Mostafa A. Borahay

Trends in the National Distribution of Laparoscopic Hysterectomies From 2003 to 2010

STUDY OBJECTIVE The purpose of this analysis was to compare the trends in undergoing laparoscopic hysterectomy (versus abdominal or vaginal hysterectomy) based on patient age, race, median income and insurance type, from 2003 to 2010. DESIGN Retrospective study (Canadian Task Force classification II-3). SETTING National sample of hospital admissions after hysterectomy. PATIENTS Health Cost and Utilization Project-Nationwide Inpatient Sample database was used to review records of women who underwent hysterectomy for either menorrhagia or leiomyoma from 2003-2010. INTERVENTION The predicted probability of undergoing laparoscopic hysterectomy was determined for each year according to patient age, race, median income, and insurance type. The slopes of these values (i.e. the trend) was compared for each subgroup (i.e. black, white, Asian, etc.) in these categories. MAIN RESULTS A total of 530, 154 cases were included in this study. Total number of hysterectomies decreased by 39% from 60,364 to 36,835 from 2003 to 2010. The percent of hysterectomies that were laparoscopic increased from 11% in 2003 to 29% in 2010. All groups analyzed experienced an increase in predicted probability of undergoing a laparoscopic hysterectomy. Of all women undergoing hysterectomy, the probability of undergoing a laparoscopic hysterectomy remained highest for women who were less than 35 years old, white, with the highest median income, and with private insurance from 2003-2010. The slope was significantly greater for (1) white females versus all other races analyzed (p<0.01), (2) females in the highest income quartile versus females in the lowest income quartile (p<0.01) and (3) females with private insurance versus females with Medicaid (p<0.01) or Medicare (p<0.01). CONCLUSIONS There remains a gap in distribution of laparoscopic hysterectomies with regards to age, race, median income and insurance type that does not seem to be closing, despite the increased availability of laparoscopic hysterectomies.

Catechol-O-Methyltransferase Expression and 2- Methoxyestradiol Affect Microtubule Dynamics and Modify Steroid Receptor Signaling in Leiomyoma Cells

Context Development of optimal medicinal treatments of uterine leiomyomas represents a significant challenge. 2-Methoxyestradiol (2ME) is an endogenous estrogen metabolite formed by sequential action of CYP450s and catechol-O-methyltransferase (COMT). Our previous study demonstrated that 2ME is a potent antiproliferative, proapoptotic, antiangiogenic, and collagen synthesis inhibitor in human leiomyomas cells (huLM). Objectives Our objectives were to investigate whether COMT expression, by the virtue of 2ME formation, affects the growth of huLM, and to explore the cellular and molecular mechanisms whereby COMT expression or treatment with 2ME affect these cells. Results Our data demonstrated that E2-induced proliferation was less pronounced in cells over-expressing COMT or treated with 2ME (500 nM). This effect on cell proliferation was associated with microtubules stabilization and diminution of estrogen receptor α (ERα) and progesterone receptor (PR) transcriptional activities, due to shifts in their subcellular localization and sequestration in the cytoplasm. In addition, COMT over expression or treatment with 2ME reduced the expression of hypoxia-inducible factor -1α (HIF-1 α) and the basal level as well as TNF-α-induced aromatase (CYP19) expression. Conclusions COMT over expression or treatment with 2ME stabilize microtubules, ameliorates E2-induced proliferation, inhibits ERα and PR signaling, and reduces HIF-1 α and CYP19 expression in human uterine leiomyoma cells. Thus, microtubules are a candidate target for treatment of uterine leiomyomas. In addition, the naturally occurring microtubule-targeting agent 2ME represents a potential new therapeutic for uterine leiomyomas.

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy.

Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.

Comparison of Perioperative Outcomes of Total Laparoscopic and Robotically Assisted Hysterectomy for Benign Pathology during Introduction of a Robotic Program

Study Objective. Prospectively compare outcomes of robotically assisted and laparoscopic hysterectomy in the process of implementing a new robotic program. Design. Prospectively comparative observational nonrandomized study. Design Classification. II-1. Setting. Tertiary caregiver university hospital. Patients. Data collected consecutively 24 months, 34 patients underwent laparoscopic hysterectomy, 25 patients underwent robotic hysterectomy, and 11 patients underwent vaginal hysterectomy at our institution. Interventions. Outcomes of robotically assisted, laparoscopic, and vaginal complex hysterectomies performed by a single surgeon for noncancerous indications. Measurements and Main Results. Operative times were 208.3 ± 59.01 minutes for laparoscopic, 286.2 ± 82.87 minutes for robotic, and 163.5 ± 61.89 minutes for vaginal (P < .0001). Estimated blood loss for patients undergoing laparoscopic surgery was 242.7 ± 211.37 cc, 137.4 ± 107.50 cc for robotic surgery, and 243.2 ± 127.52 cc for vaginal surgery (P = 0.05). The mean length of stay ranged from 1.8 to 2.3 days for the 3 methods. Association was significant for uterine weight (P = 0.0043) among surgery methods. Conclusion. Robotically assisted hysterectomy is feasible with low morbidity, a shorter hospital stay, and less blood loss. This suggests that robotic assistance facilitates a minimally invasive approach for patients with larger uterine size even during implementing a new robotic program.

Simvastatin Potently Induces Calcium-dependent Apoptosis of Human Leiomyoma Cells

Background: Statins have broad-reaching effects beyond lowering plasma lipids, including antitumor properties. Results: Simvastatin inhibits proliferation and induces calcium-dependent apoptosis of human uterine leiomyoma cells. Conclusion: We report a novel calcium-mediated pathway associated with antitumor properties of simvastatin. Significance: Simvastatin may have antitumor properties significant for the treatment of human uterine leiomyomas. Statins are drugs commonly used for the treatment of high plasma cholesterol levels. Beyond these well known lipid-lowering properties, they possess broad-reaching effects in vivo, including antitumor effects. Statins inhibit the growth of multiple tumors. However, the mechanisms remain incompletely understood. Here we show that simvastatin inhibits the proliferation of human leiomyoma cells. This was associated with decreased mitogen-activated protein kinase signaling and multiple changes in cell cycle progression. Simvastatin potently stimulated leiomyoma cell apoptosis in a manner mechanistically dependent upon apoptotic calcium release from voltage-gated calcium channels. Therefore, simvastatin possesses antitumor effects that are dependent upon the apoptotic calcium release machinery.

Incidence of occult leiomyosarcoma in presumed morcellation cases: a database study.

OBJECTIVE Our objective was to estimate the incidence of uterine leiomyosarcoma in patients with leiomyomas following laparoscopic supracervical hysterectomy and myomectomy procedures. STUDY DESIGN For this study, we analyzed records of 13,964 women aged 25-64 years who underwent laparoscopic supracervical hysterectomies or myomectomies for leiomyomas from 2002 to 2011 using Clinformatics DataMart. Patient records were divided into two groups: history of laparoscopic supracervical hysterectomy and history of myomectomy. Subjects were tracked to identify diagnosis of leiomyosarcoma within 1 year of the procedure. We analyzed data from the 25-39, 40-49, and 50-64 age brackets. Evidence was obtained from a cohort study from national private insurance claims in the US. RESULTS Our results showed the incidence of occult leiomyosarcoma developing within 1 year following supracervical hysterectomy using a laparoscopic-assisted approach are 9.8, 10.7, and 33.4 per 10,000 for the 25-39, 40-49, and 50-64 age brackets, respectively; the overall incidence rate is 13.1 per 10,000. The incidence rate of occult leiomyosarcoma developing within 1 year following myomectomy using a laparoscopic-assisted approach are 0.0, 33.8, and 90.1 per 10,000 for the 25-39, 40-49, and 50-64 age brackets, respectively; the overall incidence rate is 17.3 per 10,000. CONCLUSION Our analysis shows the overall risk of being diagnosed with occult leiomyosarcoma is 12.9 per 10,000 in laparoscopic-assisted supracervical hysterectomy and myomectomy for patients younger than 49. There is no evidence of occult leiomyosarcoma 1 year after operation for patients younger than 40 who underwent laparoscopic myomectomy.

Intermedin/Adrenomedullin 2 Is Associated With Implantation and Placentation via Trophoblast Invasion in Human Pregnancy

RATIONALE Intermedin (IMD) is a novel peptide expressed in trophoblast cells in human placenta and enhances the invasion, migration, and human leukocyte antigen class I, G (HLA-G) expression in first-trimester HTR-8SV/neo cells. We recently reported that infusion of IMD antagonist in pregnant rats is detrimental to pregnancy outcome, resulting in impaired fetoplacental growth and deformed placental vasculature. OBJECTIVE This study was undertaken to assess expression of IMD and its involvement in human implantation and early placentation and assess whether its expression is altered in spontaneous abortion. FINDINGS AND CONCLUSIONS We demonstrate for the first time that IMD is present in day 5 embryonic secretome; villous and decidual expression of IMD is higher at 6-8 weeks after a decline as gestation advances toward the second trimester; first-trimester spontaneous abortion is associated with a lower expression of IMD in serum, villi, and decidua; IMD stimulates the invasive capacity of first-trimester primary Extravillous cytotrophoblast cells; and IMD decreases elevated levels of tumor suppressor Kangia-1 in decidual explants from first-trimester spontaneous abortion. In conclusion, this study is the first to demonstrate a potential involvement of IMD in human embryo implantation and placental development via regulation of trophoblast invasion at the maternal-fetal interface and suggests a physiological role for this novel peptide in establishment of human pregnancy.

Robotic-Assisted, Ultrasound-Guided Abdominal Cerclage During Pregnancy: Overcoming Minimally Invasive Surgery Limitations?

Herein, we report robotic abdominal cerclage placement under ultrasound guidance. The da Vinci Si system (Intuitive Surgical, Sunnyvale, CA) allows a simultaneous display of the operative field and transvaginal ultrasound images. Additionally, the vaginal ultrasound probe assisted in the manipulation of the uterus to improve visualization without placing excessive pressure on the gravid uterus. Ultrasound guidance improves needle placement accuracy and reduces potential for injuries.

Mullerian Inhibiting Substance Suppresses Proliferation and Induces Apoptosis and Autophagy in Endometriosis Cells In Vitro

Objective. To determine the effects of Mullerian inhibiting substance (MIS) treatment on endometriosis cells through study of apoptosis and autophagy. Design. Experimental in vitro study. Setting. University research laboratory. Cell Line. CRL-7566 endometriosis cell line. This line was established from a benign ovarian cyst taken from a patient with endometriosis. Interventions. In vitro treatment with MIS. Main Outcome Measures. The main outcome measures were cellular viability, proliferation, cell-cycle arrest, and induction of apoptosis and autophagy in endometriotic cells. Results. MIS treatment inhibited proliferation of endometriosis cells and induced apoptosis, as indicated by Annexin V staining, and induced caspase-9 cleavage and cell-cycle arrest, as evidenced by increased expression of p27 CDK-inhibitor. MIS treatment also induced autophagy in endometriosis cells as demonstrated by a significant increase in LC3-II induction, a hallmark of autophagy. Conclusions. MIS inhibits cell growth and induces autophagy, as well as apoptosis, in ectopic endometrial cell lines. Our results suggest that MIS may have a potential as a novel approach for medical treatment of endometriosis. Further studies may be needed to test the efficacy of MIS treatment in animal models and to develop MIS treatment specifically targeted to the endometriosis.

Estrogen Receptors and Signaling in Fibroids: Role in Pathobiology and Therapeutic Implications:

Uterine fibroids are the most common gynecologic tumors with a significant medical and financial burden. Several genetic, hormonal, and biological factors have been shown to contribute to the development and growth of fibroid tumors. Of these factors, estrogen is particularly critical since fibroids are considered estrogen dependent because no prepubertal cases have been described in the literature and tumors tend to regress after menopause. Understanding the role of estrogen in fibroids is not only important for understanding the pathobiology of fibroids but also for the development of successful therapeutics. In this review, we discuss the types and structure of estrogen receptors (nuclear and membrane bound, including α and β receptors and G protein-coupled estrogen receptor 1 GPER1). Estrogen-signaling pathways in fibroids include genomic (direct and indirect) and nongenomic including Ras-Raf-MEK (MAPK/Erk Kinase)-mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)-phosphatidylinositol-3,4,5-trisphosphate (PIP3)-Akt (Protein kinase B)-mammalian target of rapamycin (mTOR) pathways; shortly Ras-Raf-MEK-MAPK and PI3K-PIP3-Akt-mTOR pathways. Several aberrations in estrogen receptors and signaling pathways are implicated in fibroid pathobiology. Current therapeutic and research agents targeting ERs/signaling include gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, aromatase inhibitors, selective ER modulators, gene therapy, and others. Future research can identify potential targets for the development of novel treatments. In particular, epigenomics of estrogen activity and individualized (precision) medicine appear to be attractive areas for future research.