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Objectives: This study aimed to evaluate trends in hospitalizations and outcomes of acute pancreatitis (AP) according to first admitting hospital unit and hospital volumes., Methods: Hospital discharge records of patients with AP admitted in the Veneto Region (Northeast Italy) during the period 2001-2015 were examined., Results: A total of 23,389 patients (54% males; mean age, 62.2 years; standard deviation, 19.3 years) were admitted for AP. Both hospitalization (32.4 to 29.5/100,000 inhabitants per year; P < 0.05) and in-hospital mortality (1.41 to 0.79/100,000 inhabitants per year; P < 0.05) decreased over the study period. Case fatality rate was altogether 3.2%. The percentages of patients admitted in surgery, nongastroenterology medical units, gastroenterology, and intensive care were 52%, 30%, 16%, and 2%, respectively. Fewer fatalities were observed in gastroenterology units (1.7%) compared with nongastroenterology medical units (4.3%; odds ratio, 0.37; 95% confidence interval, 0.28-0.49) and surgical units (2.7%; odds ratio, 0.61; 95% confidence interval, 0.47-0.80). Fatalities decreased progressively with increasing hospital volumes from 3.7% to 2.9% (P < 0.05)., Conclusion: In the Veneto Region, both hospitalizations and in-hospital mortality for AP significantly decreased over the last 15 years. Case fatality rate was lowest for patients admitted in gastroenterology units.

Gastrin has been identified as the principal effector of gastric secretion, but several studies have demonstrated its role as a biomarker of cancer risk and as a growth factor for colorectal, stomach, liver, and pancreatic cancer. Hypergastrinemia characterizes autoimmune gastritis, with body and fundic gland atrophy and increased risk for both gastric adenocarcinoma and neuroendocrine tumors. Gastric type I carcinoids develop in the context of autoimmune gastritis because of the stimulus exerted by gastrin on enterochromaffin-like cells and remain gastrin-sensitive for long durations because the removal of hypergastrinemia leads to tumor regression. The treatment of gastric carcinoid is still open to debate, but when the disease frequently relapses, or is multicentric or infiltrating, surgery is advocated or, in the alternative, a costly and long-lasting treatment with long-acting somatostatin analogues is prescribed. A technology allowing the preparation of an immunogen eliciting an immune system response with generation of antibodies against G17 has been developed. This vaccine has been tested in patients with colorectal, pancreatic or advanced gastric cancer. The vaccine has also been used in the treatment of gastric type I carcinoids, and the administration of G17DT in patients harboring these lesions leads to carcinoid regression. Antigastrin vaccination in the treatment of gastrointestinal cancer obviously needs validation, but this immunotherapy may well represent a simple, inexpensive, and active 'adjuvant' treatment.

Objective: To establish the incidence and risk factors for progression to high-grade intraepithelial neoplasia (HG-IEN) or Barrett's esophageal adenocarcinoma (BAc) in a prospective cohort of patients with esophageal intestinal metaplasia [(BE)]., Background: BE is associated with an increased risk of BAc unless cases are detected early by surveillance. No consistent data are available on the prevalence of BE-related cancer, the ideal surveillance schedule, or the risk factors for cancer., Methods: In 2003, a regional registry of BE patients was created in north-east Italy, establishing the related diagnostic criteria (endoscopic landmarks, biopsy protocol, histological classification) and timing of follow-up (tailored to histology) and recording patient outcomes. Thirteen centers were involved and audited yearly. The probability of progression to HG-IEN/BAc was calculated using the Kaplan-Meier method; the Cox regression model was used to calculate the risk of progression., Results: HG-IEN (10 cases) and EAc (7 cases) detected at the index endoscopy or in the first year of follow-up were considered to be cases of preexisting disease and excluded; 841 patients with at least 2 endoscopies {median, 3 [interquartile range (IQR): 2-4); median follow-up = 44.6 [IQR: 24.7-60.5] months; total 3083 patient-years} formed the study group [male/female = 646/195; median age, 60 (IQR: 51-68) years]. Twenty-two patients progressed to HG-IEN or BAc (incidence: 0.72 per 100 patient-years) after a median of 40.2 (26.9-50.4) months. At multivariate analysis, endoscopic abnormalities, that is, ulceration or nodularity (P = 0.0002; relative risk [RR] = 7.6; 95% confidence interval, 2.63-21.9), LG-IEN (P = 0.02, RR = 3.7; 95% confidence interval, 1.22-11.43), and BE length (P = 0.01; RR = 1.16; 95% confidence interval, 1.03-1.30) were associated with BE progression. Among the LG-IEN patients, the incidence of HG-IEN/EAc was 3.17 patient-years, that is, 6 times higher than in BE patients without LG-IEN., Conclusions: These results suggest that in the absence of intraepithelial neoplastic changes, BE carries a low risk of progression to HG-IEN/BAc, and strict surveillance (or ablative therapy) is advisable in cases with endoscopic abnormalities, LG-IEN or long BE segments.

Gastric cancer (GC) is still a leading cause of cancer-related death worldwide, and environmental, genetic, and epigenetic DNA changes are involved in the process of gastric carcinogenesis. The objective of this study was to establish the extent of DNA methylation at various CpG islands in GC and in precancerous changes [gastric noninvasive neoplasia (NIN)]. Eighty-one gastric samples were analyzed using methylation-specific PCR at several CpG islands. Thirty-eight samples were obtained at surgery [19 neoplastic (GC) and 19 nonneoplastic cancer-surrounding tissues (sGC)] and 43 at endoscopy (biopsies in 23 NIN patients and 20 controls). Hypermethylation of TPEF (a growth inhibitor), PTGER3 (a prostaglandin receptor isoform), and MINT31 (a promoter locus regulating calcium channels that is involved in p53 mutation) discriminated NIN and GC from normal mucosa, suggesting an early role as initiating events, whereas hypermethylation at ARGHAP20 developed with the progression from NIN to GC. MINT31 hypermethylation predicted persistence or worsening of NIN and cancer development. In conclusion, these data support a progressive accumulation of aberrant methylations in NIN and GC at various CpG islands with distinct time courses. With hypermethylation, the genes involved in regulating the balance between apoptosis and cell proliferation may become silenced and trigger gastric tumorigenesis. Hypermethylation of MINT31 predicted NIN persistence, as well as progression to higher grade or to GC, and might be used as a marker of GC risk.

With respect to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), primary, secondary, and tertiary prevention measures have been or should be adopted. In primary prevention, behavioral patterns represent an important risk factor for HBV infection and should be controlled, discouraging those favoring infection. Interferon treatment shows a modest effect in reducing HCC risk in treated patients, but the data obtained cannot be converted in clinical practice. Nucleoside analogs significantly reduce, but do not abolish, HCC risk in patients with cirrhosis, and should therefore be used in patients with cirrhosis and also to diminish the risk of the other potential complications. With respect to secondary prevention, surveillance with semiannual ultrasound examination is indicated in patients with HBV-related cirrhosis as well as in other subgroups of patients, depending on racial and geographical pattern. Finally, the role of interferon in tertiary prevention of HCC relapse after radical treatment is still under debate; some evidence in favor of the treatment is present, but side effects due to toxicity are frequent and severe enough to limit patients' compliance substantially. As there is definitely no agreement on the efficacy and cost-effectiveness of antiviral treatment in HCC prevention, there is still a need for well-constructed, large size, and randomized prospective trials to confirm what is still required based on expert opinion rather than on sound scientific evidence.

Gastrointestinal stromal tumors (GISTs), tumors characterized by c-KIT mutations, are the most frequent mesenchymal tumors of the digestive tract. The stomach is the most commonly involved site. Localization, size and mitotic rate are reliable predictors of survival and the two milestones of GISTs treatment are surgery and imatinib. This article is aimed to report the data of an audit, carried out on the morphological and clinical aspects of the disease and to review the present knowledge on GISTs. A total of 172 patients with GISTs (M : F=1 : 1; mean age 65 years) were recruited. The stomach was the most frequently involved site. In 50% of the cases the tumor was smaller than 5 cm, whereas major symptoms were observed in 43% of the cases. Predictors of progressive disease were present only in a small percentage of cases but the disease was in the metastatic phase in over 25% of the cases at diagnosis. Familial aggregation was rare but a consistent share of the patients (21%) had other synchronous or metachronous cancers. The most frequent mutations were in-frame deletions and point mutations of c-KIT exon 11. This report confirms in part the available data on GIST in a consecutive series of patients recruited in Italy and shows that only large collaborative multicenter studies provide data sound enough to enable making reasonable clinical and therapeutic choices, and suggests that, as a measure of secondary prevention, a diagnostic definition should be obtained in all submucosal lesions of the GI tract and that GIST patients should be screened for second tumors.

Chemoprevention means the use of agents to prevent, delay, or reverse carcinogenesis. This review was designed to critically discuss the most promising agents in colorectal cancer (CRC) chemoprevention. Aspirin is the best studied chemopreventive agent for CRC. Optimal chemoprevention requires long-term use and high dose of aspirin that may increase the risk of gastrointestinal bleeding. Nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors may also be candidates for chemoprevention. The regular use of nonsteroidal anti-inflammatory drugs, however, causes adverse effects including gastrointestinal bleeding, and cyclooxygenase-2 inhibitors may increase the risk of cardiovascular events. In patients with ulcerative colitis 5-aminosalicylates reduce the risk of CRC and dysplasia. Ursodeoxycholic acid can reduce the risk of dysplasia or CRC in patients with primary sclerosing cholangitis and ulcerative colitis. Current data are insufficient to support the use of hormone replacement therapy to reduce the risk of CRC. Statins may have chemopreventive effects, but further investigation of their overall benefits in preventing CRC is warranted. Antioxidant supplements cannot prevent CRC. The usefulness of selenium, folate, calcium, and vitamin D awaits further evaluation. Chemoprevention cannot yet be accepted as standard medical practice. Use of chemopreventive agents cannot be a substitute for colorectal surveillance.

Cathepsin B (CATB) and urokinase-type plasminogen activator (UPA) play an important part in cancer invasion and metastasis. The behavior of CATB and UPA has not been evaluated in the same experimental setting in different gastrointestinal tumors and in precancerous lesions. Serum CATB and plasma UPA levels were determined by enzyme-linked immunoadsorbent assay and their sensitivity, specificity, and diagnostic accuracy have been calculated in patients with colorectal (n=72), gastric (n=30), hepatocellular (n=28), and pancreatic cancer (n=15) as well as in gastric epithelial dysplasia (n=25), colorectal adenomas (n=30), and tumor-free control patients (n=44). Serum CATB and plasma UPA antigen concentrations were significantly higher in patients with cancer than in controls. When all tumors were considered, the sensitivity, specificity, and diagnostic accuracy of CATB (89, 86, and 89%) were higher than that of UPA (76, 70, and 74%). CATB demonstrated in all types of tumors a better diagnostic accuracy than UPA. The positive predictive values of CATB (95%) and UPA (89%) may suggest their use in the evaluation of patients with a suspicion of malignancy. CATB and UPA were significantly higher in patients with gastric epithelial dysplasia and colorectal adenomas than in controls. Antigen levels of CATB and UPA were significantly correlated in both cancers and precancerous lesions. At the time of clinical presentation, serum CATB and plasma UPA antigen levels are sensitive indicators of gastrointestinal malignancies. Determination of serum CATB and plasma UPA levels may be useful to identify patients at a higher risk for progression to cancer, who could be subjected to a more strict follow-up protocol.

Gastric carcinogenesis is a complex, multistep and multifactorial event, characterized by progressive cyto-histological dedifferentiation, in which the role of Helicobacter pylori infection has been established. Among the pathways relevant to gastric carcinogenesis and correlated with H. pylori infection, it has been demonstrated that the production of reactive oxygen species, with damage to the DNA, may be quite important. Oxidative damage, alone and/or in combination with exogenous and endogenous factors, induces several molecular changes. The assumption is that, in precancerous lesions, these molecular changes belong to the same biological spectrum as their invasive counterpart. The molecular profile of these preneoplastic lesions is heterogeneous, however, and there are still no molecular markers enabling the distinction between atypical hyperplastic lesions and low-grade noninvasive neoplasia (NiN) or between high-grade NiN and early invasive neoplasia. Indeed, within the spectrum of morphological changes characterizing this multistep evolution, dysplasia (NiN) is the lesion coming closest to the development of invasive adenocarcinoma. Several of the genetic and epigenetic alterations reported in gastric precancerous lesions affect DNA repair system genes, tumor suppressor genes, oncogenes, cell cycle regulators, growth factors, and adhesion molecules. Although we await reliable molecular markers, it is best to monitor patients harboring NiN closely with endoscopy and extensive bioptic sampling, and to eradicate any H. pylori to prevent the accumulation of oxidative DNA damage and its consequent progression. The growing body of evidence of the regression of precancerous changes and the high prevalence of superficial gastric carcinoma demonstrated in long-term follow-up studies on NiN make this approach mandatory.

Objective: To determine the long-term results of liver transplantation for well- or moderately differentiated hepatocellular carcinoma (HCC)., Summary Background Data: HCC patient selection for liver transplantation remains controversial, and deciding exclusively on the strength of criteria such as number and size of nodules appears prognostically inaccurate., Methods: Since 1991, preoperative tumor grading has been used at our center to establish whether a patient with HCC is fit for transplantation. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. Thirty-three patients with moderately or well-differentiated HCC were prospectively studied after liver transplantation. A group of 15 patients with incidental HCC transplanted during the same period were also evaluated and compared with the 33 patients with preoperatively diagnosed HCC., Results: On histologic examination, 38% of the entire group of 48 patients did not meet the "Milan criteria" and 42% were pTNM stages III and IV. The median follow-up was 44 months. The 5-year actuarial survival rate was 75% and recurrence-free survival was 92%. HCC recurred in only 3 patients (6%). The only histomorphologic variable differing significantly between incidental and nonincidental HCC was nodule size. The timing of diagnosis (incidental vs. nonincidental HCC), the Milan criteria, and the TNM stage revealed no statistically significant impact on overall and recurrence-free survival rates., Conclusions: The routine pre-orthotopic liver transplantation tumor grading may represent a valid tool in the selection of unresectable HCC patients for transplantation.

This study aimed to identify the factors associated with the development of gastric precancerous changes, in a prospective series of patients undergoing endoscopy. Risk factors and associated mucosal changes were evaluated in 134 endoscoped patients affected by chronic non-atrophic (n = 76) or atrophic gastritis (CAG) (n = 32), with or without intestinal metaplasia (IM), or lacking any major histological changes (n = 26). The following variables were taken into account: age, alcohol consumption, smoking habit, vitamin C intake (using a questionnaire), gastric juice vitamin C (HPLC on gastric juice samples obtained at endoscopy), H. pylori infection, gastric mucosa malondialdehyde (MDA; a measure of free radical production) and extent of CAG in gastric biopsies (only for IM). Tissue MDA levels were significantly higher, and vitamin C levels significantly lower in CAG and IM patients (P = 0.01). Multiple regression analysis showed significant correlations for: CAG vs age (P < 0.02), MDA (< 0.02) and gastric vitamin C (< 0.05); IM vs age (P < 0.0005), CAG (< 0.0005) and MDA (< 0.001). Using stepwise discrimination analysis, the independent variables included in the model were: for CAG, age (P < 0.003), MDA (< 0.05), gastric juice vitamin C (< 0.05); for IM, CAG (P < 0.0005), age (< 0.001), MDA (< 0.03) and vitamin C intake (< 0.05). H. pylori was not included. The major determinants for CAG and IM were age, free radical production (as measured by MDA), vitamin C (for CAG) and vitamin C intake and CAG (for IM).(ABSTRACT TRUNCATED AT 250 WORDS)

Several papers suggested a role for H. pylori infection in gastric cancer. We evaluated the prevalence of H. pylori infection in an endoscopic population of patients with gastric precancerous conditions and lesions by studying biopsies from 252 patients and recording the presence and degree of H. pylori infection. Patients were subgrouped as follows: chronic non-atrophic gastritis (CG), chronic atrophic gastritis (CAG), intestinal metaplasia (IM), epithelial dysplasia (ED) and gastric cancer (K). As control populations, patients with duodenal ulcer (DU) and patients with no endoscopic and histologic damage (CO) were investigated. H. pylori infection rate increased with age, but became significantly lower (P < 0.001) with the progression of gastric mucosal damage: DU 85%, CG 72%, CAG 58%, particularly in the antral type (39%), IM 63% overall, ED 44% and K 35%. The density of colonization showed the same trend (P < 0.001). Of the K patients, only 36% were H. pylori positive in the adjacent mucosa. Anti-H. pylori antibodies (IgG, IgA and IgM) were also tested. A concordance in the diagnosis between histology and serology was obtained in 82% of the cases. In our experience, H. pylori infection correlates inversely with the presence of gastric precancerous changes and cancer. A cautious interpretation of the epidemiological data regarding H. pylori infection and gastric cancer is therefore, in our opinion, mandatory.

Several biochemical events accompany and mediate the development of chronic liver disease and its evolution into cancer. Low plasma zinc and high copper levels have been observed in various liver diseases, such as liver cirrhosis and viral hepatitis, while increased oestradiol levels have been documented in chronic liver damage and hepatocellular carcinoma. We administered CCL4 intragastrically to 10 female Sprague Dawley rats for 30 weeks. All animals developed cirrhosis and four also developed hepatocellular carcinoma. Plasma levels of zinc, copper and oestradiol were significantly higher in the latter group than in animals with simple cirrhosis. Progesterone, AST and bilirubin showed a trend toward significant differences whereas testosterone and ALP levels were unchanged. These findings add to the evidence that sex hormones and trace elements are involved in the process of the development of chronic liver damage and carcinogenesis.

Exposure to N-nitroso-compounds and aromatic amines, xenobiotics which require an activation in order to exert their genotoxic potential, is causally associated with gastric cancer. We evaluated the capacity of microsome-containing fractions from human gastric mucosa to activate two model carcinogenic compounds. A 9,000 x g supernatant (S9) was obtained from gastric mucosal specimens and, for comparison, from human liver and aroclor-induced and non induced rat liver. The capacity of the S9 to activate N-nitrosopyrrolidine (NPY) and 2-aminofluorene (2AF) to mutagenic metabolites was tested in the Ames/Salmonella reversion assay, while dimethylnitrosamine (DMN) and aminopyrine (AP) demethylation activities were spectrophotometrically evaluated by using an enzymatic assay of the amount of formaldehyde released following the enzymatic demethylation of the corresponding substrates. Results indicate that human gastric S9 fractions may activate 2AF to a genotoxic derivative and are characterized by DMN and AP demethylase activities higher (p < 0.05) than those of human liver, when expressed in mg/protein (p < 0.05). Although the parameters evaluated can only be considered as a partial measure of the general activating capacity toward dietary and environmental procarcinogens, these results suggest that human gastric mucosa may be directly involved in the metabolic activation of these compounds to mutagenic/carcinogenic species.