Factors influencing uptake and timing of risk reducing salpingo-oophorectomy in women at risk of familial ovarian cancer: a competing risk time to event analysis.

OBJECTIVE: To evaluate factors affecting uptake of risk-reducing salpingo-oophorectomy (RRSO) over time in women at high-risk of familial ovarian cancer. DESIGN: Prospective observational cohort. SETTING: Tertiary high-risk familial gynaecological cancer clinic. POPULATION/SAMPLE: New clinic attendees between March 2004 and November 2009, fulfilling the high-risk criteria for the UK Familial Ovarian Cancer Screening Study. METHODS: Risk management options discussed included RRSO and ovarian surveillance. Outcome data were analysed from a bespoke database. The competing risk method was used to model the cumulative incidence function (CIF) of RRSO over time, and the sub-hazard ratio (SHR) was used to assess the strength of the association of variables of interest with RRSO. Gray's test was used to evaluate the difference in CIF between two groups and multivariable competing risk regression analysis was used to model the cumulative probabilities of covariates on the CIF. RESULTS: Of 1133 eligible women, 265 (21.4%) opted for RRSO and 868 (69.9%) chose screening. Women undergoing RRSO were older (49 years, interquartile range 12.2 years) than those preferring screening (43.4 years, interquartile range 11.9 years) (P < 0.0005). The CIF for RRSO at 5 years was 0.55 (95% CI 0.45-0.64) for BRCA1/2 carriers and 0.22 (95% CI 0.19-0.26) for women of unknown mutation status (P < 0.0001); 0.42 (95% CI 0.36-0.47) for postmenopausal women (P < 0.0001); 0.29 (95% CI 0.25-0.33) for parity ≥1 (P = 0.009) and 0.47 (95% CI 0.39-0.55) for a personal history of breast cancer (P < 0.0001). Variables of significance from the regression analysis were: a BRCA1/2 mutation (SHR 2.31, 95% CI 1.7-3.14), postmenopausal status (SHR 2.16, 95% CI 1.62-2.87)) and a personal history of breast cancer (SHR 1.5, 95% CI 1.09-2.06). CONCLUSIONS: Decision-making is a complex process and women opt for surgery many years after initial risk assessment. BRCA carriers, postmenopausal women and women who had breast cancer are significantly more likely to opt for preventative surgery.

Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-detected ovarian masses: a prospective cohort study within the UK collaborative trial of ovarian cancer screening (UKCTOCS).

OBJECTIVE: To estimate the risk of primary epithelial ovarian cancer (EOC) and slow growing borderline or Type I and aggressive Type II EOC in postmenopausal women with adnexal abnormalities on ultrasound. METHODS: This was a prospective cohort study in the ultrasound group of the UK Collaborative Trial of Ovarian Cancer Screening of postmenopausal women with ultrasound-detected abnormal adnexal (unilocular, multilocular, unilocular solid and multilocular solid, solid) morphology on their first scan. Women were followed up through the national cancer registries and by postal questionnaires. Absolute risks of EOC and borderline, Type I and Type II EOC within 3 years of initial scan were calculated. RESULTS: Of 48 053 women who underwent ultrasound examination and had complete scan data, 4367 (9.1% (95% CI, 8.8-9.3%)) had abnormal adnexal morphology. Median follow-up was 7.09 (25(th) -75(th) centiles, 6.03-7.92) years. Forty-seven (32 borderline or Type I, 15 Type II) were diagnosed with EOC. The overall absolute risk of EOC associated with abnormal adnexal morphology was 1.08% (95% CI, 0.79-1.43%); for borderline and Type I it was 0.73% (95% CI, 0.5-1.03%); and for Type II it was 0.34% (95% CI, 0.33-0.79%). In the subgroup (n = 741) with solid elements (unilocular solid, multilocular solid and solid) overall absolute risk was 4.45% (95% CI, 3.08-6.20%), for borderline and Type I it was 3.1% (95% CI, 1.9-4.6%) and for Type II it was 1.3% (95% CI, 0.6-2.4%). 11 982 women had both ovaries visualized and normal annual scans throughout the 3-year follow-up period. In this group, no borderline or Type I and eight Type II cancers were diagnosed. CONCLUSION: Asymptomatic postmenopausal women with ultrasound-detected adnexal abnormalities with solid elements have a 1 in 22 risk for EOC. Despite the higher prevalence of Type II EOC, the risk of borderline or Type I cancer in women with ultrasound abnormalities seems to be higher than does the risk of Type II cancer. This has important immediate implications for patients with incidental adnexal findings as well as for any future ultrasound-based screening.

Nitrogen management is essential to prevent tropical oil palm plantations from causing ground-level ozone pollution.

More than half the world's rainforest has been lost to agriculture since the Industrial Revolution. Among the most widespread tropical crops is oil palm (Elaeis guineensis): global production now exceeds 35 million tonnes per year. In Malaysia, for example, 13% of land area is now oil palm plantation, compared with 1% in 1974. There are enormous pressures to increase palm oil production for food, domestic products, and, especially, biofuels. Greater use of palm oil for biofuel production is predicated on the assumption that palm oil is an "environmentally friendly" fuel feedstock. Here we show, using measurements and models, that oil palm plantations in Malaysia directly emit more oxides of nitrogen and volatile organic compounds than rainforest. These compounds lead to the production of ground-level ozone (O(3)), an air pollutant that damages human health, plants, and materials, reduces crop productivity, and has effects on the Earth's climate. Our measurements show that, at present, O(3) concentrations do not differ significantly over rainforest and adjacent oil palm plantation landscapes. However, our model calculations predict that if concentrations of oxides of nitrogen in Borneo are allowed to reach those currently seen over rural North America and Europe, ground-level O(3) concentrations will reach 100 parts per billion (10(9)) volume (ppbv) and exceed levels known to be harmful to human health. Our study provides an early warning of the urgent need to develop policies that manage nitrogen emissions if the detrimental effects of palm oil production on air quality and climate are to be avoided.

Outcome of risk-reducing salpingo-oophorectomy in BRCA carriers and women of unknown mutation status.

OBJECTIVE: To compare surgical outcomes and occult cancer rates at risk-reducing salpingo-oophorectomy in BRCA carriers and high-risk women who had not undergone genetic testing. DESIGN: Prospective cohort study. SETTING: Tertiary high-risk familial gynaecological cancer clinic. POPULATION: Women undergoing risk-reducing salpingo-oophorectomy between January 2005 and November 2009. METHODS: Women at high-risk of ovarian/tubal cancer were identified on the basis of the inclusion criteria for the UK Familial Ovarian Cancer Screening Study. Risk management options discussed with 1456 high-risk women included risk-reducing salpingo-oophorectomy. A strict histopathological protocol with serial slicing was used to assess tubes and ovaries. RESULTS: In total, 308 high-risk women (191 with unknown mutation status; 117 known BRCA1/BRCA2 carriers) chose risk-reducing surgery; 94.5% of procedures were performed laparoscopically. The surgical complication rate was 3.9% (95% CI 2.0-6.7). Four ovarian and ten tubal occult invasive/in situ cancers were found. The overall occult invasive cancer rate was 5.1% (95% CI 1.9-10.83) in BRCA1/BRCA2 carriers and 1.05% (95% CI 0.13-3.73) in untested women. When tubal in situ cancers were included, the overall rate was 4.55% (95% CI 2.5-7.5). Two untested women with tubal carcinoma in situ were subsequently found to be BRCA carriers. The median ages of BRCA carriers (58 years; IQR 13.4 years) and untested women (49.5 years; IQR 20.6 years) with occult invasive/in situ cancer were not significantly different (P = 0.454). CONCLUSIONS: Both high-risk women of unknown mutation status and BRCA carriers have a significant (although higher in the latter group) rate of occult invasive/in situ tubal/ovarian cancer, with a similar age distribution at detection. The data has important implications for counselling high-risk women on the likelihood of occult malignancy and perioperative complications at risk-reducing salpingo-oophorectomy. Women with occult disease should be offered genetic testing.

Defining the surgical management of suspected early-stage ovarian cancer by estimating patient numbers through alternative management strategies.

OBJECTIVE: To establish the optimal management strategy for women with suspected stage 1 ovarian cancer. DESIGN: We created a flowchart to illustrate each of six hypothetical management strategies. These considered two surgical approaches (systematic lymphadenectomy versus no lymph node dissection at all) in combination with three different policies for giving adjuvant chemotherapy. SETTING: Gynaecological cancer centre, London, UK. DATA SOURCES: Patient data and published papers. METHODS: We developed a deterministic model that uses information from multiple sources to estimate patient flow through each level of a hypothesised decision tree. RESULTS: We estimated that for every 100 cases of suspected early-stage ovarian cancer, there would be 37 cases with 'apparent' stage 1 disease and that of these, two (6%) would be denied potentially life-saving adjuvant treatment if systematic lymphadenectomy was not performed. The number of women given chemotherapy would not, according to our estimates, differ greatly between the two surgical approaches, the 7% increase with systematic lymphadenectomy being because of cases identified as having nodal metastases. CONCLUSIONS: We present a model of the intraoperative decision-making process that determines the extent of the staging procedure to be performed within our department when early-stage ovarian cancer is suspected. Unless adjuvant chemotherapy is prescribed for all, systematic pelvic and para-aortic node dissection is required to optimise survival. However, in our department, this would result in 32% of women with suspected early-stage ovarian cancer undergoing systematic node dissection. This flexible focused model may facilitate multidisciplinary team discussion when this part of the surgical staging procedure is considered within the context of the population presenting to the team, the morbidity of the procedure within the department and the predictive values of frozen section within that department. As the model is not disease-specific, it may be useful for decision making in other medical disciplines.

Vulval cancer: what is an adequate surgical margin?

OBJECTIVE: To determine the accuracy of naked eye assessment of surgical margins after formalin fixation in vulval cancer in comparison with microscopic assessment. DESIGN: Retrospective review. SETTING: The Gynaecological Cancer Centre, St Bartholomew's Hospital, London, U.K. POPULATION: Patients with primary vulval cancer who underwent surgery from 1997 to 2006. METHODS: Histopathology reports were reviewed and data on surgical margins were analysed. After formalin fixation, pathologists analysed surgical margins and measured them with a ruler. This measurement was compared with microscopic measurement. Other clinicopathologic variables were also recorded and compared. MAIN OUTCOME MEASURE: Comparison between macroscopic and microscopic measurement, and the relation to clinicopathological variables. RESULTS: Naked eye assessment of surgical margins was within 2 mm of correlated microscopic measurement in 29 patients (Group 1). In ten patients the macroscopic measurement of clear margins was less than the microscopic (Group 2). In the remaining 11 cases (22%) naked eye observation overestimated the normal skin margins (Group 3). Seven patients from this group eventually fell into the unfavourable prognostic category of surgical margins <8 mm. The presence of LVSI was significantly more frequent in Group 3 than in the other two groups (p = 0.01). The difference between other variables of the study groups was statistically non-significant. CONCLUSION: Our study demonstrates that naked eye assessment of surgical margins after formalin fixation is inaccurate and that surgical margins are often inadequate. We conclude that tumours with LVSI should be considered for a wider surgical excision.

Elevation of multiple serum markers in patients with stage I ovarian cancer.

BACKGROUND: The high overall mortality from ovarian cancer (> 60%) relates, in part, to delays in diagnosis. When ovarian cancer is detected in stage I (International Federation of Gynecology and Obstetrics staging), up to 90% of patients can be cured. Transvaginal sonography can detect early-stage disease with great sensitivity, but it is expensive and lacks specificity. Although serum marker assays could provide a less expensive and more convenient initial screening test, the sensitivity of assays varies. Measurement of serum CA 125 in conjunction with ultrasound screening as a second-line test confers high specificity but detects only about one half of early stage ovarian carcinomas. PURPOSE: The purpose of this retrospective study was to determine whether assays of multiple serum markers would improve sensitivity by detecting a higher percentage of stage I ovarian cancers than the CA 125 assay alone. METHODS: Using immunoradiometric assays, we measured preoperative serum levels of CA 125 tumor-associated antigen, macrophage colony-stimulating factor (M-CSF), and OVX1 in 46 patients with stage I ovarian cancer of different histologies and 237 patients with benign pelvic masses. We also assayed sera from 204 apparently healthy women who had participated in a screening trial and remained free from cancer at 1 year of followup. All specimens were obtained from cryopreserved aliquots. Marker levels were considered to be elevated when levels of CA 125 were greater than 30 U/mL, M-CSF levels were greater than 3.1 ng/mL, or OVX1 levels were greater than 12.1 U/mL. RESULTS: At least one of the serum markers was elevated in 98% of patients with stage I ovarian cancer; CA 125 levels were elevated in 67%. By the same criteria, 11% of healthy individuals and 51% of patients with benign pelvic masses had at least one elevated marker value. Thus, the sensitivity of the combination of assays for the three serum markers was significantly greater than the sensitivity of the CA 125 assay (P < .0005) and specificity was moderate. CONCLUSION: A panel of these three tumor markers can identify early-stage ovarian cancer with extremely high sensitivity and moderate specificity. IMPLICATIONS: Elevation of one or more serum markers should be evaluated further as an indication for transvaginal sonography in apparently healthy women. Such a strategy might substantially reduce the expense and improve the specificity of screening compared to the use of ultrasound alone. Prospective studies with a large cohort of patients at high risk for ovarian cancer will be required to confirm these findings.

Strategies for improving the specificity of screening for ovarian cancer with tumor-associated antigens CA 125, CA 15-3, and TAG 72.3.

OBJECTIVE: To assess different strategies for improving the specificity of screening for ovarian cancer with tumor-associated antigens, including concomitant measurement of multiple tumor markers and serial measurement of CA 125. METHODS: A combination of CA 125, CA 15-3, and TAG 72.3 was evaluated in serum samples from 217 of 1010 apparently healthy postmenopausal women who had participated in a study of screening for ovarian cancer and who had a serum CA 125 level of 20 U/mL or greater. In addition, serial serum CA 125 levels were determined in 30 women with an initially elevated CA 125 level (30 U/mL or more) and 30 women with a CA 125 level less than 30 U/mL. RESULTS: The specificity of CA 125 at upper limits of 30 and 50 U/mL was increased from 97.0 and 99.5%, respectively, to 98.9 and 99.9% when a positive test was defined as an elevated serum CA 125 level in combination with either a CA 15-3 greater than 30 U/mL or a TAG 72.3 greater than 10 U/mL. Definition of a positive result as a serum CA 125 level greater than 50 U/mL at the initial test and greater than 30 U/mL at 3-month follow-up achieved a specificity of 99.6%. CONCLUSION: Levels of specificity suitable for screening asymptomatic postmenopausal women can be achieved using tumor-associated antigens measured serially or in combination. Further studies are required to determine the sensitivity of these strategies for preclinical ovarian cancer.

Screening for ovarian cancer.

Whilst the majority of patients with ovarian cancer present with advanced stage disease and have a poor prognosis, the outlook for women with stage I disease is relatively good. An effective screening test for early stage ovarian cancer may therefore result in a significant improvement in ovarian cancer statistics. Extremely high specificity is an essential requirement of any potential screening test in view of the need for surgical investigation of women with a positive test result. No single test has yet demonstrated sufficient specificity when used alone to screen apparently healthy postmenopausal women. A multimodal approach incorporating serum CA-125 measurement, pelvic examination and real time ultrasonography has achieved high levels of specificity. The sensitivity of this screening programme for early stage ovarian cancer is currently under investigation.

What is the true incidence of primary fallopian tube carcinoma?

Fallopian tube carcinoma can be histologically indistinguishable from and has a similar clinical behavior to epithelial ovarian carcinoma. However, it is considerably less common; only approximately 1000 cases have been recorded in the literature. In the prevalence screen of 22000 women participating in The Royal London Hospital, London, UK, ovarian cancer screening project, three cases of early stage primary fallopian tube carcinoma were diagnosed following the finding of an elevated serum level of the CA 125 antigen. The ratio of epithelial ovarian : tubal cancer developing in these postmenopausal volunteers was 6:1. This is 25-fold greater than the expected ratio. It is difficult to attribute this finding to population selection bias. However, it is possible that the screening test was particularly effective in detecting tubal carcinoma or that, in clinical practice, the true primary site of origin of some tumors classified as widely disseminated ovarian cancer is in the fallopian tube.

Ovarian cancer identified through screening with serum markers but not by pelvic imaging.

Woolas RP, Oram DH, Jeyarajah AR, Bast RC Jr, Jacobs IJ. Ovarian cancer identified through screening with serum markers but not by pelvic imaging. This study evaluated the possible role of 3 additional tumor markers to CA 125 among postmenopausal volunteers participating in a sequential multimodal ovarian cancer screening study. In 82 asymptomatic women the finding of a serum CA 125 level of > 30 U/ml precipitated pelvic ultrasound examination. Levels of CA15-3, CA72-4 and CA19-9 were subsequently determined in sera stored from the time of the CA 125 assay. Following ultrasound 29 women underwent surgery for benign conditions. The remaining 53 women underwent 2 years of surveillance. In 5 of these women a diagnosis of ovarian cancer was established between 6 and 10 months after their initial investigation. Elevated levels of at least one of the 3 additional tumor markers were present in the serum, prior to ultrasound abnormalities being detected, in 4 (80%) of the women who developed cancer. At least one of this 3-marker panel was elevated in 29% of the 48 women who have not developed cancer and 14% of the 29 women undergoing surgery for benign conditions. Information complementary to pelvic ultrasound examination for the preclinical detection of ovarian cancer could be obtained through multiple marker assay. Coordinated elevated serum levels of tumor markers could increase the sensitivity of this sequential screening protocol.

Modern antiretroviral therapy improves life expectancy of gay and bisexual males in Vancouver's West End.

This study was undertaken to evaluate the life expectancy of gay and bisexual men in the West End of Vancouver, British Columbia during two time periods. Mortality data for males were obtained for the periods 1990 to 1992 and 1995 to 1997 and population estimates were obtained from the 1991 and 1996 Census. The proportion of the male population over 20 years of age estimated to be gay and bisexual was derived from a random telephone survey. Mortality patterns were assessed by comparing changes in life expectancy at age 20 years between the periods, and by examining the life expectancy lost attributed to HIV/AIDS. Between the periods there was 3.8 +/- 3.4 years increase in life expectancy among gay and bisexual men. At exact age 20 years, life expectancy increased from 37.0 +/- 3.5 years during the period 1990 to 1992 to 40.8 +/- 2.4 years during the period 1995 to 1997. The loss of life expectancy attributed to HIV/AIDS at this age was 13.8 +/- 3.9 during the first period and 9.8 +/- 3.6 years during the second period. This gain is most likely the result of the improved efficacy of antiretroviral therapies.

A survey of current practice into the use of aesthetic inlays.

In recent years there has been a concerted effort to produce an aesthetic restoration to replace amalgam, while retaining its qualities of strength and longevity. The use of porcelains and composite resins used indirectly as inlays and onlays has today improved the qualities of directly filled composites. A survey of 310 general dental practitioners in the UK known to use this type of restoration produced 162 responses to a questionnaire to evaluate their experiences to these techniques. The majority, 85%, had used a composite inlay system for about 2 years, with a 90% success rate over this period. Information collected provided details on variations in cavity design and cementing procedures.

Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study.

OBJECTIVE: To determine the risk of invasive epithelial ovarian cancer and fallopian tube cancer associated with a raised concentration of the tumour marker CA 125 in asymptomatic postmenopausal women. DESIGN: Serum CA 125 concentration was measured annually in study participants for one to four years. Participants with a concentration > or = 30 U/ml were recalled for abdominal ultrasonography. Follow up was by annual postal questionnaire. SETTING: General practice, occupational health departments, ovarian cancer screening unit in a teaching hospital. SUBJECTS: 22,000 volunteers, all postmenopausal women > or = 45 years of age; recruited between 1 June 1986 and 1 May 1990. INTERVENTION: Surgical investigation if the ultrasound examination was abnormal. MAIN OUTCOME MEASURES: Cumulative and relative risk of developing an index cancer (invasive epithelial cancer of the ovary or fallopian tube) after a specified CA 125 result. RESULTS: 49 index cancers developed in the study population during a mean follow up of 6.76 years. The overall cumulative risk of developing an index cancer was 0.0022 for the entire study population and was lower for women with a serum CA 125 concentration < 30 U/ml (cumulative risk 0.0012) but was appreciably increased for women with a concentration > or = 30 U/ml (0.030) and > 100 U/ml (0.149). Compared with the entire study population the relative risk of developing an index cancer within one year and five years was increased 35.9-fold (95% confidence interval 18.3 to 70.4) and 14.3-fold (8.5 to 24.3) respectively after a serum CA 125 concentration > or = 30 U/ml and 204.8-fold (79.0 to 530.7) and 74.5-fold (31.1 to 178.3) respectively after a concentration > or = 100 U/ml. CONCLUSION: CA 125 is a powerful index of risk of ovarian and fallopian tube cancer in asymptomatic postmenopausal women.

Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography.

OBJECTIVE: To assess the performance of the sequential combination of serum CA 125 measurement and ultrasonography in screening for ovarian cancer. DESIGN: The serum CA 125 concentration of each subject was determined and those with a concentration > or = 30 U/ml were recalled for abdominal ultrasonography. If ultrasonography gave abnormal results surgical investigation was arranged. Volunteers were followed up by annual postal questionnaire. SETTING: General practice, occupational health departments, ovarian cancer screening clinic. SUBJECTS: 22,000 women volunteers who were postmenopausal and aged over 45 years. MAIN OUTCOME MEASURES: Apparent sensitivity, specificity, positive predictive value, years of cancer detected. RESULTS: 41 women had a positive screening result and were investigated surgically. 11 had ovarian cancer (true positive result) and 30 had other disorders or no abnormality (false positive result). Of the 21,959 volunteers with a negative screening result, eight subsequently presented clinically with ovarian cancer (false negative result) and 21,951 had not developed ovarian cancer during follow up (apparent true negative result). The screening protocol achieved a specificity of 99.9%, a positive predictive value of 26.8%, and an apparent sensitivity of 78.6% and 57.9% at one year and two year follow up respectively. The estimated number of years of cancer detected by the prevalence screen was 1.4 years. CONCLUSIONS: This screening protocol is highly specific for ovarian cancer and can detect a substantial proportion of cases at a preclinical stage. Further investigation is required to determine the effect of the screening protocol on the ratio of early to late stage disease detected and on mortality from ovarian cancer.

The impact of local surface changes in Borneo on atmospheric composition at wider spatial scales: coastal processes, land-use change and air quality.

We present results from the OP3 campaign in Sabah during 2008 that allow us to study the impact of local emission changes over Borneo on atmospheric composition at the regional and wider scale. OP3 constituent data provide an important constraint on model performance. Treatment of boundary layer processes is highlighted as an important area of model uncertainty. Model studies of land-use change confirm earlier work, indicating that further changes to intensive oil palm agriculture in South East Asia, and the tropics in general, could have important impacts on air quality, with the biggest factor being the concomitant changes in NO(x) emissions. With the model scenarios used here, local increases in ozone of around 50 per cent could occur. We also report measurements of short-lived brominated compounds around Sabah suggesting that oceanic (and, especially, coastal) emission sources dominate locally. The concentration of bromine in short-lived halocarbons measured at the surface during OP3 amounted to about 7 ppt, setting an upper limit on the amount of these species that can reach the lower stratosphere.