Inez Cooke

The usefulness of ultrasound assessment of amniotic fluid in predicting adverse outcome in prolonged pregnancy: a prospective blinded observational study.

Objective To determine whether a single ultrasound scan at or beyond 40 weeks of gestation to detect a single deepest pool of amniotic fluid <2 cm and amniotic fluid index (AFI) <5 cm is clinically useful in the prediction of subsequent adverse pregnancy outcome.

What is a reasonable time from decision‐to‐delivery by caesarean section? Evidence from 415 deliveries

Objective To determine how long it takes from the decision to achieve delivery by non‐elective caesarean section (DDI), the influence on this interval, and the impact on neonatal condition at birth.

Inhibin as a marker for ovarian cancer

Inhibin is a polypeptide hormone produced by the granulosa cells of the ovary, and is present in body fluids as dimers of various sizes each comprising an alpha- and beta-subunit. Free forms of the alpha-subunit also circulate, and the presently available radioimmunoassay (Monash assay) cannot distinguish these from biologically active dimeric inhibin. Recently we described a new two-site enzyme immunoassay able for the first time to measure the levels of dimeric inhibin throughout the human menstrual cycle. The sensitivity limit of this assay is 2 pg ml-1 in human serum with cross-reactivity against activin of 0.05%. The normal range of inhibin in post-menopausal women is < 5 pg ml-1, in pre-menopausal women 2-80 pg ml-1 (2-10 pg ml-1 in the follicular phase, 40-80 pg ml-1 in the luteal phase). This assay was used to determine inhibin levels in sera from 15 (five pre-menopausal and ten post-menopausal) patients with granulosa cell tumours of the ovary. It was raised in a pre-menopausal patient preoperatively (261 pg ml-1), in six post-menopausal patients (32, 43, 54, 66, 24 and 58 pg ml-1) and one pre-menopausal patient with recurrent tumour, (237 pg ml-1), all confirmed clinically. Inhibin was normal in six patients in remission. Oestradiol levels were normal in all patients. Serial levels of inhibin predicted recurrence before overt clinical relapse in two patients. In 29 patients with malignant epithelial ovarian tumours inhibin levels were modestly elevated in nine and normal in the rest. Three patients with endometrioid histology, two with undifferentiated tumours, three with mucinous adenocarcinoma and one with clear cell carcinoma had elevated inhibin levels. Functional inhibin is secreted by all granulosa cell tumours of the ovary studied and can be used as a tumour marker to determine response to therapy and predict recurrence and is superior to oestradiol. A more detailed analysis of the levels of inhibin, and its subunits in epithelial ovarian cancer is needed to identify the molecular forms of the immunoreactive material before optimised assays can be applied to this more common tumour.

Allele loss on chromosome arm 6q and fine mapping of the region at 6q27 in epithelial ovarian cancer.

Genetic changes have been shown to be important in determining the multistep progression of cancer. Allele loss studies and karyotypic analysis of epithelial ovarian tumours have indicated the presence of putative tumour suppressor genes on chromosomes 6, 11, 13, 17, 18, 22, and X. We have focused on chromosome arm 6q to identify the minimal region that may contain a putative tumour suppressor gene. Nineteen polymorphic microsatellite markers from 6q and one centromeric marker (D6S294) have been used to detect allele loss in 68 ovarian tumours (six benign, six borderline, and 56 with malignant histology). Allele loss was evaluated by separation of fluorescence labelled polymerase chain reaction‐amplified products. Forty‐six of fifty‐six (82%) malignant tumours showed allele loss on 6q, whereas only four of 56 had lost all the markers tested. Forty‐one of fifty‐six (73%) malignant tumours showed allele loss at 6q26‐27. The minimal region of allele loss was between markers D6S264 and D6S297 (3 cM), with maximal allele loss of 62% at D6S193 and 52% at D6S297. Three tumours showed loss of D6S193 only, while retaining flanking informative markers. Allele loss around 6q26‐27 was observed in all histological types of epithelial ovarian cancer and did not correlate with any clinical factors. In addition, there was allele loss at ESR (56%) and D6S286 (47%), though a minimal region was not defined. Allele loss at 6q12‐25 correlated significantly with endometrioid and mucinous ovarian malignant tumours (P = 0.01). The physical mapping of the region between D6S297 and D6S264 will allow the eventual identification of the putative tumour suppressor gene. Genes Chromosom Cancer 15:223–233 (1996).

The genetic analysis of ovarian cancer

Ovarian cancer represents the fifth most significant cause of cancer-related death for women and the most frequent cause of death from gynaecological neoplasia in the Western world. The incidence of ovarian cancer in the UK is over 5000 new cases every year, accounting for 4275 deaths per year (Chang et al., 1994). A recent meta-analysis of all randomised trials of patients with epithelial ovarian cancer after surgery demonstrated an overall 5 year survival of 30% (Advanced Ovarian Cancer Trialists Group, 1991). Five year survival rates are as follows: stage I, 70%; stage II, 45%; stage III, 17%; and stage IV, 5% (Chang et al., 1994). The high overall mortality is due to the majority of patients presenting with stage III and IV disease. Clearly, any methods that enable the early detection of ovarian cancer would lead to a significant decrease in mortality. Ovarian cancer encompasses a broad spectrum of lesions, ranging from localised benign tumours and tumours of borderline malignant potential, through to invasive malignant adenocarcinomas. Histologically, the common epithelial ovarian cancers, which account for 90% of all ovarian cancer, are classified into several types, that is serous, mucinous, endometrioid, clear cell, Brenner, mixed epithelial and undifferentiated tumours. The different histological subtypes reflect the considerable differentiation potential of the ovarian surface epithelium. The aetiology of ovarian cancer is not completely understood, although both epidemiological and genetic associations have been recorded. Epidemiological factors related to ovulation seem to be important (Fathalla, 1971), whereby ovarian epithelial cells undergo several rounds of division and proliferative growth to heal the wound in the epithelial surface, thereby increasing the chance of a genetic accident during the repair process, such as the activation of an oncogene or the inactivation of a tumour-suppressor gene (Berek et al., 1993). The genetic changes occurring in epithelial ovarian cancer are also poorly understood and, except for the analysis of the p53 gene, the majority have not yet been defined. This review focuses on the current understanding of cytogenetic abnormalities, linkage and allele loss studies that signpost chromosomal regions which may contain relevant genes. The emphasis of this review is on recessively acting rather than dominant genes (reviewed recently in Berchuck et al., 1992) as the isolation of tumoursuppressor genes will lay the foundation for an improved understanding of the mechanisms involved in tumorigenesis.

Immunohistochemical expression of inhibin/activin subunits in epithelial and granulosa cell tumours of the ovary.

Dimeric inhibin‐A has been shown recently by a sensitive two‐site ELISA assay to be a useful tumour marker in granulosa cell tumours of the ovary. It is also elevated in some patients with malignant epithelial ovarian tumours. To identify the precise subunits of inhibin expressed in ovarian tumours, three monoclonal antibodies, R1, E4, and INPRO (against the αC‐, βA‐, and pro‐α‐subunits, respectively), were evaluated by immunohistochemistry on a panel of six granulosa cell and nine epithelial tumours. All granulosa cell tumours stained positively with E4 and R1, suggesting expression of dimeric inhibin‐A; in two patients where serum levels were measured pre‐operatively, they were elevated. The tumours also reacted weakly with INPRO, suggesting the presence of precursor forms of the α‐subunit. Eight malignant epithelial ovarian tumours expressed the βA‐subunit only, as recognized by E4, while one tumour expressed both α‐ and βA‐subunits, which correlated with an elevated serum inhibin‐A level. Thus, while granulosa cell tumours express inhibin, the majority of epithelial tumours probably express activin, a result which needs to be confirmed by serum measurements.

Analysis of loss of heterozygosity and KRAS2 mutations in ovarian neoplasms: Clinicopathological correlations

The molecular events that give rise to ovarian epithelial neoplasms are not well understood. In particular, it is not known whether adenocarcinomas arise from benign or low malignant potential (LMP) precursors. We have examined a large series of benign (25) and LMP (31) ovarian tumors for loss of heterozygosity (LOH) at multiple loci on 17 chromosomes. LOH was observed in benign tumors on chromosomes 6 (14%) and 9 (5%) and on the X chromosome (33%) only. LOH on these chromosomes was also detected in a small number of LMP neoplasms, suggesting that these may derive sometimes from benign precursors. In addition, we examined LOH in 93 adenocarcinomas. Analysis of associations between LOH events showed that LOH on chromosomes 5 and 17 (P = 0.0002) and on chromosomes 17 and 18 (P = 0.00007) were associated significantly with each other, which suggests that these may represent cooperative, progressive events. No novel significant associations were identified between LOH events and stage, grade, or histology, which would indicate the existence of genetic heterogeneity in ovarian neoplasms. KRAS2 mutations were detected more often in LMP neoplasms than in malignant tumors (P = 0.004) and were detected more often in Stage I/II malignant tumors than in Stage III/IV malignant tumors (P = 0.033), suggesting that LMP tumors with KRAS2 mutations are unlikely to progress to frank malignancy. Univariate (but not multivariate) survival analysis showed that LOH of chromosomes 11 (P = 0.039) and 17 (P = 0.04) was associated with a significantly worse prognosis. Replication of these novel findings is necessary, and the identification, isolation, and characterization of the critical genes affected by LOH will determine their importance in the pathogenesis of ovarian malignancies. Genes Chromosom. Cancer 18:75–83, 1997.

Progesterone/progestogen releasing intrauterine systems versus either placebo or any other medication for heavy menstrual bleeding.

BACKGROUND Heavy menstrual bleeding (HMB) is an important cause of ill health in women and it accounts for 12% of all gynaecology referrals in the UK. Heavy menstrual bleeding is clinically defined as greater than, or equal to, 80mls blood loss per menstrual cycle but women may complain of excessive bleeding when their blood loss is less than 80ml. Hysterectomy is often used to treat women with this complaint but medical therapy may be a successful alternative. The intrauterine coil device was originally developed as a contraceptive but the addition of uterine relaxing hormones, or progestogens, to these devices resulted in a large reduction in menstrual blood loss. Case studies of 2 types of progesterone/progestogen releasing systems, Progestasert and Mirena, report reductions of up to 90% and dysmenorrhoea may be improved. Insertion, however, may be regarded as invasive by some women affecting its acceptability as a treatment and frequent intermenstrual bleeding and spotting is likely during the first few months. OBJECTIVES To determine the effectiveness and acceptability of progesterone/progestogen-releasing intrauterine devices in achieving a reduction in heavy menstrual bleeding. SEARCH STRATEGY All studies which might describe randomised controlled trials of progesterone/progestagen-releasing intrauterine devices for the treatment of heavy menstrual bleeding were obtained by electronic searches of the MEDLINE 1966-1999, EMBASE 1980-1999 databases and the Cochrane Library. Companies producing progestogen releasing intrauterine devices and experts in the field were contacted for information on published and unpublished trials. SELECTION CRITERIA Randomised controlled trials in women of reproductive age treated with progesterone/progestogen-releasing intrauterine devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding within either the primary care, family planning or specialist clinic setting were eligible for inclusion. Women with postmenopausal bleeding, intermenstrual or irregular bleeding, or pathological causes of heavy menstrual bleeding were excluded. DATA COLLECTION AND ANALYSIS Potential trials were independently assessed by three reviewers and five trials met the criteria for inclusion in the review. The reviewers extracted the data independently and data were pooled where appropriate. Odds ratios for dichtomous outcomes and weighted mean differences for continuous outcomes were estimated from the data. The primary outcome was reduction in menstrual blood loss but incidence of side effects, changes in quality of life and satisfaction and acceptability measures were also assessed. MAIN RESULTS Progesterone/progestogen-releasing intrauterine systems have not been compared to placebo or no treatment. Progestasert has been compared to a number of different medical therapies in one small study but no conclusions can be made about effectiveness. The levonorgestrel-releasing intrauterine device (LNG IUS) has been compared to oral cyclical norethisterone (NET) administered on days 5-26 in one trial and was significantly more effective although there was a large reduction from baseline in both groups and these differences were not perceived by the women undergoing the treatment. Some side effects were more common in the LNG IUS group but a significantly greater proportion of women in this group were satisfied and willing to continue with their treatment. In one trial of women awaiting hysterectomy where the LNG IUS was compared with a control group taking their existing medical therapy, a higher proportion of the women in the former group cancelled their planned surgery after 6 months of treatment. The levonorgestrel-releasing intrauterine device has been compared to a surgical procedure (transcervical resection of the endometrium (TCRE)) in two trials. (ABSTRACT TRUNCATED)

Decision to delivery intervals for assisted vaginal vertex delivery

Objective To describe the time interval between decision for assisted vaginal delivery and the birth of the baby in different clinical circumstances.

Should tissue from pregnancy termination and uterine evacuation routinely be examined histologically

Objective To assess the value of routine histological examination of tissue samples collected at termination of pregnancy in the first trimester and emergency surgical uterine evacuation.