (SA) in a large multicenter consortium study. DESIGN/METHODS:Multicenter retrospective cohort study. SUBJECTS/METHODS:Data were obtained from eight of the 26 fertility centers participating in the International Registry of Mosaic Embryo Transfers (IRMET) network that contributed non-mosaic WCA and SA embryo transfers between 2016 and 2026. The study included 250 embryo transfers (168 WCA and 82 SA) with complete clinical outcome documentation. Transfers were performed either with knowledge of the PGT-A result at the time of transfer or as non-selective transfers performed without knowledge of the PGT-A result. EXPOSURE/METHODS:Trophectoderm biopsy at blastocyst stage followed by PGT-A using whole-genome amplification (WGA) and next-generation sequencing (NGS). MAIN OUTCOME MEASURES/METHODS:Pregnancy and neonatal outcomes. RESULTS:Among 168 WCA transfers, including 111 performed without knowledge of the PGT-A result at the time of transfer, no live births occurred. Most transfers resulted in no pregnancy (78.6%), with smaller proportions showing biochemical pregnancy (8.3%), ectopic pregnancy (1.8%), early spontaneous abortion (9.5%), late spontaneous abortion (1.2%), or therapeutic termination (0.6%). In contrast, SA transfers (n = 82) resulted in a 17.1% live birth rate. Neonatal data available for 10 SA live births showed no differences in gestational age or birthweight compared with live births following euploid embryo transfer at the same centers, and prenatal or neonatal genetic testing were normal in all tested cases. CONCLUSIONS:In this large multicenter dataset of non-mosaic whole chromosome and segmental aneuploid embryo transfers, embryos classified as uniformly whole chromosome aneuploid produced no live births, whereas segmental aneuploid embryos retained a modest yet clinically meaningful potential for live birth. These findings support the biological validity of PGT-A classification of whole chromosome aneuploid embryos and highlight the distinct clinical implications of whole chromosome and segmental aneuploidies.