The obesity gene and colorectal cancer risk: a population study in Northern Italy.

BACKGROUND: Representing the second cause of cancer-related death after lung cancer in men and breast cancer in women, colorectal cancer (CRC) is a major health problem in Italy. Obesity is reckoned to favor CRC; however, the underlying mechanisms are unclear. Recently, a single nucleotide polymorphism (SNP) in the fat mass and obesity associated (FTO) gene was found to be significantly associated with obesity. AIMS: To establish whether the FTO SNP rs9939609 may represent a risk factor for CRC and adenoma in the Italian population. PATIENTS AND METHODS: 1,037 subjects were enrolled in the study and divided in 3 groups: CRC (341 pts., M/F=197/144, mean age=65.17±11.16 years), colorectal adenoma (385 pts., M/F=247/138, mean age=62.49±13.01 years), healthy controls (311 pts., M/F=150/161, mean age=57.31±13.84 years). DNA was extracted from whole blood, and stored frozen for rs9939609 genotyping by real-time PCR. RESULTS: The frequency of the obesity-associated mutated A allele (AA+AT) on the FTO gene was 69.77% among controls, and 71.85% and 65.71% respectively among CRC and polyp patients. Compared to control subjects the AA+AT genotype had no significant effect on the risk for either CRC (OR=1.106; CI 95%=0.788-1.550; p=0.561) or colorectal adenomas (OR=0.830; CI 95%=0.602-1.144; p=0.255). We did not observe any association between the AA genotype and CRC/polyp localization and age at diagnosis. As measured in a patient subset, carriership of the risk alleles did not reflect in a significantly altered BMI. CONCLUSION: The obesity-linked FTO variants do not play a significant role in modulating the colorectal cancer risk in the Italian population.

Outpatient care for inflammatory bowel disease at a primary referral hospital in Turin.

AIM: This was a retrospective survey of 88 inflammatory bowel disease patients (43 with ulcerative colitis, 38 with Crohn's disease, 7 with indeterminate colitis) who were visited between January 2008 and June 2009 at a newly established out-patient service at a primary care hospital in Turin. METHODS: Treatments included corticosteroids (48 courses), mesalamines (79 courses), thiopurines (46 courses), and biological drugs (three treatments). With more extra-intestinal manifestations, more steroid needs, more visits and more surgeries, Crohn's proved more fastidious than ulcerative colitis. All of the drugs used gave side-effects that required skillful action for control: switch to mercaptopurine was advantageously used to react to azathioprine intolerance. RESULTS: Percentages of steroid needs, of stable remission, and resort to surgery were 30, 50, <20 and 40, 27, 30, respectively in ulcerative colitis and Crohn's. Thiopurines played a crucial role in the maintenance of remission of ulcerative colitis: the patients maintaining remission in the absence of azathioprine had either been resected or had left-sided disease only; left-sided disease proved also fairly responsive to beclomethasone. The unusual conduction of this service by a single doctor caused an increased trust-in-physician, but also more bias and placebo effects as drawbacks. CONCLUSIONS: The results suggest that in the last 30 years management of inflammatory bowel disease has still improved mainly due to refinement of the use of traditional drugs.

Use of corticosteroids, immunomodulators, and infliximab at a third-level Day-Hospital Service of Gastro-Hepatology.

AIM: Third-level Day-Hospital Services of Gastro-Hepatology are likely to recruit patients with an increased disease severity. The burden of request for immunomodulation drugs is presently unclear. METHODS: The charts of 1 012 consecutive patients who underwent day-hospital admission were reviewed. Among them, 975 were admitted for several reasons (percutaneous liver biopsies, abdominal fluid aspirations, infiltrations of hepatic nodules, gastrointestinal endoscopies with specific treatments). Data of the remaining 37 patients were elaborated. RESULTS: Of them, 31 (83%) suffered from ulcerative colitis (UC) or Crohn's disease (CD) (17 and 14, respectively) and 6 from autoimmune type 1 hepatitis (AIH). Of the 14 non-operated UC patients, 12 were taking azathioprine (AZA) and 2 infliximab (IFX). Among CD patients, the majority received AZA (N=6) or IFX (N=6). Of the AIH patients, 5 were treated with AZA and 2 had also cyclosporine. Overall, corticosteroids (32%) and IFX (21%) ranked first and second among the induction drugs, and AZA ranked first (62%) as maintenance option. Of the 4 CD patients under IFX treatment, 2 were switched to leukapheresis for incomplete response, the third one developed thrombotic complications, and the last one achieved disease remission after 12 months. Of the 2 cases of UC, one lost response soon and was colectomized, the other is maintaining moderately active disease, requiring scheduled injections every 8 weeks. CONCLUSION: Despite the caution imposed by the very small numbers, this analysis confirms that the potent available options are difficult to be correctly positioned in the therapeutic algorithm of inflammatory bowel disease.

Fatal liver failure following food supplements during chronic treatment with montelukast.

High aminotransferases and prolonged prothrombin time on entering our liver unit were revealing parenchymal collapse for this 45-year-old obese woman; treatment failure led her to death. Autoimmunity, paracetamol use, alcoholism, and Wilson's disease were all excluded as causes. Because of chronic asthma, she had been receiving a leukotriene receptor antagonist (montelukast) for 5 years before the current presentation; 1 week before onset she had had 1 week of treatment with two dietary supplements for weight control; one of these included Garcinia Cambogia, a possible cause of two recent cases of hepatitis in the USA; in addition, both formulas contained a citrus derivative that interferes cytochrome functions. We speculate on a causal relationship between the assumption of the additives and the fatal hepatitis and envisage a synergy between the additives and montelukast, which per se has well been studied as a hepatotoxic drug. Despite the speculative nature of this presentation, we believe the warning may serve to focus attention on the uncontrolled escalation of food additives going on in these days.

The use of the anti-tumour necrosis factor monoclonal antibody--infliximab--to treat ulcerative colitis: implications and trends beyond the available data.

The monoclonal antibody to the tumour necrosis factor--infliximab--has recently been added to the list of off-label therapeutic means for ulcerative colitis. We conducted a descriptive analysis of the results from studies on the use of the drug published so far. A total of 187 patients qualified for analysis. They were divided into four main categories, including steroid-refractory and responsive adults and children. The median frequencies of an early and a sustained response were 77 and 44.5%. These data suggest that adult non-steroid-refractory, and paediatric patients may respond with the highest frequency. While it is obligatory to wait for the yield of the ongoing controlled trials before any conclusion on these indications is drawn, the data provide seminal ideas to further investigations, including the hypothesis to inaugurate with infliximab a top-down strategy for the treatment of inflammatory bowel disease.

Long-term efficacy of oral microemulsion cyclosporin for refractory ulcerative colitis.

AIM: The 60% bioavailable oral microemulsion formulation of cyclosporin (NEORAL ), has replaced the intravenous route to treat both organ transplant and immune-based disease. Its use for steroid-refractory ulcerative colitis (a recognized indication for intravenous cyclosporin) has been scanty. METHODS: Twenty-three consecutive patients (14 male/9 female, universal colitis 14/23) entered a 3-month course of NEORAL (initially dosed at 5 mg/kg/day) because of steroid-refractoriness (14 cases) and steroid-dependence (9 cases). Responders (at least showing a 50% reduction of a clinical activity score) were continued on azathioprine. The initial steroid dose was tapered on commencing NEORAL; patients requiring steroid resumption or increase in the follow-up were defined as relapsers. RESULTS: The target trough concentration of 200 ng/ml of whole blood was achieved without major titration in all but 1 patient. There were 7 non-responders (30%). Of the 16 responders (70%), 2 have not relapsed; the remaining 14 relapsed at the median time of 9.5 months (1.5-60) with 10 (71%) showing only 1 relapse. Five patients were colectomized 12 months after NEORAL (1.5-24), leaving 11 of the initial 23 (47%) with their colon. Of the 16, all but 1 had azathioprine; the median daily steroid needs fell from 32 to 5 mg. CONCLUSION: The rates of acute and chronic response of 70% and 47% achieved by NEORAL in this indication duplicate the figures achieved by the traditional schedules of cyclosporin administration.

[Need for hospital admission in patients with ulcerative colitis during maintenance with azathioprine]. / Frequenza di ricovero ospedaliero nei pazienti con rettocolite ulcerosa grave durante terapia di mantenimento con azatioprina.

AIM: The aim of this study is to analyse the clinical course of ulcerative colitis during maintenance therapy with azathioprine, a drug which is still not proved to be able to modify the natural history of the disease. METHODS: A retrospective study is made of data regarding the frequency of hospital admission for patients with ulcerative colitis referring to a gastroenterological Day-Hospital between 1991 and 2000. The disease history of these patients has been divided into 2 sections: one preceding and the other following an index-event, identified as the beginning of a maintenance regimen with azathioprine; this allowed to find possible differences in the clinical course after the index-event. Patients were controls of themselves. RESULTS: Seventeen patients qualified for analysis. Remission from an acute severe attack of ulcerative colitis was reached by intravenous or oral cyclosporine for 14 of them and by prednisone for 3 of them. The maintenance treatment with azathioprine, which started in all but 1 patient (intention-to-treat), showed a reduction in the number of hospital admissions, decreasing from a mean of 2.12+/-0.69 in the preceding 4.2+/-4.3 years to a mean of 0.12+/-0.33 in the following 5.8+/-2.5 years (p=0.000). CONCLUSIONS: Patients undergoing maintenance therapy with azathioprine showed face fewer relapses needing hospitalisation than those without azathioprine.

Infliximab for treatment of steroid-refractory ulcerative colitis.

BACKGROUND: Success achieved in two subtypes of Crohn's disease has persuaded a few investigators to experiment the monoclonal anti-tumour necrosis factor antibody infliximab in the treatment of ulcerative colitis. So far, however, the results (achieved in some 30 steroid-refractory patients included in two independent full-papers) indicate a rate of initial response of 50% and of remission of 25%. AIMS: To analyse data of an open trial conducted on consecutive steroid-refractory severely ill patients admitted to our referral Unit. PATIENTS AND METHODS: In 9 months, infliximab was given to 8 patients (4 male, 4 female aged 20-60 years) with uncontrolled ulcerative colitis of whom 6 were non-responders to parenteral steroids. All received the first infliximab dose as an intravenous infusion of 5 mg/kg. RESULTS: Of the 8, 4 (50%) did not respond to the first injection and were submitted to urgent colectomy; the other four responded clinically. Two have maintained clinical remission for 7 months, without the need for steroids; both have received daily azathioprine at 2 mg/kg, and only one has received two further infliximab injections. Of the other two, one received a second injection at week 5, despite this relapsed, and underwent elective colectomy at that time; the other relapsed at 6 months and showed a partial response to a repeat infliximab infusion. Thus, the rate of sustained response is 2/8 (25%) in this study. CONCLUSION: These results, achieved in an open uncontrolled fashion, seem to reflect those of other independent studies. In our opinion, these findings warrant an in-depth reappraisal of the indication to use infliximab as rescue treatment for refractory ulcerative colitis.

An audit of the immunosuppressive management of ulcerative colitis. A retrospective chart review from a referral Day-Hospital of Gastro-enterology.

BACKGROUND: Ulcerative colitis is a chronic inflammatory disease of the colon thought to be caused by an abnormal T-cell response to lumenal antigens. In the last 10 years immunosuppressives have been proposed to treat its severe forms including cyclosporin and azathioprine. METHODS: An analysis of 72 patients treated for severe ulcerative colitis between 1991 and 2001 at our Day Hospital permitted an audit of the efficacy of this two-drug regime. RESULTS: Overall, the percentages of patients avoiding colectomy immediately, at 1 year, and on ending the study were 68, 47 and 36%, respectively. Thirty-five (81%) of the 43 colectomies, performed as a restorative procedure, clustered in the first year after disease presentation. The risk of colectomy was significantly reduced in the subset treated with azathioprine. Of the 25 long-term responder patients avoiding colectomy, to-date 16 (64%) had at least a relapse at the median time of 17.5 months; all but 1 episodes were managed on an out-patient basis. The types and frequencies of observed side-effects were within the known therapeutic profile of the two drugs. CONCLUSIONS: A two-drug regime of cyclosporin and azathioprine can avoid colectomy for 1 year in slightly less than 50% of a cohort of severe ulcerative colitis patients and permits an acceptable long-term response in slightly less than 40%. An accurate evaluation of this policy needs to be balanced with other options, including most recently refined techniques of colectomy.

Safety and efficacy of azathioprine in the maintenance of ciclosporin-induced remission of ulcerative colitis.

BACKGROUND: It has been shown that azathioprine prolongs the response to ciclosporin of steroid-refractory ulcerative colitis, but no specific data are available concerning its toxicity in this indication. AIM AND METHODS: The charts of 21 patients with steroid-refractory ulcerative colitis who received azathioprine overlapping with a successful ciclosporin course were reviewed for the onset of toxicity. The controls consisted of 48 initial responders to steroids who received azathioprine for steroid-dependence or resistance/toxicity. RESULTS: Two of the 21 patients were withdrawn because of hypersensitivity to azathioprine. The remaining 19 were treated for a median of 18 months together with a median daily steroid dose of 35 mg (10-75 mg) to be tapered off. Toxicity (31%) included leukopenia alone (two cases), cholestasis alone (one case), cholestasis and increased amylase (one case), increased amylase alone (one case), and cutaneous infection (one case). The frequency of withdrawal was 21%. The mean daily steroid doses were reduced from 38 mg to 3.8 mg in the study cohort, and from 25 mg to 8 mg in the controls, among whom toxicity (27%) included four cases each of leukopenia and increased amylase, two cases each of alteration of liver enzymes and infection, and one case of gastric intolerance. Ten of the 48 controls (20%) were withdrawn from the study. CONCLUSION: Azathioprine is as effective and safe in the maintenance of the response of patients with steroid-refractory ulcerative colitis to ciclosporin as it is in the treatment of those who respond to steroids.

Treatment of idiopathic retroperitoneal fibrosis using cyclosporin.

The main goal of traditional treatment of idiopathic retroperitoneal fibrosis is limitation of morbidity, and surgery of already formed fibrous masses has been the main therapeutic approach. More recently, the knowledge that the disorder may be the result of an allergic reaction to atherosclerotic lipids has prompted the use of corticosteroids and cytotoxic drugs, which proved efficacious, but also toxic. On the basis of data indicating a T cell pathogenesis of idiopathic retroperitoneal fibrosis, cyclosporin, a non-cytotoxic pretranscriptional inhibitor of proinflammatory cytokines, was used to treat the case reported here. A 65 year old man with aggressive retroperitoneal fibrosis and obstructive renal failure initially received steroids, which eventually lost their efficacy and led to vertebral collapse. He responded to 5 mg/kg/day cyclosporin, with radiological reduction of tissue deposition, relief of urether compression, and reduction in acute phase reactants in the blood. Chronic disease remission required stable drug concentrations. In conclusion, progress in research into the T cell pathogenesis of idiopathic retroperitoneal fibrosis may justify attempts with drugs such as cyclosporin to block the disease at its origin rather than treating the morbidity.

Severe steroid-unresponsive ulcerative colitis: outcomes of restorative proctocolectomy in patients undergoing cyclosporin treatment.

PURPOSE: The recent introduction of the immune suppressor cyclosporin for treatment of steroid-refractory ulcerative colitis has required surgeons to perform a colectomy in those patients who eventually fail this rescue treatment, thus raising questions as to the safety of surgery as performed in patients with a heavily manipulated immune system. To assess the rates of mortality and morbidity in this setting, we studied a cohort of consecutive patients who had surgery after failing cyclosporin for refractory ulcerative colitis at our center. METHODS: Between January 1991 and December 1996, 25 patients with ulcerative colitis underwent restorative proctocolectomy performed in three steps (21 patients) and in two steps (4 patients). Seventeen of the 25 patients (68 percent) were initial nonresponders to a dose of 2 mg/kg/day of intravenous cyclosporin and underwent surgery immediately, the remaining 8 (32 percent) relapsed as outpatients on oral cyclosporin and were readmitted for surgery. RESULTS: There was no operative mortality. Nine patients of the 25 developed postoperative (early) complications (36 percent). The three-step operation subset had a 28 percent complication rate, the two-step 75 percent. Three patients needed reoperation. A total of 11 patients (44 percent) reported with late complications: two patients required surgical treatment, one for obstruction and one for pouch-perianal fistula. Three cases of pouchitis were recorded. No patient required pouch removal. CONCLUSION: Given the absence of postoperative mortality and a low overall complication rate, restorative proctocolectomy can safely be performed in patients who fail rescue treatment with a dose of 2 mg/kg of cyclosporin for steroid-refractory ulcerative colitis. Corollary evidence in this article hints but does not prove that the three-step procedure is safer than the two-step operation.