POUCHITIS: A TRIDIMENSIONAL VIEW

The preferred surgical treatment of ulcerative colitis (UC) and familial adenomatous polyposis (FAP) is represented by proctocolectomy with ileal pouch-anal anastomosis (IPAA). However, patients with UYC who have undergone IPAA are prone to develop several complications, which include surgery related/mecchanical complications; inflammatory or infectious disoreders; dysplasia or neoplasia; and systemic or metabolic disorders. Pouchitis, which is defined as the acute and/or chronic inflammation of the ileal reservoir, represent the most common long-term adverese sequela after IPAA. Gut microbiota play a pivotal role in the initiation and disease progression of pouchitis. Pouchitis can be classified according to the activity of the disease, the duration of the symptoms, the pattern of the disease or response to antibiotic therapy. Patients with IPAA for UC tend to experience a variety of symptoms that may eventually lead to pouch excision thereby necessitating the construction of a permanent ileostomy. To date, the ethiology, the diagnosis and the medical management of pouchitis represent a clinical challenge. In fact pouchitis range from a disease with an acute antibiotic-responsive presentation to a chronic antibiotic-refractory form, with subsequent different disease mechanism and clinical course. A tridimensional and multidisciplinar approach, including endoscopy, histology, and laboratory testing is widely helpful to identify the diferent phenotypes of the disease and to manage correctly its treatment

COLORECTAL CANCER IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: PRELIMINARY RESULTS FROM AN ONGOING CASE-CONTROL STUDY

Background and Aim:Understanding the risk factors for colorectal cancer (CRC) is crucial to the development of effective strategies for its prevention. meta-analysis and epidemiological studies have already shown that type 2 diabetes mellitus (DM) is associated with an increased risk of CRC and have provided data to support a positive relationship between these diseases. Material and Methods: We retrospectively evaluated 741 consecutive caucasian patients with type 2 DM who underewnt colonoscopic screening cof CRC and followed in our tertiary referrral center in 200-208 for incidence of CRC. Patients were stratified based on gender, age, body mass index (MBI), alchool and NSAIDS assumption, family history for cancer blood glycated hemoglobin levels, hypertension, hypertrigliceridemia, age at diabetes onset and duration, treatment with insulin or other hypoglicemic drugs. A total of 257 consecutive control patients were selected from a cohort of patients followed as outpatients for thyroid diseases. Results: At a median follow-up of 132,5 months (range 33,3-175,7) 56 cases of cancer (prevalence 7,56%) occurred; among these, 14 cases of CRC were reported (prevalence 18,8%) among the diabetic patients, while only one case (prevalence 0,004%) occurred in the control group, although this difference is not statistically significant (chi-square 2,9, P=0,08). Median duration of DM to CRC diagnosis was 156 months (range 1-768). At the univariate analysis older age (p=0,001), and diabetes duration (p=0,001) were related to higher risk of cancer, while metformin seems to be protective towards cancer (p=0,058). in the subset of patients with CRC, older age (p=0,001) and diabetes duration (p=0,001) were related to higher risk of CRC, such as treatment with sulphonylureas (p=0,01). Conclusions: Our preliminbar data show that the prevalence of CRC in the cohort of patients with type 2 DM was higher compared to that from our control group, and to that from the National Tumor Register up 2010 (0,5%). Furthermore we could interestingly hypotize that sulphonylureas may play a role in CRC carcinogenesis altering the physiological insulin secretion

MESENCHIMAL STEM CELLS IN INFLAMMATORY BOWEL DISEASES: CLINICAL EVIDENCES AND POTENTIAL INSIGHTS FOR THE CLINICIANS

Mesenchimal stem cells (MSCs) have been used experimentally and clinically in the treatment of a wide variety of pathologies MSCs can be safely transplanted in autologous and allogenic ways as they are non-immunogenic, and consequently represent a therapeutic option for refractory connective tissue diseases, fibrosing diseases like scleroderma and fistulizing colitis like in Crohn's disease (CD). The immunomodulatory properties of MSCs have already shown promise when used as therapy for otherwise medically refractory CD. Accumulating evidence suggests that the properties may also be exploited of several other conditions. The currently available experimental and clinical data indicate that, similar to previously obtained data in the setting of HSCT, MSC treatment for IBD is feasible and safe. aim of this review is to analyze the pathophysiological insights for the use of MSCs in inflammatory bowel diseases, and to summarize the clinical evidences about the efficacy and safety of stem cell therapy in such disorders

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

Variable Number of Tandem Repeats (VNTR) gene polymorphism of CYP2E1 in patients with pancreatic adenocarcinoma

Context: The genetic polymorphism is considered a major source of variability, influencing the levels of gene expression. Cytochrome P450 2E1 (CYP2E1) is a mixed-function oxidase involved in the metabolism of the many endogenous and exogenous substances (ethanol, chemical carcinogens) in the hepatic and pancreatic tissue. CYP2E1 gene polymorphisms can cause various abilities of metabolize xenobiotic substances within a population with consequent increased susceptibility to various diseases,including cancer. One of the polymorphisms of the CYP2E1 gene is a VNTR (Variable Number Tandem Repeat) of some sequences in its "5 '- flanking region. Method : VNTR genotype CYP2E1 was determined by RFLP-PCR performed on DNA extracted from peripheral blood lymphocytes and paraffin embedded tissue of central-western Sicilia population with PA, to confirm or exclude a correlation between certain genotypes and specific disease. A population of university students, without specific overt disease, was used as control . Results: The modal genotype, found in all subjects, was CYP2E1 VNTR A2/A2, while CYP2E1 VNTR A2/A4 was the least represented in both populations. The A2/A3 genotype was different between patients with pancreatic cancer and healthy subjects, suggesting a correlation between this genotype and pancreatic cancer. Recent studies indicated A2 allele might be associated with a negative regulation of the gene and nothing about it has been reported for the allele A3. Conclusion: Our preliminary data indicate an association between genotype A2/A3 and PA and allow us to hypothesize that the A3 allele is associated with low activity of the CYP2E1 gene. Consequently, individuals with this allelic association may have inadequate ability to metabolize toxic xenobiotic substances, condition that might increase the susceptibility to develop some cancer, including PA

Creutzfeldt-Jakob disease associated with the R208H mutation in the prion protein gene

The authors investigated a patient who died of apparent sporadic Creutzfeldt-Jakob disease (CJD) but carried a R208H substitution in the prion protein (PrP). The patient phenotype was indistinguishable from typical sporadic CJD (i.e., MM1 subtype). In addition, pathologic PrP, PrP(Sc), originated from both the normal and the mutated PRNP allele and had the same characteristics as PrP(Sc) type 1. The authors propose that the R208H mutation influences disease susceptibility without significantly affecting PrP(Sc) properties or disease phenotype

Quantitative Mass Spectrometry Analysis of the Pathological PrP Allotypes Present in the Brain of gCJD Affected Individuals

Transmissible spongiform encephalopathies (TSEs) are neurodegenerative disorders characterized by the accumulation, principally in the central nervous system (CNS), of the abnormal form (PrPTSE) of a host encoded protein, the cellular prion protein (PrPC). In humans some forms of TSEs have a genetic etiology, as they are associated to mutations in the PrP gene: thus it is extremely important to elucidate the role played by the altered residue in the pathological conversion of the protein. Aim of our work was to deduce the involvement of the mutated residue in the molecular mechanisms underlying genetic TSE pathogenesis by means of a quantitative mass spectrometry analysis of the PrPTSE allotypes accumulated in the brains of genetic Creutzfeldt-Jakob disease (gCJD) affected individuals. We have integrated our previous data on the gCJD patient carrying the R208H mutation with those regarding V210I gCJD patients in order to verify if diverse mutations regulate in a different fashion the process of molecular pathogenesis. The LC/MS (liquid chromatography/mass spectrometry) protocol developed by us (Schinin\ue0 M.E. et al., 2003. Pure Appl. Chem., 75: 317-323) has been implemented in order to set up, by means of appropriate synthetic deuterated (internal standards) and non-deuterated (calibrants) peptides, a quantitative analysis of the pathological PrP allotypes. In all cases the amount of the mutant allotype is higher than the wild-type counterpart: in the R208H subject the mutant/wild-type ratio has been again estimated and it was around 3/1, while in all the V210I individuals it was lower than 2/1. These results demonstrate that the presence of the mutation is partially involved in favouring the pathological conversion of PrP, but it is not the only factor implicated in the pathogenesis of TSEs as the ratio of the two allotypes does not reveal a significantly higher amount of the mutant allotype compared to the wild-type one. Further investigations are needed in order to elucidate the molecular mechanisms underlying the pathogenesis of genetic human TSEs

Association between single nucleotide polymorphisms (SNPs) of IL-6, TNF-alpha and VEGF-A genes, and susceptibility to hepatocellular carcinoma (HCC)

Background: Many studies have demonstrated the association between SNPs and susceptibility to the development of diseases such as autoimmune diseases and neoplasms. These allelic variations may involve regulatory and coding regions of cytokine genes and may influence their transcriptional activity and, as a consequence, their protein levels. Hepatocarcinogenesis is a multi-step and multi-factorial process in which both environmental and genetic factors are involved. Liver cirrhosis (LC) of both HBV or HCV origin is considered the most important risk factors for HCC. Objectives: We evaluated the frequency of genetic polymorphisms of the cytokines IL-6 and TNFalpha and of VEGF-A in a group of patients with HCC(n=112) and underlying LC and compared them with a group of cirrhotic patients (n=90), without HCC, and a group of age- and sex-matched controls(n=124) in order to verify an eventual correlation between the allelic variations and the risk of developing tumor. Methods: DNA extracted from whole blood of the three Sicilian groups, was used for the evaluation of SNPs using Restriction Fragment Length Polymorphisms (RFLP) method in -174 position of IL-6 gene promoter (G/C transversion, G allele is associated with higher levels of the cytokine); -308 position of TNF-alpha gene promoter (G/A transition, G allele is associated with lower levels of the cytokine); 936 position of the coding region of VEGF-A gene (G/T transition, T allele is associated with high levels of VEGF-A). Data were analyzed was performed using the chi square and the Fisher exact tests were appropriated. P value was considered significant if <0.05. Results: Genotype frequency of IL-6 -174 was: controls vs HCC p < 0.79, controls vs cirrhosis p < 0.24, HCC vs controls p < 0.22; genotype frequency of TNF-alpha -308 was: controls vs HCC p < 0.057, controls vs cirrhosis p < 0.44, HCC vs controls p < 0.06; genotype frequency of VEGF-A 936 was: controls vs HCC p < 0.21, controls vs cirrhosis p < 0.22, HCC vs controls p < 0.60. Conclusion: These results do not demonstrate a significant correlation between the allelic variants considered and the risk of developing HCC. However the trend almost statistically significant of SNP -308 of TNF-alpha may suggest that in HCC subjects there are more A carriers with a higher susceptibility to the inflammatory type which may contribute to the development of the tumor

Le societ\ue0 a partecipazione pubblica

Il Volume rappresenta un commento sistematico al Testo Unico sulle sopita a partecipazione pubblica (d.lgs 175/2016)