The Role of Nanomedicine in Benign Gynecologic Disorders.

Nanomedicine has revolutionized drug delivery in the last two decades. Nanoparticles appear to be a promising drug delivery platform in the treatment of various gynecological disorders including uterine leiomyoma, endometriosis, polycystic ovarian syndrome (PCOS), and menopause. Nanoparticles are tiny (mean size < 1000 nm), biodegradable, biocompatible, non-toxic, safe, and relatively inexpensive materials commonly used in imaging and the drug delivery of various therapeutics, such as chemotherapeutics, small molecule inhibitors, immune mediators, protein peptides and non-coding RNA. We performed a literature review of published studies to examine the role of nanoparticles in treating uterine leiomyoma, endometriosis, PCOS, and menopause. In uterine leiomyoma, nanoparticles containing 2-methoxyestradiole and simvastatin, promising uterine fibroid treatments, have been effective in significantly inhibiting tumor growth compared to controls in in vivo mouse models with patient-derived leiomyoma xenografts. Nanoparticles have also shown efficacy in delivering magnetic hyperthermia to ablate endometriotic tissue. Moreover, nanoparticles can be used to deliver hormones and have shown efficacy as a mechanism for transdermal hormone replacement therapy in individuals with menopause. In this review, we aim to summarize research findings and report the efficacy of nanoparticles and nanotherapeutics in the treatment of various benign gynecologic conditions.

Patient Experiences With Obstetric Counseling on Fetal Malpresentation.

Introduction Fetal malpresentation is a complication of pregnancy in which the fetus does not present cephalically as required for vaginal birth. After a diagnosis is made, management options include cesarean section (CS) or external cephalic version (ECV). ECV is a procedure in which providers attempt to manually maneuver the fetus to cephalic position, allowing patients to attempt vaginal birth. Selecting between CS or ECV can be a complex and stressful decision, yet literature exploring patient perspectives on counseling of these options is limited. This study aims to describe patient perspectives on decision-making when diagnosed with fetal malpresentation. Methods We included English-speaking pregnant patients greater than 18 years of age diagnosed with malpresentation at 35-37 weeks' gestation. Patients who previously underwent CS or had maternal or fetal contraindications besides malpresentation to vaginal birth requiring CS were excluded. Semi-structured interviews were conducted with participants from four obstetric clinics in Baltimore, Maryland, at time of diagnosis. Themes were derived using data analysis in NVivo 11 (released 2015, Lumivero, USA). Results We recruited 10 participants (median age = 32 years, 90% Caucasian, 70% nulliparous, 50% chose ECV). We categorized our findings into the following themes: (1) facilitators and (2) barriers to deciding on malpresentation management, (3) participant priorities and values, and (4) other methods of malpresentation management. The participants identified incorporation of statistics and medical history into counseling as facilitators and the lack of information about ECV as a significant barrier. The participants prioritized fetal safety and, among those who chose ECV, a desire to avoid CS. Chiropractors, acupuncture, and moxibustion were identified as valuable additional methods of malpresentation management. Conclusion Overall, patients desire more information about ECV when diagnosed with fetal malpresentation. Uncertainty about ECV safety is a barrier to deciding between management options. Based on our findings, obstetric providers should provide comprehensive counseling on ECV and CS. Counseling should aim to demystify ECV and quantify risk in a patient-specific context. This will allow patients to make an informed decision on the management of fetal malpresentation that aligns with their goals for pregnancy.

Patient Characteristics Associated With Embolization Versus Hysterectomy for Uterine Fibroids: A Systematic Review and Meta-Analysis.

INTRODUCTION: Black and underinsured women in the United States are more likely than their counterparts to develop uterine fibroids (UFs) and experience more severe symptoms. Uterine artery embolization (UAE), a uterine-sparing therapeutic procedure, is less invasive than the common alternative, open hysterectomy. To determine whether demographic disparities persist in UF treatment utilization, we reviewed patient characteristics associated with UAE versus hysterectomy for UF among studies of US clinical practices. METHODS: A systematic literature review was conducted via PubMed, Embase, and CINAHL (PROSPERO CRD42023455051), yielding 1,350 articles (January 1, 1995, to July 15, 2023) that outlined demographic characteristics of UAE compared with hysterectomy. Two readers screened for inclusion criteria, yielding 13 full-text US-based comparative studies specifying at least one common demographic characteristic. Random effects meta-analysis was performed on the data (STATA v18.0). Egger's regression test was used to quantify publication bias. RESULTS: Nine (138,960 patients), four (183,643 patients), and seven (312,270 patients) studies were analyzed for race, insurance status, and age as predictors of treatment modality, respectively. Black race (odds ratio = 3.35, P < .01) and young age (P < .05) were associated with UAE, whereas private insurance (relative to Medicare and/or Medicaid) was not (odds ratio = 1.06, P = .52). Between-study heterogeneity (I2 > 50%) was detected in all three meta-analyses. Small-study bias was detected for age but not race or insurance. CONCLUSIONS AND IMPLICATIONS: Knowledge of demographic characteristics of patients with UFs receiving UAE versus hysterectomy is sparse (n = 13 studies). Among these studies, which seem to be racially well distributed, Black and younger women are more likely to receive UAE than their counterparts.

Combination Therapies to Improve the Efficacy of Immunotherapy in Triple-negative Breast Cancer.

Immune checkpoint inhibition combined with chemotherapy is currently approved as first-line treatment for patients with advanced PD-L1-positive triple-negative breast cancer (TNBC). However, a significant proportion of metastatic TNBC is PD-L1-negative and, in this population, chemotherapy alone largely remains the standard-of-care and novel therapeutic strategies are needed to improve clinical outcomes. Here, we describe a triple combination of anti-PD-L1 immune checkpoint blockade, epigenetic modulation thorough bromodomain and extra-terminal (BET) bromodomain inhibition (BBDI), and chemotherapy with paclitaxel that effectively inhibits both primary and metastatic tumor growth in two different syngeneic murine models of TNBC. Detailed cellular and molecular profiling of tumors from single and combination treatment arms revealed increased T- and B-cell infiltration and macrophage reprogramming from MHCIIlow to a MHCIIhigh phenotype in mice treated with triple combination. Triple combination also had a major impact on gene expression and chromatin profiles shifting cells to a more immunogenic and senescent state. Our results provide strong preclinical evidence to justify clinical testing of BBDI, paclitaxel, and immune checkpoint blockade combination.

Uterine Transcriptome: Understanding Physiology and Disease Processes.

In recent years, transcriptomics has enabled us to gain a deeper understanding of fundamental reproductive physiology, including the menstrual cycle, through a more precise molecular analysis. The endometrial mRNA transcript levels fluctuate during the normal menstrual cycle, indicating changes in the relative recruitment and abundance of inflammatory cells, as well as changes in the receptivity and remodeling of the endometrium. In addition to providing a more comprehensive understanding of the molecular underpinnings of pathological gynecological conditions such as endometriosis, leiomyomas, and adenomyosis through RNA sequencing, this has allowed researchers to create transcriptome profiles during both normal menstrual cycles and pathological gynecological conditions. Such insights could potentially lead to more targeted and personalized therapies for benign gynecological conditions. Here, we provide an overview of recent advances in transcriptome analysis of normal and pathological endometrium.

Oxidative Stress and Antioxidants in Uterine Fibroids: Pathophysiology and Clinical Implications.

In the last few decades, our understanding of the complex pathobiology of uterine fibroid development has grown. While previously believed to be a purely neoplastic entity, we now understand that uterine fibroids possess different and equally important aspects of their genesis. An increasing body of evidence suggests that oxidative stress, the imbalance between pro- and antioxidants, is an important factor in fibroid development. Oxidative stress is controlled by multiple, interconnecting cascades, including angiogenesis, hypoxia, and dietary factors. Oxidative stress in turn influences fibroid development through genetic, epigenetic, and profibrotic mechanisms. This unique aspect of fibroid pathobiology has introduced several clinical implications, both diagnostic and therapeutic, that can aid us in managing these debilitating tumors by using biomarkers as well as dietary and pharmaceutical antioxidants for diagnosis and treatment. This review strives to summarize and add to the current evidence revealing the relationship between oxidative stress and uterine fibroids by elucidating the proposed mechanisms and clinical implications.

Menstruation in the USA.

Purpose of review: Menstruation touches all spheres of human society, including psychology, education, business, policy, race, and religion. This narrative review aims to describe the relationship menstruation holds with these spaces. Recent findings: First, menstruation plays many roles in psychology - premenstrual syndrome affects psychological wellbeing and in turn, psychological stress impacts menstruation. Functional hypothalamic amenorrhea can result when stress hormones inhibit the Hypothalamus-Pituitary-Ovarian axis. Furthermore, menstruation has many implications for all aged individuals, especially adolescents and those who are menopausal. These implications underscore the importance of proper education surrounding menstruation, which can be achieved via social media, school systems, family, and clinicians. However, menstrual health education is highly variable depending on the state and family that someone is raised in. Additionally, menstruation can pose a financial burden as menstrual products can be expensive and access to these products is limited for those who are homeless, incarcerated, and low-income. Recent public policy measures in various states have aimed to achieve "menstrual equity," by requiring public schools to supply free menstrual products in bathrooms. Furthermore, racial disparities exist with menstrual disorders. Uterine fibroids occur more frequently in Black menstruators compared to White menstruators, and Black women experience worse outcomes overall with fibroids and endometriosis management. Finally, analysis of religion and its relationship to menstruation underscores the immense stigma and "impurity" associated with menstruation. Summary: Overall, this review highlights the universality of menstruation in society. As a "fifth vital sign", there is significant room for improvement in terms of education, research, and cultural acceptance of menstruation. Future research should explore interventions to reduce these gaps.

Insights into Immune Escape During Tumor Evolution and Response to Immunotherapy Using a Rat Model of Breast Cancer.

Animal models are critical for the preclinical validation of cancer immunotherapies. Unfortunately, mouse breast cancer models do not faithfully reproduce the molecular subtypes and immune environment of the human disease. In particular, there are no good murine models of estrogen receptor-positive (ER+) breast cancer, the predominant subtype in patients. Here, we show that Nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats recapitulate the heterogeneity for mutational profiles, ER expression, and immune evasive mechanisms observed in human breast cancer. We demonstrate the utility of this model for preclinical studies by dissecting mechanisms of response to immunotherapy using combination TGFBR inhibition and PD-L1 blockade. Short-term treatment of early-stage tumors induced durable responses. Gene expression profiling and spatial mapping classified tumors as inflammatory and noninflammatory, and identified IFNγ, T-cell receptor (TCR), and B-cell receptor (BCR) signaling, CD74/MHC II, and epithelium-interacting CD8+ T cells as markers of response, whereas the complement system, M2 macrophage phenotype, and translation in mitochondria were associated with resistance. We found that the expression of CD74 correlated with leukocyte fraction and TCR diversity in human breast cancer. We identified a subset of rat ER+ tumors marked by expression of antigen-processing genes that had an active immune environment and responded to treatment. A gene signature characteristic of these tumors predicted disease-free survival in patients with ER+ Luminal A breast cancer and overall survival in patients with metastatic breast cancer receiving anti-PD-L1 therapy. We demonstrate the usefulness of this preclinical model for immunotherapy and suggest examination to expand immunotherapy to a subset of patients with ER+ disease. See related Spotlight by Roussos Torres, p. 672.