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Endometrial cancer has become the most common gynecological cancer in developed countries. Postmenopausal bleeding is indicative of the disease in only 1 of 10 women with this symptom. A noninvasive tool to identify women with cancer would be highly desirable. We analyzed more than 27,000 CpGs in normal endometrial tissue (n = 23) and endometrial cancers (n = 64) and found that DNA methylation of GALR1 is among the most frequent epigenetic alterations in this cancer. We then developed a real-time polymerase chain reaction-based GALR1 methylation test and applied this test to vaginal swabs from 79 women who presented with postmenopausal bleeding. The receiver operating characteristics area under the curve, describing sensitivity and specificity to correctly identify the 41 women with both premalignant and malignant endometrial changes, was 0.93 (95% confidence interval, 0.87-0.97; P < 0.0001).GALR1 DNA methylation is one of the most common molecular alterations in endometrial cancer, and the presence of GALR1 methylation in vaginal swabs from women with postmenopausal bleeding indicates the presence of endometrial malignancy with a sensitivity of 92.7% and a specificity of 78.9%.

Objective: To describe the outcome of primary chemotherapy for women with advanced-stage epithelial ovarian or primary peritoneal cancer and delayed surgery when optimal debulking surgery cannot be achieved at diagnosis., Methods: Between 1998 and 2006, we retrospectively reviewed the overall survival and examined prognostic markers in consecutive patients who were not suitable for initial radical surgery because of the extent of disease and/or poor performance status. They were treated with a policy of primary platinum-based chemotherapy, followed whenever possible in responding patients by debulking surgery., Results: A total of 171 patients received least one cycle of chemotherapy. Eighty-six patients proceeded to surgery and 53 (31% of 171 and 62% of 86) had optimal (<1 cm) residual disease. Eighty-five patients did not undergo surgery because they remained unfit or had not responded sufficiently to chemotherapy. The median overall survival was 18.7 months (95% confidence interval [CI], 16.5-24.2). The median OS in the surgical group for optimal and suboptimal surgery was 40.8 (95% CI, 32.5-50.0) and 22.5 (95% CI, 17.7-37.1) months (P = 0.005). On multivariate analysis, interval surgery and optimal surgery were the only independent prognostic factors (hazard ratios, 0.45 and 0.43, respectively; P = 0.009). In the nonsurgical group, CA125 response was an independent prognostic factor (hazard ratio, 0.34; P = 0.001) with an OS of 21.7 months (95% CI, 14.0-35.4) in women with a normal CA125 after treatment compared with 6.7 (95% CI, 4.5-7.8) months., Conclusions: In one third of the women, the tumor was optimally debulked after primary chemotherapy and their median survival was 40.8 months. Suboptimal debulking surgery after primary chemotherapy did not result in a better survival than that achieved after a chemotherapy response alone, suggesting that surgery may be avoided when imaging after chemotherapy demonstrates residual disease that cannot be optimally debulked.

Background: Participants in trials evaluating preventive interventions such as screening are on average healthier than the general population. To decrease this 'healthy volunteer effect' (HVE) women were randomly invited from population registers to participate in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and not allowed to self refer. This report assesses the extent of the HVE still prevalent in UKCTOCS and considers how certain shortfalls in mortality and incidence can be related to differences in socioeconomic status., Methods: Between 2001 and 2005, 202 638 postmenopausal women joined the trial out of 1 243 312 women randomly invited from local health authority registers. The cohort was flagged for deaths and cancer registrations and mean follow up at censoring was 5.55 years for mortality, and 2.58 years for cancer incidence. Overall and cause-specific Standardised Mortality Ratios (SMRs) and Standardised Incidence Ratios (SIRs) were calculated based on national mortality (2005) and cancer incidence (2006) statistics. The Index of Multiple Deprivation (IMD 2007) was used to assess the link between socioeconomic status and mortality/cancer incidence, and differences between the invited and recruited populations., Results: The SMR for all trial participants was 37%. By subgroup, the SMRs were higher for: younger age groups, extremes of BMI distribution and with each increasing year in trial. There was a clear trend between lower socioeconomic status and increased mortality but less pronounced with incidence. While the invited population had higher mean IMD scores (more deprived) than the national average, those who joined the trial were less deprived., Conclusions: Recruitment to screening trials through invitation from population registers does not prevent a pronounced HVE on mortality. The impact on cancer incidence is much smaller. Similar shortfalls can be expected in other screening RCTs and it maybe prudent to use the various mortality and incidence rates presented as guides for calculating event rates and power in RCTs involving women.

Background: The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort., Methods: We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978., Findings: 48,230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5·11 years (IQR 4·05-5·95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5·15 mm, with sensitivity of 80·5% (95% CI 72·7-86·8) and specificity of 86·2% (85·8-86·6). Sensitivity and specificity at a 5 mm or greater cutoff were 80·5% (72·7-86·8) and 85·7% (85·4-86·2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85·3% (78·2-90·8) and 80·4% (80·0-80·8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54·1% (45·3-62·8) and 97·2% (97·0-97·4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77·1% (67·8-84·3) and specificity of 85·8% (85·7-85·9). The logistic regression model identified 25% of the population as at high risk and 39·5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6·75 mm achieved sensitivity of 84·3% (71·4-93·0) and specificity of 89·9% (89·3-90·5)., Interpretation: Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Hypothesis: Higher risk of malignancy index (RMI) with multidisciplinary approach will reduce the number of referrals of ovarian masses, thus reducing the stress for patients and workload at the cancer center., Methods: Prospective observational study in which all patients with pelvic masses and an RMI lower than 450 were treated at the local hospital after discussion at multidisciplinary input. Patients with an RMI higher than 450 were referred to tertiary cancer centers. Records of multidisciplinary meetings, operative details, and histologic examination results were evaluated. Data were analyzed to calculate the predictive values and the sensitivity of this approach., Results: If the RMI cutoff of 450 alone is considered, 1 woman with invasive cancer would not have been referred. The sensitivity for invasive epithelial ovarian cancer was 96.2% or 25 of 26 patients (95% confidence interval [CI], 80.4-99.9) with a positive predictive value of 96.3% or 26 of 27 patients (95% CI, 81.0-99.9). The specificity was 98.7% or 77 of 78 patients (95% CI, 93.1-100.0). The negative predictive value was 98.7% or 76 of 77 patients (95% CI, 93.0-100.0)., Conclusions: A higher RMI with multidisciplinary approach to refer patients with pelvic masses has the potential to reduce the numbers of benign cases, thus reducing stress for patients and reducing workload at centers.

Cervical cancer is the second most common type of cancer in women worldwide. Preinvasive disease can be detected by cervical cytology. All currently available cytology technologies rely on the visual analysis of exfoliated cells from the uterine cervix. Improvement of conventional cytological screening has been proposed by the introduction of molecular-based markers applied to liquid-based cytology (LBC), the suspension of cells collected from the cervix. DNA methylation changes occur very early in carcinogenesis and identification of appropriate DNA methylation markers in such samples should be able to distinguish high-grade squamous intraepithelial lesions (HSIL) from nonspecific cytology changes and the normal cervix. To address this potential, we have undertaken a proof-of-principle study of methylation status of LBC samples from HSIL cytology cases compared against matched normal controls. Using quantitative methylation-specific PCR on 28 genes, we found SOX1, HOXA11 and CADM1 to significantly discriminate between the groups analyzed (p<0.01). Area under the receiver operating characteristic (ROC) curve (AUC) demonstrated that methylation of SOX1, HOXA11 and CADM1 could discriminate between HSIL cases and controls with high sensitivity and specificity (AUC 0.910, 0.844 and 0.760, respectively). The results were further validated in an independent set. This proof-of-principle study is the first to validate the results in an independent case/control set and presents HOXA11, a gene that is important for cervical development, as a potentially useful DNA marker in LBC samples. Further assessment of these preliminary estimates will need to be performed in a larger cohort to confirm clinical utility., (Copyright (c) 2009 UICC.)

Background: Ovarian cancer has a high case-fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS., Methods: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50-74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032., Findings: In the prevalence screen, 50 078 (98.9%) women underwent MMS, and 48 230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1894 (3.9%) women in the USS group required clinical evaluation. 97 of 50 078 (0.2%) women from the MMS group and 845 of 48 230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0-61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers., Interpretation: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.

Primary ovarian carcinoid tumours of the ovary are rare and represent less than 0.1% of ovarian malignancy. The evidence to guide treatment and prognosis of these tumours is limited. We report a case of primary ovarian mucinous carcinoid tumour, of the atypical category, in a 34-year-old nulliparous woman. Only three such cases have previously been reported. At four years from presentation, she has no signs of metastatic disease, despite delayed primary surgery and then initial conservative management. At present surgical excision with close follow-up appears to be the management of choice. This case adds to the body of evidence and demonstrates a possible good prognosis with non-aggressive behaviour in the atypical mucinous carcinoid group.

To evaluate the feasibility of total laparoscopic hysterectomy as the primary treatment for endometrial cancer in morbidly obese women, an audit was carried out during an 18-month period in a tertiary referral centre for gynaecological oncology. Four women who had laparoscopic surgery were compared with a similar cohort who had open surgery. The mean operating time was equivalent, without evidence of excess morbidity with the laparoscopic approach. However, inpatient stay was longer with open versus laparoscopic surgery (11.5 vs 4 days). Laparoscopic surgery is safe to use in morbidly obese women with endometrial cancer.

The recurrence and fertility rates in 30 women undergoing radical trachelectomy for early stage invasive cervical cancer at St Bartholomew's and Royal Marsden Hospital were reviewed. There were no recurrences, and the mean follow up was 23 months (range 1-64 months). Of 13 women trying to have a baby, eight had conceived with a total of 14 pregnancies and nine live births. Two were still trying and three were experiencing sub-fertility. There were seven premature deliveries and one late miscarriage. Six of the preterm births and the late miscarriage were associated with prelabour spontaneous rupture of membranes. This conservative yet locally radical procedure for a highly selected group of women who wished to preserve their fertility appears to offer a safe alternative to radical hysterectomy in early invasive cervical cancer.

Scleroderma (progressive systemic sclerosis) is a systemic autoimmune disorder characterised by skin sclerosis, calcinosis and changes in microvasculature. The etiology of the disease is unknown but both genetic and environmental factors have been implicated. Telangiectasia (macroscopically visible dilated skin vessels) occurring primarily on the hands and face, are a prominent feature in scleroderma and are present in the majority of patients. Similarly, telangiectasia are found in patients with hereditary hemorrhagic telangiectasia (HHT), a mutational disorder of the germline genes endoglin and ALK-1, members of the TGFbeta receptor family, expressed on endothelial cells. Our study investigated the number, distribution and microscopic characteristics of telangiectasia in both limited (n = 29) and diffuse scleroderma (n = 9) and compared findings with 3 patients with HHT. In limited scleroderma, the mean number of telangiectasia (hand and face) was 36 (0-150) compared with 23 (0-135) in diffuse scieroderma. A significant correlation was observed between the number of telangiectasia on the face and on the hands (p = 0.014). The total number of telangiectasia correlated significantly with the disease duration (p = 0.009). The spatial distribution of the telangiectasia appeared to be random on both hands and foreface in contrast with the distribution of subcutaneous calcification of the hands which occurred predominantly on the distal and flexor surfaces of the first, second and fifth digits. Nailfold microscopic capillaroscopy was performed on 12 patients. No significant correlation was observed between capillary diameter or density and with total number of telangiectasia observed macroscopically. The distribution and microscopic appearance of telangiectasia in scleroderma appeared very similar to those observed in HHT. In view of these similarities we therefore conclude that telangiectactic development in scleroderma may be associated with disorders of the TGFb receptor family proteins found on the microvasculature.

Objective: To evaluate six years experience using cervicography to triage women with borderline or mildly dyskaryotic PAP smears to either immediate colposcopy or cytological surveillance., Method: Retrospective study of 1,436 women referred to the cervicography clinic of the Whittington Hospital, London. Women with suspicious cervigrams were examined colposcopically and biopsied. Women with normal appearances at cervicography were followed-up with cytology over a period of a least two years., Results: Cervicography detected 281 out of 307 women with CIN 2/3 and 215 out of 264 women with CIN 1. The sensitivity of cervicography to detect CIN 1, 2 or 3 in women with minor PAP smear abnormalities was 92%. The specificity was 39% and 847 (59%) of the women were referred for colposcopy; 215 (15%) were lost to follow-up., Conclusions: Cervicography was a sensitive method to detect CIN in women with mild or borderline dyskaryosis on their PAP smears. However, the low specificity meant that a high proportion of the women were referred for colposcopy, and a significant proportion of women were lost to follow-up. Thus cervicography is not an efficient strategy for managing women with minor PAP smears abnormalities.

Objective: To investigate the use of hybrid capture to triage borderline and mildly abnormal PAP smears to either colposcopy or continued cytological surveillance., Method: A prospective cross-sectional study of 207 women with either mild or borderline dyskaryosis referred to the colposcopy clinic at the Whittington Hospital, London was done. Quantitative detection of oncogenic human papillomavirus deoxyribose nucleic acid was performed using the solution hybridization technique Hybrid Capture I (Digene Diagnostics). Positive or negative hybrid capture results were compared to colposcopically directed punch biopsy or loop excision of the transformation zone., Results: Hybrid capture correctly predicted 1/1 micro-invasive cancers, 23/24 CIN 3 and 20/24 CIN 2, giving a sensitivity to detect significant disease of CIN 2 or above of 90%. For CIN 1, 37/66 were HPV positive making the sensitivity to detect all grades of CIN 70%. Of women with a normal cervix, 39/92 were HPV positive and in total 58% of the women were HPV positive and would have been referred to colposcopy., Conclusions: Hybrid capture was a simple solution hybridization method which provided a sensitive method of detecting CIN 2 and above lesions in women with minor PAP smear abnormalities. However, the sensitivity for CIN 1 and the specificity were low, meaning that further improvements in the technique are needed before it can be used as a triage strategy.

The Polarprobe is a portable non invasive electronic device designed for the detection of cervical precancer and cancer. It measures both electrical and optical properties of cervical tissue to allow a real time comparison with a databank of previously determined cervical tissue types. The need for additional tests to augment or even replace the Papanicolaou smear has partly prompted its development. Indeed it has been shown to be associated with less pain and anxiety than the smear and has the capability of encouraging women to attend for screening. Some of the preliminary clinical trials on the Polarprobe are reported as well as the ongoing developments and modifications to the device.

We have investigated the expression of the aspartic proteinase cathepsin E and HLA-DR and the presence of HPV16 in normal squamous epithelium (n = 8) and low-grade (n = 21) and high-grade (n = 14) intraepithelial squamous lesions of the uterine cervix. Immunohistochemistry of cervical biopsies revealed that up-regulation of cathepsin E expression was related to increasing severity of the cervical intraepithelial neoplasia (CIN). Up-regulation of protein was associated with increased message as assessed by in situ hybridization. Langerhans cells and the majority of koilocytes did not express detectable cathepsin E levels. Although there was also an up-regulation of HLA-DR expression by cervical keratinocytes in cervical intraepithelial neoplasia lesions, as determined by immunohistochemistry, no significant correlation was found between HLA-DR and cathepsin E expression in these lesions; neither was expression of cathepsin E correlated to the presence of HPV16, detected by polymerase chain reaction. The expression of cathepsin E, an aspartic proteinase that is reported to play a role in antigen processing for presentation by class II major histocompatibility complex molecules, is associated with cellular dedifferentiation in cervical intraepithelial neoplasia.

Objective: To assess the extent to which women contribute to the decision for caesarean section and their satisfaction with the decision and procedure., Design: Observational study of women undergoing caesarean section who were interviewed using a standard proforma., Setting: University College Hospital, London., Participants: One hundred and two consecutive women undergoing caesarean section., Results: The women's perceived reason for the caesarean section agreed with the doctors' reason in 91 cases (89.2%). Only 2/29 women having elective sections stated they had no contribution, compared with 22/73 women having emergency sections (P = 0.018, two-tailed Fisher's exact test). Twenty out of 29 women (69%) having elective procedures and 37/73 women (51%) having emergency sections recorded medium or more contribution. All women except one were 50% or more satisfied with the decision. Women's satisfaction with the operation was high in the immediate post-operative period and remained so over the following six weeks. Forty-three women (49%) said they would prefer an elective section in the next pregnancy given the choice., Conclusions: Women undergoing caesarean section were well informed and took a considerable part in the decision-making process. This suggests that women's wishes may be playing a role in increasing caesarean section rates. High levels of satisfaction with both the decision and the procedure itself indicate that caesarean section is an acceptable method of delivery, particularly when an elective procedure.

We have assessed the extent to which hospital records follow the Guidelines for Medical Records and Notes published by the Royal College of Surgeons of England. Notes of 100 consecutive discharges were reviewed from two surgical units, one at a District General Hospital (DGH) and the other at a London Teaching Hospital (TH). Overall, only 65 per cent (DGH) and 67 per cent (TH) of the entries specified by College guidelines were both present and correct. Substandard categories included the regular update of notes, post-operative instructions, comments about post-operative recovery, the record of advice given to relatives and incorrect consent. The guidelines produced by the Royal College of Surgeons are being applied, but there is room for considerable improvement. Inadequate medical records limit audit and may have medico-legal consequences. We recommend regular assessment of the standard of note keeping.