C5b-9 and Interleukin-6 in Chronic Hepatitis C: Surrogate Markers Predicting Short-term Response to Interferon Alpha-2b

Background: Available data and our observations suggest that elevated levels of interleukin (IL)-6 and -10 and some complement parameters may be associated with a poor response to IFN alpha. We evaluated how baseline levels of C5b-9, IL-6, and IL-10 influence the outcome of IFN alpha treatment. Methods: Fifty-one patients with established chronic hepatitis C were enrolled and treated with IFN alpha-2b. Before and after a 12-week-IFN-treatment (3 MU or 5 MU tiw) serum levels of IL-6, IL-10, C5b-9 and RNA of hepatitis C virus (HCV) were assessed. Sera of 46 sex- and age-matched, healthy blood donors served as control. Results: While two-thirds of patients was considered 'responder', 14 patients had no significant decrease either in HCV RNA or in ALT levels. In the responder's group lower baseline levels of IL-6 and C5b-9 were found than those in the `non-responder' group. As a result of IFN therapy HCV RNA and C5b-9 levels significantly decreased. While the serum concentration of IL-6 increased during the follow-up period, regarding IL-10, no change was observed. In patients with 'low' baseline levels of C5b-9 (<2053 ng/ml) IFN alpha resulted in a significantly (P = 0.0005) higher decrease in HCV RNA level. Regarding `low' IL-6 values (<1.47 pg/ml) similar but somewhat less significant (P = 0.0039) difference was found if the change of HCV RNA was investigated. The odds ratio of patients with low IL-6 and/or C5b-9 to responding to IFN alpha treatment was almost 10 times (CI: 9.1 (1.8-50.9)) higher as compared with patients without 'low' levels of these parameters. Conclusion: Our data suggest that serum level(s) of IL-6 and/or C5b-9 taken prior to the initiation of IFN treatment may serve as surrogate marker(s) in evaluating patients with chronic hepatitis C whether to get IFN alpha in monotherapy or to consider having combination therapy in the form of IFN alpha-ribavirin.     

Low Faecal Elastase 1 Concentrations in Type 2 Diabetes Mellitus

Background: Previous studies have suggested an association between impaired pancreatic exocrine function and diabetes, but the evidence is weak because the invasive nature of the tests used to define exocrine function has led to small studies on selected patients. The availability of faecal elastase 1 as a non-invasive test has aided the detection of impaired exocrine function in population studies. We describe the association between levels of faecal elastase 1 and Type 2 diabetes. Methods:     

Bile Acid Malabsorption in Patients with Chronic Diarrhoea: Clinical Value of SeHCAT Test

Background: Bile acid malabsorption (BAM), a cause of chronic diarrhoea, can be diagnosed by the SeHCAT test. The purpose of this study was to evaluate the usefulness of SeHCAT testing by assessing the extent of BAM and describing the clinical characteristics in a group of patients with chronic diarrhoea. Clinical outcome after treatment with cholestyramine was also evaluated. Methods: During a 5-year period (1997-2001) the SeHCAT test was performed in 135 patients in whom a primary programme for diagnostic evaluation of chronic diarrhoea had not revealed a cause. File data from 133 patients could be evaluated. Results: In 44% of patients, bile acid absorption was normal with SeHCAT retention &#83 15%. Impaired SeHCAT retention was found in 56%. All patients with ileocaecal resections had retention values <10%. Patients with microscopic colitis presented with BAM in 39%. Only one patient with idiopathic BAM presented with steatorrhoea as opposed to 11 patients with type 1 and 3 BAM. Patients with idiopathic BAM and/or SeHCAT retention values <5% had the best response to treatment with cholestyramine. Conclusions: The SeHCAT test is of value in evaluation of patients with chronic diarrhoea as a second-line investigation with a high diagnostic yield. The only a priori parameter to predict BAM was the existence of ileocaecal resections. The result of the SeHCAT test seems to predict the benefit of treatment with cholestyramine.     

The Prevalence of Alpha-1 Antitrypsin Deficiency Among Patients Found to Have Airflow Obstruction

Abstract

Introduction: Alpha-1 antitrypsin deficiency (AATD) is a genetic disease that may be manifested by chronic obstructive pulmonary disease. Despite professional society guidelines that recommend broad testing of at-risk individuals, fewer than 10% of affected individuals have been identified. The goals of this study were to estimate the frequency of abnormal AAT genotypes among patients found to have fixed airflow obstruction and to assess the feasibility of having Pulmonary Function Laboratory personnel administer the study. Methods: Nineteen medical centers in the United States participated in the study. Eligible patients (> GOLD II, FEV₁/FVC ratio < 0.7, with post-bronchodilator FEV₁<80% predicted) were offered testing for AATD by the Pulmonary Function Laboratory personnel at the time of pulmonary function testing. Results: A total of 3,457 patients were tested, of whom 3152 were eligible. Deficient patients (ZZ, SZ) constituted 0.63% of subjects, while 10.88% were carriers (MS, MZ). Neither demographic (except African-American race) nor post-bronchodilator pulmonary function variables (FEV₁, FVC, FEV₁/FVC ratio, TLC, and FEV₁/FVC) allowed us to predict AAT heterozygote or deficiency status. Conclusions: The prevalence of AATD among patients undergoing pulmonary function tests with fixed airflow obstruction was 0.63%. Pulmonary Function Laboratory personnel effectively conducted the study.     

Diagnostic assessment and outcome of acute pancreatitis in Italy: Results of a prospective multicentre study: ProInf-AISP: Progetto informatizzato pancreatite acuta, Associazione Italiana Studio Pancreas, phase II

BACKGROUND AND AIM: Up till now, only one study providing practically complete information on acute pancreatitis in Italy has been published. The aim of this prospective study was to evaluate the clinical characteristics, in terms of diagnostic assessment and outcome, of a large series of patients affected by acute pancreatitis in Italy. MATERIALS AND METHODS: The study involved 56 Italian centres, homogeneously distributed throughout the entire national territory. Each participating centre was furnished with an ad hoc software including 530 items along with subsequent collection, tabulation and quality control of the data. RESULTS: One thousand five hundred and forty case report forms of patients affected by acute pancreatitis were collected but 367 of them (24%) were subsequently eliminated from the final analysis. Therefore, 1173 patients (581 females and 592 males) were recruited. Mean age of patients was 62.0+/-18.2 years (95% confidence interval, 60.9-63.0). On the basis of Atlanta classification, 1006 patients (85.8%) were defined as mild and 167 (14.2%) as severe pancreatitis. Biliary forms represented the most frequent aetiological category (813 cases, 69.3%) while alcoholic forms only 6.6% (77 cases); the remaining aetiologies accounted for 7.1% (83 cases) while 200 cases (17.1%) remained without a definite aetiological factor. Complete recovery was achieved in 1016 patients (86.6%) whereas morphological sequelae were found in 121 patients (10.3%) and mortality in 36 patients (3.1%; 0.4% in mild and 19.2% in severe acute pancreatitis). Ultrasonography was largely utilised as a first line diagnostic tool in all patients, with valuable visualisation of the pancreas in 85% of patients. Computer tomography scan was also widely used, with 66.7% of exams in mild and 33.3% in severe pancreatitis. Patients affected by biliary pancreatitis presented more severe (p=0.004) and necrotizing forms (p=0.021). Mortality was significantly related (p<0.001) with the extension of pancreatic necrosis and with an age of over 70 years. Body mass index presented significantly greater values in severe than in mild forms (p<0.001). CONCLUSIONS: Association of creatinine serum level over 2mg/dl with an abnormal chest X-ray showed a high significant correlation with a more severe outcome in terms of morphological sequelae and mortality (p=0.0001). Acute pancreatitis in Italy more commonly presents biliary aetiology and favourable outcome with low rate of complications and mortality. From a cost-effectiveness standpoint, diagnostic approach to this disease needs to be better standardised.     

GLP-1 mimetic drugs and the risk of exocrine pancreatic disease: Cell and animal studies

BackgroundGlucagon Like Peptide 1 (GLP-1) mimetic drugs or degradation inhibitors mimic the action of native GLP-1 as a incretin hormone and have become a common second line of therapy for Type 2 diabetes. However, an important clinical issue is whether these drugs increase the incidence of pancreatitis and pancreatic cancer.ObjectiveThis paper reviews the physiology of GLP-1 including its synthesis, secretion and action of the peptide. Reported effects of the mimetic drugs on the exocrine pancreas in animal studies are also reviewed.ResultsGLP-1 is synthesized in a specific class of enteroendocrine cell, the L-cell, by post-translational processing of proglucagon. It is released in response to the presence of nutrients in the small intestine and stimulates vagal afferent nerve endings as well as entering the blood where it is rapidly degraded by dipeptidyl peptidase IV. Its actions are mediated by specific G-protein coupled receptors. The major target tissues are the pancreatic islet beta cells, the brain and the heart but GLP-1 also affects gastrointestinal motility and secretion including the exocrine pancreas where its major systemic action is to inhibit secretion. In some animal, as well as human studies, the GLP-1 mimetic drugs are associated with pancreatitis or precursor lessions to pancreatic cancer but a mechanism is not clear. The most common occurrence of pathology in rodents is when the drugs are combined with a high fat diet.ConclusionsThere is nothing in the physiology of GLP-1 or animal toxicology studies to support a mechanism of action or a major concern about the action of GLP-1 mimetic drugs on the exocrine pancreas. Further studies are warranted using animal models of disease and high fat diets.     

Surgical decompression of Wirsung duct reduces serum concentration of SPINK1 in patients with chronic pancreatitis

Objectives

The primary aim of this study was to determine the blood levels of SPINK1 in patients with chronic pancreatitis (CP) submitted to surgical or endoscopic decompression of pancreatic duct (PD). Additionally, we measured trypsin activity levels.

Association of faecal elastase 1 with non-fasting triglycerides in type 2 diabetes

AimsIntestinal absorption of esterified fatty acids depends on exocrine pancreatic function and influences plasma triglycerides levels. The aim was to investigate the association of reduced exocrine pancreatic function (low fecal elastase-1; FE1) with plasma triglycerides in type 2 diabetes and controls without diabetes.MethodsFE1 (μg/g stool) and non-fasting plasma triglyceride measurements were undertaken in 544 type 2 diabetes patients (age: 63 ± 8 years) randomly selected from diabetes registers in Cambridgeshire (UK), and 544 matched controls (age, sex, practice) without diabetes. Linear regression models were fitted using FE1 as dependent and log-triglycerides as independent variable adjusting for sex, age, body mass index, alcohol consumption, serum lipase, HbA1c, and smoking.ResultsFE1 concentrations were lower (mean ± SD: 337 ± 204 vs. 437 ± 216 μg/g, p < 0.05) and plasma triglycerides were higher (geometric mean */: standard deviation factor: 2.2*/:1.9 vs. 1.6*/:1.8 mmol/l, p < 0.05) in type 2 diabetes compared to controls, respectively. Within the category of type 2 diabetes and controls separately, a 10% increase in plasma triglycerides was associated with 4.5 μg/g higher FE1 concentrations (p < 0.01) after adjusting for confounders. In contrast, in diabetes patients and controls with pathological FE1 (<100 μg/g), low FE1 levels were associated with high plasma triglycerides (significant only in controls).ConclusionsNon-fasting triglycerides were positively related to FE1 in both type 2 diabetes and controls suggesting that impairment of exocrine pancreas function is influencing plasma triglycerides. Marked loss of exocrine pancreatic function had the opposite effect, resulting in higher levels of plasma triglycerides.     

KAI1 PNA探针的制备及其在胰腺癌中的应用

目的：制备DIG标记KAI1 RNA探针和分析KAI1基因在胰腺癌中的表达。方法：以线性KAI1基因DNA质粒为模板，采用体外转录法掺入DIG-11-UTP制备RNA探针，并通过化学发光法检测。应用该探针通过Northern blot对12例正常胰腺组织和30例原发性胰腺癌组织中的KAI1基因mRNA进行分析。结果：该方法标记的KAI1 RNA探针浓度?a1ng/цl时即可检测。Northern bolt分析发现25例无转移的胰腺癌中KAI1基因在2.4kb处存在明显的杂交信号，5例发生转移的晚期胰腺癌杂交信号较弱，正常胰腺组织中该基因的表达水平呈阴性或弱阳性。结论：本法标记的KAI1RNA探针灵敏度高，KAI1基因低表达与胰腺癌转移有关。     

Exosomal glypican-1 for risk stratification of pancreatic cystic lesions: A case of pathological progression in the absence of any suspicious imaging finding

The clinical management of patients with pancreatic cystic lesions is of utmost importance to identify those at high risk for pathological progression. Current recommendations are guided by clinical presentation and radiologic criteria, but the results fall short for a disease that the only curative option is surgical resection. There is an urgent need for the introduction of biomarkers that can help in risk assessment of such lesions.We report a case of a pancreatic cystic lesion without imagiological findings suggestive of advanced disease, and high levels of a circulating biomarker, glypican-1 (GPC-1), which parallel those of patients with pancreatic cancer. One year after, the patient revealed malignant progression at follow-up.Our report is unprecedented in the literature. It describes a clinical case in which a biomarker was positive for a patient that only showed progression one year after its detection. This clinical information goes beyond the current knowledge in the field because it shows that the introduction of liquid biopsy and biomarkers is a highly promising clinical tool for the non-invasive assessment of pancreatic cancer precursor lesions, ultimately increasing the rate of patients eligible for surgical resection.     

hENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: A systematic review

High human equilibrative nucleoside transporter 1 (hENT1)-expression has shown a survival benefit in pancreatic cancer patients treated with gemcitabine in several studies. The aim of this systematic review was to summarize the results and try to assess the predictive value of hENT1 for determining gemcitabine outcome in pancreatic cancer. Relevant articles were obtained from PubMed, Embase and Cochrane databases. Studies evaluating hENT1-expression in pancreatic tumor cells from patients treated with gemcitabine were selected. Outcome measures were overall survival, disease-free survival (DFS), toxicity and response rate. The database searches identified 10 studies that met the eligibility criteria, and a total of 855 patients were included. Nine of 10 studies showed a statistically significant longer overall survival in univariate analyses in patients with high hENT1-expression compared to those with low expression. In the 7 studies that reported DFS as an outcome measure, 6 had statistically longer DFS in the high hENT1 groups. Both toxicity and response rate were reported in only 2 articles and it was therefore hard to draw any major conclusions. This review provides evidence that hENT1 is a predictive marker for pancreatic cancer patients treated with gemcitabine. Some limitations of the review have to be taken into consideration, the majority of the included studies had a retrospective design, and there was no standardized scoring protocol for hENT1-expression.     

The clinicopathological and prognostic significance of PD-L1 expression in pancreatic cancer: A meta-analysis

Background: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1(PD-1) and programmed cell death ligand 1(PD-L1) in pancreatic ductal adenocarcinoma(PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC.Data sources: Electronic search of the Pub Med, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival(OS).Results: Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry(IHC) was higher than that measured by polymerase chain reaction(PCR)(P 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS(HR = 2.34;95% CI: 1.78–3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3–4 group was higher than that in the T1-2 group(OR = 0.37; P = 0.001).Conclusions: High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.     

Efficacy of thymosin alpha-1 and interferon alpha in treatment of chronic viral hepatitis B： A randomized controlled study

INTRODUCTION Chronic hepatitis B virus (HBV) infection is a serious problem worldwide and may result in adverse sequelae, such as cirrhosis and hepatocellular carcinoma (HCC)[1-2], which is becoming more prevalent worldwide, especially in HBV-endemic area…     

Interferon Beta 1a versus Interferon Beta 1a plus Ribavirin for the Treatment of Chronic Hepatitis C in Chinese Patients: A Randomized, Placebo-Controlled Trial

For chronic hepatitis C virus (HCV) infection, the effects of current therapies are limited. To evaluate the efficacy and safety of the interferon beta-1a (IFN β-1a) versus IFN β-1a plus ribavirin (RBV) combination on Chinese treatment-naïve patients with chronic hepatitis C, a randomized, placebo-controlled study was performed. A total of 26 naïve patients histologically confirmed to have chronic hepatitis C were double-blindly and randomly assigned to receive either IFN β-1a 44 μg (12 MIU) (IFN β-1a group) or placebo (placebo group) three times per week for 12 weeks. At the end of the 12 weeks of treatment, the patients who received IFN β-1a continued to complete 24 weeks of treatment. Placebo non-responders were crossed over to IFN β-1a plus RBV (1,000–1,200 mg/day) combination therapy (IFN β-1a plus RBV group) for 24 weeks after 4 weeks washout. All patients were followed up for 24 weeks after the end of treatment. Sustained virological response (SVR) was defined as the absence of detectable HCV RNA in the serum both at the end of 24 weeks of treatment and at the end of 24 weeks of untreated follow-up. There were no differences in the clinical background between the groups before the initiation of treatment. At the end of the 12 weeks of double-blind therapy, HCV RNA was negative and undetectable in 10/11 patients (90.9%) in the IFN β-1a group and none in the placebo group. The virological response rate (14/15, 93.3%) of the IFN β-1a plus RBV group at week 12 after the initiation of therapy was similar to that of the IFN β-1a group. SVR was observed in 5/11 (45.5%) of the IFN β-1a group and 11/15 (73.3%) of the IFN β-1a plus RBV group (P = 0.23). At the end of follow-up, a biochemical response was found in 5/11 patients in the IFN β-1a group (45.5%) and 8/15 patients in the IFN β-1a plus RBV group (53.3%, P = 1.00). Multiple logistic regression analysis confirmed that an HCV RNA load lower than 1.0×10⁶ copies/ml was independently associated with SVR (OR 11.00; 95% CI 1.81–66.97; P = 0.003). The side effects were mild and similar in the two therapy groups. We conclude that IFN β-1a alone or in combination with RBV provided considerable benefit in Chinese naïve patients with chronic hepatitis C. Treatments with IFN β-1a alone or IFN β-1a plus RBV are safe and well tolerated, and may represent an alternative for chronic hepatitis C patients who are unable to tolerate pegylated interferon α.     

Up-regulation of transferrin receptor 1 in chronic hepatitis C: Implication in excess hepatic iron accumulation.

BACKGROUND/AIMS:: To clarify the mechanism of excess hepatic iron accumulation in chronic hepatitis C, we investigated the expressions of transferrin receptor 1 and divalent metal transporter 1 in hepatocytes, both of which are involved in cellular iron uptake, in relation to the degree of hepatic iron accumulation and hepatic fibrosis by immunohistochemistrical study. METHODS:: Forty-six hepatic tissues with chronic hepatitis C and five normal hepatic tissues were examined. Chemical detection of hepatic iron accumulation was performed by Perl's Prussian blue stain. The immunohistochemistrical study was performed by avidin-biotin complex method with alkaline phosphatase. RESULTS:: In chronic hepatitis C: (1) Hepatic iron accumulation was significantly increased in relation to the advance of the fibrosis. (2) Divalent metal transporter 1 decreased significantly in relation to the advance of hepatic fibrosis. (3) Transferrin receptor 1 expression was always detected, although not in normal hepatic tissues; there was no relation between expression levels and the degree of hepatic fibrosis. CONCLUSIONS:: These data demonstrated that the transferrin receptor 1 expression was up-regulated irrespective of the degree of hepatic iron accumulation, suggesting that the up-regulation of transferrin receptor 1 might act as one of the key mechanisms implicated in the accumulation of hepatic iron in chronic hepatitis C.