Mild Liver Disease Research Articles

PTU-096 Metabolic Bone Disease in Mild Chronic Liver Disease- is it Worth Checking?

IntroductionLiver cirrhosis (LC) is increasing in frequency and can cause significant morbidity including metabolic bone disease (MBD) namely osteopaenia and osteoporosis, risk factors of fractures. It is vital that patients...

Unremitting pyrexia, pancytopenia, hepatosplenomegaly, and extreme hyperferritinemia

Unremitting pyrexia, pancytopenia, hepatosplenomegaly, and extreme hyperferritinemia

Quantification of Experimental Liver Fibrosis With an Algorithm Method Based On Statistical Analysis of Signals

Ultrasonography is sensitive to detect changes in the texture of tissues. It is difficult to detect mild diffuse liver disease and follow-up patients with chronic liver diseases. The objective was to evaluate the development of liver fibrosis in an experimental model, by use of a method to quantify the homogeneity of the tissue texture.

Why do I treat HBeAg‐negative chronic hepatitis B patients with nucleos(t)ide analogues?

Products that are currently used in the treatment of chronic hepatitis B include interferon-alpha (IFNa: standard or pegylated) (PEG-IFNa) and nucleos(t)ide analogues (NAs). NAs are used in most HBeAg-negative chronic hepatitis B patients for several reasons. They can be prescribed to all chronic HBV patients, even those with contraindications to IFNa; and even IFNa candidates are usually treated with NAs because of their advantages. Administration of NAs is easier (one oral tablet per day compared with subcutaneous IFNa injections), tolerance is excellent and the safety profile is good, whereas IFNa may have adverse events and often worsens the patients' quality of life. The current first-line NA options, entecavir (ETV) and tenofovir (TDV), have minimal or no risk of long-term resistance and a virological response is achieved in almost 100% of adherent HBeAg-negative patients, thus modifying the long-term outcome. The need for long-term, perhaps indefinite, treatment is the main limitation of NAs and the finite duration (48 weeks), the main advantage of IFNa, especially in young patients of reproductive age. However, at most 25% of IFNa-treated HBeAg-negative patients achieve a sustained off-treatment response and therefore >75% of them will eventually receive NAs, even if they start with IFNa. As there will always be concerns about safety and family planning issues with long-term NA therapy, NAs should be used carefully, particularly in young chronic hepatitis B patients with mild liver disease. Novel therapeutic options are needed to increase the rates of HBsAg loss and sustained off-treatment responses.

CIHR Canadian HIV Trials Network Coinfection and Concurrent Diseases Core: Canadian Guidelines for Management and Treatment of HIV/Hepatitis C Coinfection in Adults

Hepatitis C virus (HCV) coinfection occurs in 20% to 30% of Canadians living with HIV, and is responsible for a heavy burden of morbidity and mortality. HIV-HCV management is more complex due to the accelerated progression of liver disease, the timing and nature of antiretroviral and HCV therapy, mental health and addictions management, socioeconomic obstacles and drug-drug interactions between new HCV direct-acting antiviral therapies and antiretroviral regimens. To develop national standards for the management of HCV-HIV coinfected adults in the Canadian context. A panel with specific clinical expertise in HIV-HCV co-infection was convened by The CIHR HIV Trials Network to review current literature, existing guidelines and protocols. Following broad solicitation for input, consensus recommendations were approved by the working group, and were characterized using a Class (benefit verses harm) and Level (strength of certainty) quality-of-evidence scale. All HIV-HCV coinfected individuals should be assessed for HCV therapy. Individuals unable to initiate HCV therapy should initiate antiretroviral therapy to slow liver disease progression. Standard of care for genotype 1 is pegylated interferon and weight-based ribavirin dosing plus an HCV protease inhibitor; traditional dual therapy for 24 weeks (for genotype 2/3 with virological clearance at week 4); or 48 weeks (for genotypes 2-6). Therapy deferral for individuals with mild liver disease may be considered. HIV should not be considered a barrier to liver transplantation in coinfected patients. Recommendations may not supersede individual clinical judgement.

Development and Application of Specific Cytokine Assays in Tissue Samples from a Bottlenose Dolphin with Hyperinsulinemia

Chronic inflammation has been associated with insulin resistance and type 2 diabetes (T2D) in humans. Postmortem hepatic and splenic tissue from a 46-year-old geriatric male bottlenose dolphin (Tursiops truncatus) with insulin resistance (chronic hyperinsulinemia with hyperglycemia), chronic inflammation (white blood cell count greater than 12,000 cells/μL), and mild fatty liver disease was evaluated for elevated pro-inflammatory mediators. Cytokine mRNA expression in postmortem hepatic and splenic tissue, as determined by real-time PCR, included an array of cytokines: TGF-β, TNF-α, IFN-γ, IL-2, IL-4, IL-10, IL-12p40, IL-13, and IL-18. Values from this dolphin were compared to a younger reference dolphin with no known chronic metabolic perturbations or inflammation. Levels of TGF-β, TNF-α, and IL-4 were higher in the case dolphin’s liver compared to that of the reference dolphin. In the case dolphin’s spleen, IL-10 and IFN-γ mRNA was upregulated while IL-4 was less than the reference dolphin. IL-18 and IL-13 were upregulated in both tissues. Fluorescent immunohistochemistry (IHC) utilized the following antibodies: anti-porcine IL-6, anti-bovine IFN-γ, IL-4, and IL-10, anti-human TGF-β, anti-ovine IL-1β, and anti-dolphin IL-8. Fluorescent IHC in spleen from the case dolphin revealed staining of IL-4, IL-6, IL-8, and TGF-β throughout the tissue. IL-10 and IFN-γ were seen to predominate in areas surrounding the follicles of splenic tissue. This is the first characterization of cytokine levels in dolphin hepatic and splenic tissue. While there are limitations to a case study, this report of inflammatory biomarkers in tissues of a dolphin with insulin resistance and fatty liver disease are similar to those observed in human patients.

The Influence of the Severity of Chronic Virus-Related Liver Disease on Propofol Requirements during Propofol-Remifentanil Anesthesia

PurposeThe purpose of this study was to investigate the influence of chronic virus-related liver disease severity on propofol requirements.Materials and MethodsIn this study, 48 male patients with chronic hepatitis B infection were divided into three groups according to Child-Turcotte-Pugh classification of liver function (groups A, B, and C with mild, moderate and severe liver disease, respectively). After intubation, propofol concentration was adjusted by ±0.3 µg/mL increments to maintain bispectral index in the range of 40-60. Target propofol concentrations at anesthesia initiation, pre-intubation and pre-incision were recorded.ResultsThe initial concentration used in group C was significantly lower than that used in group A or B (p<0.05), whereas no difference was observed between groups A and B. At pre-intubation, the actual required concentration of propofol increased significantly (3.2 µg/mL) in group A (p<0.05), which lead to significant differences between the groups (p<0.05). At pre-incision, the requirements for propofol decreased significantly in both groups A and B (3.0 µg/mL and 2.7 µg/mL, respectively) compared with those at pre-intubation (p<0.05), and were significantly different for all three groups (p<0.05), with group C demonstrating the lowest requirement (2.2 µg/mL). The required concentrations of propofol at pre-incision were similar to those at induction.ConclusionIn this study, propofol requirements administered by target-controlled infusion to maintain similar depths of hypnosis were shown to depend on the severity of chronic virus-related liver dysfunction. In other words, patients with the most severe liver dysfunction required the least amount of propofol.

Hepatitis B virus DNA integration in tumour tissue of a non-cirrhotic HFE-haemochromatosis patient with hepatocellular carcinoma

Co-existence of multiple causes of liver injury increases the risk of hepatocellular carcinoma (HCC) development. HCC usually develops in patients with cirrhosis although it may also occur in individuals with no or mild liver disease, in particular in cases with hepatitis B virus (HBV) infection.Here we report the case of a 43year-old man with HFE-haemochromatosis, seronegative for hepatitis B and C infections, who developed HCC in the absence of severe liver damage. Both tumoural and non-tumoural liver DNA extracts were tested by nested-PCR and primers specific for four different HBV genomic regions in order to evaluate the presence of occult HBV infection. Only X gene sequences were detected in tumour (but not in non-tumour) DNA extracts. HBV-Alu PCR showed a HBV integration involving a 5′-deleted X gene with an intact enhancer-II/basal-core promoter region. The viral-host junction sequencing revealed that this integrant was located upstream of the partitioning-defective-6-homolog-gamma gene (PARD6G) and real time-PCR quantification demonstrated that PARD6G was overexpressed in tumour compared to non-tumour liver tissues.In conclusion, the combination of HFE-haemochromatosis and occult HBV infection in this patient might have led to a sequel of cellular events that determined the development of HCC even in the absence of cirrhosis.

Molecular characterization of hepatitis B virus X gene in chronic hepatitis B patients

BackgroundHBV-X protein is associated with the pathogenesis of HBV related diseases, specially in hepatocellular carcinomas of chronic patients. Genetic variability of the X gene includes genotypic specific variations and mutations emerging during chronic infection. Its coding sequence overlaps important regions for virus replication, including the basal core promoter. Differences in the X gene may have implications in biological functions of the protein and thus, affect the evolution of the disease. There are controversial results about the consequences of mutations in this region and their relationship with pathogenesis. The purpose of this work was to describe the diversity of HBV-X gene in chronic hepatitis patients infected with different genotypes, according to liver disease.MethodsHBV-X gene was sequenced from chronic hepatitis B patient samples, analyzed by phylogeny and genotyped. Nucleotide and aminoacid diversity was determined calculating intragenetic distances. Mutations at 127, 130 and 131 aminoacids were considered in relation to liver disease.ResultsThe most prevalent genotype detected in this cohort was F (F1 and F4), followed by D and A. Most of the samples corresponding to genotypes A and F1 were HBeAg(+) and for genotypes D and F4, HBeAg(−) samples were represented in a higher percentage. Intragenetic distance values were higher in HBeAg(−) than in positive samples for all genotypes, and lower in overlapped regions, compared to single codification ones. Nucleotide and aminoacid diversities were higher in HBeAg(−), than in HBeAg(+) samples.ConclusionsIndependently of the infecting genotypes, mutations at any of 127, 130 and/or 131 aminoacid positions and HBeAg(−) status were associated with mild liver disease in this cohort.

Metals and the liver

Hereditary liver diseases resulting in copper and iron overload may cause significant morbidity and mortality if not diagnosed and treated early. The goal of this review is to highlight the key publications on genetics, diagnosis and management of hemochromatosis and Wilson disease over the past 18 months. Several recent advancements have been made in the genetic diagnosis of hemochromatosis and Wilson disease. Uncommon HFE mutations resulting in phenotypic hemochromatosis among C282Y heterozygotes have been identified from HFE gene sequencing. A serum ferritin less than 1000 μg/l in C282Y homozygotes was found to be associated with milder symptoms of hemochromatosis. Deferasirox was shown to reduce iron overload in patients with hemochromatosis and may be an option for patients who cannot tolerate phlebotomy. There was found to be evidence of genotype and phenotype correlation in Wilson disease, which can be diagnosed by genetic sequencing. A modified diagnostic guideline has been developed for children with Wilson disease with mild liver disease that increases the sensitivity and specificity of diagnosis. Also treatment with copper chelating agents has less hepatic treatment failures when compared with zinc monotherapy. Advancements in diagnosis of hemochromatosis and Wilson disease may lead to earlier diagnosis and treatment with resulting decrease in morbidity and mortality.

Acute Right Ventricular Failure in a Patient with Hepatic Cirrhosis

Pulmonary embolic disease is most commonly a manifestation of venous thromboembolism (VTE). However, fat, tumor, and air may all embolize to the pulmonary vasculature and lymphatics resulting in various clinical manifestations. Tumor emboli to small pulmonary vessels and lymphatics can lead to hypoxemic respiratory failure and shock. We present a 62-year-old male with history of mild COPD and end-stage liver disease secondary to hepatitis C admitted due to progressive shortness of breath and hypoxemia who developed shock and right ventricular failure. After a negative evaluation for venous thromboembolic disease, he had progressive respiratory and hemodynamic deterioration despite mechanical ventilation, renal replacement therapy, and vasopressive/inotropic support. Postmortem examination revealed diffuse micronodular moderately differentiated hepatocellular carcinoma (HCC) without a discrete mass, as well as numerous HCC tumor emboli to the lung and focally to the heart, consistent with disseminated hepatocellular tumor microembolism.

Neonatal Chylous Ascites Successfully Treated With MCT-Based Formula and Octreotide: A Case Report

Neonatal chylous ascites is an anomalous development of intra-abdominal lymphatic duct usually presents as a remedial challenge with symptomatic leaky lymphatics induced either as idiopathic or congenital or traumatic etiologies. In present case, female neonate developed abdominal distention on day 11 of life, just after introduction of enteral feeding. Chylous was diagnosed by paracenthesis and fluid examination. She was treated with TPN and followed by MCT based diet with octreotide. Baby was well tolerated with enteral feed and discharged on pregestimil on day 40 of life. On follow-up, baby had mild parenchymal liver disease with minimal ascites at right hepatic region at 4 months of age, which was completely resolved on 11 months. Discussed case suggests that octreotide with MCT oil based diet after TPN aids in repair of anomalous lymphatic vessel in presented rare instance of chylous ascites. doi:10.4021/ijcp102e

Impact of comorbidities on TNF inhibitor persistence in rheumatoid arthritis patients: an analysis of Korean National Health Insurance claims data

The aim of this study is to evaluate tumor necrosis factor (TNF) inhibitor persistence and the impact of comorbidity on treatment persistence in patients with rheumatoid arthritis (RA). In a Korean National Health Insurance claims database, patients with a diagnosis code of RA (M05 or M06) who started TNF inhibitor therapy between July 1, 2007 and June 30, 2008 were enrolled. The study cohort was followed until December 31, 2009. Persistence was examined using Kaplan-Meier survival analysis, and multivariate Cox proportional hazard models were developed to examine the potential impact of comorbidities on drug persistence. A total of 388 patients were enrolled in the study cohort. The mean persistence rate in the overall population was 61% at 18 months. Drug survival rates for adalimumab and etanercept at 6 months were 82 and 85%, respectively, and 73 and 78%, respectively, at 12 months. Charlson comorbidity index (CCI) scores and comorbidities such as diabetes, chronic pulmonary disease, mild liver disease, and depression at initiation were not related with drug persistence, while peptic ulcer disease (PUD) lowered the risk of discontinuation of TNF inhibitors (HR 0.73, 95% CI 0.55-0.97). Old age (HR 1.59, 95% CI 1.09-2.33) and prescription of inhibitors by an internist (HR 1.59, 95% CI 1.02-2.48) were associated with discontinuation of TNF inhibitors. The persistence of TNF inhibitors was 61% at 18 months. CCI score and other comorbidities were not related with early discontinuation of TNF inhibitors, while PUD was an independent contributing factor to TNF inhibitor persistence.

Determinants of elevated healthcare utilization in patients with COPD.

BackgroundChronic obstructive pulmonary disease (COPD) imparts a substantial economic burden on western health systems. Our objective was to analyze the determinants of elevated healthcare utilization among patients with COPD in a single-payer health system.MethodsThree-hundred eighty-nine adults with COPD were matched 1:3 to controls by age, gender and area of residency. Total healthcare cost 5 years prior recruitment and presence of comorbidities were obtained from a computerized database. Health related quality of life (HRQoL) indices were obtained using validated questionnaires among a subsample of 177 patients.ResultsHealthcare utilization was 3.4-fold higher among COPD patients compared with controls (p < 0.001). The "most-costly" upper 25% of COPD patients (n = 98) consumed 63% of all costs. Multivariate analysis revealed that independent determinants of being in the "most costly" group were (OR; 95% CI): age-adjusted Charlson Comorbidity Index (1.09; 1.01 - 1.2), history of: myocardial infarct (2.87; 1.5 - 5.5), congestive heart failure (3.52; 1.9 - 6.4), mild liver disease (3.83; 1.3 - 11.2) and diabetes (2.02; 1.1 - 3.6). Bivariate analysis revealed that cost increased as HRQoL declined and severity of airflow obstruction increased but these were not independent determinants in a multivariate analysis.ConclusionComorbidity burden determines elevated utilization for COPD patients. Decision makers should prioritize scarce health care resources to a better care management of the "most costly" patients.

Report on Response and Overall Survival of 128 Unselected, Consecutive AML Patients From the Austrian Azacitidine Registry (AAR) of the AGMT-Study Group

Abstract 4266Twelve participating centers in Austria included 257 unselected, consecutive patients with MDS, CMML or AML, who received azacitidine (AZA) between 02/2007 and 07/2011, in the nationwide Austrian Azacitidine Registry (AAR) of the AGMT-study group. This registry was approved by the national Ethics Committee and includes 128 patients with AML of all FAB-subtypes, as well as de novo AML (39%), t-AML, MDS-AML and post-CMPD-AML.This registry comprises a large number of patients with >30% bone marrow blasts (83/128) (currently off-label indication for AZA), as well as myeloproliferative AML (35/128), as defined by presence of >10.000 WBC/μ l at diagnosis. The AAR includes a high proportion of very old AML patients (median age 73a, 20% 75–79a, 24% >80a). Although the PS was generally low (22% ECOG-0, 47% ECOG-1), AML patients suffered from coronary artery disease (n=29), renal insufficiency (n=26), diabetes mellitus (n=21), a prior/concomitant solid tumor (n=17), COPD (n=14) and/or mild liver disease (n=13), respectively. Only 40% of all AML-patients included were treatment-naïve, whereas the rest was pretreated with G-CSF (12%), ESA (9%), ICT (3%) revlimid or thalidomide (6%), other agents (11%) and/or intensive chemotherapy (47%), respectively. Thus, this registry more accurately reflects a real-life treatment scenario, than most clinical trials that have strict inclusion/exclusion criteria.In the 93 patients in whom pre-AZA cytogenetics were performed, 56.9%, 25.8% and 17.2% could be grouped into IPSS good, intermediate and poor risk categories, respectively. Of these, 43 patients had MDS-specific cytogenetic aberrations (5q-, +8, -7, -7q, -Y and -20q). Most AZA-cycles were applied s.c. (89%), whereas 11% were applied i.v. Median and mean number of AZA-cycles was 4.0 and 5.6 (range 1–24), respectively. 60% of patients predominantly received the FDA-approved d1-7 schedule, whereas the non-approved alternative schedules 5-2-2, d1-5 and ‘others' were most often given in 17%, 16% and 7% of patients, respectively. The FDA-approved target dose (75mg/m2 over 7 days) was achieved in 58% of all cycles and in 61% of patients, respectively.Longitudinal repetitive analysis of serum GOT, GPT, bilirubin and creatinine over up to 24 cycles shows no relevant variation or worsening tendency of these parameters during treatment with AZA, including patients with reduced baseline renal and/or hepatic function.Reasons for termination of treatment were death for any reason (26%), disease progression or relapse (27%), no response (6%), toxicity (7%), recurrent infectious complications (2%) and other reasons (23%). Adverse events will be presented in detail (number, grade, duration, hospitalization rate, effects on AZA (dose reductions/treatment pause/termination)).Any kind of hematologic improvement (HI) was noted in 38% of patients. When looking at each lineage separately, 21/128 had HI-ery, 23/128 HI-PLT and 24/128 HI-neutrophils. 35/85 patients who were RBC-TD and 19/55 patients who were PLT-TD prior to AZA-treatment achieved transfusion independence (TI). In patients, in whom (repetitive) bone marrow analyses were performed for response evaluation (n= 56), the following best marrow responses were observed: CR (19.6%), marrow CR (7.1%), PR (33.9%), SD (30.4%) and primary PD (8.9%). At the time of writing, 35 patients had received ≤2 cycles. This number largely accounts for the patients in whom no bone marrow response evaluation was performed. The OR rate observed prior to 07/2011 was 38% (CR + marrow CR + PR + HI). When limiting response analysis to patients who received ≥2 AZA cycles, which is required for achievement of hematologic response by the IWG-criteria, ORR was 57%.The median OS was 9.5mo (95%CI 8.15–10.9). In univariate analyses, ECOG >=2 (p=.0026), circulating blasts (9.3 vs. 24.8mo; p=.0014), IPSS poor risk cytogenetics (p=.0037) and failure to achieve any HI (8.6 vs. 22.4mo; p=.0001), significantly negatively impacted OS. Prior treatment with G-CSF and/or ESA, age >80a, WBC >10G/l, BM blasts >30%, LDH >225U/l, number of cytopenic lineages as well as RBC-TD and/or PLT-TD at baseline, did not significantly impact OS (p>0.05) (detailed statistics will be presented).In conclusion, in this population of partly heavily pretreated very old patients with AML, AZA was well tolerated and yielded substantial clinical and hematological benefit, irrelevant of baseline BM blast or PB WBC count. Disclosures:Pleyer:Celgene: Research Funding. Off Label Use: Azacitidine for treatment of AML including patients with >30% bone marrow blasts. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Fridrik:Cephalon: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.

Activity of Azacitidine in 26 Unselected, Consecutive CMML Patients Included in the Austrian Azacitidine Registry (AAR) of the AGMT-Study Group

Abstract 1715Twelve participating centers in Austria included 257 unselected, consecutive patients with MDS/CMML or AML, who received azacitidine (AZA) between 02/2007 and 07/2011, in the nationwide Austrian Azacitidine Registry (AAR) of the AGMT-study group. Approval by the national Ethics Committee was obtained. The AAR includes 26 patients with CMML (10 with CMML-1, 16 with CMML-2) and is currently the 2nd largest report on CMML patients treated with AZA, the largest comprising 36 evaluable patients (Costa R. et al., Cancer, June 2011, pp2690). Myeloproliferative CMML (MP-CMML), defined as WBC>13.000/μl at diagnosis, was present in 16/26 patients, whereas 10/26 had myelodysplastic CMML (MD-CMML). Thus, the AAR includes patients for whom AZA is currently not approved by the FDA/EMEA.The AAR includes a high proportion of very old CMML patients (31% 75–79a, 15% >80a). Median age was 75a for both males (n=15) and females (n=11). Patients with various levels of PS were included (ECOG-0 (n=6), ECOG-1 (n=14), ECOG-2 (n=8) and ECOG-3 (n=4)). CMML-patients of the AAR suffered from renal insufficiency (n=8), mild liver disease (n=8), coronary artery disease (n=5), diabetes mellitus (n=5), a prior/concomitant solid tumor (n=3), COPD (n=2) and/or venous thromboembolic disease (n=1), respectively. There was no relevant difference in RBC transfusion dependence (TD) for MP-CMML vs. MD-CMML. However, PLT-TD at diagnosis was lower for MP-CMML (23%) than for MD-CMML (67%). In the 19 patients in whom pretreatment cytogenetics were performed, 15, 4 and 0 could be grouped into IPSS good, intermediate and poor risk categories, respectively. Only 57% of all included CMML-patients were treatment-naïve, whereas the rest were pretreated with ICT (10%), ESA (14%), intensive chemotherapy (21%) and other substances (17%) (mainly hydroxyurea and anagrelide) (numbers add up to more than 100% as several patients were pretreated with more than 1 agent). Thus, this registry more accurately reflects a real-life treatment scenario, than most clinical trials that have strict inclusion/exclusion criteria.Most AZA-cycles were applied s.c. (98%), whereas 2% were applied i.v. Median and mean number of AZA-cycles was 5.5 and 9 (SD 10.61; range 1–43), respectively. The FDA-approved d1-7 schedule was used in 62% of all AZA cycles, whereas the non-approved alternative schedules d1-5, 5-2-2 and ‘others' were applied in 21%, 12% and 6% of all cycles, respectively. Concerning the number of patients however, 20/26 predominantly received the d1-7 schedule. The FDA-approved target dose (75mg/m2 over 7 days) was achieved in 52% of all cycles and in 17/26 of patients, respectively.Reasons for termination of treatment with AZA were death (33%), disease progression (22%), transformation to AML (11%), no response (6%), toxicity (6%) and other reasons (22%).Any kind of HI was noted in 12/26 (46%) of patients. When looking at each lineage separately, 8/26 had HI-ery, 7/26 HI-PLT and 9/26 HI-neutrophils. 6/14 patients who were RBC-TD and 3/7 patients who were PLT-TD prior to AZA-treatment achieved transfusion independence (TI). In patients, in whom (repetitive) bone marrow aspirations/biopsies were performed for response evaluation (n= 12), the following best marrow responses were observed: CR in 4/12 (33%), marrow CR 1/12 (8%), PR in 2/12 (16%), SD in 4/12 (33%) and primary PD in 1/12 (8%). The OR rate observed prior to 07/2011 was 44% (CR + marrow CR + PR + HI). At the time of writing, 9 patients had received <=2 cycles. When limiting response analysis to patients who received >2 AZA cycles, which is required for achievement of hematologic response by the IWG-criteria, ORR was 66%. These are amongst the highest response rates observed for CMML to date.The median OS was 12.7 months (95%CI 6.9; 19.4). Median OS for patients demonstrating HI was significantly higher than for those who did not (19.4 vs. 5.6 months, p<0.0001). Detailed OS analyses and statistical analyses of various factors known or thought to influence prognosis are currently being analyzed, including MP-CMML vs. MD-CMML, CMML-1 vs. CMML-2, comparison of IPSS cytogenetic risk groups, as well as treatment-naïve vs. pretreated patients.In conclusion, in this population of partly pretreated, comorbid, very old patients with CMML, AZA was well tolerated and yielded substantial clinical and hematological benefit. Disclosures:Pleyer:Celgene: Research Funding. Off Label Use: Azacitidine for treatment of CMML including CMML-1 with transfusion-dependence and MP-CMML. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Fridrik:Cephalon: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.

The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients

BackgroundThe Charlson comorbidity index is often used to control for confounding in research based on medical databases. There are few studies of the accuracy of the codes obtained from these databases.We examined the positive predictive value (PPV) of the ICD-10 diagnostic coding in the Danish National Registry of Patients (NRP) for the 19 Charlson conditions.MethodsAmong all hospitalizations in Northern Denmark between 1 January 1998 and 31 December 2007 with a first-listed diagnosis of a Charlson condition in the NRP, we selected 50 hospital contacts for each condition. We reviewed discharge summaries and medical records to verify the NRP diagnoses, and computed the PPV as the proportion of confirmed diagnoses.ResultsA total of 950 records were reviewed. The overall PPV for the 19 Charlson conditions was 98.0% (95% CI; 96.9, 98.8). The PPVs ranged from 82.0% (95% CI; 68.6%, 91.4%) for diabetes with diabetic complications to 100% (one-sided 97.5% CI; 92.9%, 100%) for congestive heart failure, peripheral vascular disease, chronic pulmonary disease, mild and severe liver disease, hemiplegia, renal disease, leukaemia, lymphoma, metastatic tumour, and AIDS.ConclusionThe PPV of NRP coding of the Charlson conditions was consistently high.

Genetic diversity of near genome-wide hepatitis C virus sequences during chronic infection: evidence for protein structural conservation over time.

Infection with hepatitis C virus (HCV) is one of the leading causes of chronic hepatitis, liver cirrhosis and end-stage liver disease worldwide. The genetics of HCV infection in humans and the disease course of chronic hepatitis C are both remarkably variable. Although the response to interferon treatment is largely dependent on HCV genotypes, whether or not a relationship exists between HCV genome variability and clinical course of hepatitis C disease still remains unknown. To more thoroughly understand HCV genome evolution over time in association with disease course, near genome-wide HCV genomes present in 9 chronically infected participants over 83 total study years were sequenced. Overall, within HCV genomes, the number of synonymous substitutions per synonymous site (dS) significantly exceeded the number of non-synonymous substitutions per site (dN). Although both dS and dN significantly increased with duration of chronic infection, there was a highly significant decrease in dN/dS ratio in HCV genomes over time. These results indicate that purifying selection acted to conserve viral protein structure despite persistence of high level of nucleotide mutagenesis inherent to HCV replication. Based on liver biopsy fibrosis scores, HCV genomes from participants with advanced fibrosis had significantly greater dS values and lower dN/dS ratios compared to participants with mild liver disease. Over time, viral genomes from participants with mild disease had significantly greater annual changes in dN, along with higher dN/dS ratios, compared to participants with advanced fibrosis. Yearly amino acid variations in the HCV p7, NS2, NS3 and NS5B genes were all significantly lower in participants with severe versus mild disease, suggesting possible pathogenic importance of protein structural conservation for these viral gene products.

Chronic hepatitis C infection blocks the ability of dendritic cells to secrete IFN-α and stimulate T-cell proliferation

Dendritic cells (DCs) are likely to play a key role in the compromised T-cell function associated with hepatitis C Virus (HCV) infection. However, studies of DC function in HCV-infected patients to date have yielded conflicting findings possibly because of patient and virus heterogeneity. Here, we report the characterization of monocyte-derived DCs obtained from a homogenous cohort of women who were infected with HCV genotype 1b following exposure to contaminated anti-D immunoglobulin from a single donor source. Patients included in the study had not received anti-viral therapy and all had mild liver disease. We show that phenotypically normal monocyte-derived dendritic cells (MDDCs) (CD11c(+) HLA(-) DR(+) CD1a(+) CD14(lo) ) can be obtained from these patients. These cells respond to both Poly(I:C) and LPS, by up-regulating expression of CD86. They secrete high levels of IL-8 and CCL5 in response to LPS, an indication that the MyD88-dependent and MyD88-independent signalling pathways downstream of TLR4 ligation are functioning normally. However, these cells are poor stimulators of T-cell proliferation in allogeneic mixed lymphocyte reactions. Furthermore, patient MDDCs fail to secrete IFN-α in response to poly(I:C) or IFN-β stimulation. Altered DC function may contribute to impaired cellular immune responses and chronicity of disease following HCV infection in this cohort. An effective therapeutic vaccine for chronic HCV infection will most likely need to target DCs to elicit an appropriate cellular response; therefore, it is important to resolve how the DCs of different patient cohorts respond to stimulation via TLRs.

Chronic hepatitis C in children is a mild and curable liver disease

Hepatitis C virus (HCV) infection is a major health problem orldwide, but children constitute only a small portion of infected atients. HCV transmission can occur through blood transfusion, nd the incidence of HCV infection was very high in children transused before 1990 for treatment of chronic haematological diseases 1] or other diseases that required blood transfusion [2]. Since he introduction of screening for HCV infection, blood transfusions ave become safe in developed countries, and the residual risk is oday very limited. In developed countries, maternal–fetal transmission has ecome themajor risk factor for HCV in children,with an estimated isk of infection ranging from 2% to 6% [3]. The key questions to anaging children with HCV chronic infection are identifying the vailable methods for the staging of the liver fibrosis in children ith chronic HCV infection, assessing the risk of developing cirhosis, and understanding the therapeutic options for curing HCV hronic hepatitis. Percutaneous liver biopsy is still the standardmethod for definng the grade of liver inflammation, and the stage of fibrosis. The se of liver biopsy in children is limited by the risk of complicaions, and by the reluctance, from both children and their parents, o consent to this procedure. However, in the last year, two studes have been published that included children with chronic HCV nfection who had undergone liver biopsy before starting antiviral reatment. Both reported a very low percentage of children with ignificant liver fibrosis. In the study by Sokal et al. [4], more than 5% of 65 children or adolescents included in a trial of treatment ith peginterferon alpha and ribavirin had no fibrosis, or had mild brosis; none of themhad severe fibrosis or cirrhosis. Anothermulicentre, controlled trial [5] reported that only 3 out of 104 children valuated for antiviral treatmenthadhistological evidenceof portal brosis with septa. Recently, non-invasive methods for assessing iver fibrosis, in place of biopsy, have been developed. Amongst hese methods, transient elastography has been applied and studed, mainly in adult patients with chronic HCV. There are few data n stiffness measurement of the liver by FibroScan in children. A tudy performed on 116 children, with amean age of 10 years, con-