Hospital Universitari i Politècnic La Fe

The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.

In 2003, an international working group last reported on recommendations for diagnosis, response assessment, and treatment outcomes in acute myeloid leukemia (AML). Since that time, considerable progress has been made in elucidating the molecular pathogenesis of the disease that has resulted in the identification of new diagnostic and prognostic markers. Furthermore, therapies are now being developed that target disease-associated molecular defects. Recent developments prompted an international expert panel to provide updated evidence- and expert opinion-based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials. A new standardized reporting system for correlation of cytogenetic and molecular genetic data with clinical data is proposed.

The International Prognostic Scoring System (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.

Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. This gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis elegans and yeast. A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.

OBJECTIVE: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved. METHODS: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing. RESULTS: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative. CONCLUSIONS: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.

Diagnosis and management of immune thrombocytopenic purpura (ITP) remain largely dependent on clinical expertise and observations more than on evidence derived from clinical trials of high scientific quality. One major obstacle to the implementation of such studies and in producing reliable meta-analyses of existing data is a lack of consensus on standardized critical definitions, outcome criteria, and terminology. Moreover, the demand for comparative clinical trials has dramatically increased since the introduction of new classes of therapeutic agents, such as thrombopoietin receptor agonists, and innovative treatment modalities, such as anti-CD 20 antibodies. To overcome the present heterogeneity, an International Working Group of recognized expert clinicians convened a 2-day structured meeting (the Vicenza Consensus Conference) to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. These consensus criteria and definitions could be used by investigational clinical trials or cohort studies. Adoption of these recommendations would serve to improve communication among investigators, to enhance comparability among clinical trials, to facilitate meta-analyses and development of therapeutic guidelines, and to provide a standardized framework for regulatory agencies.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.

BACKGROUND: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS: A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).

OBJECTIVES: The ESPGHAN 2012 coeliac disease (CD) diagnostic guidelines aimed to guide physicians in accurately diagnosing CD and permit omission of duodenal biopsies in selected cases. Here, an updated and expanded evidence-based guideline is presented. METHODS: Literature databases and other sources of information were searched for studies that could inform on 10 formulated questions on symptoms, serology, HLA genetics, and histopathology. Eligible articles were assessed using QUADAS2. GRADE provided a basis for statements and recommendations. RESULTS: Various symptoms are suggested for case finding, with limited contribution to diagnostic accuracy. If CD is suspected, measurement of total serum IgA and IgA-antibodies against transglutaminase 2 (TGA-IgA) is superior to other combinations. We recommend against deamidated gliadin peptide antibodies (DGP-IgG/IgA) for initial testing. Only if total IgA is low/undetectable, an IgG-based test is indicated. Patients with positive results should be referred to a paediatric gastroenterologist/specialist. If TGA-IgA is ≥10 times the upper limit of normal (10× ULN) and the family agrees, the no-biopsy diagnosis may be applied, provided endomysial antibodies (EMA-IgA) will test positive in a second blood sample. HLA DQ2-/DQ8 determination and symptoms are not obligatory criteria. In children with positive TGA-IgA <10× ULN at least 4 biopsies from the distal duodenum and at least 1 from the bulb should be taken. Discordant results between TGA-IgA and histopathology may require re-evaluation of biopsies. Patients with no/mild histological changes (Marsh 0/I) but confirmed autoimmunity (TGA-IgA/EMA-IgA+) should be followed closely. CONCLUSIONS: CD diagnosis can be accurately established with or without duodenal biopsies if given recommendations are followed.

BACKGROUND: Promising results of cord-blood transplants from unrelated donors have been reported in adults. METHODS: We compared outcomes in 682 adults with acute leukemia who received a hematopoietic stem-cell transplant from an unrelated donor: 98 received cord blood and 584 received bone marrow. The transplantations were performed from 1998 through 2002 and reported to Eurocord and the European Blood and Marrow Transplant Group. RESULTS: Recipients of cord blood were younger than recipients of bone marrow (median, 24.5 vs. 32 years of age; P<0.001), weighed less (median, 58 vs. 68 kg; P<0.001), and had more advanced disease at the time of transplantation (52 percent vs. 33 percent, P<0.001). All marrow transplants were HLA matched, whereas 94 percent of cord-blood grafts were HLA mismatched (P<0.001). The median number of nucleated cells that were infused was 0.23x10(8) per kilogram of the recipient's body weight for cord blood and 2.9x10(8) per kilogram for bone marrow (P<0.001). Multivariate analysis showed lower risks of grade II, III, or IV acute graft-versus-host disease (GVHD) after cord-blood transplantation (relative risk, 0.57; 95 percent confidence interval, 0.37 to 0.87; P=0.01), but neutrophil recovery was significantly delayed (relative risk, 0.49; 95 percent confidence interval, 0.41 to 0.58; P<0.001). The incidence of chronic GVHD, transplantation-related mortality, relapse rate, and leukemia-free survival were not significantly different in the two groups. CONCLUSIONS: Cord blood from an unrelated donor is an alternative source of hematopoietic stem cells for adults with acute leukemia who lack an HLA-matched bone marrow donor.

BACKGROUND: Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy. METHODS: In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period. RESULTS: A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations. CONCLUSIONS: Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560 .).

The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence- and expert opinion-based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA- and ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.

BACKGROUND: Colonoscopy and fecal immunochemical testing (FIT) are accepted strategies for colorectal-cancer screening in the average-risk population. METHODS: In this randomized, controlled trial involving asymptomatic adults 50 to 69 years of age, we compared one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects. The primary outcome was the rate of death from colorectal cancer at 10 years. This interim report describes rates of participation, diagnostic findings, and occurrence of major complications at completion of the baseline screening. Study outcomes were analyzed in both intention-to-screen and as-screened populations. RESULTS: The rate of participation was higher in the FIT group than in the colonoscopy group (34.2% vs. 24.6%, P<0.001). Colorectal cancer was found in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group (odds ratio, 0.99; 95% confidence interval [CI], 0.61 to 1.64; P=0.99). Advanced adenomas were detected in 514 subjects (1.9%) in the colonoscopy group and 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to 2.69; P<0.001), and nonadvanced adenomas were detected in 1109 subjects (4.2%) in the colonoscopy group and 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001). CONCLUSIONS: Subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group. On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group. (Funded by Instituto de Salud Carlos III and others; ClinicalTrials.gov number, NCT00906997.).

BACKGROUND: Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA. METHODS: We randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension. RESULTS: At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range. CONCLUSIONS: Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).

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

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.)

OBJECTIVE: To report the clinical and immunological features of a novel autoantigen related to limbic encephalitis (LE) and the effect of patients' antibodies on neuronal cultures. METHODS: We conducted clinical analyses of 10 patients with LE. Immunoprecipitation and mass spectrometry were used to identify the antigens. Human embryonic kidney 293 cells expressing the antigens were used in immunocytochemistry and enzyme-linked immunoabsorption assay. The effect of patients' antibodies on cultures of live rat hippocampal neurons was determined with confocal microscopy. RESULTS: Median age was 60 (38-87) years; 9 were women. Seven had tumors of the lung, breast, or thymus. Nine patients responded to immunotherapy or oncological therapy, but neurological relapses, without tumor recurrence, were frequent and influenced the long-term outcome. One untreated patient died of LE. All patients had antibodies against neuronal cell surface antigens that by immunoprecipitation were found to be the glutamate receptor 1 (GluR1) and GluR2 subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Human embryonic kidney 293 cells expressing GluR1/2 reacted with all patients' sera or cerebrospinal fluid, providing a diagnostic test for the disorder. Application of antibodies to cultures of neurons significantly decreased the number of GluR2-containing AMPAR clusters at synapses with a smaller decrease in overall AMPAR cluster density; these effects were reversed after antibody removal. INTERPRETATION: Antibodies to GluR1/2 associate with LE that is often paraneoplastic, treatment responsive, and has a tendency to relapse. Our findings support an antibody-mediated pathogenesis in which patients' antibodies alter the synaptic localization and number of AMPARs.

Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.

Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation.