Search

Background: The histopathologic diagnosis of celiac disease (CD) may be challenging when the duodenal biopsies mucosal injury is limited. Intraepithelial T-lymphocytes (IELs) can be useful to characterize the degree of mucosal inflammation. A small fraction of IELs expresses the γδ T-cell receptor (named γδ-IELs), whose density, determined by flow cytometry or frozen section immunohistochemistry (IHC), is a specific marker for CD. Aim: To establish a new IHC assay for γδ-IELs applicable to formalin-fixed paraffin-embedded (FFPE) duodenal biopsies. Methods: We analyzed γδ-IELs using IHC in 138 duodenal biopsies using a standard IHC staining protocol with a new monoclonal antibody H-41. IELs were quantitated with digital image analysis. Results: Compared to those in non-celiac controls (n = 51), γδ-IEL density was significantly increased in newly diagnosed celiac disease patients (n = 22, p < 0.0001). In ROC-curve analysis, the cutoff of 6.5 γδ-IELs/100 enterocytes distinguished optimally active CD patients from non-celiac controls (sensitivity 96%, specificity 95%). γδ-IEL density in CD patients on a gluten-free diet (n = 53) were also higher than in controls (p < 0.0001), but lower than those in newly diagnosed CD (p < 0.0001). The diagnostic value of γδ-IELs outperformed that of CD3 + IELs in both patient groups. γδ-IELs were better than CD3 + IELs distinguishing between celiac disease and conditions histologically mimicking celiac disease (n = 12). Conclusions: Intraepithelial γδ T-lymphocytes can be stained and quantitated reliably in FFPE duodenal biopsies. The results showed excellent specificity and sensitivity for celiac disease. The new IHC method of detection of γδ-IELs is a promising addition to the routine histopathologic assessment methodology of celiac disease. [ABSTRACT FROM AUTHOR]

Purpose: For superficial colonic lesions, the NICE and Kudo classifications are used in the in vivo prediction of histology and as guide to therapy. The NICE system derives information from unmagnified NBI endoscopic images. The Kudo one necessitates a magnification, but, as this tool is not commonly available, it is applied also to characterize unmagnified pictures to compare their diagnostic performances. Methods: We conducted a prospective comparison of the NICE versus the Kudo classification for the differential diagnosis of colonic polyps taking histology as the gold standard. The inter-observer agreement for both classifications among 11 colonoscopists was also evaluated. Short unmagnified NBI videoclips of 64 colonic polyps were sent twice to the participants. In the first round, they classified the lesions according to the NICE classification; 4 months later, the same videos were assessed with the Kudo system. The diagnosis provided by the participants was grouped in non-neoplastic, non-invasive neoplasia, invasive neoplasia. Results: Overall, the diagnostic accuracy was 82% (95%CI: 79–85) with the NICE system and 81% (95%CI: 78–84) with the Kudo one (ρ = 0.78). The accuracy of the NICE classification for non-neoplastic lesions was greater compared with the Kudo's (ρ = 0.03). Sensitivity sub-analyses revealed a higher ability of the NICE in distinguishing between neoplastic vs. non-neoplastic lesions (ρ = 0.01). The overall inter-rater agreement did not differ when the classifications were compared. Conclusion: The NICE and the Kudo classifications might be considered comparable. Our data could allow the use of the NBI Kudo classification even in those centers where magnification is not available. [ABSTRACT FROM AUTHOR]

Background: For solid pancreatic masses, ultrasound endoscopic fine-needle biopsy is suggested as the front-line investigation for tissue achievement, notwithstanding the optimal performance of transabdominal ultrasound (TUS)-guided biopsy. Purpose: To reassess the efficacy and effectiveness of TUS-guided sampling and to determine the factors predictive of accurate histology. Methods: In total, 142 patients with an indication for a TUS-guided biopsy of a pancreatic mass were analyzed. A single pass of an 18-gauge Biomol needle was carried out by the Menghini technique. The accuracy, sensitivity, and specificity of the procedure in terms of correctly diagnosing an inflammatory or neoplastic lesion were determined. The patients' characteristics, the size and location of the mass, and the sonographers' experience in performing TUS were recorded. Results: The sampling was unsuccessful in 24 cases, owing to the deep localization of lesions (57%), bloating (33%), or low patient compliance (10%). The accuracy, sensitivity, and specificity of the 118 successful biopsies were 81%, 79%, and 100%, respectively. A biopsy core was obtained in 90 of the 118 patients (76%) in whom the procedure was attempted. In the multivariate analysis, lesion size (≤ 20 mm vs. > 20 mm) (OR = 5.3 [1.7–17.0]) and operator experience (OR = 4.4 [1.6–12.1]) predicted the acquisition of adequate samples. With an expert sonographer, the accuracy, sensitivity, and specificity were 87%, 85%, and 100%, respectively. Two adverse events were registered: mild abdominal pain and a hypotensive crisis. Conclusions: The present investigation highlights the optimal performance of a TUS-guided biopsy of a pancreatic mass. Because of its simplicity and safety, the procedure needs to be included among the recommended investigative options [ABSTRACT FROM AUTHOR]

Background and Aims: Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-related death. We aimed to evaluate whether gemcitabine treatment shapes the gut microbiota in a model of PDAC xenografted mice.Materials and Methods: Pancreatic cancer xenograft mice were subjected to gemcitabine injection once per week for 3 weeks to assess the tumor volume as compared to control mice injected with normal saline solution. The composition of fecal microbiota, the activation of NF-kB pathway in cancer tissues and the serum metabolomics were further analyzed.Results: Gemcitabine considerably decreases the proportion of Gram- positive Firmicutes (from about 39 to 17%) and the Gram- negative Bacteroidetes (from 38 to 17%) which are the two dominant phyla in the gut of tumor-bearing control mice. This downshift was replaced by an increase of Proteobacteria (Escherichia coli and Aeromonas hydrophila) from 15 up to 32% and Verrucomicrobia (Akkermansia muciniphila) from 5 to 33% in the gut of drug-receiving mice. An overall increase in inflammation-associated bacteria was observed upon gemcitabine. Consistently, activation of the NF-kB canonical pathway was found in cancer tissues from gemcitabine-treated mice. Serum metabolomics revealed a significant decrease of the purine compounds inosine and xanthine, and a decreasing trend for their metabolically-related molecule hypoxanthine.Discussion: Understanding chemotherapy side effects may explain the lack of activity or the chemoresistant processes and it may help to set up strategies to improve the effectiveness of therapy. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus infects ~3% of the population and it is a risk factor for hepatocarcinogenesis. The epigenetic mechanisms of HCV-induced hepatocyte transformation towards malignancy in this context are unclear.Aims: The purpose of this study was to evaluate the effect of HCV core proteins of different genotypes on DNA methyltransferases (DNMTs) induction.Materials/methods: We investigated DNMT1, DNMT3b and E-Cadherin (CDH1) mRNA and protein expression levels in an in vitro model of Huh-7 cells expressing the HCV core protein of different genotypes: 1b, 2a, 3a, 4h and 5a.Results: We found that both mRNA and protein expression levels of DNMT1 and 3b were upregulated in genotype 1b HCV core expressing cells as compared to control cells. DNMT3b mRNA levels did not change in genotypes 2a, 3a, 4h and 5a, but were upregulated at the protein level by genotype 1b, 2a, 3a. CDH1 mRNA expression was downregulated only in genotype 1b, whereas its protein expression resulted in downregulation by the HCV core of genotypes 1b, 2a and 3a. Conversely, no significant changes were observed for DNMTs and CDH1 investigated in Huh-7 cells expressing the genotypes 4h and 5a. Furthermore, we present evidence that HCV core 1b protein expression induces DNMTs overexpression through STAT3 protein as demonstrated by NSC74859 treatment. Moreover, SIRT1 inhibition affected DNMT1 and 3b expression only in HCV core protein genotype 1b expressing cells as demonstrated by treatment with its inhibitor sirtinol.Conclusions: Our findings suggest that HCV core protein could play a role in HCC development at least in part by altering DNMTs expression. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV), hepatitis C virus (HCV) and Delta (HDV) infections are a global health burden. With different routes of infection and biology, HBV, HCV and HDV are capable to induce liver cirrhosis and cancer by impinging on epigenetic mechanisms altering host cell's pathways. In the present manuscript, we reviewed the published studies taking into account the relationship between the hepatitis viruses and the DNA methyltransferases proteins. [ABSTRACT FROM AUTHOR]

Our study objective was to determine the current use of liver biopsy in chronic viral hepatitis and how patient management is affected by the procedure. Members of the Italian Association of Hospital Gastroenterologists were asked to complete a questionnaire for patients submitted to biopsy. Their clinical diagnosis was compared with the histological diagnosis. Of 660 patients evaluated, we selected 535 cases with viral infection. Concordance of clinical vs histologic diagnosis amounted to 84.3%, with 92.7% sensitivity and 32.4% specificity rates for diagnosing chronic hepatitis; the clinical diagnosis was correct in only 24 of 57 cases with cirrhosis. In 20 cases (3.7%) additional diagnoses were provided. The biopsy was rated avoidable in 36.8% of cases. Knowledge about grading and staging was considered of value in 59.6 and 66.4% of cases, respectively; however, when it became available, the scheduled treatment with interferon was not changed in 81.7 and 80.9% of cases. In the majority of patients with abnormal ALT and infection with HCV and/or HBV, histology documents mild/moderate inflammation with minimal fibrosis and liver biopsy neither increases the accuracy of clinical diagnosis nor affects the choice of therapy. The data from this study support the view that liver biopsies are less helpful than conventionally understood. [ABSTRACT FROM AUTHOR]

Aim: To evaluate similarities and differences in HCV-1 subtypes 1a and 1b in the presenting clinical features and the response to peg-interferon and ribavirin (Peg/RIBA). Patients and methods: A total of 1,233 naïve patients with HCV genotype-1 infection, 159 (13 %) with subtype 1a and 1,074 (87 %) with subtype 1b were treated with Peg-IFN/RIBA at 12 Italian centers. Covariates included in the logistic model were age, gender, BMI, serum alanine aminotransferase, serum gamma-glutamiltranspeptidase (γGT), platelets counts, liver fibrosis, the occurrence of type 2 diabetes, baseline viremia, and IL28B genotype. Results: At multivariate analysis, baseline characteristics differentiating patients with HCV-1a versus HCV-1b were young age, male gender, no F4 fibrosis, and no diabetes. SVR was achieved by 37 % of patients with subtype 1b and 45 % of those with subtype 1a, a nonsignificant difference of 8 % ( p = 0.069). In patients with subtype 1a, predictors of SVR were IL28B CC (OR 5.78, CI 1.98-16.83), RVR (OR 4.18, CI 1.66-10.55), female gender (OR 2.83, CI 1.83-6.78), and HCVRNA (OR 0.55, CI 0.32-0.96). In patients with subtype 1b, the ranking of predictors was levels RVR (OR 6.49, CI 4.32-9.73), IL28B CC (OR 3.32, CI 2.15-4.58), γGT (OR 1.59, CI 0.14-2.22), HCVRNA (OR 0.61, CI 0.47-0.79), and age (OR 0.01, CI 0.02-0.42). Conclusion: In Italy HCV-1 subtype 1a prevails in young male patients with less advanced liver damage, findings that imply a more recent spreading of the infection with this viral strain. The two HCV-1 subtypes appear equally responsive to Peg-IFN/RIBA, with IL28B genotyping and monitoring of RVR mostly influencing the therapeutic response. [ABSTRACT FROM AUTHOR]

An increasing body of evidence supports the concept of genetic heterogeneity within inflammatory bowel disease (IBD). In this study, a polymorphism of the motilin gene, which determines an amino acid substitution in the motilin protein, has been investigated in IBD patients. Fifty patients with ulcerative colitis (UC), and 52 with Crohn's disease (CD) were investigated for anti-neutrophil cytoplasmatic antibodies (ANCA) and the polymorphism in the second exon of the motilin gene. Sixty unrelated blood donors served as controls. ANCA were found in 30% of UC and 13% of CD. In controls the DNA polymorphism identified two alleles (1 and 2) at a frequency of 42% and 58%, respectively. Patients with either UC or CD showed a slight increase in the frequency of allele 2 (69% and 60%, respectively; P > 0.05 vs controls). This allele was predominant in ANCA-positive CD patients (86%; P < 0.04) while in UC it did not differ. All ANCA-positive CD patients had the disease confined to the colon. A polymorphism of second exon of the motilin gene, leading to a protein variant, is significantly more frequent in the subset of ANCA-positive CD patients. This subgroup of patients appears to share peculiar genetic and clinical features. [ABSTRACT FROM AUTHOR]

Purpose: Controversy prevails on the impact of preoperative biliary drainage (PBD) on postoperative complications and clinical outcome of pancreatic cancer. We determined whether PBD is associated with increased morbidity and mortality rates after pancreaticoduodenectomy. Methods: A total of 131 consecutive patients who underwent pancreaticoduodenectomy (93 jaundiced, 38 with no jaundice) were included in this study. Overall, 57 % of jaundiced patients underwent PBD, while 43 % were not drained. The impact of PBD on postoperative morbidity and mortality was evaluated by means of logistic regression analysis. The Kaplan-Meier method was applied to determine the effect of PBD on survival of patients with malignant lesions. Results: Mortality and morbidity rate was 3 % and 54.6 %, respectively. PBD was demonstrated to be the unique predictor of complications (odds ration [OR] = 10.18; 95 % confidence interval [CI], 3.65-28.39, p < 0.001). The jaundiced patients who were drained exhibited high frequencies of wound infection ( p < 0.001), post-pancreatectomy haemorrhage ( p = 0.0185) and hyperglycaemia ( p < 0.001). In addition, an increased frequency of pancreatic fistula emerged among drained patients compared to those who were not drained ( p = 0.036). PBD did not affect survival of patient with malignant lesions. Conclusions: With the exception of the classical indications, PBD should be carefully evaluated in patients with resectable pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Given the significant side-effects and healthcare costs associated with telaprevir- or boceprevir-combination therapy, identifying patients likely to respond to dual therapy peg-interferon (Peg-IFN)/ribavirin is highly desirable. Since the perception of how large the pool of patients who may achieve rapid virologic response (RVR) is vaguely ascertained, we searched the literature for this information. Methods: Studies on patients treated with Peg-IFN/ribavirin were identified by searching MEDLINE and analyzed by meta-analysis. The primary end point was weighted estimates of RVR. The influence on race/ethnicity, baseline viremia, type of Peg-IFN, ribavirin dosage, and significant hepatic fibrosis on the results was evaluated. Results: Across 38 studies on 13,219 patients, the fraction of RVR patients was 19.6 %. The only baseline factor influencing RVR was race/ethnicity, with higher rates in Asian (26.7 %) and Caucasian patients (22.5 %). Of the 1,735 RVR patients, 85.1 % attained sustained virologic response (SVR). In these, SVR was influenced by ribavirin dose (86.8 vs. 72.8 % for high or low), type of Peg-IFN (91.8 % for alpha-2b vs. 82.9 % for alpha-2a), and treatment duration (91.7 % for 48 weeks vs. 79.4 % for 24 weeks). Conclusions: One fifth to one fourth of hepatitis C virus genotype 1 (HCV-1) patients can be safely treated with dual therapy of Peg-IFN/ribavirin, and may be spared from cost and inconvenience of regimens considering the addition of HCV protease inhibitors. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P<0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P=7.38 × 10−4, FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P<0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P<0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P<0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology. [ABSTRACT FROM AUTHOR]

Background: Long-term prognosis for localized pancreatic cancer remains poor. We sought to assess the benefit of neoadjuvant/preoperative chemotherapy with or without radiotherapy. Methods: Prospective studies where gemcitabine with or without radiotherapy was provided before surgery in patients with initially resectable or unresectable disease were reviewed by meta-analysis. Primary outcome was survival, and secondary outcomes were tumor response after therapy, toxicity, surgical exploration, and resection rates. Results: Twenty independent studies with 707 participants were included, 366 with resectable lesions and 341 with unresectable lesions. Seven studies were phase I/II trials, 10 phase II, and 3 prospective cohort studies. Estimated 1- and 2-year survival probabilities after resection were 91.7% (95% confidence interval [CI] 75-100) and 67.2% (95% CI 38-87) for initially resectable patients, and 86.3% (95% CI 78-100) and 54.2% (95% CI 25-100) for initially unresectable patients. The complete/partial response rate was 12% (95% CI 4-23) and 27% (95% CI 18-38) in resectable and unresectable lesions, respectively. The rate of treatment-related grade 3-4 toxicity was 31% (95% CI 21-42). Of resectable patients evaluable after restaging, 91% (95% CI 83-97) underwent surgery, and 82% (95% CI 65-95) of explored patients underwent resection. R0 resections amounted to 89% (95% CI 83-94). Of unresectable patients evaluable after restaging, 39% (95% CI 28-50) underwent surgery, and 68% (95% CI 53-82) of explored patients were resected, with 60% (95% CI 50-71) R0 resections. Conclusions: Current analysis provides marginal support to the assumed benefits of neoadjuvant therapies for patients with resectable cancer, and indicates a potential advantage only for a minority of those with unresectable lesions. [ABSTRACT FROM AUTHOR]

Purpose: Cathepsin and plasmin may favor cancer cell invasion degrading extracellular matrix. Plasmin formation from plasminogen is regulated by plasminogen activator inhibitor type-1 (PAI-1). ARNTL2 activates the promoters of the PAI-1 gene, officially called SERPINE1, driving the circadian variation in circulating PAI-1 levels. Methods: We evaluated ARNTL2 and SERPINE1 expression in 50 colorectal cancer specimens and adjacent normal tissue and in colon cancer cell lines. Results: We found up-regulation of ARNTL2 ( P = 0.004) and SERPINE1 ( P = 0.002) in tumor tissue. A statistically significant association was found between high ARNTL2 mRNA levels and vascular invasion ( P < 0.0001), and between high SERPINE1 mRNA levels and microsatellite instability (MSI-H and MSI-L, P = 0.025). Sorting the subjects into quartile groups, a statistically significant association was found between high ARNTL2 expression and lymph node involvement ( P < 0.001), between high SERPINE1 expression and grading ( P < 0.001) and between high SERPINE1 expression and MSI H-L ( P < 0.0001). In SW480 cells, a more proliferative model compared to CaCo2 cells, there were higher mRNA levels of ARNTL2 ( P < 0.001) and SERPINE1 ( P = 0.001). Conclusion: ARNTL2 and SERPINE1 expression is increased in colorectal cancer and in a highly proliferative colon cancer cell line and is related to tumor invasiveness and aggressiveness. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS), or hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant condition responsible for early onset cancer mostly in the colonrectum and endometrium as well as in other organ sites. Lynch syndrome is caused by germline mutations in mismatch repair genes, prevalently in hMSH2, hMLH1, and less frequently in hMSH6 and hPMS2. Twenty-nine non-related index cases with colorectal cancer (CRC) were collected from a region in southeast Italy (Apulia). Among this set of patients, fifteen fulfilled the Amsterdam criteria II. The presence of tumor microsatellite instability (MSI) was assessed in all index cases and 19 (15 AC+/4 AC−) were classified as MSI-H. Mutation analysis performed on all patients, identified 15 pathogenic mutations in hMLH1 and 4 in hMSH2. 4/15 mutations in hMLH1 and 2/4 hMSH2 mutations have not been previously reported. Three previously reported mutations were further investigated for the possibility of a common founder effect. Genetic counseling was offered to all probands and extended to 183 relatives after molecular testing and 85 (46%) mutation carriers were identified. Eighty mutation carriers underwent an accurate clinical and instrumental surveillance protocol. Our results confirm that the identification of LS patients based exclusively on family history may miss patients carrying germline mutations in the MMR genes. Moreover, our results demonstrated that molecular screening and subsequent instrumental surveillance are very effective in identifying CRCs at earlier stages and reducing the number of deaths from secondary cancers in HNPCC patients. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study is to evaluate the impact of a fast-track protocol in a high-volume center for patients with pancreatic disorders. Background: The concept of fast-track surgery allowing accelerated postoperative recovery is accepted in colorectal surgery, but efficacy data are only preliminary for patients undergoing major pancreatic surgery. We aimed to evaluate the impact of a modified fast-track protocol in a high-volume center for patients with pancreatic disorders. Methods: Between February 2005 and January 2010, 145 subjects had resective pancreatic surgery and were enrolled in the program. Essential features of the program were no preanaesthetic medication, upper and lower air-warming device, avoidance of excessive i.v. fluids perioperatively, effective control of pain, early reinstitution of oral feeding, and immediate mobilization and restoration of bowel function following surgery. Outcome measures were postoperative complications such as pancreatic fistula, delayed gastric emptying, biliary leak, intra-abdominal abscess, post-pancreatectomy hemorrhage, acute pancreatitis, wound infection, 30-day mortality, postoperative hospital stay, and readmission rates. Results: On average, patients were discharged on postoperative day 10 (range 6-69), with a 30-day readmission rate of 6.2%. Percentage of patients with at least one complication was 38.6%. Pancreatic anastomotic leakage occurred in seven of 101 pancreatico-jejunostomies, and biliary leak in three of 109 biliary jejunostomies. Postoperative hemorrhage occurred in ten (6.9%) patients and wound infection in nine (6.2%) cases. In-hospital mortality was 2.7%. Fast-track parameters, such as normal food and first stool, correlated significantly with early discharge (<0.05). At multivariate analysis, lack of jaundice, and resumption of normal diet by the 5th postoperative day were independent factors of early discharge. Conclusion: Fast-track programs are feasible, easy, and also applicable for patients undergoing a major surgery such as pancreatic resection. [ABSTRACT FROM AUTHOR]

OBJECTIVES:The −A2518G variation in monocyte chemoattractant protein (MCP)-1 gene promoter has been associated with autoimmune diseases. Our aim was to investigate the gene polymorphism and MCP-1 plasma levels in patients with inflammatory bowel disease (IBD).METHODS:Family-based and case–control association analyses of the –A2518G polymorphism (rs1024611) were performed in 1,936 subjects (770 patients with Crohn's disease (CD), 316 patients with ulcerative colitis (UC), 302 healthy relatives (151 CD trios), and 548 healthy controls (HCs)). Extensive gene sequencing was also undertaken, and a further six single-nucleotide polymorphisms (SNPs) were genotyped in 435 CD patients and 189 HCs. MCP-1 protein plasma levels in 234 CD patients, 117 UC patients, and 108 HCs were assessed by an immunosorbent assay.RESULTS:Five SNPs in strong linkage disequilibrium (D′>0.85) were associated with CD, with the strongest signal found at the –A2518G SNP. The frequency of the G allele was significantly lower in CD patients (22.1%), compared with HCs (29.8%), both at case–control (P=6 × 10−6) and at transmission disequilibrium test analyses (T/U 41/88; P=4 × 10−4). No difference in alleles (26.1%) and genotype frequencies were found in UC patients. MCP-1 plasma levels in CD and UC patients were similar to those in HCs (P=0.38), irrespective of disease activity, or MCP-1 genotypes. However, 30 CD (13%) and 20 UC patients (17%) with extensive colonic involvement had plasma levels significantly higher than HCs (P=0.02).CONCLUSIONS:The –A2518G polymorphism seems to be associated with CD but does not influence MCP-1 plasma levels, which in contrast are increased in UC and CD with extensive colonic involvement. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Radiofrequency thermal ablation (RF) and percutaneous ethanol injection (PEI) have been employed in the treatment of small hepatocellular carcinoma (HCC) as curative treatments. The aim of the study was to review the available evidence comparing RF to PEI for small HCC.METHODS:Search strategy: Cochrane, MEDLINE, CANCERLIT, and ENBASE databases were used. Selection criteria: randomized clinical trials evaluating RF vs. PEI. Data were extracted from each randomized controlled trial (RCT). Primary outcomes were overall survival and local recurrence. Meta-analysis software was used and risk differences (RDs) and their 95% confidence intervals and Q-test for heterogeneity were calculated.RESULTS:Five RCTs were identified including 701 patients. The overall survival was significantly higher in patients treated with RF than in those treated with PEI (RD 0.116, 95% CI 0.173/0.060; heterogeneity not present). Local recurrence rate is significantly higher in patients treated with PEI than in those treated with RF. In the RF group the 1, 2, and 3 years cancer-free survival rates were significantly better than in the PEI-treated patients (respectively: RD 0.098—95% CI 0.006/0.189; heterogeneity P=0.57; RD 0.187, 95% CI 0.082/0.293; heterogeneity P=0.98; RD 0.210, 95% CI 0.095/0.325; heterogeneity P = 0.78). A small number of adverse events were reported in the two treatments.CONCLUSIONS:RF ablation is superior to PEI in the treatment of small HCC with respect to overall survival, 1, 2, and 3 years survival rates, 1, 2, and 3 cancer-free survival rates, and tumor response. RF shows a significantly smaller risk of local recurrence.Am J Gastroenterol 2009; 104:514–524; doi:10.1038/ajg.2008.80; published online 13 January 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVES: Recently, genome-wide association analyses have identified single nucleotide polymorphisms in the IRGM gene (rs1000113 and rs4958847) as strong candidate susceptibility factors for Crohn's disease (CD). The aim of our study was to test whether these variants are associated with inflammatory bowel disease (IBD) in adult- and childhood-onset Italian patients. METHODS: Allele and genotype frequencies of rs1000113 and rs4958847 were determined in 823 CD (265 younger than 19 years at diagnosis), 353 ulcerative colitis (UC) (130 younger than 19 years at diagnosis), and 578 controls. Genotype distributions were examined both within IBD clinical sub-phenotypes and CARD15 genotypes. RESULTS: rs1000113 and rs4958847 were both associated with adult-onset (P=2×10-4 ; P=2.5×10-3, respectively) and childhood-onset (P=4×10-4; P=8×10-3, respectively) CD cohorts. Similarly, the genotype frequencies remained significantly different for both variants (adult rs1000113, P=1×10-4; rs4958847, P=1×10-3; pediatric rs1000113, P=2.3×10-4; rs4958847, P=9.6×10-3). At logistic regression, the rs4958847 polymorphism was associated with fistulizing behavior (P=0.037, OR = 1.54, CI = 1.02-2.31) and perianal fistulas (P=0.045, OR = 1.55, CI = 1.01-2.38). Conversely, no association with UC and sub-phenotypes was shown. CONCLUSIONS: We replicated the previously reported associations between CD and rs1000113 and rs4958847, confirming that IRGM is a susceptibility locus only for CD, either adult- or early-onset in the Italian population; furthermore, we have also shown its influence on specific clinical features (fistulizing disease). [ABSTRACT FROM AUTHOR]

The original version of the article unfortunately contained an error in the first name and the surname of the all authors in the author group. Below is the corrected first name and the surname of the authors. [ABSTRACT FROM AUTHOR]

BACKGROUND: The most effective schedule of proton pump inhibitor (PPI) administration following endoscopic hemostasis of bleeding ulcers remains uncertain. METHODS: Patients with actively bleeding ulcers and those with nonbleeding visible vessel or adherent clot were treated with epinephrine injection and/or thermal coagulation, and randomized to receive intravenous PPIs according to an intensive regimen (80 mg bolus followed by 8 mg/h as continuous infusion for 72 h) or a standard regimen (40 mg bolus daily followed by saline infusion for 72 h). After the infusion, all patients were given 20 mg PPI twice daily orally. The primary end point was the in-hospital rebleeding rate, as ascertained at the repeat endoscopy. RESULTS: Bleeding recurred in 28 of 238 patients (11.8%) receiving the intensive regimen, and in 19 of 236 (8.1%) patients receiving the standard regimen ( P= 0.18). Most rebleeding episodes occurred during the initial 72-h infusion: 18 (7.6%) and 19 events (8.1%) in the intensive and standard groups, respectively ( P= 0.32). Mean units of blood transfused were 1.7 ± 2.1 in the intensive and 1.5 ± 2.1 in the standard regimen group ( P= 0.34). The duration of hospital stay was <5 days for 88 (37.0%) and 111 patients (47.0%) in the intensive and standard groups ( P= 0.03). There were fewer surgical interventions in the standard versus intensive regimen (1 vs 3). Five patients in each treatment group died. CONCLUSIONS: Following endoscopic hemostasis of bleeding ulcers, standard-dose PPIs infusion was as effective as a high-dose regimen in reducing the risk of recurrent bleeding. (ClinicalTrials.gov number, NCT00374101). [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIM: Nearly 25% of patients with ulcerative colitis (UC) requiring steroids therapy become steroid-dependent after 1 yr, and virtually all develop steroid-related adverse events. We planned a controlled study to investigate the efficacy and safety of dexamethasone 21-P (Dex 21-P) encapsulated into erythrocytes (DEE). MATERIALS AND METHODS: Forty patients with mild-to-moderate UC, refractory to mesalamine, were randomly assigned to one of the following three treatments: two DEE infusions 14 days apart (group A, N = 20), oral prednisolone (0.5 mg/kg for 14 days followed by a 6 mg/weekly tapering (group B, N = 10), and sham infusions (group C, N = 10). The clinical, biochemical, and endoscopic parameters were monitored at inclusion and after 8 wk. RESULTS: In group A, a mean dose of 9.9 ± 4.1 mg Dex 21-P was loaded into autologous erythrocytes at each infusion. At 8 wk, 15 patients in group A (75%), 8 in group B (80%), and 1 in group C (10%, P < 0.001 vs A and B) were in clinical and endoscopic remission. When compared with the baseline values, C-reactive protein (CRP) dropped in groups A (1.6 mg/dL vs 0.4 mg/dL, P= 0.006) and B (1.0 vs 0.5, P= 0.02), but not in group C. No steroid-related adverse events were apparent in the patient treated with DEE, compared with 8 out of 10 patients on oral steroids ( P≤ 0.01). CONCLUSION: Low doses of Dex (mean total dose ± 20 mg) loaded into autologous erythrocytes were significantly more effective than sham infusions in terms of symptoms relief, endoscopic, and biochemical improvements in UC patients refractory to mesalamine. In addition, in contrast to oral prednisolone (mean total dose ± 1 g), no steroid-related adverse events were induced. [ABSTRACT FROM AUTHOR]

Because hepatitis C virus genotypes 2 and 3 are both responsive to antiviral treatment, they have been regarded as similar. However, recent evidence has shown there may be differences between these two genotypes with regard to their clinical features and possibly responses to combined interferon and ribavirin therapy. This article reviews the recent literature analyzing these potential differences, particularly reports suggesting a relationship between high baseline viremia levels and lower treatment response in genotype 3. However, as demonstrated in recent studies considering rapid virologic response (RVR) as a criterion for shortening treatment from the standard 24 weeks to 12 or 16 weeks in patients with genotype 2 or 3, the reason for lower response in genotype 3 versus genotype 2 patients may be a lower response rate in patients without an RVR. As a consequence, treatment longer than the currently recommended 24 weeks may be required for patients with genotype 3 but not for those with genotype 2 in the absence of an RVR. Whether this lower sensitivity to treatment in a subgroup of patients with genotype 3 may be attributed to viral heterogeneity or other associated cofactors is not yet known. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To provide health-care providers, patients, and physicians with an exhaustive assessment of prospective studies on rates of complications and fatalities associated with endoscopic retrograde cholangiopancreatography (ERCP). METHODS: We searched MEDLINE (1977–2006) for prospective surveys on adult patients undergoing ERCP. “Grey literature” was sought by looking at cited references to identify further relevant studies. Data on postprocedural pancreatitis, bleeding, infections, perforations, and miscellaneous events as well as their associated fatalities were extracted independently by two reviewers. Sensitivity analysis was performed to test for data consistency between multicenter versus single center studies, and old (1977–1996) versus recent (1997–2005) reports. RESULTS: In 21 selected surveys, involving 16,855 patients, ERCP-attributable complications totaled 1,154 (6.85%, CI 6.46–7.24%), with 55 fatalities (0.33%, CI 0.24–0.42%). Mild-to-moderate events occurred in 872 patients (5.17%, CI 4.83–5.51%), and severe events in 282 (1.67%, CI 1.47–1.87%). Pancreatitis occurred in 585 subjects (3.47%, CI 3.19–3.75%), infections in 242 (1.44%, CI 1.26–1.62%), bleeding in 226 (1.34%, CI 1.16–1.52%), and perforations in 101 (0.60%, CI 0.48–0.72%). Cardiovascular and/or analgesia-related complications amounted to 173 (1.33%, CI 1.13–1.53%), with 9 fatalities (0.07%, CI 0.02–0.12%). As compared with old reports, morbidity rates increased significantly in most recent studies: 6.27% versus 7.51% ( Pc= 0.029). CONCLUSIONS: ERCP remains the endoscopic procedure that carries a high risk for morbidity and mortality. Complications continue to occur at a relatively consistent rate. The majority of events are of mild-to-moderate severity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Gene promoter methylation is an epigenetic event leading to gene silencing. This mechanism is particularly relevant in cancer since it can interfere with the activity of specific “suppressor” genes. AIM: To evaluate promoter methylation of CDH1, p16, APC, MLH1, and COX2 in patients with H. pylori ( Hp) infection before and after eradication. METHODS: Fifty-seven dyspeptic outpatients who had never performed previous endoscopy or Hp testing and treatment underwent clinical interview, endoscopy with three paired gastric biopsy specimens from the antrum, angulus, and corpus, and 13C-urea breath test (UBT). Biopsies were scored for the presence of Hp and intestinal metaplasia (IM). DNA methylation of five tumor-related genes (CDH1, p16, MLH1, APC, and COX2) was evaluated by methylation-specific PCR in each biopsy. Infected patients were given a standard eradicating treatment and, after 1 yr, underwent endoscopy with biopsies and UBT. RESULTS: Hp infection was found in 45 patients. IM was detected in 17 out of 45 (38%) infected patients. Mean number of methylated genes was 0, 1.1 ± 0.9, and 1.6 ± 0.9 among the 12 Hp−/IM−, the 28 Hp+/IM−, and the 17 Hp+/IM+ patients, respectively ( P < 0.0001). Specifically, promoter hypermethylation of CDH1, p16, APC, MLH1, and COX2 was found in 68%, 25%, 7%, 0%, and 14% of Hp+/IM− patients and in 71%, 29%, 35%, 12%, and 12% of Hp+/IM+ patients. No significant difference was found among the three groups of patients as far as age, smoking, alcohol, meat and vegetable consumption, and family history of gastric cancer were considered. Twenty-three out of 45 (51%) infected patients underwent the 1-yr follow-up endoscopy: 17 out of 23 (74%) were successfully eradicated. After Hp eradication, CDH1, p16, and APC methylation significantly decreased while COX2 methylation completely disappeared. Conversely, MLH1 methylation did not change significantly in patients with IM. CONCLUSION: Hp infection is associated with promoter methylation of genes which are relevant in the initiation and progression of gastric carcinogenesis. While CDH1 methylation seems to be an early event in Hp gastritis, MLH1 methylation occurs late along with IM. Hp eradication is able to significantly reduce gene methylation thus delaying or reversing Hp-induced gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

BACKGROUND: In patients with severe attacks of ulcerative colitis (UC), IV steroids represent the first-line treatment, leading to clinical improvement in approximately 50–60% of patients. AIM: The aim of this study was to prospectively compare the efficacy and safety of different modalities of steroid administration, and to evaluate predictors of failure to therapy. MATERIALS In a single-center, double-blind trial, consecutive patients with a severe attack of UC received AND METHODS: 1 mg/kg/day of 6-methyl-prednisolone administered randomly by either a bolus injection (group A) or continuous infusion (group B). RESULTS: Sixty-six patients were enrolled (35 men, mean age 38 ± 15, range 18–75 yr), 15 of them at their first attack of UC; in the remaining cases, the mean duration of disease was 4.5 ± 5 yr. At inclusion, forty patients (60%) had pancolitis and the remainder had left-sided colitis. Overall, thirty-three patients (50%) underwent clinical remission after 7 days of treatment: 16 of 32 in group A and 17 of 34 in group B. Thirty-one patients eventually underwent total colectomy (12 in group A and 9 in group B), which was carried out by the first month in 10 patients (5 in each group). Twenty-eight patients (15 in group A and 13 in group B) experienced steroid-related adverse reactions. All differences between groups were not statistically significant. Previous use of steroids (OR 13.6, CI 2–86) and active smoking (OR 11.6, CI 1.4–107) were independent predictors of nonresponse. CONCLUSIONS: In severe attacks of UC, methyl-prednisolone given as a continuous infusion was no better than bolus administration in terms of efficacy and safety. [ABSTRACT FROM AUTHOR]

AIM: The aim of this study was to investigate the influence of the IBD5 locus on clinical features of inflammatory bowel disease (IBD) patients, and its possible interaction with the CARD15 gene. PATIENTS AND METHODS: A cohort of 1,199 IBD patients (570 with CD and 629 with ulcerative colitis [UC]), and 357 healthy subjects were investigated. Information on clinical features was fully available for 855 IBD patients. Two SNPs in the IBD5 locus (IGR2198a_1 and IGR2096a_1) and the three major variants of CARD15 gene were genotyped in patients and controls. RESULTS: Homozygous carriers of risk alleles were significantly more frequent in CD (22.6% for IGR2198a_1, OR = 1.6, p= 0.015; 21.9% for IGR2096a_1, OR = 1.6, p= 0.012) compared to controls (16.8% and 15.7%, respectively). The homozygote frequency was also increased in UC patients, but not significantly. No significant gene-gene interaction was detected between IBD5 and CARD15. A univariate analysis detected association between IBD5 and steno/fistulizing behavior in CD patients (OR = 1.9; p= 0.004), and presence of more extensive colitis in UC patients (OR = 1.7; p= 0.01). Results from multiple logistic regression, after correction for covariates, showed that the influence of IBD5 on clinical outcome of CD was completely masked by that of CARD15, while the influence on more extensive colitis in UC patients was confirmed. CONCLUSIONS: Our study shows that presence of the IBD5 risk alleles, particularly in the homozygous state, is associated with IBD and especially with CD, without a significant epistasis with CARD15. The contribution of CARD15 risk alleles to CD clinical features is prominent on that of IBD5. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIM: Autologous erythrocytes can be used as carriers of drugs, owing to the ability of their membrane to be opened and resealed under appropriate conditions. In this pilot uncontrolled study, we investigated efficacy and safety of dexamethasone-encapsulated erythrocytes in steroid-dependent IBD patients.MATERIALS AND METHODS: Ten patients (5 with ulcerative colitis and 5 with Crohn's disease) with steroid dependency ranging from 8 to 60 months were studied. Seven of them were in clinical remission, and the remaining three had mild activity. Eight patients were also under azathioprine or 6-MP for at least 6 months (range 6–24 months), while another two patients were intolerant to both drugs. Fifty milliliters of blood were drawn from each subject; dexamethasone 21-Phosphate (Dex 21-P) was encapsulated into erythrocytes by means of specially designed equipment, and drug-loaded erythrocytes were infused into original donors. The procedure was repeated after 4 and 8 wk, and patients were instructed to withdraw corticosteroids.RESULTS: A mean dose of 5.5± 2.4 mg Dex 21-P was loaded in the erythrocytes at each treatment. Following re-infusion of loaded erythrocytes, plasma Dexamethasone (Dex) concentrations were detected after as long as 28 days. Steroids were completely withdrawn by the second month. After the third infusion, all patients, including the three with mild active disease, were in clinical remission. ESR levels dropped from 47± 27 at baseline to 27± 16 mm/h (p<0.02), and CRP levels from 1.6± 1.3 to 0.6± 0.5 mg/dl (p<0.02). After a mean follow-up of 12± 3 months, six patients relapsed, and the remaining four patients remained in remission. Pre-existing steroid-related adverse effects disappeared during the follow-up.CONCLUSIONS: Loading of Dex 21-P in autologous erythrocytes is feasible and safe. The very low dose of Dex released in blood stream was able to maintain patients in clinical remission and allowed steroids withdrawal.(Am J Gastroenterol 2005;100:1–6) [ABSTRACT FROM AUTHOR]

(Am J Gastroenterol 2005;100:868–873) [ABSTRACT FROM AUTHOR]

OBJECTIVE: To perform metaanalyses of studies on outcome of bleeding ulcers of different proton-pump inhibitors (PPIs) regimens, after stratification of patients by endoscopic stigmata, and analysis of studies with and without endotherapy.METHODS: A total of 35 randomized trials comparing PPIs to placebo and/or H2-receptor antagonists (H2RAs) in 4,843 patients with high-risk endoscopic stigmata were retrieved. Outcomes were rebleeding, surgery, and mortality.RESULTS: Monotherapy with oral or bolus PPIs was superior to placebo and H2RAs in reducing rebleeding in both bleeders and nonbleeders at index endoscopy; the need for surgery was reduced only when compared to H2RAs. In nonbleeders, PPI monotherapy was as effective as a combination of endotherapy with H2RAs. A combination of endotherapy with PPIs was superior to monotherapy in reducing bleeding and surgery, and superior to endotherapy alone in minimizing rebleeding, but not surgery; the benefit was lost when confronted to endotherapy plus H2RAs, whether PPIs were given as infusion or bolus. By pooling data from studies comparing high doses of PPIs as continuous infusionversusregular doses as intermittent bolus, rebleeding, surgery, and mortality were not significantly different.CONCLUSIONS: Combination of endotherapy with either PPIs or H2RAs is indicated for nonbleeding ulcers at endoscopy with the intent to reduce rebleeding and surgery. Its value may extend to bleeding lesions, but current data are scanty. The benefit appears to be independent from route and doses of PPIs, as oral, bolus, or infusional methods are all effective.(Am J Gastroenterol 2005;100:207–219) [ABSTRACT FROM AUTHOR]

BACKGROUND: Three major variants of the CARD15 gene confer susceptibility to Crohn's disease (CD). Whether or not these variants correlate with specific clinical features of the disease is under evaluation.AIM: We investigated the possible association of CARD15 variants with specific clinical characteristics, including the occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA), in a large cohort of inflammatory bowel disease (IBD) patients and their unaffected relatives.METHODS: Three hundred and sixteen CD patients (156 with positive family history), 408 ulcerative colitis (UC) patients (206 with positive family history), 588 unaffected relatives, and 205 unrelated healthy controls (HC) were studied. Single nucleotide polymorphisms (SNPs) R702W, G908R, and L1007finsC of the CARD15 gene were investigated and correlated to age at diagnosis, gender, family history, localization, extraintestinal manifestations, previous resective surgery, stenosing/fistulizing pattern, ANCA, and ASCA.RESULTS: Compared to HC, the frequencies of all three variants in CD were significantly increased: 8.7%versus4.1% for R702W (p<0.006), 7.3%versus2.7% for G908R (p<0.002), 9.3%versus0.7% for L1007finsC (p<0.00001). At least one risk allele was found in 38.2% (p<0.0001, compared to HC), 13.7% (NS), and 15.1% of CD, UC, and HC, respectively. The L1007finsC risk allele was also significantly increased in unaffected relatives of familial (9.5%;p<0.00001), and sporadic CD (9%;p<0.00001), compared to HC (0.7%). Sixteen healthy relatives, carriers of two risk alleles, were asymptomatic after 5–8 yr of follow-up. CD carriers of at least one variant were younger (p= 0.03), more likely to have ileal localization (p= 0.0001), stenosing pattern (p= 0.01), previous resective surgery (p= 0.0001), and presence of ASCA (p= 0.0001). No difference in SNPs frequency between familial and sporadic cases of CD was found.CONCLUSION: In our population, both familial and sporadic CD patients carrying at least one major variant of CARD15 had an aggressive clinical course.(Am J Gastroenterol 2005;100:84–92) [ABSTRACT FROM AUTHOR]

Susceptibility to alcoholic chronic pancreatitis (ACP) could be genetically determined. Mutations in cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR), and serine protease inhibitor, Kazal type 1 (SPINK1) genes have been variably associated with both the hereditary and the idiopathic form of chronic pancreatitis (CP). Our aim was to analyze the three genes in ACP patients. Mutational screening was performed in 45 unrelated ACP patients and 34 patients with alcoholic liver disease (ALD). No mutation of PRSS1 was found in ACP and ALD patients. Three mutations of CFTR were detected in four ACP patients with a prevalence (8.9%) not significantly different from that observed (3.0%) in ALD patients and from that expected (3.2%) in our geographical area. Neither compound heterozygotes for CFTR nor trans-heterozygotes for CFTR/SPINK1 were found. One ACP patient (2.2%) was found to carry the most common mutation (N34S) of SPINK1 compared to none of the ALD patients (P=NS). In five other patients (two with ACP and three with ALD) other rare variants, including P55S, were found. In contrast with the hereditary and the idiopathic forms of CP, in which mutations of PRSS1, CFTR, and SPINK1 genes may occur, ACP is still a ‘gene(s)-orphan’ disease. The supposed genetic susceptibility to ACP relies on other yet unknown gene(s) which could affect the alcohol metabolism or modulate the pancreatic inflammatory response to alcohol abuse.European Journal of Human Genetics (2003) 11, 687-692. doi:10.1038/sj.ejhg.5201035 [ABSTRACT FROM AUTHOR]

OBJECTIVES:The aim of our study was to evaluate the nature of focal liver lesions detected during the ultrasound follow-up of a population (prevalently anti-hepatitis C virus [anti-HCV] positive) with chronic liver disease.METHODS:The study population consisted of 1827 consecutive newly diagnosed chronic liver disease cases without liver nodules at enrollment. Patients were screened at 4-month intervals by ultrasound and serum α-fetoprotein assessment. All lesions detected on imaging studies (except those accompanied by diagnostic α-fetoprotein levels) were subjected to biopsy (histology and cytology).RESULTS:During the 7-yr follow-up period (mean = 43.1 months), one or more solid focal lesions were found in 287 patients. α-Fetoprotein was diagnostic for hepatocellular carcinoma in 51 patients. Ultrasound-guided fine-needle biopsy was performed in the remaining 236 patients, yielding a diagnosis in 214: 198 hepatocellular carcinomas, 11 dysplastic nodules, and five B-cell non-Hodgkin’s lymphomas (all confined to the liver and all in patients with chronic HCV infection). Twenty-two patients with nondiagnostic biopsies received diagnoses of hepatocellular carcinoma (20) or dysplastic nodules (two) based on arteriography or surgical biopsy.CONCLUSIONS:Focal lesions arising in patients with HCV-related chronic liver disease can be other than hepatocellular carcinoma, and ultrasound-guided fine-needle biopsy plays an important role in their diagnosis. The prevalence of non-Hodgkin’s lymphoma in this selected population was 0.31%. The fact that all five lymphoma patients had cirrhosis related to hepatitis C strengthens the hypothesis of an etiological correlation between the latter infection and B-cell lymphoproliferative disorders. [Copyright &y& Elsevier]

OBJECTIVE: Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn's disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families. METHODS: In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year (<1 yr or ≥1 yr). Statistical analysis was performed with x², Fisher's, Mann-Whitney U, and binomial probability tests, when appropriate. RESULTS: A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization (p < 0,4) in CD families and extensive colitis (p < 0,05) in UC families was demonstrated. A generation difference of 15-20 yr in mean ages at onset of symptoms and at diagnosis was recorded. No features of more aggressive disease in subsequent generations and no differences in gender of transmitting parents and relatives were found, CONCLUSIONS: Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15-20 yr earlier than in previous generations without features of increased severity. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Recent studies in familial Crohn's disease (CD) have suggested that anti-Saccharomyces cerevisiae mannan antibodies (ASCAs) may represent a new specific marker of genetic susceptibility. In this study we aimed to assess the importance of ASCAs by comparing their presence in a large number of patients with sporadic and familial occurrence of CD or ulcerative colitis (UC) and their unaffected relatives. METHODS: Serum samples from 96 patients with sporadic CD, 97 patients with sporadic UC, and 30 unrelated healthy controls were tested tor ASCAs by a standard ELISA method. Moreover, 73 families with two or more members affected by CD and/or UC were recruited. From these families 58 CD patients, S4 UC patients, and 216 unaffected first degree relatives were investigated. RESULTS: ASCAs were detected in 34 of 96 patients with sporadic CD (35%, p < 0.01 vs controls), 11 of 97 patients with sporadic UC (12%), and two of 50 controls (4%). ASCAs were significantly (p < 0.04) more frequent in patients with familial CD (55%) and familial UC (25%) than in sporadic cases. Moreover. ASCAs were found in 25% of unaffected relatives, and this rate did not significantly differ in CD, UC, and mixed families (28%, 26%, and 22%, respectively). CONCLUSIONS: In this study we confirm that ASCAs occur particularly frequently in CD patients, especially with the presence of a positive family history. However, they are also significantly increased in UC patients with a family history and in a considerable number of unaffected relatives of inflammatory bowel disease families, irrespective of the characteristics of their families (UC, CD, mixed, ASCA positive, and ASCA negative). The presence of ASCAs in unaffected relatives might point toward a genetic predisposition to either CD or UC. [ABSTRACT FROM AUTHOR]

OBJECTIVES: A novel rifabutin-based therapy is able to cure Helicobacter pylori infection in most patients who have failed eradication after standard proton pump inhibitor (PPI)-based triple therapy. We compared this regimen with the quadruple therapy. METHODS: A total of 135 patients were randomized into three groups who were treated for 10 days with pantoprazole 40 mg b.i.d., amoxycillin 1 g b.i.d., and rifabutin 150 mg o.d. (RAP150 group), or 300 mg o.d. (RAP300 group), and pantoprazole 40 mg b.i.d., metronidazole 250 mg t.i.d., bismuth citrate 240 mg b.i.d., and tetracycline 500 mg q.i.d. (QT group). Before therapy, patients underwent endoscopy with biopsies for histology, culture and antibiotic susceptibility tests. H. pylori eradication was assessed by the 13C-urea breath test. RESULTS: On intention-to-treat analysis, eradication rates (with 95% confidence intervals [CI]) were 66.6% (53-80%) in the RAP150 and QT groups, respectively, and 86.6% (76-96%) in RAP300 group (p < 0.025). Most patients harboring metronidazole- and clarithromycin-resistant strains were eradicated at an equal rate by each of the three regimens. Side effects were observed in 9% and 11% of rifabutin-treated patients, and in 47% of those on quadruple therapy (p < 0.0001). CONCLUSIONS: In patients who failed standard eradicating treatments, a 10-day course of rifabutin with pantoprazole and amoxycillin is more effective and well tolerated than the quadruple therapy. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a chronic relapsing disorder affecting the gastro-intestinal tract and is subdivided into two main subtypes: Crohn's disease (CD) and ulcerative colitis (UC). Although the aetiology of IBD is unknown, a strong genetic susceptibility is suggested and different candidate regions have been identified for both CD and UC. The IBD1 region on chromosome 16 has been confirmed to be important for susceptibility to CD, whereas conflicting evidence has been obtained for UC. We performed a combined linkage and segregation analysis in the identified IBD1 region on a sample of 82 extended families with IBD using a parametric method implemented in the computer program COMDS. This approach allows simultaneous evaluation of linkage while estimating the mode of inheritance and to include severity of the trait to characterise the CD and UC phenotypes. Our results are consistent with the presence of a major gene in the IBD1 region close to D16S408 involved in both UC and CD. Furthermore, our data support evidence that a single mutation in the gene leads more frequently to UC, whereas inheritance of two mutant alleles results in the more severe CD. In our study the IBD1 locus was found to have a major role in IBD predisposition in the Italian population. [ABSTRACT FROM AUTHOR]

A Correction to this paper has been published: https://doi.org/10.1007/s00384-021-03905-x [ABSTRACT FROM AUTHOR]

OBJECTIVE: Our aim was to test the hypothesis that anticardiolipin antibodies (aCL) may cause an antiphospholipid syndrome and thrombotic events in patients with liver disease. METHODS: aCL were measured in 116 healthy controls and 372 patients with liver disease of different stage and etiology: 136 cases secondary to hepatitis C virus (HCV) infection, 139 due to hepatitis B virus (HBV) infection, 69 with alcoholic liver damage, and 28 cryptogenic in origin. Prior thrombotic events were recorded. The results were related to age, gender, stage, severity, and etiology of the liver disease, as well as to the occurrence of organ- and nonorgan-specific autoantibodies. RESULTS: aCL were positive in 4.4% of controls and in 18.8% of patients (p < 0.0002). Patients with aCL were more frequently men with an advanced cirrhosis and simultaneous occurrence of anti-smooth-muscle antibodies (ASMA) in serum (p < 0.0006); their liver damage was often secondary to HBV (37.3%) or alcohol abuse (18.5%). At conditional logistic regression analysis, only the presence of ASMA (odds ratio [OR] = 3.02, 95% confidence interval [CI] 1.7-5.5, p = 0.0003), HBV (OR = 3.4, 95% CI 1.6-7.2, p = 0.0013), or alcoholic liver disease (OR = 5.3, 95% CI 2.3-12.2, p = 0.0001) were independently associated with aCL. Thrombosis was encountered in 24 patients (6.4%). At conditional logistic regression analysis, thrombosis was significantly associated with advanced age (OR = 1.07, 95% CI 1.0-1.1, p = 0.0094), development of hepatocellular carcinoma (OR = 17.8, 95% CI 1.6-196.0,p = 0.01), HBV etiology (OR = 6.3, 95% CI, 1.6-24.6,p = 0.0076), or cryptogenic liver disease (OR = 54.8, 95% CI 5-599.9, p = 0.001). Of the five patients with newly documented portal thrombosis during the follow-up, only one tested positive for aCL. CONCLUSIONS: In patients with nonautoimmune liver disease, aCL production is an epiphenomenon of the liver damage and is not associated with thrombotic complications. These data do not support the hypothesis that HCV is a cause of the antiphospholipid syndrome. [ABSTRACT FROM AUTHOR]

Objective: Uncontrolled, retrospective clinical studies have recently claimed that HCV infection could trigger the onset of diabetes mellitus (DM). We sought to verify the association between DM and liver diseases of different etiology, stage, and severity in a prospective study including gender- and age-matched controls. Methods: Two hundred forty-seven patients with liver cirrhosis (184 men, 116 with an associated hepatocellular carcinoma, 34% in Child-Pugh's class A) were evaluated (group 1). One hundred fifty-seven (63.5) of them were HCV positive, 38 (15.5%) HBV positive, 49 (19.8%) alcohol abusers, and three (1.2%) cryptogenic. Two control groups were also included. The first control group consisted of 138 patients with chronic hepatitis due to HCV infection (73.9%), HBV infection (15.9%), or alcohol abuse (10.2%) (group 2). The second control group included 494 patients with an acute osteoarticular trauma, age- and gender-matched with patients in group 1 (group 3). Results: Diabetes mellitus was present in 32.3%, 3.6%, and 9.7% of patients in groups 1, 2, and 3, respectively. When compared with controls (group 3), DM was significantly less frequent in group 2 (p < 0.004) and significantly more frequent in group 1 (p < 0.0001). The prevalence of DM was not different among patients with HCV, HBV infection, or alcohol abuse. In group 3, the prevalence of DM appeared to increase steadily with age. On the contrary, in patients with liver cirrhosis (group 1) DM was detected in about 20-30% of cases in all decades of age. In group 2, diabetics were found only in the 7th and 8th decades of life. At multivariate analysis cirrhosis and age were the only two factors independently associated with DM; odds ratios were 12.5 (95% confidence interval [C.I.], 6.74-20.4) for cirrhosis, and 1.47 for age (95% C.I. 0.39-2.55). Conclusions: Our findings disprove HCV infection as a trigger factor for DM, which should not be listed among the various... [ABSTRACT FROM AUTHOR]

Objective: Functional dyspepsia (FD) is a syndrome in which several causes are probably involved. Our aim was to investigate the association between specific dyspeptic symptoms and Helicobacter pylori infection or delayed gastric emptying. Methods: Nine hundred thirty-five consecutive outpatients with unexplained dyspepsia were studied. After appropriate investigation, 304 patients were diagnosed as affected by chronic FD and were tested for H. pylori infection and gastric emptying of solids by means of 13C-urea and 13C-octanoic acid breath tests. Four dyspeptic symptoms (epigastric pain or burning, postprandial fullness, nausea, and vomiting) were scored as absent, mild, moderate, or severe (0-3) according to their influence on the patients' activities. Symptoms of irritable bowel syndrome and gastroesophageal reflux disease were also assessed. On the basis of symptom scores, three groups were identified: "prevalent pain" (10.5%), "prevalent discomfort" (32.6%), and "unclassifiable" dyspepsia (56.9%). Results: Of the 304 patients with FD, 208 (68.4%) were H. pylori-positive on urea breath test. Gastric emptying was delayed in 99 subjects (32.6%). Patients with "prevalent pain" were infected significantly more often (81.2% vs 59.6%; p = 0.026) and less frequently had delayed gastric emptying) (6.2% vs 40.4%;p = 0.0001) than those with "prevalent discomfort." H. pylori infection was independently associated with age ≥40 yr and epigastric pain or burning ≥2 (odds ratio [OR] and 95% confidence interval [CI] 4.09 [2.39-7.00] and 1.70 [1.04-2.77], respectively). Delayed gastric emptying was independently associated with a cumulative score ≥6 for postprandial fullness, nausea, and vomiting (OR [95% CI]: 3.13 [1.06-9.18]). H. pylori status had no influence on gastric emptying. Logistic regression analysis showed that delayed gastric emptying, female sex, and concomitant symptoms of... [ABSTRACT FROM AUTHOR]

A 37-year-old man, previously submitted to colectomy for ulcerative pancolitis unresponsive to medical therapy, presented with nausea, vomiting, epigastric pain, and bloody diarrhea. An upper gastrointestinal endoscopy revealed mucosal friability, petechiae, and erosions throughout the duodenum, whereas prestomal ileum showed large ulcers and pseudopolyps. Histologically, a dense inflammation chiefly composed of lymphocytes and plasma cells with few neutrophils was detected. No bacteria, protozoa, and fungi could be detected. Despite intensive care, intra-1194 venous antibiotics and steroids, the patient died of diffuse intravascular coagulation and multiorgan failure. At post-mortem examination severe ulcerative lesions were observed scattered throughout the duodenum up to the distal ileum. The dramatic clinical presentation with fatal outcome, the widespread ulcers throughout the intestine, and the histological picture are peculiar features in our patient which can not be ascribed to any type of the ulcerative jejunoenteritis so far reported. Patients with pancolitis and diffuse ileal involvement do not necessarily have Crohn's disease but rather may have ulcerative colitis. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that inherited factors influence susceptibility to inflammatory bowel disease (IBD), and some candidate loci have been described. In order to verify whether the same loci are responsible for predisposition to IBD in our population, we carried out a linkage study in a series of 58 Italian families with Crohn's disease (CD) and ulcerative colitis (UC). HLA-DQ alleles, motilin gene, and 34 microsatellites flanking the previously described loci on chromosomes 3, 6, 7, 12 and 16 were analysed by non-parametric linkage analysis in 16 and 23 families with CD and UC, respectively, and in 19 families where CD and UC coexisted. Non parametric analysis using GENEHUNTER yielded maximum NPL scores for marker D16S408 in all IBD families combined (2.71, P = 0.003), for marker D16S419 in CD (1.97, P = 0.026) and for marker D16S514 in UC families (2.44, P = 0.007). These markers map in the previously described IBD1 region. No significant linkage was found for markers of chromosomes 3, 6, 7 and 12. The present study performed in a Southern European population provides additional support for the conclusion that the IBD1 locus has a clear role in the genetic susceptibility to IBD. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the usefulness of routine ultrasound assessment of puncture site before performing percutaneous biopsy in diffuse liver disease. Seven hundred fifty-three consecutive patients were studied retrospectively. Methods: Serial scanning of the last intercostal spaces allowed us to establish the most suitable access to the thicker liver parenchyma (assessing the most favorable angulation of the needle too), avoiding the puncture of adjacent organs; no more than 1 min was necessary for such a determination. Results: In 99.4% of patients, a definitive or indicative pathological diagnosis of chronic liver disease was obtained. Only one hemorrhagic complication (0.13%) occurred, requiring no surgical treatment or blood transfusion. Three cases of vasovagal reaction occurred (0.40%): two of these recovered spontaneously, while the other one needed i. v. administration of atropine. Mortality was 0 in our series. Conclusions: Routine ultrasound of the puncture site is a quick method of assessment, allowing one to increase the diagnostic yield of percutaneous liver biopsy and to maintain low complication rates for such a procedure. [ABSTRACT FROM AUTHOR]

The levels of serum immunoreactive trypsinogen and P-isoamylase in response to Bombesin intravenous infusion were evaluated in 25 controls, 18 patients with documented chronic pancreatitis, and nine subjects with nonpancreatic gastroenterological diseases. Mean immunoreactive trypsinogen peak values were significantly higher in controls and gastroenterological diseases than in chronic pancreatitis, but there was marked overlap in individual values between the three groups. As for P-isoamylase, a statistical difference was detected only between mean peak concentrations of control versus chronic pancreatitis. Integrated responses for both enzymes did not result in a better discrimination between controls, chronic pancreatitis, and gastroenterological diseases, 1 his study confirms that evocative tests are of limited value in the diagnosis of pancreatic disease. [ABSTRACT FROM AUTHOR]

Levels of a new carbohydrate antigen CA 19-9, which is a monosialo-ganglioside identified by a monoclonal antibody raised against colorectal carcinoma cells, were compared to carcinoembryonic antigen and tissue polypeptide antigen assays in 250 sera from patients with different pancreatic diseases including acute pancreatitis, chronic pancreatitis, and pancreatic cancer. All three tumoral markers were elevated at the onset of an acute pancreatic attack in a few patients. All but five patients with chronic pancreatitis displayed normal levels with each of the three markers; in two of these five cases an extraintestinal cancer was later discovered. CA 19-9 displayed higher sensitivity and predictive value of a negative result than the other two markers. The best operational characteristic of CA 19-9 was its high predictive value for a positive test which suggests a "ruling in" usage of it for pancreatic cancer diagnosis. CA 19-9 assay was of extreme value in disclosing both localized and metastatic pancreatic cancer while the other two markers were more often positive in the latter case. Of 71 cancer patients with positive markers, only four would have escaped a right diagnosis by assaying CA 19-9 alone. [ABSTRACT FROM AUTHOR]

Serum immunoreactive cationic trypsinogen (ICT) response to bolus injection of secretin (1 Clinical Units/ kg of body weight) has been evaluated in 123 normal controls and related to sex, age, smoking habit, and alcohol and coffee consumption. A 100% increase of serum immunoreactive cationic trypsinogen levels after secretin has been considered as a positive response (R+). When the population was considered as a whole, 55% of subjects proved to be R+ and the remaining were R-. In the R+ group the serum immunoreactive cationic trypsinogen response was appreciated as early as 5 min after secretin and even after 2 min in the few cases in which it was evaluated. It is suggested that this direct leakage of the proenzyme from the pancreas may be due to an increased sensitivity of the pancreas to secretin. Coffee consumption and age of subjects did not affect the test. Male sex, smoking habit, and alcohol intake were associated with a significantly higher percentage of R+. Therefore, we suggest that alcohol and smoking might result in the development of biochemical abnormalities in pancreatic function before the appearance of clinical evidence of pancreatic disease. [ABSTRACT FROM AUTHOR]

The authors present a case of exocrine pancreatic insufficiency in a 37 yr old woman treated for pulmonary tuberculosis. The exocrine pancreatic failure is suggested to be secondary to previous pancreatic tuberculosis since no other cause of pancreatic disease was found and the diarrhea with steatorrhea started 6 mth after the lung disease. Steatorrhea was promptly reverted after institution of oral therapy with pancreatic supplements and the patient gained 7 kg of body weight during the successive follow-up of 4 yr. [ABSTRACT FROM AUTHOR]

Droplet digital PCR was used to validate miR-1290 as circulating biomarker for pancreatic cancer (PC). The diagnostic performance of miR-1290 was evaluate in 167 PC patients and 267 healthy subjects at clinical risk of developing the disease (HS). MiR-1290 plasma levels were compared to CA 19-9 determinations, and the combination of the two biomarkers was also taken into account. Plasma levels of miR-1290 were higher in PC patients compared to HS (p = 2.55 × 10−16). A similar trend was observed for CA 19-9 determinations (p = 1.03 × 10−47). ROC curve analysis revealed that miR-1290 in combination with CA 19-9 was effective for discriminating between PC patients and HS (AUC = 0.956, 95% CI = 0.933-0.979) than the two biomarkers tested alone (miR-1290: AUC = 0.734, 0.678-0.789; CA 19-9: AUC = 0.914, 0.877-0.951). The discriminating ability was higher when only PC patients with low or slightly increased CA 19-9 levels were compared with HS. MiR-1290 concentrations were not able to differentiate between PC patients with single or multiple risk factors for developing PC. Our data suggest that the absolute quantification of circulating miR-1290 levels does not allow to select patients at clinical risk of PC for entry into a surveillance program, and underline the methodological challenges still existing in utilizing circulating miRNAs as new promising biomarkers for PC. [ABSTRACT FROM AUTHOR]