Molecular differences between RER+ and RER- sporadic endometrial carcinomas in a large population-based series.

Studies, to date, have suggested that there are distinct molecular differences between microsatellite stable (RER(-)) and unstable (RER(+)) solid tumors, such as colorectal carcinoma. We investigated a range of molecular events including mutation frequency of K-ras, microsatellite instability within the coding region of TGF-beta RII, BAX, and IGF-IIR, loss of expression of p53, hMLH1, hMSH2, hMSH6, and PTEN, and methylation of hMLH1, hMSH2, and PTEN within a large population-based series of sporadic endometrial carcinomas to establish whether there are distinct differences between replication error repair (RER(+)) and RER(-) cases. RER(+) endometrial carcinomas tended to be diploid with normal p53 expression, compared with RER(-) cases. Mutations in TGF-beta RII, IGF-IIR, and BAX were rare, but there was a strong association between mutation and RER(+) status. Methylation and loss of hMLH1 expression were significantly more common in RER(+) cases, as was methylation of PTEN. K-ras mutations were equally frequent in RER(+) and RER(-) cases. Despite the absence of distinct clinicopathological differences between RER(+) and RER(-) cases in this series of sporadic endometrial carcinomas, our results confirm that there are molecular differences between RER(+) and RER(-) cases, but the molecular events occurring in RER(+) endometrial carcinomas differ from those seen in RER(+) colorectal carcinomas.

Frequency and prognostic impact of microsatellite instability in a large population-based study of endometrial carcinomas.

The replication error repair (RER) phenotype has been reported in 9-43% of sporadic endometrial carcinomas, but there are conflicting data about its effect on prognosis in this disease. This study was performed to establish the frequency of the RER phenotype and to determine its effect on prognosis in a population-based series of 259 endometrial carcinomas with long-term follow-up. Five mononucleotide and dinucleotide microsatellite markers on different chromosomes were analyzed, and tumors exhibiting microsatellite instability at two or more loci were classified as RER+. A total of 116 of 259 tumors (45%) were RER+. The 5-year survival rate for the RER- group was 76.2% compared with 79.6% for RER+ cases (P = 0.6). The 5-year recurrence-free survival rate among the 228 patients surgically treated for cure was 80.6% in the RER- group compared with 83.6% in the RER+ group (P = 0.6). The analysis indicates that the RER phenotype is common in endometrial carcinomas, but there is no association with prognosis in this large population-based series of endometrial carcinomas.

Social and behavioural factors associated with HIV seroconversion in homosexual men attending a central London STD clinic: a feasibility study.

An unmatched retrospective case control study was conducted to test the feasibility of investigating social and behavioural factors which may have contributed to recent HIV seroconversion in a group of homosexual men. Participants, recruited from a London sexually transmitted disease (STD) clinic, were sexually active and had had a negative HIV test with a subsequent test (positive (cases) or negative (controls)) within three to 15 months. Twenty cases and 22 controls were recruited between February and October 1995. There was no difference between cases and controls in: the number of regular or casual sexual partners, the proportion who were unaware of their regular partners' serostatus (cases 60%, controls 59%), or the proportion who had known HIV-positive regular partners (cases 20%, controls 23%). A significant difference in sexual behaviour was found only when the HIV status of partners, if known, was taken into account: cases were more likely than controls to have had unprotected receptive anal intercourse with a partner not known to be HIV-negative (OR = 5.5, CI = 1.15-29.50). Fifty per cent of the cases and 27% of the controls acquired acute STDs between the two HIV tests. All participants achieved high self-efficacy scores, but the controls believed their peers placed a greater value on safer sex. Cases cited emotional issues and the use of drugs and alcohol as contributing to their seroconversion, whereas controls cited a commitment to safer sex and the avoidance of high-risk situations as contributing to their remaining HIV-negative. The results illustrate the importance of acknowledging the concept of 'negotiated safety' in studies of sexual behaviour; seroconversion was only associated with unprotected sex with a partner not known to be HIV-negative. Despite high self-efficacy scores, indicating the skills to negotiate safer sex, high levels of unsafe anal intercourse were reported. Differences between cases and controls included the importance of safer sex, periods of emotional vulnerability, influence of peers and the appropriate use of condoms. There is a need for these results to be confirmed in a larger and more powerful study.

Performance of ultrasound as a second line test to serum CA125 in ovarian cancer screening.

OBJECTIVE: To assess the performance of ultrasonography in a multimodal ovarian cancer screening strategy. DESIGN: Prospective ovarian cancer screening trial between December 1986 and June 1993. SETTING: General practice, occupational health departments and an ovarian cancer screening clinic at a London teaching hospital. POPULATION: Postmenopausal women, > or = 45 years with a raised CA125. METHODS: Volunteers with a CA125 > or = 30 U/mL underwent a pelvic ultrasound. Scans were classified as normal, abnormal (ovarian volume > or = 8.8 mL) or equivocal (normal volume with abnormal morphology). Abnormal ovarian morphology was subclassified as simple cyst (single, thin walled cyst with no septa or papillary projections) or complex (all other abnormalities). Volunteers with abnormal scans were referred for a gynaecological opinion. Follow up was via the cancer registry and postal questionnaires. MAIN OUTCOME MEASURES: Sensitivity, specificity and positive predictive value of different ultrasound criteria for detection of index cancer (e.g. primary invasive epithelial carcinoma of the ovary and fallopian tube). RESULTS: Seven hundred and forty-one women underwent 1,219 scans and 20 index cancers occurred during a median follow up of 6 x 8 years. The sensitivity for detection of ovarian cancer of different ultrasound criteria was 100% for abnormal morphology, 89 x 5% for abnormal volume and 84% for complex morphology. The highest specificity (97%) and positive predictive value (37 x 2%) was achieved using complex morphology. CONCLUSION: A variety of ultrasound criteria can achieve high sensitivity, specificity and positive predictive value for index cancers in postmenopausal women with an elevated CA125. Use of ovarian morphology to interpret ultrasound may increase sensitivity and use of complex ovarian morphology may increase the positive predictive value.

Ultrasound assessment of ovarian cancer risk in postmenopausal women with CA125 elevation.

We have previously shown that, in asymptomatic post-menopausal women, serum CA125 elevation is associated with a 36-fold increase in risk of ovarian cancer. This study was undertaken to assess the value of pelvic ultrasound for further stratification of ovarian cancer risk. Of 22,000 post-menopausal women, aged > or = 45 participating in an Ovarian Cancer Screening Trial, 741 with a CA125 > or = 30 U ml(-1) underwent pelvic ultrasonography. Twenty index cancers (primary invasive epithelial carcinomas of the ovary and fallopian tube) were diagnosed amongst these 741 women during a median follow-up of 6.8 years. Ultrasound results separated the women with CA125 elevation into two groups. Those with normal ovarian morphology had a cumulative risk (CR) of index cancer of 0.15% (95% confidence interval (CI) 0.02-1.12) which is similar to that of the entire population of 22,000 women (0.22%, 95% CI 0.18-0.30). In contrast, women with abnormal ovarian morphology had a CR of 24% (15-37) and a significantly increased relative risk (RR) of 327 (156-683). Ultrasound can effectively separate post-menopausal women with raised CA125 levels into those with normal scan findings who are not at increased risk of index cancer and those with abnormal findings who are at substantially increased risk of index cancer.

Screening for ovarian cancer.

Ovarian cancer is predominantly a disease of postmenopausal women which presents at a late stage and has an overall 5-year survival of less than 30%. If detected at stage I, survival is dramatically increased and this would suggest that screening for ovarian cancer may reduce mortality. However, the inaccessibility of the ovaries and the absence of a confirmed premalignant condition make screening for preclinical disease difficult. Recent advances in tumour marker interpretation and ultrasound technology have now allowed screening for ovarian cancer to become a real possibility. CA 125 is the most widely used tumour marker for ovarian cancer and it has been shown to be elevated several years before clinical presentation. A new approach to the interpretation of sequential CA 125 results, which uses a mathematical algorithm to determine an individual's risk of cancer, has improved the sensitivity of CA 125 in screening asymptomatic postmenopausal women. Screening using transvaginal ultrasound, Doppler and morphological indices gives encouraging results but, used alone, it currently lacks the specificity required of a screening test for the general population. Multimodal screening using tumour markers and ultrasound in combination gives high sensitivity and specificity and is also the most cost-effective potential screening strategy. The sensitivity and specificity of these techniques are sufficient to warrant large-scale clinical trials of ovarian cancer screening. Three such trials are currently underway and, in due course, will establish whether any screening strategy will ultimately reduce mortality from ovarian cancer.

Effect of salbutamol on gas compression in cystic fibrosis and asthma.

In cystic fibrosis (CF), it has been suggested that increases in FEV1 postbronchodilator (BD) can be accompanied by paradoxical decreases in isovolume maximal flow at 25% of vital capacity (V25iso) measured from maximum expiratory flow-volume curves (MEFVC), raising concerns about determining the benefits of BD in CF. MEFVC measured using expired volume has been shown to be subject to errors due to gas compression. In the present study, BD response was assessed in 91 patients with asthma and 78 with CF using the percentage of change in FEV1 and V25iso determined using MEFVC from both mouth (m) and plethysmograph (p) volumes. From the two curves, volume of compression (Vcomp) was measured. Baseline measurements were similar for both groups, except that the residual volume to total lung capacity ratio (RV/TLC) was higher and Vmax25 and FVC were lower in CF. Both groups showed significant (p < 0.05) increases in FVC, FEV1, and V25iso after BD. The percentage of change in FEV1 correlated with the percentage of change in V25iso (r = 0.53 for CF and 0.66 for asthma, p < 0.001). Baseline Vcomp25 was higher in asthma than in CF. The percentage of change in V25iso was not related to the change in Vcomp25iso for either group. Only four patients with CF showed a paradoxical decrease in V25iso, and the differences in flow were small. Two had an increase in Vcomp and two had a decrease. We conclude that paradoxical decreases in V25iso are rare, are associated with small changes in flow, and are not related to changes in Vcomp.(ABSTRACT TRUNCATED AT 250 WORDS)