Search

Hydroxylative dearomatization reactions of phenols (HPD) offer an efficient way to assemble complex, biologically relevant scaffolds. Despite this, enantioselective hydroxylative phenol dearomatizations for the construction of bicyclo[2.2.2]octenones are classically limited to stoichiometric chiral reagents, and a practical, enantioselective catalytic method has remained elusive. Herein, we describe a highly enantioselective, organocatalytic tandem o-HPD-[4+2] reaction. Our methodology utilizes a chiral oxaziridinium organocatalyst, that is available in both enantiomeric forms, to afford dearomatized products in high enantioselectivity over a range of phenol substitution patterns. This approach was applied to the highly enantioselective synthesis of (+)-biscarvacrol (99 : 1 e.r.) and (-)-bis(2,6-xylenol) (94 : 6 e.r.). The practicality of our conditions was demonstrated at gram-scale, using an amine precatalyst, accessible in a single synthetic step.

To investigate whether HE4 and CA125 could identify endometrioid adenocarcinoma patients who might most benefit from full staging surgery with lymphadenectomy.Sequential patients with a preoperative banked serum and histology of endometrioid adenocarcinoma of endometrium who had undergone surgical staging with lymph node dissection over a 5-year period between 2011 and 2016 were included from a tertiary Gynaecological Cancer Centre, Dublin, Ireland. Preoperative serum HE4 and CA125 were measured using ELISA, with the cut-offs HE4 81 pmol/L and CA125 35 U/ml. Predictive values were estimated using AUC, sensitivity, specificity and odds ratios.9.5% of the cohort had lymph node metastases. A HE4 cut-off of 81 pmol/L yielded a sensitivity of 78.6% and specificity of 53.4% for predicting lymph node metastases. Sensitivity of CA125 at 35 U/ml was 57% and specificity 91.4%. The AUC was 0.66 (0.52-0.80) for HE4 and 0.74 (0.58-0.91) for CA125. Sensitivity was 92.8% and specificity 51.1% when an elevation of either HE4 or CA125 was included, AUC was 0.72 (0.61-0.83), this combination yielded the highest NPV of 98.6%. Sensitivity was 42.9% and specificity 93.8% if both markers were elevated simultaneously, AUC was 0.68 (0.51-0.86). Preoperative clinical predictors of high-grade preoperative histology and radiology had sensitivities of 21.4% and 41.7%, respectively. Patients with a HE4 above 81 pmol/L had an odds ratio of 4.2 (1.12-15.74), p 0.05, of lymph node metastases and CA125 had an odds ratio of 14.2 (4.16-48.31), p 0.001.Serum HE4 and CA125 improved on existing methods for risk stratification of endometrioid carcinomas and warrant further investigation.

Hydroxylative dearomatization reactions of phenols (HPD) offer an efficient way to assemble complex, biologically relevant scaffolds. Despite this, enantioselective hydroxylative phenol dearomatizations for the construction of bicy-clo[2.2.2]octenones are classically limited to stoichiometric chiral reagents, and a practical, enantioselective catalytic method has remained elusive. Herein, we describe a highly enantioselective, organocatalytic tandem o-HPD-[4+2] reaction. Our methodology utilizes a chiral oxaziridinium organocatalyst that affords high enantioselectivity for a wide range of phenol substitution patterns, and was applied in the synthesis of (+)-biscarvacrol and bis(2,6-xylenol). The practicality of our conditions were demonstrated at gram-scale, using an amine precatalyst that can be accessed in a single synthetic step.

The mortality associated with cervical cancer can be reduced if detected at the precancer stage, but current methods are limited in terms of subjectivity, cost and time. Optical spectroscopic methods such as Raman spectroscopy can provide a rapid, label-free and nondestructive measurement of the biochemical fingerprint of a cell, tissue or biofluid. Previous studies have shown the potential of Raman spectroscopy for cervical cancer diagnosis, but most were pilot studies with small sample sizes. The aim of this study is to show the clinical utility of Raman spectroscopy for identifying cervical precancer in a large sample set with validation in an independent test set. Liquid-based cervical cytology samples (n = 662) (326 negative, 200 cervical intraepithelial neoplasia (CIN)1 and 136 CIN2+) were obtained as a training set. Raman spectra were recorded from single-cell nuclei and subjected to a partial least squares discriminant analysis (PLSDA). In addition, the PLSDA classification model was validated using a blinded independent test set (n = 69). A classification accuracy of 91.3% was achieved with only six of the blinded samples misclassified. This study showed the potential clinical utility of Raman spectroscopy with a good classification of negative, CIN1 and CIN2+ achieved in an independent test set.

Background: Information concerning the health-related quality-of-life (HRQoL) consequences of colposcopy is limited, particularly over time. In a longitudinal study, we investigated women’s HRQoL at 4, 8 and 12 months post colposcopy and the factors associated with this. Methods: Women attending colposcopy at two large hospitals affiliated with the national screening programme in Ireland were invited to complete questionnaires at 4, 8 and 12 months post colposcopy. HRQoL was measured using the EQ-5D-3L and compared across a range of socio-demographic, clinical and attitudinal variables. A mixed-effects logistic multivariable model was employed to investigate associations between these variables and low HRQoL. Results: Of 584 women initially recruited, 429, 343 and 303 completed questionnaires at 4, 8 and 12 months, respectively. The mean overall HRQoL score for the sample across all time points was 0.90 (SD 0.16). Approximately 18% of women experienced low HRQoL at each of the three time points. In multivariable testing, over the entire 12-month follow-up period, non-Irish nationals (OR 8.99, 95% CI 2.35–34.43) and women with high-grade referral cytology (OR 2.78, 95% CI 1.08–7.13) were at higher odds of low HRQoL. Women who were past (OR 0.20, 95% CI 0.07–0.58) or never (OR 0.42, 95% CI 0.16–1.12) smokers were at lower odds of low HRQoL than current smokers. As women’s satisfaction with their healthcare increased their odds of experiencing low HRQoL fell (OR per unit increase 0.51, 95% CI 0.34–0.75). Conclusions: Women’s HRQoL did not change over the 12 months post colposcopy, but some subgroups of women were at higher risk of experiencing low HRQoL. These subgroups may benefit from additional support.

Background Considering the shared aetiology of Human Papillomavirus infections in oropharyngeal and cervical cancers and the possible role for sexual transmission, several key aspects of the relationship between cervical and oral infections merit investigation, including prevalence of concomitant oral HPV infection and type-specific concordance with concurrent cervical infections. Methods A cross-section study was performed on women referred to colposcopy clinics with cytological abnormalities and a cervical HPV infection. An oral rinse sample was taken from the participants at their baseline visit for HPV testing, and a demographic and risk factor questionnaire was also administered. HPV DNA testing was carried out on the Cobas 4800 platform and extended genotyping was carried out with the INNO-LiPA HPV Genotyping Extra II assay. HPV genotyping was also carried out on the concurrent cervical tissue samples on all women who had a positive oral HPV infection. Results The prevalence of oral HPV infections was 10.0% (95%CI:5.9-13.7) in the study population. HPV18 was the most frequent genotype (7.0%). Concordant oral and cervical HPV infections were detected in 28.6% of women. Age (P = 0.005) and level of education (P = 0.02) were are significantly associated with a prevalent oral HPV infection. Conclusion Concomitant oral HPV infections were present in 10.0% of women referred to colposcopy with a pre-existing cervical HPV infections and cytological abnormalities. Although mild type-specific concordance was observed between oral and cervical HPV infections, findings suggest that infections at these sites may not be independent of each other.

Background The aim of this study was to evaluate the clinical performance of the Cobas 4800 HPV test and the Aptima HPV assay for the detection of CIN2+ disease in women referred to colposcopy with minor cytological abnormalities. Methods ThinPrep liquid-based cytology samples were collected from 562 women referred to colposcopy with minor cytological abnormalities. HPV testing by both assays was performed on these samples. Clinical performances for detection of histologically diagnosed CIN2+ and CIN3+ were calculated. Results HPV prevalence by the Cobas 4800 HPV test was 58.2% and 53.0% women tested positive with the Aptima HPV assay in the entire study population. The Aptima HPV assay and the Cobas 4800 HPV test displayed equivalent sensitivity of 90.2% (95%CI, 83.4-94.9) for the detection of CIN2+ disease. However, the Aptima HPV assay displayed greater specificity of 61.0% (95% CI, 54.0-68.0) when compared to the Cobas 4800 HPV test 53.0% (95% CI, 46.0-60.0), and this was significantly higher (P = .0004). The Aptima HPV assay also displayed higher specificity 76.5% (95% CI, 66.0-85.0) in the ASCUS category in comparison to the Cobas 4800 HPV test 65.0% (95% 54.0-75.0) which was statistically significant (P = .004). Conclusions Both the tests displayed similar sensitivity. However, the Aptima HPV assay was significantly more specific in the identification of women with CIN2+ disease in a colposcopy referral population.

Introduction/Background Endometrial cancer (EC) is the most common gynaecological malignancy. The mainstay of treatment is surgical resection. Currently, there are no sensitive and specific biomarkers for EC. Human Epididymis protein 4 (HE4) shows promise as a diagnostic and prognostic marker. We investigated the sensitivity of preoperative serum HE4 for predicting high-risk EC. Methodology 206 patients were recruited from the DISCOVARY bioresource between 2011 and 2016. Demographic and tumour characteristics were recorded. Preoperative serum HE4 and CA125 was measured using Fujirebio Diagnostic ELISA Kits, with the cut-off points of HE4 70 pmol/L and CA125 35 U/ml. ELISA results were correlated with clinicopathological details. Statistical analysis was performed using SPSS. Results The cohort comprised of endometrioid adenocarcinomas (n=167) representing over 80% of the malignant cohort, carcinosarcoma (MMMT) (n=14), serous (n=17), mixed (n=6), mucinous (n=1) and clear cell (n=1). Using a cut-off of 70 pmol/L, serum HE4 had a sensitivity of 75.9% for predicting >50% myometrial invasion, more than twice the sensitivity of CA125 for >50% myometrial invasion (27.8%). Specificities were similar at 93.6% for HE4 and 95.1% for CA125. HE4 was more sensitive for predicting the presence of LVSI in EC (71%), compared to CA125 (34%). HE4 had a sensitivity of 89.6% and specificity of 46.2% for predicting lymphadenopathy, compared to a sensitivity of 46% and a specificity of 90.7% with CA125. Conclusion HE4 showed a high sensitivity for predicting the presence of high ­risk prognostic factors. Clinically, HE4 may have a role in supplementing transvaginal ultrasound in EC diagnosis. Furthermore, preoperative HE4 may supplement imaging studies when stratifying EC patients as high­ or low­ risk, enabling personalisation of surgical management, and improved outcomes. Further work is needed on establishing relevant cut-offs for high-risk cohorts. Disclosure ELISA kits were supplied by Fujirebio Diagnostics.

e17576 Background: Cancer cachexia is associated with considerable morbidity and mortality, yet its prevalence in gynaecological malignancy is unknown. Prevalence of cachexia in de novo gynaecological cancer patients and the impact of cachexia on clinical parameters and patient-reported outcomes were investigated. Methods: A prospective, exploratory study of newly diagnosed gynaecological cancer patients was conducted at St. James’s Hospital, the largest treatment provider for gynaecological malignancy in the Republic of Ireland. Patients recently diagnosed with a gynaecological cancer were eligible. Demographics, oncological history, Clavien Dindo Classification and length of stay were collected from participants’ medical record. A questionnaire completed by participants on 3 consecutive days collected data on height, weight, weight history, recent dietary intake, nutritional impact symptoms and functional status. Cachexia was defined using the criteria established in 2011 (Fearon and Strasser et al, 2011). Participants’ staging computed tomography scans were utilised for body composition analysis. Descriptive statistics, Mann Whitney U tests and Chi-square were used to summarise and identify significant associations between variables. Logistic regression was used to model predictors of cachexia. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire in conjunction with EORTC gynaecological cancer-specific modules assessed quality of life. Results: A total of 94 participants were recruited. All five gynaecological cancers were represented. Prevalence of cachexia was 21.4% and was highest in patients with cervical cancer. Any weight loss in the previous month was predictive of developing cachexia. Low albumin and anorexia were associated with cachexia, although neither reached significance. Median post-operative length of stay for cachectic patients was 5 days (range 1-57) compared to 4 days (range 0-27) for non-cachectic patients (p = 0.682). 60% of cachectic patients had some post-operative complication. Cachectic patients were more symptomatic and had lower functional status in all quality of life categories, with the exception of emotional function. Conclusions: As prevalence of cachexia in this population is at least 22%, we strongly recommend screening for cachexia at all clinical assessments. Although weight loss and body mass index can identify the majority of cachectic patients, skeletal muscle mass index should also be included where possible. Its incorporation into standard radiology assessment of cancer patients would be optimal. Further research is warranted in a larger population to fully elucidate the predictors of cachexia. Quality of life is a useful means to monitor symptoms and functional status which may contribute to or exacerbate cachexia.

Simple Summary Persistent high-risk human papillomavirus (HPV) infection can lead to cervical precancer and cancer. Recently, HPV testing has been introduced for primary cervical screening, but the HPV DNA test cannot distinguish between transient and persistent HPV infection. Thus, there is an unmet clinical need to develop a new test to identify women with a high-risk persistent HPV infection. Raman spectra were recorded from cervical smear samples (n = 60) and, on the basis of HPV DNA and HPV mRNA test results, a classifier was developed to identify persistent HPV infection. A further blinded independent test set (n = 14) was used to validate the model, and sensitivity of 90% and specificity of 100% were achieved. Improved triage would allow women with a high-risk persistent HPV infection to be referred for immediate treatment, while women with a low-risk transient infection could avoid overtreatment. Abstract The role of persistent high-risk human papillomavirus (HPV) infection in the development of cervical precancer and cancer is now well accepted, and HPV testing has recently been introduced for primary cervical screening. However, the low specificity of HPV DNA testing can result in large numbers of women with an HPV-positive result, and additional triage approaches are needed to avoid over-referral to colposcopy and overtreatment. The aim of this study was to assess Raman spectroscopy as a potential triage test to discriminate between transient and persistent HPV infection. HPV DNA status and mRNA status were confirmed in ThinPrep® cervical samples (n = 60) using the Cobas 4800 and APTIMA HPV test, respectively. Raman spectra were recorded from single-cell nuclei and subjected to partial least squares discriminant analysis (PLSDA). In addition, the PLSDA classification model was validated using a blinded independent test set (n = 14). Sensitivity of 85% and specificity of 92% were achieved for the classification of transient and persistent HPV infection, and this increased to 90% sensitivity and 100% specificity when mean sample spectra were used instead of individual cellular spectra. This study showed that Raman spectroscopy has potential as a triage test for HPV-positive women to identify persistent HPV infection.

Some women experience distress during colposcopy examinations which is partly related to women's fear, or experience, of pain during the procedure. However, little is known about women's sensory experiences of colposcopy (other than pain) or what might impact on these experiences. The aim of this study was to explore women's sensory experiences of colposcopy and related procedures and identify factors which influenced negative sensory experiences.In-depth interviews were conducted with 23 women who had undergone, for the first time, a colposcopy (some with related procedures, including punch biopsies and loop excision) as part of follow-up for abnormal cervical cytology. Interviews were analysed thematically using the Framework Approach to organise the data and identify emerging higher-order themes.Women described a range of sensory experiences including pain or discomfort, cramping, stinging and cold sensations (due to the application of acetic acid to the cervix). Four key themes emerged as important aspects of the overall sensory experience: levels of pain, treatment-specific sensations, anaesthetic-specific sensations and solution-specific sensations. Factors that may influence women having a negative sensory experience were sensory expectations of the procedure(s) and lack of preparatory sensory information.Our study provides unique in-depth insight into women's sensory experiences of colposcopy and related procedures and suggests women require more preparatory sensory information. The issues identified as contributing to women having a negative sensory experience may help inform the development of pre-colposcopy information which may better prepare women with abnormal cervical cytology for follow-up examinations.

Objective Little is known about which women are at greatest risk of adverse psychological after-effects following colposcopy. This study examined time trends in, and identified predictors of, anxiety and specific worries over 12 months. Methods Women attending two hospital-based colposcopy clinics for abnormal cervical cytology were invited to complete psychosocial questionnaires at 4, 8 and 12 months following colposcopy. General anxiety and screening-specific worries (about cervical cancer, having sex and future fertility) were measured. Generalised estimating equations were used to assess associations between socio-demographic, lifestyle and clinical variables and risk of psychological outcomes. Results Of 584 women initially recruited, 429, 343 and 303 completed questionnaires at 4, 8 and 12 months, respectively. Screening-specific worries declined significantly over time but were still relatively high at 12 months: 23%, 39% and 18% for worries about cervical cancer, fertility and having sex, respectively. Anxiety remained stable (20%) over time. Risks of cervical cancer worry and anxiety were both almost double in women without private health insurance (cervical cancer worry: OR = 1.80, 95% CI 1.25–2.61; anxiety: OR = 1.84, 95% CI 1.20–2.84). Younger women (

Background Women who have an abnormal cervical cytology test may be referred for a colposcopy. Accumulating evidence suggests some women may experience distress after colposcopy. This exploratory study examined women's differing experiences of post-colposcopy distress with the aim of identifying factors that are predictive of, or protective against, distress. Methods We carried out semistructured, qualitative interviews with 23 women who had undergone colposcopies. Interviews were transcribed verbatim, coded, and analyzed thematically. The Framework Approach was used to summarize and organize the data and identify emerging higher order themes. Results Two forms of post-colposcopy distress emerged: 1) short term and 2) long term. Short-term distress was experienced immediately after the colposcopy and in the days afterward, and was usually related to the physical experience of the colposcopy. Long-term distress typically persisted over time and was related to concerns about fertility, cervical cancer, and sexual intercourse. The drivers of short-term and long-term distress differed. Factors related to short-term distress were feeling unprepared for the procedure, having a negative experience of the procedure, and attending the clinic alone. Factors related to long-term distress were future intentions to have (more) children, having physical after-effects of the procedure that impacted on the woman's life, and being under on-going clinic surveillance. Absence of these factors (e.g., being accompanied to the clinic) was protective against short- and long-term distress. Conclusions Colposcopy can lead to short- and long-term post-procedural distress for some women. We identified a range of factors, some potentially modifiable, that seem to influence the chances of experiencing distress. These results may inform the development of strategies or interventions aimed at preventing or minimizing distress after colposcopy and related procedures.

The aim of the study was to determine the incidence and aetiology of peripartum hysterectomy (PH) for major obstetric haemorrhage (MOH) in our population and to compare estimated blood loss (EBL), blood transfusion, surgical complications and duration of hospital stay in PH that was anticipated and PH that was unanticipated. 26 cases of MOH requiring PH were identified from 50,548 women who delivered between 1 January 2006 and 31 December 2011 (0.5/1000). PH was anticipated in 17 and unanticipated in 9 cases. When compared, the anticipated group was more likely to have placenta accreta 15/17 (88%) vs 4/9 (44%): p = 0.03 and a gynaecological oncologist as the principal operator 15/17 (88%) vs 3/9 (33%): p = 0.007. The EBL 5.5 ± 3.7 SD vs 6.6 ± 3.9 SD l; p = 0.5, units of red cell concentrate or RCC transfused 7 ± 5 SD vs 9 ± 5 SD: p = 0.3, and mean operating time 134 ± 60 SD vs 190 ± 96 SD min: p = 0.07 were less in the anticipated than the unanticipated group, but not significantly so. The intraoperative complication rate 7/17 (41%) vs 3/9 (33%): p = 1.0 and the mean duration of hospital stay 7 ± 1 SD vs 8 ± 3 SD days: p = 0.27 were similar in both groups. PH is associated with a large volume of blood loss and significant surgical complications regardless of whether the procedure is anticipated or not.

Ovarian cancer is the seventh most common cancer in women and the most frequent cause of gynaecological malignancy-related mortality in women. Currently, no standardized reliable screening test exists. MicroRNA profiling has allowed the identification of signatures associated with diagnosis, prognosis and response to treatment of human tumours. The aim of this study was to determine if a microRNA signature could distinguish between malignant and benign ovarian disease. A training set of 5 serous ovarian carcinomas and 5 benign serous cystadenomas were selected for the initial experiments. The validation set included 20 serous ovarian carcinomas and 20 benign serous cystadenomas. The serum/plasma focus microRNA Exiqon panel was used for the training set. For the validation set a pick and mix Exiqon panel, which focuses on microRNAs of interest was used. A panel of 4 microRNAs (let-7i-5p, miR-122, miR-152-5p and miR-25-3p) was significantly down regulated in cancer patients. These microRNAs target WNT signalling, AKT/mTOR and TLR-4/MyD88, which have previously been found to play a role in ovarian carcinogenesis and chemoresistance. let-7i-5p, miR-122, miR-152-5p and miR-25-3p could act as diagnostic biomarkers in ovarian cancer.

Objective To estimate prevalence of post-colposcopy physical after-effects and investigate associations between these and subsequent psychological distress. Design Longitudinal survey. Setting Two hospital-based colposcopy clinics. Population Women with abnormal cytology who underwent colposcopy (±related procedures). Methods Questionnaires were mailed to women 4, 8 and 12 months post-colposcopy. Details of physical after-effects (pain, bleeding and discharge) experienced post-colposcopy were collected at 4 months. Colposcopy-specific distress was measured using the Process Outcome-Specific Measure at all time-points. Linear mixed-effects regression was used to identify associations between physical after-effects and distress over 12 months, adjusting for socio-demographic and clinical variables. Main outcome measures Prevalence of post-colposcopy physical after-effects. Associations between the presence of any physical after-effects, awareness of after-effects, and number of after-effects and distress. Results Five-hundred and eighty-four women were recruited (response rate = 73, 59 and 52% at 4, 8 and 12 months, respectively). Eighty-two percent of women reported one or more physical after-effect(s). Multiple physical after-effects were common (two after-effects = 25%; three after-effects = 25%). Psychological distress scores declined significantly over time. In adjusted analyses, women who experienced all three physical after-effects had on average a 4.58 (95% CI: 1.10–8.05) higher distress scored than those who experienced no after-effects. Women who were unaware of the possibility of experiencing after-effects scored significantly higher for distress during follow-up. Conclusions The prevalence of physical after-effects of colposcopy and related procedures is high. The novel findings of inter-relationships between awareness of the possibility of after-effects and experiencing multiple after-effects, and post-colposcopy distress may be relevant to the development of interventions to alleviate post-colposcopy distress. Tweetable abstract Experiencing multiple physical after-effects of colposcopy is associated with psychological distress.

Little is known about which women are at greatest risk of adverse psychological after-effects following colposcopy. This study examined time trends in, and identified predictors of, anxiety and specific worries over 12 months.Women attending two hospital-based colposcopy clinics for abnormal cervical cytology were invited to complete psychosocial questionnaires at 4, 8 and 12 months following colposcopy. General anxiety and screening-specific worries (about cervical cancer, having sex and future fertility) were measured. Generalised estimating equations were used to assess associations between socio-demographic, lifestyle and clinical variables and risk of psychological outcomes.Of 584 women initially recruited, 429, 343 and 303 completed questionnaires at 4, 8 and 12 months, respectively. Screening-specific worries declined significantly over time but were still relatively high at 12 months: 23%, 39% and 18% for worries about cervical cancer, fertility and having sex, respectively. Anxiety remained stable (20%) over time. Risks of cervical cancer worry and anxiety were both almost double in women without private health insurance (cervical cancer worry: OR = 1.80, 95% CI 1.25-2.61; anxiety: OR = 1.84, 95% CI 1.20-2.84). Younger women (40 years) had higher risk of fertility worries. Non-Irish women had higher risk of anxiety (OR = 2.13, 95% CI 1.13-4.01).Screening-specific worries declined over time but anxiety remained stable. Notable proportions of women still reported adverse outcomes 12 months following colposcopy, with predictors varying between outcomes. Women in socio-demographically vulnerable groups were at greatest risk of adverse psychological outcomes. This information could inform development of interventions to alleviate psychological distress post-colposcopy.

Objective To evaluate pretreatment tumour volume as a predictor of survival in patients with cervical cancer using both endovaginal and external coil magnetic resonance imaging in order to achieve high spatial resolution and delineate small volume disease. Design A retrosfection case series. Setting A tertiary referral centre for gynaecological oncology. Population/Sample One hundred and six consecutive women with invasive carcinoma of the cervix underwent endovaginal and external coil magnetic resonance imaging on a 0.5-T or 1.5-T scanner. Methods T2-W FSE images, sagittal and transverse to the cervix, were obtained and tumour volume was calculated on the sagittal images by the standard technique of multiplying the sum of the areas by the slice thickness. Patients were treated in accordance with normal clinical practice and their subsequent outcome was recorded. The relationships between clinical or imaging parameters and survival were assessed with Cox's proportional hazard method. Main outcome measures Disease-free survival. Results In 89 of these women, the tumour was Stage I and 88 of the 106 were treated principally by surgery. The median tumour volume was 4.75 cm3 (upper and lower quartiles 22 and 0.6). The median length of follow up of surviving patients was 223 weeks (quartiles 158 and 274 weeks). Stage, treatment type, lymphovascular space involvement, invasion of the parametrium, closeness of the excision margin, lymph node metastases, and magnetic resonance imaging measurements of tumour volume, parametrial invasion and lymph node disease were all significantly associated with survival in univariate analysis. Only magnetic resonance imaging measurement of tumour volume remained consistently and strongly associated with survival after multivariate analysis of parameters available prior to treatment (P= 0.001, Wald statistic 10.74). A receiver operating characteristic curve of tumour volume and disease-free survival confirmed the utility of this investigation and suggested that a cutoff around 13.0 cm3 would predict survival with a positive predictive value of 0.93 and a negative predictive value of 0.75. Conclusion Magnetic resonance imaging assessment of tumour volume using both an endovaginal and an external coil approach provides an accurate prediction of prognosis in cervical cancer and defines a population of women at high risk of recurrence and death. The predictive value of this investigation is superior to the clinical and histological parameters previously used. Use of this technique permits a more accurate choice of treatment options. These results suggest that it is the size of tumour burden that determines the outcome rather than invasion beyond the anatomical margins of the uterus.

The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p

The clinical performance of the cobas human papillomavirus (HPV) test for detection of high-grade disease in a colposcopy-referred population was compared with that of Hybrid Capture 2 (HC2). The overall agreement between the tests was 92.3%. Clinical sensitivity and specificity for detection of cervical intraepithelial neoplasia grade 2 or greater (CIN2+) were 90.0% and 55.5% for cobas and 90.5% and 50.2% for HC2, respectively. In conclusion, both tests showed comparable performance for detection of CIN2+.

Cervical screening programmes are moving towards HPV testing as part of the screening process and as a triage for colposcopy. Three HPV detection methods were evaluated using cervical cytology specimens from colposcopy patients. PreservCyt™ liquid based cytology specimens from 241 women attending colposcopy clinics with greater than 2 persistently abnormal smears were recruited through the Coombe Women and Infants University Hospital, Dublin. HPV DNA was detected by Hybrid Capture (HC2) for 13 high-risk HPV types, Full-Spectrum HPV (FS-HPV) for 49 high and low-risk types and Molecular Beacon Real-Time HPV assay (MBRT-HPV) for 16 high and low-risk types. HPV genotyping was performed using Linear Array HPV Assay (LA-HPV). HPV was detected in 83.3% (195/234), 91.9% (217/236) and 80.1% (169/211) of cytology specimens by HC2, FS-HPV and MBRT-HPV, HPV DNA detection assays. The sensitivity of the assays for the detection of high-risk HPV in cytology specimens that had a Cervical Intraepithelial Neoplasia Grade 2+ result by histology were, 98%, 97% and 94% for HC2, FS-HPV and MBRT-HPV assays with positive predictive values of 94.1%, 94.1% and 97.3%. The most common HPV genotypes were HPV 16, 31, 33, 58, 42, 61 and 53, and the most common high-risk HPV genotypes were HPV 16, 31, 33, 58, 18, 45, 59, 51, 56 and 39, with detection of multiple infections in 57.7% of all cases. FS-HPV and MBRT-HPV are highly sensitive and have a similarly high PPV as the HC2 assay for detection of HPV in patients with Cervical Intraepithelial Neoplasia Grade 2+ disease. HPV genotyping of women with persistent abnormalities is warranted prior to the introduction of HPV DNA testing in a colposcopy setting.

Platinum resistance is a major cause of treatment failure in ovarian cancer. We previously identified matrix metalloproteinase 9 (MMP-9) as a potential therapeutic target of chemoresistant disease. A2780cis (cisplatin-resistant) and A2780 (cisplatin-sensitive) ovarian carcinoma cell lines were used. The cytotoxic effect of MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) alone or in combination with cisplatin was determined using high content screening. Protein expression was examined using immunohistochemistry and ELISA. Co-incubation of cisplatin and an MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) resulted in significantly greater cytotoxicity as compared to either treatment alone in a cisplatin resistant MMP-9 overexpressing cell line; A2780cis. In addition, pre-incubating with MMP-9i prior to cisplatin further enhances the cytotoxic effect. No significant difference was observed in MMP-9 protein in tissue but a trend towards increased MMP-9 was observed in recurrent serum. We propose that MMP-9/MMP-2i may be utilized in the treatment of recurrent/chemoresistant ovarian cancers that overexpress MMP-9 mRNA but its role in vivo remains to be evaluated.

Email: Alexandros Laios alxlaios2000@yahoo.com; Sharon A O'Toole* shotoole@tcd.ie; Richard Flavin flavinr@tcd.ie; Cara Martin cmartin2@tcd.ie; Martina Ring mring@coombe.ie; Noreen Gleeson noreengleeson@eircom.net; Tom D'Arcy tsdarcy@indigo.ie; Eamonn PJ McGuinness gynaesec@stjames.ie; Orla Sheils osheils@tcd.ie; Brian L Sheppard bshepprd@tcd.ie; John J O' Leary olearyjj@tcd.ie * Corresponding author

The aim of this study was to assess whether microvessel density (measured by CD31), vascular endothelial growth factor (VEGF) or multidrug resistance (MDR1) could determine the response to chemotherapy or act as prognostic factors in ovarian cancer.Seventy-nine ovarian specimens were immunostained. Pearson correlation, 1-way ANOVA and chi-square were used for univariate analysis. Kaplan Meier survival curves were used, log-rank was used for univariate analysis and a Cox proportional hazards regression model was used for multivariate evaluation. Response to chemotherapy was assessed after 6 months and again after 1 year.Quantifying VEGF proved to be a valuable independent prognostic indicator in progression-free survival (PFS) (p0.05) and overall survival (OS) (p0.0001). VEGF correlated with response to chemotherapy at the 6-month interval (r=0.446, p0.001) but failed to correlate at the 1-year interval. Increased staining with CD31 was associated with decreased PFS (p0.01) and OS (p0.01) in univariate but not multivariate analysis. MDR1 failed to act as a prognostic marker or as a predictor of response to chemotherapy.VEGF correlates with response to chemotherapy at the 6-month but not the 12-month interval. What should our criteria be for determining sensitivity to chemotherapy? CD31, VEGF and MDR1 do play a role in some ovarian malignancies but other factors are likely to be involved and perhaps molecular profiling will determine which factors will be important for determining the response to chemotherapy.

Background Peripartum Hysterectomy (PH) is a rare complication of pregnancy 1 . This study sought to determine the rate of PH in our population and compare aetiology and clinical outcomes in cases of PH that are anticipated and unanticipated. Method Cases of PH for obstetric haemorrhage between 2006 and 2011 were identified from an MOH database. Data included maternal demographics, subspecialty of operator, aetiology for PH, estimated blood loss(EBL), RCC units transfused, surgical complications and length of hospital stay. Results 26 cases of PH (0.6/1000) were identified; 17 anticipated and 9 unanticipated. Placenta accreta (PA) was the indication for PH in 15/17 anticipated and 4/9 unanticipated cases. The remaining cases were attributed to uterine rupture (3/9), placenta previa, cervical ectopic and atony. Discussion The majority of cases of PH are anticipated because of prenatal diagnosis of placenta accreta and are more likely to undergo elective delivery by a gynae-oncologist. Despite this EBL, RCC transfusion and postoperative complications are not significantly different from unanticipated cases of PH, possibly reflecting the severity of cases diagnosed antenatally. Continuing research is required to improve the prenatal diagnosis of placenta accreta and to reduce perioperative blood loss with measures such as interventional radiology 2 . References Flood et al . Changing trends in peripartum hysterectomy over the last four decades. Am J Obstet Gynecol 2009 Jun; 200(6):632.e1–6. Angstmann et al. Surgical management of placenta accreta: a cohort series and suggested approach. Am J Obstet Gynecol 2010 Jan; 202(1):38.e1–9. Epub 2009 Nov 17.

Background MicroRNAs (miRNAs) are small, noncoding RNAs that negatively regulate gene expression by binding to target mRNAs. miRNAs have not been comprehensively studied in recurrent ovarian cancer, yet an incurable disease. Results Using real-time RT-PCR, we obtained distinct miRNA expression profiles between primary and recurrent serous papillary ovarian adenocarcinomas (n = 6) in a subset of samples previously used in a transcriptome approach. Expression levels of top dysregulated miRNA genes, miR-223 and miR-9, were examined using TaqMan PCR in independent cohorts of fresh frozen (n = 18) and FFPE serous ovarian tumours (n = 22). Concordance was observed on TaqMan analysis for miR-223 and miR-9 between the training cohort and the independent test cohorts. Target prediction analysis for the above miRNA "recurrent metastatic signature" identified genes previously validated in our transcriptome study. Common biological pathways well characterised in ovarian cancer were shared by miR-9 and miR-223 lists of predicted target genes. We provide strong evidence that miR-9 acts as a putative tumour suppressor gene in recurrent ovarian cancer. Components of the miRNA processing machinery, such as Dicer and Drosha are not responsible for miRNA deregulation in recurrent ovarian cancer, as deluded by TaqMan and immunohistochemistry. Conclusion We propose a miRNA model for the molecular pathogenesis of recurrent ovarian cancer. Some of the differentially deregulated miRNAs identified correlate with our previous transcriptome findings. Based on integrated transcriptome and miRNA analysis, miR-9 and miR-223 can be of potential importance as biomarkers in recurrent ovarian cancer.