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Background Ovarian cancer is seventh most common cancer in women worldwide. Approximately 1.3% of women will be diagnosed with ovarian cancer at some point during their life time. The majority of tumours arise from surface of the ovary (epithelial). Two thirds of these women will present with advanced disease, requiring aggressive treatment, which includes debulking surgery (removal of as much disease as possible) and chemotherapy. However, most women (75%) with advanced epithelial ovarian cancer (EOC) will relapse following surgery and chemotherapy. Patients who relapse are treated with either platinum or non-platinum drugs and this is dependent on the platinum-sensitivity and platinum-free interval. These drug regimens are generally well-tolerated although there are potential severe side effects. New treatments that can be used to treat recurrence or prevent disease progression after first-line or subsequent chemotherapy are important, especially those with a low toxicity profile. Hormones such as luteinising hormone releasing hormone (LHRH) agonists have been used in the treatment of relapsed EOC. Some studies have shown objective remissions, while other studies have shown little or no benefit. Most small studies report a better side-effect profile for LHRH agonists when compared to standard chemotherapeutic agents used in EOC. Objectives To compare the effectiveness and safety of luteinising hormone releasing hormone (LHRH) agonists with chemotherapeutic agents or placebo in relapsed epithelial ovarian cancer (EOC). Search methods We searched the Cochrane Gynaecological Cancer Group trials register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase up to January 2016. We also searched registers of clinical trials and abstracts of scientific meetings. Selection criteria Randomised controlled trials (RCTs) that compared LHRH agonists with chemotherapeutic agents or placebo in relapsed EOC. Data collection and analysis Two review authors independently assessed whether relevant studies met the inclusion criteria, retrieved data and assessed risk of bias. Main results Two studies, including 97 women, met our inclusion criteria: one assessed LHRH agonist (leuprorelin) use in relapsed (platinum-resistant and platinum-refractory) EOC in comparison with a chemotherapeutic agent (treosulfan) (Du Bois 2002); the other examined LHRH agonist (decapeptyl) versus a placebo (Currie 1994). Since both studies had different control groups, a meta-analysis was not possible. There may be little or no difference between treatment with leuprorelin or treosulfan in overall survival (OS) (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.58 to 1.67; very low-quality evidence) or progression-free survival (PFS) at six and 12 months (risk ratio (RR) 0.61, 95% CI 0.22 to 1.68, and RR 0.65, 95% CI 0.12 to 3.66; very low-quality evidence), respectively (Du Bois 2002). The duration of follow-up was 2.5 years and quality of life (QoL) was not reported in this study. Alopecia and fatigue were probably more common with treosulfan than leuprorelin (alopecia RR 0.32, 95% CI 0.12 to 0.91 (very low-quality evidence)). There may be little or no difference in other Grade 3/4 side effects: nausea and vomiting (RR 0.65, 95% CI 0.12 to 3.66 (very low-quality evidence)); neurotoxicity (RR 0.32, 95% CI 0.01 to 7.71 (very low-quality evidence)) and neutropenia (RR 0.97, 95% 0.06 to 14.97 (very low-quality evidence)), The Currie 1994 study, which compared decapeptyl treatment with placebo, reported mean PFS of 16 weeks verus 11.2 weeks, respectively. No relative effects measures or P value at a particular time point were reported. Overall survival (OS) and QoL outcomes were not reported. In addition, adverse events were only mentioned for the decapeptyl group. Adverse events were incompletely reported (no adverse events in decapeptyl group, but not reported for the placebo group). Authors' conclusions Based on this review of two small RCTs, there is not enough evidence to comment on the safety and effectiveness of LHRH agonists in the treatment of platinum-refractory and platinum-resistant (relapsed) EOC. Overall, the quality of evidence for all outcomes (including OS, PFS, QoL and adverse events) is very low.

The impact of age upon therapeutic response to unfractionated heparin (UFH) in children is proposed to reflect quantitative and potentially qualitative differences in coagulation proteins across childhood. This study explores the UFH-dependent tissue factor pathway inhibitor (TFPI) release in children compared to previously published data in adults. Children

Paediatric recommendations for unfractionated heparin (UFH) management are extrapolated from adult trials, a practice that may contribute to the inferior UFH-related outcomes in children compared to adults. This is the first study to determine UFH concentration in a population of children and correlated UFH concentration with measures of UFH effect. Correlation coefficients between protamine titration (concentration) and activated partial thromboplastin time (APTT), anti- activated factor X (Xa) assay and thrombin clotting time (effect) were 0·59, 0·46 and 0·52 respectively. A protamine titration level of 0·2-0·4 iu/ml in children was not equivalent to an anti-Xa assay of 0·35-0·7 iu/ml but to an anti-Xa assay 0·17-0·85 iu/ml. In addition, use of the anti-Xa or protamine titration assays to establish an APTT therapeutic range resulted in upper limits of APTT ranges exceeding 200 s. Existing methods for determining therapeutic ranges for UFH in adult populations do not produce equivalent ranges in children. As a result, paediatric clinical guidelines that state a therapeutic range for UFH can be determined using a protamine titration assay of 0·2–0·4 iu/ml or an anti-Xa assay of 0·35-0·7 iu/ml are not based on appropriate evidence. There is an urgent need for change in our approach to the use of UFH in children.

SummaryPrevious studies investigating continuous unfractionated heparin (UFH) therapy report age-related differences in UFH response in children, as measured by APTT and anti-Xa assay. This study determined the age-related response following administration of a single UFH bolus of 75–100 IU/kg in children. Venous blood samples were collected from children (n=56) at 15, 30, 45 and 120 minutes post-UFH. Anti-Xa, anti-IIa, APTT, TCT and protamine titration were performed on all samples. Age-dependent differences in the effect and concentration of UFH were identified for the anti-Xa, anti-IIa and protamine titration as-says, respectively. In addition, a trend suggesting a proportional increase in anti-Xa and anti-IIa-mediated UFH effect with age was evident. Logistic regression demonstrated an increase in protamine titration of 0.6 IU/ml for every year of age in samples collected 15 minutes post-UFH. UFH-mediated anti-IIa activity was reduced compared to anti-Xa activity across childhood, with a two-fold increase in anti-Xa to anti-IIa ratio in infants less than one year of age compared to teenagers in the setting of high UFH concentrations. This study demonstrates that the previously reported age-dependent response to UFH occurs in the context of an age-dependent serum concentration of UFH. The trend toward increased UFH serum concentration and anticoagulant activity with age may be related to short-term differences in UFH binding to coagulant and competitive plasma proteins in vivo.

Introduction Anti-Factor Xa (Anti-Xa) assays specifically determine the anticoagulant activity of UFH by measuring the ability of heparin-bound Antithrombin (AT) to inhibit a single enzyme, Factor Xa (FXa). Recent improvements in the automation, cost-effectiveness and accessibility of the assay to clinicians, have resulted in the Anti-Xa assay becoming a part of daily clinical practice in many institutions. Objectives We hypothesized that different Anti-Xa assays have different applicability for use in clinical settings, depending on the amount of UFH administered. This was investigated in a tertiary paediatric institution. Materials and methods Samples were collected from children receiving Low-dose of UFH of at least 10 IU/kg/h, with or without a previous bolus of up to 25 IU/kg/h, within the previous 6 h in the PICU and HDU. High-dose UFH population consisted of children undergoing Cardiac Catheterization (CC), who received a bolus of UFH of 100 IU/kg body weight, 30 min prior to sampling. Results and conclusions The Anti-Xa activity for a given dose of UFH was found to vary significantly based on the Anti-Xa assay and the population being monitored. Our study suggests that the MODIFIED COMATIC Anti-Xa assay provides the best physiological measure of the UFH effect in children, as it does not introduce sources of error, such as exogenous AT, which may increase the measured ant Factor Xa activity, nor Dextran Sulphate which can displace plasma protein bound heparin and once again leading to falsely elevated assay results. Further studies that include assessment of clinical outcomes are required to confirm the applicability of use of this particular assay in monitoring UFH therapy.

Objectives To evaluate the use of image-guided biopsy (IGB) in routine clinical practice to obtain site-specific diagnoses in women presenting with peritoneal carcinomatosis (PC). Study design Retrospective case study. Setting Tertiary referral centre. Population A total of 149 consecutive women with PC who underwent IGB. Methods Biopsy was performed in women considered unsuitable for primary surgery because of poor performance status or disease unlikely to be optimally debulked, with a prior history of malignancy or where there was clinicoradiological uncertainty about primary tumour site. Standard haematoxylin–eosin histological analysis was supplemented with immunohistochemistry. Main outcome measures The rate of site-specific diagnosis. Results A total of 149 women underwent IGB using computed tomography or ultrasound over a 6-year period. The only complication was one rectus sheath haematoma. In 138 (93%) women, a site-specific cancer diagnosis was made on the IGB (including 111 mullerian tract, 8 gastrointestinal tract, 4 breast and 3 lymphoma); in ten women, a repeat biopsy was necessary, giving an overall failure rate of 7%. In a further six women, malignancy was confirmed but a site-specific diagnosis could not be made, and in four women, biopsy showed benign tissue. A site-specific diagnosis was obtained in 29 of the 32 women (94%) with previous malignancy, of which 18/32 (56%) showed a new primary cancer. Conclusions IGB is a safe and accurate technique for providing site-specific diagnoses in women with PC in routine clinical practice, including those with a previous relevant malignancy. IGB can replace laparoscopic or open biopsy in defining primary therapeutic options. The data would suggest that the biopsy should be performed with ultrasound where feasible.

Purpose: Germline mutations in the BRCA1 and BRCA2 genes confer increased susceptibility to ovarian cancer. There is evidence that tumors in carriers may exhibit a distinct distribution of pathological features, but previous studies on the pathology of such tumors have been small. Our aim was to evaluate the morphologies and immunophenotypes in a large cohort of patients with familial ovarian cancer. Experimental Design: We performed a systematic review of ovarian tumors from 178 BRCA1 mutation carriers, 29 BRCA2 mutation carriers, and 235 controls with a similar age distribution. Tumors were evaluated by four pathologists blinded to mutation status. Both morphological features and immunochemical staining for p53 and HER2 were evaluated. Results: Tumors in BRCA1 mutation carriers were more likely than tumors in age-matched controls to be invasive serous adenocarcinomas (odds ratio, 1.84; 95% confidence interval, 1.21–2.79) and unlikely to be borderline or mucinous tumors. Tumors in BRCA1 carriers were of higher grade (P < 0.0001), had a higher percentage solid component (P = 0.001), and were more likely to stain strongly for p53 (P = 0.018). The distribution of pathological features in BRCA2 carriers was similar to that in BRCA1 carriers. Conclusions: Use of pathological features can substantially improve the targeting of predictive genetic testing. Results also suggest that BRCA1 and BRCA2 tumors are relatively aggressive and may be expected to have poor prognosis, although this may be treatment dependent.

Objective: To assess whether reservoir pressure (Pres) in young individuals with a compliant aorta is uniform throughout the aorta, as has recently been reported in older adults with cardiovascular disease (1). Methods: High fidelity pressure was measured with a Verrata wire (Philips Volcano) in 5 aortic locations (ascending-to-abdominal) via pull-back in 11 children with a normal aorta (age 10.4 ± 4.9 years, mean ± SD). Pres was calculated using the ‘pressure-only’ approach (2), with exponential fitting over the whole of diastole (1) (WholeDia) or the period when pressure declined in an approximately exponential fashion (ExpDia). Results: ExpDia produced a better fit than WholeDia (R2=0.99 ± 0.01 vs 0.91 ± 0.11, P < 0.001). Pres amplitude (ΔPres) in the ascending aorta from WholeDia fitting (12.0 ± 4.1 mmHg) was less than with ExpDia fitting (19.0 ± 5.2, P = 0.001). The zero-flow asymptotic pressure (Pinf) obtained from the fitting procedure was negative (non-physiological) in 76% (WholeDia) and 44% (ExpDia) of recordings, but fixing Pinf to 37 mmHg (average of physiological values) had little effect on the resulting ΔPres. ΔPres varied by 5.7 ± 3.0 mmHg (WholeDia) and 7.3 ± 3.7 mmHg (ExpDia) between aortic locations (both P

Objective: This study investigated the accuracy of two oscillometric devices for measuring brachial and central blood pressures (BP) in children and adolescents, using high fidelity intra-arterial measurements as a gold-standard reference. Methods: 57 children and adolescents aged 9.5 ± 4.6 years (mean ± SD, range 3 to 17, 74% 0.18). Results in sub-groups ≥13 and

Objective: The aims of this study in children were to 1) evaluate two brachial oscillometric devices for estimating central augmentation index (AIx) and reflection magnitude (RM), and 2) test whether AIx or RM are associated with left ventricular mass index (LVMI). Methods: Intra-aortic (IA) AIx was calculated from high-fidelity pressure measured with a Verrata wire (Philips Volcano) in 60 children (9.2 ± 4.7 years) with unobstructed aorta undergoing clinically-indicated catheterisation. AIx was also obtained from SphygmoCor XCEL (SC, AtCor) and/or Mobil-o-Graph (MB, IEM) brachial oscillometric devices. RM(IA) was calculated via wave separation using a representative normalised flow waveform obtained from MRI in a separate group of normal adolescents, RM(SC) via the triangulation method, and RM(MB) provided by the proprietary software. LVMI was estimated via echocardiography. Results: Invasive vs non-invasive AIx and RM are compared in the Table. AIx(IA) correlated weakly with AIx(SC) (R = 0.27, P = 0.04) but not AIx(MB) (P = 0.4). Neither RM(SC) nor RM(MB) correlated with RM(IA) (P = 0.13 and P = 0.96 respectively). RM(IA) was moderately correlated with AIx(IA) (R = 0.69, P < 0.001) and weakly correlated with AIx(SC) (R = 0.36, P = 0.007) but not AIx(MB) (P = 0.7). In a multivariable regression, height (P < 0.001) and RM (IA) (P = 0.04) were independently and positively associated with LVMI (adjusted R2 = 0.24), whereas there were no associations of any AIx or non-invasively estimated RM with LVMI. Conclusion: Central AIx and RM were poorly estimated by SC and MB in children. Unlike RM(IA), none of the non-invasive indices of wave reflection correlated with LVMI, likely due to inadequate estimation of the central pressure waveform shape in this age group.

Necrosis in pathologic specimens of ovarian cancer is well documented; however, computed tomography (CT) evidence of gaseous necrosis in the absence of fistulation with bowel has not yet been described. We report three cases of ovarian adenocarcinoma that on CT showed evidence of gross gaseous necrosis, mimicking a pelvic abscess.

Objective To assess the role of neural networks in predicting the likelihood of malignancy in women presenting with ovarian tumours. Design Retrospective case study. Setting University Department of Obstetrics and Gynaecology, St James's Hospital, Leeds. Methods Information from 217 cases with histologically proven benign, borderline or malignant tumours was extracted for study. Four variables (age, ultrasound findings with and without colour Doppler imaging and CA125) were entered in the neural network classifier. The neural network results were compared with logistic regression analysis. Results When used in the neural network the variables of age, CA125 and ultrasound score produced the best result with a sensitivity of 95% and a corresponding specificity of 78% in predicting malignancy. Logistic regression gave a sensitivity or 82% for a specificity of 51%. Conclusion The neural network is a good method of combining diagnostic variables and may be a useful predictor of malignancy in women presenting with ovarian tumours. A comparison of the performance of the neural network with conventional diagnostic methods would be warranted prior to use in clinical practice.

A major function of calcitonin in humans appears to be maintenance of the skeleton. There is a marked sex difference in circulating calcitonin levels: women have much lower levels. This has led to speculation that calcitonin lack may be one factor involved in the pathogenesis of postmenopausal bone loss. We have measured levels of calcitonin and the other major calcium-regulating hormones in healthy women during the early menopause, and studied the effects of reversing their oestrogen deficiency with natural and synthetic oestrogen. The major findings were that calcitonin levels were increased by oestrogen administration (P less than 0.02-less than 0.001) and that the levels of the bone-resorbing hormones, parathyroid hormone and 1,25 dihydroxyvitamin D, were not higher in postmenopausal than in premenopausal women. We suggest that loss of oestrogen at the menopause accelerates the natural age-related decline of calcitonin secretion, thus further decreasing the calcitonin levels. This leads to increased sensitivity of the skeleton to the actions of the bone-resorbing hormones. It seems likely that the well-known effect of oestrogen in preventing postmenopausal bone loss is achieved, at least in part, by enhancement of calcitonin secretion.