Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort.

Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients treated with lamivudine. Whether HCC rates are comparable in patients treated with the current first-line antivirals remains uncertain. We estimated the incidence and evaluated predictors of HCC in a large nationwide prospective cohort (HepNet.Greece) of HBeAg-negative CHB patients treated with entecavir. HBeAg-negative CHB patients from the same cohort who were initially treated with lamivudine were used as controls. We included 321 patients treated with entecavir for a median of 40 months and 818 patients treated initially with lamivudine for a median of 60 months. In the entecavir group, HCC developed in 4 of 321 (1.2%) patients at a median of 1.5 (range: 1.0-4.5) years, while the cumulative HCC incidence was significantly higher in cirrhotics than noncirrhotics (1, 3, 5 years: 0%, 3%, 9% vs 1%, 1%, 1%; P = 0.024) and in older patients (P = 0.026). Entecavir compared with lamivudine group patients had lower HCC incidence (1, 3, 5 years: 0.3%, 1.2%, 2.8% vs 0.7%, 3.8%, 5.6%; P = 0.024). However, in multivariable Cox regression analysis, the HCC risk was independently associated with older age (P < 0.001), male gender (P = 0.011) and cirrhosis (P = 0.025), but not with the initial agent. In conclusion, our large nationwide study indicates that the HCC risk remains increased in entecavir-treated HBeAg-negative CHB patients with cirrhosis, particularly of older age, at least for the first 5 years. The HCC risk does not seem to be significantly reduced with entecavir compared with antiviral therapy starting with lamivudine.

Serotonin transporter and G protein beta 3 subunit gene polymorphisms in Greeks with irritable bowel syndrome.

BACKGROUND: Polymorphisms in the serotonin transporter (SERT) and G protein ß3 subunit (GNB3) genes might contribute to the pathophysiology of irritable bowel syndrome (IBS). Association studies of SERT and GNB3 polymorphisms and IBS have shown diverse results among different populations, which might be due to subject composition differences. AIMS: The aim of the study was to assess the potential association between SERT and GNB3 polymorphisms and IBS in Greeks. METHODS: A total of 124 patients with IBS diagnosed according to the Rome III criteria and 238 healthy individuals were included in the study. SERT and GNB3 gene polymorphisms were genotyped using polymerase chain reaction-based methods. RESULTS: It was shown that the frequencies of the SS genotype and S allele of the serotonin transporter polymorphism were significantly associated with IBS (P = 0.0314 and P = 0.019, respectively). TT genotype and T allele frequencies of G protein ß3 subunit showed also significant difference between the IBS patients and healthy controls IBS (P = 0.0163 and P = 0.0001, respectively). None of the clinical symptoms analyzed was significantly associated with the polymorphisms tested. CONCLUSIONS: The results suggest that SERT and GNB3 gene polymorphisms might be associated with irritable bowel syndrome predisposition in Greeks.

Impact of beta-glucan on the faecal microbiota of polypectomized patients: a pilot study.

Beta-glucans are polysaccharides present in the cell walls of higher plants, in the seeds of some cereals, and certain yeasts and fungi also produce them. It is suggested that they exhibit, among many other health benefits, protective effects against carcinogenesis in the colon, but there is not enough human data to support this. The aim of the study was to determine the effect of barley-derived beta-glucan in the gut microbiota of polypectomized patients. Subjects were randomly assigned to consume 125 g of bread per day with beta-glucan (3 g/d), or without (placebo group), for 3 months. Thirty-three polypectomized men and women (mean age 57.6 years) were recruited into the study, but only 20 completed. Subjects did not consume any probiotics, prebiotics or antibiotics 2 months prior the intervention, or during the study. Stool samples were collected at baseline, on days 30 and 90 of intervention, as well as 2 weeks after the intervention, for enumeration of total aerobes and anaerobes, coliforms, E. coli, enterococci, Bacteroides spp., Clostridium perfringens, bifidobacteria, lactobacilli and Candida spp. Faecal bacterial enzyme activity (beta-glucuronidase and beta-glucosidase), pH, faecal moisture and the concentration of volatile fatty acids in the faeces were measured. Gastrointestinal symptoms were also recorded. Overall, no significant differences were observed in bacterial viable counts between the two feeding groups. Group specific analysis for ß-glucan group revealed significantly decreased total coliform counts on the 30th day of the trial compared to the baseline (p = 0.041). Clostridium perfringens concentration increased without reaching statistical significance, on the 30th day, while it decreased significantly on the 90th day of the intervention compared to the 30th day (p = 0.016). An increase was noted in the molar ratio of acetate on the 90th day of the trial compared to placebo (p = 0.018). The molar ratio of butyrate presented a trend to increase on the 30th day, which decreased (p = 0.013) on the 90th day and then increase 2 weeks after the intervention (p = 0.017) compared to placebo. A decrease was recorded in the ß-glucan group in the bloating and abdominal pain score after the 30th day of the intervention (Day 30-37) compared to placebo. During ß-glucan administration we did not observe any changes on beta-glucuronidase or beta-glucosidase activity, faecal pH, or on faecal moisture.

Epithelial cell turnover, p53 and bcl-2 protein expression during oncogenesis of early and advanced gastric cancer in a Western population.

OBJECTIVES: To investigate epithelial cell turnover alterations, and p53, bcl-2 protein expression during development of early and advanced gastric cancer in a Western population. METHODS: We investigated cell apoptosis and proliferation rates, p53 and bcl-2 protein expression in 17 early and 34 advanced gastric carcinomas and in the adjacent non-dysplastic mucosa. Cell proliferation, p53 and bcl-2 expression were detected immunohistochemically using MIB-1, anti-p53 and anti-bcl-2 monoclonal antibodies. Apoptosis was measured by TUNEL. The rate of the positive stained cells (labelling index) was count using image analysis technique. RESULTS: No difference was observed of either apoptotic (10 vs. 11) or proliferation (35 vs. 25) index between early and advanced cancers. However, the apoptotic index was significantly higher in intestinal type advanced tumors. While both apoptotic and proliferation indices were significantly higher in tumors than in the adjacent mucosa, no difference was observed of either apoptotic (2 vs. 2) or proliferation (8 vs. 13) index between the tissues adjacent to early and advanced tumors. p53 protein expression was significantly higher in advanced cancers (7 vs. 5, p=0.001) and in the non-dysplastic tissue adjacent to advanced tumors (3.5 vs. 2, p=0.001). bcl-2 labelling index was significantly higher in the mucosa adjacent to advanced carcinomas (15 vs. 5, p=0.016) but this difference did not reach significance in the tumors (20 vs. 15, p=0.37). CONCLUSIONS: Our data indicate similar cell turnover during tumorigenesis of early and advanced cancer. p53 and bcl-2 protein accumulation is more intense in gastric mucosa adjacent to advanced tumors and p53 immunoreactivity peaks in advanced carcinomas.

Comparison of T- and Z-score in identifying risk factors of osteoporosis in inflammatory bowel disease patients.

OBJECTIVE: Most studies have shown contradictory results regarding predictive factors of osteoporosis in inflammatory bowel disease (IBD). Since in these studies either T- or Z-scores has been used, our aim was to compare T- and Z-score in identifying risk factors of osteoporosis in IBD patients. MATERIALS AND METHODS: Bone density was measured by dual X-ray absorptiometry (DXA) at L2-L4 of the spine and femoral neck in 122 patients. Twenty-two clinical parameters were recorded prior to DXA and evaluated by univariate and multivariate analysis. RESULTS: On multivariate analysis, cumulative steroid dose was a predictive factor of femoral neck T-score (p<0.001) and Z-score (p=0.001). Age was a predictive factor of femoral neck T-score (p<0.001). BMI was a predictive factor of femoral neck Z-score (p=0.03). None of the other 19 variables tested had any predictive value for bone density. Age >or=55 years was a risk factor of low femoral neck T-score (OR 5.08, 95% CI 1.90-13.57, p=0.001), as was cumulative dose of prednisolone >or=5 g (OR 3.41, 95% CI 1.50-7.73, p=0.004). CONCLUSIONS: There is a discordance of results depending on whether T- or Z-scores are used in analysis. Among 22 parameters, cumulative steroid dose and age proved to be the most important factors.

The role of NSAIDs in colon cancer prevention.

Experiments in animals and population-based studies have shown the efficacy of nonsteroidal antiinflammatory drugs in colorectal cancer prevention. COX-2 is overexpressed in dysplastic and neoplastic epithelium. COX-2 is a key-enzyme in several tumorigenic pathways, such as promotion of tumor angiogenesis. Non-selective inhibition of COX enzyme demonstrates a protective effect as well, suggesting that more than one mechanism takes place in neoplastic transformation. Blockade of COX enzyme by NSAIDs down-regulates its metabolic product prostaglandin E2. Inhibition of PGE2 seems to have a negative effect in cancer occurrence. Induction of apoptosis is another mechanism that explains the protective effect of NSAIDs. The recently discovered PPARdelta factor, is also overexpressed in neoplastic tissue, and may be a mediator through which COX-2 exerts its oncogenic effect.

The Bcl-2/Bax system and apoptosis in ulcerative colitis.

BACKGROUND/AIMS: Ulcerative colitis (UC) constitutes a chronic inflammatory process of the colon of unknown etiology. Current data support a pivotal role of apoptosis in the evolution of pathogenesis of UC. We performed a prospective study in order to determine the role of Bcl-2, Bax and Bcl-x in the apoptotic pathway in UC. METHODOLOGY: We included 23 patients with UC and 11 controls. Histological severity of the disease was assessed according to the Sidney classification system. Patients in the UC group were divided in 2 groups according to histological severity of the disease. The TUNEL method was used for the in situ evaluation of apoptosis. Immunohistochemical staining was used for the detection of Bax, Bcl-2, Bcl-x. For the assessment of cellular proliferation we used the monoclonal antibody Ki67. Appropriate statistical methods were applied. RESULTS: Overall 77 specimens were assessed; 57 from UC patients and 20 from controls. Bcl-2, Bax and Bcl-x were upregulated in the group of patients with UC compared to controls. Nevertheless, Bax in epithelial cells and Bcl-x in lymphocytes were downregulated in patients with moderate/severe disease (p = 0.029 and 0.04 respectively). A weak correlation between epithelial apoptosis and Bcl-x expression in lymphocytes (r = 0.31, p = 0.02) was found. An even weaker correlation was also noticed between the epithelial component apoptosis and Bax in lymphocytes (r = 0.02, p = 0.07). CONCLUSIONS: Bcl-2/Bax system does not appear to be involved in the induction of apoptosis in UC. Activation of intraepithelial lymphocytes may be associated with epithelial apoptosis or simply represent epiphenomena related to the inflammatory process.

Small bowel capsule endoscopy for the investigation of obscure gastrointestinal bleeding: When we should do it and what should we expect.

Obscure gastrointestinal bleeding is defined as bleeding of unknown origin that persists or recurs (i.e. recurrent or persistent iron deficiency anemia, fecal occult blood test positivity or visible bleeding) after a negative initial workout that necessarily includes gastroscopy and colonoscopy. In clinical practice, small bowel capsule endoscopy is recommended as a third stage examination in these patients, since it is a simple, safe, non-invasive and reliable test. To date there are three available small bowel capsule systems that have gained FDA approval and their diagnostic yield has shown to be superior to other diagnostic modalities for the investigation of the small bowel in patients with obscure gastrointestinal bleeding. The test should be performed as close to the bleeding episode as possible and the administration of a purgative bowel preparation before the administration of capsule endoscopy is recommended by the European Society of Gastrointestinal Endoscopy (ESGE). Issues that still remain to be solved are the definition of bleeding lesions and what really represents a positive finding, as well as the question of whether the outcome of patients with obscure gastrointestinal bleeding is altered after the test, i.e. to better define subgroups of patients that will mostly benefit from capsule endoscopy. In the future small bowel capsule endoscopy might be able to get guided, while tissue samples might be available as well. (Acta gastro-enterol. belg., 2016, 79, 355-362).

The puzzle of somatostatin: action, receptors, analogues and therapy.

The scientific search for the revelation of the multiple physiological aspects of somatostatin has already begun. Investigators have managed to clarify many pathophysiological processes that have been influenced or regulated by somatostatin. The focus of future research seems to be the therapeutic application of this accumulated knowledge. The aim of this study is to collect the available information on the action, receptors and use of somatostatin analogues in human tissues. For this reason findings were based on Internet search and complete studies with abstracts written in English. A special mention on the influence of somatostatin on the immune system and inflammatory bowel disease is also included.

Different aspects in functional dyspepsia.

Functional dyspepsia is still a puzzling medical problem. The causes are unknown, the pathogenetic mechanisms are uncertain, the management is controversial and medications are many times insufficient. The research so far has given conflicting results at all levels of investigation. This study represents an effort to collect all available data concerning the most disputed issues of functional dyspepsia. Topics regarding Helicobacter pylori eradication, pathophysiology, endoscopic and histologic correlations with symptomatology, the placebo effect and management options are presented following an evidence-based approach. Many articles, published in recent years, are discussed in order to obtain an overall insight of this peculiar symptom complex, named functional dyspepsia.

Systemic absorption of 5-aminosalicylic acid in patients with inactive ulcerative colitis treated with olsalazine and mesalazine.

OBJECTIVE: To compare the systemic load of 5-aminosalicylic acid (5-ASA) as a basis for potential long-term toxicity during treatment in usual dosage with olsalazine (Dipentum) and one controlled-release mesalazine preparation (Salofalk) in patients with inactive ulcerative colitis. DESIGN: Open, randomized, crossover study. TREATMENT SCHEDULE: Olsalazine 500 mg twice daily for 7 days and mesalazine 500 mg thrice daily for 7 days consecutively. PATIENTS: Fifteen patients (12 males/3 females) aged between 18-70 years with ulcerative colitis in endoscopically confirmed remission for at least one month. METHODS: A morning predose plasma sample and a 24-h urine collection on days 6 and 7 of each course were obtained from all patients for quantitative determination of 5-ASA and acetyl-5-ASA (Ac-5-ASA) concentrations. High performance liquid chromatography was used and all analyses were performed blindly on coded samples. RESULTS: Treatment with mesalazine compared with olsalazine gave significantly higher levels of 5-ASA and Ac-5-ASA in plasma and urine. Maximum values and ranges of all variables were higher in the mesalazine group than in the olsalazine group. It is noteworthy that there was clear discriminance in the range of urine 5-ASA and Ac-5-ASA concentrations after mesalazine and olsalazine treatment. CONCLUSION: 1. The mesalazine preparation used, in comparison with olsalazine given in usual dosages, causes significantly higher levels of 5-ASA and Ac-5-ASA in plasma and urine in patients with inactive ulcerative colitis. 2. The lower systemic load of 5-ASA may reduce the potential risk of adverse events and in particular of nephrotoxicity.

p53 protein accumulation and colonic adenoma recurrence.

OBJECTIVES: The prognostic value of p53 protein accumulation in colonic adenomas is still controversial. The aim of the present study was to determine whether the evaluation of p53 protein accumulation in newly diagnosed colonic adenomas could predict the development of metachronous adenomas. DESIGN/METHODS: Fifty-five patients who underwent prior endoscopic polypectomy for colonic adenomas were colonoscopically re-evaluated at 24-38 months after index colonoscopy. In cases with more than one adenoma, the one with the greatest diameter and the most serious histology was taken into account. p53 protein expression was immunohistochemically examined using specific monoclonal antibody. RESULTS: p53 protein was detected in 41.8% of the 55 index adenomas. Recurrent adenomas were present in 21 patients (38.2%). Metachronous adenomas were present in 56.5% of patients with p53-positive index adenomas and in 25% of those with p53-negative index adenomas (odds ratio 3.90, P = 0.018). Among patients with 1 or 2 index adenomas, metachronous adenomas were found in 50% of those with p53-positive index adenomas and in 22.6% of those with p53-negative index adenomas (odds ratio 3.43, P= 0.042). Multivariate stepwise logistic regression analysis revealed that number of index adenomas per patient (1 or 2 versus > 2) and p53 expression (positive versus negative) in index adenomas contain independent prognostic information for adenoma recurrence (chi2 = 8.2, P= 0.004 and chi2 = 4.08, P = 0.04 respectively). Patients aged < 60 years developed recurrent adenomas relatively more frequently if they had a p53-positive index adenoma (P= 0.068). In the subgroup of patients aged < 60 years with 1 or 2 index adenomas, the recurrence of adenomas was more frequent in those with a p53-positive index adenoma but the difference did not reach statistical significance (P= 0.13). CONCLUSIONS: Our data suggest that p53 expression in index adenomas is associated with recurrent colonic adenomas.

Genes and gastric cancer.

Gastric cancer remains quite a common malignancy and counts among the most important causes of cancer-related death worldwide. Although the pathogenesis is multifactorial, familial aggregation in a significant proportion of cases suggests the importance of genetic predisposition. The association between the E-cadherin/CDH1 gene germline mutations and the development of diffuse gastric cancer was the first evidence for a molecular basis of gastric cancer in predisposed families and led many authorities in the world to produce guidelines regarding the management of such families members. The recent advances in genetics resulted in the discovery of numerous genetic events occurring during the course of gastric carcinogenesis (activation of oncogenes, silencing of tumor suppressor genes, mutations in DNA-repairing genes) and contributed to a better understanding in pathogenesis. Many genetic changes described have been found to affect tumor's biological behavior. In this article the authors attempt a review of all the molecular alterations in gastric cancer described in the literature and their impact on the management of patients with an inherited predisposition to gastric cancer. The promising role of gene therapy in the treatment of gastric cancer in the near future is also commented on.

A family of five first degree relatives affected by Lynch II syndrome.

Hereditary non-polyposis colorectal cancer (Lynch syndromes) has been reported in the international literature over the last decade. We now present a case of a family with Lynch II syndrome, in which five first-degree relatives were affected by colorectal cancer; in addition, the two female patients had ovarian or breast cancer.

Predictors of the early development of advanced metachronous colon adenomas.

BACKGROUND/AIMS: In order to reduce the number of colonoscopies performed for the surveillance of patients after polypectomy, suitable predictors of adenomas recurrence are needed. The aim of this study was to find predictors of the early development of metachronous adenomas and specifically of advanced ones. MATERIALS AND METHODS: Forty-four patients underwent total colonoscopy 24-26 months after initial endoscopic polypectomy. All polyps were endoscopically removed and an adenoma was considered as advanced if the diameter was > 1 cm and/or villous component and/or severe dysplasia were present. RESULTS: Metachronous adenomas were detected in 16 (36.4% patients. Five (11.4%) of them had advanced metachronous adenomas. Early recurrence of adenomas was significantly correlated with the total number of indices adenomas (p = 0.027). On the contrary, the presence of metachronous adenomas was not related to any of the patients' characteristics nor to the site and the histology of the indices adenomas. The development of advanced metachronous adenomas during the same period was significantly correlated with patients' age, as it was observed only in patients aged > or = 60 years (5/21 or 23.8%) and in none of the patients aged < 60 years (Odds ratio: 15.7, p = 0.02). Logistic regression analysis revealed that patient's age was the only significant predictor of the early development of advanced metachronous adenomas (beta = 0.40, p = 0.02) and that the number of the indices adenomas was the only significant predictor for the recurrence of all adenomas (beta = 1.59, p = 0.02). CONCLUSIONS: 1. Only patients aged > or = 60 years seem to develop advanced metachronous adenomas two years after polypectomy and 2. The likelihood for developing metachronous adenomas during the same period is related to the number of indices adenomas.

Seasonal variation in exacerbations of ulcerative colitis.

BACKGROUND/AIMS: The aim of this study was to determine whether there is seasonal variability in exacerbations of ulcerative colitis. METHODOLOGY: The timing of ulcerative colitis relapses was retrospectively studied in a group of consecutive patients with quiescent ulcerative colitis. Ninety-four patients were followed-up at least every three months for a mean of 29.3 (range: 12-67) months. RESULTS: In total, 248 relapses of ulcerative colitis were observed with a mean number of 2.6 (range: 0-9) per patient. The timing of the relapses was characterized by a clear monthly and seasonal pattern (p < 0.001). In particular, the occurrence of relapses peaked during October and November (observed/expected (O/E): 30/20 in both months) and showed three troughs: during July and August, during December, and during February (O/E: 13/21, 7/21, 8/20, and 15/21, respectively). Moreover, the relapse rate was high during autumn and spring (O/E: 84/62 and 72/61, respectively) and low during summer and winter (O/E: 45/61 and 47/64, respectively). CONCLUSIONS: These data support the premise that there is seasonal variability in terms of relapses in ulcerative colitis patients and suggest that the role of seasonal triggering factors must be further investigated.

[Primary angiosarcoma of the spleen. Apropos of a new case]. / Angiosarcome primitif de la rate. A propos d'un nouveau cas.

The authors report a new case of primary angiosarcoma of the spleen and, after a review of the literature, they discuss its clinical, diagnostic and therapeutic problems. Primary angiosarcoma of the spleen is a very rare tumor. The diagnosis should be suspected in the case of a patient with splenomegaly and unexplained anemia, with no evidence of lymphoma, leukemia or myelofibrosis. In 30% of cases, the tumor presents in the form of spontaneous rupture of the spleen. The prognosis is very poor, as it is a highly malignant tumor, even more so in the presence of early metastases with or without spontaneous rupture of the organ. Splenectomy prior to rupture could increase the survival. Patients with or without metastatic disease may be treated by combination chemotherapy, which still remains empirical and palliative.

Similar response to adalimumab in patients with active Crohn's disease either naive to biologic agents or with prior loss of response or intolerance to infliximab.

UNLABELLED: The aim of this study was to investigate the efficacy of adalimumab, in patients with moderately active Crohn's disease (CD), either naive to biologic agents or with prior loss of response or intolerance to infliximab. MATERIAL AND METHOD: A total number of 30 patients with moderately active CD (14 men, 16 women, aged 38.5 +/- 14.4 yr) either naive to biologic agent treatment (19 pts (65%)) or with loss of response or intolerance to infliximab (11 pts (35%)), were enrolled to 4-wk trial with treatment with subcutaneous adalimumab 160 mg injection at week 0, 80 mg at week 2 and then 40 mg every other week. Outcome measures included the ability to tolerate adalimumab and clinical remission (defined as a CDAI score < or =150 points) and clinical response (defined as a decrease in the CDAI) > or =70 points). Eleven patients (37%) were smokers, 5(16%) ex-smokers and 14 (47%) non-smokers. Five patients (16%) had a positive family history for IBD. Duration of disease was 10.7 +/- 8.1 yr. Coexistence of extraintestinal manifestations was noticed in 12 (40%) patients. Vienna Classification of CD was A1=24 (80%), A2=6 (20%), L1=8 (26.7%), L2=6 (20%), L3=15 (50%), L4=1 (3.3%), B1=15 (50%), B2=5 (16.7%), B3=10 (33.3%). RESULTS: Remission was observed in 19 (63.3%) and clinical response in 9 (30%) patients. Two patients (6.7%) showed no response. No significant differences between patients with loss of response or intolerance to infliximab and the group of naive patients were noticed. Comparison between smokers and non smokers revealed significant difference in the response rate in favour of non-smokers (P < 0.002). A trend (P = 0.064) towards a significant difference in the response rate of the group of smokers according to the number of cigarettes smoked per day was observed. Patients with short duration of disease (<10 yr) had significantly better response compared to the group of patients with long (>10 yr) duration of disease. Similarly, patients with extraintestinal manifestations showed significantly better response (P = 0.044). None of the patients in both groups experienced acute or delayed hypersensitivity reactions during treatment with adalimumab. CONCLUSION: Adalimumab is well tolerated and appears to be a beneficial option for patients with CD who have not previously treated with biologic agents or have lost their response to, or cannot tolerate infliximab, with non-smokers, patients with short duration of CD, and patients with extraintestinal manifestations having a better clinical response.