Interventions for the treatment of Paget's disease of the vulva.

BACKGROUND: This is an updated version of the original Cochrane Review published in Issue 10, 2013.Extramammary Paget's disease is a rare form of superficial skin cancer. The most common site of involvement is the vulva. It is seen mainly in postmenopausal white women. Paget's disease of the vulva often spreads in an occult fashion, with margins extending beyond the apparent edges of the lesion. There is a range of interventions from surgical to non-invasive techniques or treatments. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment and with minimisation of morbidity from radical surgery. There is little consensus regarding treatment. Surgery, by default, is the most common treatment, but it is challenging to excise the disease adequately, and recurrence is common, leading to repeated operations, and destruction of anatomy. Alternative treatments of photodynamic therapy, laser therapy, radiotherapy, topical treatments or even chemotherapy have been mooted, and it is important to evaluate the available evidence. It is essential to assess whether newer cell-specific treatments, such as photodynamic therapy and imiquimod, can reduce the need for radical surgery. OBJECTIVES: To evaluate the benefits and harms of different treatment modalities for the management of Paget's disease of the vulva. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid) and Embase (via Ovid) up to 8 May 2018. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) and well-designed non-randomised studies that compared different interventions in women with Paget's disease of the vulva, DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We found no trials and, therefore, analysed no data. MAIN RESULTS: The search for the original version of the review identified 635 unique references. We found 31 references (which reported on 30 studies) in full text after inspection of titles and abstracts, but we excluded them all as they did not meet the inclusion criteria. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease. Surgery continues to be the mainstay of treatment in the current literature, with other treatments limited to case reports or treatment of inoperable or recurrent disease.This update between September 2013 and May 2018 identified 35 new studies. None of these met the inclusion criteria. There was only one prospective study of 5% imiquimod in recurrent Paget's disease of the vulva, which although of good quality only included eight women. AUTHORS' CONCLUSIONS: Since the last version of the review was published there are many more cases in the literature reporting a clinical response to 5% imiquimod cream. There is one prospective study of eight women treated with 5% imiquimod for recurrent Paget's disease of the vulva, and one prospective trial of 20 women was due to be reported. This increasing evidence for the safety and efficacy of 5% imiquimod will be helpful for women and clinicians alike. Ideally, a multicentre RCT of reasonable size is needed, but ongoing publications of high-quality non-randomised prospective studies will enhance the current available literature.

A survey of anesthetic preference and preoperative anxiety in hip and knee arthroplasty patients: the utility of the outpatient preoperative anesthesia appointment.

PURPOSE: The general public's perceptions of anesthesia and the risks associated with it may be skewed. The outpatient preoperative appointment with an anesthesiologist allows for patient education regarding different anesthetic options and counseling regarding anxiety related to anesthesia and surgery. This study investigates whether the preoperative appointment for hip and knee arthroplasty alters patient preference for general or spinal anesthesia and reduces patient anxiety. METHODS: Sixty-two patients undergoing hip or knee arthroplasty were administered two verbal questionnaires at the preoperative clinic. The first questionnaire was completed prior to meeting the anesthesiologist and addressed patient anesthetic preferences, previous anesthetic experiences, and perioperative anxiety and need for information using the Amsterdam Preoperative Anxiety and Information Scale (APAIS). The second questionnaire was completed immediately following the appointment and addressed the patient's anesthetic preference, reasons for any preference changes, and anxiety levels and need for information using the APAIS. The clinic anesthesiologist was blinded to the nature of the study. RESULTS: Following the clinic appointment, a significant decrease in patients wanting general anesthesia (from 48 to 18%, P < 0.001) and a significant increase in patients wanting spinal anesthesia (from 39 to 76%, 95%, P < 0.01) was noted. A significant decrease in overall anxiety and anxiety related to the patients' upcoming surgeries and need for information was also noted. CONCLUSIONS: The preoperative anesthesia meeting serves an important role in educating patients regarding anesthesia, and can influence patients' choice of anesthetic while also reducing overall patient anxiety.

De novo mutations revealed by whole-exome sequencing are strongly associated with autism.

Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.

Role of Systematic Lymphadenectomy to Tailor Adjuvant Therapy in Early Endometrial Cancer.

OBJECTIVE: The long-standing protocol at our center for apparent stage I and II endometrial cancers comprises hysterectomy and bilateral salpingo-oophorectomy without lymphadenectomy. Adjuvant treatment is based in line with Postoperative Radiation Therapy in Endometrial Carcinoma 1 protocol. Our aim was to quantify the number of patients who would avoid external beam radiation therapy (EBRT) in our institution if we adopted a protocol of lymphadenectomy to tailor adjuvant EBRT and its impact on cost and quality of life. DESIGN: Retrospective case-cohort study. SETTING: Gynecological oncology center. METHODS: All endometrial cancers treated from 2007 to 2012 were included. The European Organization for Research and Treatment of Cancer (EORTC) quality of life (QLQ-30) and endometrial cancer specific (EN-24) questionnaires were used to measure the quality of life. The NHS tariff for EBRT, VBT and lymphadenectomy were obtained from our Trust's contract with the local commissioning groups. MAIN OUTCOME MEASURES: Quality of life and cost. RESULTS: Systematic pelvic lymphadenectomy in early endometrial cancers of all grades would avoid EBRT in 23.3% of patients, and if performed for grade 2 and 3 cancers, 39.5% of patients would avoid EBRT. The global health scores were significantly lower, and pain scores were considerably higher in patients who received EBRT. Performing systematic lymphadenectomy and tailored adjuvant therapy in grade 2 and 3 endometrial cancers would save £134,691 and for all grades save £37,161 for every 100 patients treated with early endometrial cancer. CONCLUSION: Systematic lymphadenectomy with tailored adjuvant therapy may offer better QoL with reduced cost to NHS without a reduction in overall survival.

Bias in Before-After Studies: Narrative Overview for Anesthesiologists.

Before-after study designs are effective research tools and in some cases, have changed practice. These designs, however, are inherently susceptible to bias (ie, systematic errors) that are sometimes subtle but can invalidate their conclusions. This overview provides examples of before-after studies relevant to anesthesiologists to illustrate potential sources of bias, including selection/assignment, history, regression to the mean, test-retest, maturation, observer, retrospective, Hawthorne, instrumentation, attrition, and reporting/publication bias. Mitigating strategies include using a control group, blinding, matching before and after cohorts, minimizing the time lag between cohorts, using prospective data collection with consistent measuring/reporting criteria, time series data collection, and/or alternative study designs, when possible. Improved reporting with enforcement of the Enhancing Quality and Transparency of Health Research (EQUATOR) checklists will serve to increase transparency and aid in interpretation. By highlighting the potential types of bias and strategies to improve transparency and mitigate flaws, this overview aims to better equip anesthesiologists in designing and/or critically appraising before-after studies.

Type II or type III radical hysterectomy compared to chemoradiotherapy as a primary intervention for stage IB2 cervical cancer.

BACKGROUND: Cervical cancer is the fourth most common cancer in women, with 528,000 estimated new cases globally in 2012. A large majority (around 85%) of the disease burden occurs in low- and middle-income countries (LMICs), where it accounts for almost 12% of all female cancers. Treatment of stage IB2 cervical cancers, which sit between early and advanced disease, is controversial. Some centres prefer to treat these cancers by radical hysterectomy, with chemoradiotherapy reserved for those at high risk of recurrence. In the UK, we treat stage IB2 cervical cancers mainly with chemoradiotherapy, based on the rationale that a high percentage will have risk factors necessitating chemoradiotherapy postsurgery. There has been no systematic review to determine the best possible evidence in managing these cancers. OBJECTIVES: To determine if primary surgery for stage IB2 cervical cancer (type II or type III radical hysterectomy with lymphadenectomy) improves survival compared to primary chemoradiotherapy.To determine if primary surgery combined with postoperative adjuvant chemoradiotherapy, for stage IB2 cervical cancer increases patient morbidity in the management of stage IB2 cervical cancer compared to primary chemoradiotherapy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 3), MEDLINE via Ovid (1946 to April week 2, 2018) and Embase via Ovid (1980 to 2018 week 16). We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies up to April 2018. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs), quasi-RCTs or non-randomised studies (NRSs) comparing surgery to chemoradiotherapy in stage IB2 cervical cancers. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, abstracted data, assessed risk of bias and analysed data using standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified 4968 records from the literature searches, but we did not identify any RCTs that compared primary surgery with chemoradiotherapy in stage IB2 cervical cancer.We found one NRS comparing surgery to chemoradiotherapy in IB2 and IIA2 cervical cancers which met the inclusion criteria. However, we were unable to obtain data for stage IB2 cancers only and considered the findings very uncertain due to a high risk of selection bias. AUTHORS' CONCLUSIONS: There is an absence of high-certainty evidence on the relative benefits and harms of primary radical hysterectomy versus primary chemoradiotherapy for stage IB2 cervical cancer. More research is needed on the different treatment options in stage IB2 cervical cancer, particularly with respect to survival, adverse effects, and quality of life to facilitate informed decision-making and individualised care.

No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins.

Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2) in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs) have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk.

The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: To assess the within-trial cost-effectiveness of an NHS ovarian cancer screening (OCS) programme using data from UKCTOCS and extrapolate results based on average life expectancy. METHODS: Within-trial economic evaluation of no screening (C) vs either (1) an annual OCS programme using transvaginal ultrasound (USS) or (2) an annual ovarian cancer multimodal screening programme with serum CA125 interpreted using a risk algorithm (ROCA) and transvaginal ultrasound as a second-line test (MMS), plus comparison of lifetime extrapolation of the no screening arm and the MMS programme using both a predictive and a Markov model. RESULTS: Using a CA125-ROCA cost of £20, the within-trial results show USS to be strictly dominated by MMS, with the MMS vs C comparison returning an incremental cost-effectiveness ratio (ICER) of £91 452 per life year gained (LYG). If the CA125-ROCA unit cost is reduced to £15, the ICER becomes £77 818 per LYG. Predictive extrapolation over the expected lifetime of the UKCTOCS women returns an ICER of £30 033 per LYG, while Markov modelling produces an ICER of £46 922 per QALY. CONCLUSION: Analysis suggests that, after accounting for the lead time required to establish full mortality benefits, a national OCS programme based on the MMS strategy quickly approaches the current NICE thresholds for cost-effectiveness when extrapolated out to lifetime as compared with the within-trial ICER estimates. Whether MMS could be recommended on economic grounds would depend on the confirmation and size of the mortality benefit at the end of an ongoing follow-up of the UKCTOCS cohort.

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.

BACKGROUND: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. METHODS: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. FINDINGS: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS. INTERPRETATION: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. FUNDING: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

Reducing Artifactual EGFR T790M Mutations in DNA from Formalin-Fixed Paraffin-Embedded Tissue by Use of Thymine-DNA Glycosylase.

BACKGROUND: False-positive EGFR T790M mutations have been reported in formalin-fixed lung tumors, but the cause of the false positives has not been identified. The T790M mutation results from a C>T change at the cytosine of a CpG dinucleotide. The presence or absence of methylation at this cytosine has different consequences following deamination, resulting in a thymine or uracil, respectively, both of which however result in an artifactual change. Uracil-DNA glycosylase (UDG) can be used to eliminate DNA templates with uracil residues but is not active against artifactual thymines. We therefore investigated the use of thymine-DNA glycosylase (TDG) to reduce artifactual T790M mutations. METHODS: Formalin-fixed normal lung tissues and lung squamous cell carcinomas were tested to measure the frequency of false-positive EGFR mutations by use of droplet digital PCR before and after treatment with either UDG or TDG. Methylation at the cytosine at EGFR T790 was assessed by pyrosequencing and by analysis of public databases. RESULTS: Artifactual EGFR T790M mutations were detected in all of the archival formalin-fixed normal lung and lung squamous cell carcinomas at mutant allele frequencies of 1% or lower. The cytosine at EGFR T790 showed high levels of methylation in all lung cancer samples and normal tissues. Pretreatment of the formalin-fixed DNA with either UDG or TDG reduced the false EGFR T790M mutations, but a greater reduction was seen with the TDG treatment. CONCLUSIONS: Both U:G and T:G lesions in formalin-fixed tissue are sources of false-positive EGFR T790M mutations. This is the first report of the use of TDG to reduce sequence artifacts in formalin-fixed DNA and is applicable to the accurate detection of mutations arising at methylated cytosines.

Pre- or postoperative interscalene block and/or general anesthesia for arthroscopic shoulder surgery: a retrospective observational study.

PURPOSE: Arthroscopic shoulder surgery can be performed with an interscalene brachial plexus block (ISBPB) alone, ISBPB combined with general anesthesia (GA), or GA alone. Postoperative pain is typically managed with opioids; however, both GA and opioids have adverse effects which can delay discharge. This retrospective study compares the efficacy of four methods of anesthesia management for arthroscopic shoulder surgery. METHODS: Charts of all patients who underwent shoulder surgery by a single surgeon from 2012-2015 were categorized by analgesic regimen: GA only (n = 177), single-shot ISBPB only (n = 124), or pre- vs postoperative ISBPB combined with GA (ISBPB + GA [n = 72] vs GA + ISBPB [n = 52], respectively). The primary outcome measure was the time to discharge from the postanesthesia care unit (PACU). RESULTS: Mean (SD) time in the PACU ranged from 70.5 (39.9) min for ISBPB only to 111.2 (56.9) min for GA only. Use of ISBPB in any combination and regardless of timing resulted in significantly reduced PACU time, with a mean drop of 27.2 min (95% confidence interval [CI], 17.3 to 37.2; P < 0.001). The largest mean pairwise difference was between GA only and ISBPB only, with a mean difference of 40.7 min (95% CI, 25.5 to 55.8; P < 0.001). Use of ISBPB also reduced pain upon arrival at the PACU and, in some cases, upon discharge from the PACU (i.e., ISBPB only but not ISBPB + GA compared with GA). An ISBPB (alone or prior to GA) also reduced analgesic requirements. CONCLUSION: Previously reported benefits of an ISBPB for arthroscopic shoulder surgery are confirmed. Postoperative ISBPBs may also be beneficial for reducing pain and opioid requirements and could be targeted for patients in severe pain upon emergence. A sufficiently powered randomized-controlled trial could determine the relative efficacy, safety, and associated financial implications associated with each method.

Traumatic Neuroma After Hysterectomy and Bilateral Salpingo-Oophorectomy: A Rare Cause of Post Hysterectomy Pelvic Pain.

The cause of posthysterectomy pain is frequently undiagnosed, and a presumed diagnosis of adhesions is made. Surgical division of adhesions often fails to alleviate the pain. As a result, posthysterectomy pain is seldom investigated despite being associated with a significant deterioration in the quality of life. We report a case of posthysterectomy bilateral neuroma of the autonomic nerves to the ovary that leads to significant pelvic pain. Excision of these neuromas resulted in complete resolution of pelvic pain and significant improvement in the quality of life. This interesting observation does not support the widespread use of laparoscopy for posthysterectomy pain but should be considered in patients with pain that occurs at an interval after hysterectomy who have had no pelvic pain preceding the hysterectomy.

Intraperitoneal ketorolac for post-cholecystectomy pain: a double-blind randomized-controlled trial.

PURPOSE: Ketorolac is a parenterally active nonsteroidal anti-inflammatory drug with localized anti-inflammatory properties. We examine the postoperative analgesic efficacy of locally administered intraperitoneal (IP) ketorolac compared with intravenous (IV) ketorolac during laparoscopic cholecystectomy. METHODS: With institutional ethics approval, 120 patients undergoing elective laparoscopic cholecystectomy were randomized to receive intraoperative 1) IP ketorolac 30 mg + intravenous saline (IP group), 2) intraperitoneal saline + IV ketorolac 30 mg (IV group), or 3) intraperitoneal saline + intravenous saline (Control group) under standardized anesthesia. The primary and secondary outcomes were postoperative fentanyl requirements in the postanesthesia care unit and the time to first analgesic request, respectively. Other outcomes examined included abdominal pain (at rest and with coughing), shoulder pain, nausea, vomiting, and any other postoperative complications. RESULTS: On average, patients receiving IP ketorolac required less (mean difference, 29 µg; 95% confidence interval [CI], 2 to 56; P = 0.04) fentanyl than patients in the Control group but a similar (mean difference, 16 µg; 95% CI, 12 to 43; P = 0.27) amount compared to patients in the IV group. There was an increase in the median (interquartile range [IQR]) time to first request in the IP group (43[30-52] min) compared with the Control group (35 [27-49]min; P = 0.04) but no difference between the IP group compared with the IV group (47 [40-75] min; P = 0.22). Shoulder pain and resting pain were reduced with IP and IV ketorolac compared with Control, but there was no difference between the IP and IV groups. No differences were observed in any other outcomes, side effects, or complications attributable to opioids or ketorolac at any time points. CONCLUSION: This study did not demonstrate any advantage for the off-label topical intraperitoneal administration of ketorolac in this surgical population. Intraperitoneal and IV ketorolac showed comparable analgesic efficacy following laparoscopic cholecystectomy.

Interventions for the treatment of Paget's disease of the vulva.

BACKGROUND: Extra-mammary Paget's disease is a rare form of superficial skin cancer. The most common site of involvement is the vulva. It is seen mainly in postmenopausal white women. Paget's disease of the vulva often spreads in an occult fashion, with margins extending beyond the apparent edges of the lesion. There is a range of interventions from surgical to non-invasive techniques or treatments. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment and with minimisation of morbidity from radical surgery. There is little consensus regarding treatment. Surgery, by default, is the most common treatment, but it is challenging to excise the disease adequately, and recurrence is common, leading to repeated operations, and destruction of anatomy. Alternative treatments of photodynamic therapy, laser therapy, radiotherapy, topical treatments or even chemotherapy have been mooted, and it is important to evaluate the available evidence. It is essential to assess whether newer cell-specific treatments, such as photodynamic therapy and imiquimod, can reduce the need for radical surgery. OBJECTIVES: To evaluate the benefits and harms of different treatment modalities for the management of Paget's disease of the vulva. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to September 2013. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles and contacted experts in the field. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) and well-designed non-randomised studies that compared different interventions in women with Paget's disease of the vulva, DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We found no trials and, therefore, no data were analysed. MAIN RESULTS: The search strategy identified 635 unique references. We found 31 references (which reported on 30 studies) in full text after inspection of titles and abstracts, but we excluded them all as they did not meet the inclusion criteria. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease. Surgery continues to be the mainstay of treatment in the current literature, with other treatments limited to case reports or treatment of inoperable or recurrent disease. AUTHORS' CONCLUSIONS: We found no reliable evidence to inform decisions about different interventions for women with Paget's disease of the vulva. Ideally, a multicentre RCT of reasonable size is needed. In particular, evidence regarding the increasing use of imiquimod would be helpful to women and clinicians alike. Well-designed non-randomised studies, that use multivariate analysis to adjust for baseline imbalances, as well as other key methodological strengths, are also lacking.

Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort.

BACKGROUND: The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort. METHODS: We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978. FINDINGS: 48,230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5·11 years (IQR 4·05-5·95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5·15 mm, with sensitivity of 80·5% (95% CI 72·7-86·8) and specificity of 86·2% (85·8-86·6). Sensitivity and specificity at a 5 mm or greater cutoff were 80·5% (72·7-86·8) and 85·7% (85·4-86·2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85·3% (78·2-90·8) and 80·4% (80·0-80·8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54·1% (45·3-62·8) and 97·2% (97·0-97·4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77·1% (67·8-84·3) and specificity of 85·8% (85·7-85·9). The logistic regression model identified 25% of the population as at high risk and 39·5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6·75 mm achieved sensitivity of 84·3% (71·4-93·0) and specificity of 89·9% (89·3-90·5). INTERPRETATION: Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding.

Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

BACKGROUND: Ovarian cancer has a high case-fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. METHODS: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50-74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032. FINDINGS: In the prevalence screen, 50 078 (98.9%) women underwent MMS, and 48 230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1894 (3.9%) women in the USS group required clinical evaluation. 97 of 50 078 (0.2%) women from the MMS group and 845 of 48 230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0-61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers. INTERPRETATION: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.

A Case Report: Establishing a Definitive Airway in a Trauma Patient With a King Laryngeal Tube In Situ in the Presence of a Closed Head Injury and Difficult Airway: "Between the Devil and the Deep Blue Sea".

Airway management in trauma is a crucial skill, because patients are at risk of aspiration, hypoxia, and hypoventilation, all of which may be fatal in the setting of increased intracranial pressure. The King Laryngeal Tube reusable supraglottic airway (King Systems, Noblesville, IN) allows for temporary management of a difficult airway but poses a challenge when an attempt is made to exchange the device for an endotracheal tube, often managed by emergency tracheostomy. We describe a novel fiberoptic, video laryngoscope-assisted approach to intubation in a difficult trauma airway with an in situ King Laryngeal Tube.

EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons.

The sorting of activated receptors into distinct endosomal compartments is essential to activate specific signaling cascades and cellular events including growth and survival. However, the proteins involved in this sorting are not well understood. We discovered a novel role of EndophilinAs in sorting of activated BDNF-TrkB receptors into late endosomal compartments. Mice lacking all three EndophilinAs accumulate Rab7-positive late endosomes. Moreover, EndophilinAs are differentially localized to, co-traffic with, and tubulate, distinct endosomal compartments: In response to BDNF, EndophilinA2 is recruited to both early and late endosomes, EndophilinA3 is recruited to Lamp1-positive late endosomes, and co-trafficks with Rab5 and Rab7 in both the presence and absence of BDNF, while EndophilinA1 colocalizes at lower levels with endosomes. The absence of all three EndophilinAs caused TrkB to accumulate in EEA1 and Rab7-positive endosomes, and impaired BDNF-TrkB-dependent survival signaling cascades. In addition, EndophilinA triple knockout neurons exhibited increased cell death which could not be rescued by exogenous BDNF, in a neurotrophin-dependent survival assay. Thus, EndophilinAs differentially regulate activated receptor sorting via distinct endosomal compartments to promote BDNF-dependent cell survival.

Contamination: a comparison of 2 personal protective systems.

BACKGROUND: The purpose of this study was to examine the difference in self-contamination rates and levels of contact and droplet protection associated with enhanced respiratory and contact precautions (E-RCP) and a personal protective system that included a full body suit, personal protective equipment and a powered air-purifying respirator (PAPR). METHODS: In this prospective, randomized, controlled crossover study, 50 participants donned and removed E-RCP and PAPR in random order. Surrogate contamination consisted of fluorescein solution and ultraviolet (UV) light- detectable paste, which was applied after each ensemble was donned. A blinded evaluator inspected participants for contamination using a UV lamp after removal of each ensemble. Areas of contamination were counted and measured in square centimetres. Donning and removal violations were recorded. The primary end point was the presence of any contamination on the skin or base clothing layer. RESULTS: Participants wearing E-RCP were more likely to experience skin and base-clothing contamination; their contamination episodes measuring > or = 1 cm2 were more frequent, and they had larger total areas of contamination (all p < 0.0001). The anterior neck, forearms, wrists and hands were the likeliest zones for contamination. Participants donning PAPR committed more donning procedure violations (p = 0.0034). Donning and removing the PAPR system took longer than donning and removing E-RCP garments (p < 0.0001). INTERPRETATION: Participants wearing E-RCP were more likely to experience contamination of their skin and base clothing layer. Those wearing PAPR required significantly more time to don and remove the ensemble and violated donning procedures more frequently.