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Context: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women associated with an increased risk of endometrial hyperplasia. We sought to study the effects of metformin treatment (widely used in the management of PCOS women) on human endometrial adenocarcinoma cells., Objectives: To study the effects of metformin treatment on in vitro invasion and metastasis in human endometrial adenocarcinoma cells. Also, given the link between inflammation with endometrial cancer invasion and metastasis, we explored the roles of nuclear factor-κB (NF-κB), matrix metalloproteinases (MMPs) as well as v-akt murine thymoma viral oncogene homolog 1 (Akt) and extracellular signal-regulated kinases (Erk(1/2)) signaling pathways., Design: Sera were obtained from PCOS and control subjects. In vitro invasion were assessed in human endometrial cells (ECC-1 cells) by wound-healing motility and migration assays. NF-κB was studied by stably transfecting ECC-1 cells with a cis-reporter plasmid containing luciferase reporter gene linked to five repeats of NF-κB binding sites. The gelatinolytic activities of secreted MMP-2/9 in conditioned media were measured by gelatin zymography. Akt and Erk(1/2) phosphorylation were assessed by Western blotting., Results: In vitro invasion in ECC-1 cells was significantly attenuated by sera from PCOS women after 6 months of metformin treatment (850 mg twice daily) compared to matched controls (P < 0.01). These effects appear to be associated with NF-κB, MMP-2/9, as well as Akt and Erk(1/2) pathways that are known to be important regulators of inflammation, tumor invasion and metastasis., Conclusions: Metformin, potentially, may serve as adjuvant treatment in the management of patients with endometrial cancer.

The objective of this study was to determine whether nuclear morphometric data can predict survival, disease progression, and chemotherapeutic response in ovarian serous carcinoma. Nuclear morphometric parameters were determined from archival hematoxylin and eosin sections of 132 serous tumors. Clinicopathologic and morphometric parameters were evaluated as to their individual and independent prognostic value and prediction of chemotherapy response. Nuclear parameters were found to strongly correlate with extent of disease residuum, tumor grade, and FIGO stage. Univariate analysis revealed stage, grade, preoperative CA125, presence of ascites, extent of disease residuum, standard deviation of nuclear area (SDNA), nuclear perimeter (NP), SDNP, nuclear length (NL), nuclear breadth (NB), orthoferet, and equivalent diameter (ED) to be significant predictors of overall survival (OS) and disease-free survival (DFS). Grade, stage, extent of disease residuum, presence of ascites, SDNA, NP, NL, NB, and orthoferet were found to be significant predictors of chemotherapy response. Multivariate analysis revealed extent of disease residuum (P

The objective of this study was to determine whether syntactic structure analysis (SSA) can predict survival outcome and chemotherapeutic response in ovarian carcinoma. Syntactic structure analysis parameters, blindly determined in archived hematoxylin and eosin sections of 132, International Federation of Gynecology and Obstetrics (FIGO) stage I to IV serous ovarian tumors, and clinicopathologic parameters were evaluated as to their univariate and multivariate prognostic value and ability to predict chemotherapy response as measured by changes in CA125 levels. Univariate analysis revealed FIGO stage, tumor grade, preoperative CA125, presence of ascites, extent of disease residuum, and the SSA parameters minimum spanning tree (min MST), maximum MST (max MST), percent connectivity to 1, and 2 nearest neighbors to be significant predictors of overall survival and disease-free survival. Tumor grade, FIGO stage, extent of disease residuum, presence of ascites, and percent connectivity to 2 nearest neighbors were found to be significant predictors of chemotherapy response. Multivariate analysis revealed extent of disease residuum to be a significant predictor for overall survival (P

The study objective was to determine the prognostic value of assessment of staining of p53 and bcl-2 in a well-selected group of serous ovarian carcinomas. Immunohistochemical detection was used to identify both p53 and bcl-2 positive tumors. One hundred thirty-two tumors were analyzed for positivity of staining, grade of staining intensity, and for p53 alone, percent expression rates. These were analyzed alongside traditional clinicopathologic parameters for their ability to predict overall survival (OS), disease-free survival (DFS), and response to chemotherapy (CR). Univariate COX analysis revealed percent p53 expression (P = 0.012) and p53 grade (P = 0.01) to be significant predictors of DFS. Neither the p53 nor bcl-2 measurement parameters were found significant for OS or prediction of CR. On multivariate analysis, incorporating clinicopathologic parameters, p53 parameters did not retain independent significance for any outcome measure. As in primary reported studies, bcl-2 was not found to be of clear independent prognostic value in this group of ovarian tumors. If mutation of p53 and its consequent overexpression is an early event in ovarian tumorigenesis, then p53 assessment may prove useful prognostically in the assessment of either low-grade ovarian carcinomas, as a possible indicator for progression, or in early-stage ovarian tumors, as a marker of tumor aggression or likelihood of recurrence. p53 analysis of a larger group of stage I ovarian tumors would be desirable to further explain the potential association with DFS.

The study objective was to determine whether tumor vascularity correlates with patient survival, to compare newer semiautomated methods of angiogenesis assessment to older methods, and to determine if advanced image analysis methods can offer useful patient outcome data in serous ovarian cancer. Using the specific endothelial marker CD34, microvessel determinations were quantified in 132 serous ovarian tumors by manual counting at final magnifications of x 200 and x 400 in the most highly vascular areas. Computer-assisted image analysis microvessel counts, endothelial area estimates, and minimum spanning tree (MST) analysis of capillary architecture, which involves assessment of intercapillary distances, were correlated with traditional manual techniques.Manual, semiautomated, and advanced image analysis methods were found to be highly reproducible and express strong correlation with one another. Univariate cyclooxygenase analysis revealed angiogenesis parameters to be highly significant predictors for overall survival (OS) and disease-free survival. Multivariate cyclooxygenase analysis revealed maximum MST (P = 0.009), length MST (P = 0.005), 1 nearest neighbor (P

The records of 208 women were reviewed to quantify the long-term treatment failures of large loop excision of the transformation zone (LLETZ) in the treatment of cervical intraepithelial neoplasia (CIN) grade III. The rate of dyskariotic smears fell from 8% at 6 months to 2.3% at 48 months. The excision was considered incomplete in 84 cases (40.3%) of which 40 had endocervical margins involved. Thirty-five per cent of women with incomplete excision of CIN at the endocervical margin and 9% with complete excision had a dyskariotic smear within 4 years following LLETZ. These findings were statistically significant (P = 0.003 and 0.02 respectively). However, 5% only of women in the former group had cytological treatment failure at 6 months. There was no significant association between age and incidence of treatment failure. Further data are required to determine the risk of recurrence beyond 4 years before recommendations could be made about the duration of annual screening.

Aims: Little information is available on the patterns of integration into the host chromosomal DNA of cervical carcinomas of human papillomavirus type 18 (HPV-18) DNA, which is associated with up to 20% of these carcinomas. Because integration of the viral genome may be extremely important in the pathogenesis of cervical carcinoma, the aim of this study was to investigate which regions of HPV-18 DNA are integrated into the cellular DNA of cervical carcinomas., Methods: Southern analysis using four subgenomic probes covering the entire HPV-18 genome was used to map viral DNA integrated within cellular DNA. The polymerase chain reaction (PCR) was used to confirm the presence of specific regions of the viral genome., Results: In all 11 carcinomas there was a single major HPV-18 DNA integrant, retaining approximately 4000 bp of HPV-18 DNA, indicating that approximately half of the virus genome had been lost upon integration. Southern analysis suggested strongly that the viral breakpoint was within the E1/E2 gene boundary, with concomitant loss of part or all of the E2 ORF (open reading frame), all of the E4, E5, and L2 ORFs and part of the L1 ORF. These data were supported by the PCR results, which confirmed that the region of integrated HPV-18 DNA from nucleotides 6558 to 162 was present in all the carcinoma samples studied. Assuming that no genomic rearrangements, deletions, or insertions had occurred, 4131 bp of integrated HPV-18 DNA could be accounted for in eight cervical carcinoma samples. The results of Southern analysis also suggested that integration of HPV-18 DNA may have occurred at a specific host chromosomal site., Conclusions: Broadly, the viral sequences retained upon HPV-18 integration resemble those found when HPV-16 is integrated. However, it appears that the HPV-18 E2 region is more consistently deleted.

We have measured evoked changes in plasma renin concentration (PRC), plasma renin substrate (PRS) amd plasma aldosterone concentration (ALD) during the infusion of angiotensin II (AII) with and without the simultaneous administration of prostaglandin E2, 5 micrograms min-1 i.v. (PGE2) or prostaglandin E1, 15 ng kg-1 min-1 (PGE1). Experiments have been carried out using PGE2 in 20 patients, and in 5 patients to date with PGE1. AII alone (16 ng kg-1 min-1 i.v.) significantly reduced PRC in both groups of patients without altering PRS, while ALD concentrations more than doubled. The infusion of PGE2 stimulated basal PRC; PGE1 at the dose used did not alter PRC. Neither prostaglandin altered basal RS or ALD concentrations. When AII was infused simultaneously, PRC was again suppressed, in the presence of PGE2. However, only minimal feedback suppression occurred when PGE1 was being used. Furthermore, AII was still associated with a more than two-fold rise in ALD concentration when given together with PGE2, but the rise was considerably smaller and not significant in the presence of PGE1. PGE2 is a known stimulus to renin secretion, apparently acting directly at the juxtaglomerular apparatus. These preliminary results suggest that while a similar mechanism exists in second trimester human pregnancy, PGE1 may have a different effect. The apparent blockade of the normal feedback suppression of PRC in the presence of increased PGE1 concentrations by raised concentrations of AII is especially interesting.

Chromosome banding studies were carried out on both partners of 182 consecutive couples with a history of two or more spontaneous abortions. Seventeen abnormal karyotypes were detected. This represents a frequency of 4.67 per cent, which is higher than hitherto reported. The pregnancy outcome in 105 couples with normal and abnormal karyotype was compared and no significant difference was found.

To investigate the ability of steroid hormones to interact with endometrium, particularly in cases of unexplained subfertility, intact cells were incubated with tritiated progesterone and oestradiol and their uptake into the nuclei was measured. Samples were taken at dilatation and curettage from 23 fertile women, 14 women with unexplained primary subfertility, and 9 patients whose primary subfertility could be explained. Serum oestradiol and progesterone levels were not significantly different between the three groups, nor were values of 3H-oestradiol uptake. However, low (below 5 pmol/mg DNA) values for nuclear 3H-progesterone uptake were present in most samples from women with unexplained subfertility but in only about half of the women in the other two groups. This biochemical defect may be the cause of some cases of unexplained subfertility.

Seventy-nine patients with evaluable epithelial ovarian cancer following primary laparotomy and treated with one of three primary cis-platinum-containing regimens were studied to determine the rate at which clinical cytoreduction occurred and whether a rapid response to treatment was of prognostic significance by improving progression free interval (PFI) or survival. A rapid response to treatment improved PFI in patients treated with single agent cis-platinum (P = 0.04) and increased survival in patients treated with a sequential cis-platinum based combination regimen (P = 0.03). The rate of cytoreduction was not a significant variable, however, in a multiple regression analysis of prognostic factors. Over 75% of all clinical responses, regardless of the regimen, had begun by the completion of the third course of chemotherapy. We conclude that response to active chemotherapy is a rapid phenomenon in ovarian cancer and this has important implications in both the decision to change drug therapy and the timing of further surgical effort.

Management of early endometrial carcinoma is controversial in regard to timing and indication of adjunctive radiation therapy. Two hundred eighty patients with stage I carcinoma of the endometrium are analyzed: 135 patients were treated with surgery only and 61 patients underwent preoperative and 83 patients postoperative radiation therapy. The overall survival was 94%. Recurrence rates in all three treatment arms were equal. Tumor grade was found to change from the diagnostic D&C specimen to the definite surgical specimen in 31% of all cases and in 50% of all grade 3 lesions. As only 39% of all patients required postoperative radiation therapy with equal survival, a primary surgical approach spares the majority of patient unnecessary treatment and preserves prognostically important histology.

The outcome of pregnancy following amniocentesis was studied prospectively in 517 consecutive patients undergoing amniocentesis in a single centre. The outcome in 289 of these pregnancies was compared with that in 289 control patients strictly matched for social class, age and parity. There were no significant differences in fetal loss, perinatal mortality or vaginal bleeding between the amniocentesis and control groups. There were significantly more congenital abnormalities in the amniocentesis group (P less than 0.01). These appear to be associated with the amniocentesis procedure and not with the occurrence of raised maternal serum alpha-fetoprotein levels. Although there was an increased risk of preterm delivery (P less than 0.02) there was no significant difference in the distribution of birthweights by centiles for gestational age between amniocentesis and control groups. There was a significant association between intrauterine growth retardation and raised serum alpha-fetoprotein (P less than 0.005). It is concluded that where the indications are strong, amniocentesis continues to be justified.