Canonical and uncanonical pathogenic germline variants in colorectal cancer patients by next-generation sequencing in a European referral center.

BACKGROUND: Despite increasing use of next-generation sequencing (NGS), data concerning the gain in germline pathogenic variants (PVs) remain scanty, especially with respect to uncanonical ones. We aimed to verify the impact of different cancer predisposition genes (CPGs) on colorectal cancer (CRC) in patients referred for genetic evaluation. MATERIALS AND METHODS: We enrolled for NGS, by Illumina TruSight Cancer panel comprising 94 CPGs, 190 consecutive subjects referred for microsatellite instability (MSI) CRC, polyposis, and/or family history. RESULTS: Overall, 51 (26.8%) subjects carried 64 PVs; PVs coexisted in 4 (7.8%) carriers. PVs in mismatch repair (MMR) genes accounted for one-third of variant burden (31.3%). Four Lynch syndrome patients (20%) harbored additional PVs (HOXB13, CHEK2, BRCA1, NF1 plus BRIP1); such multiple PVs occurred only in subjects with PVs in mismatch syndrome genes (4/20 versus 0/31; P = 0.02). Five of 22 (22.7%) patients with MSI cancers but wild-type MMR genes harbored PVs in unconventional genes (FANCL, FANCA, ATM, PTCH1, BAP1). In 10/63 patients (15.9%) with microsatellite stable CRC, 6 had MUTYH PVs (2 being homozygous) and 4 exhibited uncanonical PVs (BRCA2, BRIP1, MC1R, ATM). In polyposis, we detected PVs in 13 (25.5%) cases: 5 (9.8%) in APC, 6 (11.8%) with biallelic PVs in MUTYH, and 2 (3.9%) in uncanonical genes (FANCM, XPC). In subjects tested for family history only, we detected two carriers (18.2%) with PVs (ATM, MUTYH). CONCLUSION: Uncanonical variants may account for up to one-third of PVs, underlining the urgent need of consensus on clinical advice for incidental findings in cancer-predisposing genes not related to patient phenotype.

Autonomic nervous system dysregulation in irritable bowel syndrome.

BACKGROUND: Autonomic nervous system (ANS) regulation may be altered in functional diseases, including irritable bowel syndrome (IBS), but published data are not clear to date. The aim of the study was to analyze ANS function in IBS subjects classified by Rome III criteria and healthy controls using standardized technique. METHODS: ANS activity was evaluated by autoregressive spectral analysis of RR interval and systolic arterial pressure variabilities, to obtain indices of sympatho-vagal modulation of the heart and of spontaneous cardiac baroreflex (α index). A symptom list was used to score 18 somatic complaints (score 0-180) (4SQ). Fatigue and stress were assessed through the use of a global scoring index (0-10). KEY RESULTS: We enrolled 41 IBS subjects (29 F, age 40 ± 2 years) and 42 healthy matched controls. Heart rate was higher in IBS than control subjects (69 ± 2 vs 61 ± 1; p < 0.001). The total variance of RR interval variability, and α index, were significantly lower in IBS compared to controls (1983.12 ± 384.64 ms(2) vs 4184.55 ± 649.59 ms(2) ; 18.1 ± 2 ms/mmHg vs 29 ± 3 ms/mmHg; p < 0.01). The α index results showed an inverse correlation with stress scores and somatic symptoms. CONCLUSIONS & INFERENCES: IBS subjects display a significant reduction in α index, an established marker of cardiac baroreflex. ANS dysfunction appears to be involved in the pathophysiology of IBS and its assessment may open new perspectives for clinical management of patients suffering from IBS.

Molecular heterogeneity and prognostic implications of synchronous advanced colorectal neoplasia.

BACKGROUND: It is uncertain whether synchronous colorectal cancers (S-CRCs) preferentially develop through widespread DNA methylation and whether they have a prognosis worse than solitary CRC. As tumours with microsatellite instability (MSI) may confound the effect of S-CRC methylation on outcome, we addressed this issue in a series of CRC characterised by BRAF and MS status. METHODS: Demographics, clinicopathological records and disease-specific survival (DSS) were assessed in 881 consecutively resected CRC undergoing complete colonoscopy. All tumours were typed for BRAF(c.1799T>A) mutation and MS status, followed by search of germ-line mutation in patients with MSI CRC. RESULTS: Synchronous colorectal cancers (50/881, 5.7%) were associated with stage IV microsatellite-stable (MSS) CRC (19/205, 9.3%, P=0.001) and with HNPCC (9/32, 28%, P<0.001). BRAF mutation (60/881, 6.8%) was associated with sporadic MSI CRC (37/62, 60%, P<0.001) but not with S-CRC (3/50, 6.0%, P=0.96). Synchronous colorectal cancer (HR 1.82; 95% CI 1.15-2.87; P=0.01), synchronous advanced adenoma (HR 1.81; 95% CI 1.27-2.58; P=0.001), and BRAF(c.1799T>A) mutation (HR 2.16; 95% CI 1.25-3.73; P=0.01) were stage-independent predictors of death from MSS CRC. Disease-specific survival of MSI CRC patients was not affected by S-CRC (HR 0.74; 95% CI 0.09-5.75; P=0.77). CONCLUSION: Microsatellite-stable CRCs have a worse prognosis if S-CRC or synchronous advanced adenoma are diagnosed. The occurrence and the enhanced aggressiveness of synchronous MSS advanced neoplasia are not associated with BRAF mutation.

Early expression of the fractalkine receptor CX3CR1 in pancreatic carcinogenesis.

BACKGROUND: In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI. METHODS: We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-Kras(G12D) mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells. RESULTS: In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1(+) and -CL1(+). In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours. CONCLUSION: Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.

Safety of cold polypectomy for <10mm polyps at colonoscopy: a prospective multicenter study.

BACKGROUND: Cold polypectomy techniques (without electrocautery) by means of biopsy forceps or snare are widely adopted for the removal of subcentimetric polyps. However, few data are available on the safety of this approach. The aim of this study was to assess the safety of cold polypectomy for subcentimetric polyps, as well as the rate of advanced neoplasia in these lesions. PATIENTS AND METHODS: In a prospective multicenter trial, consecutive patients with at least one < 10-mm polyp at colonoscopy were prospectively included. All of the < 10-mm polyps detected within the study period were removed by cold polypectomy. The rates of immediate or delayed bleeding and other complications were assessed at 7 and 30 days after cold polypectomy by telephone calls. The rate of advanced histology was also assessed. Predictive variables of postpolypectomy bleeding or advanced neoplasia were identified by multivariate analysis. RESULTS: A total of 1015 < 10-mm polyps in 823 patients (15.5 % on antiplatelet agents) were removed. Of these, 822 (81 %) were ≤ 5 mm and 193 (19 %) were 6 - 9 mm. Immediate postpolypectomy bleeding occurred in 18 patients, corresponding to a per-patient and per-polyp bleeding rate of 2.2 % (95 % confidence interval [CI] 1.2 % - 3.2 %) and 1.8 % (95 %CI 1 % - 2.6 %), respectively. Therapy with antiplatelet agents (odds ratio [OR] 4; 95 %CI 1.5 - 10.6) and larger polyp size (OR 2; 95 %CI 1.1 - 6.9) were independent predictors of bleeding. Bleeding was successfully treated by endoscopic hemostasis in all cases and required no further medical intervention. Advanced neoplasia prevalence in polyps ≤ 5 mm was as high as 8.7 %. CONCLUSIONS: The results from this study showed the high safety of a cold polypectomy approach for subcentimetric polyps. This was due to the low rate of postpolypectomy bleeding and to the high efficacy of endoscopic hemostasis in its treatment. The high rate of advanced neoplasia in polyps ≤ 5 mm should prompt some caution on the management of these lesions following detection at computed tomography colonography or colon capsule endoscopy.

Balanced Propofol Sedation in Patients Undergoing EUS-FNA: A Pilot Study to Assess Feasibility and Safety.

Introduction and aims. Balanced propofol sedation (BPS) administered by gastroenterologists has gained popularity in endoscopic procedures. Few studies exist about the safety of this approach during endosonography with fine needle aspiration (EUS-FNA). We assessed the safety of BPS in EUS-FNA. Materials and methods. 112 consecutive patients, referred to our unit to perform EUS-FNA, from February 2008 to December 2009, were sedated with BPS. A second gastroenterologist administered the drugs and monitorized the patient. Results. All the 112 patients (62 males, mean age 58.35) completed the examination. The mean dose of midazolam and propofol was, respectively, of 2.1 mg (range 1-4 mg) and 350 mg (range 180-400). All patients received oxygen with a mean flux of 4 liter/minute (range 2-6 liters/minute). The mean recovery time after procedure was 25 minutes (range 18-45 minutes). No major complications related to sedation were registered during all procedures. The oxygen saturation of all patients never reduced to less than 85%. Blood systolic pressure during and after the procedure never reduced to less than 100 mmHg. Conclusions. In our experience BPS administered by non-anaesthesiologists provided safe and successful sedation in patients undergoing EUS-FNA.

Oesophageal motility and bolus transit abnormalities increase in parallel with the severity of gastro-oesophageal reflux disease.

BACKGROUND: Limited data are available regarding the frequency of oesophageal motility and bolus transit abnormalities in subgroups of patients with gastro-oesophageal reflux disease (GERD). AIM: To assess oesophageal motility and bolus transit in endoscopically defined GERD subgroups. METHODS: Patients (N=755) with typical reflux symptoms underwent upper endoscopy, conventional or impedance oesophageal manometry and/or impedance-pH testing. They were divided into: erosive oesophagitis (EO; N=340), Barrett Oesophagus (BO; N=106), non-erosive reflux disease (NERD; endoscopy-, abnormal pH and/or SAP/SI+; N=239) and functional heartburn (FH; endoscopy-, normal pH and SAP/SI-; N=70). Manometric patterns and bolus transit were defined according to previously published criteria. RESULTS: Increasing GERD severity was associated with decreased lower oesophageal sphincter resting pressure (P< 0.05) and distal oesophageal amplitude (P<0.01), higher prevalence of hiatal hernia (P<0.01) and increased prevalence of ineffective oesophageal motility (P<0.01). Patients with EO and BO had a significantly lower percentage of complete bolus transit compared with NERD and FH (P<0.01). Overall, abnormal bolus transit (ABT) for liquid swallows was found in 12% of FH, 20% of NERD, 54% of EO and 56% of BO (P<0.01). Combined impedance-manometry showed abnormal oesophageal function in 4% of FH, 4% of NERD, 22% of EO and 21% of BO patients with normal oesophageal manometry. CONCLUSIONS: Oesophageal motility abnormalities increase in parallel with the severity of GERD from NERD to EO and BO. Bolus transit abnormalities in severe reflux disease underscore the importance of impaired oesophageal function in the development of mucosal injury.

Prospective comparison of computed tomography enterography and magnetic resonance enterography for assessment of disease activity and complications in ileocolonic Crohn's disease.

BACKGROUND: Studies comparing magnetic resonance enterography (MRE) and computerized tomography enterography (CTE) for Crohn's disease (CD) are scarce. METHODS: The aim of this study was to prospectively compare the sensitivity, specificity, and accuracy of abdominal MRE and CTE to assess disease activity and complications (fistulas, strictures) in ileocolonic CD. A total of 44 patients (23 male; 21 female; mean age 44) with ileocolonic CD underwent both MR and CT in a short time interval (mean 5 days). A 16-slice CT with intravenous contrast and an MRI with oral and paramagnetic intravenous contrast were performed. Ileocolonoscopy was used as the reference standard. Sensitivity values of CT and MR for detection of extraenteric signs of disease were compared with the McNemar test, with results of imaging studies, surgery, and physical examination as reference standards. RESULTS: No significant differences in sensitivity, specificity, and accuracy were observed between MRE and CTE regarding the following parameters at the patient level: localization of CD (P = 1.0), bowel wall thickening (P = 1.0), bowel wall enhancement (P = 1.0), enteroenteric fistulas (P = 0.08), detection of abdominal nodes (P = 1.0), and perivisceral fat enhancement (P = 0.31). MR was significantly superior compared to CT in detecting strictures (P = 0.04). Per segment analysis showed that MRE was significantly superior to CTE in detecting ileal wall enhancement (P = 0.02). CONCLUSIONS: MR and CT are equally accurate to assess disease activity and bowel damage in CD. MR may be superior to CT in detecting intestinal strictures and ileal wall enhancement. MR may represent an alternative technique to CT in assessing ileocolonic CD.

Adalimumab in Crohn's disease: tips and tricks after 5 years of clinical experience.

INTRODUCTION: Three anti TNF-α agents have currently been approved for the treatment of moderate-to-severe or complicated Crohn's disease (CD): infliximab, certolizumab and adalimumab. Infliximab is effective in CD, but for reasons linked to its chimeric structure, response to treatment may be lost overtime and as a result, it can sometimes be unable to provide long term durable treatment of CD. Adalimumab, a fully human anti TNF-α antibody, demonstrates similar treatment efficacy as infliximab and certolizumab, and can easily be self-administered at home. AIM AND METHODS: A literature search in the Cochrane, MEDLINE, PUBMED, Ovid MEDLINER® and EMBASE databases has been performed on the efficacy, safety and the impact adalimumab has on the quality of life and natural history of CD. Abstracts presented at the DDW, UEGW and ECCO Congresses have also been reviewed as well as references from review articles, meta-analysis studies and published RCTs. RESULTS: Adalimumab induced remission of CD in 64% of patients, and maintained remission in more than 80% of initial responders. Adalimumab did not significantly increase the risk of adverse events compared with conventional medication up to 3 years of follow-up. Adalimumab reduces more than 50% the risk for hospitalisation and surgery due to CD. It is also effective for fistula closure, for the healing of the mucosa, and improving quality of life. CONCLUSION: Adalimumab is effective in the induction and maintenance of clinical remission in CD and is generally well tolerated. It has been proved to have a positive impact by improving quality of life of patients, and reducing the need for hospitalisation and surgery due to CD. According to the European Crohn's and Colitis Organisation (ECCO), infliximab or adalimumab can be used for the treatment of fistulizing CD.

Transoral treatment of Zenker diverticulum: flexible endoscopy versus endoscopic stapling. A retrospective comparison of outcomes.

Transoral stapled diverticulo-esophagostomy (TSDE) has gained increased popularity in surgical treatment of Zenker diverticulum (ZD). One of the advantages of this approach is early rehabilitation with significant decrease in patient morbidity and time to resumption of oral intake as compared with open treatment. The section of the septum between the diverticulum and the esophagus with a flexible endoscopic (ES) approach has also been proposed since mid-90s as an alternative for treatment of ZD. Both these approaches are a minimally invasive approach to treat ZD. We compared the TSDE management of ZD versus the ES treatment in a retrospective consecutive series of patients who were referred to either the ES or surgical unit of our Institute. Fifty-eight consecutive patients underwent treatment for ZD either by TSDE or ES. The two techniques were evaluated for length of hospital stay, diverticulum size, resumption of oral intake, resolution of dysphagia, and complications. Clinical outcome was evaluated throughout a symptom score from 0 to 3, calculated before and after the procedure. The two groups were compared on the various parameters using a Mann--Whitney test. Twenty-eight patients underwent ES and 30 TSDE for ZD. In both groups, a significant decrease in postoperative versus preoperative dysphagia was reported. The average length of hospital stay wasn't significantly different in the two groups (3.38 days for TSDE vs. 2.42 days for ES). The overall complication rate was similar in the two groups. There were two cases in the ES group and three cases in the TDSE group that required an ES revision to take down a residual diverticular wall that produced a mild but persistent dysphagia. Minimally invasive treatment of ZD both with ES and with TSDE is a valuable option for this disease: both techniques are safe and effective, with similar outcome in terms of hospital stay, symptom reduction, and complication rate. Long-term results have to be evaluated.

Endoscopic flexible treatment of Zenker's diverticulum: a modification of the needle-knife technique.

BACKGROUND AND STUDY AIM: Endoscopic treatment of Zenker's diverticulum has been successfully reported over the last 10 years using different approaches. The hook-knife is a new device originally developed for endoscopic submucosal dissection procedures. This study aimed to investigate the safety and efficacy of endoscopic myotomy performed with the hook-knife. PATIENTS AND METHOD: From July 2005, 32 consecutive patients (23-male, mean age 74.8 years) with dysphagia secondary to the presence of Zenker's diverticulum were prospectively enrolled. Myotomy was performed using a straight-end transparent hood to the tip of the scope and the hook-knife for the incision of the bridge between the Zenker's diverticulum and the esophagus. Clinical outcome was evaluated assigning a dysphagia symptom score from 0 (symptoms absent) to 4 (inability to swallow saliva). RESULTS: General anesthesia was used in 4 patients, deep sedation with propofol in 23 patients, while midazolam was used in 5 patients. The mean procedural time was 28 minutes. Complications occurred in 2 patients (6.25 %). At 1 month follow-up, the mean dysphagia score was significantly improved from 2.9 to 0.6 ( P < 0.001) with 87.5 % of patients free of symptoms and 4 patients with dysphagia that was persistent but milder than before the treatment. Three of these 4 patients underwent a successful second endoscopic treatment with complete relief of dysphagia; one was not re-treated because of advanced age (92 years). During the follow-up period (23.87 +/- 9.6 months), 2 patients developed dysphagia recurrence. The overall success rate was 90.6 %. CONCLUSIONS: Diverticulectomy with a flexible scope and the hook-knife may represent a safe and effective alternative treatment for patients with Zenker's diverticulum.

New drug delivery systems in inflammatory bowel disease: MMX and tailored delivery to the gut.

UNLABELLED: Inflammatory bowel diseases are chronic diseases that affect the gastrointestinal tract. Mesalamine, corticosteroids, immunosuppressants and biological agents are currently used to treat these diseases. Due to inadequacies of the currently available delivery systems, a large number of patients do not respond to treatment, especially when they are affected by distal colonic disease. Multimatrix (MMX) technology comprises hydrophilic and lipophilic excipients, enclosed within a gastro-resistant, pH-dependent coating. This new delivery technology has been used to modify some commonly used drugs, including mesalamine and budesonide, as well as heparin, which are now being investigated for their utility in the management of IBD. AIM: The aim of this review is to explore the MMX delivery technology and its efficacy for the treatment of IBD. RESULTS: The results of various studies involving MMX drugs have been published. Mesalamine MMX induces clinical and endoscopic remission in patients with mild to moderate ulcerative colitis (UC) compared with placebo. Positive results have also been observed with MMX budesonide in two phase I studies. In a pilot study involving ten patients with UC, efficacy of heparin-MMX as an IBD therapy was observed. CONCLUSION: MMX is a promising new delivery system that can improve efficacy of current and new drugs, augmenting targeting to the affected tract, thereby increasing response and remission rates for those drugs in patients with IBD.

Emerging biologics in the treatment of inflammatory bowel disease: what is around the corner?

Inflammatory bowel diseases (IBD) are idiopathic chronic inflammations: the etiology of Crohn's disease (CD) and ulcerative colitis (UC) is still largely unknown. Environmental and genetic factors in combination with the microbial flora or specific microorganisms trigger an event, leading to the activation of an intestinal immune response. Immune and non-immune cells create a cross talk via the secretion of soluble mediators and expression of cell adhesion molecules, resulting in further cell activation. Mediators such as cytokines and chemokines play a role in cell recruitment and polarization, intercellular signal amplification or activation and differentiation. Considering these aspects, medical management of inflammatory bowel disease has changed considerably over the past decade. Advances in biotechnology has allowed for the introduction of many biologic therapies, other than anti-TNF therapies. Many of these drugs showed clinical benefit for induction and maintenance therapy, both in UC and CD. Although numerous, at present only monoclonal anti-TNF antibodies are currently available worldwide. Other biological agents have been tested or are under evaluation. This paper systematically reviews the mechanism-of-action, efficacy, short-term and, where available, long-term safety of biological agents that have been approved for the treatment of IBD or are under evaluation which target different molecules other than tumor necrosis factor alpha (TNF-alpha).

Review article: anti-fibrotic agents for the treatment of Crohn's disease - lessons learnt from other diseases.

BACKGROUND: The current therapies for Crohn's disease (CD) are mainly focused on blockade of inflammation. Fibrosis remains one of the major complications of CD often leading to surgery, affecting patients' quality-of-life. AIM: To summarize the published data regarding the potential anti-fibrotic role of drugs commonly used in CD and the most effective anti-fibrotic drugs used in other diseases evaluating their potential use to treat intestinal fibrosis in CD. METHODS: A literature search was performed in the PubMed, Medline, Cochrane and EMBASE databases, considering in vitro, animal and human studies on fibrosis in inflammatory bowel disease and other similar chronic pathologies. RESULTS: Treatment of fibrosis in CD is limited to surgery or endoscopic dilatation, although some of the drugs currently used may have anti-fibrotic activity. In other diseases, anti-fibrotic agents are already used or are in preclinical or clinical trials. ACE inhibitors, Angiotensin Receptor Blockers, and HMG-CoA inhibitors merit further investigation in CD because of their role in preventing fibrosis in cardiovascular and renal diseases. CONCLUSIONS: Anti-fibrotic drugs are under evaluation or already used in clinical practice in other chronic inflammatory diseases. In CD, there is a great need for investigation into agents that may prevent, reduce or reverse intestinal fibrosis.

Review article: anti TNF-alpha induced psoriasis in patients with inflammatory bowel disease.

BACKGROUND: Anti TNF-alpha agents are used successfully for several autoimmune diseases, including IBD and psoriasis. An emerging challenge is the increasing incidence of anti TNF-alpha induced psoriasis. A total of 120 cases have been currently reported, of whom 18 patients were treated with biological agents for IBD. OBJECTIVES: To analyse all cases of anti TNF-alpha induced psoriasis in patients with IBD in the literature and to investigate potential mechanisms of action. METHODS: A literature review was performed in the PubMed, Medline, Cochrane and EMBASE databases, with simple analysis of demographic data, drug administration and psoriasis onset. Risk and incidence patient/year/duration (pyd) was calculated. RESULTS: A total of 18 patients with IBD treated by anti TNF-alpha agents developed drug-induced psoriasis of which, 17 patients developed with infliximab, one with adalimumab. The most frequent time of onset is between 3rd and 4th infusion of infliximab. Withdrawal of infliximab led to regression of lesions in 16 patients. In six patients, infliximab was reintroduced with no further recurrence of psoriasis. CONCLUSIONS: Although anti TNF-alpha induced psoriasis is extremely rare, understanding the mechanism will be a key step towards better realizing the role played by TNF-alpha and its pharmacological inhibitors in immune-mediated diseases.

Clinical experience with a new endoscopic over-the-scope clip system for use in the GI tract.

BACKGROUND: The newly designed over-the-scope clip (OTSC) seems to overcome several limitations of current clipping system, such as size and opening-closing force, allowing better control of gastric or colonic bleeding and/or deep wall defect or perforation. AIMS: The aim of this retrospective analysis was to describe the new endoscopic device and evaluate our first clinical experience. PATIENTS AND METHODS: We treated with the OTSC system 9 patients (range, 58-85 years; 6 men, 3 women) with bleeding and/or deep wall lesions of the GI tract. The OTSC system is composed of an application cap, which is mounted onto the distal tip of the endoscope and a connected releasing mechanism, installed on the handle of the scope. The rotation of the handle allows the release of the clip by a two tube sliding mechanism. RESULTS: All applications resulted successful, i.e. haemostasis was achieved, and/or wall defects could be closed. No complication was observed that could be ascribed to the clip itself or to the technique. CONCLUSIONS: The OTSC system is a new endoscopic tool for compression of large tissue areas and its indications are nonvaricose bleedings difficult to control and lesions or perforations of the GI tract. The initial clinical use of this clipping device proved to be efficient and effective.

Endoclipping for gastric perforation secondary to second session of EMRC in locally residual early gastric cancer: a case report.

A 72-year-old woman underwent gastric endoscopic mucosal resection with a cap-fitted endoscope for an adenocarcinoma in situ. She was scheduled for endoscopic follow-up at 1 and 3 months after the procedure. By the third month of follow up, biopsies of a slightly depressed scar area showed an high grade epithelial dysplasia. For this reason a second endoscopic resection (ER) was performed using the oblique soft cap. A perforation in the site of endoscopic resection was immediately observed. The complication was treated successfully by the application of seven clips.

Differences and evolution of the methods for the assessment of microsatellite instability.

Microsatellite instability (MSI) originates from the systematic accumulation of uncorrected deletion/insertion in repetitive DNA tracts in cancer cells with a deficient mismatch repair system. Among colorectal cancers, the MSI signature identifies hereditary cases arising in patients with germline mutations in hMLH1, hMSH2, PMS2 and a fraction of those with hMSH6 mutations, as well as sporadic cancers with epigenetic hMLH1 promoter hypermethylation. Considering the specific pathogenesis, pathological features, natural history and response to 5-fluoro-uracil-based chemotherapy of the MSI cancers, confusion about the genetic markers for MSI recognition seems surprising. In this clinically relevant field, an agreement has not been reached concerning the use of di- or mononucleotide markers for MSI assessment. The Revised Bethesda Guidelines still recommend a panel of markers consisting of mono- and dinucleotides, despite being questioned whether it is congruous to continue to use dinucleotide markers for MSI identification. In any event, no single marker is accurate enough for MSI testing, and an awareness of their pros and cons is required for proper interpretation of results. In recent years, several papers have reported different prevalence of MSI in unrelated series, largely depending on the detection and classification method, suggesting that MSI test interpretation also requires the understanding of the phenomenon rather than simply the crude satisfaction of panel recommendations. Inaccuracies can otherwise lead to under- or overdiagnosis and inaccurate disease classification, which always have a negative impact on the clinical practice of medicine.

Colifagina, a novel preparation of 8 lysed bacteria ameliorates experimental colitis.

Immune reactivity towards the bacterial intestinal flora plays an important part in the pathogenesis of inflammatory bowel disease. Administration of probiotic bacteria has beneficial effects on infectious and inflammatory diseases, principally in bowel disorders. However, little is known about the administration of soluble bacterial antigens in intestinal inflammation. We investigated the therapeutic effects of colifagina in experimental colitis. To assess this effect, C57BL/6 mice with dextran sulphate sodium-induced colitis were treated with colifagina, or with a placebo, for a period of 10 days. The mice were monitored, and inflammation was assessed by disease activity index (DAI). Analysis of fecal IgA concentration and measurement of IgA and inflammatory chemokine production in organ colonic culture was performed by ELISA. Clinically and histologically, bacterial-lysate-treated mice revealed significantly fewer DAI and a reduction of colonic histological inflammation. Treatment of healthy mice with colifagina significantly increased the fecal concentration of IgA and IgA production in organ culture. Colifagina administration in DSS-treated mice significantly increased the fecal concentration of IgA and IgA production in organ culture. MIP-1, MIP-2 and RANTES concentrations in colonic organ culture were significantly lower in colifagina-treated mice than in the placebo group. The use of colifagina is effective in amelioration of murine colitis.