Emanuele Sinagra

Dismicrobism in inflammatory bowel disease and colorectal cancer: Changes in response of colocytes

Patients with inflammatory bowel disease (IBD) have an increased risk of 10%-15% developing colorectal cancer (CRC) that is a common disease of high economic costs in developed countries. The CRC has been increasing in recent years and its mortality rates are very high. Multiple biological and biochemical factors are responsible for the onset and progression of this pathology. Moreover, it appears absolutely necessary to investigate the environmental factors favoring the onset of CRC and the promotion of colonic health. The gut microflora, or microbiota, has an extensive diversity both quantitatively and qualitatively. In utero, the intestine of the mammalian fetus is sterile. At birth, the intestinal microbiota is acquired by ingesting maternal anal or vaginal organisms, ultimately developing into a stable community, with marked variations in microbial composition between individuals. The development of IBD is often associated with qualitative and quantitative disorders of the intestinal microbial flora (dysbiosis). The healthy human gut harbours about 10 different bacterial species distributed in colony forming units which colonize the gastrointestinal tract. The intestinal microbiota plays a fundamental role in health and in the progression of diseases such as IBD and CRC. In healthy subjects, the main control of intestinal bacterial colonization occurs through gastric acidity but other factors such as endoluminal temperature, competition between different bacterial strains, peristalsis and drugs can influence the intestinal microenvironment. The microbiota exerts diverse physiological functions to include: growth inhibition of pathogenic microorganisms, synthesis of compounds useful for the trophism of colonic mucosa, regulation of intestinal lymphoid tissue and synthesis of amino acids. Furthermore, mucus seems to play an important role in protecting the intestinal mucosa and maintaining its integrity. Changes in the microbiota composition are mainly influenced by diet and age, as well as genetic factors. Increasing evidence indicates that dysbiosis favors the production of genotoxins and metabolites associated with carcinogenesis and induces dysregulation of the immune response which promotes and sustains inflammation in IBD leading to carcinogenesis. A disequilibrium in gut microflora composition leads to the specific activation of gut associated lymphoid tissue. The associated chronic inflammatory process associated increases the risk of developing CRC. Ulcerative colitis and Crohns disease are the two major IBDs characterized by an early onset and extraintestinal manifestations, such as rheumatoid arthritis. The pathogenesis of both diseases is complex and not yet fully known. However, it is widely accepted that an inappropriate immune response to microbial flora can play a pivotal role in IBD pathogenesis.

Cyclosporine or infliximab as rescue therapy in severe refractory ulcerative colitis: early and long-term data from a retrospective observational study.

INTRODUCTION About 30-40% of patients with acute severe ulcerative colitis (UC) fail to respond to intensive intravenous (iv) corticosteroid treatment. Iv cyclosporine and infliximab are an effective rescue therapy in steroid-refractory UC patients but up to now it is still unclear which is the best therapeutic choice. METHODS We reviewed our series of severe steroid-refractory colitis admitted consecutively since 1994 comparing two historical cohort treated with iv cyclosporine (2 mg/kg) or iv infliximab (5 mg/kg). The main outcome was the colectomy rate at 3 months, 12 months and at the end of the follow-up. RESULTS A total of 65 patients were included: 35 in the cyclosporine group and 30 in the infliximab one. At 3 months the colectomy rate was 28.5% in the cyclosporine group and 17% in the infliximab group (p=0.25), while 48% versus 17% at 12 months (p=0.007, OR 4.7; 95% CI: 1.47-15.16). The 1-2-3 year cumulative colectomy rates were 48%, 54%, 57% in the cyclosporine group, and 17%, 23%, 27% in the infliximab group. At the end of the follow-up the colectomy rate was 60% versus 30% (p=0.04, HR 2.2; 95% CI: 1.11-4.86). High level of C reactive protein (p=0.04), extensive disease (p=0.01) and no azathioprine treatment (p<0.001) were related to the risk of colectomy. CONCLUSION This study, despite being retrospective, indicates that both cyclosporine and infliximab are effective in avoiding a colectomy in steroid-refractory UC patients. During the follow-up the risk of a colectomy is higher in patients treated with cyclosporine than with infliximab.

INFLAMMATION IN IRRITABLE BOWEL SYNDROME: MYTH OR NEW TREATMENT TARGET?

Low-grade intestinal inflammation plays a key role in the pathophysiology of irritable bowel syndrome (IBS), and this role is likely to be multifactorial. The aim of this review was to summarize the evidence on the spectrum of mucosal inflammation in IBS, highlighting the relationship of this inflammation to the pathophysiology of IBS and its connection to clinical practice. We carried out a bibliographic search in Medline and the Cochrane Library for the period of January 1966 to December 2014, focusing on publications describing an interaction between inflammation and IBS. Several evidences demonstrate microscopic and molecular abnormalities in IBS patients. Understanding the mechanisms underlying low-grade inflammation in IBS may help to design clinical trials to test the efficacy and safety of drugs that target this pathophysiologic mechanism.

Heart failure and anti tumor necrosis factor-alpha in systemic chronic inflammatory diseases

Tumor necrosis factor alpha (TNF-alpha) antagonists have emerged as an effective therapy for patients with diseases as Crohns disease, rheumatoid arthritis, and other chronic systemic inflammatory diseases. In the last years, there has been a growing interest in the role that inflammatory cytokines, which sustain the pathogenesis of these diseases, plays in regulating cardiac structure and function, particularly in the progression of chronic heart failure. In fact there is an increase of anti-TNF alpha levels in advanced heart failure but the treatment with anti-TNF alpha has been shown to worsen the prognosis of heart failure in randomized controlled trials. Patients with rheumatoid arthritis have an increased risk for cardiovascular disease and anti-TNF alpha therapy seems to be beneficial on the risk of cardiovascular disease. In Crohns disease the increased risk of cardiovascular disease is controversial and therefore it is impossible to demonstrate an effect in reduction of the risk; however, heart failure in patients treated with anti-TNF alpha, despite in a small proportion, has been observed. On the basis of this observation, anti-TNF alpha therapy is contraindicated in patients with Crohns disease and III-IV New York Heart Association heart failure class.

Psychopharmacological Treatment and Psychological Interventions in Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) accounts for 25% of gastroenterology output practice, making it one of the most common disorders in this practice. Psychological and social factors may affect the development of this chronic disorder. Furthermore, psychiatric symptoms and psychiatric diseases are highly prevalent in this condition, but the approach to treating these is not always straightforward. As emphasized in the biopsychosocial model of IBS, with regard to the modulatory role of stress-related brain-gut interactions and association of the disease with psychological factors and emotional state, it proves useful to encourage psychopharmacological treatments and psychosocial therapies, both aiming at reducing stress perception. The aim of this paper is to analyze the effectiveness of psychopharmacological treatment and psychological interventions on irritable bowel syndrome.

Multifocal pyoderma gangrenosum resistant to infliximab in active ulcerative colitis: don't forget the role of cyclosporin.

A 25-year-old woman with ulcerative colitis (UC) was referred in January 2011 to our department with multifocal necrotic, painful skin ulcers developed on the abdominal wall, on the left tibia, and on the right thigh. In February 2009 she was operated on, in another center, by total colectomy with subsequent ileostomy due to refractoriness to medical therapy (steroids and azathioprine). Two months after there was the onset of a peristomal lesion compatible with a peristomal pyoderma gangrenosum (PG). The diagnosis was established after dermatological consultation. In July 2009 she underwent to recanalization. In October 2009 the PG was initially treated with infliximab (IFX), with a dose regimen of 5 mg/kg at 0 and 2 weeks and then monthly until January 2010, with regression of the peristomal lesion. In May 2010 there was a recurrence of the peristomal PG, which was again treated with IFX, adopting the same regimen, but without regression of the lesion. Furthermore, in November 2010 there was the appearance of another two lesions, on the left tibia zone and on the right abdominal wall; thus, IFX was stopped. Therapy was again started with corticosteroids, without any clinical improvement. In December 2010 there was a recurrence of UC, with the onset of bloody diarrhea and the further appearance of another lesion, similar to the others, on the right thigh; thus, she was referred to our unit. At admission she presented, in the above-mentioned anatomical sites, with painful ulcers with violaceous, inflammatory, undermined borders with pustules on a necrotic base, the largest ones with a diameter of 12 7 cm, on the abdominal wall (Fig. 1). A further dermatological consultation confirmed again the diagnosis of PG. Bacterial cultures of the ulcers were negative. Her bowel complaints regressed after treatment with corticosteroid. Immunosuppressive treatment was also started with oral cyclosporin A (CsA) (5 mg/kg), based on the diagnosis of PG and the refractoriness of the previous treatment with IFX, obtaining a gradual morphologic and symptomatologic regression of the lesions. The patient was discharged with an indication to continue the immunosuppressive treatment with oral CsA, monitoring the cyclosporinemia every 2 weeks, and slowly tapering corticosteroids. At the first outpatient control, 2 weeks after discharge, the two lesions on the abdominal wall were in initial regression, while the lesion on the left tibia and on the right thigh were improved but not completely regressed. The dosage of CsA was optimal (156 ng/mL), while the bowel complaint of the patient was constantly in remission. At the last outpatient control, in June 2011, she was in optimal clinical and nutritional status, and both the intestinal and the dermatological complaints (Fig. 2) were in remission. The prevailing therapeutic strategy of PG is based on systemic immunosuppression, using corticosteroids, CsA, or biologic therapy. However, no trial has compared the efficacy of different immunosuppressive drugs. CsA, at doses ranging from 3 to 5 mg/kg/day, has been shown to be effective in case reports, published FIGURE 1. Pyoderma gangrenosum of the left tibial zone before the treatment with oral Cyclosporin. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Screening of colorectal cancer: present and future

ABSTRACT Introduction: Colorectal cancer (CRC) is the third most common cancer in males and second in females, and the fourth most common cause of cancer death worldwide. Currently, about 60–70% of diagnosed cases in symptomatic patients are detected at an advanced stage of disease. Earlier stage detection through the use of screening strategies would allow for better outcomes in terms of reducing the disease burden. Areas covered: The aim of this paper is to review the current published evidence from literature which assesses the performance and effectiveness of different screening tests for the early detection of CRC. Expert commentary: Adequate screening strategies can reduce CRC incidence and mortality. In the last few decades, several tests have been proposed for CRC screening. To date, there is still insufficient evidence to identify which approach is definitively superior, and no screening strategy for CRC can therefore be defined as universally ideal. The best strategy would be the one that can be economically viable and to which the patient can adhere best to over time. The latest guidelines suggest colonoscopy every 10 years or annual fecal immuno-chemical test (FIT) for people with normal risk, while for individuals with high risk or hereditary syndromes specific recommendations are provided.

The Role of Portal Vein Thrombosis in the Clinical Course of Inflammatory Bowel Diseases: Report on Three Cases and Review of the Literature

Inflammatory bowel diseases are associated with an increased risk of vascular complications. The most important are arterial and venous thromboembolisms, which are considered as specific extraintestinal manifestations of inflammatory bowel diseases. Among venous thromboembolism events, portal vein thrombosis has been described in inflammatory bowel diseases. We report three cases of portal vein thrombosis occurring in patients with active inflammatory bowel disease. In two of them, hepatic abscess was present. Furthermore, we performed a systematic review based on the clinical literature published on this topic.

Advanced endoscopic imaging for surveillance for dysplasia and colorectal cancer in inflammatory bowel disease: could the pathologist be further helped?

Patients with inflammatory bowel disease (IBD) have an increased risk of developing intestinal cancer. The magnitude of that increased risk as well as how best to mitigate it remain a topic of ongoing investigation in the field. It is important to quantify the risk of colorectal cancer in association with IBD. The reported risk varies widely between studies. This is partly due to the different methodologies used in the studies. Because of the limitations of surveillance strategies based on the detection of dysplasia, advanced endoscopic imaging and techniques involving the detection of alterations in mucosal antigens and genetic abnormalities are being investigated. Development of new biomarkers, predicting future occurrence of colonic neoplasia may lead to more biomarker-based surveillance. There are promising results that may lead to more efficient surveillance in IBD patients and more general acceptance of its use. A multidisciplinary approach, involving in particular endoscopists and pathologists, together with a centralized patient management, could help to optimize treatments and follow-up measures, both of which could help to reduce the IBD-associated cancer risk.

Self-Expandable Metal Stent Placement for Closure of a Leak after Total Gastrectomy for Gastric Cancer: Report on Three Cases and Review of the Literature

In the setting of the curative oncological surgery, the gastric surgery is exposed to complicated upper gastrointestinal leaks, and consequently the management of this problem has become more critically focused than was previously possible. We report here three cases of placement of a partially silicone-coated SEMS (Evolution Controlled Release Esophageal Stent System, Cook Medical, Winston-Salem, NC, USA) in patients who underwent total gastrectomy with Roux-en-Y end-to-side esophagojejunostomy for a gastric adenocarcinoma. The promising results of our report, despite the small number of patients, suggest that early stenting (through a partially silicone-coated SEMS) is a feasible alternative to surgical treatment in this subset of patients. In fact, in the treatment of leakage after total gastrectomy, plastic stents and totally covered metallic stents may not adhere sufficiently to the esophagojejunal walls and, as a result, migrate beyond the anastomosis. However, prospective studies with a larger number of patients might assess the real effectiveness and safety of this procedure.