Gareth Evans

Survival in women with MMR mutations and ovarian cancer; A multicentre study in Lynch Syndrome kindreds

Background Women with a germline mutation in one of the MMR genes MLH1, MSH2 or MSH6 reportedly have 4–12% lifetime risk of ovarian cancer, but there is limited knowledge on survival. Prophylactic bilateral salpingo-oophorectomy (PBSO) has been suggested for preventing this condition. Aim The purpose of this retrospective multicentre study was to describe survival in carriers of pathogenic mutations in one of the MMR genes, and who had contracted ovarian cancer. Methods Women who had ovarian cancer, and who tested positive for or were obligate carriers of an MMR mutation, were included from 11 European centres for hereditary cancer. Most women had not attended for gynaecological screening. Crude and disease specific survival was calculated by the Kaplan–Meier algorithm. Results Among the 144 women included, 81.5% had FIGO stage 1 or 2 at diagnosis. 10 year ovarian cancer specific survival independent of staging was 80.6%, compared to less than 40% that is reported both in population based series and in BRCA mutation carriers. Disease specific 30 year survival for ovarian cancer was 71.5%, and for all hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome related cancers including ovarian cancer it was 47.3%. Conclusions In the series examined, infiltrating ovarian cancer in Lynch syndrome had a better prognosis than infiltrating ovarian cancer in BRCA1/2 mutation carriers or in the general population. Lifetime risk of ovarian cancer of about 10% and a risk of dying of ovarian cancer of 20% gave a lifetime risk of dying of ovarian cancer of about 2% in female MMR mutation carriers.

Presenting UML Software Engineering Diagrams to Blind People

The TeDUB system promises to deliver a UML diagram tool accessible to blind software engineers. The system uses a number of different interfaces and representation techniques to overcome the challenges of making diagrams created with the Unified Modeling Language usable for blind people. The system is entirely automated and does not require special preparation of UML diagrams by a sighted user. The results of evaluation of the system with thirty-six users were positive. The system was well-received and the participants were able to complete set UML tasks.

Screen magnifiers: evolution and evaluation

While the new generation of screen magnifiers might offer more features, they might not necessarily become more effective. The paper considers how performing usability studies helps researchers understand issues related to screen magnifier design, especially in terms of interface, functions, and features.

Development of an electronic pictorial asthma action plan and its use in primary care

OBJECTIVE Self-management education and the issuing of a written action plan improve outcomes for asthma. Many do not receive a plan and some cannot use the written word. We have developed an electronic pictorial asthma action plan (E-PAAP). METHODS A pictorial action plan was incorporated into a software package. 21 general practices were offered this tool and the software was loaded onto 63 desktop computers (46 GPs and 17 nurses). Usage was assessed and health care professionals questioned as to its use. RESULTS 190 plans had been printed in a 4-month period (17 for test purposes). The individual usage rate ranged from 0 to 28 plans. Doctors printed 73% (139/190) a mean of 3 per doctor and nurses printed 27% a mean of 2 per nurse (37/190). Excluding the test copies, 116/173(67%) were printed as picture and text together. CONCLUSION Nearly half of all healthcare professionals used the E-PAAP software. Usage was skewed with some individuals using the software significantly more than others. The software package should help overcome problems of access to paper templates, by calculating peak flow action thresholds and by prompting correct completion. Barriers to the use of asthma action plans, such as perceived time constraints, persist. PRACTICE IMPLICATIONS The development of an electronic asthma action plan facilitates health professional access to a basic template and prompts the user as to correct usage. It is to be hoped that such facilitation enhances the number of action plans issued and in this study GPs were greater users than the nurses.

The dental phenotype in familial adenomatous polyposis: diagnostic application of a weighted scoring system for changes on dental panoramic radiographs

A weighted scoring system (Dental Panoramic Radiograph Score) taking into consideration the nature, extent, and site of osseous and dental changes on dental panoramic radiographs in familial adenomatous polyposis is described. The weighting takes into consideration the incidence of the anomaly in the general population. The reliability of the system was tested by application to 85 people known to be affected by clinical or mutation analysis, 30 people lacking mutation in the adenomatous polyposis gene, and 19 people shown to be at low risk (< 1%) by linkage analysis. Using the highest thresholds, a specificity of 100% and sensitivity of approximately 68% was obtained. If all positive findings were considered as significant, sensitivity was increased to approximately 82% but the specificity was reduced to approximately 88%. Significant DPRS findings were observed at a significantly higher frequency in patients aged over 20 compared to the patients aged 20 and under. Overall, approximately 68% of the affected subjects had significant changes, and approximately 18% had normal appearance on DPR, with the remainder having changes classified as minimal or equivocal.

Automated Braille production from word-processed documents

This paper describes a novel method for automatically generating Braille documents from word-processed (Microsoft Word) documents. In particular it details how, by using the Word Object Model, the translation system can map the layout information (format) in the print document into an appropriate Braille equivalent.

Java-Powered Braille Slate Talker

A new device, the Braille Slate Talker, is introduced. An ordinary hand held device (a PDA) is used with a fixed layout plastic guide placed over the touch screen to allow Braille input. Contracted Braille is converted to text by a table-driven state machine. Programs are written in Java language to provide full hardware and software platform independence. Future network applications will use Sun’s Jini technology.

Low prevalence of germline BRCA1 mutations in early onset breast cancer without a family history.

Editor—Germline mutations in the BRCA1 and BRCA2 genes cause predisposition to breast and ovarian cancer.1Epidemiological evidence and linkage studies suggested that the likelihood that a woman with breast cancer has a genetic susceptibility to the condition is greater the younger she was at diagnosis and with increasing extent of family history of the disease. Studies of the prevalence of germline mutations in BRCA1 and BRCA2 in women with breast cancer has enabled the frequency of mutations to be determined in women with different ages at diagnosis and extent of family history of breast cancer.2 3 The CASH study into the attributable risk of breast and ovarian cancer estimated that 33% of all breast cancers diagnosed by the age of 29 years, and 22% diagnosed by the age of 30-39 years, are the result of an inherited mutation.4However, the proportion of breast cancer cases diagnosed by 40 years resulting from a BRCA1 mutation was predicted to be 5.3%.5 Previous population based studies of the prevalence of BRCA1 mutations in early onset breast cancer have been in cases unselected for family history, and the majority of mutation carriers detected did have some degree of family history of either breast or ovarian cancer.6-10 The aim of this study was to establish the prevalence of BRCA1 mutations in a large series of British patients with a young age of onset and no known family history of the disease, since such patients are referred relatively frequently for genetic counselling. The presence of BRCA1 mutations in a significant proportion of these patients would have important implications for the planning of a mutation screening strategy in diagnostic services. Patients were ascertained from the Imperial …

Better life expectancy in women with BRCA2 compared with BRCA1 mutations is attributable to lower frequency and later onset of ovarian cancer

Purpose: No formal assessment of life expectancy in women with BRCA1 and BRCA2 mutations in these genes has been reported previously. We have evaluated life expectancy using actuarial analysis and assessed the effect of breast and ovarian cancers on premature death in >1,000 BRCA1/2 carriers. Methods: Families with pathogenic mutations in BRCA1 and BRCA2 have been ascertained in a 10-million population region of United Kingdom since 1996. Mutation carriers and their first-degree relatives were used in an analysis of breast and ovarian cancer incidence and mortality as well as to derive and compare an actuarial assessment of life expectancy. Results: Six hundred twelve BRCA1 and 482 BRCA2 female mutation carriers were identified from 482 families. Life expectancy was significantly reduced for BRCA1 carriers compared with BRCA2 (P = 0.0002). This effect was attributable to an increased death rate from ovarian cancer (P = 0.04). Kaplan-Meier analysis revealed a better long-term survival from early-stage ovarian cancer in BRCA2 carriers but no significant differences in deaths from breast cancer or from women presenting with late-stage ovarian cancer. There was no other major contributing cause to death other than breast/ovarian cancer in BRCA1/2 female carriers. Conclusion: Interventions to reduce ovarian cancer incidence are likely to have a greater effect on life expectancy in BRCA1 compared with BRCA2 carriers. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1535–42)

Increased rate of missense/in-frame mutations in individuals with NF1- related pulmonary stenosis: a novel genotype–phenotype correlation

Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35=26% vs 25/2322=1.1%, P value<0.001). Stratification according to mutation type showed that the increased PS rate appears to be driven by the NFNS group with non-truncating mutations. Eight of twelve (66.7%) NFNS cases with non-truncating mutations had PS compared with a 1.1% PS frequency in NF1 in general (P<0.001); there was no increase in the frequency of PS in NFNS patients with truncating mutations. Eight out of eleven (73%) individuals with NF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (P<0.015). Only three cases of WS have been published with intragenic mutations, two of three had non-truncating mutations. Therefore, PS in NF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype–phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.