University Hospital Leipzig

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

BACKGROUND: The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. METHODS: In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS: The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer's lactate. CONCLUSIONS: The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

BACKGROUND: Trials comparing the effectiveness and safety of weight-loss diets are frequently limited by short follow-up times and high dropout rates. METHODS: In this 2-year trial, we randomly assigned 322 moderately obese subjects (mean age, 52 years; mean body-mass index [the weight in kilograms divided by the square of the height in meters], 31; male sex, 86%) to one of three diets: low-fat, restricted-calorie; Mediterranean, restricted-calorie; or low-carbohydrate, non-restricted-calorie. RESULTS: The rate of adherence to a study diet was 95.4% at 1 year and 84.6% at 2 years. The Mediterranean-diet group consumed the largest amounts of dietary fiber and had the highest ratio of monounsaturated to saturated fat (P<0.05 for all comparisons among treatment groups). The low-carbohydrate group consumed the smallest amount of carbohydrates and the largest amounts of fat, protein, and cholesterol and had the highest percentage of participants with detectable urinary ketones (P<0.05 for all comparisons among treatment groups). The mean weight loss was 2.9 kg for the low-fat group, 4.4 kg for the Mediterranean-diet group, and 4.7 kg for the low-carbohydrate group (P<0.001 for the interaction between diet group and time); among the 272 participants who completed the intervention, the mean weight losses were 3.3 kg, 4.6 kg, and 5.5 kg, respectively. The relative reduction in the ratio of total cholesterol to high-density lipoprotein cholesterol was 20% in the low-carbohydrate group and 12% in the low-fat group (P=0.01). Among the 36 subjects with diabetes, changes in fasting plasma glucose and insulin levels were more favorable among those assigned to the Mediterranean diet than among those assigned to the low-fat diet (P<0.001 for the interaction among diabetes and Mediterranean diet and time with respect to fasting glucose levels). CONCLUSIONS: Mediterranean and low-carbohydrate diets may be effective alternatives to low-fat diets. The more favorable effects on lipids (with the low-carbohydrate diet) and on glycemic control (with the Mediterranean diet) suggest that personal preferences and metabolic considerations might inform individualized tailoring of dietary interventions. (ClinicalTrials.gov number, NCT00160108.)

BACKGROUND: Uncontrolled studies suggested that aerosolized iloprost, a stable analogue of prostacyclin, causes selective pulmonary vasodilatation and improves hemodynamics and exercise capacity in patients with pulmonary hypertension. METHODS: We compared repeated daily inhalations of 2.5 or 5.0 microg of iloprost (six or nine times per day; median inhaled dose, 30 microg per day) with inhalation of placebo. A total of 203 patients with selected forms of severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (New York Heart Association [NYHA] functional class III or IV) were included. The primary end point was met if, after week 12, the NYHA class and distance walked in six minutes were improved by at least one class and at least 10 percent, respectively, in the absence of clinical deterioration according to predefined criteria and death. RESULTS: The combined clinical end point was met by 16.8 percent of the patients receiving iloprost, as compared with 4.9 percent of the patients receiving placebo (P=0.007). There were increases in the distance walked in six minutes of 36.4 m in the iloprost group as a whole (P=0.004) and of 58.8 m in the subgroup of patients with primary pulmonary hypertension. Overall, 4.0 percent of patients in the iloprost group (including one who died) and 13.7 percent of those in the placebo group (including four who died) did not complete the study (P=0.024); the most common reason for withdrawal was clinical deterioration. As compared with base-line values, hemodynamic values were significantly improved at 12 weeks when measured after iloprost inhalation (P<0.001), were largely unchanged when measured before iloprost inhalation, and were significantly worse in the placebo group. Further significant beneficial effects of iloprost treatment included an improvement in the NYHA class (P=0.03), dyspnea (P=0.015), and quality of life (P=0.026). Syncope occurred with similar frequency in the two groups but was more frequently rated as serious in the iloprost group, although this adverse effect was not associated with clinical deterioration. CONCLUSIONS: Inhaled iloprost is an effective therapy for patients with severe pulmonary hypertension.

Mitral and tricuspid are increasingly prevalent. Doppler echocardiography not only detects the presence of regurgitation but also permits to understand mechanisms of regurgitation, quantification of its severity and repercussions. The present document aims to provide standards for the assessment of mitral and tricuspid regurgitation.

Abstract

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

Patients with cirrhosis in Child-Pugh class C or those in class B who have persistent bleeding at endoscopy are at high risk for treatment failure and a poor prognosis, even if they have undergone rescue treatment with a transjugular intrahepatic portosystemic shunt (TIPS). This study evaluated the earlier use of TIPS in such patients.We randomly assigned, within 24 hours after admission, a total of 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy to treatment with a polytetrafluoroethylene-covered stent within 72 hours after randomization (early-TIPS group, 32 patients) or continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapy-EBL group, 31 patients).During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapy-EBL group as compared with 1 patient in the early-TIPS group (P=0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapy-EBL group versus 97% in the early-TIPS group (P<0.001). Sixteen patients died (12 in the pharmacotherapy-EBL group and 4 in the early-TIPS group, P=0.01). The 1-year actuarial survival was 61% in the pharmacotherapy-EBL group versus 86% in the early-TIPS group (P<0.001). Seven patients in the pharmacotherapy-EBL group received TIPS as rescue therapy, but four died. The number of days in the intensive care unit and the percentage of time in the hospital during follow-up were significantly higher in the pharmacotherapy-EBL group than in the early-TIPS group. No significant differences were observed between the two treatment groups with respect to serious adverse events.In these patients with cirrhosis who were hospitalized for acute variceal bleeding and at high risk for treatment failure, the early use of TIPS was associated with significant reductions in treatment failure and in mortality. (Current Controlled Trials number, ISRCTN58150114.)

BACKGROUND: In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, the majority of patients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial. METHODS: In this multicenter trial, we randomly assigned 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock to one of two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end point was a composite of death or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke. RESULTS: At 30 days, the composite primary end point of death or renal-replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit-lesion-only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.01). The relative risk of death in the culprit-lesion-only PCI group as compared with the multivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P=0.03), and the relative risk of renal-replacement therapy was 0.71 (95% CI, 0.49 to 1.03; P=0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups. CONCLUSIONS: Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI. (Funded by the European Union 7th Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549 .).

Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease.

This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047.

We present here the first update of the 2013 EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) Guidelines and Recommendations on the clinical use of elastography, focused on the assessment of diffuse liver disease. The first part (long version) of these Guidelines and Recommendations deals with the basic principles of elastography and provides an update of how the technology has changed. The practical advantages and disadvantages associated with each of the techniques are described, and guidance is provided regarding optimization of scanning technique, image display, image interpretation, reporting of data and some of the known image artefacts. The second part provides clinical information about the practical use of elastography equipment and the interpretation of results in the assessment of diffuse liver disease and analyzes the main findings based on published studies, stressing the evidence from meta-analyses. The role of elastography in different etiologies of liver disease and in several clinical scenarios is also discussed. All of the recommendations are judged with regard to their evidence-based strength according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. This updated document is intended to act as a reference and to provide a practical guide for both beginners and advanced clinical users.

Abstract Obesity contributes to reduced life expectancy, impaired quality of life, and disabilities, mainly in those individuals who develop cardiovascular diseases, type 2 diabetes, osteoarthritis, and cancer. However, there is a large variation in the individual risk to developing obesity-associated comorbid diseases that cannot simply be explained by the extent of adiposity. Observations that a proportion of individuals with obesity have a significantly lower risk for cardiometabolic abnormalities led to the concept of metabolically healthy obesity (MHO). Although there is no clear definition, normal glucose and lipid metabolism parameters—in addition to the absence of hypertension—usually serve as criteria to diagnose MHO. Biological mechanisms underlying MHO lower amounts of ectopic fat (visceral and liver), and higher leg fat deposition, expandability of subcutaneous adipose tissue, preserved insulin sensitivity, and beta-cell function as well as better cardiorespiratory fitness compared to unhealthy obesity. Whereas the absence of metabolic abnormalities may reduce the risk of type 2 diabetes and cardiovascular diseases in metabolically healthy individuals compared to unhealthy individuals with obesity, it is still higher in comparison with healthy lean individuals. In addition, MHO seems to be a transient phenotype further justifying therapeutic weight loss attempts—even in this subgroup—which might not benefit from reducing body weight to the same extent as patients with unhealthy obesity. Metabolically healthy obesity represents a model to study mechanisms linking obesity to cardiometabolic complications. Metabolically healthy obesity should not be considered a safe condition, which does not require obesity treatment, but may guide decision-making for a personalized and risk-stratified obesity treatment.

Wilson disease is an inherited autosomal recessive disorder of hepatic copper metabolism leading to copper accumulation in hepatocytes and in extrahepatic organs such as the brain and the cornea. Originally Wilson disease was described as a neurodegerative disorder associated with cirrhosis of the liver. Later, Wilson disease was observed in children and adolescents presenting with acute or chronic liver disease without any neurologic symptoms. While diagnosis of neurologic Wilson disease is straightforward, it may be quite difficult in non-neurologic cases. Up to now, no single diagnostic test can exclude or confirm Wilson disease with 100% certainty. In 1993, the gene responsible for Wilson disease was cloned and localized on chromosome 13q14.3 (MIM277900) (1, 2). The Wilson disease gene ATP7B encodes a P-type ATPase. More than 200 disease causing mutations of this gene have been described so far (3). Most of these mutations occur in single families, only a few are more frequent (like H1069Q, 3400delC and 2299insC in Caucasian (4-6) or R778L in Japanese (7), Chinese and Korean patients). Studies of phenotype-genotype relations are hampered by the lack of standard diagnostic criteria and phenotypic classifications. To overcome this problem, a working party discussed these problems in depth at the 8th International Meeting on Wilson disease and Menkes disease in Leipzig/Germany (April 16-18, 2001). After the meeting, a preliminary draft of a consensus report was mailed to all active participants and their comments were incorporated in the final text.

BACKGROUND: Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside polymerase inhibitor dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis. METHODS: We randomly assigned 380 patients with Child-Pugh class A cirrhosis to receive either 12 or 24 weeks of treatment with ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. The rate of sustained virologic response in each group was compared with the estimated rate with a telaprevir-based regimen (47%; 95% confidence interval [CI], 41 to 54). A noninferiority margin of 10.5 percentage points established 43% as the noninferiority threshold; the superiority threshold was 54%. RESULTS: A total of 191 of 208 patients who received 12 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 91.8% (97.5% CI, 87.6 to 96.1). A total of 165 of 172 patients who received 24 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 95.9% (97.5% CI, 92.6 to 99.3). These rates were superior to the historical control rate. The three most common adverse events were fatigue (in 32.7% of patients in the 12-week group and 46.5% of patients in the 24-week group), headache (in 27.9% and 30.8%, respectively), and nausea (in 17.8% and 20.3%, respectively). The hemoglobin level was less than 10 g per deciliter in 7.2% and 11.0% of patients in the respective groups. Overall, 2.1% of patients discontinued treatment owing to adverse events. CONCLUSIONS: In this phase 3 trial of an oral, interferon-free regimen evaluated exclusively in patients with HCV genotype 1 infection and cirrhosis, multitargeted therapy with the use of three new antiviral agents and ribavirin resulted in high rates of sustained virologic response. Drug discontinuations due to adverse events were infrequent. (Funded by AbbVie; TURQUOISE-II ClinicalTrials.gov number, NCT01704755.).

Excess mortality in persons with severe mental disorders (SMD) is a major public health challenge that warrants action. The number and scope of truly tested interventions in this area remain limited, and strategies for implementation and scaling up of programmes with a strong evidence base are scarce. Furthermore, the majority of available interventions focus on a single or an otherwise limited number of risk factors. Here we present a multilevel model highlighting risk factors for excess mortality in persons with SMD at the individual, health system and socio-environmental levels. Informed by that model, we describe a comprehensive framework that may be useful for designing, implementing and evaluating interventions and programmes to reduce excess mortality in persons with SMD. This framework includes individual-focused, health system-focused, and community level and policy-focused interventions. Incorporating lessons learned from the multilevel model of risk and the comprehensive intervention framework, we identify priorities for clinical practice, policy and research agendas.

The association between obesity and impaired insulin sensitivity has long been recognized, although a subgroup of obese individuals seems to be protected from insulin resistance. In this study, we systematically studied differences in adipose tissue biology between insulin-sensitive (IS) and insulin-resistant (IR) individuals with morbid obesity. On the basis of glucose infusion rate during euglycemic hyperinsulinemic clamps, 60 individuals with a BMI of 45 +/- 1.3 kg/m(2) were divided into an IS and IR group matched for age, sex, and body fat prior to elective surgery. We measured fat distribution, circulating adipokines, and parameters of inflammation, glucose, and lipid metabolism and characterized adipose tissue morphology, function, and mRNA expression in abdominal subcutaneous (sc) and omental fat. IS compared with IR obese individuals have significantly lower visceral fat area (138 +/- 27 vs. 316 +/- 91 cm(2)), number of macrophages in omental adipose tissue (4.9 +/- 0.8 vs. 13.2 +/- 1.4%), mean omental adipocyte size (528 +/- 76 vs. 715 +/- 81 pl), circulating C-reactive protein, progranulin, chemerin, and retinol-binding protein-4 (all P values <0.05), and higher serum adiponectin (6.9 +/- 3.4 vs. 3.4 +/- 1.7 ng/ml) and omental adipocyte insulin sensitivity (all P values <0.01). The strongest predictors of insulin sensitivity by far were macrophage infiltration together with circulating adiponectin (r(2) = 0.98, P < 0.0001). In conclusion, independently of total body fat mass, increased visceral fat accumulation and adipose tissue dysfunction are associated with IR obesity. This suggests that mechanisms beyond a positive caloric balance such as inflammation and adipokine release determine the pathological metabolic consequences in patients with obesity.

BACKGROUND: In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. METHODS: We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia. CONCLUSIONS: Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL-2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.).

AIMS: This European Association Cardiovascular Imaging (EACVI) Expert Consensus document aims at defining the main quantitative information on cardiac structure and function that needs to be included in standard echocardiographic report following recent ASE/EACVI chamber quantification, diastolic function, and heart valve disease recommendations. The document focuses on general reporting and specific pathological conditions such as heart failure, coronary artery and valvular heart disease, cardiomyopathies, and systemic diseases. METHODS AND RESULTS: Demographic data (age, body surface area, blood pressure, and heart rhythm and rate), type (vendor and model) of ultrasound system used and image quality need to be reported. In addition, measurements should be normalized for body size. Reference normal values, derived by ASE/EACVI recommendations, shall always be reported to differentiate normal from pathological conditions. This Expert Consensus document suggests avoiding the surveillance of specific variable using different ultrasound techniques (e.g. in echo labs with high expertise in left ventricular ejection fraction by 3D and not by 2D echocardiography). The report should be also tailored in relation with different cardiac pathologies, quality of images, and needs of the caregivers. CONCLUSION: The conclusion should be concise reflecting the status of left ventricular structure and function, the presence of left atrial and/or aortic dilation, right ventricular dysfunction, and pulmonary hypertension, leading to an objective communication with the patient health caregiver. Variation over time should be considered carefully, taking always into account the consistency of the parameters used for comparison.

BACKGROUND: Risk stratification and therapeutic decision-making for myelodysplastic syndromes (MDS) are based on the International Prognostic Scoring System–Revised (IPSS-R), which considers hematologic parameters and cytogenetic abnormalities. Somatic gene mutations are not yet used in the risk stratification of patients with MDS. METHODS: To develop a clinical-molecular prognostic model (IPSS-Molecular [IPSS-M]), pretreatment diagnostic or peridiagnostic samples from 2957 patients with MDS were profiled for mutations in 152 genes. Clinical and molecular variables were evaluated for associations with leukemia-free survival, leukemic transformation, and overall survival. Feature selection was applied to determine the set of independent IPSS-M prognostic variables. The relative weights of the selected variables were estimated using a robust Cox multivariable model adjusted for confounders. The IPSS-M was validated in an external cohort of 754 Japanese patients with MDS. RESULTS: We mapped at least one oncogenic genomic alteration in 94% of patients with MDS. Multivariable analysis identified TP53multihit, FLT3 mutations, and MLLPTD as top genetic predictors of adverse outcomes. Conversely, SF3B1 mutations were associated with favorable outcomes, but this was modulated by patterns of comutation. Using hematologic parameters, cytogenetic abnormalities, and somatic mutations of 31 genes, the IPSS-M resulted in a unique risk score for individual patients. We further derived six IPSS-M risk categories with prognostic differences. Compared with the IPSS-R, the IPSS-M improved prognostic discrimination across all clinical end points and restratified 46% of patients. The IPSS-M was applicable in primary and secondary/therapy-related MDS. To simplify clinical use of the IPSS-M, we developed an open-access Web calculator that accounts for missing values. CONCLUSIONS: Combining genomic profiling with hematologic and cytogenetic parameters, the IPSS-M improves the risk stratification of patients with MDS and represents a valuable tool for clinical decision-making. (Funded by Celgene Corporation through the MDS Foundation, the Josie Robertson Investigators Program, the Edward P. Evans Foundation, the Projects of National Relevance of the Italian Ministry of University and Research, Associazione Italiana per la Ricerca sul Cancro, the Japan Agency for Medical Research and Development, Cancer Research UK, the Austrian Science Fund, the MEXT [Japanese Ministry of Education, Culture, Sports, Science and Technology] Program for Promoting Research on the Supercomputer Fugaku, the Japan Society for the Promotion of Science, the Taiwan Department of Health, and Celgene Corporation through the MDS Foundation.)