Quality of Life after Laparoscopic and Open Abdominal Myomectomy.

STUDY OBJECTIVE: To evaluate the baseline and postoperative changes in quality of life and symptom-severity scores in women undergoing laparoscopic or open abdominal myomectomy for symptomatic myomas. DESIGN: Prospective cohort study of patients choosing myomectomy for symptomatic uterine myomas. SETTING: Academic medical center. PATIENTS: A total of 143 women enrolled in the study. Of these, 80 women completed both a preoperative questionnaire and at least 1 postoperative questionnaire between 6 and 27 months after surgery. INTERVENTIONS: A total of 52 women had open abdominal myomectomy, and 28 had laparoscopic myomectomy between October 2014 and September 2017. MEASUREMENTS AND MAIN RESULTS: The results of the Uterine Fibroid Symptom and Health-Related Quality-of-Life Questionnaire were compared before and after laparoscopic or open myomectomy. Women undergoing open abdominal myomectomy had larger and more numerous myomas than women undergoing laparoscopic myomectomy. Baseline quality-of-life scores were less adversely affected for women having laparoscopic myomectomy (mean [standard deviation], 57 [24] laparoscopic vs 43 [19] open abdominal, p = .01). However, baseline symptom-severity scores were statistically similar (49 [22] for laparoscopic and 57 [20] for open abdominal, p = .08) approaches. Six to 12 months after surgery, both open abdominal and laparoscopic surgeries provided excellent and similar improvements in symptom-severity and quality of life (postoperative symptoms severity scores, mean [standard deviation], 20 [14] laparoscopic vs 13 [11] open abdominal, p = .24 and quality-of-life scores, mean [standard deviation], 91 [16] laparoscopic vs 88 [17] open abdominal, p = .49). These improvements were sustained for women who returned questionnaires up to 27 months of follow-up. CONCLUSION: Women with symptomatic myomas have a compromised quality of life, and they experience a similarly dramatic improvement in quality of life and decrease in symptom-severity after both laparoscopic and open abdominal myomectomies.

Indications for morcellation in gynecologic surgery.

PURPOSE OF REVIEW: Minimally invasive gynecologic procedures, in particular laparoscopic hysterectomy and myomectomy, often require tissue morcellation. RECENT FINDINGS: Whether morcellated or not, myometrial cells can be found in the abdomen and pelvis after either laparoscopic or open myomectomy. Following morcellation, careful inspection for and removal of tissue fragments and copious irrigation and suctioning of fluid can remove residual tissue and cells without the use of containment bags. The dogma of not 'cutting-through' cancer is not correct for many surgical specialties and irrelevant with regards to leiomyosarcoma (LMS) and minimally invasive gynecologic surgery. Eliminating residual disease in the pelvis and abdomen should be the goal of myomectomy or hysterectomy. SUMMARY: Morcellation of excised tissue is necessary for many women with symptomatic fibroids who choose to undergo laparoscopic myomectomy or hysterectomy. LMS is an uncommon disease, with a poor prognosis due to early hematogenous metastasis to lung, bone and liver. Preoperatively, it is often difficult to differentiate from benign fibroids. LMS has a high propensity for local recurrence despite performance of total hysterectomy. Efforts to remove all tissue and cells from the pelvis and abdomen should be the goal of minimally invasive surgery with morcellation.

Intracellular ascorbate tightens the endothelial permeability barrier through Epac1 and the tubulin cytoskeleton.

Vitamin C, or ascorbic acid, both tightens the endothelial permeability barrier in basal cells and also prevents barrier leak induced by inflammatory agents. Barrier tightening by ascorbate in basal endothelial cells requires nitric oxide derived from activation of nitric oxide synthase. Although ascorbate did not affect cyclic AMP levels in our previous study, there remains a question of whether it might activate downstream cyclic AMP-dependent pathways. In this work, we found in both primary and immortalized cultured endothelial cells that ascorbate tightened the endothelial permeability barrier by ∼30%. In human umbilical vein endothelial cells, this occurred at what are likely physiologic intracellular ascorbate concentrations. In so doing, ascorbate decreased measures of oxidative stress and also flattened the cells to increase cell-to-cell contact. Inhibition of downstream cyclic AMP-dependent proteins via protein kinase A did not prevent ascorbate from tightening the endothelial permeability barrier, whereas inhibition of Epac1 did block the ascorbate effect. Although Epac1 was required, its mediator Rap1 was not activated. Furthermore, ascorbate acutely stabilized microtubules during depolymerization induced by colchicine and nocodazole. Over several days in culture, ascorbate also increased the amount of stable acetylated α-tubulin. Microtubule stabilization was further suggested by the finding that ascorbate increased the amount of Epac1 bound to α-tubulin. These results suggest that physiologic ascorbate concentrations tighten the endothelial permeability barrier in unstimulated cells by stabilizing microtubules in a manner downstream of cyclic AMP that might be due both to increasing nitric oxide availability and to scavenging of reactive oxygen or nitrogen species.

Intracellular Ascorbate Prevents Endothelial Barrier Permeabilization by Thrombin.

Intracellular ascorbate (vitamin C) has previously been shown to tighten the endothelial barrier and maintain barrier integrity during acute inflammation in vitro. However, the downstream effectors of ascorbate in the regulation of endothelial permeability remain unclear. In this study, we evaluated ascorbate as a mediator of thrombin-induced barrier permeabilization in human umbilical vein endothelial cells and their immortalized hybridoma line, EA.hy926. We found that the vitamin fully prevented increased permeability to the polysaccharide inulin by thrombin in a dose-dependent manner, and it took effect both before and after subjection to thrombin. Thrombin exposure consumed intracellular ascorbate but not the endogenous antioxidant GSH. Likewise, the antioxidants dithiothreitol and tempol did not reverse permeabilization. We identified a novel role for ascorbate in preserving cAMP during thrombin stimulation, resulting in two downstream effects. First, ascorbate maintained the cortical actin cytoskeleton in a Rap1- and Rac1-dependent manner, thus preserving stable adherens junctions between adjacent cells. Second, ascorbate prevented actin polymerization and formation of stress fibers by reducing the activation of RhoA and phosphorylation of myosin light chain. Although ascorbate and thrombin both required calcium for their respective effects, ascorbate did not prevent thrombin permeabilization by obstructing calcium influx. However, preservation of cAMP by ascorbate was found to depend on both the production of nitric oxide by endothelial nitric-oxide synthase, which ascorbate is known to activate, and the subsequent generation cGMP by guanylate cyclase. Together, these data implicate ascorbate in the prevention of inflammatory endothelial barrier permeabilization and explain the underlying signaling mechanism.

Ascorbic acid prevents VEGF-induced increases in endothelial barrier permeability.

Vascular endothelial growth factor (VEGF) increases endothelial barrier permeability, an effect that may contribute to macular edema in diabetic retinopathy. Since vitamin C, or ascorbic acid, can tighten the endothelial permeability barrier, we examined whether it could prevent the increase in permeability due to VEGF in human umbilical vein endothelial cells (HUVECs). As previously observed, VEGF increased HUVEC permeability to radiolabeled inulin within 60 min in a concentration-dependent manner. Loading the cells with increasing concentrations of ascorbate progressively prevented the leakage caused by 100 ng/ml VEGF, with a significant inhibition at 13 µM and complete inhibition at 50 µM. Loading cells with 100 µM ascorbate also decreased the basal generation of reactive oxygen species and prevented the increase caused by both 100 ng/ml VEGF. VEGF treatment decreased intracellular ascorbate by 25%, thus linking ascorbate oxidation to its prevention of VEGF-induced barrier leakage. The latter was blocked by treating the cells with 60 µM L-NAME (but not D-NAME) as well as by 30 µM sepiapterin, a precursor of tetrahydrobiopterin that is required for proper function of endothelial nitric oxide synthase (eNOS). These findings suggest that VEGF-induced barrier leakage uncouples eNOS. Ascorbate inhibition of the VEGF effect could thus be due either to scavenging superoxide or to peroxynitrite generated by the uncoupled eNOS, or more likely to its ability to recycle tetrahydrobiopterin, thus avoiding enzyme uncoupling in the first place. Ascorbate prevention of VEGF-induced increases in endothelial permeability opens the possibility that its repletion could benefit diabetic macular edema.

What is the Future of Open Intraperitoneal Power-Morcellation of Fibroids?

In November 2014, the Food and Drug Administration (FDA) calculated that for every 498 women having surgery for presumed fibroids, one woman would be found to have an occult leiomyosarcoma (LMS). The FDA issued a safety communication warning against the use of laparoscopic morcellators in the majority of women undergoing myomectomy or hysterectomy for treatment of fibroids. This communication was prompted by concern that if a patient had an occult LMS, the morcellator might spread tumor cells within the peritoneal cavity. We submit that the FDA directive was based on a flawed and misleading analysis. More rigorous evidence estimates the prevalence of LMS among women operated upon for presumed uterine fibroids at approximately one in 2000 women, significantly lower than the FDA's estimate. In addition, there is no reliable evidence that morcellation influences survival or that power-morcellation is inferior to vaginal or mini-lap morcellation with a scalpel. Recent publication shows that open surgery carries more risk for women when compared with minimally invasive surgery. Although the possibility of occult LMS should be considered by women and their gynecologists, we suggest that current morcellation techniques be continued for women who wish to benefit from minimally invasive surgery. Investigation into new and, hopefully, better morcellating devices may make the procedure safer for women.

Ascorbic acid transport in brain microvascular pericytes.

Intracellular vitamin C, or ascorbic acid, has been shown to prevent the apoptosis of cultured vascular pericytes under simulated diabetic conditions. We sought to determine the mechanism by which ascorbate is transported into pericytes prior to exerting this protective effect. Measuring intracellular ascorbate, we found that pericytes display a linear uptake over 30 min and an apparent transport Km of 21 µM, both of which are consistent with activity of the Sodium-dependent Vitamin C Transporter 2 (SVCT2). Uptake of both radiolabeled and unlabeled ascorbate was prevented by inhibiting SVCT2 activity, but not by inhibiting the activity of GLUT-type glucose transporters, which import dehydroascorbate to also generate intracellular ascorbate. Likewise, uptake of dehydroascorbate was prevented with the inhibition of GLUTs, but not by inhibiting the SVCT2, indicating substrate specificity of both transporters. Finally, presence of the SVCT2 in pericytes was confirmed by western blot analysis, and immunocytochemistry was used to localize it to the plasma membrane and intracellular sites. Together, these data clarify previous inconsistencies in the literature, implicate SVCT2 as the pericyte ascorbate transporter, and show that pericytes are capable of concentrating intracellular ascorbate against a gradient in an energy- and sodium-dependent fashion.

Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review.

There is concern that morcellation of occult leiomyosarcomas during surgery to treat presumed myomas may substantially worsen patient outcome. We reviewed the existing medical literature to better understand whether such a risk was demonstrable and, if so, what the magnitude of that risk might be. We identified 4864 articles initially, of which 60 were evaluated in full. Seventeen were found to have outcomes information and are included in this review. Six studies addressed the question of whether morcellation of occult leiomyosarcomas resulted in inferior outcomes as compared with en bloc uterine and tumor removal. In these 6 studies, results suggested that en bloc removal may result in improved survival and less recurrence; however, the data are highly biased and of poor quality. There is no reliable evidence that morcellation, power or otherwise, substantially results in tumor upstaging. There is no evidence from these 17 studies that power morcellation differs in any way from other types of morcellation or even simple myomectomy insofar as patient outcome. Whether electromechanical morcellation poses a unique danger to the patient with occult leiomyosarcoma is an unanswered question and one clearly in need of more extensive investigation before conclusions are drawn and policies created.

Management of Hemorrhage During Gynecologic Surgery.

Surgical blood loss of >1000 mL or blood loss that requires a blood transfusion usually defines intraoperative hemorrhage. Intraoperative hemorrhage has been reported in 1% to 2% of hysterectomy studies. Cardiovascular instability with significant hypotension often results from a loss of 30% to 40% of the patient's blood volume and >40% blood loss is life threatening. Preparation, planning, and practicing for a massive hemorrhage is essential for all surgeons and gynecologic operating room teams. Emergency steps should be written and posted in the operating room and rehearsed quarterly.

Ascorbic acid prevents high glucose-induced apoptosis in human brain pericytes.

High glucose concentrations due to diabetes increase apoptosis of vascular pericytes, impairing vascular regulation and weakening vessels, especially in brain and retina. We sought to determine whether vitamin C, or ascorbic acid, could prevent such high glucose-induced increases in pericyte apoptosis. Culture of human microvascular brain pericytes at 25 mM compared to 5mM glucose increased apoptosis measured as the appearance of cleaved caspase 3. Loading the cells with ascorbate during culture decreased apoptosis, both at 5 and 25 mM glucose. High glucose-induced apoptosis was due largely to activation of the receptor for advanced glycation end products (RAGE), since it was prevented by specific RAGE inhibition. Culture of pericytes for 24h with RAGE agonists also increased apoptosis, which was completely prevented by inclusion of 100 µM ascorbate. Ascorbate also prevented RAGE agonist-induced apoptosis measured as annexin V binding in human retinal pericytes, a cell type with relevance to diabetic retinopathy. RAGE agonists decreased intracellular ascorbate and GSH in brain pericytes. Despite this evidence of increased oxidative stress, ascorbate prevention of RAGE-induced apoptosis was not mimicked by several antioxidants. These results show that ascorbate prevents pericyte apoptosis due RAGE activation. Although RAGE activation decreases intracellular ascorbate and GSH, the prevention of apoptosis by ascorbate may involve effects beyond its function as an antioxidant.

The utility of MRI for the surgical treatment of women with uterine fibroid tumors.

Determination of the reasonable treatment options and the appropriate clinical treatment of women with uterine fibroid tumors often depends on the ability of imaging modalities to accurately detect and localize fibroid tumors. Magnetic resonance imaging (MRI) gives the most complete evaluation (sizes, positions, number) of submucous, intramural, and subserosal myomas and is the most sensitive modality for the detection of small fibroid tumors. MRI allows the evaluation of fibroid tumor proximity to the bladder, rectum, and endometrial cavity, helps define what can be expected at surgery, and may help the gynecologist avoid missing fibroid tumors during surgery. MRI can also make the diagnosis of adenomyosis reliably and may be able to identify uterine sarcoma when present.

COVID-19 and postural tachycardia syndrome: a case series.

BACKGROUND: Postural tachycardia syndrome (PTS) is a novel identified sequela of COVID-19 infection. This observational study describes clinical presentation, testing, and treatment response in seven patients diagnosed with PTS following COVID-19 infection. CASE SUMMARY: A total of seven active patients (three collegiate athletes, one recreational athlete, two registered nurses, one hospitality employee), age 24 ± 6 years, and six females were followed for a mean of 152 ± 105 days after contracting COVID-19. Tilt table was performed to establish the diagnosis. The most common presenting symptoms were palpitations (7/7), dyspnoea (6/7), and gastrointestinal complaints (5/7). One patient required hospitalization for symptom management. The mean latency of PTS onset following COVID-19 was 21 ± 15 days. Electrocardiograms (ECGs) demonstrated sinus rhythm in all patients, one with resting sinus tachycardia. Echocardiogram demonstrated normal systolic and diastolic left ventricular function in all patients. On tilt table testing, baseline heart rate (HR) was 72 ± 12 with maximum HR reaching 136 ± 13. Six of seven patients failed to respond to supportive therapy alone, and two patients failed medical management with ivabradine, midodrine, and/or metoprolol. Of three severely symptomatic patients, two demonstrated some degree of clinical recovery with intravenous immunoglobulin (IVIG). DISCUSSION: This novel case series describes the development of PTS in the context of COVID-19 infection. Severity of symptoms and response to treatment was heterogeneous. Interestingly, patients were poorly responsive to traditional PTS treatments, but IVIG showed potential as a possible therapeutic strategy for refractory PTS in two patients, particularly following COVID-19 infection.

Massive cotyledenoid leiomyoma treated with uterine-conserving surgery.

OBJECTIVE: To describe and illustrate a massive cotyledenoid leiomyoma treated with uterine-conserving surgery. DESIGN: Case report. SETTING: Medical center. PATIENTS: A 39-year-old woman with a large abdominal mass and a magnetic resonance imaging scan showing a 28-cm multi-lobulated mass. INTERVENTIONS: Laparotomy and myomectomy. MAIN OUTCOME MEASURES: Recurrence and need for repeat surgery. RESULTS: No recurrence at 8 years of follow-up. CONCLUSIONS: Cotyledonoid leiomyomas are rare. These benign tumors may be suspected preoperatively based on MRI appearance. Frozen section suggests a benign process and uterine-conserving surgery may be successfully accomplished.

Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study.

OBJECTIVE: To report long-term health outcomes and mortality after oophorectomy or ovarian conservation. METHODS: We conducted a prospective, observational study of 29,380 women participants of the Nurses' Health Study who had a hysterectomy for benign disease; 16,345 (55.6%) had hysterectomy with bilateral oophorectomy, and 13,035 (44.4%) had hysterectomy with ovarian conservation. We evaluated incident events or death due to coronary heart disease (CHD), stroke, breast cancer, ovarian cancer, lung cancer, colorectal cancer, total cancers, hip fracture, pulmonary embolus, and death from all causes. RESULTS: Over 24 years of follow-up, for women with hysterectomy and bilateral oophorectomy compared with ovarian conservation, the multivariable hazard ratios (HRs) were 1.12 (95% confidence interval [CI] 1.03-1.21) for total mortality, 1.17 (95% CI 1.02-1.35) for fatal plus nonfatal CHD, and 1.14 (95% CI 0.98-1.33) for stroke. Although the risks of breast (HR 0.75, 95% CI 0.68-0.84), ovarian (HR 0.04, 95% CI 0.01-0.09, number needed to treat=220), and total cancers (HR 0.90, 95% CI 0.84-0.96) decreased after oophorectomy, lung cancer incidence (HR=1.26, 95% CI 1.02-1.56, number needed to harm=190), and total cancer mortality (HR=1.17, 95% CI 1.04-1.32) increased. For those never having used estrogen therapy, bilateral oophorectomy before age 50 years was associated with an increased risk of all-cause mortality, CHD, and stroke. With an approximate 35-year life span after surgery, one additional death would be expected for every nine oophorectomies performed. CONCLUSION: Compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy for benign disease is associated with a decreased risk of breast and ovarian cancer but an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer. In no analysis or age group was oophorectomy associated with increased survival.

Elective oophorectomy for benign gynecological disorders.

OBJECTIVE: To review the risks and benefits of elective oophorectomy and to make a clinical recommendation for an appropriate age when benefits of this procedure outweigh the risks. DESIGN: The risks and benefits of oophorectomy as detailed in published articles are reviewed with regard to quality-of-life issues and mortality outcomes in oophorectomized versus non-oophorectomized women from five diseases linked to ovarian hormones (coronary heart disease, ovarian cancer, breast cancer, stroke, and hip fracture). RESULTS: Numerous reports link oophorectomy to higher rates of cardiovascular disease, osteoporosis, hip fractures, dementia, short-term memory impairment, decline in sexual function, decreased positive psychological well-being, adverse skin and body composition changes, and adverse ocular changes, as well as more severe hot flushes and urogenital atrophy. The potential benefits associated with oophorectomy include prevention of ovarian cancer, a decline in breast cancer risk, and a reduced risk of pelvic pain and subsequent ovarian surgery. In our study of long-term mortality after oophorectomy using Markov modeling, preservation of ovaries until women are at least aged 65 years was associated with higher survival rates. For women between ages 50 and 54 with hysterectomy and ovarian preservation, the probability of surviving to age 80 was 62% versus 54% if oophorectomy was performed. This 8% difference in survival is primarily due to fewer women dying from cardiovascular heart disease and/or hip fracture. This survival advantage far outweighs the 0.47% increased mortality rate from ovarian cancer prevented by oophorectomy. If surgery occurred between ages 55 and 59, the survival advantage was 4%. After age 64 there were no significant differences in survival rates. Prior literature supports our conclusion of a benefit over risk for ovarian conservation. CONCLUSIONS: Elective oophorectomy is associated with short-and long-term health consequences that merit serious consideration. For women with an average risk of ovarian cancer, ovarian conservation until at least age 65 seems to benefit long-term survival.

U.S. Food and Drug Administration's Guidance Regarding Morcellation of Leiomyomas: Well-Intentioned, But Is It Harmful for Women?

The U.S. Food and Drug Administration (FDA) is warning against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for the treatment of leiomyomas because of the concern for inadvertent spread of tumor cells if an undiagnosed cancer were present. The authors, representing a 45-member review group, reviewed the current literature to formulate prevalence rates of leiomyosarcoma in women with presumed leiomyomas and to asses reliable data regarding patient survival after morcellation. The authors disagree with the FDA's methodology in reaching their conclusion and provide clinical recommendations for care of women with leiomyomas who are planning surgery.

Ovarian conservation at the time of hysterectomy for benign disease.

OBJECTIVE: Prophylactic oophorectomy is often recommended concurrent with hysterectomy for benign disease. The optimal age for this recommendation in women at average risk for ovarian cancer has not been determined. METHODS: Using published age-specific data for absolute and relative risk, both with and without oophorectomy, for ovarian cancer, coronary heart disease, hip fracture, breast cancer, and stroke, a Markov decision analysis model was used to estimate the optimal strategy for maximizing survival for women at average risk of ovarian cancer. For each 5-year age group from 40 to 80 years, 4 strategies were compared: ovarian conservation or oophorectomy, and use of estrogen therapy or nonuse. Outcomes, as proportion of women alive at age 80 years, were measured. Sensitivity analyses were performed, varying both relative and absolute risk estimates across the range of reported values. RESULTS: Ovarian conservation until age 65 benefits long-term survival for women undergoing hysterectomy for benign disease. Women with oophorectomy before age 55 have 8.58% excess mortality by age 80, and those with oophorectomy before age 59 have 3.92% excess mortality. There is sustained, but decreasing, benefit until the age of 75, when excess mortality for oophorectomy is less than 1%. These results were unchanged following multiple sensitivity analyses and were most sensitive to the risk of coronary heart disease. CONCLUSION: Ovarian conservation until at least age 65 benefits long-term survival for women at average risk of ovarian cancer when undergoing hysterectomy for benign disease.