Anna Pozza

Inflammatory colonic carcinogenesis: A review on pathogenesis and immunosurveillance mechanisms in ulcerative colitis

Ulcerative colitis (UC) is characterized by repeated flare-ups of inflammation that can lead to oncogenic insults to the colonic epithelial. UC-associated carcinogenesis presents a different sequence of tumorigenic events compared to those that contribute to the development of sporadic colorectal cancer. In fact, in UC, the early events are represented by oxidative DNA damage and DNA methylation that can produce an inhibition of oncosuppressor genes, mutation of p53, aneuploidy, and microsatellite instability. Hypermethylation of tumor suppressor and DNA mismatch repair gene promoter regions is an epigenetic mechanism of gene silencing that contribute to tumorigenesis and may represent the first step in inflammatory carcinogenesis. Moreover, p53 is frequently mutated in the early stages of UC-associated cancer. Aneuploidy is an independent risk factor for forthcoming carcinogenesis in UC. Epithelial cell-T-cell cross-talk mediated by CD80 is a key factor in controlling the progression from low to high grade dysplasia in UC-associated carcinogenesis.

Nonalcoholic fatty liver disease, adiponectin and insulin resistance in dipper and nondipper essential hypertensive patients.

Objective The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is multifactorial, and the presence of insulin resistance is recognized as the pathophysiological hallmark of this condition. Arterial hypertension is referred as an insulin-resistant state, and insulin resistance may substantially contribute to the cardiovascular risk in this disorder. We examined the inter-relationship between insulin sensitivity, adiponectin levels, and NAFLD in hypertensive patients with different circadian blood pressure profiles. Methods Eighty never-treated patients with essential hypertension were selected for having a nocturnal decrement of blood pressure that was at least 10% (dippers, n = 47) or less than 10% (nondippers, n = 33) of daytime values. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for hepatic disease. The two groups were similar as to sex, age, and BMI. Abdominal fat distribution and NAFLD were assessed by ultrasonography. Results Hepatic steatosis was detected in 57.5% of all patients. Nondippers showed a higher prevalence of NAFLD than dippers (81.8 vs. 40.4%, P < 0.005). Insulin and the homeostasis model of assessment index were higher (P < 0.001) and adiponectin was lower (P < 0.001) in nondippers than in dippers, whereas no difference was found in regional fat, liver enzymes, and other metabolic parameters. At multivariate analysis, factors independently associated with nondipping were insulin (P < 0.05) and adiponectin (P < 0.01) with the homeostasis model of assessment index being of borderline significance. Conclusion In the absence of major risk factors for the development of NAFLD, a high prevalence of liver steatosis was associated with insulin resistance and low adiponectin levels in essential hypertensive patients with a nondipping profile.

Diffusion-weighted magnetic resonance for assessing ileal Crohn's disease activity

Background:Endoscopy and imaging objectively assess Crohns disease (CD) activity. Magnetic resonance enterography (MRE) uses no ionizing radiation, carries no significant morbidity, and is highly sensitive in revealing soft tissues inflammation. Diffusion-weighted imaging can distinguish intestinal inflammation from a lower diffusion of water molecules giving rise to a reduced apparent diffusion coefficient. The magnetic resonance index of activity score and, more recently, the Clermont score were recently developed for staging CD activity. The aim of this study was to compare the MRE scores and the Simple Endoscopic Score for CD in identifying ileal CD activity. Methods:Fifty-five patients with ileal and ileocolonic CD were consecutively enrolled between June 2012 and June 2013. All patients underwent clinical examination, biochemical tests, MRE, and colonoscopy to assess disease activity. Results:MRE assessed active ileal disease in 31 patients (56.3%). The Clermont score significantly correlated with the magnetic resonance index of activity score (r = 0.91; P < 0.0001) and the Simple Endoscopic Score for CD (r = 0.76; P < 0.0001). The apparent diffusion coefficient correlated with the Simple Endoscopic Score for CD (r = −0.63; P < 0.0001) especially in unoperated patients. Conclusions:The Clermont score and the apparent diffusion coefficient value can stage ileal CD, avoiding the need to use contrast agents.

Cytokine network in rectal mucosa in perianal Crohn's disease: Relations with inflammatory parameters and need for surgery†

Background: Nowadays anti‐TNF‐&agr; antibodies are used for the treatment of perianal Crohns disease (CD). Nevertheless, this treatment is effective in only a part of these patients and recent studies suggested a role for other cytokines in chronic bowel inflammation. The aim of this study was to assess the cytokine profile in the rectal mucosa of patients affected by perianal CD and to understand its relations with the systemic cytokine profile and inflammatory parameters and the need for surgery. Methods: Seventeen patients affected by perianal CD, 7 affected by CD without perianal involvement, and 17 healthy controls were enrolled and underwent blood sampling and endoscopy. During endoscopy rectal mucosal samples were taken and the expression of TNF‐&agr;, IL‐6, IL‐1&bgr;, IL‐12, and TGF‐&bgr;1 was quantified with enzyme‐linked immunosorbent assay (ELISA). Local cytokine levels were compared and correlated with diagnosis, therapy, phenotype (fistulizing and stenosing), and disease activity parameters. Results: In the group with perianal CD, rectal mucosal IL‐1&bgr;, IL‐6, and serum IL‐6 and TNF‐&agr; were higher than in patients with small bowel CD and healthy controls. IL‐12 and TGF‐&bgr;1 mucosal levels did not show any differences among the 3 groups. Mucosal IL‐6 significantly correlated with the Perianal Crohns Disease Activity Index and mucosal TNF‐&agr; and IL‐1&bgr;. Mucosal TNF‐&agr; and IL‐1&bgr; showed a direct correlation with the histological grade of disease activity. Conclusions: The cytokines network analysis in perianal CD shows the important involvement of IL‐1&bgr;, IL‐6, and TNF‐&agr;. Furthermore, mucosal levels of IL‐6 and IL‐12 are predictors of recurrence and of need for surgery in perianal CD patients.

Health-Related Quality of Life after Colonic Resection for Diverticular Disease: Long-term Results

Background and AimsWhile colonic resection is standard practice in complicated colonic diverticular disease (DD), treatment of uncomplicated diverticulitis is, as yet, unclear. The aim of the present study was to evaluate the long-term clinical outcome and quality of life in DD patients undergoing colonic resection compared to those receiving medical treatment only.Patients and MethodsSeventy-one consecutive patients who were admitted to our surgical department with left iliac pain and endoscopical or radiological diagnosis of DD were enrolled in this trial. Disease severity was assessed with Hinchey scale. Twenty-five of the patients underwent colonic resection, while 46 were treated with medical therapy alone. After a median follow-up of 47 (3–102) months from the time of their first hospital admission, the patients responded to the questions of the Cleveland Global Quality of Life (CGQL) questionnaire and to a symptoms questionnaire during a telephone interview. Admittance and surgical procedures for DD were also investigated, and surgery- and symptoms-free survival rates were calculated. Nonparametric tests and survival analysis were used.ResultsThe CGQL total scores and symptom frequency rate were found to be similar in the two groups (resection vs nonresection). Only current quality of health item was significantly worse in patients who had undergone colonic resection (p = 0.05). No difference was found in the rate and in the timing of surgical procedures and hospital admitting for DD in the two groups. In particular, the nine patients classified as Hinchey 1 who underwent surgery reported the same quality of life, symptoms frequency, operation, and hospital admitting rate as those who had been admitted with the same disease class but who received medical treatment only.ConclusionsOur results indicate that there does not seem to be any long-term advantage to colonic resection which should be considered only in patients presenting complicated DD.

Magnetic Resonance Enterography for Crohn’s Disease: What the Surgeon Can Take Home

BackgroundCrohn’s disease (CD) is a life-long, chronic, relapsing condition requiring often morphological assessment. MR enterography (MRE) offers advantages of not using ionizing radiation and yielding intraluminal and intra-abdominal informations. The aim of our study was to identify how MRE can be useful in planning surgical procedures.Patients and MethodsIn this retrospective study, 35 patients who underwent MRE and then surgery for CD were enrolled from 2006 to 2010. MRE findings were compared to intraoperative findings. Histology of operative specimens, systemic inflammatory parameters, and fecal lactoferrin were also evaluated. Cohen’s κ agreement test, sensitivity and sensibility, uni-/multivariate logistic regression, and non-parametric statistics were performed.ResultsMRE identified bowel stenosis with a sensitivity of 0.95 (95% CI 0.76–0.99) and a specificity of 0.72 (95% CI 0.39–0.92). The concordance of MRE findings with intraoperative findings was high [Cohen’s κ = 0.72 (0.16)]. Abscesses were detected at MRE with a sensitivity of 0.92 (95% CI 0.62–0.99) and a specificity of 0.90 (95% CI 0.69–0.98) with a Cohen’s κ = 0.82 (0.16). The grade of proximal bowel dilatation resulted to be a significant predictor of the possibility of using strictureplasty instead of/associated to bowel resection either at univariate or at multivariate analysis.ConclusionOur study confirmed that MRE findings correlate significantly with disease activity. Detailed information about abscess could suggest percutaneous drainage that could ease the following surgery or avoid emergency laparotomy. Proximal bowel dilatation can suggest the possibility to perform bowel sparing surgery such as strictureplasty.

Diverting loop ileostomy after restorative proctocolectomy: predictors of poor outcome and poor quality of life

Aim  Diverting loop ileostomy is used to minimize the impact of anastomotic complication after restorative proctocolectomy (RPC). However, the ileostomy itself may have complications and therefore affect quality of life (QOL). The aim of this study was to analyse the predictors of complications of the ileostomy formation and closure and of the QOL of these patients.

A systematic review of diagnostic procedures to detect midgut neuroendocrine tumors

The aim of this work was to assess the diagnostic yield of some clinical diagnostic procedures utilized to establish a diagnosis of midgut neuroendocrine tumors (NETs). Medical databases published between 1982 and 2007 were analyzed. Seventeen observational studies, including 629 patients, met the inclusion criteria. Urinary 5‐HIAA is the first test to prescribe in patients with flushing or persistent, unexplained diarrhea. Abdominal CT scan and OctreoScan should be prescribed whenever NET is suspected. J. Surg. Oncol. 2010;102:877–888.

Mucosal immune environment in colonic carcinogenesis: CD80 up-regulation in colonic dysplasia in ulcerative colitis.

BACKGROUND In patients with ulcerative colitis (UC) the inconsistency between the rate of dysplasia and actual cancer incidence suggests the presence of an immunosurveillance mechanism. The aim of our study was to analyse the expression of CD80 and CD86 during the different stages of UC-associated and in non-inflammatory carcinogenesis. PATIENTS AND METHODS Sixty-two patients affected with UC, UC with colonic dysplasia, UC and cancer, colonic adenoma, or colonic cancer and 11 healthy subjects were enrolled in our study. Tissue samples were taken from surgical specimens during colonic resection or during colonoscopy. Mucosal mRNA expression of CD80 and CD86 was quantified with real time polymerase chain reaction (RT-PCR). CD80, CD86 and p53 expressions and lamina propria mononuclear cell populations (CD3, CD20 and CD68) were analysed by immunohistochemistry. Mucosal levels of IL-1β, IL-2 and IFN-γ were measured with immunometric assays. RESULTS Among UC patients, CD80 protein expression was higher in those with dysplasia (p=0.017). In non-inflammatory carcinogenesis pathway CD80 protein and mRNA expressions were lower compared to the corresponding steps in the UC pathway. CD80 expression was directly correlated with the lamina propria mononuclear cell populations (T and B lymphocytes and monocytes). CD80 protein, but not CD80 mRNA, expression was significantly and directly correlated with IL-2 expression. CONCLUSION CD80 resulted to be up-regulated in UC with dysplasia, while it was down-regulated in cancer. CD80 mucosal levels correlate with lamina propria T-cell and with IL-2 expression suggesting that it may elicit an active role in the immunosurveillance mechanism.

Mucosal immune environment in colonic carcinogenesis: CD80 expression is associated to oxidative DNA damage and TLR4-NFκB signalling.

BACKGROUND CD80 has been thought to play an active role in immunosurveillance as it has been found to be up-regulated in ulcerative colitis (UC) patients with dysplasia. The aim of the present study was to analyse early events in UC-related and non-inflammatory carcinogenesis with reference to CD80 expression to clarify what stimuli are involved in its up-regulation in these patients. PATIENTS AND METHODS Sixty-two patients affected with UC, UC with dysplasia, UC and cancer, colonic adenoma, or colonic cancer and 11 healthy subjects were enroled in our study. Tissue samples were taken from surgical specimens during colonic resection or during colonoscopy. Mucosal mRNA expression of Toll-like receptor-4 (TLR4) and nuclear factor-kappaB (NF-κB) was quantified with Real Time RT-PCR. TLR4, β-catenin and p53 expressions were analysed by immunohistochemistry. Mucosal levels of activated NF-κB were measured with immunometric assays while 8-Hydroxydeoxyguanosine (8-OHdG) levels were quantified by high-performance liquid chromatography with electrochemical detection (HPLC-ED). Non-parametric tests were used for statistical analysis. RESULTS 8-OHdG mucosal levels were higher in the patients with UC + dysplasia with respect to those in the patients with UC only (p=0.03). CD80 mRNA mucosal levels were directly correlated with 8-OHdG mucosal levels (τ=0.26, p=0.04), TLR4 protein expression (τ=0.45, p<0.01) and NF-κB mRNA expression and activity (τ=0.24, p=0.02; τ=0.34, p=0.02, respectively). CD80 protein expression, instead, was directly correlated with 8-OHdG mucosal levels (τ=0.19, p=0.05) and inversely correlated with TLR4 mRNA expression (τ=-0.25, p=0.03). CONCLUSION Oxidative DNA damage peaked in UC-related dysplasia and was found to be directly correlated to CD80 expression. The direct correlation between TLR4 protein expression and CD80 mRNA and the indirect correlation between CD80 protein and TLR4 mRNA expressions give substance to the hypothesis that they play a role in immunosurveillance. No significant correlations between CD80 expression and p53 and β-catenin accumulation during oncogenesis were, instead, observed.