Circulating IL-8 levels are increased in patients with type 2 diabetes and associated with worse inflammatory and cardiometabolic profile.

AIMS: Interleukin-8 (IL-8) is a chemokine involved in systemic immunity, macrophages infiltration and activation in adipose tissue and may play a significant role in the pathogenesis of type 2 diabetes (T2D) and atherosclerosis. Aims of this study were to evaluate circulating IL-8 levels in adult patients with T2D in comparison with non-diabetic subjects and to describe clinical and biochemical correlates of IL-8 concentration. METHODS: For this cross-sectional study, we enrolled 79 consecutive T2D individuals referring to our diabetes outpatient clinics at Sapienza University of Rome, and 37 sex, age and BMI comparable non-diabetic subjects as a control group. Clinical parameters and medical history were recorded; fasting blood sampling was performed for biochemistry and for measuring serum IL-8, IL-6, TNF-α, CRP, adiponectin and 25(OH)vitamin D [25(OH)D] levels. RESULTS: Patients with T2D exhibited significantly higher serum IL-8 levels than non-diabetic subjects (69.27 ± 112.83 vs. 16.03 ± 24.27 pg/mL, p < 0.001). In diabetic patients, increased IL-8 concentration correlated with higher IL-6 (p < 0.001), TNF-α (p = 0.02), FBG (p = 0.035), HbA1c (p = 0.04) and LDL-C (p = 0.04) and with lower adiponectin (p = 0.02) and 25(OH)D (p = 0.003) concentrations. CONCLUSIONS: Patients with T2D display a marked elevation of circulating IL-8 levels which identify subjects with worse inflammatory, glycometabolic and lipid profile and lower vitamin D levels. Further studies are warranted for evaluating a possible role of IL-8 as a novel marker for risk stratification in T2D patients.

The vitamin D receptor (VDR) gene rs11568820 variant is associated with type 2 diabetes and impaired insulin secretion in Italian adult subjects, and associates with increased cardio-metabolic risk in children.

BACKGROUND AND AIMS: 1α,25-dihydroxyvitamin-D3, the biologically active vitamin D, plays a central role in several metabolic pathways through the binding to the vitamin D receptor (VDR). VDR has been shown to be involved in cardiovascular diseases, cancer, autoimmunity and type 2 diabetes mellitus (T2DM). Several polymorphisms in the VDR gene have been described. Among these, the rs11568820 G-to-A nucleotide substitution was found to be functional, modulating the transcription of the VDR gene. Objective of this study was to perform an association study between rs11568820 polymorphism and T2DM in a cohort of Italian adults with T2DM and in non-diabetic controls. To add further insight into the role of VDR gene we explored whether this association begins early in life in overweight/obese children, or becomes manifest only in adulthood. METHODS AND RESULTS: As many as 1788 adults and 878 children were genotyped for the rs11568820 polymorphism. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose and insulin levels. Indices of insulin-resistance and secretion were also calculated. The AA genotype was significantly more frequent in adults with T2DM compared to controls (7.5% vs. 4.6%, P = 0.037), and conferred a higher risk of T2DM (ORHom = 1.69C.I. = [1.13-2.53], P = 0.011). In the adult cohort, rs11568820 was also associated with reduced indices of ß-cell insulin secretion. In children, the AA genotype was associated with 2 h high-normal glucose, a marker of cardio-metabolic risk. CONCLUSIONS: Our study demonstrates for the first time that VDR gene AA carriers have higher risk of T2DM and impaired insulin secretion. In children, the association between AA homozygous and high-normal 2h glucose suggests that mild alterations associated with this genotype may appear early in life.

Human equilibrative nucleoside transporter 1 and carcinoma of the ampulla of Vater: expression differences in tumour histotypes.

The human equilibrative nucleoside transporter 1 (hENT1) is the major means by which gemcitabine enters human cells; recent evidence exists that hENT1 is expressed in carcinoma of the ampulla of Vater and that it should be considered as a molecular prognostic marker for patients with resected ampullary cancer. Aim of the present study is to evaluate the variations of hENT1 expression in ampullary carcinomas and to correlate such variations with histological subtypes and clinicopathological parameters. Forty-one ampullary carcinomas were histologically classified into intestinal, pancreaticobiliary and unusual types. hENT1 and Ki67 expression were evaluated by immunohistochemistry, and apoptotic cells were identified by the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate biotin nick end labelling (TUNEL) method. hENT1 overexpression was detected in 63.4% ampullary carcinomas. A significant difference in terms of hENT1 and Ki67 expression was found between intestinal vs. pancreaticobiliary types (P=0.03 and P=0.009 respectively). Moreover, a significant statistical positive correlation was found between apoptotic and proliferative Index (P=0.036), while no significant correlation was found between hENT1 and apoptosis. Our results on hENT1 expression suggest that classification of ampullary carcinoma by morphological subtypes may represent an additional tool in prospective clinical trials aimed at examining treatment efficacy; in addition, data obtained from Ki67 and TUNEL suggest a key role of hENT1 in tumour growth of ampullary carcinoma.

Effect of ursodeoxycholic acid on inflammatory infiltrate in gallbladder muscle of cholesterol gallstone patients.

BACKGROUND: Reduced gallbladder (GB) contractility and chronic inflammatory changes in the mucosa have been reported in patients with cholesterol gallstones (GS). Ursodeoxycholic acid (UDCA) restores GB contractility and antagonises liver macrophage activation. In the colon, hydrophobic bile acid, not hydrophilic UDCA, induces mast cell degranulation. We studied the presence of monocyte/macrophage infiltrate, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, the number of total and degranulated mast cells in the GB muscle layer of cholesterol GS patients, and the effect of UDCA administration. METHODS: Gallbladder tissue was obtained from cholesterol GS patients, either treated or untreated with UDCA (10 mg kg(-1) day(-1)) for 30 days prior to surgery. Gallbladders removed for neoplastic diseases, not involving GB, were evaluated for control purposes. The presence of monocytes/macrophages (CD68 positive), granulocytes, and mast cells, and the COX-2 and iNOS expression, was determined immunohistochemically. KEY RESULTS: The number of CD68, granulocytes, mast cells, COX-2 and iNOS positive cells was significantly higher in the muscle layer of GS patients than in controls. Compared to untreated patients, those treated with UDCA showed significantly lower levels of CD68, COX-2 positive cells and degranulated mast cells and a lesser number of iNOS positive cells and granulocytes. CONCLUSIONS & INFERENCES: An inflammatory monocyte/macrophage, mast cell and granulocyte infiltrate is present in the GB muscle layer of GS patients. Ursodeoxycholic acid decreases macrophages, degranulated mast cells and COX-2 expression. These results suggest that monocytes/macrophages and degranulating mast cells contribute to muscle cell dysfunction in cholesterol GS patients and support the anti-inflammatory effect of UDCA.

How to predict a high rate of inappropriateness for upper endoscopy in an endoscopic centre?

BACKGROUND: Inappropriateness of upper endoscopy (EGD) indication causes decreased diagnostic yield. Our aim of was to identify predictors of appropriateness rate for EGD among endoscopic centres. METHODS: A post-hoc analysis of two multicentre cross-sectional studies, including 6270 and 8252 patients consecutively referred to EGD in 44 (group A) and 55 (group B) endoscopic Italian centres in 2003 and 2007, respectively, was performed. A multiple forward stepwise regression was applied to group A, and independently validated in group B. A <70% threshold was adopted to define inadequate appropriateness rate clustered by centre. RESULTS: discrete variability of clustered appropriateness rates among the 44 group A centres was observed (median: 77%; range: 41-97%), and a <70% appropriateness rate was detected in 11 (25%). Independent predictors of centre appropriateness rate were: percentage of patients referred by general practitioners (GP), rate of urgent examinations, prevalence of relevant diseases, and academic status. For group B, sensitivity, specificity and area under receiver operating characteristic curve of the model in detecting centres with a <70% appropriateness rate were 54%, 93% and 0.72, respectively. CONCLUSIONS: A simple predictive rule, based on rate of patients referred by GPs, rate of urgent examinations, prevalence of relevant diseases and academic status, identified a small subset of centres characterised by a high rate of inappropriateness. These centres may be presumed to obtain the largest benefit from targeted educational programs.

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.

Promyelocytic leukemia (PML) gene expression is a prognostic factor in ampullary cancer patients.

BACKGROUND: Promyelocytic leukemia (PML) tumor suppressor gene plays a key role in acute PML pathogenesis but its involvement in pathogenesis and prognosis of solid cancers has not been defined yet. PATIENTS AND METHODS: In all, 62 ampullary adenocarcinoma patients who underwent curative surgery between 1996 and 2005 were included. Expression analysis of PML was carried out by immunohistochemical staining and correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: In 24 tumor specimens (38.7%), PML was classified as absent, in 16 (25.8%) as focally expressed and in 22 (35.5%) as diffusely expressed. By univariate analysis, DFS was significantly influenced by pathological T stage (P=0.03), lymph nodal involvement (P=0.002), and PML expression (P=0.001). DFS in patients without PML expression was 28.0 months versus 45.1 and 75.5 for patients with focal and diffuse expression, respectively. OS in the group of patients without PML expression, with focal expression, and with diffuse expression was 40, 48, and 77 months, respectively (P=0.002). By a multivariate analysis, PML expression was the strongest prognostic factor for DFS (P=0.003) and the only statically significant prognostic factor for OS (P=0.009). CONCLUSIONS: Our preliminary data suggest PML as a novel prognostic tool for ampullary cancer patients.

Circulating substance P levels and shoulder joint contracture after arthroscopic repair of the rotator cuff.

OBJECTIVE: To determine the plasma levels of substance P (SP) in patients with postoperative stiffness after arthroscopic rotator cuff repair. DESIGN: Plasma samples were obtained at 15 months from surgery from two groups of patients who underwent arthroscopic repair of a rotator cuff tear. In group 1, 30 subjects (14 men, 16 women; mean age 64.6 years, range 47 to 78) with shoulder stiffness 15 months after arthroscopic rotator cuff repair were recruited. In group 2, 30 patients (11 men, 19 women; mean age 57.8 years, range 45 to 77) were evaluated 15 months after successful arthroscopic rotator cuff repair. Immunoassays were performed with commercially available assay kits to measure the plasma levels of SP. RESULTS: Plasma levels of SP in patients with postoperative stiffness were significantly greater than those in the control group (mean 81.06 (SD 27.76) versus 23.49 (5.64), p<0.05). CONCLUSIONS: The plasma concentrations of substance P in patients with shoulder stiffness after arthroscopic rotator cuff repair are higher compared with plasma levels of SP in patients with a good postoperative outcome. The neuronal upregulation of SP shown in the plasma of patients with postoperative shoulder stiffness may underlie not only the symptoms but also its development of adhesive capsulitis.

Cost-effectiveness of capsule endoscopy in screening for colorectal cancer.

BACKGROUND AND STUDY AIMS: Capsule endoscopy (Pillcam Colon) has recently shown acceptable accuracy in detecting colonic lesions when compared with colonoscopy. The aim of this analysis is to provide a model to assess the cost and effectiveness of population-based screening for colorectal cancer (CRC) using capsule endoscopy and to compare the cost-effectiveness with that of a colonoscopy screening program. METHODS: The cost-effectiveness of two screening strategies using colonoscopy or capsule endoscopy were compared by a computer model based on a Markov process. In this model, a hypothetical population of 100,000 individuals aged 50 years and over, undergoes a 10 yearly screening procedure. Different thresholds for postcapsule polypectomy referral were simulated. RESULTS: At baseline, the incremental cost-effectiveness (compared with no screening) of colonoscopy and capsule endoscopy was $ 16,165 and $ 29,244 per life-year saved, respectively. When equal compliance was simulated, the colonoscopy program was more effective and less costly than a strategy based on capsule endoscopy. When simulating an initial compliance to capsule endoscopy 30% better than colonoscopy, capsule endoscopy became the more effective and more cost-effective option. A 20% better compliance was sufficient when a higher accuracy of capsule endoscopy for polyps was assumed. A 6 mm threshold for polypectomy referral was associated with a substantial cost reduction in the capsule endoscopy program with only a small loss of efficacy. CONCLUSIONS: The cost-effectiveness of capsule endoscopy depends mainly on its ability to improve compliance to CRC screening.

Human equilibrative nucleoside transporter 1 (hENT1) protein is associated with short survival in resected ampullary cancer.

BACKGROUND: Gemcitabine is an acceptable alternative to best supportive care in the treatment of advanced biliary tract cancers. The human equilibrative nucleoside transporter 1 (hENT1) is a ubiquitous protein and is the major means by which gemcitabine enters human cells. Moreover, recent reports indicate a significant correlation between immunohistochemical variations of hENT1 in tumor samples and survival after gemcitabine therapy in patients with solid tumors. MATERIALS AND METHODS: We used immunohistochemistry to assess the abundance and distribution of hENT1 in tumor samples from radically resected cancer of the ampulla, and sought correlations between immunohistochemical results and clinical parameters including disease outcomes. RESULTS: In the 41 individual tumors studied, 12 (29.3%) had uniformly high hENT1 immunostaining. Statistical analysis showed a significant correlation between hENT1 and Ki-67 (P = 0.04). No statistical significant differences were found between immunohistochemical findings and patient characteristics (sex, age, and tumor-node-metastasis). On univariate analysis, hENT1 and Ki-67 expression were associated with overall survival (OS). Specifically, those patients with overexpression of hENT1 showed a shorter OS (P = 0.022) and those with high Ki-67 staining showed a shorter survival (P = 0.05). CONCLUSIONS: hENT1 expression is a molecular prognostic marker for patients with resected ampullary cancer and holds promise as a predictive factor to assist in chemotherapy decisions.

Q&A on diagnosis, screening and follow-up of colorectal neoplasia.

The impressive and brisk evolution of medical science prevents many physicians from a thorough update on all the research fields. Colorectal cancer diagnosis, screening and follow-up is well known to require a multi-disciplinary approach, as it is faced by several specialties such as primary care physicians, gastroenterologists, non-gastroenterologist internists, radiologists and surgeons. To address this issue in a mutual perspective, we focused on the main points of the epidemiology, diagnosis, screening and follow-up of colorectal neoplasia by using a simple "Question & Answers" structure.

Projected impact of colorectal cancer screening with computerized tomographic colonography on current radiological capacity in Europe.

BACKGROUND: The impact of a primary colorectal cancer screening with computerized tomographic colonography on current radiological capacity is unknown. The multispecialty needs for computerized tomographic examinations raise some doubts on the feasibility of a mass colorectal cancer screening with computerized tomographic colonography. AIM: To assess whether the number of available computerized tomographic units in Europe is adequate to cover population screening with computerized tomographic colonography. METHODS: A mathematical and a Markov model were, respectively, used to assess the number of computerized tomographic colonography procedures needed to be performed each day in the start-up and in the steady-state phases of a colorectal cancer screening programme in Europe. Such outcome was divided for the total number of computerized tomographic machines aged <10 years estimated to be present in the European hospitals. RESULTS: At a simulated 30% compliance, 28 760 130 European people would need to be screened by the 3482 available computerized tomographic units in a 5-year start-up period, corresponding to 6.6 CTC/CT unit/day. Assuming a 10-year repetition of computerized tomographic colonography between 50 and 80 years, the number of computerized tomographic colonography needed to be performed in the steady-state period appeared to be 4.3/CT unit/day. CONCLUSIONS: The current radiological capacity may cover the need for a primary colorectal cancer screening with computerized tomographic colonography in a steady state. On the other hand, a substantial implementation of the current computerized tomographic capacity or a synergistic approach with other techniques seems to be necessary for the start-up period.

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.

COX-2 expression in lobular in situ neoplasia of the breast: correlation with histopathological grading system according to the Tavassoli classification.

AIMS: There is considerable evidence to link cyclooxygenase (COX)-2 to the development of cancer. The aim of this study was to assess COX-2 expression and its subcellular localization in lobular in situ neoplasia (LIN) of the breast and to verify differences in COX-2 expression between different grades of lesions according to the Tavassoli classification. METHODS AND RESULTS: We analysed the expression of COX-2 protein by immunohistochemistry in tissue samples of 51 LIN lesions classified into three grades according to the Tavassoli classification. COX-2 immunostaining was observed in 78.4% of LIN samples and showed a prevalent membranous rather than cytoplasmic pattern. COX-2 was expressed in 16/17 (94.1%) LIN1, 22/25 (88%) LIN2 and 2/9 (22.2%) LIN3. As regards COX-2 expression, a statistically significant difference was found between LIN1 and LIN3 (P = 0.001) and between LIN2 and LIN3 (P =0.001). No difference was found between LIN1 and LIN2. Moreover, a significant negative correlation was found between LIN grade and COX-2 expression (P < 0.0001). CONCLUSIONS: COX-2 is highly expressed in LIN, supporting a role for this protein in the early stage of breast carcinogenesis, representing the rationale for using COX-2 selective inhibitors in the earliest stages of breast cancer.

The colorectal malignant polyp: scoping a dilemma.

Colorectal adenomas containing invasive carcinoma represent the majority of early colorectal cancers. The malignant polyp carries a significant risk of lympho-haematic metastasis and mortality due to the penetration of cancerous cells into the submucosal layer. The therapeutic dilemma is whether to perform endoscopic or surgical resection. A thorough assessment of the endoscopic, histological and clinical variables is needed to unravel the best treatment for each patient. In particular, a unique staging of such lesions, based on certain histopathological features, has been deeply implicated in the therapeutic choice. Aim of this article is to review the main endoscopic, histological and clinical features of the malignant polyp in order to propose a systematic management of this lesion.