Polymorphisms in histone deacetylases improve the predictive value of IL-28B for chronic hepatitis C therapy.

Histone deacetylases (HDACs) influence many cellular processes, including the modulation of signal transducer and activator of transcription activity (STAT) in response to interferon (IFN). To identify genetic markers that help optimize the IL-28B prediction of chronic hepatitis C (CHC) sustained virological response (SVR), we evaluated 27 single-nucleotide polymorphisms (SNPs) in HDAC1-11. Three SNPs, rs3778216, rs976552 and rs368328 in HDAC2, HDAC3 and HDAC5, respectively, were independently associated with SVR (P<0.05). The addition of these three HDAC's SNPs to the IL-28B predictive model (area under the curve (AUC)=0.630) rendered an important improvement of AUC-receiver operating characteristic value (AUC=0.747, P=0.021). Chi-squared Automatic Interaction Detector (CHAID) analysis denoted the significance of the rs3778216 C/C genotype in identifying a group of good responders despite carrying IL-28B T allele (79.2% of SVR), whereas HDAC5 G allele characterized a subgroup with poor response rate (25.5%). However, HDAC3 rs976552 did not display a relevant role for the hierarchical classification of patients. Variables related to SVR in hepatitis C virus genotype 1 (HCV-1) cohort were the same of those obtained for the overall population. Interestingly, in non-HCV-1 patients (n=56) the HDAC2 C/C genotype was the unique predictive variable related to SVR (AUC=0.733, P<0.007). Thus, these preliminary results suggest the potential usefulness of combined IL-28B and HDAC genotyping for the CHC patients' classification by likelihood of an SVR.

Genetic variants of interferon-stimulated genes and IL-28B as host prognostic factors of response to combination treatment for chronic hepatitis C.

Chronic hepatitis C (CHC) is a worldwide health problem that is highly related to liver fibrosis, cirrhosis, and hepatocellular carcinoma. The achievement of response to the current standard of care-pegylated interferon plus ribavirin-has recently been described to be associated with single-nucleotide polymorphisms (SNPs) near the IL-28B gene. Additionally, baseline expression levels of genes involved in interferon (IFN)-stimulated genes (ISGs) have been found to be related to treatment outcome. In the present study, 285 patients were genotyped for 63 SNPs within genes of the IFN signaling pathway (IPGs) and ISGs. Two ISG polymorphisms-OASL rs12819210 (odds ratio (OR)=2.1, P=0.03) and IFIT1 rs304478 (OR=2.5, P=0.01)-were found to be independent predictive factors of sustained virological response (SVR) after adjusting for other clinical covariates. Furthermore, the predictive value of IL-28B SNP was notably improved by simultaneous genotyping of rs12819210 and rs304478, particularly in patients with the worst prognosis (viral genotype 1, area under the curve (AUC)=0.74). In conclusion, ISG SNPs could constitute a valuable tool for individualizing CHC therapy.

Peripheral blood monocyte subsets predict antiviral response in chronic hepatitis C.

BACKGROUND: Hepatitis C virus infection evolves into chronic progressive liver disease in a significant percentage of patients. Monocytes constitute a diverse group of myeloid cells that mediate innate and adaptive immune response. In addition to proinflammatory CD16+ monocytes, a Tie-2+ subgroup - Tie-2 expressing monocytes (TEMs) - that has robust proangiogenic potential has been recently defined. AIM: To study the heterogeneity of peripheral blood monocytes in chronic hepatitis C (CHC) patients and to examine their proposed pathophysiological roles on disease progression and response to antiviral therapy. METHODS: We studied CD16+ and Tie-2+ peripheral monocyte subpopulations in 21 healthy subjects and 39 CHC patients in various stages of disease and responses to antiviral treatment using flow cytometry. Expression profiles of proangiogenic and tissue remodelling factors in monocyte supernatants were measured using ELISA and protein arrays. Intrahepatic expression of CD14, CD31 and Tie-2 was analysed using immunofluorescence. RESULTS: Increases of certain peripheral monocyte subsets were observed in the blood of CHC patients, wherein those cells with proinflammatory (CD16+) or proangiogenic (TEMs) potential expanded (P < 0.005, both). Notably, TEMs were significantly increased in nonresponders, particularly those with lower CD16 expression. In addition, many angiogenic factors were differentially expressed by peripheral monocytes from control or CHC patients, such as angiopoietin-1 and angiogenin (P < 0.05). Interestingly, intrahepatic TEMs were distinguished within portal infiltrates of CHC patients. CONCLUSIONS: These findings suggest for the first time the relevance of peripheral monocytes phenotypes for the achievement of response to treatment. Hence, the study of monocyte subset regulation might effect improved CHC prognoses and adjuvant therapies.

Current antiviral combination therapy for chronic hepatitis C patients who failed to interferon alfa-based treatment.

WHAT IS KNOWN AND OBJECTIVE: Interferon-alfa-based therapy is effective in the treatment of Hepatitis C. However, some patients fail to respond and others relapse, after initially responding. Our objective was to assess the efficacy, safety and predictive factors for sustained virological response (SVR) to peginterferon plus ribavirin in chronic hepatitis C patients who failed to interferon-alfa (IFNα)-based therapy. METHODS: Seventy-five consecutive patients who failed to IFNα-based therapy were retreated with peginterferon plus ribavirin. Of these patients, 85% were infected by genotype 1. The primary endpoint was SVR. RESULTS AND DISCUSSION: Of 75 non-responder (n = 54) or relapser patients (n = 21), 50 were previously treated with IFNα-monotherapy and 25 with IFNα plus ribavirin. Global SVR rate was 41.3%: for patients re-treated with IFNα the response was 48% whilst for those retreated with IFNα plus ribavirin, it was 28%. For previous non-responders the SVR rate was 37% and for relapsers it was 52.4%. WHAT IS NEW AND CONCLUSION: Retreatment with peginterferon plus ribavirin is an effective option for some chronic hepatitis C non-responder or relapser patients. Higher SVR rate was achieved in relapsers and in those patients who received IFNα monotherapy previously.

Hepatic fibrosis in patients with chronic hepatitis C assessed by transient elastography: implications for determining the efficacy of antiviral therapy.

BACKGROUND: The efficacy of combination therapy with peginterferon plus ribavirin to eradicate viral infection in patients with chronic hepatitis C (CHC) is well established; moreover, it is able to arrest or even reverse liver fibrosis. AIMS: To analyze the measurements of hepatic stiffness as an index of liver fibrosis using transient elastography (TE) in patients who underwent a sustained virological response (SVR) during long-term follow-up; comparing the changes in the severity of fibrosis with non-responders patients. MATERIAL AND METHODS: After hepatic fibrosis was studied in three patients with CHC who underwent a SVR during long-term follow up, a prospective study was initiated in 24 patients with CHC who received combination therapy to compare the evolution of fibrosis in those with SVR and those who were non-responders. The genotype of hepatitis C virus (HCV) and the degree of viremia were determined. METAVIR scoring system was used for liver fibrosis. Hepatic stiffness was measured by TE. RESULTS: Of the initial three patients pre-treatment liver biopsies revealed active disease and fibrosis (stage 3) in two and mild fibrosis (stage 1) in one. After several years of follow up serum AST/ALT levels were normal and HCV RNA was undetectable in each case; in contrast to the baseline histological assessments of fibrosis, values for hepatic stiffness (3.4-6.9 KPa) were compatible with an absence of any appreciable hepatic fibrosis. In the prospective study, 8 patients underwent a SVR and 16 were non-responders. TE indicated that the severity of hepatic fibrosis in the SVR group improved in 7 (88%) patients, whereas in the non-responder it improved in only 4 (25%) (p < 0.05). The difference between development of severe fibrosis (F > or = 3) in responders and non-responders was not significant (p = 0.23), possibly due to the small sample size. CONCLUSIONS: Regression of hepatic fibrosis appears to be common in patients with CHC who undergo a SVR. TE is a simple non-invasive technique that enables multiple assessments of the severity of hepatic fibrosis to be made efficiently during long-term follow-up of patients with CHC who receive combination antiviral therapy.

Hepatic fibrosis in patients with chronic hepatitis C assessed by transient elastography: implications for determining the efficacy of antiviral therapy

Background: the efficacy of combination therapy with peginterferonplus ribavirin to eradicate viral infection in patients withchronic hepatitis C (CHC) is well established; moreover, it is ableto arrest or even reverse liver fibrosis.Aims: to analyze the measurements of hepatic stiffness as anindex of liver fibrosis using transient elastography (TE) in patients who underwent a sustained virological response (SVR) duringlong-term follow-up; comparing the changes in the severity of fibrosis with non-responders patients. Material and methods: after hepatic fibrosis was studied in three patients with CHC who underwent a SVR during long-term follow up, a prospective study was initiated in 24 patients withCHC who received combination therapy to compare the evolution of fibrosis in those with SVR and those who were non-responders.The genotype of hepatitis C virus (HCV) and the degree of viremia were determined. METAVIR scoring system was used for liver fibrosis. Hepatic stiffness was measured by TE. Results: of the initial three patients pre-treatment liver biopsiesrevealed active disease and fibrosis (stage 3) in two and mildfibrosis (stage 1) in one. After several years of follow up serum AST/ALT levels were normal and HCV RNA was undetectable ineach case; in contrast to the baseline histological assessments of fibrosis, values for hepatic stiffness (3.4-6.9 KPa) were compatible with an absence of any appreciable hepatic fibrosis. In the prospective study, 8 patients underwent a SVR and 16 were nonresponders.TE indicated that the severity of hepatic fibrosis in theSVR group improved in 7 (88%) patients, whereas in the non-responderit improved in only 4 (25%) (p < 0.05). The difference between development of severe fibrosis (F>=3) in responders andnon-responders was not significant (p = 0.23), possibly due to the small sample size...(AU)

[Difficulties and controversies in hospitalized patients with lower gastrointestinal bleeding]. / Dificultades y controversias en el manejo hospitalario de la hemorragia digestiva baja.

OBJECTIVES: Lower intestinal bleeding (LGIB) is a frequent reason for hospitalization; however, the prognostic factors have not been clearly defined. The aim of this paper was to analyze several clinical parameters and the management of this entity in our department from 2005 to 2007. MATERIAL AND METHODS: all hospitalized patients with LGIB were retrospectively (2005-2006) and prospectively (2006-2007) included. Medical records, physical examination (anal digital examination included), blood testing, and colonoscopic examination (in most of patients) were performed. RESULTS: 137 patients were included during 2005-2006: 36% of them required blood transfusion; thirty-one percent of patients showed previous episodes of LGIB, and 62% had a favorable outcome. Time from admission to colonoscopy was 4.1 days, and length of stay was 10.2 days. In the 2006-2007 study 96 patients were included: 42% of them required blood transfusion, thirty-three percent of patients showed previous episodes of LGIB, and 68% had a favorable outcome. Time from admission to colonoscopy was 2.6 days, and length of stay was 7.7 days. The most frequent etiology was diverticulosis in both studies. CONCLUSIONS: Hospital length of stay and time from admission to colonoscopy in patients with LGIB was reduced by 25% and 37%, respectively, in the 2005-2006 period with regard to the 2006-2007 one; however, there were no more bleeding points or a decrease in bleeding recurrence.

Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other oral agents.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Unresectable disease patients have median survival of few months. There is a substantial need for novel treatments for patients with advanced HCC. AIM: To provide an update review of mechanism of hepatocarcinigenesis and systemic therapies for HCC and the relevant role of Sorafenib in patients with advanced disease. METHODS: A Medline search was performed to identify pertinent original research and review articles. Selected references in these articles were also evaluated. RESULTS: Systemic chemotherapy for HCC has been quite ineffective. Preclinical studies demonstrated that Raf/MAPK-ERK kinase (MEK)/Extracellular signal regulated kinase (ERK) pathway has a role in HCC. HCC tumours are highly vascularized and vascular endothelial growth factor (VEGF) augments HCC development and metastasis. Sorafenib blocks tumour cell proliferation by targeting Raf/MEK/ERK signalling and exerts an antiangiogenic effect by targeting VEGF receptors-2/3 and platelet derived growth factor receptor beta tyrosine kinases. CONCLUSIONS: Currently available therapies are not effective for patients with advanced HCC. Sorafenib has demonstrated for the first time to prolong survival in patients with advanced HCC, and it is the new reference standard for systemic treatment in these patients.

Dificultades y controversias en el manejo hospitalario de la hemorragia digestiva baja / No disponible

Objetivos: la hemorragia digestiva baja (HDB) es una causa frecuentede ingreso hospitalario; pese a ello, no se conocen con exactitudlos factores que influyen en su evolución. Los objetivos de estetrabajo fueron comparar los cambios en el manejo de la HDB ennuestro Servicio entre los años 2005 y 2007, así como analizar diferentesparámetros que pudieran influir en su pronóstico.Pacientes y métodos: se incluyeron retrospectivamente todoslos ingresos por HDB durante el periodo 2005-2006 y prospectivamentelos del 2006-2007. En todos se realizó historia clínica,exploración –incluyendo tacto rectal– y análisis sanguíneo.Se realizó colonoscopia en la mayoría de los pacientes.Resultados: se incluyeron 137 pacientes en el 2005-2006: requirierontransfusión de hemoderivados el 36%. El 31% había presentadoalgún episodio de HDB previamente. El 62% presentó unaevolución favorable. El tiempo desde el ingreso hasta la colonoscopiay la estancia media fueron de 4,1 y 10,2 días respectivamente. En el2006-2007 se incluyeron 96 pacientes: requirieron transfusión el42%. El 33% había presentado HDB previamente. La evolución fuefavorable en el 67%. El tiempo hasta la colonoscopia y la estanciamedia fueron de 2,6 y 7,7 días respectivamente. Los divertículos fueronel hallazgo más frecuente en ambos periodos.Conclusiones: durante el 2006-2007 la estancia media delos pacientes con HDB ingresados en el Servicio de Aparato Digestivose redujo respecto al 2005-2006 en un 25% y el tiempode realización de la colonoscopia en un 37%; esto no logró máslocalizaciones del punto sangrante ni una disminución en la recurrenciade la hemorragia

Objectives: lower intestinal bleeding (LGIB) is a frequent reasonfor hospitalization; however, the prognostic factors have notbeen clearly defined. The aim of this paper was to analyze severalclinical parameters and the management of this entity in our departmentfrom 2005 to 2007.Material and methods: all hospitalized patients with LGIBwere retrospectively (2005-2006) and prospectively (2006-2007)included. Medical records, physical examination (anal digital examinationincluded), blood testing, and colonoscopic examination(in most of patients) were performed.Results: 137 patients were included during 2005-2006: 36%of them required blood transfusion; thirty-one percent of patientsshowed previous episodes of LGIB, and 62% had a favorable outcome.Time from admission to colonoscopy was 4.1 days, andlength of stay was 10.2 days. In the 2006-2007 study 96 patientswere included: 42% of them required blood transfusion, thirtythreepercent of patients showed previous episodes of LGIB, and68% had a favorable outcome. Time from admission tocolonoscopy was 2.6 days, and length of stay was 7.7 days. Themost frequent etiology was diverticulosis in both studies.Conclusions: hospital length of stay and time from admissionto colonoscopy in patients with LGIB was reduced by 25% and37%, respectively, in the 2005-2006 period with regard to the2006-2007 one; however, there were no more bleeding points ora decrease in bleeding recurrence

Predictive graphical model, network-based medical tool for the prognosis of chronic hepatitis C patients treated with peg-interferon plus ribavirin.

BACKGROUND: There are few model networks to predict treatment outcome in viral hepatitis. AIM: To develop an easy bioinformatics platform based on algorithm decisions (Bayesian network) for a more efficient prediction of treatment response. METHODS: Totally 385 consecutive chronic hepatitis C (CHC) treated patients were included. More than 40 variables were analysed. Data from 308 patients were used to build the variable model network using DLIFE platform based on predictive graphical models. The prediction accuracy of the bioinformatics network was compared with the true data collected in a retrospective study. The model was then validated twice with external data from CHC patients treated in other hospitals. RESULTS: The accuracy of this bioinformatics network for treatment response in our 308 patients was 83.3%, which is higher than the accuracy obtained by physicians on the basis of study of clinical data and their own experience (50-65%). The receiver operator characteristic curve areas after validation with another cohort of patients were: 0.91 for sustained virological response, one for nonresponse, and 0.81 for relapse. DLIFE offered a diagnostic accuracy of 81.3%, which is a clear improvement compared with unassisted prognosis (50-65%). CONCLUSIONS: This bioinformatics platform (DLIFE) accurately predicts the outcome of CHC combination therapy, improving treatment decisions and reducing costs. This bioinformatics platform allows integrating widespread data sources and permits predicting the clinical outcome of a particular patient using a general predictive graphical model.

Treatment regimens for patients with chronic hepatitis C.

Infection by the hepatitis C virus (HCV) is a major public health problem, with more than 170 million people infected throughout the world. The infection prevalence, with small regional differences, is estimated in 1-3% of the global population. HCV is the most frequent cause of chronic liver disease and 20-30% of patients develop cirrhosis with a risk of hepatocellular carcinoma. Nowadays, pegylated interferon-a (PEG-IFN) in combination with ribavirin, a nucleoside analogue, is the current treatment for chronic hepatitis C (CHC), with less adverse effects and better compliance. Dosage and duration depend on some factors as weight, genotype, viral load and a rapid virological response presented by the patient. One of the most relevant aspects in the treatment of CHC is how to manage the group of non-responder or relapser patients to previous treatments. As such, a substantial proportion of patients had already been unsuccessfully treated with interferon-based therapies and these patients claim for an optimal therapeutic option. The future treatment of CHC walk along through the association of two or three drugs, including nucleoside/nucleotide analogues, higher PEG-IFN initial dosages (induction) or longer treatments duration, or combination of helicase and protease inhibitors.

Clinical and pathological characteristics and response to combination therapy of genotype 4 chronic hepatitis C patients: experience from a spanish center.

This observational study evaluated the characteristics of genotype 4 chronic hepatitis C (CHC) patients and their response to combination therapy in Spain. 383 patients with CHC, 44 with genotype 4-HCV infection, were investigated. Nineteen genotype 4-HCV infected patients received IFNalpha-2b (3 MU three times weekly) plus ribavirin (1-1.2 g/day) and ten received Peg-IFNalpha-2b (1.5 microg/kg/week) plus ribavirin (1-1.2 g/day) for 12 months. A sustained virological response (SVR) was evaluated. Genotype 4-HCV was detected in 11.5% of patients, and was significantly associated with a higher proportion of infection through intravenous drug use (46% vs 11%; p<0.001), a higher alcohol intake (35% vs. 7%; p<0.001), higher proportion of anti-HBc positivity (41% vs. 22%; p<0.05), lower ALT (87+/-50 vs. 139+/-142 IU/L; p<0.001) and AST (53+/-30 vs. 85+/-126 IU/L; p<0.001) levels, lower viremia (4.1 +/- 7.7 (x 10(5)) vs . 7.3 +/- 9.8 IU(x 10(5) )/mL) p<0.05) and less fibrosis (stage 3-4 in 21% vs. 32%; p<0.06). Sixteen (55%) out of the 29 patients treated with combination therapy achieved a sustained virological response (SVR) while 10 (36%) were non-responders and 3 (9% relapsed. In conclusion, the lower stage of fibrosis, lower viremia and higher SVR rate than genotype 1 suggest a less aggressive pattern of diseased caused by this genotype.

Hepatitis crónica C: tratamiento de los pacientes no respondedores y con recaídas / Chronic hepatitis C: treatment of nonresponders with recurrence

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The colorectal carcinoma prognosis factors. Significance of diagnosis delay.

INTRODUCTION: detection of early-stage colorectal carcinoma (CRC)--( Dukes A or B)--provides better survival rates in these patients. Thus, the effectiveness of screening programs in asymptomatic patients or of early diagnosis in symptomatic individuals has been postulated. The aim of this study was to establish whether a delay in diagnosis or other factors are related to CRC stage. PATIENTS AND METHODS: a retrospective study was performed on 96 patients with CRC. Age at diagnosis, gender distribution, intestinal disorders, diagnosis delay, primary sign and -regarding CRC- localization, stage (Dukes) and grade of differentiation (well differentiated; non-well differentiated; poorly differentiated) were recorded. RESULTS: diagnosis delay was 185 +/- 190 days. Patients delay in obtaining a diagnosis was 119 +/- 158 days. In 40% of patients CRC was diagnosed at an early stage (Dukes A or B), and in 13% CRC was poorly differentiated. The only factor with an independent effect on Dukes stage was tumor differentiation (p: 0.0012). Distal location was associated with less advanced tumors without statistical significance (p: 0.156). CONCLUSION: based on the presented data, a greater effort regarding screening programs for healthy people seems warranted, as improved survival has been demonstrated when diagnosis delay is reduced, particularly in patients with the highest mean delay.

Spanish scientific output on Helicobacter pylori. A study through Medline.

OBJECTIVES: to analyze scientific output from Spanish hospitals in relation to Helicobacter pylori infection. METHODS: papers collected from the Medline database between January 1988 and December 2003 were selected. Our search strategy was: "Helicobacter pylori" [MeSH] AND ((Spain [AD] OR Espana [AD] OR Spanien [AD] OR Espagne [AD] OR Espanha [AD]) OR (Spanish [LA]) OR Spain). The following was analyzed: geographic area, Spanish or foreign publication, topic, and year of publication. Output and impact bibliometric markers were evaluated. RESULTS: in all, 691 papers were identified, of which 241 were excluded. Number of papers went from 2 in 1988 to 47 in 2002 and 13 in 2003. There were more reports in Spanish versus foreign journals (58 vs. 42%). In the first 5 years the areas with greater output were associated with diagnosis and microbiology (33 and 20%), whereas therapy was the predominating subject during the last 5 years (27%). Original papers were most common among publications (69%). Hospitals with highest output included La Princesa (24%) and Ramón y Cajal (17.6%) in Madrid, and Parc Taulí in Barcelona (6.4%). Mean impact factor progressively increased from 1.826 in 1988 to 2.142 in 2002 and 2.493 in 2003. CONCLUSIONS: the production and impact of documents published by Spanish scientists regarding H. pylori infection considerably increased during the past two decades.

Sustained virological response to peginterferon plus ribavirin in chronic hepatitis C genotype 1 patients is associated with a persistent Th1 immune response.

BACKGROUND: An impairment of cellular immune response may contribute to the persistency of hepatitis C virus infection. AIM: To analyse the Th1/Th2 cytokine profile in peripheral blood CD4(+) and CD8(+) T cells from patients with chronic hepatitis C (CHC) during treatment with pegylated interferon-alpha2a plus ribavirin and to correlate the Th1/Th2 balance with virological response (SVR). METHODS: Prospective longitudinal study: 44 naïve genotype 1 CHC patients received PEG-IFNalpha2a plus ribavirin for 48 weeks: 26 (59.1%) achieved a SVR, 13 relapsed (29.5%) and 5 (11.4%) were non-responders. Sixteen healthy controls were analysed. The production of IL-4, IFNgamma and TNFalpha by CD4(+) and CD8(+) T cells was measured using flow cytometry, both in resting and phorbol-ester-stimulated cells. RESULTS: First three months of treatment: the synthesis of TNFalpha by phorbol-ester-stimulated-CD4(+) T cells was higher in patients with SVR (P < 0.01). At the end of treatment, SVR was associated with higher intracellular expression of IFNgamma by stimulated-CD4(+) and CD8(+) T cells (P < 0.05). At the end of follow-up, a higher intracellular expression of IFNgamma by CD4(+) T cells was associated with a SVR. CONCLUSIONS: A Th1-type immune response was associated with achievement of a SVR, as indicated by the persistent elevation of intracellular IFNgamma and TNFalpha.