Recurrence patterns in patients with abnormal cardiophrenic lymph nodes at ovarian cancer diagnosis.

OBJECTIVES: Metastases in cardiophrenic lymph nodes noted at diagnosis of epithelial ovarian cancer confer a poor prognosis. It is unclear if cardiophrenic nodal metastases portend an atypical pattern of recurrence. We report on patients with radiographically involved cardiophrenic lymph nodes who underwent optimal primary debulking surgery to describe patterns of recurrence and response to chemotherapy. METHODS: Patients undergoing primary debulking surgery for stage IIIC/IV epithelial ovarian carcinoma with residual disease ≤1.0 cm at our institution from 2003 to 2011 with a pre-operative computed tomography (CT) scan were identified. Scans were reviewed by blinded radiologists, who identified abnormal cardiophrenic lymph nodes via a qualitative assessment scale based on size, heterogeneity, and architecture. RESULTS: Of the 250 patients identified, a recurrence site was documented in 22/27 (81.5%) with abnormal pre-operative cardiophrenic lymph nodes (defined by an elevated Qualitative Assessment Scale (QAS) score of ≥4), and in 128/223 (57.4%) without abnormal pre-operative cardiophrenic lymph nodes. Median short axis and long axis lymph node diameters for these patients was 9 (range 6-15) mm and 15 (range 11-22) mm, respectively. Cardiophrenic lymph nodes were resected in one patient. Patients with abnormal cardiophrenic nodes are more likely to have synchronous recurrence in thorax/pelvis and abdomen (50.0% (11/22) vs 25.0% (32/128), p=0.02) and less likely to have isolated recurrence in pelvis or abdomen (40.9% (9/22) vs 68.0% (87/128)). All patients who had a CT scan after six cycles of chemotherapy had improvement (defined as reduction of QAS score) in cardiophrenic lymphadenopathy. CONCLUSIONS: Despite cardiophrenic adenopathy demonstrating a complete radiographic response to chemotherapy, their presence pre-operatively is associated with an increased risk of recurrence in the thorax. Knowledge of this propensity to recur in the thorax is important to ensure all extra-abdominal recurrence sites are diagnosed and managed appropriately.

Metabolomic identification of novel diagnostic biomarkers in ectopic pregnancy.

INTRODUCTION: Ectopic pregnancy (EP) is a potentially life-threatening condition and early diagnosis still remains a challenge, causing a delay in management leading to tubal rupture. OBJECTIVES: To identify putative plasma biomarkers for the detection of tubal EP and elucidate altered biochemical pathways in EP compared to intrauterine pregnancies. METHODS: This case-control study included prospective recruitment of 39 tubal EP cases and 89 early intrauterine pregnancy controls. Plasma samples were biochemically profiled using proton nuclear magnetic resonance spectroscopy (1H NMR). To avoid over-fitting, datasets were randomly divided into a discovery group (26 cases vs 60 controls) and a test group (13 cases and 29 controls). Logistic regression models were developed in the discovery group and validated in the independent test group. Area under the receiver operating characteristics curve (AUC), 95% confidence interval (CI), sensitivity, and specificity values were calculated. RESULTS: In total 13 of 43 (30.3%) metabolite concentrations were significantly altered in EP plasma (p < 0.05). Metabolomic profiling yielded significant separation between EP and controls (p < 0.05). Independent validation of a two-metabolite model consisting of lactate and acetate, achieved an AUC (95% CI) = 0.935 (0.843-1.000) with a sensitivity of 92.3% and specificity of 96.6%. The second metabolite model (D-glucose, pyruvate, acetoacetate) performed well with an AUC (95% CI) = 0.822 (0.657-0.988) and a sensitivity of 84.6% and specificity of 86.2%. CONCLUSION: We report novel metabolomic biomarkers with a high accuracy for the detection of EP. Accurate biomarkers could potentially result in improved early diagnosis of tubal EP cases.

Should mucosal bowel invasion in ovarian cancer be assigned to FIGO stage IV disease?

OBJECTIVES: The FIGO staging consensus agreement from 2012 indicates that bowel mucosal invasion for epithelial ovarian cancer (EOC) should be assigned to stage IV disease. Finding no evidence justifying this recommendation, we examined the impact of recto-sigmoid colonic invasion on survival based on depth of invasion. METHODS: Patients having recto-sigmoid resection to achieve complete gross resection for stage IIIC/IV EOC between 2003 and 2011 were included. For this study, mucosal invasion alone was not considered as stage IV. Degree of bowel invasion was defined as: serosal/subserosal vs. muscularis/submucosa/mucosa. Patients with only mesenteric invasion were excluded. Intraperitoneal disease (IP) dissemination patterns were defined as pelvic, lower abdomen, upper abdomen, and miliary disease. Comparisons between groups were evaluated using the log-rank test for progression-free and overall survival (PFS, OS) and the chi-square test for IP dissemination pattern. RESULTS: Eighty-five patients were included with a mean age of 64.5 years. Most cases were serous (87.1%) and stage IIIC (83.5%). There were 53 (62.4%) patients with serosal/subserosal and 32 (37.6%) with muscularis/submucosa/mucosa invasion. Although not statistically significant, PFS and OS both favored cases with deeper invasion (muscularis/submucosa/mucosa vs. serosal/subserosal invasion: median PFS, 33.5 vs. 18.2 months, p = 0.34; median OS, 82.3 vs. 51.5 months, p = 0.46). When comparing patterns of disease dissemination, we observed that patients with serosal/subserosal invasion (vs. those with deeper invasion) tended to have more upper abdominal or miliary disease (67.9% vs. 48.4%, p = 0.08). CONCLUSIONS: Depth of recto-sigmoid colon wall invasion does not have prognostic significance. Our observations do not support assignment to a higher FIGO stage (IV) based solely on this factor.

Clinical significance of enlarged cardiophrenic lymph nodes in advanced ovarian cancer: Implications for survival.

OBJECTIVE: Advanced ovarian cancer (OC) commonly spreads to cardiophrenic lymph nodes (CPLNs), and is often visible on preoperative imaging. We investigated the prognostic significance of abnormal CPLNs in OC detected by preoperative CT scans using three different definitions. METHODS: Patients undergoing primary debulking surgery for stage IIIC/IV with residual disease (RD) ≤1.0cm and a preoperative abdominopelvic CT scan available were included. Scans were reviewed by two blinded radiologists. We characterized abnormal CPLNs using three different definitions: i) qualitative assessment score (QAS); ii) nodes >7mm on the short axis; or, iii) nodes ≥10mm on the short axis. We compared overall survival (OS) using the log-rank test. RESULTS: Of the 253 patients (mean age 64.0years), 136 had no gross residual disease (NGR) and 117 had RD. By the QAS definition, CPLNs were abnormal in 28 (11.1%) patients and removed in one case. Among patients with NGR, presence of abnormal CPLNs was associated with worse OS (median OS, 38.4 vs. 69.6months, p=0.08). We observed no association between abnormal CPLNs and OS among patients with RD (median OS, 37.5 vs. 28.5months, p=0.49). OS was significantly better in NGR group without abnormal CPLNs (median OS for NGR vs. RD, 69.6 vs. 28.5months, p<0.001); however, there was no difference in OS between patients with NGR versus RD when abnormal CPLNs were present (median OS, 38.4 vs. 37.5months, p=0.99). Lack of benefit from NGR when abnormal CPLNs were present was observed for all three definitions tested. CONCLUSION: Abnormal CPLNs are an important predictor of survival in advanced stage OC. Management of abnormal CPLNs should be considered in treatment planning when the goal is NGR.

Case for a role of the microbiome in gynecologic cancers: Clinician's perspective.

In this review, we aimed to provide insight into the microbiome and its association with endometrial and ovarian cancer and their risk factors. We reviewed the literature focusing on the relationship between the microbiome and cancer, as well as the relationship between gynecologic diseases and cancers. The human body contains different kinds of microorganisms in various body parts, which is termed the microbiome. The number of microorganisms that live in and on the human body is greater than that of the human germ and somatic cells by 10-fold. The relationship between a human and their microbiome is complex; it is also one of the most important components of homeostasis. Impairment of microbiome-host homeostasis has been associated with obesity, several cancers, preterm labor, inflammatory and allergic conditions and neurodevelopmental disorders. Direct and strong causal relationships have been established for several cancers and microorganisms, such as gastric lymphoma and Helicobacter pylori infection. Interestingly, eradication of the infectious agents has also been shown to be therapeutic. The association between cancer and the microbiome, however, is more complicated than a 1 bacteria-1 cancer model, and a shift in a healthy microbiome can result in various cancers via inflammation, change in microenvironment or DNA-damaging toxins. The human microbiome is an integral part of homeostasis. Understanding the mechanisms that cause dysbiosis will enable us to elucidate the pathways that result in malignancy and investigate new treatment modalities.

Synergistic effect of MEK inhibitor and metformin combination in low grade serous ovarian cancer.

OBJECTIVE: Low-grade serous ovarian cancer (LGSOC) constitutes 5-8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor. METHODS: Three LGSOC lines (VOA1056, VOA1312 and VOA5646) were treated with metformin, trametinib or 2-deoxyglucose (2DG) alone or in combination with metformin. Proliferation was measured by MTT assay over a period of four days. Protein expression was measured by western blotting. Seahorse Analyzer was used to measure effect of metformin on glycolysis and mitochondrial respiration. RESULTS: All LGSOC cell lines showed significant inhibition with metformin in a dose- and time-dependent manner. Trametinib significantly inhibited the growth of Ras mutated LGSOC lines (VOA1312 and VOA1056), while VOA5646 cells without RAS mutation did not show any response. Metformin and trametinib combination showed synergistic inhibition of RAS mutated VOA1312 and VOA1056 cells, but not for non-Ras mutated VOA5646 cells. Metformin and trametinib increased phosphorylated AMPK expression in LGSOC lines with combination showing stronger expression. Trametinib decreased 42/44 mitogen activated kinase phosphorylation in all cell lines, while metformin and combination had no significant effect. 2-DG significantly inhibited glycolysis in all LGSOC lines and combination with metformin showed synergistic inhibitory effect. CONCLUSIONS: Metformin alone or in combination with MEK and glycolytic inhibitors may be a potential therapy for LGSOC, a cancer that is indolent but chemo-resistant.

Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer.

BACKGROUND: Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin. METHODS: Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects. RESULTS: We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model. CONCLUSION: Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy.

Targeting of free fatty acid receptor 1 in EOC: A novel strategy to restrict the adipocyte-EOC dependence.

OBJECTIVES: Adipocyte derived free fatty acids (FFA) promote epithelial ovarian cancer (EOC) by acting as a fuel source to support the energy requirement of the cancer cells. FFA may also exert biological effects through signaling pathways. Recently, a family of FFA activated G-protein coupled receptors (FFAR/GPCRs) was identified. Our objective was to investigate the role of FFAR/GPCRs in EOC and assess their potential as therapeutic targets. METHODS: The mRNA (RT-PCR) expression of FFAR/GPCR family members (FFAR1/GPR40; FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120 and GPR84) was examined in: (1) a syngeneic mouse model of EOC fed high energy diet (60% fat) or regular diet (30% fat), (2) EOC cell lines exposed to free fatty acids and (3) specimens from 13 histologically normal ovaries and 28 high grade ovarian serous carcinomas. The GPR 40 antagonist, GW1100, was used to inhibit FFAR1/GPR40 and cell survival was assayed by MTT in various cell lines. RESULTS: High Grade Serous carcinoma specimens expressed significantly increased GPR40 compared to normal ovaries (p=0.0020). Higher expression was noted in advanced stage disease. ID8 ovarian tumors from mice fed with high fat diet also showed higher GPR40 expression. Exposing EOC cells to FFAs, increased GPR40 expression. Treatment of EOC cell lines with GW100 resulted in growth inhibition and was associated with an alteration in their energy metabolism. CONCLUSION: FFA-induced cancer cell growth may be partly mediated through FFAR1/GPR40. Targeting of FFAR1/GPR40 may be an attractive treatment strategy in EOC, and possibly offers a targeted treatment for a subset of EOC patients.

Significance of lymphovascular space invasion in uterine serous carcinoma: what matters more; extent or presence?

To analyze the clinical significance of the extent of lymphovascular space invasion (LVI) in patients with uterine serous carcinoma. After IRB approval, 232 patients with uterine serous carcinoma from the pathology databases of 4 large academic institutions were included. Patients were divided into 3 groups based on extent of LVI. Extensive LVI (E-LVI) was defined as ≥3 vessel involvement; low LVI (L-LVI) was defined <3 vessel involvement; and the third group consisted of tumors with no LVI (A-LVI). The association between LVI and myometrial invasion, cervical involvement, lower uterine segment involvement, positive peritoneal washings, lymph node involvement, stage, and survival were analyzed. Of 232 patients, 47 had E-LVI (20.3%), 83 had L-LVI (35.8%), and 102 had A-LVI (44%). A total of 9.8% of the patients with A-LVI had lymph node involvement as compared with 18.1% in the L-LVI group and 55.4% in the E-LVI group (P<0.0001). Fifty-nine percent of the patients in A-LVI, 85% in L-LVI, and 100% in the E-LVI group demonstrated myometrial invasion (P<0.0001). Cervical involvement was noted in 23%, 43%, 66% (P<0.0001) and lower uterine segment involvement involvement in 31%, 43%, and 42% of A-LVI, L-LVI, and E-LVI (P<0.0001), respectively. Stage III and IV disease were seen in 29%, 38%, and 79% of the patients with A-LVI, L-LVI, and E-LVI, respectively (P<0.0001). The median overall survival was 172, 95, and 39 mo for the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). The racial distribution was significant with African American patients demonstrating significantly more L-LVI (27.8%) and E-LVI (40.4%) when compared with A-LVI (19.6%) (P=0.040). In a subgroup analysis including patients with Stage I and II (n=123) revealed median survivals of 172, 169, and 38 mo in the A-LVI, L-LVI, and E-LVI groups, respectively (P<0.0001). Fifty percent of these patients with E-LVI, 20% in L-LVI group, and 15% in A-LVI group had disease recurrence (P=0.040). The extent of LVI was associated with multiple pathologic factors and was found to be a negative prognostic factor for overall survival and disease recurrence.

Management of squamous cell vulvar cancer: a review.

Squamous cell vulvar cancer is a rare gynecologic malignancy. Standard treatment for early stage disease consists of wide radical excision of the primary tumor with inguinal-femoral lymphadenectomy or sentinel lymph node mapping/biopsy. Because of the general paucity of patients with advanced vulvar cancer, there is no standard therapy for advanced disease and therefore treatment should be individualized. Intergroup trials are needed to clarify the value of chemoradiation, neoadjuvant chemotherapy and targeted therapy in patients with advanced squamous cell cancer of the vulva to identify modalities with the best therapeutic index and lowest morbidity.

Clinical and pathologic characteristics of serous carcinoma confined to the endometrium: a multi-institutional study.

The objective of this study was to analyze the clinical and pathologic factors in patients with uterine serous carcinoma confined to the endometrium. A total of 236 uterine serous carcinoma patients from the pathology databases of 4 large academic institutions were included in the study. Clinical and pathologic variables were analyzed, including patient demographics, tumor size (≤2 vs. >2 cm), myometrial invasion, lymphovascular invasion, lymph node status, tumor location (endometrium vs. polyp), cervical involvement, lower uterine segment involvement, FIGO stage, pelvic washings, recurrence, overall survival, and progression-free survival. Of 236 patients, 55 (23%) had tumors limited to the endometrium. Forty-four patients (80%) had Stage IA tumors. The tumor was confined to a polyp in 17 (30.9%) patients. Twenty patients (36.4%) had tumor sizes >2 cm and 12 (21.8%) exhibited lymphovascular invasion. Only 3 patients (5.4 %) had cervical stromal involvement. Thirty-three (66%) patients underwent pelvic and para-aortic lymphadenectomy with 2 positive para-aortic lymph nodes identified. Seven (12.7%) patients had positive washings, whereas 8 patients (14.5 %) had disease recurrence. At a median follow-up of 46 months, there was no difference in overall survival (P = 0.216) or progression-free survival (P=0.063) between patients with tumors confined to a polyp, patients with tumors confined to the endometrium, and patients with tumors present in both polyp and the endometrium. Uterine serous carcinoma with only endometrial involvement, even when confined to a polyp, can be associated with poor prognosis, further stressing the importance of complete surgical staging and adjuvant treatment in this setting.

Vulvar/vaginal melanoma: an updated surveillance epidemiology and end results database review, comparison with cutaneous melanoma and significance of racial disparities.

OBJECTIVE: We aimed to compare the differences in demographic features, clinicopathologic features, and survival in patients with vulvar/vaginal melanoma versus cutaneous melanoma with a special emphasis on race. MATERIALS AND METHODS: Data were obtained from the Surveillance Epidemiology and End Results database from 1973 to 2008. Kaplan-Meier curves and Cox multivariate model were used for statistical analysis. RESULTS: Seven hundred sixty-two patients with vulvar/vaginal melanoma and 55,485 patients with cutaneous melanoma patients were included in the study. Twenty-eight patients of the vulvar/vaginal group and 334 patients of the cutaneous group were black (3.6% vs 0.6%, respectively). The median age at the time of diagnosis was 68 years in the vulvar/vaginal group and 52 years in the cutaneous group (P < 0.0001). Three hundred fifty patients (45.9%) in the vulvar/vaginal and 46,499 patients (83.8%) in the cutaneous group presented with localized disease (P < 0.0001), whereas 64 patients (8.4%) in the vulvar/vaginal group and 1520 patients (2.7%) in cutaneous group presented with advanced disease (P = 0.0081). The median survival of the black patients was 16 months in the vulvar/vaginal group and 124 months in the cutaneous melanoma group (P < 0.0001). The median survival in the nonblack population was 39 months in the vulvar/vaginal group compared to 319 months in the cutaneous melanoma group (P <0.0001). In multivariate analysis performed for patients between 1988 and 2008, age, stage, and positive lymph nodes were negative independent prognostic factors for survival in vulvar/vaginal melanoma; whereas age, race, stage, radiation therapy, and lymph node positivity were negative prognostic factors in cutaneous melanoma. CONCLUSION: These findings emphasize that cutaneous and vulvar/vaginal melanomas have different clinicopathologic features and survival patterns.

Ghrelin and motilin levels in hyperemesis gravidarum.

PURPOSE: Ghrelin, an endogenous ligand for the growth hormone secratogogue receptor, and its receptors are found in the reproductive organs and placenta. Motilin is produced from the endocrine cells of the duodeno jejunal mucosa and considered to be a regulator of interdigestive migrating contractions. Aim of this study is to investigate ghrelin and motilin levels in patients with hyperemesis gravidarum. METHODS: A total of 56 patients with singleton pregnancies in the first trimester were recruited in the study, 39 with hyperemezis gravidarum and 17 normal pregnant women. Patients with medical complications and body mass index <18 or >25 were excluded. Fasting plasma ghrelin and motilin concentrations were measured. Fasting blood glucose, liver enzymes, blood urea nitrogen, creatinin, estradiol, progesterone, human chorionic gonadotropin, and thyroid function tests were also investigated. RESULTS: Ghrelin levels were significantly higher in patients with hyperemesis group than the normal pregnant women (p = 0.025). Serum estradiol levels were also higher in the hyperemesis group (p = 0.001). No significant difference was observed in plasma motilin levels between the two groups. In correlation analyses, maternal ghrelin was positively correlated with estradiol (r = 0.29, p = 0.029) in the whole cohort. CONCLUSION: There are a few studies about the course of circulating ghrelin levels during human pregnancy. Ghrelin administration increases food intake through central mechanisms but its effects on appetite in relation to human pregnancy is unknown. The increased levels of ghrelin in hyperemesis gravidarum might be a compensatory mechanism to restore the energy metabolism of the pregnant women.

Serological investigation of the role of selected sexually transmitted infections in the aetiology of ectopic pregnancy.

OBJECTIVES: To investigate the association between selected sexually transmitted infections (STIs) and the later occurrence of ectopic pregnancy. METHODS: A total of 125 women with ectopic pregnancy and 125 pregnant controls were recruited between January 2003 and February 2005 at Dr. Zekai Tahir Burak Women's Health Education and Research Hospital, in Ankara, Turkey. Enzyme-linked immunosorbent assay was used to determine the prevalence of serum antibodies to Chlamydia (C.) trachomatis and to Herpes simplex virus (HSV)-2 IgG and, indirect immunofluorescence test was used to determine the prevalence of serum antibodies to Mycoplasma (M.) hominis and Ureaplasma (U.) urealyticum. RESULTS: The prevalence of C. trachomatis Ig G antibody in women with ectopic pregnancy (31/125; 25%) was significantly higher than in controls (12/125; 9.6%) (crude Odds Ratio [OR]: 3.1, 95% confidence interval [CI]: 1.51-6.38; p = 0.001). However, there was no significant association between C. trachomatis IgM; M. hominis IgG, IgM; U. urealyticum IgG, IGM; and HSV-2 IgG, and ectopic pregnancy. CONCLUSIONS: Previous chlamydial infection plays an important role in the aetiology of ectopic pregnancy. There was no association between M. hominis, U. urealyticum and HSV-2 infections, and ectopic pregnancy.

Twin pregnancies with single fetal death: analysis of 38 cases.

The objective of this study is to evaluate fetal and maternal outcomes of twin pregnancies with intrauterine single fetal death. In 13 cases, intrauterine death of one fetus was found during the first trimester; in 25 cases, it was found after the first trimester. Obstetric complications and fibrinogen levels were compared. There were no significant differences in the number of preterm delivery, preeclampsia, and intrauterine growth restriction and there were significant differences in gestational age at delivery and birth weight between groups. Coagulation disorders did not occur. The risk for adverse pregnancy outcomes with a single fetal death during and after the first trimester is similar.

Clinical/pathologic features and patient outcome in early onset endometrial carcinoma: a population based analysis and an institutional perspective from the Detroit metropolitan area, Michigan.

OBJECTIVE: Analyze tumor characteristics and outcomes in patients with endometrial carcinoma (EC)<40 years of age and compare them to the characteristics of patients ≥ 40 years of age. METHODS: 10,700 patients (305 patients <40 years of age) diagnosed between 1988 and 2007 with EC from the Metropolitan Detroit Cancer Surveillance System (MDCSS), and 884 patients (42 patients <40 years of age) diagnosed between 1996 and 2008 with EC from our institutional database were identified. Differences in clinical and demographic variables by age (<40 vs. ≥ 40) were assessed for statistical significance by chi-square tests. Cox proportional hazards models were used to calculate adjusted hazard ratios (HR) and their 95% confidence intervals (95% CI) to assess the risk of death from all causes. RESULTS: MDCSS based analysis: Patients<40 were more likely to present with low grade tumors (p<0.0001) and endometroid histology (p=0.0004) but less likely to undergo surgery (p=0.0007) or radiotherapy (p=0.0007). A multivariate analysis confirmed the significance of age, grade, and stage in all patients, and that of histologic type, surgery, and race in patients ≥ 40 as independent prognostic factors for overall survival. Institution based analysis: Patients<40 had a higher proportion of patients with BM I ≥ 30 (p=0.04), and presented with a higher frequency of well differentiated (p=0.04) endometrioid tumors (p=0.004) that are less prone to have deep myometrial invasion (p=0.008). CONCLUSION: This study supports the hypothesis of a disease that is biologically and genetically heterogeneous among women of different ages and ethnicities.

Clear cell carcinoma arising in the abdominal wall: two case reports and literature review.

Clear cell carcinoma originating in the abdominal wall is rare and usually develops within endometriotic implants in the scar. We describe 2 patients: a 42 year old with a 15 cm mass on the abdominal wall treated with neoadjuvant chemotherapy and excision and a 51 year old with a 6 cm abdominal mass treated with excision and adjuvant radiotherapy.

Role of oxidative stress in preeclampsia and intrauterine growth restriction.

AIM: The aim of the present study was to evaluate the role of oxidative stress and DNA damage in preeclampsia and intrauterine growth restriction (IUGR). MATERIAL AND METHODS: Twenty-four patients with preeclampsia, 20 patients with IUGR fetus and 37 healthy pregnant women were enrolled in the study. The total oxidant status (TOS) and antioxidant status (TAS) of plasma were measured using a novel automated colorimetric measurement method. Sister chromatid exchange (SCE) and micronuclei analysis were performed on peripheral blood lymphocytes of cases and controls. RESULTS: Women whose pregnancies were complicated with preeclampsia and IUGR had elevated levels of TOS and TAS when compared with healthy pregnant women (median TOS values: 9.73, 10.6 and 8.06, P = 0.001; median TAS values: 1. 77, 1.54 and 1.44, P < 0.001, respectively). The frequencies of SCE were only found to be increased in women with IUGR fetus compared with healthy pregnant women (8.81 vs 7.5, respectively, P = 0.02). Multivariable linear regression analysis for both TOS and TAS showed a significant relation between these variables and uric acid. CONCLUSION: Increased oxidative stress and antioxidative defense mechanisms may contribute to disease processes both in preeclampsia and IUGR.

Evidence of fetal central nervous system injury in isolated congenital heart defects: microcephaly at birth.

OBJECTIVE: We sought to ascertain the risk of reduced fetal brain growth in cases of isolated congenital heart defect (CHD) based on microcephaly at birth. STUDY DESIGN: In a case-control study, head circumference was compared in 401 newborns with isolated CHD with 401 control subjects. Microcephaly was defined as head circumference below third percentile. The rates of microcephaly in multiple different categories of major CHD were ascertained along with logistic regression analyses to determine the specific types of cardiac defects that were significantly associated with microcephaly. RESULTS: Isolated CHD in the fetus was associated with an increased risk of microcephaly as were tetralogy of Fallot, coarctation/aortic arch hypoplasia, and hypoplastic left ventricle syndrome. Tetralogy of Fallot odds ratio, 2.6; 95% confidence interval, 1.1-6.3; P < .04 and coarctation/aortic arch hypoplasia, odds ratio, 2.8; 95% confidence interval, 1.5-5.1; P < .001 were significant independent predictors of microcephaly. CONCLUSION: The finding of microcephaly at birth in nonsyndromic CHD provides strong evidence in support of intrauterine hypoxic central nervous system damage. Potential changes in prenatal management including aggressive antepartum surveillance and earlier delivery warrant urgent consideration.

Bioenergetic Adaptations in Chemoresistant Ovarian Cancer Cells.

Earlier investigations have revealed that tumor cells undergo metabolic reprogramming and mainly derive their cellular energy from aerobic glycolysis rather than oxidative phosphorylation even in the presence of oxygen. However, recent studies have shown that certain cancer cells display increased oxidative phosphorylation or high metabolically active phenotype. Cellular bioenergetic profiling of 13 established and 12 patient derived ovarian cancer cell lines revealed significant bioenergetics diversity. The bioenergetics phenotype of ovarian cancer cell lines correlated with functional phenotypes of doubling time and oxidative stress. Interestingly, chemosensitive cancer cell lines (A2780 and PEO1) displayed a glycolytic phenotype while their chemoresistant counterparts (C200 and PEO4) exhibited a high metabolically active phenotype with the ability to switch between oxidative phosphorylation or glycolysis. The chemosensitive cancer cells could not survive glucose deprivation, while the chemoresistant cells displayed adaptability. In the patient derived ovarian cancer cells, a similar correlation was observed between a high metabolically active phenotype and chemoresistance. Thus, ovarian cancer cells seem to display heterogeneity in using glycolysis or oxidative phosphorylation as an energy source. The flexibility in using different energy pathways may indicate a survival adaptation to achieve a higher 'cellular fitness' that may be also associated with chemoresistance.