Regulation of apoptosis is impaired in atrophic gastritis associated with gastric cancer.

BACKGROUND: Gastric premalignant conditions, atrophic gastritis (AG) and intestinal metaplasia (IM) are characterized by an increase of proliferation and a reduction of apoptosis in epithelial cells. The epithelial cell kinetics in AG and IM in gastric mucosa adjacent to gastric cancer is still unclear. The aim of this study was to evaluate the epithelial cell turnover and expression of proliferation and apoptosis-related genes in gastric cancer (GC) and adjacent mucosa with atrophic gastritis or intestinal metaplasia (AG/IM GC+), as well as in atrophic gastritis or intestinal metaplasia mucosa of patients without GC (AG/IM GC-) and in control biopsy samples of non-transformed gastric mucosa (Control). METHODS: We selected 58 patients (M: F = 34:24; age range 20-84 years, median 61.06 years) with 4 well defined histological conditions: 20 controls with histological finding of non-transformed gastric mucosa, 20 patients with AG or IM (AG/IM GC-), and 18 patients with intestinal type gastric adenocarcinoma (GC) and AG or IM in the adjacent mucosa (3 cm from the macroscopic tumour margin, AG/IM GC+). We performed an immunohistochemical staining of Ki67 and TUNEL and quantitative RT-PCR to determine the expression of PCNA and Bax/Bcl-2. RESULTS: The immunohistochemical expression of Ki67 and TUNEL in AG/IM GC- was significantly increased compared to not transformed gastric mucosa (p < 0.0001) but not compared to AG/IM in gastric mucosa adjacent to GC. Levels of Bcl-2 were reduced in GC and AG/IM GC- compared to controls as well as in AG/IM GC- compared to AG/IM in mucosa adjacent to GC+ (p < 0.05). Proliferation and apoptosis markers did not correlate with H.pylori status in our study population. CONCLUSIONS: In AG/IM associated with GC, no significant changes in the epithelial cell turnover were detected. Decreased Bcl-2 gene expression signified atrophic gastritis and IM in presence of cancer, as well as intestinal type gastric adenocarcinoma.

Use of robotic colonoscopy in patients with previous incomplete colonoscopy.

OBJECTIVE: Conventional colonoscopy (CC) is the gold standard to diagnostic and therapeutic approach to colon. However, in few cases, cecal intubation could fail due to colon anatomy, patient compliance and physician expertise. Endotics robotic colonoscopy is a novel, safe, mini-invasive modality to explore the entire colon. Our aim was to assess, in a retrospective study, Endotics ability of cecal intubation in all cases in which CC failed. PATIENTS AND METHODS: Between January 2008 and December 2012, 276 Endotics robotic colonscopy examinations were performed at the Gastroenterology and Metabolic Diseases Unit of Pisa University Hospital, Pisa, Italy, in a series of consecutive patients who had undergone CC and failed cecal intubation. RESULTS: We assessed the cecal intubation rate in 102 patients addressed to Endotics after previous incomplete CC. Overall, endotics system was successful in 93.1% of the incomplete conventional colonoscopy cases (95% performance). CONCLUSIONS: Whenever the intended exploration of the entire colon with CC failed, the endotics robotic endoscopy represented a useful tool as it helped examine the entire colon in almost all cases.

Expression of basic fibroblastic growth factor, syndecan 1 and tumour necrosis factor α in resected acute colonic diverticulitis.

AIM: Inflammation and fibrosis are present in both colonic diverticulitis and Crohn's disease (CD). The molecular pattern of basic fibroblastic growth factor (bFGF) and syndecan 1 (SD1) expression is altered in stenosing CD, but their expression in resected complicated colonic diverticulitis (ACD) is unknown. METHOD: The expression of bFGF, SD1 and tumour necrosis factor α (TNF-α) in 20 patients after resection of ACD was compared with 15 patients having a resection for CD. Analysis was conducted using real-time reverse transcriptase polymerase chain reaction in biopsy samples. RESULTS: Lymphocytic and neutrophil inflammation scores were similar in both groups (P = 0.771 and P = 0.562). TNF-α and bFGF expression was significantly higher in ACD than in CD (P < 0.0001 and P = 0.009). SD1 expression was similar in both groups (P = 0.841). CONCLUSION: TNF-α and bFGF are significantly overexpressed in ACD with respect to CD, whilst SD1 levels do not differ. The findings confirm that inflammation and its association with altered molecular patterns of mucosal healing may play an important role in the phenotype of the diseases.

Mucosal expression of basic fibroblastic growth factor, Syndecan 1 and tumor necrosis factor-alpha in diverticular disease of the colon: a case-control study.

BACKGROUND: Inflammation may be detected in diverticular disease (DD), and fibrosis may also develop. We assessed the mucosal expression of bFGF, SD1, and TNF-α in DD according to the severity of the disease. Moreover, we assessed the response to therapy of these cytokines in acute uncomplicated diverticulitis (AUD). METHODS: Fifteen patients affected by AUD and seven patients affected by symptomatic uncomplicated diverticular disease (SUDD) were enrolled. Patients with asymptomatic diverticulosis (AD), segmental colitis associated with diverticulosis (SCAD), ulcerative colitis (UC), and healthy subjects (HC) served as control groups. KEY RESULTS: The expression of bFGF, SD1, and TNF-α was significantly higher in diverticulitis than in healthy controls, in diverticulosis, and in uncomplicated diverticular disease. Cytokines were significantly higher in uncomplicated diverticular disease than in healthy controls. Cytokine expression in diverticulitis did not differ significantly from that of ulcerative colitis. After treatment, TNF-α expression dropped significantly. CONCLUSIONS & INFERENCES: Mucosal TNF-α is overexpressed only in symptomatic DD, while SD1 and bFGF are already overexpressed in AD. Finally, TNF-α but not SD1 or bFGF expression seems to be influenced by the treatment in AUD.

Musosal tumour necrosis factor α in diverticular disease of the colon is overexpressed with disease severity.

AIM: Inflammation occurs in diverticular disease (DD), but there is little information on inflammatory cytokines such as tumour necrosis factor α (TNF-α). The aim of this study was to assess TNF-α expression in DD and to see whether it is related to the severity of the disease. METHOD: Twenty-four patients with symptomatic DD were divided into those with acute uncomplicated diverticulitis (AUD) (12 patients) and those with symptomatic uncomplicated diverticular disease (SUDD) (12 patients). Twelve further patients with asymptomatic diverticulosis (AD), six with segmental colitis associated with diverticulosis (SCAD), with ulcerative colitis (UC) and six healthy individuals (HC) were enrolled as controls. TNF-α expression in the colonic mucosa was assessed by the amount of mRNA codifying for the synthesis of TNF-α. RESULTS: TNF-α expression was significantly higher in AUD than in HC (P=0.0007), in AD (P=0.0001) and in SUDD (P=0.0179). It was significantly higher also in SUDD than in HC (P=0.0007) and in AD (P=0.0001). TNF-α expression in AUD did not differ significantly from that in UC (P=0.0678) and SCAD (P=0.0610). It was significantly higher in UC, SCAD and AUD than in SUDD (P=0.0007, P=0.0001, P=0.0179). CONCLUSION: TNF-α expression in DD seems to be related to the severity of the disease. In particular, it appears to be overexpressed in DD with inflammation (AUD and SUDD) compared with DD without (AD).

Pathways and gene expression profiles in hepatocellular carcinoma.

Hepatocarcinogenesis is a process attributed to progressive genomic changes which alter the hepatocellular phenotype producing cellular intermediates evolving into clearly neoplastic cells (hepatocellular carcinoma, HCC). During the preneoplastic phase, the liver is often the site of chronic hepatitis and/or cirrhosis, and this process leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that develop genetic and chromosomal alterations. At the moment three main molecular pathways of liver carcinogenesis have been described and several attempts of genetic classification of HCC have been proposed. The definition of genomic and molecular changes which occur during the development of HCC should improve the classification and prognostis of liver tumors. The development of sorafenib and other new targeted developing therapies were rendered possible by the discovery and understanding of the molecular and genetic pathogenesis of hepatocellular carcinoma. Besides viruses, such as Hepatitis B virus (HBV) and Hepatitis C virus (HCV), may contribute to cancer development by several ways; however, additional factors, such as host immunity and chronic inflammation and host cellular mutations also play a role in the transformation process. The understanding of these pathways will in the future enable the clinician to focus the treatment patients with HCC and customize single or combination therapy.

Segmental colitis associated with diverticula: a rare clinical entity and a new challenge for the gastroenterologist.

BACKGROUND AND AIM: Segmental colitis associated with diverticula (SCAD) has recently drawn a particular attention in the field of rare forms of colitis because of some peculiarities suggesting both its autonomy as a clinical entity and a resemblance with the most relevant forms of inflammatory bowel diseases (IBD). Aim of this review was to report the state of art on this topic. METHODS: Epidemiological, clinical, endoscopic/histological and diagnostic features are described. Moreover, from both the pathogenetic and therapeutic point of view, new relevant information is highlighted regarding the possible role of tumour necrosis factor alpha (TNF-alpha) in mucosal inflammation. RESULTS: SCAD would appear as a rare autonomous clinical entity distinctive of old age, although it is still not well defined. It is likely that prevalence of SCAD could have been underestimated in the past since its main clinical presentation (namely bleeding without pain) is often found in elderly patients with diverticula. Endoscopy and histology could be helpful to discriminate it from infectious diverticulitis. Increasing evidence encourages the concept that SCAD includes pathogenetic and therapeutic aspects peculiar of IBD. This could be relevant for clinical management of SCAD. Indeed, the resolution of a severe, refractory case of SCAD has been recently reported with biological drugs used for IBD therapy. This observation could encourage, in the near future, the use of biological therapy in severe forms of SCAD as an alternative to surgery.

ER-beta expression in large bowel adenomas: implications in colon carcinogenesis.

BACKGROUND: A pivotal role of oestrogen receptor-beta has been suggested in colon carcinogenesis in humans. However, few data are available on oestrogen receptor-beta in colorectal pre-cancerous lesions. AIM: In the present study, we evaluated oestrogen receptor-beta expression and its possible correlation with proliferative activity and apoptosis in colorectal adenomas and normal colon tissue. PATIENTS/METHODS: Adenomatous tissue from 25 patients with colonic polyps, and normal tissue from 25 controls were used. Oestrogen receptor-beta expression, colonocyte proliferation (expressed as PCNA positivity) and apoptosis were evaluated. RESULTS: In adenomatous tissue, a significant reduction of oestrogen receptor-beta was observed compared to normal mucosa (10.1+/-5.5% vs. 44.2+/-13.7; p<0.03), while the expression of oestrogen receptor-alpha remained unvaried. Cell proliferative activity significantly increased in adenomatous tissue compared to normal mucosa (59.3+/-7.1 vs. 18.5+/-8.8; p<0.0001), doubling the PCNA/apoptosis ratio. An inverse correlation was found between oestrogen receptor-beta and PCNA expression in adenomas (r=-0.81), a datum confirmed by confocal microscopy evaluation. CONCLUSIONS: Our data demonstrate, for the first time, a significant reduction of oestrogen receptor-beta expression already in the pre-cancerous phase of colon carcinogenesis. This suggests a role of selective oestrogen receptor-beta agonists in the prevention of colorectal cancer.

Systematic review: Endoscopic dilatation in Crohn's disease.

BACKGROUND: Endoscopic dilatation for Crohn's disease has been evaluated only in some small and heterogeneous studies. AIM: To evaluate any association between the main clinical variables and endoscopic variables and the efficacy and safety of endoscopic dilatation in Crohn's disease. METHODS: A Medline search regarding pneumatic dilatation in Crohn's disease was performed. Several technical and clinical variables were extracted from each study to build up a descriptive, pool-data analysis. Data on individual patients were extracted from suitable studies to create a simulated population upon which a multivariate statistical analysis was performed. RESULTS: Thirteen studies enrolling 347 Crohn's disease patients were reviewed. Endoscopic dilatation was mainly applied to postsurgical strictures, being technically successful in 86% of the cases. Long-term clinical efficacy was achieved in 58% of the patients. Mean follow-up was as long as 33 months, corresponding to 800 patient years of follow-up. Major complication rate was 2%, being higher than 10% in two series. At multivariate analysis, a stricture length < or = 4 cm was associated with a surgery-free outcome (OR: 4.01; 95% CI: 1.16-13.8; P < 0.028). CONCLUSIONS: Endoscopic dilatation is an effective and safe treatment for short strictures caused by Crohn's disease, impacting substantially on the natural history of these patients.

Tumor necrosis factor alpha in ulcerative colitis and diverticular disease associated colitis.

Conventional treatment of moderate-severe ulcerative colitis (UC) has resulted in only a limited therapeutic benefit. Advancing knowledge of UC pathogenesis and recent advances in biotechnology have led to the development of biological agents that selectively target individual inflammatory pathways. In particular, the role of tumor necrosis factor alpha (TNF-alpha) in UC pathogenesis has been clarified by serological and immunohistochemical studies in humans and by experimental models. Clinical efficacy of anti-TNF-alpha therapy with infliximab has been assessed in two large controlled trials, showing a good compromise between therapeutic gain and safety. The aim of this review is to provide an insight into the role of TNF-alpha and anti-TNF-alpha therapy in patients with UC and diverticular disease associated colitis.

Tumour necrosis factor alpha down-regulation parallels inflammatory regression in ulcerative colitis patients treated with infliximab.

BACKGROUND: Treatment with the anti-tumour necrosis factor alpha monoclonal antibody infliximab has been shown to be effective in moderate-to-severe ulcerative colitis. However, its effect on the mucosal histopathological abnormalities of this disease is largely unknown. This study aimed to assess the immunohistological effect of infliximab in ulcerative colitis. METHODS: Nine patients with moderate-to-severe ulcerative colitis received infliximab (5mg/kg) at weeks 0, 2 and 6, respectively. Colonic biopsies were collected before therapy and at week 10, when the Mayo score (including the endoscopic subscore) was also assessed. Severity of inflammation was evaluated by histologic score and histomorphometry. Immunohistochemical staining with antibody against tumour necrosis factor alpha was performed on all biopsies and expressed as percentage of positive stromal cells/1000 counted (tumour necrosis factor alpha score). RESULTS: A profound down-regulation of mucosal tumour necrosis factor alpha occurred in all the six patients who achieved a clinical response, but not in the three who did not respond. Median tumour necrosis factor alpha score dropped from 44.8 (range 35-58.3) to 12.8 (range 5.3-15.3) in the responders (p=0.03), whilst it remained unchanged in the non-responders. Such effect was related with a dramatic regression of the median histologic score, which dropped from 2.7 (range 2-3) to 0.5 (range 0.0-1.5) in responder patients (p=0.002). This was related to a virtual disappearance of neutrophils in responders (r=0.72; p=0.002; Spearman's test), but not in those who did not improve. Tumour necrosis factor alpha score appeared to be correlated with the histologic, endoscopic and clinical activity. CONCLUSIONS: A profound tumour necrosis factor alpha down-regulation appears to be strictly associated with a dramatic regression of the inflammation in patients with moderate-to-severe ulcerative colitis treated with infliximab. Such immunohistochemical effect seems to be critical for a clinical and endoscopic response to therapy.