Queen Elizabeth Hospital Birmingham

The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. There have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis of AML, leading to an update of the disease classification, technological progress in genomic diagnostics and assessment of measurable residual disease, and the successful development of new therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 inhibitors. These advances have prompted this update that includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations.

BACKGROUND: The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results. METHODS: In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation. RESULTS: The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors. CONCLUSIONS: Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.

BACKGROUND: The comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain. METHODS: We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths. RESULTS: There were 17 prostate-cancer-specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P=0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P=0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P=0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). CONCLUSIONS: At a median of 10 years, prostate-cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.

BACKGROUND: Sentinel lymph node biopsy in women with operable breast cancer is routinely used in some countries for staging the axilla despite limited data from randomized trials on morbidity and mortality outcomes. We conducted a multicenter randomized trial to compare quality-of-life outcomes between patients with clinically node-negative invasive breast cancer who received sentinel lymph node biopsy and patients who received standard axillary treatment. METHODS: The primary outcome measures were arm and shoulder morbidity and quality of life. From November 1999 to October 2003, 1031 patients were randomly assigned to undergo sentinel lymph node biopsy (n = 515) or standard axillary surgery (n = 516). Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy (depending on the protocol at the treating institution). Intention-to-treat analyses of data at 1, 3, 6, and 12 months after surgery are presented. All statistical tests were two-sided. RESULTS: The relative risks of any lymphedema and sensory loss for the sentinel lymph node biopsy group compared with the standard axillary treatment group at 12 months were 0.37 (95% confidence interval [CI] = 0.23 to 0.60; absolute rates: 5% versus 13%) and 0.37 (95% CI = 0.27 to 0.50; absolute rates: 11% versus 31%), respectively. Drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly lower in the sentinel lymph node biopsy group (all P < .001), and axillary operative time was reduced (P = .055). Overall patient-recorded quality of life and arm functioning scores were statistically significantly better in the sentinel lymph node biopsy group throughout (all P < or = .003). These benefits were seen with no increase in anxiety levels in the sentinel lymph node biopsy group (P > .05). CONCLUSION: Sentinel lymph node biopsy is associated with reduced arm morbidity and better quality of life than standard axillary treatment and should be the treatment of choice for patients who have early-stage breast cancer with clinically negative nodes.

There is extensive evidence showing that improving eye health contributes directly and indirectly to achieving many Sustainable Development Goals, including reducing poverty and improving work productivity, general and mental health, and education and equity. Improving eye health is a practical and cost-effective way of unlocking human potential. Eye health needs to be reframed as an enabling, cross-cutting issue within the sustainable development framework.

Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.

Controversy still exists on the optimal surgical resection for potentially curable gastric cancer. Much better long-term survival has been reported in retrospective/non-randomized studies with D2 resections that involve a radical extended regional lymphadenectomy than with the standard D1 resections. In this paper we report the long-term survival of patients entered into a randomized study, with follow-up to death or 3 years in 96% of patients and a median follow-up of 6.5 years. In this prospective trial D1 resection (removal of regional perigastric nodes) was compared with D2 resection (extended lymphadenectomy to include level 1 and 2 regional nodes). Central randomization followed a staging laparotomy. Out of 737 patients with histologically proven gastric adenocarcinoma registered, 337 patients were ineligible by staging laparotomy because of advanced disease and 400 were randomized. The 5-year survival rates were 35% for D1 resection and 33% for D2 resection (difference -2%, 95% CI = -12%-8%). There was no difference in the overall 5-year survival between the two arms (HR = 1.10, 95% CI 0.87-1.39, where HR > 1 implies a survival benefit to D1 surgery). Survival based on death from gastric cancer as the event was similar in the D1 and D2 groups (HR = 1.05, 95% CI 0.79-1.39) as was recurrence-free survival (HR = 1.03, 95% CI 0.82-1.29). In a multivariate analysis, clinical stages II and III, old age, male sex and removal of spleen and pancreas were independently associated with poor survival. These findings indicate that the classical Japanese D2 resection offers no survival advantage over D1 surgery. However, the possibility that D2 resection without pancreatico-splenectomy may be better than standard D1 resection cannot be dismissed by the results of this trial.

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BACKGROUND: Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes. METHODS: We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle. RESULTS: The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life. CONCLUSIONS: In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

BACKGROUND: The recent recognition that coronary-artery stenting has improved the short- and long-term outcomes of patients treated with angioplasty has made it necessary to reevaluate the relative benefits of bypass surgery and percutaneous interventions in patients with multivessel disease. METHODS: A total of 1205 patients were randomly assigned to undergo stent implantation or bypass surgery when a cardiac surgeon and an interventional cardiologist agreed that the same extent of revascularization could be achieved by either technique. The primary clinical end point was freedom from major adverse cardiac and cerebrovascular events at one year. The costs of hospital resources used were also determined. RESULTS: At one year, there was no significant difference between the two groups in terms of the rates of death, stroke, or myocardial infarction. Among patients who survived without a stroke or a myocardial infarction, 16.8 percent of those in the stenting group underwent a second revascularization, as compared with 3.5 percent of those in the surgery group. The rate of event-free survival at one year was 73.8 percent among the patients who received stents and 87.8 percent among those who underwent bypass surgery (P<0.001 by the log-rank test). The costs for the initial procedure were $4,212 less for patients assigned to stenting than for those assigned to bypass surgery, but this difference was reduced during follow-up because of the increased need for repeated revascularization; after one year, the net difference in favor of stenting was estimated to be $2,973 per patient. CONCLUSION: As measured one year after the procedure, coronary stenting for multivessel disease is less expensive than bypass surgery and offers the same degree of protection against death, stroke, and myocardial infarction. However, stenting is associated with a greater need for repeated revascularization.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

BACKGROUND: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. OBJECTIVES: To provide evidence-based or expert recommendations for the diagnosis and management of ALS based on a literature search and the consensus of an expert panel. METHODS: All available medical reference systems were searched, and original papers, meta-analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus. RECOMMENDATIONS: Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non-invasive positive-pressure ventilation also improves survival and quality of life. Maintaining the patient's ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end-of-life care should be discussed early with the patient and carers, respecting the patient's social and cultural background.

Recent studies report benefits from corticosteroid treatment in patients with septic shock. This review summarizes the physiology of the corticosteroid response in acute illness. The authors present an updated, practical approach to the diagnosis and treatment of hypoadrenalism in acutely ill patients. Supplemental corticosteroid treatment may be beneficial in many critical illnesses.

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.

This document provides an update to the European Respiratory Society (ERS)/American Thoracic Society (ATS) technical standards for single-breath carbon monoxide uptake in the lung that was last updated in 2005. Although both D LCO (diffusing capacity) and T LCO (transfer factor) are valid terms to describe the uptake of carbon monoxide in the lung, the term D LCO is used in this document. A joint taskforce appointed by the ERS and ATS reviewed the recent literature on the measurement of D LCO and surveyed the current technical capabilities of instrumentation being manufactured around the world. The recommendations in this document represent the consensus of the taskforce members in regard to the evidence available for various aspects of D LCO measurement. Furthermore, it reflects the expert opinion of the taskforce members on areas in which peer-reviewed evidence was either not available or was incomplete. The major changes in these technical standards relate to D LCO measurement with systems using rapidly responding gas analysers for carbon monoxide and the tracer gas, which are now the most common type of D LCO instrumentation being manufactured. Technical improvements and the increased capability afforded by these new systems permit enhanced measurement of D LCO and the opportunity to include other optional measures of lung function.

This collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.

Since 1968 the European Liver Transplant Registry (ELTR) collects prospectively the data of liver transplantation (LT) in 145 centers all over Europe. It represents more than 95% of the overall European data compared to the published official figures [[1]International figures on organ donation and transplantation activities 2009. http://www.transplant-observatory.org.Google Scholar]. This collection is made prospectively through a standardized questionnaire. The first part of the questionnaire includes items regarding date and indication for LT, donor and recipient data, surgical technique of LT, and the immediate postoperative immunosuppression therapy. The second part concerns graft and patient outcome, and immunosuppressive regimen follow-up. Participation in the ELTR is voluntary and a standard computerized database is provided to contributing centers with detailed instructions for the collection of accurate and uniform information [[2]Adam R. McMaster P. O’Grady J.G. Castaing D. Klempnauer J.L. Jamieson N. et al.Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry.Liver Transpl. 2003; 9: 1231-1243Crossref PubMed Scopus (492) Google Scholar]. Along with reports concerning LT for specific hepatic diseases [3Mentha G. Giostra E. Majno P.E. Bechstein W.O. Neuhaus P. O’Grady J. et al.Liver transplantation for Budd-Chiari syndrome: a European study on 248 patients from 51 Centres.J Hepatol. 2006; 44: 520-528Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 4Lerut J. Orlando G. Adam R. Sabbà C. Pfitzmann R. Klempnauer J. et al.Liver transplantation for hereditary hemorrhagic telangiectasia: Report of the European Liver Transplant Registry.Ann Surg. 2006; 244: 854-862Crossref PubMed Scopus (2) Google Scholar, 5Mutimer D.J. Gunson B. Chen J. Berenguer J. Neuhaus P. Castaing D. et al.Impact of donor age and year of transplantation on graft and patient survival following liver transplantation for hepatitis C virus.Transplantation. 2006; 81: 7-14Crossref PubMed Scopus (142) Google Scholar, 6De Kerckhove L. De Meyer M. Verbaandert C. Mourad M. Sokal E. Goffette P. et al.The place of liver transplantation in Caroli’s disease and syndrome.Transpl Int. 2006; 19: 381-388Crossref PubMed Scopus (83) Google Scholar, 7Melzi M.L. Kelly D.A. Colombo C. Jara P. Manzanares J. Colledan M. et al.Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry.Transpl Int. 2006; 19: 726-731Crossref PubMed Scopus (56) Google Scholar, 8Lerut J.P. Orlando G. Adam R. Schiavo M. Klempnauer J. Mirza D. et al.The place of liver transplantation in the treatment of hepatic epitheloid hemangioendothelioma: Report of the European Liver Transplant Registry.Ann Surg. 2007; 246: 949-957Crossref PubMed Scopus (146) Google Scholar, 9Burra P. Senzolo M. Adam R. Delvart V. Karam V. Germani G. et al.Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry).Am J Transplant. 2010; 10: 138-148Crossref PubMed Scopus (254) Google Scholar, 10Schramm C. Bubenheim M. Adam R. Karam V. Buckels J. O‘Grady J.G. et al.Primary liver transplantation for autoimmune hepatitis: a comparative analysis of the European Liver Transplant Registry.Liver Transpl. 2010; 16: 461-469PubMed Google Scholar, 11Mergental H. Porte R.J. Liver transplantation for unresectable hepatocellular carcinoma in patients without liver cirrhosis.Transpl Int. 2010; 23: 662-667Crossref PubMed Scopus (25) Google Scholar, 12Wahlin S. Stål P. Adam R. Karam V. Porte R. Seehofer D. et al.Liver transplantation for erythropoietic protoporphyria in Europe.Liver Transpl. 2011; 17: 1021-1026PubMed Google Scholar], ELTR has allowed the development of risk models for liver-transplantation mortality according to the characteristics of the donor and recipient, and of the transplant procedure [13Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Burroughs A.K. Sabin C.A. Rolles K. Delvart V. Karam V. Buckels J. et al.3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.Lancet. 2006; 367: 225-232Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. Quality of the data is assessed routinely. A regular auditing process is conducted each year to ensure the reliability of the scientific analysis of the data, a control of the good adequacy between ELTR questionnaire and patient charts is performed by randomly conducted audit visits. Results of these audit visits have indicated that ELTR data were reliable and the scientific results of ELTR can be considered credible and representative of LT in Europe [15Karam V. Gunson B. Roggen F. Grande L. Wannoff W. Janssen M. et al.Quality control of the European Liver Transplant Registry: Results of audit visits to the contributing Centres.Transplantation. 2003; 75: 2167Crossref PubMed Scopus (48) Google Scholar, 16Morris P. Monaco A. Quality control of transplant registries.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (4) Google Scholar, 17Hanto D. Reliability of voluntary and compulsory databases and registries in the United States.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (20) Google Scholar, 18Van Der Meulen J. Jacob M. Copley L. Assessing the quality of the data in a transplant registry: the European Liver Transplant Registry.Transplantation. 2003; 75: 2164Crossref PubMed Scopus (24) Google Scholar]. In addition, a control quality program has been developed internally. The data are subjected to checks for completeness, consistency, and range. Comprehensive logical intra- and inter-updates are performed. Moreover, the ELTR has established agreements with the European Organ Sharing Organizations (OSO): United Kingdom Transplant Service Support Authority (UKTransplant), Spanish Organizaciòn Nacional de Transplantes (ONT), Scandinavian Scanditransplant (SKT), Dutch Transplant Foundation (NTS), Eurotransplant (ET), French Agence de la Biomédecine (ABM) to exchange data collected from European Centers and to cross check common data between OSO and ELTR. We have first considered all data since 1968 to show the evolution of results of LT in Europe since its initial development. The rest of the analysis has been undertaken during two different periods: (a) from January 1988 to December 2009 (89,865 LT – 80,347 patients), where the date from January 1988 was chosen as corresponding to the diffusion of cyclosporine-based immunosuppression and to the standardization of the surgical procedure, (b) the last 10-year period data from January 2000 to December 2009 (54,088 LT – 48,218 patients) to give a more recent evaluation of LT results in Europe. Data were analyzed as a whole without distinction of pediatric transplants that represent 10% of LTs in Europe. Data are analyzed with Statistical Analysis System (SAS). The dynamics of data control are continued during the statistical analyzes. Calculation of survival rates are determined by the actuarial method. From May 1968 to December 2009, the ELTR collected data concerning 93,634 liver transplantations (LTs) in 83,816 patients from 145 centers of 26 countries (Fig. 1). These data give a comprehensive overview of the status and evolution of LT in Europe. Both the number of transplant centers and the annual number of LTs performed in Europe have gradually increased since the creation of ELTR (Fig. 2). However, after an exponential increase from the eighties, a plateau has become to be reached in recent years with about 5800 LTs performed all over Europe.Fig. 2Evolution of 93,634 LTs performed in Europe since May 1968. Arrows indicate the year the first LT was performed in indicated countries. ∗This decrease is owed to the fact that some centers did not yet send their updating further to the recent changes of the questionnaire.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Main indications for LT in Europe with the corresponding graft and patient survival rates at 1, 5 and 10 years are listed in Table 1. Cirrhosis is the most frequent indication (52%), mainly related to either viral infection (21% with 13% of hepatitis C virus infection (HCV) and 7% of hepatitis B virus infection (HBV)), or alcohol abuse (19%). Combined viral and alcoholic (ALD) cirrhosis represents 3% of cases, with 2% of HCV–ALD. Cirrhosis is followed by three major indications: primary liver tumors (14% with 12.1% of hepatocellular carcinoma), cholestatic disease (11%), and acute hepatic failure (8%, 2% of which are virus-related). Cholestatic disease includes primary biliary cirrhosis (6%) and extra-hepatic biliary atresia (4%). Primary sclerosing cholangitis represents 4% of cases. Biliary atresia is the most frequent indication (57%) in the pediatric population, followed by metabolic disease (19%). Metabolic disease represents 6% of indications with familial amyloïdotic polyneuropathy as the major indication (2%), followed by three indications of equal frequency (1%): Wilson disease, alpha-1-antitrypsin deficiency and hemochromatosis. Secondary tumors (mainly carcinoid), Budd Chiari and benign liver tumors (mainly polycystic disease) represent only 1% of indications in Europe.Table 1Primary indications for LT in Europe and the corresponding survival. Open table in a new tab The percentage of main indications for LT has significantly changed with time. While cancers represented 50% of indications before 1980, they dramatically decreased during the nineties (10%) before resuming a linear increase since 2000, to currently represent more than 20%. Conversely, acute hepatic failure that led anecdotally to LT before 1986 has since become a recognized indication for LT. (Fig. 3). In the 10 recent years, two groups of indication have shown an increase: primary liver tumors (16%), mainly related to HCC, and cirrhosis (53%), mainly alcoholic (20%). Drug-related fulminant hepatitis is henceforth the leading disease in the group of acute hepatic failures. In the same way, primary sclerosing cholangitis is the main indication in the group of cholestatic diseases. Patient and graft survival of this 10-recent-year population are summarized in Table 1. One, 3 and 6-month patient’s survivals were 90%, 85% and 82% before 2000. Survival rates dramatically increased to reach 94%, 91% and 88%, respectively. The critical period for post-LT outcome is the first 6 months: 46% of deaths and 65% of re-LT occurs within 6 months after LT (Fig. 4). In 49% of cases, re-LT is indicated in the month after primary LT, and one quarter of deaths occurs within the first month after LT. Data represented in Table 2, Table 3 correspond to main cause of death or graft failure. Main causes of death in the 18,186 patients (about 23%) who died after primary LT or re-LT were, by decreasing order: (1) general causes as multiple organ failure and cerebrovascular, cardiovascular, pulmonary, and renal complications (29%); (2) recurrence of primary disease (20%), mostly cancer (11%); (3) sepsis (18%) mostly bacterial (9%); (4) technical complications (5%), mostly hemorrhage and vascular (3%); and (5) rejection (4%) mostly chronic (3%) (Table 2). Intra-operative deaths and primary non-function represented 3% of all deaths. When we consider only the patients who survive beyond 6 months (Fig. 5), there are less technical complications, infection and general complications (cerebrovascular, cardiovascular, pulmonary, and renal), but more tumoral and non-tumoral recurrences, de novo tumor and rejection.Table 2Post-LT mortality after first LT in Europe. Complications correspond to first declared cause of death according to date of occurrence. Open table in a new tab Table 3Recipient graft survival according to the type of LT in Europe. Open table in a new tab The data of the last 10 years show a decrease in overall mortality (16%) with the same distribution of the causes of death observed in the population from 1988. When all indications are considered during the entire study period, patient survival rates are 82% at 1 year, 71% at 5 years, 61% at 10 years, 51% at 15 years and 43% at 20 years. When we consider only the patients who survive beyond 6 months, patient survival rates are dramatically higher (96% at 1 year, 83% at 5 years, 71% at 10 years, 61% at 15 years and 52% at 20 years). After an improvement between 1988 and 2000, the survival of these patients appears to be relatively steady since 2000 (Fig. 6). Survival has improved regularly year after year, reaching 85% at 1 year after 2004 compared with 76% in 1990–1994 and only 33% before 1985 (Fig. 7). The improvement concerns all the indications but particularly LT for cancers (Fig. 8).Fig. 8Patient survival according to indication for and year of LT.View Large Image Figure ViewerDownload Hi-res image Download (PPT) When we consider the last 10-year period, survival of patients in the recent 10 years has improved to reach 85% at 1 year and at 5 years. of LTs have been performed in pediatric patients with of than years. survival in is significantly than in adults In the pediatric population, survival is for years and for 3 to 15 years In the 10 last years, the of pediatric LT has decreased to and the corresponding 5 is than in adults The patient survival is significantly for cirrhosis than for primary liver tumors and acute hepatic failure In viral and have a survival than with or The survival rates in metabolic diseases cholestatic disease and biliary disease of the percentage of in these of survival rates at 1, 5 and 15 and 20 years according to the primary indication are listed in Table 1. survival in the last 10-year population was improved in all the most in survival was observed in LTs for primary liver which is liver and acute hepatic failure The of were were than years, were than years. percentage of are from than years in in and in in to the between a and a relatively donor (Fig. survival were from than years was significantly higher than that with from than years at 5 years, 71% at and 50% graft there is to among without risk (Fig. graft survival according to donor Large Image Figure ViewerDownload Hi-res image Download (PPT) When we consider the last 10-year period, graft survival was with than years and with donor than years. However, are more to of than years were in than years, and only were in than years, at in the in survival. In to the survival of pediatric LT an of recipient age is observed for Survival rates are for adults years, for years, and for than years. However, age of has increased during the last and patients than years, who represented less than in the represented of transplant in 2009 (Fig. When we consider the last 10-year period, survival has increased in all the of to reach for adults of years, for years and over years. of LTs were and were were and to In and LTs have survival. In LTs have a survival than LTs LTs have a decreased graft survival as compared to and LTs However, of these in indications 50% survival in patients to a 5 in the last 10-year population was improved in all the groups of type the most in survival was observed in However, only of LTs were than LTs were and of were to LTs have been in recent years before 2000 after In the were represented by (2%), (6%) and transplants 1, 15 and graft survivals of each type of graft are summarized in Table Survival at 5 years was between liver and but than that of and higher than that of and and represented of overall LTs with a graft survival as compared to in indications survival and in indications survival was was less than and of was for When we consider the last 10-year period, graft survival has increased in all of graft to reach for for and for The ELTR has data concerning related LTs performed in centers from 20 countries from to December 2009 (Fig. 1). The results of this technique be published In adults represented 65% of Since pediatric The donor surgical mortality was graft survival of was for than for adults graft survival of was than LT for was for adults graft more technical complications more infection more rejection more tumor recurrence but less general complications and less disease recurrence after than after LT was indicated in mainly for technical complications vascular and biliary for primary non-function and for rejection mainly chronic of primary disease was in only of (Table of re-LT after the first LT in Europe. The complications correspond to the first cause of failure declared according to of occurrence. Open table in a new tab graft survival rates for the second and LTs were and significantly than for primary LT – (Fig. The data of the last 10 years show a decrease in the of re-LT with an increase of technical complications and a decrease of rejection Moreover, graft survival was increased in all the of re-LT and the between primary LT and LT has been more than the ELTR is a to the evolution and results of LT in Europe. It is representative of LT in Europe of LTs to a control of data audit visits to randomly its scientific has been [15Karam V. Gunson B. Roggen F. Grande L. Wannoff W. Janssen M. et al.Quality control of the European Liver Transplant Registry: Results of audit visits to the contributing Centres.Transplantation. 2003; 75: 2167Crossref PubMed Scopus (48) Google Scholar, 16Morris P. Monaco A. Quality control of transplant registries.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (4) Google Scholar, 17Hanto D. Reliability of voluntary and compulsory databases and registries in the United States.Transplantation. 2003; 75: 2162Crossref PubMed Scopus (20) Google Scholar, 18Van Der Meulen J. Jacob M. Copley L. Assessing the quality of the data in a transplant registry: the European Liver Transplant Registry.Transplantation. 2003; 75: 2164Crossref PubMed Scopus (24) Google Scholar]. LTs year are currently performed in a number to that of the United However, donation rates in Europe more than in United for Organ Sharing has by the donation in Europe in followed by most of the European countries with a of organ donation between 20 and to that of in the and which has the donation in figures on donation and European for the Quality of Transplant Scholar]. with a donor that represents the most of LT, to LT as or related LTs are for of all more these give results to that for LT and a number of patients to LT. they from the centers [13Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Burroughs A.K. Sabin C.A. Rolles K. Delvart V. Karam V. Buckels J. et al.3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.Lancet. 2006; 367: 225-232Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. This is to the risk for in of has been between the and the of the risk of donor mortality and In of two main from the European (1) as cirrhosis to represent the main indication of LT with more than of the and a within this group of patients with alcoholic and virus C related (2) the major is for mainly HCC, which represents currently of all after a decrease from 50% in the to only 10% in the The of patients within the V. E. R. S. A. F. et al.Liver transplantation for the treatment of hepatocellular in patients with J PubMed Scopus Google with results of survival between and benign hepatic disease this of the most in the evolution of LT is the improvement of results with leading to a survival of all indications This results from a surgical a of patients and an improved post-LT of complications and immunosuppressive therapy. The improvement is particularly for mainly hepatocellular carcinoma as with a of in survival rates from to This was with the data of the last 10 years with an improved survival of and recipient age the quality of the as shown by a analysis of ELTR data on mortality after LT [13Adam R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 14Burroughs A.K. Sabin C.A. Rolles K. Delvart V. Karam V. Buckels J. et al.3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.Lancet. 2006; 367: 225-232Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. However, they are not of the fact that donor age has been as an risk of outcome R. Cailliez V. Majno P. Karam V. McMaster P. Calne Y.C. et al.Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study.Lancet. 2000; 356: 621Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar], the evolution that are to the donor recipient age has been considered as with higher the but LT to improved results and of has not changed with is the critical period of the first 6 months more the first year to the outcome of the than a of the deaths and three of within the first year after LT. that patients have reached the first year after LT, they have an to survive at When 7% of patients), re-LT is with less results than the first LT. However, there is that consider this a to a new LT that a of with the in to of the of the of survival is observed between first and second LT and LTs are not with results than of second of the of recent years has been the development of performed by of the centers. with LT, to more patients with but with to decrease as as for the to be of for mortality and for postoperative However, has to decrease in recent years in Europe the in the where has decreased in liver Full Text Full Text PDF PubMed Scopus Google Scholar]. liver are by accurate information about donor to data is and these from liver donor registries and of donor an for centers with deaths to these to the liver transplantation liver donor where we J 2006; PubMed Scopus Google Scholar, Adam R. J. deaths of hepatic for donor liver Transpl. 2006; PubMed Scopus Google Scholar]. In LT is a of liver disease, acute liver failure and It is relatively as compared to the initial years. are to more of the donor Survival is gradually in to in the surgical procedure and of immunosuppressive therapy. to of liver are to the organ This development the of the evaluation of the in the of countries represent a in the increase the donor to patient death on the and to equal to good indications of LT have become the main of a treatment that of patients to survive at 5 years. The declared that they not have to regarding or of with to this The are to all the 145 contributing centers listed at the following The is by a from and a of the – de ELTR is a of the European Liver and Transplant

OBJECTIVE: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations. EVIDENCE: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS: ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.

OBJECTIVE: Utilizing a standardized dataset with specific definitions to prospectively collect international data to provide a benchmark for complications and outcomes associated with esophagectomy. SUMMARY OF BACKGROUND DATA: Outcome reporting in oncologic surgery has suffered from the lack of a standardized system for reporting operative results particularly complications. This is particularly the case for esophagectomy affecting the accuracy and relevance of international outcome assessments, clinical trial results, and quality improvement projects. METHODS: The Esophageal Complications Consensus Group (ECCG) involving 24 high-volume esophageal surgical centers in 14 countries developed a standardized platform for recording complications and quality measures associated with esophagectomy. Using a secure online database (ESODATA.org), ECCG centers prospectively recorded data on all resections according to the ECCG platform from these centers over a 2-year period. RESULTS: Between January 2015 and December 2016, 2704 resections were entered into the database. All demographic and follow-up data fields were 100% complete. The majority of operations were for cancer (95.6%) and typically located in the distal esophagus (56.2%). Some 1192 patients received neoadjuvant chemoradiation (46.1%) and 763 neoadjuvant chemotherapy (29.5%). Surgical approach involved open procedures in 52.1% and minimally invasive operations in 47.9%. Chest anastomoses were done most commonly (60.7%) and R0 resections were accomplished in 93.4% of patients. The overall incidence of complications was 59% with the most common individual complications being pneumonia (14.6%) and atrial dysrhythmia (14.5%). Anastomotic leak, conduit necrosis, chyle leaks, recurrent nerve injury occurred in 11.4%, 1.3%, 4.7%, and 4.2% of cases, respectively. Clavien-Dindo complications ≥ IIIb occurred in 17.2% of patients. Readmissions occurred in 11.2% of cases and 30- and 90-day mortality was 2.4% and 4.5%, respectively. CONCLUSION: Standardized methods provide contemporary international benchmarks for reporting outcomes after esophagectomy.