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Purpose: This study aimed at evaluating the lymph node (LN) harvest after both open and laparoscopic colorectal cancer surgery., Methods: In the period between 1996 and 2009, 404 patients with colorectal cancer underwent open resection, whereas 147 patients underwent laparoscopic surgery., Results: The overall number of harvested LNs was significantly higher in the laparoscopic group than in the open one (16.5 vs. 14.3, P<0.001). A higher number of LNs was found in moderately differentiated tumors of the laparoscopic group when compared with the open surgery group (16.7 vs. 14.2, P<0.01). The numbers of harvested LNs in the proximal tumors and in stage II and III tumors were higher in the laparoscopic group than in the open group (18.9 vs. 15.4, P<0.001; 17.9 vs. 14.2, P=0.002; 17.3 vs. 15.3, P=0.02, respectively)., Conclusions: Laparoscopic surgery for colorectal cancer can achieve LN retrieval similar to that achieved by the open approach.

Gastric cancer is a significant cause of morbidity and mortality worldwide. Surgical resection remains the primary curative treatment for gastric adenocarcinoma, but the poor (15-35%) survival rate at 5 years has prompted many studies for new therapeutic strategies, such as specific immunotherapy. The aim of this study was to analyze the functional properties of the T cell response to different antigen peptides related to gastric cancer in patients with gastric adenocarcinoma. To this purpose, we have cloned and characterized tumor-infiltrating T cells (TILs) isolated from the neoplastic gastric tissue samples. A T cell response specific to different peptides of gastric cancer antigens tested was documented in 17 out of 20 patients, selected for their HLA-A02 and/or -A24 alleles. Most of the cancer peptide-specific TILs expressed a Th1/Tc1 profile and cytotoxic activity against target cells. The effector functions of cancer peptide-specific T cells obtained from the peripheral blood of the same patients were also studied. The majority of peripheral blood peptide-specific T cells also expressed the Th1/Tc1 functional profile. In conclusion, in most of the patients with gastric adenocarcinoma, a specific type-1 T cell response to gastric cancer antigens was detectable and would have the potential of hamper tumor cell growth. However, in order to get tumor cell killing in vivo, the activity and the number of cancer peptide-specific Th1/Tc1 cells probably need to be enhanced by vaccination with the appropriate cancer antigenic peptides or by injection of the autologus tumor peptide-specific T cells expanded in vitro.

Purpose: Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation., Experimental Design: Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines. The effects of the CB1 agonist arachinodyl-2'-chloroethylamide and the CB2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-alpha production were evaluated. The knockdown of TNF-alpha mRNA was obtained with the use of selective small interfering RNA., Results: We show that the CB1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor. The activation of the CB1 and, more efficiently, of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells. Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis. The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF-alpha mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation., Conclusions: The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF-alpha acts as a link between cannabinoid receptor activation and ceramide production.

The hMLH1 gene lies in the linkage susceptibility region to inflammatory bowel disease (IBD) on 3p21. A single nucleotide polymorphism, 655A>G, in exon 8 of the gene causes an I219V change in the MLH1 protein. To test whether hMLH1 may confer susceptibility to ulcerative colitis (UC), we investigated an association between the 655A>G polymorphism and the disease. DNA-based technologies were used to analyze the 655A>G polymorphism in 201 UC patients and 126 healthy ethnically matched controls. The comparison of the allelic frequencies of the 655A>G polymorphism in UC patients and healthy controls did not show significant differences. However, genotype frequencies at the hMLH1 655 position were found to be significantly different when patients with and without refractory UC were compared. This was mainly attributable to a higher level of homozygosity for the G allele in refractory UC patients. Almost 5 times as many (4.9 times) refractory UC patients carried the GG genotype compared with nonrefractory patients (P < 0.0001). The present study provides evidence that the hMLH1 gene is involved in genetic susceptibility to refractory UC. If confirmed by other studies, the GG genotype at position 655 of the hMLH1 gene may represent a useful predictive factor for the clinical management of UC patients.

Objective: In Crohn's disease (CD), the relationship between genetic predisposition and smoking has not been well defined. The aim of this study was to compare the smoking habits at the time of the diagnosis of CD patients having familial occurrence of inflammatory bowel disease (IBD) with those of some control groups., Methods: In a multicenter study, 136 CD patients with a relative with IBD, 272 healthy controls matched for sex and age, 500 CD patients without familial occurrence of IBD, and 84 ulcerative colitis patients (UC) with familial occurrence of IBD were personally interviewed about their smoking habits. In addition, data for 35 healthy siblings of patients with familial CD were collected by interviewing the patients' relatives., Results: The prevalence of smokers was found significantly higher in CD patients with a family history for IBD than in healthy controls and in familial UC patients (OR 2.28 CI 1.5-3.48 and OR 5.81 CI 3.15-10.75, respectively). No significant difference was found either in the percentage of smokers or in the number of cigarettes smoked per day between familial and sporadic CD patients. Among all siblings of CD patients, 72% of affected siblings and 34% of healthy siblings were smokers, concordant with their relatives., Conclusions: In CD patients with familial occurrence of IBD, the percentage of smokers is elevated. It is possible that in a genetically predisposed population, smoking could be an important environmental factor in determining CD or expressing this disease instead of UC.

Background & Aims: All patients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) residing in Florence, Italy, in 1978-1992 were identified and included in a population-based study of cancer risk evaluation., Methods: A total of 920 patients were followed up (median, 11 years), and 64 newly diagnosed malignancies were identified by linkage to the local cancer registry. Expected cases were calculated on the basis of age- and sex-specific cancer incidence rates to estimate relative risks in comparison with the general population., Results: Overall, cancer incidence rates were not increased. A significant excess risk of Hodgkin's disease was observed among patients with UC (standardized incidence ratio, 9.3; 95% confidence interval [CI], 2.5-23.8). Respiratory tract cancers were significantly reduced to one fourth of the expected rate in patients with UC, but tended to be increased among patients with CD, who had a 50% higher risk of cancer at all sites. Only a nonsignificant, modestly increased risk of colorectal cancer was observed., Conclusions: A strongly increased risk of Hodgkin's disease was evident in this first cancer follow-up of a representative series of patients with UC in a Mediterranean country. Two divergent risk patterns of respiratory tract cancers, possibly explained by differences in smoking habits, emerged in the 2 inflammatory bowel diseases.

Dietary determinants of colorectal mucosa proliferation were studied in 69 subjects previously operated for at least two sporadic colon adenomas. Information on recent dietary habits was collected by a validated food frequency questionnaire, and proliferation was measured by [3H]thymidine incorporation in colorectal biopsies by determining the labeling index (LI) and the percentage of LI in the upper part of the crypt, two parameters that are increased in subjects at high risk of colon cancer. The LI was significantly higher in women as compared with men (P = 0.01). Diet showed several associations with colorectal mucosa proliferation: (a) subjects in the highest tertile of fish consumption had a significantly lower LI (P = 0.0013) compared with those in the lower tertiles [5.20 +/- 1.87 versus 6.80 +/- 2.18 (mean +/- SD)]; (b) subjects with a low red meat consumption had lower proliferation in the upper part of the crypt [2.38 +/- 2.10, 5.30 +/- 4.62, and 5.89 +/- 4.82 in the low, middle, and high tertile of consumption, respectively (mean +/- SD); P = 0.0093]; (c) according to estimated nutrient intakes, the LI was lower in subjects reporting a high intake of starch (P = 0.006) and higher in subjects with a low intake of beta-carotene (P = 0.002). The results show that subjects reporting a diet rich in fish, starch, and beta-carotene and low in red meat had lower colorectal mucosa proliferation and a normal pattern of proliferation along the crypt. Given the correlation between colorectal proliferative activity and colon cancer risk, such a dietary pattern might be beneficial for subjects at high risk of colon cancer.

Background: A recent population-based epidemiological study identified the patients with a diagnosis of ulcerative colitis or Crohn's disease resident in the metropolitan Florence area in the period 1978-1992 and defined their vital status on 31 December, 1992., Aims: To estimate the completeness of Inflammatory Bowel Disease prevalent case ascertainment in the study area., Subjects and Methods: In a Registry, specifically developed during the study, 767 patients fulfilled the criteria for the definition of prevalent cases as of 31 December, 1992. At the same time, we had access to an independent source of potential patients: the Regional Health Department kept a list of all Inflammatory Bowel Disease patients allowed free access to specific health care provided only to selected diagnostic categories. We then compared the two different sources and used a capture recapture analysis to estimate the number of cases missed by both sources., Results: A total of 331 patients were reported by both sources, 436 were found only in the Registry while a large group of potential cases not present in our Registry was found only in the List. After careful confirmation of the diagnosis for each individual patient and contact with his/her physician, we identified an additional 102 cases that were included in the final population series of 869 prevalent cases. This capture-recapture analysis led to a revised estimate of 1,003 prevalent cases, suggesting that 134 patients had been missed by both sources, resulting in an Inflammatory Bowel Disease prevalence rate of 186 per 100,000., Conclusions: According to this method our previous study underestimated the true prevalence of 13.4% (95% confidence interval: 9.8-16.6%). On account of some degree of negative dependence between the two sources the loss was probably in the lower range of this interval. Completeness of case ascertainment should be evaluated and discussed in all studies designed to provide population-based estimates for health care planning.

Colorectal mucosal proliferation is supposed to predict colon cancer risk. We investigated whether a low-sucrose diet might reduce colorectal mucosal proliferation in a group of patients at higher risk of colorectal cancer after at least two colon adenoma resections. In a pilot phase, 14 patients [12 men and 2 women, 60.3 +/- 5 (SD) yr] were instructed to adopt a low-sucrose diet for one month. Colorectal biopsies were taken twice in the same patients, at the start and the end of the intervention period, and mucosal proliferation was measured by [3H]thymidine uptake in vitro and autoradiography. Although compliance of study participants to dietary modification was high, only a few agreed to two consecutive endoscopies; thus we carried out a randomized study, and 107 patients were assigned to a low-sucrose diet (50 treated patients: 31 men and 19 women, 59.7 +/- 7.5 yr) or instructed to continue their usual diet for one month (55 control patients: 32 men and 23 women, 59.6 +/- 7.7 yr). At the end of this period, colorectal biopsies were obtained. The results of the pilot phase and the randomized study showed that a low-sucrose diet for one-month did not affect proliferation or the distribution of proliferation activity along the crypt. The food-frequency questionnaires indicated that treated patients consumed significantly less sucrose (and fewer total calories) during the dietary modification. Urinary fructose, a measure of dietary sucrose intake, was also reduced at the end of the intervention period. In conclusion, we found no evidence that a low-sucrose diet for one month influences colorectal mucosal proliferation.

Aims: This large-scale study was aimed at evaluating the long-term history of Crohn's disease in a cohort of consecutive patients referred to the Careggi Hospital in Florence from January 1973 to June 1996., Patients: A total of 382 patients (187 females, 195 males; mean age of 47 years) were included in our study. The median follow-up was more than 11 years and only 46 patients (12%) had a follow-up of less than 1 year. The main endpoints evaluated in these patients included mortality for any cause, disease-specific mortality, recurrences, and need for surgery. Furthermore, in a subgroup of 130 patients observed during the last 6 months of our study, a more detailed assessment of the disease was carried out in which the distribution of inflammatory, fibrostenosing and fistulizing forms was determined., Results: Our results showed that the disease-specific mortality rate was extremely low (around 3% at 10 years and 5% at 20 years), but the rate of recurrence was approximately 50% at 3 years and more than 60% at 6 years. Surgery was needed in more than 50% of the patients over the 10 years following diagnosis, and the risk of a second operation was of a further 30% within 4 years of the first operation., Conclusions: These epidemiological data emerging from our study are interesting since a large patient population was evaluated and the duration of the follow-up is extremely long.

Background: Extraintestinal manifestations can complicate the course of ulcerative colitis and can influence the prognosis., Aims: Sixty-eight patients of the metropolitan area of Florence with ulcerative colitis in clinical and endoscopic remission were evaluated to establish the presence of spondyloarthritis., Patients and Methods: Each patient was studied through clinical and radiological evaluations to assess the presence of joint involvement., Results: We found signs of spondyloarthritis in 19 patients (27.9%). Four of them had a classic ankylosing spondylitis (5.8%) and in 3 of them the aplotype HLA B27 was present. Sacroileitis was found in 9 (13.2%) patients (monolateral in 5 cases and bilateral in 4). Six patients (8.8%) showed an unclassifiable form of arthritis, fulfilling the Amor criteria. In 13 of 19 patients with spondyloarthritis, we found a pancolic extension of disease (68.4%)., Conclusions: The results obtained from our series of ulcerative colitis patients reveal a lower proportion of cases of spondyloarthritis than that found in other Italian studies. We are planning further investigations on a larger population to better assess the prevalence of spondyloarthritis in ulcerative colitis patients.

A recent literature overview has estimated the long term frequency of the main outcomes of Crohn's disease (e.g. relapses, hospitalisations and surgery). Using these frequency data, we defined a model for the long term course of the disease. In this model, the quality-of-life (QOL) scores for the main levels of disease severity were determined by a panel of expert gastroenterologists. We conducted a combined analysis of these long term clinical data and of this QOL information to determine the cost-utility ratio of long term maintenance therapy with mesalazine (mesalamine) in patients with inactive Crohn's disease. After obtaining the cost-of-illness data needed for this analysis from a recent study conducted in the UK, we completed our incremental cost-utility analysis, in which mesalazine was compared with no maintenance treatment, using 2 hypothetical groups of 100 patients. These 2 groups were assumed to have the same general characteristics as those found in a group of 583 patients included in a recent meta-analysis. Our cost-utility evaluation included 5% annual discounting. In the mesalazine group, the overall lifetime costs for the 100 patients were around $US5 100,000 with an overall utility value of about 1700 quality-adjusted life years (QALYs). Both the lifetime costs and the utility values for the placebo (no treatment) group were very similar to those calculated for the mesalazine group. Our cost-utility analysis showed that mesalazine maintenance therapy was associated with a cost of about $US5000 per QALY gained. There was, therefore, a small incremental benefit obtained, albeit with a very small incremental cost. Sensitivity analyses confirmed these results. In conclusion, our study showed that long term maintenance therapy with mesalazine in patients with inactive Crohn's disease should not be discouraged on the basis of preliminary cost-utility considerations. However, long term placebo-controlled studies of mesalazine are urgently needed to better define the long term prognosis of these patients.

Seven patients with inactive ulcerative colitis and seven patients with Crohn's disease (5 inactive, 2 mildly active) received interferon treatment for associated chronic active hepatitis. Neither relapse (except in one patient) nor worsening of the clinical course of the inflammatory bowel disease was observed during treatment. According to these results chronic active hepatitis associated with inflammatory bowel disease can be treated with interferon without the risk of deteriorating the course of the inflammatory bowel disease.

We performed a 12-month clinical trial to compare the relative effectiveness of an intermittent 5-ASA regimen and a continuous 5-ASA regimen for the maintenance treatment of patients with ulcerative colitis in remission. Fifty patients with ulcerative colitis in remission for a minimum period of 1 month participated in the study. Twenty five patients received an intermittent treatment with 5-ASA tablets (2.4 g for the first week of each month) and 25 received a continuous treatment with tablets (1.6 g each day). Patients were assessed clinically every two months and endoscopically every 6 months. Our results show that the two treatments were equally effective. The relapse-free rates at 12 months were 71% in patients receiving the intermittent treatment and 66% in patients given the continuous treatment. This difference is not statically significant. Further studies are needed to assess whether the intermittent regimen can be an alternative to life-long treatment in patients who have maintained remission for a long period of time.

Objectives: We conducted a meta-analysis of the published randomized clinical trials to evaluate the effectiveness of 5-aminosalicylic acid (5-ASA) for maintaining remission in inactive Crohn's disease., Methods: The trials were identified by standard computerized techniques for literature search. All studies included in the meta-analysis were aimed at evaluating the effectiveness of 5-ASA in comparison with a control group receiving either no treatment or placebo., Results: Our meta-analysis of five clinical trials published as full-length articles indicates that 5-ASA significantly reduces the relapse frequency in patients with inactive Crohn's disease [odds-ratios (95% CI): 0.56 (0.37-0.84) at 6 months, 0.47 (0.33-0.67) at 12 months, 0.53 (0.38-0.73) at 24 months]. The pooled relapse-free rates in the treatment group were 91% at 6 months, 84% at 12 months, and 72% at 24 months; the corresponding rates in the control group were 77%, 60%, and 52%. A second meta-analysis, conducted using the additional information deriving from four randomized trials published as abstracts, gave essentially the same results., Conclusions: Whereas our meta-analysis shows that the effectiveness of 5-ASA is statistically significant, a simple pharmacoeconomic assessment indicates that the cost for preventing each relapse can lie between $4,000 and $10,000. This cost compares favorably with the average cost for treating a relapse.

Ulcerative colitis (UC) is a disease condition which typically affects young people; pregnancy is therefore frequent in women with this disease. 5-aminosalicylic acid (5-ASA) is known to be efficacious in maintaining remission of UC, but its safety in pregnancy has not yet been established. In the present study, the safety of 5-ASA was assessed in 16 women with UC (mean age: 31 years, range 25-35) who had a total of 19 pregnancies over the period from 1988 to 1992. All the patients were in clinical remission of UC at the beginning of pregnancy and were receiving a regular maintenance therapy with 5-ASA (ASACOL tablets, 1.2 g/day). During pregnancy, 4 women had a clinical relapse requiring treatment with higher doses of 5-ASA and, in some cases, with steroids. Our observations confirm that the treatment with 5-ASA does not affect the course of pregnancy nor does it damage the fetus, but it can protect from recurrences of UC.

The epidemiology of inflammatory bowel disease (IBD) in southern Europe is still not well-known. Sporadic reports have suggested a lower incidence and a milder course of the disease in Italy, but conclusive data are still lacking. To shed light on this issue, we conducted a retrospective study of IBD incidence (from January 1978 to December 1987) in the metropolitan area of Florence (650,000 inhabitants). We also estimated IBD prevalence at December 31, 1987. Our study included both in-patients and out-patients referred to the Gastroenterological and Surgical Departments of the area. The diagnosis was based on well-established clinical, endoscopical, radiological, histological and surgical criteria. Overall, nine-hundred IBD patients were identified, but only 359 (195 males, 164 females) met the eligibility criteria for inclusion in the incidence study (area of residence and period of diagnosis); of these, 263 had ulcerative colitis (UC), 96 had Crohn's disease (CD), and 6 had IBD. The average incidence rate of CD was 1.5/100,000 per year while its prevalence was 17.3/100,000. The average incidence rate of UC was 4.0/100,000 per year and the prevalence was 49.6/100,000. Both the incidence and the prevalence rates for UC and CD were higher in males than in females. This retrospective, hospital-based study shows that, in this area, the incidence rate of IBD has steadily increased over the period considered. Further studies specifically focused on risk factors are needed.

A combined therapy with 5-aminosalicylic (5-ASA) tablets (1.6gr/day) and 5-ASA enemas (4gr/twice weekly) was evaluated for maintaining remission of ulcerative colitis in 40 patients. All patients were in complete remission which had been maintained for at least 1 month. The remission was assessed by clinical, endoscopic and histological criteria. Clinical and endoscopical evaluations were performed at intervals of 2 and 6 months, respectively. The relapse-rate associated with this combined therapy was 7.5% at 6 months and 16% at 12 months. In comparison with previous investigations using continuous sulphasalazine, our study showed that the combination of 5-aminosalicylic tablets and enemas provided low relapse rates both at 6 and 12 months, suggesting a potential effectiveness in this form of treatment. Further studies are needed to confirm this result with controlled clinical trials.

The accuracy of ultrasonography (US) in diagnosing active inflammatory bowel disease (IBD) is assessed on the basis of a randomized prospective study of 61 patients. Twenty-six of the patients were affected with Crohn's disease (CD) and 12 with ulcerative colitis, while the remaining 23 patients were control subjects with no specific chronic IBD. The US signs considered as significant for active CD and UC were: --visualization of a typical target image, that is a hyperechoic center corresponding to luminal bowel content, surrounded by a hypoechoic ring corresponding to loop walls; --at least 2 of the following: solid abdominal mass, distended loops, luminal narrowing, reduced peristalsis, stiff loops, and accumulation of fluid between the loops. US sensitivity and specificity for CD were 77% and 95.6%, respectively. As for UC, no significant results were obtained. In our experience, US is a reliable method for detecting alterations and, especially, complications typical of CD in its active phase. Considering the young age of the patients affected with CD and the number of exams they must undergo, US is considered as a useful tool in disease follow-up.

Sixty patients who had presented recently with a relapse of mild to moderate ulcerative colitis with rectosigmoid involvement were randomly assigned to treatment with either 5-aminosalicylic acid enemas (N = 29) or oral sulfasalazine (N = 31). All patients were in remission, which was documented by clinical, histologic, and endoscopic criteria. Five-aminosalicylic acid treatment was administered on an intermittent schedule, consisting of 4 gm daily for the first seven days of each month; sulfasalazine was given as continuous therapy (2 gm daily as oral tablets). The study period was 2 years. Overall, 9 relapses occurred in the 5-aminosalicylic acid group and 12 occurred in the sulfasalazine group. The actuarial relapse rate at 12 months was 20 percent in the 5-aminosalicylic acid group and 24 percent in the sulfasalazine group; at 24 months, these rates were 37 and 43 percent, respectively. The actuarial relapse curves of the two groups were very similar. The relapse severity was also similar between the two groups. These results show that the authors proposed schedule of maintenance treatment with high-dose 5-aminosalicylic acid enemas is effective in subjects with rectosigmoiditis. This form of intermittent therapy may therefore be proposed for maintaining remission in patients who are refractory to oral and/or rectal treatment with sulfasalazine and steroids or who are intolerant or allergic to sulfasalazine. Treatment with 5-aminosalicylic acid enemas for seven days each month can also constitute an alternative for patients who favor the intermittent schedule over the classic continuous regimen of oral administrations.