CARATTERIZZAZIONE CLINICA E PROGNOSTICA DEI PATTERNS DI SCOMPENSO DELLA CIRROSI EPATICA

Il decorso clinico della cirrosi epatica è classicamente suddiviso in due fasi, la cirrosi compensata e quella scompensata, che è caratterizzata dalla comparsa delle complicanze della cirrosi (ascite, encefalopatia epatica, sanguinamento da ipertensione portale) e da peggior prognosi. Recentemente le osservazioni derivanti dallo studio PREDICT hanno posto l’attenzione sull’Acute Decompensation (AD), cioè lo sviluppo di complicanze della cirrosi che richiedono il ricovero ospedaliero. Tuttavia, le complicanze della cirrosi non sempre richiedono ricovero ospedaliero e possono svilupparsi in modo progressivo, come nel caso della formazione di ascite o una lieve encefalopatia epatica; questa tipologia di scompenso è stata definita Non Acute Decompensation (NAD). Al momento non esistono informazioni riguardo all’incidenza e all’impatto prognostico della NAD e se questa presenti una prognosi differente rispetto a quella dei pazienti con AD. L’obiettivo dello studio è stato quindi la valutazione dell’incidenza e delle caratteristiche di NAD e AD in un gruppo di pazienti con cirrosi epatica seguiti ambulatorialmente e l’impatto prognostico di questi due pattern di scompenso. Sono stati arruolati consecutivamente 749 pazienti cirrotici seguiti ambulatorialmente, che sono stati seguiti fino alla fine del follow up (Agosto 2021) oppure fino alla morte o al trapianto di fegato. Sono stati raccolti i dati clinici e bioumorali all’inclusione, così come lo sviluppo di complicanze della cirrosi (versamento ascitico, encefalopatia epatica o sanguinamento gastrointestinale), che sono stati considerati come AD qualora determinassero un ricovero ospedaliero o NAD nel caso venissero gestiti ambulatorialmente. 379 pazienti (50.6%) non hanno sviluppato alcun episodio di scompenso, mentre in 163 pazienti (21.8%) il primo scompenso è stato una NAD (144 con ascite, 57 encefalopatia epatica, 2 sanguinamento gastrointestinale) ed in 207 (27.6%) è stato una AD (77 sotto forma di ascite, 87 di encefalopatia epatica e 43 di sanguinamento). Durante il follow up, 216 (28.8%) pazienti sono deceduti e 145 (19.4%) sono stati trapiantati. La sopravvivenza a 120 mesi è risultata significativamente superiore nei pazienti che non hanno sviluppato scompenso (79.6%) rispetto sia ai pazienti che avevano sviluppato come primo scompenso NAD o AD (33.7% e 21.3%, rispettivamente; p<0.001). La sopravvivenza nei pazienti con NAD è risultata lievemente superiore rispetto a quella osservata nei pazienti con AD (p=0.03). 83 pazienti con NAD (50.9%) hanno successivamente sviluppato una AD. Non si sono evidenziate differenze significative in termini di sopravvivenza a 120 mesi tra i pazienti che hanno sviluppato una AD dopo NAD e quelli che hanno avuto solo AD, mentre entrambi questi gruppi hanno dimostrato una sopravvivenza inferiore ai pazienti che avevano presentato solo una NAD. Tutti e 3 i pattern di scompenso (solo NAD, NAD seguito da AD e AD) hanno presentato una sopravvivenza significativamente inferiore rispetto ai pazienti non scompensati. All’analisi multivariata, l’età (HR 1.05, 95% CI 1.03-1.06), il MELD (HR 1.10, 95% CI 1.06-1.15), la presenza di varici all’inclusione (HR 1.48, 95% CI 1.03-2.11), l’albumina (HR 0.94, 95% CI 0.92-0.97), la MAP (HR 0.98, 95% CI 0.97-0.99), l’aver ricevuto un trattamento eziologico efficace (HR 0.38, 95% CI 0.27-0.58) e lo sviluppo di NAD (HR 2.65, 95% CI 1.70-4.11) o di AD (HR 3.51, 95% CI 2.28-5.38) sono risultati predittori indipendenti di mortalità. In più del 20% dei pazienti con cirrosi epatica lo scompenso della cirrosi si manifesta inizialmente come NAD, spesso precede l’AD e si associa ad una riduzione di sopravvivenza. I pazienti che sviluppano NAD devono essere trattati con estrema attenzione e monitorati strettamente per prevenire eventuali sviluppi di AD. Il trattamento eziologico della cirrosi si è confermato il più importante predittore di prevenzione dello scompenso.Background and aims: The clinical course of liver cirrhosis is classically divided into two phases, compensated and decompensated cirrhosis, the latter characterized by the onset of complications (ascites, hepatic encephalopathy, bleeding from portal hypertension) and a worse prognosis. Recently, the observations resulting from the PREDICT study highlighted the role of Acute Decompensation (AD), i.e. the development of complications of cirrhosis that require hospitalization. However, complications of cirrhosis do not necessarily require hospitalization and can develop progressively, as is the case of slow and progressive development of ascites or mild grade 1 or 2 hepatic encephalopathy. This type of decompensation has recently been defined as Non Acute Decompensation (NAD). At present time, there is no information regarding the incidence and prognostic impact of NAD and whether it has a different prognosis than that of patients with AD. The aim of the study was therefore to evaluate the incidence and characteristics of NAD and AD in a group of outpatients with liver cirrhosis and the prognostic impact of these two decompensation patterns. Patients and Methods: 749 outpatients with cirrhosis were enrolled and consequently followed up until the end of the study (August 2021) or until death or liver transplantation. Clinical and biochemical data at inclusion were collected, as well as the development of complications of cirrhosis (ascites, hepatic encephalopathy or gastrointestinal bleeding), which were considered as AD if they resulted in hospitalization or NAD if they were managed at our outpatient clinic. Results: 379 patients (50.6%) did not develop any decompensation, while in 163 patients (21.8%) the first decompensation was NAD (144 with ascites, 57 hepatic encephalopathy, 2 gastrointestinal bleeding) and in 207 (27.6%) it was AD (77 ascites, 87 hepatic encephalopathy and 43 bleeding). During follow up, 216 patients (28.8%) died and 145 (19.4%) were transplanted. Survival at 120 months was significantly higher in patients who did not develop any decompensation (79.6%) than in patients who developed NAD or AD (33.7% and 21.3%, respectively; p <0.001). Survival in patients with NAD was slightly higher than that observed in patients with AD (p =0.03). Eighty-three patients with NAD (50.9%) subsequently developed AD. There was no significant difference in 120-month survival between patients who developed AD after NAD and those who only had AD, while both of these groups showed shorter survival than patients who had only NAD. All three decompensation patterns (only NAD, NAD followed by AD and AD) had significantly shorter survival than non-decompensated patients. At multivariate analysis, age (HR 1.05, 95% CI 1.03-1.06), MELD (HR 1.10, 95% CI 1.06-1.15), the presence of varices at inclusion (HR 1.48, 95% CI 1.03- 2.11), albumin (HR 0.94, 95% CI 0.92-0.97), MAP (HR 0.98, 95% CI 0.97-0.99), having received effective etiological treatment (HR 0.38, 95% CI 0.27-0.58 ) and the development of NAD (HR 2.65, 95% CI 1.70-4.11) or AD (HR 3.51, 95% CI 2.28-5.38) were independent predictors of mortality. Conclusions: In more than one out of five outpatients with liver cirrhosis, the first decompensation is a NAD, which often precedes AD and is associated with a decreased survival. Patients who develop NAD must be treated with extreme care and monitored closely to prevent any development of AD. The etiological treatment of cirrhosis has been confirmed as the most important predictor of prevention of decompensation of cirrhosis

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Nitrogen deposition outweighs climatic variability in driving annual growth rate of canopy beech trees: Evidence from long-term growth reconstruction across a geographic gradient

In this study, we investigated the role of climatic variability and atmospheric nitrogen deposition in driving long-term tree growth in canopy beech trees along a geographic gradient in the montane belt of the Italian peninsula, from the Alps to the southern Apennines. We sampled dominant trees at different developmental stages (from young to mature tree cohorts, with tree ages spanning from 35 to 160&nbsp;years) and used stem analysis to infer historic reconstruction of tree volume and dominant height. Annual growth volume (G V ) and height (G H ) variability were related to annual variability in model simulated atmospheric nitrogen deposition and site-specific climatic variables, (i.e. mean annual temperature, total annual precipitation, mean growing period temperature, total growing period precipitation, and standard precipitation evapotranspiration index) and atmospheric CO 2 concentration, including tree cambial age among growth predictors. Generalized additive models (GAM), linear mixed-effects models (LMM), and Bayesian regression models (BRM) were independently employed to assess explanatory variables. The main results from our study were as follows: (i) tree age was the main explanatory variable for long-term growth variability; (ii) GAM, LMM, and BRM results consistently indicated climatic variables and CO 2 effects on G V and G H were weak, therefore evidence of recent climatic variability influence on beech annual growth rates was limited in the montane belt of the Italian peninsula; (iii) instead, significant positive nitrogen deposition (N dep ) effects were repeatedly observed in G V and G H ; the positive effects of N dep on canopy height growth rates, which tended to level off at N dep values greater than approximately 1.0&nbsp;g&nbsp;m −2 &nbsp;y −1 , were interpreted as positive impacts on forest stand above-ground net productivity at the selected study sites

Can the Multidimensional Prognostic Index (MPI) be a predictive instrument for mortality in older adult liver transplant candidates?

PurposeThe most recent guidelines recommend that selection of liver transplant recipient patients be guided by a multidimensional approach that includes frailty assessment. Different scales have been developed to identify frail patients and determine their prognosis, but the data on older adult candidates are still inconclusive. The aim of this study was to compare the accuracy of the Liver Frailty Index (LFI) and the Multidimensional Prognostic Index (MPI) as predictors of mortality in a cohort of older people patients being evaluated for liver transplantation.MethodsThis retrospective study was conducted on 68 patients > 70 years being followed at the University Hospital of Padua in 2018. Clinical information on each patient, Model For End-Stage Liver Disease (MELD), Body Mass Index (BMI), Activities of Daily Living (ADL), Mini Nutritional Assessment (MNA), LFI, MPI, and date-of-death, were recorded. The observational period was 3 years.ResultsWe studied 68 individuals (25 women), with a mean age 72.21 & PLUSMN; 1.64 years. Twenty-five (36.2%) patients died during the observational period. ROC curve analysis showed both MPI and LFI to be good predictors of mortality (AUC 0.7, p = 0.007, and AUC 0.689, p = 0.015, respectively). MELD (HR 1.99, p = 0.001), BMI (HR 2.34, p = 0.001), and poor ADL (HR 3.34, p = 0.04) were risk factors for mortality in these patients, while male sex (HR 0.1, p = 0.01) and high MNA scores (HR 0.57, p = 0.01) were protective factors.ConclusionOur study confirmed the prognostic value of MPI in older adult patients awaiting liver transplantation. In this cohort, good nutritional status and male sex were protective factors, while high MELD and BMI scores and poor functional status were risk factors.Key summary pointsAimThe aim of this study was to compare the accuracy of the Liver Frailty Index (LFI) and the Multidimensional Prognostic Index (MPI) as predictors of mortality in a cohort of older adult patients being evaluated for liver transplantationFindingsOn the 68 patients studied, ROC curve analysis showed that MPI was similar or slightly better than LFI as predictor of mortality (AUC 0.7, p=0.007, and AUC 0.689, p=0.015, respectively).MessageIn older people patients listed for liver transplantation, MPI is as good a prognostic tool as LFI for predicting mortality

Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients

Beta-thalassemia is a common monogenic disorder due to mutations in the beta-globin gene and gene therapy, based on autologous transplantation of genetically corrected haematopoietic stem cells (HSCs), holds the promise to treat patients lacking a compatible bone marrow (BM) donor. We recently showed correction of murine beta-thalassemia by gene transfer in HSCs with the GLOBE lentiviral vector (LV), expressing a transcriptionally regulated human beta-globin gene. Here, we report successful correction of thalassemia major in human cells, by studying a large cohort of pediatric patients of diverse ethnic origin, carriers of different mutations and all candidates to BM transplantation. Extensive characterization of BM-derived CD34(+) cells before and following gene transfer shows the achievement of high frequency of transduction, restoration of haemoglobin A synthesis, rescue from apoptosis and correction of ineffective erythropoiesis. The procedure does not significantly affect the differentiating potential and the relative proportion of haematopoietic progenitors. Analysis of vector integrations shows preferential targeting of transcriptionally active regions, without bias for cancer-related genes. Overall, these results provide a solid rationale for a future clinical translation

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism

Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression

The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing.

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.We thank the DKFZ Genomics and Proteomics Core Facility and the OICR Genome Technologies Platform for provision of sequencing services. Financial support was provided by the consortium projects READNA under grant agreement FP7 Health-F4-2008-201418, ESGI under grant agreement 262055, GEUVADIS under grant agreement 261123 of the European Commission Framework Programme 7, ICGC-CLL through the Spanish Ministry of Science and Innovation (MICINN), the Instituto de Salud Carlos III (ISCIII) and the Generalitat de Catalunya. Additional financial support was provided by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants #01KU1201A, MedSys #0315416C and NGFNplus #01GS0883; the Ontario Institute for Cancer Research to PCB and JDM through funding provided by the Government of Ontario, Ministry of Research and Innovation; Genome Canada; the Canada Foundation for Innovation and Prostate Cancer Canada with funding from the Movember Foundation (PCB). PCB was also supported by a Terry Fox Research Institute New Investigator Award, a CIHR New Investigator Award and a Genome Canada Large-Scale Applied Project Contract. The Synergie Lyon Cancer platform has received support from the French National Institute of Cancer (INCa) and from the ABS4NGS ANR project (ANR-11-BINF-0001-06). The ICGC RIKEN study was supported partially by RIKEN President’s Fund 2011, and the supercomputing resource for the RIKEN study was provided by the Human Genome Center, University of Tokyo. MDE, LB, AGL and CLA were supported by Cancer Research UK, the University of Cambridge and Hutchison-Whampoa Limited. SD is supported by the Torres Quevedo subprogram (MI CINN) under grant agreement PTQ-12-05391. EH is supported by the Research Council of Norway under grant agreements 221580 and 218241 and by the Norwegian Cancer Society under grant agreement 71220-PR-2006-0433. Very special thanks go to Jennifer Jennings for administrating the activity of the ICGC Verification Working Group and Anna Borrell for administrative support.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1000