University Hospital of Bern

BACKGROUND: Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. METHODS: Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. RESULTS: A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. CONCLUSIONS: The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.

Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.

BACKGROUND: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. RESULTS: The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. CONCLUSIONS: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Understanding of the gut-liver axis is important for the up-to-date management of liver cirrhosis, and changes of intestinal functions form the core of this interesting research field. &lt;b&gt;&lt;i&gt;Summary:&lt;/i&gt;&lt;/b&gt; Most investigators noted small intestinal dysmotility in their patients with liver cirrhosis. Marked changes in the contraction pattern were observed in early manometric studies. The orocecal transit time, particularly small intestinal transit, has generally been reported to be prolonged, which has been demonstrated in multiple investigations to be related to the severity of the liver disease (e.g., Child-Pugh class), the presence of small intestinal bacterial overgrowth (SIBO) and hepatic encephalopathy (HE) as well as a history of spontaneous bacterial peritonitis. Bacteriologically proven SIBO in proximal jejunal aspiration has been reported to be present in up to 59% of cirrhotic patients and is associated with systemic endotoxemia. Clinical and experimental studies suggest that delayed small bowel transit in liver cirrhosis may lead to SIBO, which could contribute to the symptoms of abdominal pain and diarrhea. In addition to autonomic neuropathy, metabolic derangements and diabetic state, SIBO itself may delay intestinal transit in cirrhotic patients. Several studies, both from the West and the East, have shown that the gut microbiota is altered in cirrhotic patients and particularly those with HE. Further, a quantitative change in &lt;i&gt;Bacteroides/Firmicutes&lt;/i&gt; ratio, with a prevalence of potentially pathogenic bacteria (e.g., &lt;i&gt;Enterobacteriaceae&lt;/i&gt;) and reduction in specific commensals (e.g., &lt;i&gt;Lachnospiraceae&lt;/i&gt;), has been described. Structural and functional changes in the intestinal mucosa that contribute to increases in intestinal permeability for bacteria and their products have been observed in patients with liver cirrhosis, which is considered as an important pathogenetic factor for several complications. The mechanism of intestinal barrier dysfunction in cirrhosis is multifactorial, including alcohol, portal hypertension (vascular congestion and dysregulation), endotoxemia, SIBO, local inflammation and, most likely, immunological factors and medications. &lt;b&gt;&lt;i&gt;Key Messages:&lt;/i&gt;&lt;/b&gt; This review summarizes major achievements regarding intestinal dysfunction in cirrhosis for future gastroenterology research. The question of whether this intestinal barrier dysfunction is accompanied and/or at least partly caused by structural and functional changes in the epithelial tight junction proteins is as yet unsolved. Development of new strategies to modulate gut-liver interaction is urgently needed.

In this paper we report the set-up and results of the Multimodal Brain Tumor Image Segmentation Benchmark (BRATS) organized in conjunction with the MICCAI 2012 and 2013 conferences. Twenty state-of-the-art tumor segmentation algorithms were applied to a set of 65 multi-contrast MR scans of low- and high-grade glioma patients-manually annotated by up to four raters-and to 65 comparable scans generated using tumor image simulation software. Quantitative evaluations revealed considerable disagreement between the human raters in segmenting various tumor sub-regions (Dice scores in the range 74%-85%), illustrating the difficulty of this task. We found that different algorithms worked best for different sub-regions (reaching performance comparable to human inter-rater variability), but that no single algorithm ranked in the top for all sub-regions simultaneously. Fusing several good algorithms using a hierarchical majority vote yielded segmentations that consistently ranked above all individual algorithms, indicating remaining opportunities for further methodological improvements. The BRATS image data and manual annotations continue to be publicly available through an online evaluation system as an ongoing benchmarking resource.

Spontaneous ruptures of hepatocellular carcinoma (HCC) are rare. Nevertheless they may lead to difficult decisions in the emergency situation. The acute therapies include conservative treatment, transarterial embolization and surgery. Curative treatment of HCC can be achieved by liver resection solely. The decision-making depends on prognostic patient's factors, such as hepatic viral infection status, Child-Pugh grade, liver cirrhosis and number of tumors. In this case transarterial embolization was preferable as a bridging therapy prior to further diagnostics and therapy, to lower the perioperative morbidity and mortality. The therapy of these cases needs an interdisciplinary approach to choose the best possible procedure in each case.

BACKGROUND: Among patients with acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, less than 40% regain functional independence when treated with intravenous tissue plasminogen activator (t-PA) alone. Thrombectomy with the use of a stent retriever, in addition to intravenous t-PA, increases reperfusion rates and may improve long-term functional outcome. METHODS: We randomly assigned eligible patients with stroke who were receiving or had received intravenous t-PA to continue with t-PA alone (control group) or to undergo endovascular thrombectomy with the use of a stent retriever within 6 hours after symptom onset (intervention group). Patients had confirmed occlusions in the proximal anterior intracranial circulation and an absence of large ischemic-core lesions. The primary outcome was the severity of global disability at 90 days, as assessed by means of the modified Rankin scale (with scores ranging from 0 [no symptoms] to 6 [death]). RESULTS: The study was stopped early because of efficacy. At 39 centers, 196 patients underwent randomization (98 patients in each group). In the intervention group, the median time from qualifying imaging to groin puncture was 57 minutes, and the rate of substantial reperfusion at the end of the procedure was 88%. Thrombectomy with the stent retriever plus intravenous t-PA reduced disability at 90 days over the entire range of scores on the modified Rankin scale (P<0.001). The rate of functional independence (modified Rankin scale score, 0 to 2) was higher in the intervention group than in the control group (60% vs. 35%, P<0.001). There were no significant between-group differences in 90-day mortality (9% vs. 12%, P=0.50) or symptomatic intracranial hemorrhage (0% vs. 3%, P=0.12). CONCLUSIONS: In patients receiving intravenous t-PA for acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, thrombectomy with a stent retriever within 6 hours after onset improved functional outcomes at 90 days. (Funded by Covidien; SWIFT PRIME ClinicalTrials.gov number, NCT01657461.).

Correction: Volume: 292 Pages: 160-162 DOI: 10.1016/j.atherosclerosis.2019.11.020 Published: JAN 2020

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

The accurate identification and description of the genes in the human and mouse genomes is a fundamental requirement for high quality analysis of data informing both genome biology and clinical genomics. Over the last 15 years, the GENCODE consortium has been producing reference quality gene annotations to provide this foundational resource. The GENCODE consortium includes both experimental and computational biology groups who work together to improve and extend the GENCODE gene annotation. Specifically, we generate primary data, create bioinformatics tools and provide analysis to support the work of expert manual gene annotators and automated gene annotation pipelines. In addition, manual and computational annotation workflows use any and all publicly available data and analysis, along with the research literature to identify and characterise gene loci to the highest standard. GENCODE gene annotations are accessible via the Ensembl and UCSC Genome Browsers, the Ensembl FTP site, Ensembl Biomart, Ensembl Perl and REST APIs as well as https://www.gencodegenes.org.

A multitude of factors including biochemical, genetic, and acquired abnormalities may contribute to osteoarthritis of the hip. Although the pathomechanism of degenerative process affecting the dysplastic hip is well understood, the exact pathogenesis for idiopathic osteoarthritis has not been established. Based on clinical experience, with more than 600 surgical dislocations of the hip, allowing in situ inspection of the damage pattern and the dynamic proof of its origin, we propose femoroacetabular impingement as a mechanism for the development of early osteoarthritis for most nondysplastic hips. The concept focuses more on motion than on axial loading of the hip. Distinct clinical, radiographic, and intraoperative parameters can be used to confirm the diagnosis of this entity with timely delivery of treatment. Surgical treatment of femoroacetabular impingement focuses on improving the clearance for hip motion and alleviation of femoral abutment against the acetabular rim. It is proposed that early surgical intervention for treatment of femoroacetabular impingement, besides providing relief of symptoms, may decelerate the progression of the degenerative process for this group of young patients.

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

BACKGROUND: We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer. METHODS: After undergoing surgery with curative intent, 167 patients were randomly assigned to receive radiotherapy alone (66 Gy over a period of 6 1/2 weeks) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1, 22, and 43 of the radiotherapy regimen. RESULTS: After a median follow-up of 60 months, the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone (P=0.04 by the log-rank test; hazard ratio for disease progression, 0.75; 95 percent confidence interval, 0.56 to 0.99), with 5-year Kaplan-Meier estimates of progression-free survival of 47 percent and 36 percent, respectively. The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group (P=0.02 by the log-rank test; hazard ratio for death, 0.70; 95 percent confidence interval, 0.52 to 0.95), with five-year Kaplan-Meier estimates of overall survival of 53 percent and 40 percent, respectively. The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group (P=0.007). The estimated five-year cumulative incidence of local or regional relapses (considering death from other causes as a competing risk) was 31 percent after radiotherapy and 18 percent after combined therapy. Severe (grade 3 or higher) adverse effects were more frequent after combined therapy (41 percent) than after radiotherapy (21 percent, P=0.001); the types of severe mucosal adverse effects were similar in the two groups, as was the incidence of late adverse effects. CONCLUSIONS: Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications.

BACKGROUND: Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, but little is known about their effects in severe heart failure. METHODS: We evaluated 2289 patients who had symptoms of heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less than 25 percent. In a double-blind fashion, we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for heart failure was continued. Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs were excluded. RESULTS: There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.00013, unadjusted; P=0.0014, adjusted for interim analyses). A total of 507 patients died or were hospitalized in the placebo group, as compared with 425 in the carvedilol group. This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol (95 percent confidence interval, 13 to 33 percent; P<0.001). The favorable effects on both end points were seen consistently in all the subgroups we examined, including patients with a history of recent or recurrent cardiac decompensation. Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons (P=0.02). CONCLUSIONS: The previously reported benefits of carvedilol with regard to morbidity and mortality in patients with mild-to-moderate heart failure were also apparent in the patients with severe heart failure who were evaluated in this trial.

BACKGROUND: Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. METHODS: In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. RESULTS: A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). CONCLUSIONS: The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .).

The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver. Nor do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

BACKGROUND: Although transcatheter aortic-valve replacement (TAVR) is an accepted alternative to surgery in patients with severe aortic stenosis who are at high surgical risk, less is known about comparative outcomes among patients with aortic stenosis who are at intermediate surgical risk. METHODS: We evaluated the clinical outcomes in intermediate-risk patients with severe, symptomatic aortic stenosis in a randomized trial comparing TAVR (performed with the use of a self-expanding prosthesis) with surgical aortic-valve replacement. The primary end point was a composite of death from any cause or disabling stroke at 24 months in patients undergoing attempted aortic-valve replacement. We used Bayesian analytical methods (with a margin of 0.07) to evaluate the noninferiority of TAVR as compared with surgical valve replacement. RESULTS: A total of 1746 patients underwent randomization at 87 centers. Of these patients, 1660 underwent an attempted TAVR or surgical procedure. The mean (±SD) age of the patients was 79.8±6.2 years, and all were at intermediate risk for surgery (Society of Thoracic Surgeons Predicted Risk of Mortality, 4.5±1.6%). At 24 months, the estimated incidence of the primary end point was 12.6% in the TAVR group and 14.0% in the surgery group (95% credible interval [Bayesian analysis] for difference, -5.2 to 2.3%; posterior probability of noninferiority, >0.999). Surgery was associated with higher rates of acute kidney injury, atrial fibrillation, and transfusion requirements, whereas TAVR had higher rates of residual aortic regurgitation and need for pacemaker implantation. TAVR resulted in lower mean gradients and larger aortic-valve areas than surgery. Structural valve deterioration at 24 months did not occur in either group. CONCLUSIONS: TAVR was a noninferior alternative to surgery in patients with severe aortic stenosis at intermediate surgical risk, with a different pattern of adverse events associated with each procedure. (Funded by Medtronic; SURTAVI ClinicalTrials.gov number, NCT01586910 .).

BACKGROUND: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. METHODS: The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. RESULTS: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. CONCLUSIONS: One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.

This guidance provides a data-supported approach to risk stratification, diagnosis, and management of patients with cirrhosis and portal hypertension (PH). A guidance document is different from a guideline. Guidelines are developed by a multidisciplinary panel of experts who rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations Assessment, Development, and Evaluation system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence. This guidance focuses on PH, varices, and variceal hemorrhage (VH), and statements are based on the following: (1) review of the recent literature using PubMed, giving more weight to large, well-designed, prospective trials and well-performed meta-analyses; (2) several consensus conferences among experts; and (3) the authors' years of experience caring for patients with cirrhosis and varices. Management of ascites and encephalopathy is addressed in other documents. When little or no data exist from well-designed, prospective trials, emphasis is given to results from large series and reports from recognized experts. In this case, clinical studies needed to clarify that management are specified in a section on future research. Practice guidelines for the diagnosis and treatment of gastroesophageal VH were published in 2007, endorsed by the American Association for the Study of Liver Diseases (AASLD), American College of Gastroenterology, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy (ASGE).1 Since then, a number of randomized, controlled trials (RCTs) have advanced our approach to managing VH. Additionally, four international consensus conferences were held since then, where experts in the field evaluated the changes in pathophysiology, diagnosis, and management of varices and VH. These include two AASLD/European Association for the Study of the Liver single-topic conferences in 2007 (many of the recommendations from this conference were incorporated into the aforementioned guidelines)2 and in 2013, and two Baveno consensus conferences in 20103 and in 2015.4 In this updated practice guidance, recommendations derived from these consensus conferences were also incorporated, particularly those from the latest Baveno conference that took place in Baveno, Italy, in April 2015. Perhaps the most relevant change in these recommendations has been the recognition of the different stages of cirrhosis,5 so that recommendations are now focused on risk stratification and individualizing care for PH. Intended for use by health care providers, this guidance identifies preferred approaches to the diagnostic, therapeutic, and preventive aspects of care of patients with PH. As with other guidance documents, it is not intended to replace clinical judgment, but rather to provide general guidance applicable to the majority of patients. They are intended to be flexible, in contrast to formal treatment recommendations or standards of care, which are inflexible policies designed to be followed in every case. Clinical considerations may justify a course of action that differs from this guidance. Cirrhosis is a chronic condition with a high mortality. It constitutes the fifth-leading cause of adult deaths and ranks eighth in economic cost among the major illnesses.6 Cirrhosis is a heterogeneous disease that cannot be studied or managed as a single entity and is classified in two main prognostic stages: compensated and decompensated cirrhosis.5, 7 This classification depends on the presence or absence of clinically evident decompensating events (specifically ascites, VH, and encephalopathy [HE]), with a median survival in the compensated stage that exceeds 12 years, whereas it is only 1.8 years in patients who develop decompensation.8 The Child-Turcotte-Pugh (CTP) classification has been used to stratify patients with cirrhosis. Patients with cirrhosis belonging to the CTP-A class are compensated, whereas those in the CTP-B/C class are mostly decompensated. PH is the initial and main consequence of cirrhosis and is responsible for the majority of its complications. In fact, it has been shown that portal pressure (PP), determined by the hepatic venous pressure gradient (HVPG), is better than liver biopsy in predicting development of complications of cirrhosis in patients with chronic liver disease (CLD) without cirrhosis on liver biopsy.9 Therefore, a new entity denominated compensated advanced chronic liver disease (cACLD) has been proposed, emphasizing that PH may occur before a formal anatomical diagnosis of cirrhosis is established.4 This entity would encompass patients with cirrhosis and those with advanced liver fibrosis with PH (HVPG > 5 mm Hg). For ease of understanding, in the rest of this guidance, the entity of cACLD will be referred to as compensated cirrhosis (CC), both terms being interchangeable and acceptable by consensus.4 The stage of CC is asymptomatic, and it is the longest stage. Pathophysiological mechanisms are evolving at this stage, and therefore several substages are being recognized. Based on PP, patients with CC can be divided into those with mild PH (HVPG > 5 but < 10 mm Hg) and those with clinically significant portal hypertension (CSPH), defined by an HVPG ≥10 mm Hg. CSPH is associated with an increased risk of developing varices,10 overt clinical decompensation (ascites, VH, and HE),11 postsurgical decompensation,12 and hepatocellular carcinoma (HCC).13 This substaging is not only prognostically important, but, as mentioned below, the mechanisms maintaining PH at these substages are different, and therefore their therapeutic approach will be different. CSPH is present in approximately 50%-60% of patients with CC without gastroesophageal varices (GEV).10 Patients with GEV have, by definition, CSPH, because patients with GEV have an HVPG of at least 10 mm Hg.14, 15 Prognosis is worse in patients with CC with GEV compared to those without GEV.16, 17 Therefore, among patients with CSPH, two substages are recognized based on the absence or presence of GEV. It is important to recognize that although PH and its direct consequences (varices) form the bases of staging in CC, liver insufficiency, even at this stage, plays an important role, given that serum albumin and the Model for End-Stage Liver Disease (MELD) score are also independent predictors of decompensation.11 VH constitutes a decompensating event, but its mortality differs whether it presents as an isolated complication of cirrhosis (20% 5-year mortality) or whether it presents in association with other complications (over 80% 5-year mortality).8 Whereas in the past, emphasis had been placed on managing the direct complications of PH, varices, and VH, it is now clear that these complications cannot be considered in an isolated manner. Rather, they should be considered in the context of advances in the staging of cirrhosis and in the context of other complications of cirrhosis that may occur concomitant or subsequent to development of varices and VH.4 Stages of PH in cirrhosis are depicted in Fig. 1, and goals of therapy at each stage are shown in Table 1. Stages and substages of cirrhosis. The two main stages are the compensated and decompensated stages. The latter is characterized by the presence of clinically overt complications: ascites, VH, or HE. The compensated stage is the longest stage, and it is asymptomatic. There are at least two main substages of compensated cirrhosis with different prognostic and predominant pathophysiological mechanisms: patients with mild PH and those with CSPH. Patients in the latter stage are at risk of developing decompensation, particularly those who have GEV. The decompensated stage is much shorter and can rapidly progress to a stage of further decompensation in which renal failure (HRS) and liver failure (encephalopathy and jaundice) develop, leading to a high mortality. GEV are present in approximately 50% of patients with cirrhosis, but this depends on the clinical stage. In patients with CC, GEV are present in 30%-40%, whereas they can be present in up to 85% of patients with decompensated cirrhosis.18, 19 In patients with CC, varices develop at a rate of 7%-8% per year,10 and progression from small to large varices occurs at a rate of 10%-12% per year, with decompensated cirrhosis being an independent predictor of progression.20 VH occurs at a rate of around 10%-15% per year and depends on the severity of liver disease, size of varices, and presence of red wale marks (areas of thinning of the variceal wall).21, 22 Six-week mortality, which is now recognized as the primary endpoint to assess the impact of therapies for acute VH,4 ranges between 15% and 25%.23-25 Other factors associated with poor outcomes in patients with VH are the presence of bacterial infections and an HVPG >20 mm Hg, which is mostly observed in patients belonging to the CTP-C class.26, 27 If untreated, recurrent VH occurs in 60% of patients, usually within 1-2 years of index hemorrhage.28 Obesity and alcohol use are associated conditions of prognostic relevance in patients with cirrhosis, independent of etiology. Obesity has been shown to predict worsening of liver fibrosis, cirrhosis decompensation, and lack of regression of cirrhosis in patients with viral cirrhosis,29-31 whereas even moderate alcohol intake can lead to worsening PP and has been shown to worsen prognosis of hepatitis C virus (HCV)- and nonalcoholic steatohepatitis (NASH)-related cirrhosis.32, 33 Therefore, although beyond the scope of this guidance, weight loss and alcohol abstinence are important considerations in patients with cirrhosis. PP increases initially as a consequence of an increased intrahepatic resistance to portal flow attributed to structural mechanisms (e.g., fibrous tissue, vascular distortion from regenerative nodules, and microthrombi; Fig. 2). This "structural" component, which explains around 70% of the increased intrahepatic resistance, could be targeted by treating the etiology of cirrhosis, the use of antifibrotic agents, and even anticoagulants.34 However, at least one third of the increased intrahepatic resistance is attributed to an increased intrahepatic vascular tone, which, in turn, is attributed to endothelial dysfunction resulting mostly from reduced nitric oxide (NO) bioavailability.35 This "functional" component is amenable to vasodilators (such as nitrates, alpha-adrenergic antagonists, and angiotensin-2 blockers).36 These drugs should not be used alone, given that they also cause systemic vasodilatation, decrease arterial blood pressure, and may worsen sodium retention. A conceptually more appealing approach to ameliorate the functional component is to use drugs that will reduce PP by improving endothelial dysfunction, such as statins.37 An added advantage of these drugs is that, by causing intrahepatic vasodilatation, they may improve hepatic blood flow and liver function. Statins in particular also have antifibrotic properties.34 Pathogenesis of PH and sites of action of currently recommended therapies to reduce PP or obliterate varices. In cirrhosis, PP increases initially as a consequence of an increased intrahepatic resistance to portal flow attributed to structural mechanisms (e.g., fibrous tissue, regenerative nodules) and an increased intrahepatic vascular tone (functional component). One of the initial consequences of PH is the formation of portosystemic collaterals. Concomitant or even preceding development of collaterals, splanchnic vasodilatation occurs, leading to increased flow into the gut and into the portal venous system. Vasodilation leads to activation of neurohumoral and vasoconstrictive systems, sodium and water retention, increased blood volume, and increased cardiac output; that is, a hyperdynamic circulatory state that further increases portal venous inflow and PP. Additionally, activated vasoconstrictive systems to further contribute to intrahepatic vasoconstriction. Treatment of etiology, by ameliorating fibrosis/inflammation, target the mechanical component of the increased intrahepatic resistance. Vasodilators (like the α-adrenergic blocking effect of carvedilol) target its functional component (this is the site of action of statins). NSBBs (β2-adrenergic blocking effect), SMT, and VP act by causing splanchnic vasoconstriction, thereby reducing portal venous inflow. NSBBs also act by decreasing cardiac output (β1-adrenergic blocking effect). The TIPS connects the hypertensive portal vein with a normotensive hepatic vein, thereby bypassing the site of increased resistance. Varices can be obliterated either endoscopically (EVL or cyanoacrylate injection) or by an endovascular approach (BRTO). One of the initial consequences of PH is the formation of portosystemic collaterals, the most important being those that develop through the coronary and/or short gastric veins and constitute GEV. Although formation of collaterals had been assumed to be the result of dilatation of preexisting vascular channels, research studies have implicated a process of neoangiogenesis.38 Concomitant or even preceding the development of collaterals, splanchnic vasodilatation occurs, leading to increased flow into the gut and into the portal venous system. Therefore, even when portal flow is entirely diverted through collaterals, PH persists.39 Increased splanchnic NO production is the main factor that leads to vasodilatation and increased splanchnic blood flow. Hyperglucagonemia and neoangiogenesis further contribute to the increased splanchnic blood flow that maintains the portal hypertensive state.38 Vasodilation occurs not only in the splanchnic, but also in the systemic circulation (manifested clinically as arterial hypotension), leading to activation of neurohumoral and vasoconstrictive systems, sodium and water retention, increased blood volume, and increased cardiac output, that is, a hyperdynamic circulatory state that further increases portal venous inflow and PP. Additionally, norepinephrine, angiotensin-2, and antidiuretic hormone (activated neurohumoral and vasoconstrictive systems) further contribute to intrahepatic vasoconstriction. Drugs that act by causing splanchnic vasoconstriction, such as non-selective beta-blockers (NSBBs; propranolol, nadolol, and carvedilol), vasopressin (VP), and its analogue, terlipressin, and somatostatin (SMT) and its analogues (octreotide, vapreotide) are known to reduce PP and constitute the current mainstay in the treatment of varices and VH. Given that these drugs act by decreasing flow to the splanchnic circulation and liver, an improvement in liver function would not be expected. β-1 adrenergic blockade decreases portal flow through a decrease in cardiac output, and β-2 blockade decreases portal flow through splanchnic vasoconstriction by unopposed α-adrenergic activity. Therefore, it is essential that beta-blockers used in the treatment of PH be nonselective. Importantly, the effect of NSBBs in decreasing flow is more related to their β-2 blocking effect rather than to their β-1 effect40 and explains the lack of correlation between decreases in PP and decreases in heart rate.41 Carvedilol, an NSBB with anti-α1 adrenergic (vasodilator) activity, acts as an NSBB decreasing portal flow, but also acts as a vasodilator (intrahepatic circulation). HVPG response is greater with carvedilol than with propranolol or nadolol, but, given its vasodilatory properties, carvedilol is associated with a greater decrease in mean arterial pressure (MAP).42 It has been recently shown that patients with mild PH (HVPG > 5 but < 10 mm Hg) have a normal cardiac index (i.e., they have not yet developed the hyperdynamic circulatory state), whereas those with CSPH, especially if varices are present, have already developed a hyperdynamic state. Accordingly, response to NSBB in patients with mild PH is suboptimal compared to that of those with CSPH,43 indicating that there is no role for NSBB in the setting of mild PH. Endoscopic variceal ligation (EVL) is a local therapy that consists of placing rubber bands around esophageal varices (EV) in repeated sessions until they become obliterated. Because it is a local therapy that has no effect on PH, recurrence of varices is the rule, and patients require indefinite endoscopic monitoring. Local therapies for management of gastric (mostly cardiofundal) varices consist of the (1) transendoscopic obturation by injection of cyanoacrylate glue into the varices or (2) transvenous obliteration by instillment of sclerosants and/or liquid embolic agents into a gastro-/splenorenal collateral through the left renal vein aided by balloon occlusion, that is, balloon occluded retrograde transvenous obliteration (BRTO).44 In patients with decompensated cirrhosis, placement of the transjugular intrahepatic portosystemic shunt (TIPS) by interventional radiological techniques that consist of connecting the hypertensive portal vein with a normotensive hepatic vein by a coated stent causes a significant decrease, and even normalization, of PP. Therefore, in patients with functional TIPS stents, there is no need for other therapies for PH (e.g., NSBB, EVL). PH is defined as a portal pressure gradient (the difference in pressure between the portal vein and the hepatic veins) greater than 5 mm Hg. The best method to assess PP is through the catheterization of the hepatic vein with determination, through a balloon catheter, of the HVPG, which is the difference between the wedged (or occluded) hepatic venous pressure and the free hepatic venous pressure.45 Normal HVPG is 3-5 mm Hg. It should be underlined that the wedged (occluded) pressure (and, consequently, the HVPG) is a measure of sinusoidal pressure and does not provide useful data in prehepatic or presinusoidal PH (Table 2). An HVPG over 5 mm Hg identifies patients with cACLD/CC secondary to conditions associated with sinusoidal hypertension (Table 2). As mentioned above, PH is further defined as mild PH (HVPG > 5 but < 10 mm Hg) and as CSPH (HVPG ≥ 10 mm Hg). Above this threshold of 10 mm Hg, all the complications of PH are more likely to appear (varices, clinical decompensation). In patients with GEV (who, by definition, have CSPH), an HVPG > 12 mm Hg identifies bleeding risk, mostly because there is clear evidence that shows that reducing the HVPG to levels of 12 mm Hg or below is associated with protection from variceal hemorrhage (VH).28 An HVPG > 16 mm Hg indicates a higher risk of death.46 As mentioned previously, an HVPG ≥20 mm Hg predicts failure to control bleeding, early rebleeding, and death during acute VH,27, 47 and in patients with cirrhosis awaiting liver transplantation, each 1-mm-Hg increase in HVPG predicts a 3% increase in the risk of death in a median follow-up of 19 months.48 Despite the crucial role of HVPG in the determination of CSPH and other outcomes, HVPG measurements require specific expertise, are invasive, relatively expensive, and not available in all centers. Therefore, HVPG measurements are not considered standard of care for every patient with cirrhosis, particularly because noninvasive or surrogate indicators are increasingly utilized at most centers. In a step-wise diagnostic approach, specific signs of PH should be first looked for on physical examination. They include spider nevi or visible abdominal portosystemic collaterals. The absence of physical signs cannot be used to rule out CSPH. Among laboratory data, a low platelet count is the most common laboratory sign of PH; it correlates slightly with HVPG and with the presence of GEV. However, taken alone, it is not to either or CSPH or GEV. the other the of platelet count with other noninvasive the noninvasive diagnosis of provides and evidence of associated with cirrhosis and PH. The presence of circulation on or vein, and left and short gastric veins) or the of a of flow within the portal is specific for and is to CSPH. other signs of PH have been such as dilatation of portal vein and the of portal vein (or their as index of the portal Although taken is a but sign of PH, the size of the should be when with platelet count and liver it provides data on the presence of The to assess liver a physical of liver by the of liver fibrosis has a major in this by has for patients with and without CSPH, with a mean the of in a recent on studies and can be currently considered the of the noninvasive diagnosis of PH. However, most of the data have been in patients with viral cirrhosis and cirrhosis. other and data in patients who have require further studies have shown that the best to CSPH is with a diagnostic over In a prospective HVPG ≥10 mm Hg and were in predicting In a large an size count > specific in in CSPH with a of Importantly, these have to be considered in the context of clinical In this a recent prospective a based on measurements in the context of the presence of and/or a platelet count and the of patients with CC in CSPH would be more by has been recently as a more related to PH, with In fact, > better than and to HVPG in predicting first clinical decompensation in one However, cannot be by without a and cannot be if the is not Therefore, measurements by cannot be recommended in clinical direct of the liver and is but and results with higher and in the of CSPH. is an that provides data on and of much of the liver and compared to Although has been shown to be in the staging of liver data its diagnostic in the diagnosis of CSPH are with one that determined by of clinical decompensation in patients with studies are needed in this the presence and size of varices and presence of red wale marks an and that is not free of studies have looked for noninvasive of the presence of varices varices, those so as to the need for The of in predicting the presence of GEV is between and and the use of to GEV is not However, are to rule out varices in patients with In with platelet count identifies patients at low risk of These data have been mostly from patients with viral cirrhosis. in patients with cirrhosis, liver disease, and in those with cirrhosis response are consensus among and review of the it that patients with CC with by and a platelet count were to have varices and could be in studies have these and that of can be In patients with cirrhosis secondary to hepatitis an size count < in out this can be to patients with cirrhosis attributed to other to be Because measurements of are more with of this is a in and out varices and to other in data in and American patients are Patients without evidence of CSPH should be to of the if data on this specific are data from published that and platelet count could be The of new portosystemic collaterals during follow-up has been shown to be associated with variceal formation and as is Therefore, when for evidence of worsening PH should be Patients without varices on constitute an of given that their has not yet been particularly with the of therapies that the that if liver is (e.g., in and lack of in and/or of disease are present (e.g., should be repeated at in the absence of are considered Although there are no data to if several of are for varices. In patients with small varices on who are not for primary is It has been that if the liver is (e.g., in and lack of in and/or of disease are present (e.g., should be repeated at in the absence of are considered Because development of decompensation could worsening of PH and liver dysfunction with a higher of cirrhosis, patients with no or small varices on should have a when and if decompensation in HVPG, or during have been shown to be of In patients with a of VH, a decrease in HVPG to than 12 mm Hg or a decrease greater than from the risk of recurrent ascites, and In patients with CC, in HVPG from have been associated with a in development of varices,10 first VH, and studies that the need for HVPG to assess response to therapy can be by the acute response to propranolol during a single but this further there have been no (e.g., that with changes in As mentioned above, therapy of varices and VH should be to the different clinical stages of cirrhosis and PH that are shown in Table 1. The of therapy for patients at an early stage is to the development of stages. Varices and VH should be managed in the context of the presence (or of other complications of (e.g., ascites, and therefore the or of the patient with should be considered in the of the different In the compensated the is to that is, the is not only to varices or VH, but also to the other complications of cirrhosis. In to specific therapies that will be below, in the compensated every should be taken to the and to associated such as and liver given that these in can decrease portal pressure and reduce the risk of This stage is defined by an HVPG but < 10 mm Hg. Patients in this stage not have varices or

This paper is the first in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn's disease. Surgical management as well as special situations including management of perianal Crohn's disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].