Prevalence of Bleeding and Thrombosis in Critically Ill Patients with Chronic Liver Disease

INTRODUCTION:  Hemorrhage and venous thromboembolism (VTE) are recognized complications of chronic liver disease (CLD), but their prevalence and risk factors in critically ill patients are uncertain. PATIENTS AND METHODS:  We studied a retrospective cohort of patients with CLD nonelectively admitted to a specialist intensive care unit (ICU) determining the prevalence and timing of major bleeding and VTE (early, present on admission/diagnosed within 48 hours; later, diagnosed >48 hours post-ICU admission). Associations with baseline clinical and laboratory characteristics, multiorgan failure (MOF), blood product administration, and mortality were explored. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. RESULTS:  Of 623 patients with median age 52, bleeding (>48 hours after admission) occurred in 87 (14%) patients. Bleeding was associated with greater illness severity and increased mortality. Gastrointestinal bleeding accounted for 72% of events, secondary to portal hypertension in >90%. Procedure-related bleeding was uncommon. VTE occurred in 125 (20%) patients: early VTE in 80 (13%) and involving the portal vein in 85%. Later VTE affected 45 (7.2%) patients. Hepatocellular carcinoma (HCC) and nonalcoholic liver disease were independently associated with early VTE (OR: 2.79, 95% CI: 1.5-5.2 and OR: 2.32, 95% CI: 1.4-3.9, respectively), and HCC, sepsis, and cryoprecipitate use with late VTE (OR: 2.45, 95% CI: 1.11-5.43; OR: 2.26, 95% CI: 1.2-4.3; and OR: 2.60, 95% CI: 1.3-5.1). CONCLUSION:  VTE was prevalent on admission to critical care and less commonly developed later. Bleeding was associated with MOF and increased mortality. Severe MOF was not associated with an increased rate of VTE which was linked with HCC, and specific etiologies of CLD

Expression of progenitor cell markers in hepatocellular carcinoma: correlation with stage and prognosis

Aims: In human hepatocellular carcinoma (HCC), keratin 19 (K19), Epithelial Cell Adhesion Molecule (EpCAM) and CD117 (c-KIT) immunopositivity indicate possible hepatic progenitor cell (HPC) origin. Methods and Results: We assessed the expression of K19, EpCAM and CD117 by immunohistochemistry in 89 HCC from Greek patients (mean age 66.7±11.3 years, male 74.7%) followed-up for 39.625.3 months in correlation with clinico-pathological parameters and survival. K19-, EpCAM- and CD117-specific immunoexpression was detected in tumour cells of 9/89 (10.11%), 12/78 (15.38%) and 3/89 (3.37%) HCC, respectively. K19-positivity tended to correlate with microvascular invasion (p=0.054). In univariate analysis, K19-positivity and microvascular invasion were associated with decreased recurrence-free (RFS) (p<0.001 and p=0.004, respectively) and overall survival (OS) (p=0.002 and p=0.029, respectively). EpCAM- and CD117-positivity did not correlate with survival. K19-positive/EpCAM-positive cases showed significantly decreased RFS (p<0.001) and OS (p=0.001) compared to K19-negative/EpCAM-negative cases. In multivariate analysis, K19-positivity emerged as an independent predictor of RFS (OR=7.84,95%CI=2.658-22.912;p<0.001) and OS (OR=3.845 95%CI=1.401-10.549;p=0.009). Conclusions: K19 immunoexpression is an independent predictor of RFS and OS in a cohort of Greek HCC and could be used for subgrouping HCC according to tumor aggressiveness. Co-expression of K19 and EpCAM may represent a poor prognostic signature for human HCC.Ο ηπατοκυτταρικός καρκίνος είναι ένας ετερογενής όγκος με διακριτές υποομάδες που διαφέρουν ως προς την κυτταρική προέλευση και την πρόγνωση. Η έκφραση της Κ19, του EpCAM και του CD117 (KIT) ενδέχεται να συσχετίζονται με την πιθανή προέλευση του ΗΚΚ από προγονικά κύτταρα και με δυσμενή πρόγνωση και φτωχή ιστολογική διαφοροποίηση. Σκοπός μελέτης: Με τη μέθοδο της ανοσοιστοχημείας μελετήθηκε η έκφραση της Κ19, του Epithelial Cell Adhesion Molecule (EpCAM) και του CD117 (KIT) σε ασθενείς με ΗΚΚ με σκοπό τον προσδιορισμό της πιθανής προέλευσης από προγονικά κύτταρα. Μέθοδοι και αποτελέσματα: Η έκφραση της Κ19, του EpCAM και του CD117 εξετάστηκε σε ένα σύνολο 89 Καυκάσιων Ελλήνων ασθενών (μέση ηλικία 66.7±11.3 χρόνια, άνδρες 74.7%) που παρακολουθήθηκαν για 39.625.3 μήνες. Η έκφραση των παραπάνω δεικτών συσχετίστηκε με κλινικοπαθολογοανατομικές παραμέτρους και επιβίωση. Ειδική ανοσοιστοχημική έκφραση της Κ19, του EpCAM και του CD117 βρέθηκε αντίστοιχα στους 9/89 (10.11%), 12/78 (15.38%) και 3/89 (3.37%) των ασθενών με ΗΚΚ. Η έκφραση της Κ19 έτεινε να συσχετιστεί με την μικροαγγειακή διήθηση (p =0.054). Σε μονοπαραγοντική ανάλυση, η έκφραση της Κ19 και η μικροαγγειακή διήθηση συσχετίστηκαν με μειωμένη επιβίωση ελευθέρας νόσου (p<0.001 και p=0.004, αντίστοιχα) και συνολική επιβίωση (p=0.002 και p=0.029, αντίστοιχα). Η έκφραση του EpCAM και του CD117 δεν συσχετίστηκε σε βαθμό στατιστικής σημαντικότητας με την επιβίωση. Ασθενείς με ΗΚΚ θετικά τόσο για την Κ19 όσο και για το EpCAM είχαν στατιστικώς σημαντική μειωμένη επιβίωση ελευθέρας νόσου (p<0.001) και συνολική επιβίωση (p=0.001) σε σύγκριση με τους ασθενείς που ήταν αρνητικοί και για τους δυο δείκτες. Σε πολυπαραγοντική ανάλυση, η έκφραση της Κ19 φάνηκε να είναι ανεξάρτητος προγνωστικός παράγοντας μειωμένης επιβίωσης ελευθέρας νόσου (OR=7.84,95%CI=2.658-22.912;p<0.001) και συνολικής επιβίωσης (OR=3.845 95%CI=1.401-10.549;p=0.009). Συμπεράσματα: Η έκφραση της Κ19 είναι ένας ανεξάρτητος προγνωστικός παράγοντας επιβίωσης ελευθέρας νόσου και συνολικής επιβίωσης στους ασθενείς με ΗΚK και είναι αξιόπιστος δείκτης επιθετικότητας στον ΗΚΚ. Επιπλέον, η ταυτόχρονη έκφραση της Κ19 και του EpCAM, ενδέχεται να προσδιορίζει όγκους με περαιτέρω δυσμενή πρόγνωση στους ασθενείς με ΗΚΚ

Adaptive immunity in hepatocellular carcinoma: prognostic and therapeutic implications

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and has a poor prognosis. Host immunity can either protect or promote tumor growth by the predominance and activation of certain subsets of immune cells. It has been established that antigens such as AFP, MAGE, glypican 3 and NY-ESO, which are highly expressed in HCC, are potential targets for T-cell responses. Several studies have come to the conclusion that cytotoxic T-cell infiltration of the tumors is indicative of a better survival, whereas the predominance of suppressor cells is associated with a worse outcome and lower survival rates. Finally, certain therapeutic strategies, including radiofrequency ablation and chemoembolization, can enhance the release and exposure of tumor antigens, which might help to overcome the immune tolerance towards the tumor. Therefore, such immune-stimulating therapeutic interventions in combination with immunotherapy strategies represent a promising future approach for HCC treatment

Alpha-fetoprotein as a predictor of hepatocellular carcinoma recurrence following liver transplantation

Alpha-fetoprotein (AFP) has been increasingly recognised as a valuable marker in predicting HCC recurrence post-liver transplantation. Moreover, its secretion has been associated with poor histological tumour characteristics as it reflects an aggressive tumour biological behaviour. This review aims to summarise the emerging evidence on the use of AFP either as an independent marker, or as a variable incorporated into prognostic models. For this purpose, an electronic PubMed literature search was performed. Due to the heterogeneity of the reported studies, drawing clear conclusions about the optimum AFP cut-off level to predict recurrence is difficult. Models that include AFP at different cut-offs have been shown be superior to Milan criteria in predicting disease recurrence, but need to be prospectively validated in order to confirm their prognostic value. Until more refined methods for selecting patients become available, existing evidence support the use of AFP in decision models for liver transplantation

Cardiolipin Antibody: A Potential Biomarker for Depression

Background: Inflammation plays a pivotal role in the etiopathology of Major Depressive Disorder (MDD), at least in a subset of patients. It is crucial to first establish which specific inflammatory biomarkers are of clinical utility. Anti-cardiolipin antibody (aCL IgM) is an inflammatory marker that has the potential to be such a candidate but there are insufficient studies to confirm this potential. Objective: To investigate the baseline titer level and the longitudinal progression of plasma titers of aCL IgM in MDD subjects receiving antidepressant therapy in comparison to healthy control (HC) subjects; to determine if changes in aCL IgM plasma titers correlate to changes in depressive symptoms; and, to ascertain if baseline aCL IgM plasma titers could predict treatment response. Methods: Forty-eight medically healthy outpatients diagnosed with MDD were enrolled in one of two groups in two sequentially conducted clinical trials. In Group-E, patients received a 12-week regimen of escitalopram (n = 20). Those in Group-Q received a 12-week regimen of quetiapine (n = 28). The main outcome measure was plasma aCL IgM titers, the Hamilton Rating Scale for Depression (HAM-D17) and the Hamilton Rating Scale for Anxiety (HAM-A). There were 16 HC subjects. Results: When Group-Q and Group-E participants were grouped together (n = 48), MDD subjects had an elevated baseline aCL IgM (19.9 &mu;g/mL) compared to HC subjects (8.32 &mu;g/mL) (p = 0.006). aCL IgM correlated significantly with HAM-D17 scores at baseline in MDD subjects (p = 0.0185, r = 0.296). Examining the individual groups, Group-Q MDD patients had a significantly elevated baseline aCL IgM (p = 0.008) while Group-E&rsquo;s MDD patients did not. On the other hand, only Group-E MDD patients showed a significant correlation at baseline between aCL IgM and HAM-A score (p = 0.0392, r = 0.4327); they also showed a significant inverse correlation between week 12 HAMD-17 Item #10 (Anxiety, Psychic) and week 12 aCL IgM titer (p = 0.0268, r = &minus;0.5516). Conclusions: MDD patients had significantly higher plasma titers of aCL IgM when compared to HC subjects. Moreover, at baseline, the higher the aCL IgM titer, the higher the depression severity, as measured by HAMD-17 score. However, this study did not demonstrate that aCL IgM titers changed significantly throughout a 12-week course of antidepressant treatment and revealed no correlation between changes in depressive symptoms and changes in aCL IgM titers. Baseline aCL IgM could not predict treatment response. We conclude that, despite lacking predictive ability as regards treatment response, plasma titers of aCL IgM have a diagnostic potential in MDD that necessitates further exploration

Liver disease in adult transfusion-dependent beta-thalassaemic patients: investigating the role of iron overload and chronic HCV infection

Background Iron overload and hepatitis-C virus (HCV) infection, have been implicated in the evolution of liver disease, in patients with transfusion-dependent beta-thalassaemia major (BTM). However, the impact of these factors in late stages of liver disease in adults with BTM, has not been extensively studied. Aims To investigate serum indices of iron overload, HCV infection and liver disease, in a cohort of 211 adult Greek patients with BTM, in relation with the findings from liver biopsies. Methods In this cross-sectional study, 211 patients with BTM were enrolled and studied, in relation with HCV infection, ferritin, transaminases, chelation treatment and antiviral treatment. Based on 109 patients biopsied, we correlated liver fibrosis, haemosiderosis and inflammation, with serum indices and HCV status Results Among all patients, 74.4% were anti-HCV positive (HCV+). Ferritin was positively correlated with transaminases and negatively correlated with age, while it was not significantly different among HCV+ and HCV patients. Among the HCV+ patients, 55.4% reported antiviral treatment, while genotype 1 predominated. In a subfraction of 109 patients, in which liver biopsy was performed, 89% were HCV+ and 11% HCV. Fibrosis was significantly correlated with age (P=0.046), AST (P=0.004), ALT (P=0.044) and inflammation (P&lt;0.001). Advanced fibrosis was present with even minimal haemosiderosis, independently of ferritin values or HCV history. Conclusions These data suggest that in the late stages of liver disease in BTM patients, iron overload may be the critical determinant, since fibrosis is related to the minimal haemosiderosis, independently of HCV history

Co-designed Innovation and System for Resilient Exascale Computing in Europe: From Applications to Silicon (EuroEXA)

EuroEXA targets to provide the template for an upcoming exascale system by co-designing and implementing a petascale-level prototype with ground-breaking characteristics. To accomplish this, the project takes a holistic approach innovating both across the technology and the application/system software pillars. EuroEXA proposes a balanced architecture for compute and data-intensive applications, that builds on top of cost-efficient, modular-integration enabled by novel inter-die links, utilises a novel processing unit and embraces FPGA acceleration for computational, networking and storage operations. EuroEXA hardware designers work together with system software experts optimising the entire stack from language runtimes to low-level kernel drivers, and application developers that bring in a rich mix of key HPC applications from across climate/weather, physical/energy and life-science/bioinformatics domains to enable efficient system co-design and maximise the impact of the project