Exit strategies in inflammatory bowel disease: Looking beyond anti-tumor necrosis factors.

The long-term management of patients with inflammatory bowel disease (IBD) is still a matter of debate, and no clear guidelines have been issued. In clinical practice, gastroenterologists often have to deal with patients in prolonged remission after immunomodulatory or immunosuppressive therapies. When planning an exit strategy for drug withdrawal, the risk of disease relapse must be balanced against the risk of drug-related adverse events and healthcare costs. Furthermore, there is still a dearth of data on the withdrawal of novel biologics, such as the anti-α4ß7 integrin antibody (vedolizumab) and anti-IL12/23 antibody (ustekinumab), as well as the small molecule tofacitinib. Models for estimating the risk of disease relapse and the efficacy of retreatment should be evaluated according to the patient's age and IBD phenotype. These models should guide clinicians in programming a temporary drug withdrawal after discussing realistic outcomes with the patient. This would shift the paradigm from an exit strategy to a holiday strategy.

Appropriateness and yield of surveillance colonoscopy in first-degree relatives of colorectal cancer patients: A 5-year follow-up population-based study.

BACKGROUND AND AIMS: There are few prospective data about the use of surveillance colonoscopy and the risk of recurrent neoplasia in first degree relatives (FDRs) of colorectal cancer (CRC) patients. We examined the use and yield of surveillance colonoscopy in a population-based screening program (Trentino, Italy) METHODS: 1252 FDRs have been included in this study. We calculated compliance (percentage of FDRs who underwent surveillance colonoscopy among those eligible), appropriateness of colonoscopy (appropriate if performed within 6 months of the guidelines recommended interval) and diagnostic yield for neoplasia. We compared these data with those of 765 individuals without a family history (FH) of CRC who underwent screening colonoscopy in the same period (controls). RESULTS: Compliance and appropriateness were higher in FDRs than in controls (93.0% vs. 48.0%; p < 0.001; 59.6% vs. 18.8%; p < 0.0001, respectively). Younger age, female sex, FH of CRC and both non-advanced adenomas (nAA) and advanced adenomas (AA) at screening colonoscopy were predictors of appropriate surveillance. The cumulative incidence of nAA and AA was similar in FDRs and controls (31.7% and 4.9% in FDRs, including three invasive cancers; 32.4% and 5.8% in controls, respectively). CONCLUSION: FH does not increase the risk of AA in a 5-year follow-up; appropriate surveillance practices in FDRs could be highly expected in an organized screening program.

Oxidative DNA damage in Barrett mucosa: correlation with telomeric dysfunction and p53 mutation.

BACKGROUND: Barrett esophagus develops in a scenario of chronic inflammation, linked to free radical formation and oxidative DNA damage. Eight-hydroxydeoxyguanosine, the main oxidative DNA adduct, is partially repaired by a glycosylase (OGG1) whose polymorphism is associated to a reduced repair capacity. Telomeres are particularly prone to oxidative damage, which leads to shortening and cell senescence, while elongation, by telomerase activity, is linked to cell immortalization and cancer. Limited data are available on this point with respect to Barrett esophagus. This study aimed to evaluate the link among 8-hydroxydeoxyguanosine, OGG1 polymorphism, telomerase activity, telomere length, and p53 mutation in Barrett progression. METHODS: Forty consecutive patients with short- and long-segment Barrett esophagus and 20 controls with gastroesophageal reflux disease without Barrett esophagus were recruited. Analysis of biopsy samples was undertaken to study 8-hydroxydeoxyguanosine levels, OGG1 polymorphism, telomerase activity, and telomere length. Serum samples were obtained for p53 mutation. RESULTS: Controls had significantly lower levels of 8-hydroxydeoxyguanosine and telomerase activity, with normal telomere length and no p53 mutation. In short-segment Barrett esophagus, 8-hydroxydeoxyguanosine levels were higher and telomeres underwent significant shortening, with stimulation of telomerase activity but no p53 mutations. In long-segment Barrett esophagus, 8-hydroxydeoxyguanosine reached maximal levels, with telomere elongation, and 42 % of the patients showed p53 mutation. CONCLUSIONS: In Barrett patients, with disease progression, oxidative DNA damage accumulates, causing telomere instability, telomerase activation, and, in a late phase, mutations in the p53 gene, thus abrogating its activity as the checkpoint of proliferation and apoptosis, and facilitating progression to cancer.

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.

Long-term follow-up of Barrett's epithelium: medical versus antireflux surgical therapy.

BACKGROUND: Barrett's esophagus (BE) is the most serious complication of GERD. In BE patients, this observational study compares the effects of antireflux surgery versus antisecretory medical therapy. METHODS: Overall, 89 BE patients (long BE = 45; short BE = 44) were considered: 45 patients underwent antireflux surgery and 44 underwent medical therapy. At both initial and follow-up endoscopy, symptoms were assessed using a detailed questionnaire; BE phenotypic changes [intestinal metaplasia (IM) presence/type, Cdx2 expression] were assessed by histology (H&E), histochemistry (HID), and immunohistochemistry. Surgical failures were defined as follows: (1) abnormal 24-h pH monitoring results after surgery, (2) endoscopically evident recurrent esophagitis, and (3) recurrent hiatal hernia or slipped fundoplication on endoscopy or barium swallow. RESULTS: Reversion of IM was observed in 12/44 SSBE and 0/45 LSBE patients (p < 0.01). Reversion was more frequently observed after effective antireflux surgery than after medical treatment (p = 0.04). In patients with no further evidence of IM after therapy, Cdx2 expression was also absent (p = 0.02). The extent of IM was reduced, and the IM phenotype improved in SSBE patients after surgery. CONCLUSIONS: Patients with short BE (but not those with long BE) may benefit from surgically reducing the esophagus' exposure to GE reflux; among these patients, successful surgery carries a higher IM reversion rate than medical treatment.

Gastric type I carcinoid: a pilot study with human G17DT immunogen vaccination.

CONTEXT: Gastric type I carcinoid is a rare neoplasm, deriving from enterochromaffin-like cells (ECL), mainly affecting women with autoimmune gastritis. The approach to treatment, either endoscopic, medical or surgical, is not well defined, particularly in multifocal tumours or carcinoids with rapid growth/frequent recurrence. OBJECTIVE: To determine whether an anti-G17 vaccination might interfere on the natural history of gastric type I carcinoid. SETTING: Padua teaching Hospital, outpatient clinic. DESIGN AND PATIENTS: Three patients with type I gastric carcinoid in autoimmune gastritis were administered, after informed consent and ethic committee approval, with a vaccine against gastrin 17 (G17), a synthetic peptide that stimulates specific and high-affinity anti-G17 antibodies, and followed up endoscopically and clinically for a mean of 36 months. MAIN OUTCOME MEASURES: Gastric histology and specifically carcinoid growth/recurrence and trend in time in gastrin, G17, pepsinogens, chromogranin A and clinical parameters. RESULTS: Following vaccination, carcinoid regression was observed in 2/3 patients and, in one of the patients, even the disappearance of ECL hyperplasia, with a reduced ECL cells stimulation, confirmed by a significant reduction in chromogranin A levels. Regression was observed in the two patients that showed a more clear local response to the vaccine. Increased autoantibody titre was observed, but no appearance of new autoimmune diseases. CONCLUSIONS: Anti-G17 vaccination induced regression of type I gastric carcinoid and could be considered for the treatment of this tumour, when endoscopic removal is not indicated.

Helicobacter pylori, inflammation, oxidative damage and gastric cancer: a morphological, biological and molecular pathway.

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.

Indefinite for non-invasive neoplasia lesions in gastric intestinal metaplasia: the immunophenotype.

BACKGROUND: In the Padova International Classification, gastric precancerous lesions are labelled as "indefinite for non-invasive neoplasia" (Indef-NiN) cytohistological alterations mimicking non-invasive neoplasia (NiN), but lacking all the attributes required for a definite NiN categorisation. AIM: To apply a panel of immunohistochemical (IHC) markers of cell proliferation (Mib1), intestinal differentiation (Cdx2), apoptosis (pro-caspase 3) and cell immortalisation (hTERT) to compare the IHC profiles of a series of precancerous lesions arising in gastric intestinalised (ie, IM-positive) glands. MATERIALS AND METHODS: By applying the histological criteria consistently provided by both the Padova Classification and the World Health Organization International Agency, 112 consecutive cases were considered: intestinal metaplasia (IM; n = 54), Indef-NiN in IM-positive gastric glands (n = 28) and low-grade (LG) NiN (n = 30). In each histological category, the expression of the marker was separately scored in superficial, proliferative and coil compartments. RESULTS: In all glandular compartments, Mib1, Cdx2, hTERT and pro-caspase 3 were consistently more expressed in LG-NiN than in either IM or Indef-NiN lesions (analysis of variance: p<0.001). Significant ORs (calculated by ordinal logistic regression analysis for each glandular compartment) associated IM, Indef-NiN and LG-NiN with the expression of the considered markers. CONCLUSIONS: A consistent overexpression (unrestricted to the proliferative zone) of IHC markers of cell proliferation, intestinal differentiation, decreased apoptosis and cell immortalisation differentiates LG-NiN from both (simple) IM and Indef-NiN (arising in IM). An increased proliferative activity in the proliferative zone discriminates Indef-NiN lesions (ie, hyperproliferative IM) from IM. Such divergent IHC profiles may provide a rationale for scheduling follow-up protocols more properly tailored on the patient's risk for cancer.