Early preantral follicles of the domestic cat express gonadotropin and sex steroid signaling potential.

Key biomolecular processes, which regulate primordial ovarian follicle dormancy and early folliculogenesis in mammalian ovaries, are not fully understood. The domestic cat is a useful model to study ovarian folliculogenesis and is the most relevant for developing in vitro growth methods to be implemented in wild felid conservation breeding programs. Previously, RNA-sequencing of primordial (PrF), primary (PF), and secondary follicle (SF) samples from domestic cat implicated ovarian steroidogenesis and steroid reception during follicle development. Here, we aimed to identify which sex steroid biosynthesis and metabolism enzymes, gonadotropin receptors, and sex steroid receptors are present and may be potential regulators. Differential gene expression, functional annotation, and enrichment analyses were employed and protein localization was studied too. Gene transcripts for PGR, PGRMC1, AR (steroid receptors), CYP11A1, CYP17A1, HSD17B1 and HSD17B17 (steroidogenic enzymes), and STS (steroid metabolizing enzyme) were significantly differentially expressed (Q values of ≤0.05). Differential gene expression increased in all transcripts during follicle transitions apart from AR which decreased by the secondary stage. Immunohistochemistry localized FSHR and LHCGR to oocytes at each stage. PGRMC1 immunostaining was strongest in granulosa cells, whereas AR was strongest in oocytes throughout each stage. Protein signals for steroidogenic enzymes were only detectable in SFs. Products of these significantly differentially expressed genes may regulate domestic cat preantral folliculogenesis. In vitro growth could be optimized as all early follicles express gonadotropin and steroid receptors meaning hormone interaction and response may be possible. Protein expression analyses of early SFs supported its potential for producing sex steroids.

The NICE classification for 'Ultra-radical (extensive) surgery for advanced ovarian cancer' guidance does not meaningfully predict postoperative complications: a cohort study.

OBJECTIVE: To determine which descriptors of cytoreductive surgical extent in advanced ovarian cancer (AOC) best predict postoperative morbidity. DESIGN: Retrospective notes review. SETTING: A gynaecological cancer centre in the UK. POPULATION: Six hundred and eight women operated on for AOC over a period of 114 months at a tertiary cancer centre, between 16 August 2007 and 16 February 2017. METHODS: Outcome data were analysed by six approaches to classify the extent of surgery: standard/ultra-radical surgery; standard/radical/supra-radical surgery; presence/absence of gastrointestinal resections; low/intermediate/high surgical complexity score (SCS); presence of bowel anastomoses and/or diaphragmatic surgery; and the presence/absence of multiple bowel resections. MAIN OUTCOME MEASURES: Major (grades 3-5) postoperative morbidity and mortality. RESULTS: Forty-three (7.1%) patients experienced major complications. Grade-5 complications occurred in six patients (1.0%). Patients who underwent multiple bowel resections had a relative risk (RR) of 7.73 (95% confidence interval, 95% CI 3.92-15.26), patients with a high SCS had an RR of 6.12 (95% CI 3.25-11.52), patients with diaphragmatic surgery and gastrointestinal anastomosis had an RR of 5.57 (95% CI 2.65-11.72), patients with 'any gastrointestinal resection' had an RR of 4.69 (95% CI 2.66-8.24), patients with ultra-radical surgery had an RR of 4.65 (95% CI 2.26-8.79), and patients with supra-radical surgery had an RR of 4.20 (95% CI 2.35-7.51) of grades 3-5 morbidity, compared with patients undergoing standard surgery as defined by the National Institute for Health and Care Excellence (NICE) in the UK. No significant difference was seen in the rate of major morbidity between standard (6/59, 10.2%) and ultra-radical (9/81, 11.1%) surgery within the cohort who had intermediate complex surgery (P > 0.05). CONCLUSIONS: The numbers of procedures performed significantly correlate with major morbidity. The number of procedures performed better predicted major postoperative morbidity than the performance of certain 'high risk' procedures. We recommend using SCS to define a higher risk operation. NICE should re-evaluate the use of the term 'ultra-radical' surgery. TWEETABLE ABSTRACT: Multiple bowel resection is the best predictor of morbidity and is more predictive than 'ultra-radical surgery'.

Adjacent Lichen Sclerosis predicts local recurrence and second field tumour in women with vulvar squamous cell carcinoma.

OBJECTIVE: In this study, we investigated if the presence of histologically abnormal epithelium adjacent to the primary tumour influenced the frequency, timing, and topography of local vulvar recurrences (LVR) following treatment for squamous cell carcinoma of the vulva (VSCC). METHODS: The study population comprised a cohort of 201 consecutive cases with incident VSCC. LVR were categorised as local relapses (LR) if they occurred <2cm from the tumour margins, and as second field tumours (SFT) when ≥2cm from these margins. Univariable and multivariable competing risk modelling was performed to identify the prognostic factors associated with local disease recurrence. RESULTS: The characterization of the epithelium adjacent to the invasive component was possible for 199 (99.0%) patients. Of these, 171 (85.9%) were found to have intraepithelial abnormalities found adjacent to the surgical specimen. Multivariable analyses revealed that, following adjustment, Lichen Sclerosis (LS) was associated with an increase in the incidence of LVR, LR and SFT (SHRs: 3.4, 2.7 and 4.4, respectively). Although the incidence of LR and SFT in women with LS associated VSCC was similar, the peak incidence of SFT occurred more than two years before that of LR. CONCLUSIONS: Women with VSCC arising in a field of LS may continue to have an increased risk of developing LR and SFT for many years after resection of their primary tumour. Our study suggests that these women should be followed up more regularly so that LVR can be detected earlier; unless a more robust surveillance programme or chemopreventative treatments become available.

Temporal analysis of dissolution by-products and genotoxic potential of spherical zinc-silicate bioglass: "imageable beads" for transarterial embolization.

Embolization of vascular tumors is an important tool in minimally invasive surgical intervention. Radiopaque, non-degradable, and non-deformable spherical zinc-silicate glass particles were produced in a range of 45-500 µm. Three size ranges (45-150, 150-300, and 300-500 µm) were used in the current study. The glass microspheres were eluted in polar (saline solution) and non-polar (dimethyl sulfoxide) medium, and ion release profiles were recorded using inductively coupled plasma atomic emission spectroscopy. Approximately 80% of Gaussian distribution was achieved by simple sieving. The ions released from the microspheres were dependent upon surface area to volume ratio as well as the nature of elution media. Greater ions were released from smaller particles (45-150 µm) having largest surface area in polar medium. For the genotoxicity bacterial mutation Ames assay, the concentrations of all the ions were well below their therapeutic concentration reported in the literature. No mutagenic effect was observed in the bacterial mutation Ames test. Hence, it can be concluded that the glass microspheres produced herein are non-mutagenic further supporting the materials potential as a suitable embolic agent.

Should pelvic exenteration for symptomatic relief in gynaecology malignancies be offered?

OBJECTIVE: To review the outcomes of pelvic exenterative surgery done with a palliative intent and evaluate its role in relapsed gynaecology malignancies. METHOD: This is a retrospective cohort study between April 2009 and May 2012 in Oxford Gynaecological Cancer Centre. Patients were identified from the oncology surgical database. RESULTS: 18 patients were identified with a mean age 54 (26-79) years, who underwent surgery for symptomatic recurrent cancer. All except one patient had radiotherapy prior to surgery. 12 patients had cervical cancer, five had vulval cancer and one had endometrial cancer. About half of the patients had major surgical complications; however, majority was patients satisfied with the outcome. CONCLUSION: Pelvic exenteration in this context carries considerable morbidity and in this series achieved good symptom control with a mean overall survival of 11 months. Careful patient selection, adequate counselling and ongoing support are imperative of successful outcome.

Characterization of PLGA based composite nerve guidance conduits: effect of F127 content on modulus over time in simulated physiological conditions.

PLGA/pluronic F127 based nerve guidance conduits (NGCs) for peripheral nerve regeneration offer excellent potential for clinical use. To date, little emphasis has been directed towards the effect of pluronic F127 on their subsequent mechanical properties as a function of degradation time or the physiological environment. This report was designed to redress the balance. This study synthesised 5 groups of 20wt% PLGA NGCs with varied additions of pluronic F127 (range 0-5wt%) to obtain Young's Moduli (E) in the range of 7-107MPa, depending on degradation conditions and pluronic F127 content.

FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy.

Several nerve guidance conduits (NGCs) and nerve protectant wraps are approved by the US Food and Drug Administration (FDA) for clinical use in peripheral nerve repair. These devices cover a wide range of natural and synthetic materials, which may or may not be resorbable. This review consolidates the data pertaining to all FDA approved materials into a single reference, which emphasizes material composition alongside pre-clinical and clinical safety and efficacy (where possible). This article also summarizes the key advantages and limitations for each material as noted in the literature (with respect to the indication considered). In this context, this review provides a comprehensive reference for clinicians which may facilitate optimal material/device selection for peripheral nerve repair. For materials scientists, this review highlights predicate devices and evaluation methodologies, offering an insight into current deficiencies associated with state-of-the-art materials and may help direct new technology developments and evaluation methodologies thereof.

Aggressive angiomyxoma: a case series and literature review.

BACKGROUND: Aggressive angiomyxoma was identified as a distinct clinicopathologic entity in 1983 and since then fewer than 250 cases of these rare tumors have been reported in world literature. These tumors usually arise in the pelvis and perineal regions, most often in women of the reproductive age group; however a few cases of its occurrence outside the pelvis have also been reported. PATIENTS AND METHODS: We report a series of 7 women treated in our institute in the last 8 years. Relevant literature on aggressive angiomyxoma was looked at and various management options reviewed. CONCLUSION: Aggressive angiomyxomas are locally aggressive, notorious for local recurrence and extremely rare to metastasize. While surgery remains the mainstay of treatment, there has been a definite shift towards less radical forms of excision, over the years. Various adjuvant treatment modalities have also been tried to reduce tumor recurrence.

Relationship between physical activity measured using accelerometers and energy expenditure measured using doubly labelled water in Indian children.

BACKGROUND/OBJECTIVES: To test the association between physical activity measured using accelerometer counts (Actigraph) and energy expenditure (EE) measured using the doubly labelled water (DLW) method in free-living children in India. The aim of this study was to explore the usefulness of Actigraphs in estimating EE. SUBJECTS/METHODS: Total EE (TEE) was measured in 58 children aged 8-9 years over a period of 2 weeks using the DLW technique. Physical activity level (PAL) was estimated from TEE, and the basal metabolic rate was predicted from weight. Physical activity was measured simultaneously using the Actigraph accelerometers (MTI AM7164 and GT1M). TEE was also calculated from the Actigraph counts using a published equation. RESULTS: TEE (mean: 6.6 vs 5.7 MJ, P=0.04) and Actigraph counts (counts/minute: 557 vs 465, P=0.02; total counts: 445 534 vs 354 748, P=0.004) were higher in boys than in girls. There were no significant correlations between either total Actigraph counts (r=0.15, P=0.3) or counts/minute (r=0.18, P=0.2), and TEE estimated using DLW. Similarly, there were no significant correlations between Actigraph counts and PAL (r=0.10, P=0.5; r=0.17, P=0.2, respectively). The Bland-Altman analysis showed poor agreement between TEE estimated using the DLW method and TEE derived from the Actigraph equation. CONCLUSIONS: Activity measured using Actigraph accelerometers was not related to TEE and PAL derived using the DLW technique in children in Mysore. Actigraphs may not be useful in predicting EE in this setting, but may be better used for judging activity patterns.

Bacterial delivery of a novel cytolysin to hypoxic areas of solid tumors.

The efficacy of current anti-cancer gene therapies is limited by the inability of gene vectors to penetrate the poorly vascularized, hypoxic regions of tumors, leaving these sites untreated. We describe a new approach for targeting gene therapy to these sites, which employs an attenuated strain of the non-pathogenic bacterium, Salmonella typhimurium, carrying an exogenous (that is, reporter or therapeutic) gene under the regulation of a new, highly hypoxia-inducible promoter (FF+20(*)). This bacterial vector was seen to rapidly migrate into, and thrive in, hypoxic areas of both mammary tumor spheroids grown in vitro and orthotopic mammary tumors after systemic injection. Using the reporter gene construct, FF+20(*)-lacZ, we show that bacterial expression of high levels of beta-galactosidase occurred only in hypoxic/necrotic sites of spheroids and tumors. We then replaced the reporter gene with one encoding a novel cytotoxic protein (HlyE) and showed that this was also expressed by bacteria only in hypoxic regions of murine mammary tumors. This resulted in a marked increase in tumor necrosis and reduced tumor growth. Our system represents a promising new strategy for delivering gene therapy to poorly vascularized regions of tumors and shows, for the first time, the efficacy of HlyE as an anti-tumor agent.

Endometrial atypical hyperplasia and subsequent diagnosis of endometrial cancer: a retrospective audit and literature review.

This study investigates the rate of endometrial carcinoma found at hysterectomy in women with a biopsy diagnosis of atypical endometrial hyperplasia, in the John Radcliffe Hospital, Oxford. The Gynecologic Oncology Group (GOG) recently reported a rate of 42.6% in a large prospective study in the USA (Trimble et al. 2006). This retrospective study has identified a similar rate of 45.9% at the John Radcliffe. There is much interest in conservative therapies for atypical endometrial hyperplasia, but with such a high incidence of endometrial carcinoma in cases of atypical endometrial hyperplasia diagnosed by endometrial biopsy, it would seem prudent to exercise caution when considering any conservative therapy.

Cervical screening result communication: a focus-group investigation of English women's experiences and needs.

OBJECTIVE: To explore English women's experiences of cervical screening result communication. DESIGN: Qualitative study consisting of seven focus groups conducted between May 2005 and April 2006. PARTICIPANTS: 33 women with a range of screening results (normal, inadequate, borderline and abnormal) who had recently been for cervical screening, and five women who had attended a colposcopy appointment for the first time following screening. SETTING: Three screening centres (Hampshire, Reading and Sheffield) and one colposcopy clinic (Oxford) in England. RESULTS: Unsatisfactory result communication (eg, delivery of out-of-date and conflicting information) on the part of both screening centres and primary care teams was highlighted. Variable levels of general practitioner involvement in screening result provision were experienced; result-giving strategies included personal as well as generic letters and telephone calls. Means for improving women's understanding of abnormal results were described including the use of diagrams to explain the progression of cell changes, the provision of updates regarding any changes in cell abnormalities between screening tests (ie, lesion progression or regression) and contact with a knowledgeable "intermediary" outside primary care. CONCLUSIONS: The timely provision of appropriate information is an important aspect of any screening programme. Our findings suggest that there is scope for improvement in both the delivery and content of cervical screening result notifications. Regular review of patient result-giving strategies on the part of screening centres and general practices could help ensure that screening programme standards for written information are met. Enhanced communication between primary care teams and screening centres could facilitate the provision of consistent and clear result messages thereby improving women's cervical screening experiences.

Identifying symptoms of ovarian cancer: a qualitative and quantitative study.

INTRODUCTION: Symptoms of ovarian cancer are often vague and consequently a high proportion of women with ovarian cancer are not referred to the appropriate clinic. OBJECTIVE: To identify diagnostic factors for ovarian cancer. DESIGN: A qualitative and quantitative study. SETTING: Four UK hospitals. SAMPLE: One hundred and twenty-four women referred to hospital with suspected ovarian malignancy. METHODS: Women were interviewed prior to diagnosis (n = 63), or soon after. A thematic analysis was conducted. Emergent symptoms were quantitatively analysed to identify distinguishing features of ovarian cancer. MAIN OUTCOMES: Symptoms in women with and without ovarian cancer. RESULTS: Diagnoses comprised 44 malignancies, 59 benign gynaecological pathologies and 21 normal findings. Of the malignancies, 25 women had stage III or more disease, with an average age of 59 years. The benign/normal cohort was significantly younger (48 years). Multivariate analysis revealed persistent abdominal distension (OR 5.2, 95% CI 1.3-20.5), postmenopausal bleeding (OR 9.2, 95% CI 1.1-76.1), appetite loss (OR 3.2, 95% CI 1.1-9.2), early satiety (OR 5.0, 95% CI 1.6-15.7) and progressive symptoms (OR 3.6, 95% CI 1.3-9.8) as independent, statistically significant variables associated with ovarian cancer. Fluctuating distension was not associated with ovarian cancer (OR 0.4, 95% CI 0-4.1). Women frequently used the term bloating, but this represented two distinct events: persistent abdominal distension and fluctuating distension/discomfort. CONCLUSIONS: Ovarian cancer is not a silent killer. Clinicians should distinguish between persistent and fluctuating distension. Recognition of the significance of symptoms described by women could lead to earlier and more appropriate referral.

The management of ovarian carcinoma.

Interest in the management of ovarian cancer is still high and research headed to improve survival rates, particularly in case of advanced disease. The outcomes of screening and its potential effects in stage shift and impact on mortality is of great importance. The actual timing of primary radical surgery in advanced disease has been addressed in two large studies, which essentially also investigate the role of neoadjuvant chemotherapy. This may open a new approach to therapy, but the outcomes of these studies should still provide the evidence to support this approach. The same case can be made in relation to managing relapsed disease. Without doubt, the future interventions in women with ovarian cancer, in terms of surgery and chemotherapeutic approaches, will evolve in a more accurate individualisation of therapy, so that, some account of the tumour biology is inherent within the decisions as to the optimum treatments.

Cystic struma ovarii presenting as pseudo-Meigs' syndrome with elevated CA125 levels. A case report and review of the literature.

Struma ovarii is a rare ovarian teratoma consisted predominantly of mature thyroid tissue. Although the vast majority of strumas are benign, they can present mimicking malignancy. We report a case of a postmenopausal woman who presented with a large pelvic mass, ascites, and high CA125 levels. Further investigation confirmed the existence of bilateral pleural effusions. The patient underwent laparotomy, and histology revealed a benign struma ovarii. Twelve months after the removal of the tumor, the patient remained disease free, with no clinical or radiologic evidence of effusion, and normal CA125 levels. This is only the fifth case in the English literature of a benign struma ovarii presenting as pseudo-Meigs' syndrome with elevated CA125. Struma ovarii should be included in the differential diagnosis of a pelvic mass that presents with ascites, hydrothorax, and elevated tumor markers.

Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer.

BACKGROUND: Epithelial ovarian cancer presents at an advanced stage in the majority of patients. These women require chemotherapy and surgery for optimal treatment. Conventional treatment is to perform surgery first and then give chemotherapy. However, it is important to determine whether there is any advantage to using chemotherapy prior to surgery. OBJECTIVES: To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy prior to debulking surgery (neoadjuvant chemotherapy) compared with conventional treatment where chemotherapy follows maximal debulking surgery. SEARCH STRATEGY: RCTs were identified by searching The Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, 2006), MEDLINE (Silver Platter, from 1966 to 1st Sept 2006), EMBASE via Ovid (from 1980 to 1st Sept 2006), CANCERLIT (from 1966 to 1st Sept 2006), PDQ (search for open and closed trials) and MetaRegister (most current search Sept 2006). SELECTION CRITERIA: Women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III-IV); randomized allocation to treatment groups which compared platinum-based chemotherapy before debulking surgery with platinum-based chemotherapy following debulking surgery. DATA COLLECTION AND ANALYSIS: Data were extracted by three independent authors, and the quality of included trials was assessed by three independent authors. MAIN RESULTS: One RCT was identified as meeting the inclusion criteria. This trial randomized 85 women and compared standard debulking surgery followed by eight cycles of platinum-based chemotherapy with pre-operative intra-arterial platinum-based chemotherapy and ovarian artery embolization followed by debulking surgery and seven cycles of platinum-based chemotherapy. There was no statistical difference in median overall survival (OS) between the two treatment groups. Three on-going RCTs were identified and their results are awaited. AUTHORS' CONCLUSIONS: There is as yet no good evidence that neoadjuvant chemotherapy prior to debulking surgery for women with advanced epithelial ovarian cancer is superior to conventional debulking surgery and platinum-based chemotherapy.

Management of minor cervical cytological abnormalities: a systematic review and a meta-analysis of the literature.

BACKGROUND: A significant number of women are diagnosed with a low grade cytological abnormality on cervical screening. Many authorities recommend surveillance as spontaneous regression might occur. However, protracted attendance for cytological follow-up decreases with time and might put some women at risk of developing invasive disease. The aim of this review was to assess management options for women with minor cervical disease. METHODS: An electronic literature search was conducted. All randomised controlled studies comparing immediate colposcopy to cytological surveillance in women with cervical atypia/borderline nuclear changes or low-grade lesions were included. The main outcomes studied were the default rates from the colposcopy clinic and the histological status of biopsies within immediate management protocols compared to biopsies taken on completion of surveillance. Pooled relative risks and 95% confidence intervals were calculated using a random-effect model and inter-study heterogeneity was assessed with Cochrane's Q-test. RESULTS: Three randomised controlled trials identified from the literature search with different surveillance periods were combined. The analysis revealed that compliance with follow-up declines over time and reaches significance at the end of 24 months of surveillance (RR: 74.10 [10.36, 529.79]). There was a significantly higher incidence of HPV and CIN 1 in those women referred to immediate colposcopy/treatment compared to those at the end of 24 months surveillance period (32% vs 21%) (RR 1.49, 95% CI 1.17-1.90) and (21% vs 8%) (RR 2.58, 95% CI 1.69-3.94), respectively, possibly explained by spontaneous regression of clinically non-important lesions. Finally, there was no significant difference in the incidence of CIN2 or worse at initial colposcopy compared with the observation group (24 months) (RR 1.72, 95% CI 0.85-3.48). CONCLUSION: Cytological surveillance puts women at risk as many show poor compliance and such women might have occult high grade abnormalities. A general policy should be immediate colposcopy for all women after a single low grade cervical smear.

Vaginal vault smears after hysterectomy for reasons other than malignancy: a systematic review of the literature.

BACKGROUND: Vaginal vault smears are used to detect persisting neoplasia of the lower genital tract after hysterectomy. Recent data suggest both widespread use and uncertain evidence of their effectiveness. OBJECTIVES: To identify and synthesise evidence on the use and effectiveness of vaginal vault smears and to assess the quality. SEARCH STRATEGY 'vault smear' OR 'vaginal vault smear' OR 'cervical vault smear' OR ('Hysterectomy') AND ('Follow up' OR 'Smear'). SELECTION CRITERIA Primary research, women who had a hysterectomy and were followed up by vault cytology. DATA COLLECTION AND ANALYSIS: Systematic search (eight electronic databases), supplemented by contact with experts and review of bibliographies. Two independent reviewers determined eligibility/validity and extracted data concerning test performance characteristics. Quality was assessed according to the established criteria. RESULTS: Of 441 unique references, only 19 were suitable. Quality of studies varied considerably and few were of 'high' methodological quality. Studies were geographically diverse, and were published over more than 40 years in 16 journals. From the higher scoring papers, there were 11 659 hysterectomies [6546, benign; 76, cervical intraepithelial neoplasia (CIN) I/CIN II; 5037, CIN III]. Proportions of abnormal vault smears and abnormal biopsies during follow up increased with worsening histology at hysterectomy (P < 0.0001 and P = 0.0001). There was only one report of vaginal cancer subsequent to hysterectomy for CIN and insufficient data to allow for reliable meta-analysis. CONCLUSIONS: Vault smears cause anxiety, consume resources and their value is largely unproven. Inconsistency of study design and limited methodological quality means that the value of vault smears could not be established. High-quality research is required to ensure that the guidelines are evidence based.