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Showing papers by "St Bartholomew's Hospital published in 2015"


Journal ArticleDOI
TL;DR: Active surveillance for CSI testis cancer leads to excellent outcomes and the vast majority of relapses occur within 2 years of orchiectomy for CSI nonseminoma and within 3 years for CSI seminoma.
Abstract: Purpose To evaluate the performance of active surveillance as a management strategy in broad populations and to inform the development of surveillance schedules by individual patient data regarding timing and type of relapse. Methods Retrospective study including data from 2,483 clinical stage I (CSI) patients, 1,139 CSI nonseminoma and 1,344 CSI seminoma managed with active surveillance, with the majority treated between 1998 and 2010. Clinical outcomes including relapse and death, time distribution, extent of relapse and method of relapse detection observed on active surveillance were recorded. Results Relapse occurred in 221 (19%) CSI-nonseminoma and 173 (13%) CSI-seminoma patients. Median time to relapse was 4 months (range, 2-61 months), 8 months (range, 2-77 months) and 14 months (range, 2-84 months) for lymphovascular invasion–positive CSI nonseminoma, lymphovascular invasion–negative CSI nonseminoma and CSI seminoma. Most relapses were observed within the first 2 years/3 years after orchiectomy fo...

251 citations


Reference EntryDOI
TL;DR: Randomised controlled trials with women who had chronic pelvic pain, excluding endometriosis, primary dysmenorrhoea, pain due to chronic pelvic inflammatory disease, or irritable bowel syndrome were conducted.
Abstract: Background: Chronic pelvic pain is common in women in the reproductive and older age groups and causes disability and distress. Often investigation by laparoscopy reveals no obvious cause for the pain. As the pathophysiology of chronic pelvic pain is not well understood its treatment is often unsatisfactory and limited to symptom relief. Currently the main approaches to treatment include counselling or psychotherapy, attempts to provide reassurance by using laparoscopy to exclude serious pathology, progestogen therapy such as medroxyprogesterone acetate, and surgery to interrupt nerve pathways. Objectives: We aimed to identify and review treatments for chronic pelvic pain in women. The review included studies of patients with a diagnosis of pelvic congestion syndrome or adhesions but excluded those with pain known to be caused by i) endometriosis, ii) primary dysmenorrhoea (period pain), iii) pain due to active chronic pelvic inflammatory disease, or iv) irritable bowel syndrome. Search strategy: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials (searched 20th January 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005), and reference lists of articles. Selection criteria: Randomised controlled trials (RCTs) with women who had chronic pelvic pain. The review authors were prepared to consider studies of any intervention including lifestyle, physical, medical, surgical and psychological treatments. Outcome measures were pain rating scales, quality of life measures, economic analyses and adverse events. Data collection and analysis: For each included trial, information was collected including the method of randomisation, allocation concealment and blinding. Data were extracted independently by the two review authors using forms designed according to the Cochrane guidelines. Main results: Nineteen studies were identified of which fourteen were of satisfactory methodological quality. Five studies were excluded. Progestogen (medroxyprogesterone acetate) was associated with a reduction of pain during treatment while goserelin gave a longer duration of benefit. Counseling supported by ultrasound scanning was associated with reduced pain and improvement in mood. A multidisciplinary approach was beneficial for some outcome measures. Benefit was not demonstrated for adhesiolysis (apart from where adhesions were severe), uterine nerve ablation, sertraline or photographic reinforcement after laparoscopy. Writing therapy and static magnetic field therapy showed some evidence of short-term benefit. Authors' conclusions: The range of proven effective interventions for chronic pelvic pain remains limited and recommendations are based largely on single studies. Given the prevalence and healthcare costs associated with chronic pelvic pain in women, randomised controlled trials of other medical, surgical and psychological interventions are urgently required. Chronic pelvic pain is common in women in the reproductive and older age groups and it causes disability and distress that result in significant costs to health services. The pathogenesis of chronic pelvic pain is poorly understood. Often investigation by laparoscopy reveals no obvious cause for the pain. There are several possible explanations for chronic pelvic pain including undetected irritable bowel syndrome, and central sensitisation of the nervous system. A vascular hypothesis proposes that pain arises from dilated pelvic veins in which blood flow is markedly reduced. As the pathophysiology of chronic pelvic pain is not well understood, its treatment is often unsatisfactory and limited to symptom relief. Currently the main approaches to treatment include counseling or psychotherapy, attempts to provide reassurance using laparoscopy to exclude serious pathology, progestogen therapy such as with medroxyprogesterone acetate and surgery to interrupt nerve pathways.

194 citations


Journal ArticleDOI
TL;DR: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS and has shown significant improvements on metyrapone, first evaluation to last review.
Abstract: Background: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. Objective: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. Design: This was designed as a retrospective, multicenter study. Setting: Thirteen University hospitals were studied. Patients: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). Measurements: Measurements included biochemical parameters of activity of CS: mean serum cortisol “day-curve” (CDC) (target 150–300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). Results: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 μg/dL] vs 348.6 nmol/L [12.6 μg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 μg/dL] vs 491.1 nmol/L [17.8 μg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 μg/24 h] vs 452.6 nmol/24 h [164 μg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 μg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 μg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. Conclusions: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS. Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating effective biochemical control (1). Where a cause amenable to surgical intervention is identified, surgery at a center with appropriate expertise is the optimum management. Nevertheless, many patients need urgent control of severe or persisting hypercortisolemia. Options for medical treatment include steroidogenesis enzyme inhibitors suitable for all causes of CS (ketoconazole, metyrapone, mitotane), agents to suppress ACTH in Cushing's disease (CD), such as dopamine agonists and pasireotide, and the glucocorticoid receptor antagonist, mifepristone (2, 3). The modern use of ketoconazole has recently been reported in a multicenter French Study (4), although its availability in the United States has been restricted after an Food and Drug Administration safety warning for hepatotoxicity in 2013 (5, 6), but it is widely available in Europe in 2015 (7).The cortisol-lowering effect of metyrapone was described as early as 1958 by Liddle et al (8), with later reports confirming metyrapone as a potent inhibitor of the steroidogenesis enzyme 11β-hydroxylase (8, 9). Since then, it has been used as a diagnostic test of adrenal reserve and to treat the hypercortisolism of CS. Despite its widespread use, data on metyrapone are scarce, with the largest study to date (including 91 patients) being published over 25 years ago (10). Here, we have assessed the effectiveness of metyrapone therapy in a contemporary series of patients with CS, by performing a retrospective study of patients treated in the United Kingdom.

166 citations


Journal ArticleDOI
TL;DR: The specificity of DBT and 2D was better than 2D alone but there was only marginal improvement in sensitivity, and the performance of synthetic 2D appeared to be comparable to standard 2D.
Abstract: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 4. See the HTA programme website for further project information.

164 citations


Journal ArticleDOI
TL;DR: Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff, suggesting reliance on predefined single-threshold rules may result in biomarkers of value being discarded in the context of cancer screening.
Abstract: Purpose Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates. Patients and Methods In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves. Results After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P .0027) higher than that for a single-threshold rule (0.869). Conclusion Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded.

156 citations


Journal ArticleDOI
TL;DR: The first phase of a randomized controlled trial (RCT), Genetic Cancer Prediction through Population Screening (GCaPPS), was conducted in an Ashkenazi Jewish (AJ) community as a population-model as mentioned in this paper.
Abstract: Important advances in understanding germ-line predisposition to familial cancer have led to the identification of several rare high-penetrance genes causing cancer syndromes: BRCA1/BRCA2 (familial breast and/or ovarian cancer) and mismatch-repair genes (Lynch Syndrome). BRCA1/2 carriers have a 50% to 80% risk of breast cancer, a 20% to 45% risk of ovarian cancer (OC), and a 5% to 25% risk of prostate cancer (1–5). Established management strategies for high-risk individuals include: 1) risk-reducing salpingo-oophorectomy (RRSO) to prevent tubal/ovarian cancer (hazard ratio [HR] = 0.21) (which also halves breast cancer risk in premenopausal women) (6), 2) risk-reducing mastectomy to prevent breast cancer (7–9), 3) early onset breast screening (MRI/mammograms), and 4) preimplantation genetic diagnosis. Within the UK National Health Service (NHS), genetic mutation testing is limited to individuals with cancer from high-risk families (carrier probability ≥20% in the general population and ≥10% in the Jewish population) or individuals from families with a confirmed BRCA mutation who request referral to specialist genetic clinics. This family history (FH)–based approach requires individuals/general practitioners to recognize and act on a clinically significant FH. Mutation carriers who lack/are unaware of their FH, who do not recognize the risk associated with FH or are not proactive in seeking advice, are inevitably excluded (10–12). Most of these current approach–associated limitations could be overcome by systematic population-based testing. The literature indicates that genetic counseling/testing is associated with psychological benefits in noncarriers and has no substantial adverse psychological consequences for carriers (8,13). However, available data are predominantly from trials in highly selected samples of individuals with a strong FH of cancer, and the results cannot be generalized to the general population. There is no established model for population-based testing of dominant mutations, and the best way to deliver this service on a population basis is unknown.(13) We describe results from the first phase of a novel randomized controlled trial (RCT), Genetic Cancer Prediction through Population Screening (GCaPPS). The objective was to assess the benefits/disadvantages of a population-based approach to genetic testing for high penetrance–dominant gene mutations compared with the conventional FH-based approach. The RCT design provided a basis for comparison of psychological and quality-of-life differences between population-based and FH-based testing. We based the trial in an Ashkenazi Jewish (AJ) community as a population-model and used BRCA1/2-mutations as our disease-model. These choices were guided by the higher prevalence of three BRCA1/2 founder mutations in the AJ population.

146 citations


Journal ArticleDOI
TL;DR: Risk prediction models improve the predictive accuracy of PSA testing to detect prostate cancer (PCa), and future developments in the use of PCa risk models should evaluate its clinical effectiveness in practice.

144 citations


Journal ArticleDOI
TL;DR: In this article, a decision-analytic model was developed to compare lifetime costs and effects amongst Ashkenazi Jewish women in the UK of BRCA founder-mutation testing amongst: 1) all women with a strong FH (≥10% mutation risk) and 2) just those with a weaker FH.
Abstract: Background: Population-based testing for BRCA1/2 mutations detects the high proportion of carriers not identified by cancer family history (FH)–based testing. We compared the cost-effectiveness of population-based BRCA testing with the standard FH-based approach in Ashkenazi Jewish (AJ) women. Methods: A decision-analytic model was developed to compare lifetime costs and effects amongst AJ women in the UK of BRCA founder-mutation testing amongst: 1) all women in the population age 30 years or older and 2) just those with a strong FH (≥10% mutation risk). The model assumes that BRCA carriers are offered risk-reducing salpingo-oophorectomy and annual MRI/mammography screening or risk-reducing mastectomy. Model probabilities utilize the Genetic Cancer Prediction through Population Screening trial/published literature to estimate total costs, effects in terms of quality-adjusted life-years (QALYs), cancer incidence, incremental cost-effectiveness ratio (ICER), and population impact. Costs are reported at 2010 prices. Costs/outcomes were discounted at 3.5%. We used deterministic/probabilistic sensitivity analysis (PSA) to evaluate model uncertainty. Results: Compared with FH-based testing, population-screening saved 0.090 more life-years and 0.101 more QALYs resulting in 33 days’ gain in life expectancy. Population screening was found to be cost saving with a baseline-discounted ICER of -£2079/QALY. Population-based screening lowered ovarian and breast cancer incidence by 0.34% and 0.62%. Assuming 71% testing uptake, this leads to 276 fewer ovarian and 508 fewer breast cancer cases. Overall, reduction in treatment costs led to a discounted cost savings of £3.7 million. Deterministic sensitivity analysis and 94% of simulations on PSA (threshold £20 000) indicated that population screening is cost-effective, compared with current NHS policy. Conclusion: Population-based screening for BRCA mutations is highly cost-effective compared with an FH-based approach in AJ women age 30 years and older.

143 citations


Journal ArticleDOI
TL;DR: In this article, the authors investigated the possible coexistence of pituitary adenoma and pheo/PGL and found that mutations in the genes known to cause PPGL can rarely be associated with pituitaries, whereas mutation in a gene predisposing to Pituitary Adenomas (MEN1) can be associated this article.
Abstract: Objective: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. Design: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. Setting: The study was conducted at university hospitals. Patients: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. Outcome: Outcomes included genetic screening and clinical characteristics. Results: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. Conclusions: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

139 citations


Journal ArticleDOI
TL;DR: The BCSH Committee National Amyloidosis Centre, Division of Medicine, UCL, London, Department of Haematology, Bristol Haem atology and Oncology Centre, Bristol, and Department ofHaematologists, Birmingham Heartlands Hospital and School of Cancer Sciences are thanked.
Abstract: Julian D. Gillmore, Ashutosh Wechalekar, Jenny Bird, Jamie Cavenagh, Stephen Hawkins, Majid Kazmi, Helen J. Lachmann, Philip N. Hawkins and Guy Pratt on behalf of the BCSH Committee National Amyloidosis Centre, Division of Medicine, UCL, London, Department of Haematology, Bristol Haematology and Oncology Centre, Bristol, Department of Haematology, St Bartholomew’s Hospital, London, Department of Haematology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, Departments of Oncology and Haematology, Guy’s & St Thomas’ NHS Foundation Trust, London, and Department of Haematology, Birmingham Heartlands Hospital and School of Cancer Sciences, University of Birmingham, Birmingham, UK

122 citations


Journal ArticleDOI
Claire Palles1, Laura Chegwidden2, Xinzhong Li2, John M. Findlay1, Garry Farnham2, Francesc Castro Giner1, Maikel P. Peppelenbosch3, Michal Kovac1, Claire L. Adams2, Hans Prenen4, Sarah Briggs1, Rebecca Harrison5, Scott Sanders6, David MacDonald7, Chris Haigh, Art Tucker8, Sharon Love, Manoj Nanji9, John deCaestecker10, David Ferry11, Barrie Rathbone5, Julie Hapeshi, Hugh Barr, Paul Moayyedi12, Peter Watson13, Barbara Zietek9, Neera Maroo9, Timothy J. Underwood14, Lisa Boulter14, Hugh McMurtry15, David Monk, Praful Patel16, Krish Ragunath17, David Al Dulaimi18, Iain A. Murray19, Konrad Koss, Andrew Veitch11, Nigel Trudgill, Chuka U. Nwokolo20, Bjorn Rembacken21, Paul Atherfold22, Elaine K. Green2, Yeng Ang23, Yeng Ang24, Ernst J. Kuipers3, Wu Chow25, S Paterson26, Sudarshan R. Kadri5, Ian L P Beales, Charles Grimley, Paul Mullins27, Conrad Beckett28, Mark Farrant29, Andrew Dixon, Sean M. Kelly30, Matthew W. Johnson, Shahjehan Wajed31, Anjan Dhar32, Elinor J. Sawyer9, Rebecca Roylance33, Lynn Onstad34, Marilie D. Gammon35, Douglas A. Corley34, Nicholas J. Shaheen36, Nigel C. Bird37, Laura J. Hardie33, Brian J. Reid34, Brian J. Reid38, Weimin Ye39, Geoffrey Liu40, Yvonne Romero41, Leslie Bernstein42, Anna H. Wu43, Alan G. Casson44, Rebecca C. Fitzgerald45, David C. Whiteman46, Harvey A. Risch47, David M. Levine, Tom L. Vaughan34, Auke P. Verhaar3, Jan H.M. Van den Brande3, Eelke L A Toxopeus, Manon C.W. Spaander3, Bas P. L. Wijnhoven, Luc J. W. van der Laan, Kausilia K. Krishnadath48, Cisca Wijmenga49, Gosia Trynka49, Ross McManus49, John V. Reynolds50, Jacintha O'Sullivan50, Padraic MacMathuna51, Sarah A. McGarrigle50, Dermot Kelleher51, Severine Vermeire4, Isabelle Cleynen4, Raf Bisschops4, Ian Tomlinson1, Janusz Jankowski52, Janusz Jankowski53 
Wellcome Trust Centre for Human Genetics1, University of Plymouth2, Erasmus University Rotterdam3, Katholieke Universiteit Leuven4, Leicester Royal Infirmary5, Warwick Hospital6, University of British Columbia7, St Bartholomew's Hospital8, Queen Mary University of London9, Leicester General Hospital10, New Cross Hospital11, McMaster-Carr12, Queen's University Belfast13, Southampton General Hospital14, Lancashire Teaching Hospitals NHS Foundation Trust15, University of Southampton16, University of Nottingham17, Worcestershire Acute Hospitals NHS Trust18, Royal Cornwall Hospital19, Coventry Health Care20, Leeds General Infirmary21, University of Oxford22, Salford Royal NHS Foundation Trust23, Wigan24, Forth Valley Royal Hospital25, Norfolk and Norwich University Hospitals NHS Foundation Trust26, Bradford Royal Infirmary27, Royal United Hospital28, Kettering General Hospital29, Luton and Dunstable University Hospital NHS Foundation Trust30, Durham University31, Guy's and St Thomas' NHS Foundation Trust32, Fred Hutchinson Cancer Research Center33, University of North Carolina at Chapel Hill34, University of California, San Francisco35, University of Sheffield36, University of Leeds37, Karolinska Institutet38, Princess Margaret Cancer Centre39, Mayo Clinic40, Beckman Research Institute41, University of Southern California42, University of Saskatchewan43, University of Cambridge44, QIMR Berghofer Medical Research Institute45, Yale University46, University of Washington47, University of Groningen48, Trinity College, Dublin49, Mater Misericordiae University Hospital50, Imperial College London51, University Hospitals Coventry and Warwickshire NHS Trust52, University of Warwick53
TL;DR: 2 loci associated with risk of Barrett's esophagus encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Journal ArticleDOI
TL;DR: This poster presents a poster presented at the 2016 British Association for the Advance Study of Oncology and Haematology Congress (BAS) to discuss the science and practice of cell reprograming and its applications in medicine and cancer.
Abstract: National Amyloidosis Centre, Division of Medicine, UCL, London Department of Haematology, Bristol Haematology and Oncology Centre, Bristol Department of Haematology, St Bartholomew's Hospital, London Department of Haematology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool Departments of Oncology and Haematology, Guy's & St Thomas' NHS Foundation Trust, London Department of Haematology, Birmingham Heartlands Hospital and School of Cancer Sciences, University of Birmingham, Birmingham

Journal ArticleDOI
TL;DR: The concept of central sensitisation as a physiological basis for the functional somatic syndromes is addressed and may represent an endophenotypic vulnerability to the development of these syndrome that potentially explains why they cluster together.

Journal ArticleDOI
TL;DR: Cediranib has significant efficacy when added to carboplatin and paclitaxel in the treatment of metastatic or recurrent cervical cancer, accompanied by an increase in toxic effects (mainly diarrhoea, hypertension, and febrile neutropenia).
Abstract: Summary Background Patients treated with standard chemotherapy for metastatic or relapsed cervical cancer respond poorly to conventional chemotherapy (response achieved in 20–30% of patients) with an overall survival of less than 1 year. High tumour angiogenesis and high concentrations of intratumoural VEGF are adverse prognostic features. Cediranib is a potent tyrosine kinase inhibitor of VEGFR1, 2, and 3. In this trial, we aimed to assess the effect of the addition of cediranib to carboplatin and paclitaxel chemotherapy in patients with metastatic or recurrent cervical cancer. Methods In this randomised, double-blind, placebo-controlled phase 2 trial, which was done in 17 UK cancer treatment centres, patients aged 18 years or older initially diagnosed with metastatic carcinoma or who subsequently developed metastatic disease or local pelvic recurrence after radical treatment that was not amenable to exenterative surgery were recruited. Eligible patients received carboplatin AUC of 5 plus paclitaxel 175 mg/m 2 by infusion every 3 weeks for a maximum of six cycles and were randomised centrally (1:1) through a minimisation approach to receive cediranib 20 mg or placebo orally once daily until disease progression. The stratification factors were disease site, disease-free survival after primary therapy or primary stage IVb disease, number of lines of previous treatment, Eastern Cooperative Oncology Group performance status, and investigational site. All patients, investigators, and trial personnel were masked to study drug allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat, and the safety analysis included all patients who received at least one dose of study drug. This trial is registered with the ISCRTN registry, number ISRCTN23516549, and has been completed. Findings Between Aug 19, 2010, and July 27, 2012, 69 patients were enrolled and randomly assigned to cediranib (n=34) or placebo (n=35). After a median follow-up of 24·2 months (IQR 21·9–29·5), progression-free survival was longer in the cediranib group (median 8·1 months [80% CI 7·4–8·8]) than in the placebo group (6·7 months [6·2–7·2]), with a hazard ratio (HR) of 0·58 (80% CI 0·40–0·85; one-sided p=0·032). Grade 3 or worse adverse events that occurred in the concurrent chemotherapy and trial drug period in more than 10% of patients were diarrhoea (five [16%] of 32 patients in the cediranib group vs one [3%] of 35 patients in the placebo group), fatigue (four [13%] vs two [6%]), leucopenia (five [16%] vs three [9%]), neutropenia (10 [31%] vs four [11%]), and febrile neutropenia (five [16%] vs none). The incidence of grade 2–3 hypertension was higher in the cediranib group than in the control group (11 [34%] vs four [11%]). Serious adverse events occurred in 18 patients in the placebo group and 19 patients in the cediranib group. Interpretation Cediranib has significant efficacy when added to carboplatin and paclitaxel in the treatment of metastatic or recurrent cervical cancer. This finding was accompanied by an increase in toxic effects (mainly diarrhoea, hypertension, and febrile neutropenia). Funding Cancer Research UK and AstraZeneca.

Journal ArticleDOI
TL;DR: The United Kingdom uveal melanoma guideline development group used an evidence based systematic approach (Scottish Intercollegiate Guidelines Network (SIGN) to make recommendations in key areas of uncertainty in the field including: the use and effectiveness of new technologies for prognostication, the appropriate pathway for the surveillance of patients following treatment for primary uvea melanoma.

Journal ArticleDOI
TL;DR: 3 strategies for catheter ablation of paroxysmal AF using the Cryoballoon using a combined approach using wide encirclement with RFCA followed by 2 CRYO applications to each vein are compared.
Abstract: The CRYO Versus RF TrialIntroduction Catheter ablation of paroxysmal AF using the Cryoballoon (CRYO) has yielded similar success rates to conventional wide encirclement using radiofrequency catheter ablation (RFCA), but randomized data are lacking. Pilot data suggested a high success rate with a combined approach (COMBINED) using wide encirclement with RFCA followed by 2 CRYO applications to each vein. We compared these 3 strategies in a randomized controlled trial. Methods and Results Patients undergoing first time paroxysmal AF ablation were randomized to RFCA, CRYO, or COMBINED. Patients were followed up at 3, 6, and 12 months with 7 days of ambulatory ECG monitoring. Success was defined as freedom from arrhythmia without antiarrhythmic drugs after a single procedure. A total of 237 patients were randomized. Success at 1 year was achieved in 47% in the RFCA group, 67% in the CRYO group, and 76% in the COMBINED group (P < 0.001 for RFCA vs. CRYO, P<0.001 for RFCA vs. COMBINED, and P = 0.220 for CRYO vs. COMBINED). Procedure time was 211 (IQR 174–256) minutes for RFCA compared to 167 (136–202) minutes for CRYO and 278 (243–327) minutes for COMBINED (P < 0.001 for RFCA vs. COMBINED, RFCA vs. CRYO, and CRYO vs. COMBINED groups). Conclusions Pulmonary vein isolation for paroxysmal AF is faster with CRYO and results in a higher single procedure success rate than conventional point by point RFCA. The COMBINED approach was not superior to CRYO alone.

Journal ArticleDOI
TL;DR: P/D, hyperthermic pleural lavage with povidone-iodine, prophylactic chest wall radiotherapy, and systemic chemotherapy is a safe and well-tolerated multimodality therapy in patients with malignant pleural mesothelioma.

Journal ArticleDOI
TL;DR: Whether hysterectomy, in addition to standard treatment with radiation or chemotherapy, or both, in women with locally advanced cervical cancer (stage IB2 to III) is safe and effective compared with standard treatment alone is determined.
Abstract: Background Cervical cancer is the second commonest cancer among women up to 65 years of age and is the most frequent cause of death from gynaecological cancers worldwide. Sources suggest that a very high proportion of new cervical cancer cases in developing countries are at an advanced stage (IB2 or more) and more than a half of these may be stage III or IV. Cervical cancer staging is based on findings from clinical examination (FIGO) staging). Standard care in Europe and US for stage IB2 to III is non-surgical treatment (chemoradiation). However in developing countries, where there is limited access to radiotherapy, locally advanced cervical cancer may be treated with a combination of chemotherapy and hysterectomy (surgery to remove the womb and the neck of the womb, with or without the surrounding tissues). It is not certain if this improves survival. Therefore, it is important to systematically assess the value of hysterectomy in addition to radiotherapy or chemotherapy, or both, as an alternative intervention in the treatment of locally advanced cervical cancer (stage IB2 to III). Objectives To determine whether hysterectomy, in addition to standard treatment with radiation or chemotherapy, or both, in women with locally advanced cervical cancer (stage IB2 to III) is safe and effective compared with standard treatment alone. Search methods We searched the Cochrane Gynaecological Cancer Group Trials Register, CENTRAL, MEDLINE, EMBASE and LILACS up to February 2014. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. Selection criteria We searched for randomised controlled trials (RCTs) that compared treatment protocols involving hysterectomy versus radiotherapy or chemotherapy, or both, in women with advanced stage (IB2 to III) cervical cancer presenting for the first time. Data collection and analysis We assessed study eligibility independently, extracted data and assessed risk of bias. Where possible, overall and progression or disease-free survival outcomes were synthesised in a meta-analysis using the random-effects model. Adverse events were incompletely reported so results of single trials were described in narrative form. Main results We included seven RCTs (1217 women) of varying methodological quality in the review; most trials were at moderate or high risk of bias. Three were multi-centre trials, two were single-centre trials, and in two trials it was unclear if they were single or multi-centre. These trials compared the following interventions for women with locally advanced cervical cancer (stages IB2 to III): hysterectomy (simple or radical) with radiotherapy (N = 194) versus radiotherapy alone (N = 180); hysterectomy (simple or radical) with chemoradiotherapy (N = 31) versus chemoradiotherapy alone (N = 30); hysterectomy (radical) with chemoradiotherapy (N = 111) versus internal radiotherapy with chemoradiotherapy (N = 100); hysterectomy (simple or radical) with upfront (neoadjuvant) chemotherapy (N = 298) versus radiotherapy alone (N = 273). One trial (N = 256) found no difference in the risk of death or disease progression between women who received attenuated radiotherapy followed by hysterectomy and those who received radiotherapy (external and internal) alone (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.61 to 1.29). This trial also reported no difference between the two groups in terms of adverse effects (18/129 grade 3 or 4 adverse effects in the hysterectomy and radiation group and 19 cases in 18/121 women in the radiotherapy alone group). There was no difference in 5-year tumour-free actuarial survival (representation of the probable years of survivorship of a defined population of participants) or severe complications (grade 3) in another trial (N = 118) which reported the same comparison (6/62 versus 6/56 in the radiation with surgery group versus the radiotherapy alone group, respectively). The quality of the evidence was low for all these outcomes. One trial (N = 61) reported no difference (P value > 0.10) in overall and recurrence-free survival at 3 years between chemoradiotherapy and hysterectomy versus chemoradiotherapy alone (low quality evidence). Adverse events and morbidity data were not reported. Similarly, another trial (N = 211) found no difference in the risk of death (HR 0.65, 95% CI 0.35 to 1.21, P value = 0.19, low quality evidence), disease progression (HR 0.70, 95% CI 0.31 to 1.34, P value = 0.24, low quality evidence) or severe late complications (P value = 0.53, low quality evidence) between women who received internal radiotherapy versus hysterectomy after both groups had received external-beam chemoradiotherapy. Meta analysis of three trials of neoadjuvant chemotherapy and hysterectomy versus radiotherapy alone, assessing 571 participants, found that women who received neoadjuvant chemotherapy plus hysterectomy had less risk of death than those who received radiotherapy alone (HR 0.71, 95% CI 0.55 to 0.93, I2 = 0%, moderate quality evidence). However, a significant number of the participants that received neoadjuvant chemotherapy plus hysterectomy had radiotherapy as well. There was no difference in the proportion of women with disease progression or recurrence between the two groups (RR 0.75, 95% CI 0.53 to 1.05, I2 = 20%, moderate quality evidence). Results of single trials reported no apparent (P value > 0.05) difference in long-term severe complications, grade 3 acute toxicity and severe late toxicity between the two groups (low quality evidence). Quality of life outcomes were not reported in any of the trials. Authors' conclusions From the available RCTs, we found insufficient evidence that hysterectomy with radiotherapy, with or without chemotherapy, improves the survival of women with locally advanced cervical cancer who are treated with radiotherapy or chemoradiotherapy alone. The overall quality of the evidence was variable across the different outcomes and was universally downgraded due to concerns about risk of bias. The quality of the evidence for neoadjuvant chemotherapy and radical hysterectomy versus radiotherapy alone for survival outcomes was moderate, with evidence from other comparisons of low quality. This was mainly based on poor reporting and sparseness of data where results were based on single trials. More trials that assess medical management with and without hysterectomy may test the robustness of the findings of this review as further research is likely to have an important impact on our confidence in the estimate of effect.

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TL;DR: This is the first randomized, placebo-controlled trial with a novel combination of G-CSF and IC cell therapy that demonstrates an improvement in cardiac function, symptoms, and biochemical parameters in patients with DCM.
Abstract: Aims The REGENERATE-DCM trial is the first phase II randomized, placebo-controlled trial aiming to assess if granulocyte colony-stimulating factor (G-CSF) administration with or without adjunctive intracoronary (IC) delivery of autologous bone marrow-derived cells (BMCs) improves global left ventricular (LV) function in patients with dilated cardiomyopathy (DCM) and significant cardiac dysfunction. Methods and results Sixty patients with DCM and left ventricular ejection fraction (LVEF) at referral of ≤45%, New York Heart Association (NYHA) classification ≥2 and no secondary cause for the cardiomyopathy were randomized equally into four groups: peripheral placebo (saline), peripheral G-CSF, peripheral G-CSF and IC serum, and peripheral G-CSF and IC BMC. All patients, except the peripheral placebo group, received 5 days of G-CSF. In the IC groups, this was followed by bone marrow harvest and IC infusion of cells or serum on Day 6. The primary endpoint was LVEF change from baseline to 3 months, determined by advanced cardiac imaging. At 3 months, peripheral G-CSF combined with IC BMC therapy was associated with a 5.37% point increase in LVEF (38.30% ± 12.97 from 32.93% ± 16.46 P = 0.0138), which was maintained to 1 year. This was associated with a decrease in NYHA classification, reduced NT-pro BNP, and improved exercise capacity and quality of life. No significant change in LVEF was seen in the remaining treatment groups. Conclusion This is the first randomized, placebo-controlled trial with a novel combination of G-CSF and IC cell therapy that demonstrates an improvement in cardiac function, symptoms, and biochemical parameters in patients with DCM.

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TL;DR: Contact force sensing technology improves acute pulmonary vein isolation durability; however, its impact on the clinical outcome of ablating atrial fibrillation (AF) is unknown.
Abstract: Contact Force Sensing AF Ablation Outcomes Introduction Contact force sensing (CFS) technology improves acute pulmonary vein isolation durability; however, its impact on the clinical outcome of ablating atrial fibrillation (AF) is unknown. Methods and Results First time AF ablation procedures employing CFS from 4 centers were matched retrospectively to those without CFS in a 1:2 manner by type of AF. Freedom from atrial tachyarrhythmia was defined as the primary outcome measure, and fluoroscopy time the secondary outcome measure. Nineteen possible explanatory variables were tested in addition to CFS. A total of 600 AF ablation procedures (200 using CFS and 400 using non-CFS catheters) performed between 2010 and 2012 (46% paroxysmal, 36% persistent, 18% long-lasting persistent) were analyzed. The mean follow-up duration was 11.4 ± 4.7 months—paroxysmal AF 11.2 ± 4.1 CFS versus 11.3 ± 3.9 non-CFS (P = 0.745)—nonparoxysmal AF 10.4 ± 4.5 CFS versus 11.9 ± 5.4 non-CFS (P = 0.015). The use of a CFS catheter independently predicted clinical success in ablating paroxysmal AF (HR 2.24 [95% CIs 1.29–3.90]; P = 0.004), but not nonparoxysmal AF (HR 0.73 [0.41–1.30]; P = 0.289) in a multivariate analysis that included follow-up duration. Among all cases, the use of CFS catheters was associated with reduced fluoroscopy time in multivariate analysis (reduction by 7.7 [5.0–10.5] minutes; P < 0.001). Complication rates were similar in both groups. Conclusions At medium-term follow-up, CFS catheter technology is associated with significantly improved outcome of first time catheter ablation of paroxysmal AF, but not nonparoxysmal AF. Fluoroscopy time was lower when CFS technology was employed in all types of AF ablation procedures.

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TL;DR: A systematic review was undertaken to assess the clinical efficacy of non‐invasive high‐intensity focused ultrasound (HIFU) ablation in the treatment of breast cancer.
Abstract: Background A systematic review was undertaken to assess the clinical efficacy of non-invasive high-intensity focused ultrasound (HIFU) ablation in the treatment of breast cancer. Methods MEDLINE/PubMed library databases were used to identify all studies published up to December 2013 that evaluated the role of HIFU ablation in the treatment of breast cancer. Studies were eligible if they were performed on patients with breast cancer and objectively recorded at least one clinical outcome measure of response (imaging, histopathological or cosmetic) to HIFU treatment. Results Nine studies fulfilled the inclusion criteria. The absence of tumour or residual tumour after treatment was reported for 95·8 per cent of patients (160 of 167). No residual tumour was found in 46·2 per cent (55 of 119; range 17–100 per cent), less than 10 per cent residual tumour in 29·4 per cent (35 of 119; range 0–53 per cent), and between 10 and 90 per cent residual tumour in 22·7 per cent (27 of 119; range 0–60 per cent). The most common complication associated with HIFU ablation was pain (40·1 per cent) and less frequently oedema (16·8 per cent), skin burn (4·2 per cent) and pectoralis major injury (3·6 per cent). MRI showed an absence of contrast enhancement after treatment in 82 per cent of patients (31 of 38; range 50–100 per cent), indicative of coagulative necrosis. Correlation of contrast enhancement on pretreatment and post-treatment MRI successfully predicted the presence of residual disease. Conclusion HIFU treatment can induce coagulative necrosis in breast cancers. Complete ablation has not been reported consistently on histopathology and no imaging modality has been able confidently to predict the percentage of complete ablation. Consistent tumour and margin necrosis with reliable follow-up imaging are required before HIFU ablation can be evaluated within large, prospective clinical trials.

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TL;DR: The purpose of this paper is to discuss the emerging functional MRI techniques and their applications in predicting treatment response, detecting residual disease and early recurrent disease to optimize the treatment options available using diffusion-weighted imaging and dynamic contrast enhancement particularly in cervical and endometrial cancer.
Abstract: Magnetic resonance imaging (MRI) has an established role in imaging pelvic gynaecological malignancies. It is routinely used in staging endometrial and cervical cancer, characterizing adnexal masses, selecting optimal treatment, monitoring treatment and detecting recurrent disease. MRI has also been shown to have an excellent performance and an evolving role in surveillance of patients after chemoradiotherapy in cervical cancer, post-trachelectomy, detecting early recurrence and planning exenterative surgery in isolated central recurrences in both cervical and endometrial cancer and in young patients on surveillance for medically managed endometrial cancer. However, conventional MRI still has limitations when the morphological appearance of early recurrent or residual disease overlaps with normal pelvic anatomy or treatment effects in the pelvis. In particular, after chemoradiotherapy for cervical cancer, distinguishing between radiotherapy changes and residual or early recurrent disease within the cervix or the vaginal vault can be challenging on conventional MRI alone. Therefore, there is an emerging need for functional imaging to overcome these limitations. The purpose of this paper is to discuss the emerging functional MRI techniques and their applications in predicting treatment response, detecting residual disease and early recurrent disease to optimize the treatment options available using diffusion-weighted imaging and dynamic contrast enhancement particularly in cervical and endometrial cancer.

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TL;DR: With overlapping phenotypes and modest interobserver agreement, OSSN and benign conjunctival lesions are not reliably distinguished clinically and point-of-care diagnostic tools may help.
Abstract: Importance There is a trend toward treating conjunctival lesions suspected to be ocular surface squamous neoplasia (OSSN) based on the clinical impression. Objective To describe the presentation of OSSN and identify clinical features that distinguish it from benign lesions and subsequently evaluate their recognizability. Design, setting, and participants Prospective multicenter study in Kenya from July 2012 through July 2014 of 496 adults presenting with conjunctival lesions. One histopathologist examined all specimens. Six additional masked ophthalmologists independently examined photographs from 100 participants and assessed clinical features. Exposures Comprehensive history, slitlamp examination, and photography before excision biopsy. Main outcomes and measures Frequency of clinical features in OSSN and benign lesions were recorded. Proportions and means were compared using χ2, Fisher exact test, or t test as appropriate. Interobserver agreement was estimated using the κ statistic. Examiners' assessments were compared with a reference. Results Among 496 participants, OSSN was the most common (38%) histological diagnosis, followed by pterygium (36%) and actinic keratosis (19%). Patients with OSSN were slightly older (mean [SD] age, 41 [11.6] vs 38 [10.9] years; P = .002) and tended to have lower levels of education than patients with benign lesions (P = .001). Females predominated (67% of OSSN vs 64% of benign lesions; P = .65). Human immunodeficiency virus infection was common among patients with OSSN (74%). The most common location was the nasal limbus (61% OSSN vs 78% benign lesions; P Conclusions and relevance With overlapping phenotypes and modest interobserver agreement, OSSN and benign conjunctival lesions are not reliably distinguished clinically. Point-of-care diagnostic tools may help.

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TL;DR: This is the first model that accounts for all OvC familial aggregation and would be useful in the OvC genetic counselling process, and assumes that the half of the female population at highest genetic risk will account for 92% of all OvCs.
Abstract: Background Although BRCA1 and BRCA2 mutations account for only ∼27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1, BRCA2 and other familial factors. Therefore, a currently unresolved problem in clinical genetics is how to counsel women with family history of OvC but no identifiable BRCA1/2 mutations. Methods We used data from 1548 patients with OvC and their relatives from a population-based study, with known BRCA1/2 mutation status, to investigate OvC genetic susceptibility models, using segregation analysis methods. Results The most parsimonious model included the effects of BRCA1/2 mutations, and the residual familial aggregation was accounted for by a polygenic component (SD 1.43, 95% CI 1.10 to 1.86), reflecting the multiplicative effects of a large number of genes with small contributions to the familial risk. We estimated that 1 in 630 individuals carries a BRCA1 mutation and 1 in 195 carries a BRCA2 mutation. We extended this model to incorporate the explicit effects of 17 common alleles that are associated with OvC risk. Based on our models, assuming all of the susceptibility genes could be identified we estimate that the half of the female population at highest genetic risk will account for 92% of all OvCs. Conclusions The resulting model can be used to obtain the risk of developing OvC on the basis of BRCA1/2, explicit family history and common alleles. This is the first model that accounts for all OvC familial aggregation and would be useful in the OvC genetic counselling process.

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01 Oct 2015-Europace
TL;DR: Catheter ablation of AF safety and efficacy in DM patients is similar to general population, especially when performed in younger patients with satisfactory glycemic control, and reduces the amount of patients requiring AADs.
Abstract: Aims Diabetes mellitus (DM) and atrial fibrillation (AF) share pathophysiological links, as supported by the high prevalence of AF within DM patients. Catheter ablation of AF (AFCA) is an established therapeutic option for rhythm control in drug resistant symptomatic patients. Its efficacy and safety among patients with DM is based on small populations, and long-term outcome is unknown. The present systematic review and meta-analysis aims to assess safety and long-term outcome of AFCA in DM patients, focusing on predictors of recurrence. Methods and results A systematic review was conducted in MEDLINE/PubMed and Cochrane Library. Randomized controlled trials, clinical trials, and observational studies including patients with DM undergoing AFCA were screened and included if matching inclusion and exclusion criteria. Fifteen studies were included, adding up to 1464 patients. Mean follow-up was 27 (20–33) months. Overall complication rate was 3.5 (1.5–5.0)%. Efficacy in maintaining sinus rhythm at follow-up end was 66 (58–73)%. Meta-regression analysis revealed that advanced age ( P < 0.001), higher body mass index ( P < 0.001), and higher basal glycated haemoglobin level ( P < 0.001) related to higher incidence of arrhythmic recurrences. Performing AFCA lead to a reduction of patients requiring treatment with antiarrhythmic drugs (AADs) from 55 (46–74)% at baseline to 29 (17–41)% ( P < 0.001) at follow-up end. Conclusions Catheter ablation of AF safety and efficacy in DM patients is similar to general population, especially when performed in younger patients with satisfactory glycemic control. Catheter ablation of AF reduces the amount of patients requiring AADs, an additional benefit in this population commonly exposed to adverse effects of AF pharmacological treatments.

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TL;DR: Of interest, the effect of GVHD on decreasing relapse was similar in patients with sensitive disease and chemoresistant disease, which reinforces the use of RIC allo-HCT as a platform for immunotherapy in FL and MCL patients.

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TL;DR: The role of miRNAs in the Notch-pathway is focused on and how they regulate CSC self-renewal, differentiation and tumorigenesis by direct/indirect targeting of the NotCh- Pathway.
Abstract: MicroRNAs (miRNAs) have been implicated in the development of some if not all cancer types and have been identified as attractive targets for prognosis, diagnosis and therapy of the disease. MiRNAs are a class of small non-coding RNAs (20-22 nucleotides in length) that bind imperfectly to the 3’-untranslated region of target mRNA regulating gene expression. Aberrantly expressed miRNAs in cancer, sometimes known as oncomiRNAs, have been shown to play a major role in oncogenesis, metastasis and drug resistance. Amplification of oncomiRNAs during cancer development correlates with the silencing of tumor suppressor genes; on the other hand, down-regulation of miRNAs has also been observed in cancer and cancer stem cells (CSCs). In both cases, miRNA regulation is inversely correlated with cancer progression. Growing evidence indicates that miRNAs are also involved in the metastatic process by either suppressing or promoting metastasis-related genes leading to the reduction or activation of cancer cell migration and invasion processes. In particular, circulating miRNAs (vesicle-encapsulated or non-encapsulated) have significant effects on tumorigenesis: membrane-particles, apoptotic bodies and exosomes have been described as providers of a cell-to-cell communication system transporting oncogenic miRNAs from tumors to neighboring cells and distant metastatic sites. It is hypothesized that MiRNAs control cancer development in a traditional manner, by regulating signaling pathways and factors. In addition, recent developments indicate a non-conventional mechanism of cancer regulation by stem cell reprogramming via a regulatory network consisting of miRNAs and Wnt/β-catenin, Notch, and Hedgehog signaling pathways, all of which are involved in controlling stem cell functions of CSCs. In this review, we focus on the role of miRNAs in the Notch pathway and how they regulate CSC self-renewal, differentiation and tumorigenesis by direct/indirect targeting of the Notch pathway.

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TL;DR: This multicentre prospective audit benchmarks the considerable morbidity associated with gynaecological oncology surgery and identifies significant patient and surgical factors that influence this risk.
Abstract: There are limited data on surgical outcomes in gynaecological oncology. We report on predictors of complications in a multicentre prospective study. Data on surgical procedures and resulting complications were contemporaneously recorded on consented patients in 10 participating UK gynaecological cancer centres. Patients were sent follow-up letters to capture any further complications. Post-operative (Post-op) complications were graded (I–V) in increasing severity using the Clavien-Dindo system. Grade I complications were excluded from the analysis. Univariable and multivariable regression was used to identify predictors of complications using all surgery for intra-operative (Intra-op) and only those with both hospital and patient-reported data for Post-op complications. Prospective data were available on 2948 major operations undertaken between April 2010 and February 2012. Median age was 62 years, with 35% obese and 20.4% ASA grade ⩾3. Consultant gynaecological oncologists performed 74.3% of operations. Intra-op complications were reported in 139 of 2948 and Grade II–V Post-op complications in 379 of 1462 surgeries. The predictors of risk were different for Intra-op and Post-op complications. For Intra-op complications, previous abdominal surgery, metabolic/endocrine disorders (excluding diabetes), surgical complexity and final diagnosis were significant in univariable and multivariable regression (P<0.05), with diabetes only in multivariable regression (P=0.006). For Post-op complications, age, comorbidity status, diabetes, surgical approach, duration of surgery, and final diagnosis were significant in both univariable and multivariable regression (P<0.05). This multicentre prospective audit benchmarks the considerable morbidity associated with gynaecological oncology surgery. There are significant patient and surgical factors that influence this risk.

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TL;DR: Despite the significant delays between the start of antifungal therapy and bronchoscopy, unlike microscopy and culture, the biomarkers remained informative and the combination of LFD and qPCR allows the sensitive and specific detection of IPA.
Abstract: Clinical experience with the impact of serum biomarkers for invasive fungal disease (IFD) varies markedly in hemato-oncology. Invasive pulmonary aspergillosis (IPA) is the most common manifestation, so we evaluated biomarkers in bronchoalveolar lavage (BAL) fluid. An Aspergillus-specific lateral-flow device (LFD), quantitative real-time PCR (qPCR), and the galactomannan (GM) test were used with 32 BAL fluid samples from 32 patients at risk of IPA. Eight patients had proven IPA, 3 had probable IPA, 6 had possible IPA, and 15 patients had no IPA by European Organization for Research and Treatment of Cancer Invasive Fungal Infections Cooperative Group/Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (EORTC/MSG) criteria. The diagnostic accuracies of the tests were evaluated, and pairwise agreement between biomarkers was calculated. The diagnostic performance of the EORTC/MSG criteria was evaluated against the test(s) identified to be the most useful for IPA diagnosis. Using the EORTC/MSG criteria, the sensitivities of qPCR and LFD were 100% and the sensitivity of the GM test was 87.5% (GM test index cutoff, >0.8), with the tests having specificities of between 66.7 and 86.7%. The agreement between the results of qPCR and LFD was almost perfect (Cohen's kappa coefficient = 0.93, 95% confidence interval, 0.81 to 1.00). LFD and qPCR combined had a sensitivity of 100% and a specificity of 85.7%. Calcofluor staining and culture of all BAL fluid samples were negative for fungal infection. The median time from the start of mold-active antifungal therapy to the time of collection of BAL fluid was 6 days. Reversing roles and using dual testing by LFD and qPCR to classify cases, the EORTC/MSG criteria had a sensitivity of 83.3%. All three tests are useful for the diagnosis of IPA in BAL fluid samples. Despite the significant delays between the start of antifungal therapy and bronchoscopy, unlike microscopy and culture, the biomarkers remained informative. In particular, the combination of LFD and qPCR allows the sensitive and specific detection of IPA.

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TL;DR: This guideline replaces the 2007 BashH herpes guidelines and includes new sections on herpes proctitis, key points to cover with patients regarding transmission and removal of advice on the management of HSV in pregnancy which now has a separate joint BASHH/RCOG guideline.
Abstract: These guidelines concern the management of anogenital herpes simplex virus infections in adults and give advice on diagnosis, management, and counselling of patients. This guideline replaces the 2007 BASHH herpes guidelines and includes new sections on herpes proctitis, key points to cover with patients regarding transmission and removal of advice on the management of HSV in pregnancy which now has a separate joint BASHH/RCOG guideline.