PurposeThere are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients.MethodsStakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice.ResultsGuidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer.ConclusionThis document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

SummaryThe extracellular matrix (ECM) can induce chemotherapy resistance via AKT-mediated inhibition of apoptosis. Here, we show that loss of the ECM protein TGFBI (transforming growth factor beta induced) is sufficient to induce specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells. Paclitaxel-resistant cells treated with recombinant TGFBI protein show integrin-dependent restoration of paclitaxel sensitivity via FAK- and Rho-dependent stabilization of microtubules. Immunohistochemical staining for TGFBI in paclitaxel-treated ovarian cancers from a prospective clinical trial showed that morphological changes of paclitaxel-induced cytotoxicity were restricted to areas of strong expression of TGFBI. These data show that ECM can mediate taxane sensitivity by modulating microtubule stability.

DW MR imaging has superior diagnostic accuracy in the assessment of myometrial invasion and significantly higher staging accuracy compared with DCE MR imaging.

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This study investigates the clinical course of low grade squamous intraepithelial lesions (LSIL), HPV status and HPV16-specific immune response in a large prospective study of 125 women with LSIL followed cytologically, virologically and histologically. Women with low-grade abnormal smears were recruited and followed-up for one year. Colposcopy, cervical biopsy for histology and brushings for HPV typing was performed at recruitment, 6 months (no biopsy) and upon completion of the study at one year. HPV16-specific T-cell responses were analysed by interferon-c ELISPOT at entry, 6 and 12 months. Infection with multiple HPV types was detected in 70% of all patients, HPV16 was found in 42% of the patients. LSIL lesions progressed to HSIL in 24%, persisted in 60% and regressed to normal in 16% of the patients. No difference was observed in the clearance rate of infections with single or multiple HPV types among the groups with a different histological outcome. HPV16-specific type 1 T-cell responses were detected in only half of the patients with an HPV161 LSIL, and predominantly reactive to HPV16 E2 and E6. Interestingly, the presence of HPV16 E2-specific T-cell responses correlated with absence of progression of HPV161 lesions (p 5 0.005) while the detection of HPV16 E6 specific reactivity was associated with persistence (p 5 0.05). This large prospective study showed that the majority of LSIL persisted or progressed within the first year.This was paralleled by immune failure as most of the patients with an HPV161 LSIL failed to react to peptides of HPV16 E2, E6 or E7.Cervical cancer is preceded by a spectrum of epithelial atypia known as cervical intraepithelial neoplasia (CIN) or squamous intraepithelial lesions (SIL) characterized by disturbances of cellular maturation, stratification and cytological atypia of increasing severity. CIN/SIL are caused by persistent infection with one of a subset of genital human papillomaviruses (HPV), in particular HPV type 16. Natural history studies 1 show that most (90%) low grade cervical intraepithelial neoplasia (CIN 1) regress spontaneously and this is attributed to the development of HPV antigen specific cellular immune responses 2 but 30-40% of CIN3 progress to invasive cervical cancer 3 and spontaneous regression is relatively uncommon. The key role of the adaptive cellular immune system in protection against HPV-induced lesions is indicated by the high incidence of persistent HPV-infections and subsequent HPV-related malignancies in immunosuppressed individuals 4 and the observation that only a small fraction of infected non-immunosuppressed subjects develop progressing epithelial lesions or cancer. 5 Composite data indicate the importance of CD4þ T-cells in the control of HPV-induced diseases as more severe lesions are observed in patients with low numbers of circulating CD4þ cells 6,7 and the increase in CD4 count, after anti-retroviral treatment, correlates with the regression of HPV-induced CIN lesions in HIV þ patients. 8 At the time of spontaneous regression of HP...

Objective To review antenatal and intrapartum assessment of pregnancies complicated by gastroschisis. Design Retrospective descriptive study. Setting University College Hospital, London. Subjects 24 consecutive cases of gastroschisis between 1986 and 1991. Results The gestational age at sonographic diagnosis was 20.3 weeks (SD 6.77) and at birth was 36.5 weeks (SD 2.06). There were 21 live births, all with good surgical outcome. There were 16 vaginal deliveries and eight caesarean sections. The elective sections were for oligohydramnios and dilated bowel (1) and clinically suspected growth retardation (1); the intrapartum caesarean sections were for fetal distress (4) and premature breech presentation (2). There were six with dilated gut on ultrasound; one of these ended in a stillbirth. There was a significant association between gut dilatation and caesarean section for fetal distress (P= 0.004). There was also a significant association between meconium staining and fetal distress (P= 0.021). Of these babies, 46% were ≤ third centile for corrected birth weight. Conclusions While half of the babies with gastroschisis were small for gestational age at birth, reliable antenatal prediction of birth weight is difficult. Gut dilatation may be an indicator of either antenatal or intrapartum fetal distress, but does not correlate with poor neonatal surgical outcome. We suggest close antenatal surveillance of fetal wellbeing in all cases of gastroschisis because, in addition to growth retardation, many show some evidence of fetal distress and 12.5% end in stillbirth, even when appropriately grown.

BackgroundOver recent years genetic testing for germline mutations in BRCA1/BRCA2 has become more readily available because of technological advances and reducing costs.ObjectiveTo explore the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (EOC).MethodsBetween 1 July 2013 and 30 June 2015 women newly diagnosed with EOC were recruited through six sites in East Anglia, UK into the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. Eligibility was irrespective of patient age and family history of cancer. The psychosocial arm of the study used self-report, psychometrically validated questionnaires (Depression Anxiety and Stress Scale (DASS-21); Impact of Event Scale (IES)) and cost analysis was performed.Results232 women were recruited and 18 mutations were detected (12 in BRCA1, 6 in BRCA2), giving a mutation yield of 8%, which increased to 12% in unselected women aged <70 years (17/146) but was only 1% in unselected women aged ≥70 years (1/86). IES and DASS-21 scores in response to genetic testing were significantly lower than equivalent scores in response to cancer diagnosis (p<0.001). Correlation tests indicated that although older age is a protective factor against any traumatic impacts of genetic testing, no significant correlation exists between age and distress outcomes.ConclusionsThe mutation yield in unselected women diagnosed with EOC from a heterogeneous population with no founder mutations was 8% in all ages and 12% in women under 70. Unselected genetic testing in women with EOC was acceptable to patients and is potentially less resource-intensive than current standard practice.

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