Leslie A. Garrett

Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein

Cigarette smoking impairs endothelial function. Hydroxymethylglutaryl (HMG) CoA reductase inhibitors (statins) may favorably affect endothelial function via nonlipid mechanisms. We tested the hypothesis that statins would improve endothelial function independent of changes in lipids in cigarette smokers. Twenty normocholesterolemic cigarette smokers and 20 matched healthy control subjects were randomized to atorvastatin 40 mg daily or placebo for 4 weeks, washed out for 4 weeks, and then crossed-over to the other treatment. Baseline low-density lipoprotein (LDL) levels were similar in smokers and healthy subjects, 103±22 versus 95±27 mg/dL, respectively (P=NS) and were reduced similarly in smokers and control subjects by atorvastatin, to 55±30 and 58±20 mg/dL, respectively (P=NS). Vascular ultrasonography was used to determine brachial artery, flow-mediated, endothelium-dependent, and nitroglycerin-mediated, endothelium-independent vasodilation. To elucidate potential molecular mechanisms that may account for changes in endothelial function, skin biopsy specimens were assayed for eNOS mRNA, eNOS activity, and nitrotyrosine. Endothelium-dependent vasodilation was less in smokers than nonsmoking control subjects during placebo treatment, 8.0±0.6% versus 12.1±1.1%, (P=0.003). Atorvastatin increased endothelium-dependent vasodilation in smokers to 10.5±1.3% (P=0.017 versus placebo) but did not change endothelium-dependent vasodilation in control subjects (to 11.0±0.8%, P=NS). Endothelium-independent vasodilation did not differ between groups during placebo treatment and was not significantly affected by atorvastatin. Multivariate analysis did not demonstrate any association between baseline lipid levels or the change in lipid levels and endothelium-dependent vasodilation. Cutaneous nitrotyrosine levels and skin microvessel eNOS mRNA, but not ENOS activity, were increased in smokers compared with controls but unaffected by atorvastatin treatment. Atorvastatin restores endothelium-dependent vasodilation in normocholesterolemic cigarette smokers independent of changes in lipids. These results are consistent with a lipid-independent vascular benefit of statins but could not be explained by changes in eNOS message and tissue oxidative stress. These findings implicate a potential role for statin therapy to restore endothelial function and thereby investigate vascular disease in cigarette smokers.

An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies.

Objectives Abdominal radical trachelectomy (ART) is a type C resection (uterine vessels ligated at origin from the hypogastric vessels). Questions arise as to whether fertility is maintained after ART, particularly when uterine vessels are sacrificed. We report an international series on ART to describe fertility and oncologic outcomes. Methods Databases at 3 institutions were queried to identify patients planned for ART from 1999 to 2011. Clinical and demographic data were gathered. Results One hundred one patients underwent ART. Mean age was 31 years (range, 19–43 years). Histologic classifications were adenocarcinoma (n = 54), squamous cell carcinoma (n = 40), adenosquamous carcinoma (n = 6), and clear cell carcinoma (n = 1). Twenty patients (20%) required conversion to hysterectomy (10 margins and 10 nodes). Eight patients underwent completion hysterectomy owing to the following: positive margins on final pathology (n = 3), patient’s choice (n = 4), or recurrence (n = 1). Postoperatively, 20 patients (20%) received adjuvant chemotherapy and/or radiation (4 final pathology margins and 16 nodes). Four patients (4%) had recurrence and lived 22 to 35 months after diagnosis. Of the 70 women who had neither hysterectomy nor adjuvant therapy, 38 (54%) attempted pregnancy and 28 (74%) achieved pregnancy. Thirty-one pregnancies resulted in 16 (52%) third trimester deliveries. Six patients are currently pregnant with outcomes pending. Conclusions These data demonstrate that ART preserves fertility and maintains excellent oncologic outcomes. Most women (74%) attempting pregnancy after ART are able to achieve pregnancy and deliver in the third trimester (52%). Preservation of the uterine vasculature is not necessary for fertility; obstetrical outcomes are similar to those of the historical vaginal radical trachelectomy cohorts.

Risk Factors for a Serous Cancer Precursor (“p53 signature”) in Women with Inherited BRCA Mutations

OBJECTIVES Pelvic (ovarian) serous carcinomas frequently contain p53 mutations. Recently, a candidate serous cancer precursor (the p53 signature) with p53 mutations and other features in common with serous cancer has been discovered in distal fallopian tube mucosa. This study examined the relationship of putative ovarian cancer risk factors with the presence of p53 signatures in women with BRCA mutations (BRCA+). METHODS Fallopian tubes from 75 BRCA+ women were immunostained for p53 signatures and correlated with age at first childbirth, parity, oral contraceptive use, body mass index (BMI), and BRCA subtype (1 or 2). Statistical analysis was performed with the T-test or Chi-square analysis and logistic regression adjusting for age and parity. RESULTS Thirty-eight percent of the tubes contained p53 signatures, which were significantly associated with older age at first childbirth (mean 30.8 vs. 28.4 years; p=0.04) and lower parity (mean 1.4 vs. 2.2; p=0.01) in univariate analyses. The unadjusted odds ratios were 3.8 (p-trend=0.04) for first childbirth>/=30 years versus <30 and 0.2 (p-trend=0.01) for parity >/= 3 versus nulliparous women. After adjusting for age and parity, the trend for age at first childbirth became non-significant (adjusted odds ratio 3.5; p-trend=0.15), while that for parity remained significant (adjusted odds ratio 0.2; p-trend 0.02). CONCLUSIONS The p53 signature is significantly associated with lower parity and possibly higher age at first childbirth, further linking this entity to serous cancer via risk factors associated with ovulation. The p53 signature merits consideration as a surrogate marker for serous cancer risk.

Evidence for cancer stem cells contributing to the pathogenesis of ovarian cancer

Ovarian cancer represents the most lethal gynecologic malignancy, primarily due to a lack of early detection, which results in most patients being diagnosed at an advanced stage of disease. Though the ovarian surface epithelium is thought to provide the primary site of tumorigenesis, the exact etiology of the various tumor types associated with this disease remain undefined. Recent evidence suggests that ovarian tumors, like other solid tumors, contain distinct populations of cells that are responsible for tumor initiation, maintenance and growth. These specialized cells, termed cancer stem cells, display some of the hallmarks of normal stem cells and are thought to evade current chemotherapeutic strategies, resulting in an increased risk of recurrence. Here we review evidence for the existence of cancer stem cells in ovarian malignancies and their contribution to the pathology of this disease, critically evaluate the methods used for ovarian cancer stem cell definition and isolation, and discuss their clinical relevance.

Endothelin-1 and Vascular Tone in Subjects With Atherogenic Risk Factors

Abstract—Endothelin-1 (ET-1) is a potent vasoconstrictor that increases vascular tone in the resistance vessels of subjects with hypertension. It is unclear whether endogenous ET-1 affects resistance-vessel function equally in patients with other cardiovascular risk factors. Vasoconstriction to ET-1 is mediated principally via the endothelin-A (ETA) receptor on vascular smooth muscle cells. Accordingly, we used an ETA-specific antagonist, BQ-123, to test the hypothesis that endogenous ET-1 increases vascular resistance selectively in subjects with hypertension compared with other risk factors. BQ-123 was infused at 100 nmol/min for 80 minutes into the brachial artery of 10 subjects with hypertension (mean±SEM arterial pressure, 106±5 mm Hg), 12 subjects with hypercholesterolemia (mean±SEM total cholesterol, 7.1±0.2 mmol/L), 10 active smokers (mean±SEM, 42±11 pack-years), and 11 healthy, age-matched individuals. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. BQ-123 dilated resistance arterioles in hypertensive subjects, with FBF’s increasing by 46±7% from baseline (P <0.001). BQ-123 increased FBF to a lesser extent in hypercholesterolemic (24±5%, P <0.001) and healthy (20±8%, P =0.007) individuals but did not affect FBF significantly in smokers (10±8%, P =0.185). The vasodilator response in hypertensive subjects, but not in hypercholesterolemic patients or smokers, was significantly greater than that in healthy individuals (P =0.012). Endogenous ET-1, acting via the ETA receptor, increases resistance-vessel tone in subjects with hypertension more than in subjects with hypercholesterolemia or in smokers. These results indicate that ET-1 contributes more to the pathophysiology of hypertension than of other risk factors in subjects without overt atherosclerosis.

Prognostic determinants in patients with stage I uterine papillary serous carcinoma: a 15-year multi-institutional review.

Objective The aim of this retrospective, multi-institutional study was to evaluate the importance of surgical staging for stage I uterine papillary serous carcinomas (UPSCs) to determine optimal management of this rare tumor. Methods With institutional review board approval from both participating institutions, all patients with 2009 International Federation of Gynecology and Obstetrics stage I mixed serous and UPSC diagnosed between January 1, 1992, and December 31, 2007, were identified at the 2 institutions. Clinical factors were correlated using Spearman correlation coefficients, Kaplan-Meier survival estimates and a Cox proportional hazards model. Results Of the 204 UPSC patients treated during this period, 84 were classified as stage I, with substages as follows: stage IA, n = 71; stage IB, n = 13. Thirty-seven patients (44%) had a history of a second cancer (22 breast tumors, 9 synchronous müllerian cancers). Surgical staging with at least hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and bilateral pelvic lymph node dissection was performed in 60 (71%) of 84 patients. The median survival for all patients was 10 years. Univariate analysis revealed surgical staging (P < 0.001), normal preoperative CA-125 (P < 0.001), and absence of additional cancers (P < 0.01) to be associated with improved survival. Age-adjusted multivariate analysis incorporating these factors revealed that advancing substage (hazard ratio, 4.59; P < 0.05), a second malignancy (hazard ratio, 2.75; P < 0.04), and surgical staging (hazard ratio, 0.18; P < 0.001) were independent factors associated with overall survival. In a subset analysis excluding patients with a second malignancy, substage (hazard ratio, 3.52; P < 0.05), and surgical staging (hazard ratio, 0.16; P < 0.001) were independent factors affecting overall survival. Conclusions Independent of adjuvant chemotherapy or radiation, stage of disease, comprehensive surgical staging, and the presence of a second malignancy were predictors of overall survival.

Epidemiologic correlates of ovarian cortical inclusion cysts (CICs) support a dual precursor pathway to pelvic epithelial cancer.

OBJECTIVE Many ovarian carcinomas are presumed to arise within ovarian cortical inclusion cysts (CICs). This study examined the frequency of ovarian CICs in relation to epidemiologic risk factors in women with BRCA1 and BRCA2 (BRCA+) mutations. METHODS BRCA+ women who underwent risk-reducing bilateral salpingo-oophorectomy were studied (n=74). Fifteen demographic variables (e.g., age at time of surgery, age at first birth, age at menopause, body mass index (BMI), gravidity) from a review of the medical records and three pathologic variables (cystic and atretic follicles, corpora lutea) were recorded. Statistical associations were made using T-test or Chi Square analysis and logistic regression analysis for p-trend. RESULTS Women whose ovaries contained 7 for more CICs were older at first birth (p=0.034), surgery (p=0.059), menopause (p=0.046) and had a higher BMI (p=0.034) than those with <7 CICs. Regression analysis revealed a significant association between CICs and increasing BMI (p=0.01). CONCLUSIONS CICs correlate with greater body mass index, similar to low-grade serous and endometrioid tumors and in contrast to high-grade serous carcinoma and its putative precursor in the fallopian tube. A model is presented for ovarian and tubal pathways to pelvic cancer that are linked to different microscopic precursors with distinct epidemiologic correlates.

Modest benefit of total parenteral nutrition and chemotherapy after venting gastrostomy tube placement

OBJECTIVE The aim of the study is to review a single institutions experience with gastrostomy tubes (GTs) performed for malignant bowel obstruction from gynecologic cancers. METHODS Women with gynecologic cancers who underwent venting GT placement from 2000 to 2008 were identified and clinical data were extracted. Logistic regression and spearman correlational coefficients were used to determine relationships between variables. Survival analysis was performed using the Kaplan-Meier method and a Cox proportional hazard model. RESULTS We identified 115 women who underwent GT placement, the majority of whom were diagnosed with ovarian cancer (84%). Median time from cancer diagnosis to GT placement was 2.2 years. Median survival following GT placement was 5.6 weeks. A majority (56%) developed GT complications requiring GT revision. While burden of disease as assessed on CT scan by the validated peritoneal cancer index (PCI) was not associated with survival, low CA-125 within one week of GT placement was associated with improved survival (p<0.01). TPN was administered in 36% of women, was associated with concurrent chemotherapy (p<0.001) and a 5 week survival benefit (p<0.01). Chemotherapy after GT was administered in 40% of women and was associated with a 10 week survival benefit (p<0.001). Age-adjusted multivariate analysis identified chemotherapy as the only independent variable associated with survival. CONCLUSIONS Women with malignant bowel obstructions from gynecologic cancers requiring palliative GT placement had a guarded prognosis measured in weeks. Gastrostomy tubes near the end of life had a high rate of complications requiring medical intervention. Chemotherapy after GT was associated with TPN administration, and both were associated with a modest extension in survival.

Laparoendoscopic single-site radical hysterectomy: the first report of LESS type III hysterectomy involves a woman with cervical cancer.

Laparoendoscopic single-site surgery is a logical advance in the evolution of minimally invasive surgery and is being utilized to perform increasingly complex procedures. We report its use for completion of radical hysterectomy as treatment for cervical cancer.

The role of radical surgery in the management of acquired uterine arteriovenous malformation

Background: Acquired arteriovenous malformations (AVMs) can develop after uterine instrumentation. The increased risks of vascular changes, including abnormal placentation, after repeated cesarean sections are well studied. Herein, we describe a patient with delayed hemorrhage from a uterine AVM, following dilation and curettage for a cesarean scar pregnancy. Case: A 32-year-old G3P2 presented with a cesarean scar ectopic pregnancy managed with dilation and curettage, which incurred a 1,500-ml blood loss. Within 6 weeks, she returned with 2 episodes of vaginal bleeding. Initial angiography demonstrated a high-flow arteriovenous fistula, which was coiled. Vaginal hemorrhage recurred; repeat angiography demonstrated a large AVM. Gelfoam embolization of the bilateral internal iliac arteries reduced the vascularity of the AVM. The AVMs location, starting at the left lateral apex of the cesarean scar and extending into the parametrium, necessitated a radical hysterectomy. Pathologic examination revealed a placenta percreta extending into the parametrium. Conclusion: The prevalence of uterine AVMs has increased with the rise in surgical obstetrics. In patients with a failed prior interventional procedure, surgical management is necessary to prevent life-threatening hemorrhage. The location of the AVM within the abnormal uterine scar tissue requires familiarity with radical pelvic surgical techniques that are normally used in cancer surgery in order to definitively treat this delayed obstetrical complication.