Association of adult attachment with delays in accessing specialist care in women with ovarian cancer.

OBJECTIVE: Advanced stage at diagnosis and delayed presentation are common in ovarian cancer (OC). The objective of the current study was to explore the association of adult attachment pattern with delays in accessing specialist oncology care in patients with OC. METHODS: A cross-sectional structured interview study of patients with OC presenting to an Indian cancer center was undertaken. Consenting patients completed Experiences of Close Relationships-Relationship Style questionnaire (ECR-RS) and Medical Outcome Survey-Social Support Survey (MOS-SSS). Multivariate linear regression with "time to presentation to cancer specialist" as the dependent variable was undertaken. RESULTS: In all, 132 of 155 (85%) patients with OC who were invited were interviewed. An increased ECR-RS attachment anxiety score (P = .01) and being part of a multigenerational extended household (P = .04) were both independently associated with delay in presentation to a cancer specialist. There was no association between delay in presentation and social support. CONCLUSIONS: Among patients with OC, adult attachment may contribute to delays in presentation. It may be important for the cancer symptom awareness efforts in primary care to include educating physicians on recognizing and interacting with patients with insecure attachment styles. The association of delays in presentation for women with OC living in multigenerational extended households needs more indepth exploration.Supplemental data for this article is available online at https://doi.org/10.1080/07347332.2022.2025510 .

Attitudes towards a programme of risk assessment and stratified management for ovarian cancer: a focus group study of UK South Asians' perspectives.

OBJECTIVE: Population-based risk assessment, using genetic testing and the provision of appropriate risk management, could lead to prevention, early detection and improved clinical management of ovarian cancer (OC). Previous research with mostly white British participants found positive attitudes towards such a programme. The current study aimed to explore the attitudes of South Asian (SA) women and men in the UK with the aim of identifying how best to implement such a programme to minimise distress and maximise uptake. DESIGN: Semistructured qualitative focus group discussions. SETTING: Community centres across North London and Luton. PARTICIPANTS: 49 women and 13 men who identified as SA (Indian, Pakistani or Bangladeshi), which constitutes the largest non-European ethnic minority group in the UK. METHODS: Seven community-based focus groups were held. Group discussions were transcribed verbatim, coded and analysed thematically. RESULTS: Awareness and knowledge of OC symptoms and specific risk factors was low. The programme was acceptable to most participants and attitudes to it were generally positive. Participants' main concerns related to receiving a high-risk result following the genetic test. Younger women may be more cautious of genetic testing, screening or risk-reducing surgery due to the importance of marriage and childbearing in their SA cultures. CONCLUSIONS: A crucial first step to enable implementation of population-based genetic risk assessment and management in OC is to raise awareness of OC within SA communities. It will be important to engage with the SA community early on in programme implementation to address their specific concerns and to ensure culturally tailored decision support.

Quality Assessment and Production of Human Cells for Clinical Use.

Cell transplantation therapy aspires to repair and restore lost function while minimizing the risk of harm. The potential for harm arises from cell instability, variability, inappropriate behavior, and/or transmission of adventitious pathogens. Quality assured and controlled assessment and production of human cells for clinical use ensures that the risk of harm is minimized. Application of quality standards requires thorough planning and consultation with regulatory authorities on process and product specifications, as early as possible at the research and development (R&D) stage. Here we outline considerations applicable to all human cells in relation to regulatory governance, the route to the clinic and Cell Therapy Product (CTP) characterization, with special emphasis on human pluripotent stem cells (hPSC).

Health care professionals' attitudes towards population-based genetic testing and risk-stratification for ovarian cancer: a cross-sectional survey.

BACKGROUND: Ovarian cancer is usually diagnosed at a late stage when outcomes are poor. Personalised ovarian cancer risk prediction, based on genetic and epidemiological information and risk stratified management in adult women could improve outcomes. Examining health care professionals' (HCP) attitudes to ovarian cancer risk stratified management, willingness to support women, self-efficacy (belief in one's own ability to successfully complete a task), and knowledge about ovarian cancer will help identify training needs in anticipation of personalised ovarian cancer risk prediction being introduced. METHODS: An anonymous survey was distributed online to HCPs via relevant professional organisations in the UK. Kruskal-Wallis tests and pairwise comparisons were used to compare knowledge and self-efficacy scores between different types of HCPs, and attitudes toward population-based genetic testing and risk stratified management were described. Content analysis was undertaken of free text responses concerning HCPs willingness to discuss risk management options with women. RESULTS: One hundred forty-six eligible HCPs completed the survey: oncologists (31%); genetics clinicians (30%); general practitioners (22%); gynaecologists (10%); nurses (4%); and 'others'. Scores for knowledge of ovarian cancer and genetics, and self-efficacy in conducting a cancer risk consultation were generally high but significantly lower for general practitioners compared to genetics clinicians, oncologists, and gynaecologists. Support for population-based genetic testing was not high (<50%). Attitudes towards ovarian cancer risk stratification were mixed, although the majority of participants indicated a willingness to discuss management options with patients. CONCLUSIONS: Larger samples are required to investigate attitudes to population-based genetic testing for ovarian cancer risk and to establish why some HCPs are hesitant to offer testing to all adult female patients. If ovarian cancer risk assessment using genetic testing and non-genetic information including epidemiological information is rolled out on a population basis, training will be needed for HCPs in primary care to enable them to provide appropriate support to women at each stage of the process.

Anticipated health behaviour changes and perceived control in response to disclosure of genetic risk of breast and ovarian cancer: a quantitative survey study among women in the UK.

BACKGROUND: Genetic risk assessment for breast cancer and ovarian cancer (BCOC) is expected to make major inroads into mainstream clinical practice. It is important to evaluate the potential impact on women ahead of its implementation in order to maximise health benefits, as predictive genetic testing without adequate support could lead to adverse psychological and behavioural responses to risk disclosure. OBJECTIVE: To examine anticipated health behaviour changes and perceived control to disclosure of genetic risk for BCOC and establish demographic and person-specific correlates of adverse anticipated responses in a population-based sample of women. DESIGN: Cross-sectional quantitative survey study carried out by the UK Office for National Statistics in January and March 2014. SETTING: Face-to-face computer-assisted interviews conducted by trained researchers in participants' homes. PARTICIPANTS: 837 women randomly chosen from households across the UK identified from the Royal Mail's Postcode Address File. OUTCOME MEASURES: Anticipated health behaviour change and perceived control to disclosure of BCOC risk. RESULTS: In response to a genetic test result, most women (72%) indicated 'I would try harder to have a healthy lifestyle', and over half (55%) felt 'it would give me more control over my life'. These associations were independent of demographic factors or perceived risk of BCOC in Bonferroni-corrected multivariate analyses. However, a minority of women (14%) felt 'it isn't worth making lifestyle changes' and that 'I would feel less free to make choices in my life' (16%) in response to BCOC risk disclosure. The former belief was more likely to be held by women who were educated below university degree level (P<0.001) after adjusting for other demographic and person-specific correlates. CONCLUSION: These findings indicate that women in the UK largely anticipate that they would engage in positive health behaviour changes in response to BCOC risk disclosure.

Impact of a decision aid about stratified ovarian cancer risk-management on women's knowledge and intentions: a randomised online experimental survey study.

BACKGROUND: Risk stratification using genetic and other types of personal information could improve current best available approaches to ovarian cancer risk reduction, improving identification of women at increased risk of ovarian cancer and reducing unnecessary interventions for women at lower risk. Amounts of information given to women may influence key informed decision-related outcomes, e.g. knowledge. The primary aim of this study was to compare informed decision-related outcomes between women given one of two versions (gist vs. extended) of a decision aid about stratified ovarian cancer risk-management. METHODS: This was an experimental survey study comparing the effects of brief (gist) information with lengthier, more detailed (extended) information on cognitions relevant to informed decision-making about participating in risk-stratified ovarian cancer screening. Women with no personal history of ovarian cancer were recruited through an online survey company and randomised to view the gist (n = 512) or extended (n = 519) version of a website-based decision aid and completed an online survey. Primary outcomes were knowledge and intentions. Secondary outcomes included attitudes (values) and decisional conflict. RESULTS: There were no significant differences between the gist and extended conditions in knowledge about ovarian cancer (time*group interaction: F = 0.20, p = 0.66) or intention to participate in ovarian cancer screening based on genetic risk assessment (t(1029) = 0.43, p = 0.67). There were also no between-groups differences in secondary outcomes. In the sample overall (n = 1031), knowledge about ovarian cancer increased from before to after exposure to the decision aid (from 5.71 to 6.77 out of a possible 10: t = 19.04, p < 0.001), and 74% of participants said that they would participate in ovarian cancer screening based on genetic risk assessment. CONCLUSIONS: No differences in knowledge or intentions were found between women who viewed the gist version and women who viewed the extended version of a decision aid about risk-stratified ovarian cancer screening. Knowledge increased for women in both decision aid groups. Further research is needed to determine the ideal volume and type of content for decision aids about stratified ovarian cancer risk-management. TRIAL REGISTRATIONS: This study was registered with the ISRCTN registry; registration number: ISRCTN48627877 .

Awareness, knowledge, perceptions, and attitudes towards genetic testing for cancer risk among ethnic minority groups: a systematic review.

BACKGROUND: Genetic testing for risk of hereditary cancer can help patients to make important decisions about prevention or early detection. US and UK studies show that people from ethnic minority groups are less likely to receive genetic testing. It is important to understand various groups' awareness of genetic testing and its acceptability to avoid further disparities in health care. This review aims to identify and detail awareness, knowledge, perceptions, and attitudes towards genetic counselling/testing for cancer risk prediction in ethnic minority groups. METHODS: A search was carried out in PsycInfo, CINAHL, Embase and MEDLINE. Search terms referred to ethnicity, genetic testing/counselling, cancer, awareness, knowledge, attitudes, and perceptions. Quantitative and qualitative studies, written in English, and published between 2000 and 2015, were included. RESULTS: Forty-one studies were selected for review: 39 from the US, and two from Australia. Results revealed low awareness and knowledge of genetic counselling/testing for cancer susceptibility amongst ethnic minority groups including African Americans, Asian Americans, and Hispanics. Attitudes towards genetic testing were generally positive; perceived benefits included positive implications for personal health and being able to inform family. However, negative attitudes were also evident, particularly the anticipated emotional impact of test results, and concerns about confidentiality, stigma, and discrimination. Chinese Australian groups were less studied, but of interest was a finding from qualitative research indicating that different views of who close family members are could impact on reported family history of cancer, which could in turn impact a risk assessment. CONCLUSION: Interventions are needed to increase awareness and knowledge of genetic testing for cancer risk and to reduce the perceived stigma and taboo surrounding the topic of cancer in ethnic minority groups. More detailed research is needed in countries other than the US and across a broader spectrum of ethnic minority groups to develop effective culturally sensitive approaches for cancer prevention.

Evidence of Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom Familial Ovarian Cancer Screening Study.

Purpose To establish the performance of screening with serum cancer antigen 125 (CA-125), interpreted using the risk of ovarian cancer algorithm (ROCA), and transvaginal sonography (TVS) for women at high risk of ovarian cancer (OC) or fallopian tube cancer (FTC). Patients and Methods Women whose estimated lifetime risk of OC/FTC was ≥ 10% were recruited at 42 centers in the United Kingdom and underwent ROCA screening every 4 months. TVS occurred annually if ROCA results were normal or within 2 months of an abnormal ROCA result. Risk-reducing salpingo-oophorectomy (RRSO) was encouraged throughout the study. Participants were observed via cancer registries, questionnaires, and notification by centers. Performance was calculated after censoring 365 days after prior screen, with modeling of occult cancers detected at RRSO. Results Between June 14, 2007, and May 15, 2012, 4,348 women underwent 13,728 women-years of screening. The median follow-up time was 4.8 years. Nineteen patients were diagnosed with invasive OC/FTC within 1 year of prior screening (13 diagnoses were screen-detected and six were occult at RRSO). No symptomatic interval cancers occurred. Ten (52.6%) of the total 19 diagnoses were stage I to II OC/FTC (CI, 28.9% to 75.6%). Of the 13 screen-detected cancers, five (38.5%) were stage I to II (CI, 13.9% to 68.4%). Of the six occult cancers, five (83.3%) were stage I to II (CI, 35.9% to 99.6%). Modeled sensitivity, positive predictive value, and negative predictive value for OC/FTC detection within 1 year were 94.7% (CI, 74.0% to 99.9%), 10.8% (6.5% to 16.5%), and 100% (CI, 100% to 100%), respectively. Seven (36.8%) of the 19 cancers diagnosed < 1 year after prior screen were stage IIIb to IV (CI, 16.3% to 61.6%) compared with 17 (94.4%) of 18 cancers diagnosed > 1 year after screening ended (CI, 72.7% to 99.9%; P < .001). Eighteen (94.8%) of 19 cancers diagnosed < 1 year after prior screen had zero residual disease (with lower surgical complexity, P = .16) (CI, 74.0% to 99.9%) compared with 13 (72.2%) of 18 cancers subsequently diagnosed (CI, 46.5% to 90.3%; P = .09). Conclusion ROCA-based screening is an option for women at high risk of OC/FTC who defer or decline RRSO, given its high sensitivity and significant stage shift. However, it remains unknown whether this strategy would improve survival in screened high-risk women.

Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer.

Breast cancer is the most common female cancer, affecting approximately one in eight women during their lifetime in North America and Europe. Receptor Activator of NF-kB Ligand (RANKL), its receptor RANK and the natural antagonist osteoprotegerin (OPG) are essential regulators of bone resorption. We have initially shown that RANKL/RANK are essential for hormone-driven mammary epithelial proliferation in pregnancy and RANKL/RANK have been implicated in mammary stem cell biology. Using genetic mouse-models, we and others identified the RANKL/RANK system as a key regulator of sex hormone, BRCA1-mutation, and oncogene-driven breast cancer and we proposed that RANKL/RANK might be involved in the initiation of breast tumors. We now report that in postmenopausal women without known genetic predisposition, high RANKL and progesterone serum levels stratify a subpopulation of women at high risk of developing breast cancer 12-24 months before diagnosis (5.33-fold risk, 95%CI 1.5-25.4; P=0.02). In women with established breast cancer, we demonstrate that RANKL/OPG ratios change dependent on the presence of circulating tumor cells (CTCs). Finally, we show in a prospective human breast cancer cohort that alterations in RANKL/OPG ratios are significantly associated with breast cancer manifestation. These data indicate that the RANKL/RANK/OPG system is deregulated in post-menopausal women at high risk for breast cancer and in women with circulating tumor cells. Thus, serum levels of RANKL/OPG are potentially indicative of predisposition and progression of breast cancer in humans. Advancement of our findings towards clinical application awaits prior validation in independent patient cohorts.

Genetic testing and personalized ovarian cancer screening: a survey of public attitudes.

BACKGROUND: Advances in genetic technologies are expected to make population-wide genetic testing feasible. This could provide a basis for risk stratified cancer screening; but acceptability in the target populations has not been explored. METHODS: We assessed attitudes to risk-stratified ovarian cancer (OC) screening based on prior genetic risk assessment using a survey design. Home-based interviews were carried out by the UK Office of National Statistics in a population-based sample of 1095 women aged 18-74. Demographic and personal correlates of attitudes to risk-stratified OC screening based on prior genetic risk assessment were determined using univariate analyses and adjusted logistic regression models. RESULTS: Full data on the key analytic questions were available for 829 respondents (mean age 46 years; 27 % 'university educated'; 93 % 'White'). Relatively few respondents felt they were at 'higher' or 'much higher' risk of OC than other women of their age group (7.4 %, n = 61). Most women (85 %) said they would 'probably' or 'definitely' take up OC genetic testing; which increased to 88 % if the test also informed about breast cancer risk. Almost all women (92 %) thought they would 'probably' or 'definitely' participate in risk-stratified OC screening. In multivariate logistic regression models, university level education was associated with lower anticipated uptake of genetic testing (p = 0.009), but with more positive attitudes toward risk-stratified screening (p <0.001). Perceived risk was not significantly associated with any of the outcome variables. CONCLUSIONS: These findings give confidence in taking forward research on integration of novel genomic technologies into mainstream healthcare.

Osteoprotegerin (OPG), The Endogenous Inhibitor of Receptor Activator of NF-κB Ligand (RANKL), is Dysregulated in BRCA Mutation Carriers.

Breast cancer development in BRCA1/2 mutation carriers is a net consequence of cell-autonomous and cell nonautonomous factors which may serve as excellent targets for cancer prevention. In light of our previous data we sought to investigate the consequences of the BRCA-mutation carrier state on RANKL/osteoprotegerin (OPG) signalling. We analysed serum levels of RANKL, OPG, RANKL/OPG complex, oestradiol (E2), and progesterone (P) during menstrual cycle progression in 391 BRCA1/2-mutation carriers and 782 noncarriers. These studies were complemented by analyses of RANKL and OPG in the serum and mammary tissues of female cynomolgus macaques (n = 88) and serum RANKL and OPG in postmenopausal women (n = 150). BRCA-mutation carriers had lower mean values of free serum OPG in particular in BRCA1-mutation carriers (p = 0.018) compared with controls. Among BRCA1/2 mutation carriers, lower OPG levels were associated with germline mutation locations known to confer an increased breast cancer risk (p = 0.003). P is associated with low OPG levels in serum and tissue, particularly in BRCA-mutation carriers (rho = - 0.216; p = 0.002). Serum OPG levels were inversely correlated (rho = - 0.545, p < 0.001) with mammary epithelial proliferation measured by Ki67 expression and increased (p = 0.01) in postmenopause. The P-RANKL/OPG system is dysregulated in BRCA-mutation carriers. These and previously published data provide a strong rationale for further investigation of antiprogestogens or an anti-RANKL antibody such as denosumab for breast cancer prevention.

Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality. METHODS: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided. RESULTS: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)). CONCLUSIONS: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.

PURPOSE: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. PATIENTS AND METHODS: The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis. RESULTS: In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). CONCLUSION: These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.

Adjusting the frequency of mammography screening on the basis of genetic risk: Attitudes among women in the UK.

PURPOSE: To explore public attitudes towards modifying frequency of mammography screening based on genetic risk. METHODS: Home-based interviews were carried out with a population-based sample of 942 women aged 18-74 years in the UK. Demographic characteristics and perceived breast cancer (BC) risk were examined as predictors of support for risk-stratified BC screening and of the acceptability of raised or lowered screening frequency based on genetic risk, using multivariate logistic regression. RESULTS: Over two-thirds of respondents (65.8%) supported the idea of varying screening frequency on the basis of genetic risk. The majority (85.4%) were willing to have more frequent breast screening if they were found to be at higher risk, but fewer (58.8%) were willing to have less frequent screening if at lower risk (t (956) = 15.6, p < 0.001). Ethnic minority status was associated with less acceptability of more frequent screening (OR = 0.40, 95% CI = 0.21-0.74), but there were no other significant demographic correlates. Higher perceived risk of BC was associated with greater acceptability of more frequent screening (OR = 1.71, 95%CI = 1.27-2.30). CONCLUSION: Women were positive about adjusting the frequency of mammography screening in line with personal genetic risk, but it will be important to develop effective communication materials to minimise resistance to reducing screening frequency for those at lower genetic risk.

Use and perceived efficacy of complementary and alternative medicines after discontinuation of hormone therapy: a nested United Kingdom Collaborative Trial of Ovarian Cancer Screening cohort study.

OBJECTIVE: Given that the Women's Health Initiative reported in 2002 increased risks of breast cancer and cardiovascular events with hormone therapy (HT) use and many women discontinued use, we assessed the use and perceived efficacy of complementary and alternative medicines (CAMs) for menopausal symptom relief after discontinuation of HT. METHODS: Postmenopausal women aged 50 to 65 years within the United Kingdom Collaborative Trial of Ovarian Cancer Screening who were willing to take part in a secondary study were mailed a survey to evaluate menopausal symptom management. Use and perceived efficacy of CAMs for relief of vasomotor symptoms (VMS) upon discontinuation of HT were examined. RESULTS: The survey was sent to 15,000 women between July 2 and July 9, 2008. Seventy-one percent (10,662 of 15,000) responded, and 10,607 women with complete data were included. Ever use of HT was reported by 60.2% (6,383 of 10,607). At survey completion, 79.3% (5,060 of 6,383) had discontinued HT, with 89.7% (4,540 of 5,060) of the latter reporting using one or more CAMs for VMS relief. About 70.4% (3,561 of 5,060) used herbal remedies, with evening primrose oil (48.6%; 2,205 of 4,540) and black cohosh (30.3%;1,377 of 4,540) being most commonly used. Exercise was used by 68.2% (3,098 of 4,540), whereas other behavioral/lifestyle approaches were less frequently reported (13.9%; 629 of 4,540). Contrarily, more women (57%-72%) rated behavioral/lifestyle approaches as effective compared with herbal remedies (28%-46%; rating ≥4 on a "helpfulness" scale from 1-10). Among medical treatments, selective serotonin reuptake inhibitors were used by 10% and rated effective by 72.1%. CONCLUSIONS: Although more women use over-the-counter medicines, behavioral/lifestyle approaches seem to provide better relief of VMS. There is a pressing need for better evidence-based lay information to support decision-making on CAM use for relief of VMS.

Population-based genetic risk prediction and stratification for ovarian cancer: views from women at high risk.

There is an opportunity to improve outcomes for ovarian cancer (OC) through advances in risk stratification, early detection and diagnosis. A population-based OC genetic risk prediction and stratification program is being developed. A previous focus group study with individuals from the general population showed support for the proposed program. This qualitative interview study explores the attitudes of women at high risk of OC. Eight women participated in one-on-one, in-depth, semi-structured interviews to explore: experiences of learning of OC risk, risk perceptions, OC knowledge and awareness, and opinions on risk stratification approach. There was evidence of strong support for the proposed program. Benefits were seen as providing reassurance to women at low risk, and reducing worry in women at high risk through appropriate clinical management. Stratification into 'low' and 'high' risk groups was well-received. Participants were more hesitant about stratification to the 'intermediate' risk group. The data suggest formats to effectively communicate OC risk estimates will require careful thought. Interactions with GPs were highlighted as a barrier to OC risk assessment and diagnosis. These results are encouraging for the possible introduction and uptake of a risk prediction and stratification program for OC in the general population.

Identifying hopelessness in population research: a validation study of two brief measures of hopelessness.

OBJECTIVE: Hopelessness is an important construct in psychosocial epidemiology, but there is great pressure on the length of questionnaire measures in large-scale population and clinical studies. We examined the validity and test-retest reliability of two brief measures of hopelessness, an existing negatively worded two-item measure of hopelessness (Brief-H-Neg) and a positively worded version of the same instrument (Brief-H-Pos). DESIGN: Cohort study. SETTING: Control arm of the UK Collaborative Trial of Ovarian Cancer Screening. PARTICIPANTS: A non-clinical research-based sample of 5000 postmenopausal women selected from 56 512 participants. PRIMARY AND SECONDARY OUTCOME MEASURES: Spearman's rank correlation of brief measures of hopelessness with the Beck Hopelessness Scale (BHS). Spearman's rank correlation with the Centre for Epidemiological Studies Depression Scale (CES-D) and change in mean score on repeat testing. METHODS: Two short hopelessness measures, a negatively worded brief measure of hopelessness (Brief-H-Neg) and a positively worded brief measure of hopelessness (Brief-H-Pos), were administered by postal questionnaire to 5000 women together with the 20-item BHS and 20-item CES-D. The Brief-H-Neg and Brief-H-Pos were readministered to 500 women after a 2-week interval. RESULTS: 2413 postmenopausal women (mean age 68.9 years) completed the questionnaire. The Brief-H-Neg and Brief-H-Pos correlated 0.93 and 0.87 with the BHS after correction for attenuation and their association with the CES-D mirrored that seen with the BHS (Spearman's rank correlation 0.88 and 0.68, respectively). There was no change in mean scores on the two measures with repeat testing in the 433 women who completed them and test-retest reliability was good (intraclass correlations Brief-H-Neg 0.67 and Brief-H-Pos 0.72). CONCLUSIONS: These findings provide support for the validity of the Brief-H-Neg and Brief-H-Pos. These brief measures are likely to be useful in large population studies assessing hopelessness. TRIAL REGISTRATION NUMBER: NCT00058032.

The sex hormone system in carriers of BRCA1/2 mutations: a case-control study.

BACKGROUND: Penetrance for breast cancer, ovarian cancer, or both in carriers of BRCA1/BRCA2 mutations is disproportionately high. Sex hormone dysregulation and altered end-organ hormone sensitivity might explain this organ-specific penetrance. We sought to identify differences in hormone regulation between carriers of BRCA1/2 and women who are negative for BRCA1/2 mutations. METHODS: We assessed endometrial thickness for each menstrual cycle day (as an index of hormone regulation) in 393 scans from 228 women in the UK Familial Ovarian Cancer Screening Study (UK FOCSS) known to carry either mutation and 1573 scans from 754 women known to be negative for the mutations. To quantify differences in endometrial thickness we focused on days 10-14 and days 21-26, and calculated the area under the curve. We then compared serum oestradiol and progesterone titres during these days of the menstrual cycle in the same groups. Follicular and luteal oestradiol and progesterone serum titres were grouped into quartiles and odds ratios were calculated with logistic regression. FINDINGS: Follicular phase endometrial thickness of carriers of the mutations adjusted for age and day of the menstrual cycle was higher (odds ratio [OR] 1·11, 95% CI 1·03-1·20; p=0·0063) and luteal phase endometrial thickness lower (0·90, 0·83-0·98; p=0·027) than for women negative for the mutations. Median luteal phase titres of progesterone were 121% higher (p=0·00037) in carriers than in women negative for the mutations, and for oestradiol were 33% higher (p=0·007)-ie, 59% of carriers had concentrations of serum progesterone that would have been in the top quartile of concentrations in the control group (OR 8·0, 95% CI 2·1-52·57; p=0·008). INTERPRETATION: Carriers of BRCA1/BRCA2 mutations are exposed to higher titres of oestradiol and progesterone-known risk-factors for breast cancer. Higher titres of oestradiol in carriers are compatible with this hormone having a role in ovarian carcinogenesis in such women. Our findings could not be explained by differential contraceptive pill use.

A qualitative study of women's experiences of familial ovarian cancer screening.

OBJECTIVE: One risk management strategy that women at increased familial risk of ovarian cancer may use is screening. Until recently, this has been available as part of the UK Familial Ovarian Cancer Screening Study (UKFOCSS), using ultrasound scans of the ovaries and tumour marker blood tests. The present study aimed to gain an in-depth understanding of women's experiences of participating in ovarian cancer screening. METHODS: Semi-structured interviews were conducted with 48 UKFOCSS participants. Interviews were recorded, transcribed and relevant sections analysed using a framework approach. RESULTS: Screening provided women with reassurance which they found beneficial. A sense of privilege, as well as feeling proactive in potentially detecting ovarian cancer at an early stage was described. The wider benefit to research and the potential impact this could have on others was also important to women. Negative experiences of screening included worry about the screening tests and results, false reassurance by test results and disappointment with ineffective screening. Aspects of the screening study, such as the logistics, organisation and communication, were described as both good and problematic. When weighed up by the women, most described an overall positive experience of screening. CONCLUSIONS: Women reported both positive and negative experiences of screening. Overall, screening seemed to be an acceptable risk management strategy to most women who participated in this interview study. Improvements could be made particularly in helping women to understand the limitations of familial ovarian cancer screening in order to avoid false reassurance.

SCF/KIT inhibition has a cumulative but reversible effect on the self-renewal of embryonic stem cells and on the survival of differentiating cells.

The receptor tyrosine kinase c-KIT is expressed in embryonic stem cells (ESCs) and adult stem cells, and many functional studies have demonstrated the importance of the SCF/KIT signaling pathway in adult stem cell maintenance. In this study, we show that a high level of KIT expression in wild-type ESCs correlates with an enhanced self-renewal and that inhibition of KIT signaling in ESCs for extended periods of time has a cumulative but reversible effect on self-renewal. Together these data suggest that continued KIT signaling in some cells within a self-renewing ESC population is required for optimal ESC function. Using a KIT blocking antibody, we recapitulated the phenotype we previously reported for genetically deficient KIT-null cells, demonstrating that SCF/KIT signaling is essential for the survival of differentiating ESCs. Here we show that this phenotype is also reversible. Pharmacological inhibition of JNK also had a cumulative but reversible detrimental effect on the survival of differentiating cells, thus recapitulating the Kit null phenotype and implicating JNK as a downstream mediator of KIT signaling. In contrast, the self-renewal of ESCs was unaffected by prolonged exposure to the JNK inhibitor, suggesting that JNK-independent downstream pathways are involved in KIT-mediated ESC self-renewal whereas KIT-mediated survival of differentiating ESC is likely to be JNK dependent.