M. Piciocchi

Oxidative Stress and Inducible Nitric Oxide Synthase Induction in Carcinogenesis

Background: Chronic inflammation is linked to an increased risk of cancer. The molecular mechanisms underlying this correlation have been long investigated and it is well known that the inflammatory cells recruited in the inflamed tissues release chemical mediators, in particular reactive oxygen species (ROS). With respect to digestive systems, ROS have been implicated in a number of pathologies, including Helicobacter pylori-related gastritis, Barrett’s esophagus, inflammatory disease of the lower gastrointestinal tract, alcoholic liver disease and several other types of toxic and virus-mediated liver injury. ROS levels within cells and tissues are controlled by numerous antioxidant defense mechanisms, but in inflammation, ROS overproduction exceeds defenses and damage intracellular macromolecules, including nucleic acids, with formation of potentially mutagenic and carcinogenic DNA adducts. Aims: This paper summarizes our own experience investigating the link between inflammation, ROS production and oxidative DNA damage as well as the impact of the above events on cytokine and growth factor release, oncogene activation, telomere instability and microRNA in H. pylori-related gastritis, Barrett’s esophagus and, in particular, hepatitis C virus-related liver disease. The paper also describes, at least in part, the complex scenario involving nitric oxide production and its impact in some gastrointestinal diseases, as well as a number of other molecular and biochemical changes related to ROS production and inflammation. Conclusions: The paper falls obviously short of being an exhaustive summary of our understanding, but the data reported are intended as a stimulus to broaden the knowledge on the topic, also in view of the possible therapeutic implications of any advance obtained.

Diagnostic and prognostic role of SCCA-IgM serum levels in hepatocellular carcinoma (HCC).

The serpin squamous cell carcinoma antigen complexed with IgM (SCCA‐IgM) has been reported as a promising serological marker for hepatocellular carcinoma (HCC). We aimed to further evaluate SCCA‐IgM diagnostic accuracy and to determine its prognostic role.

MINT31 methylation in gastric noninvasive neoplasia: potential role in the secondary prevention of gastric cancer.

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.

Focus on histological abnormalities of intrahepatic vasculature in chronic viral hepatitis

The histological intrahepatic microvasculature lesions have not been deeply investigated outside the setting of portal hypertension. The aim of this study was to analyse the type and the prevalence of microvasculature abnormalities and their correlation with inflammatory activity, fibrosis stage and tissue markers of fibrogenesis, angiogenesis and oxidative DNA damage in liver biopsies obtained from patients with chronic viral hepatitis.

Squamous Cellular Carcinoma Antigen Serum Determination as a Biomarker of Barrett Esophagus and Esophageal Cancer: A Phase III Study

Goal: To evaluate the potential role of the determination of the immunocomplexed form of squamous cell carcinoma antigen [SCCA-immunoglobulin (Ig)M] for the screening of Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). Background: The cost-effectiveness of surveillance in BE is still debated and the use of biomarkers in screening and surveillance still not recommended. No information is available regarding SCCA-IgM determination in BE. Study: SCCA-IgM levels were determined (enzyme-linked immunosorbent assay) in 231 patients prospectively recruited, 71 with BE, 53 with EAC, and 107 controls, including 42 blood donors and 65 patients with gastroesophageal reflux. SCCA-IgM cutoffs between BE/EAC and controls and for BE “at risk” versus short nondysplastic BE were calculated by receiver operating characteristic curves. Immunostaining for SCCA-IgM was obtained in a subgroup of patients. Results: Median SCCA-IgM values were significantly higher in BE and EAC than in controls (P=0.0001). Patients with SCCA-IgM levels above the cutoff had a 33 times higher relative risk of harboring BE or EAC (P=0.0001). Patients “at risk,” with long or dysplastic BE had SCCA-IgM levels significantly higher than those with short nondysplastic BE (P=0.035) and patients with SCCA-IgM above the cutoff had a 8 times higher relative risk of having BE “at risk.” SCCA was expressed in Barrett mucosa but not in cardiac metaplasia. Conclusions: Serum SCCA-IgM determination allows the identification of patients at risk for BE/EAC and the stratification of BE patients in subgroups with different cancer risk. Because of the still limited number of controls, large, prospective studies are required to confirm this evidence.

Letter: coffee and chronic liver damage.

SIRS, We read with interest the recent article on the potential approaches to the treatment of hepatitis C virus (HCV)-related hepatitis in patients either not eligible or not responding to interferon-based protocols. Sofosbuvir-based regimens will dramatically reduce the size of the problem, but still a share of patients will be not eligible for treatment and the behavioural and alimentary indications we give them will maintain a general relevance. One of the authors’ conclusions is that the consumption of two or more cups of coffee per day is recommended in patients with chronic HCV infection and in support of the thesis, we think it is useful to quote two results we recently reached. The first is that the daily consumption of three or more cups of coffee in patients with HCV-related liver disease is associated with a halving of the levels of 8-hydroxydeoxyguanosine (8-OHdG) in circulating nucleated cells. Eight-OHdG is a marker of free radical-mediated oxidative DNA damage, an adduct causing DNA mutation involved in carcinogenesis and its reduction supports the protective role of coffee in the development of advanced liver damage and HCC. The second result is that, in a prospective randomised study on coffee consumption in patients with HCVrelated hepatitis, we demonstrated that drinking four cups of coffee per day is correlated with reduced collagen synthesis and oxidative DNA damage and an increase in telomere length and circulating markers of apoptosis (Table 1), both protective factors in liver carcinogenesis. HCV-related hepatitis is not the only potential target, as coffee may also be of benefit in non-alcoholic fatty liver disease (NAFLD), which is an additional risk factor for HCC, due to its protective effect also with respect to NAFLD progression. In summary, coffee appears to be protective in liver damage progression, irrespective of the aetiology. Its use should be recommended and the mechanisms and compounds involved further investigated.