Impact of environmental and dietary factors on the course of inflammatory bowel disease

Besides their possible effects on the development of inflammatory bowel disease (IBD), some environmental factors can modulate the clinical course of both ulcerative colitis (UC) and Crohn's disease (CD). This review is mainly devoted to describing the current knowledge of the impact of some of these factors on the outcome of IBD, with special emphasis on smoking and diet. Although the impact of smoking on the susceptibility to develop CD and UC is firmly established, its influence on the clinical course of both diseases is still debatable. In CD, active smoking is a risk factor for postoperative recurrence. Beyond this clinical setting, smoking cessation seems to be advantageous in those CD patients who were smokers at disease diagnosis, while smoking resumption may be of benefit in ex-smokers with resistant UC. The role of dietary habits on the development of IBD is far from being well established. Also, food intolerances are very frequent, but usually inconsistent among IBD patients, and therefore no general dietary recommendations can be made in these patients. In general, IBD patients should eat a diet as varied as possible. Regarding the possible therapeutic role of some dietary components in IBD, lessons should be drawn from the investigation of the primary therapeutic effect of enteral nutrition in CD. Low-fat diets seem to be particularly useful. Also, some lipid sources, such as olive oil, medium-chain triglycerides, and perhaps omega-3 fatty acids, might have a therapeutic effect. Fermentable fiber may have a role in preventing relapses in inactive UC.     

Safety of Varenicline for Smoking Cessation in Psychiatric and Addicts Patients

The safety of varenicline in the treatment of tobacco dependence has been questioned, in psychiatric patients. However, most published studies have not included psychiatric patients. Objective: Assess the safety of varenicline for smoking cessation in patients with psychiatric disorders. Methods: This is a prospective, longitudinal, multicenter study. The sample is composed of three groups (patients with psychotic disorder, patients with alcohol dependence disorder and patients addicts in methadone maintenance treatment). Patients were recruited consecutively between September 2008 and June 2009 from 11 centers. All patients received a standardized smoking cessation program with varenicline and psychological support. Adverse events of the drug were monitored at weeks 1, 2, 4, 6, 8, and 12 of treatment. Bivariate analysis has been used. Results: None of the 90 patients included, presented a serious adverse event. The most frequent adverse effect was dry mouth (28.9%), followed by the presence of flatulence (27.8%), abnormal dreams (27.8%), and nausea (22%), especially between weeks 2 and 6 of treatment. None of the patients referred intense suicidal ideation, although two referred to moderate suicidal ideation, which was solved in one case and in the other, treatment was discontinued. Four participants (4.4%) abandoned treatment because of gastrointestinal symptoms. The initial dose of varenicline was reduced in 25% of patients during the study. Conclusions: Gastrointestinal adverse events are the most incident in this sample of psychiatric patients and no exacerbation of psychiatric symptoms was detected, thus indicating a good safety record for varenicline use for smoking cessation in psychiatric patients.     

Discovery and validation of an INflammatory PROtein-driven GAstric cancer Signature (INPROGAS) using antibody microarray-based oncoproteomics

This study aimed to improve gastric cancer (GC) diagnosis by identifying and validating an INflammatory PROtein-driven GAstric cancer Signature (hereafter INPROGAS) using low-cost affinity proteomics. The detection of 120 cytokines, 43 angiogenic factors, 41 growth factors, 40 inflammatory factors and 10 metalloproteinases was performed using commercially available human antibody microarray-based arrays. We identified 21 inflammation-related proteins (INPROGAS) with significant differences in expression between GC tissues and normal gastric mucosa in a discovery cohort of matched pairs (n=10) of tumor/normal gastric tissues. Ingenuity pathway analysis confirmed the “inflammatory response”, “cellular movement” and “immune cell trafficking” as the most overrepresented biofunctions within INPROGAS. Using an expanded independent validation cohort (n = 22), INPROGAS classified gastric samples as “GC” or “non-GC” with a sensitivity of 82% (95% CI 59-94) and a specificity of 73% (95% CI 49-89). The positive predictive value and negative predictive value in this validation cohort were 75% (95% CI 53-90) and 80% (95% CI 56-94), respectively. The positive predictive value and negative predictive value in this validation cohort were 75% (95% CI 53-90) and 80% (95% CI 56-94), respectively. Antibody microarray analyses of the GC-associated inflammatory proteome identified a 21-protein INPROGAS that accurately discriminated GC from noncancerous gastric mucosa.     

Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin

Cancer cells expressing constitutively active phosphatidylinositol-3 kinase (PI3K) are proliferative regardless of the absence of insulin, and they form dietary restriction (DR)-resistant tumors in vivo. Because the binding of insulin to its receptors activates the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade, activating mutations in the PIK3CA oncogene may determine tumor response to DR-like pharmacological strategies targeting the insulin and mTOR pathways. The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin-related (systemic) and mTOR-related (cell-autonomous) effects. However, it remains unclear whether PIK3CA-activating mutations might preclude the anti-cancer activity of metformin in vivo. To model the oncogenic PIK3CA-driven early stages of cancer, we used the clonal breast cancer cell line MCF10DCIS.com, which harbors the gain-of-function H1047R hot-spot mutation in the catalytic domain of the PI3KCA gene and has been shown to form DR-refractory xenotumors. To model PIK3CA-activating mutations in late stages of cancer, we took advantage of the isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor using the highly metastatic colorectal cancer cell line SW48. MCF10DCIS.com xenotumors, although only modestly affected by treatment with oral metformin (approximately 40% tumor growth inhibition), were highly sensitive to the intraperitoneal (i.p.) administration of metformin, the anti-cancer activity of which increased in a time-dependent manner and reached >80% tumor growth inhibition by the end of the treatment. Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues. Whereas SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing metformin significantly reduced the growth of SW48-mutated (PIK3CAH1047R/+) xenotumors by approximately 50%. Thus, metformin can no longer be considered as a bona fide DR mimetic, at least in terms of anti-cancer activity, because tumors harboring the insulin-unresponsive, DR-resistant, PIK3CA-activating mutation H1047R remain sensitive to the anti-tumoral effects of the drug. Given the high prevalence of PIK3CA mutations in human carcinomas and the emerging role of PIK3CA mutation status in the treatment selection process, these findings might have a significant impact on the design of future trials evaluating the potential of combining metformin with targeted therapy.     

Open-label trial on efficacy and security of treatment with gemcitabine and oral modulation with tegafur and levofolinic acid (GEMTG) in patients with advanced pancreatic cancer

Aim

Advanced pancreatic cancer has a bad prognosis, with a median overall survival (OS) no longer than 4–6 months. Since the end of last century, monotherapy with gemcitabine has remained the elective therapy, but new schedules are needed in order to improve these results. We aim to evaluate the efficacy of tegafur and levofolinic acid (LV) associated with gemcitabine, as well as its toxicity, progressionfree survival and OS in advanced pancreatic cancer.

Patients and methods

An open-label, multicentric, prospective, non-controlled trial was carried out on patients with advanced or disseminated pancreatic cancer. Gemcitabine 1250 mg/m² was administered on the 1st and 8th days of the cycle, tegafur 750 mg/m²/day for 21 consecutive days and LV 25 mg/day continuously, every 28 days, with a maximum of six cycles. The primary variable was tumour overall response rate (ORR). Secondarily, time to progression (TTP), OS and scheme toxicity were determined.

Results

Forty patients were recruited; the male/female ratio was 30:10, with a mean age of 61 years. Forty percent had a Karnofsky index of 90% or 100%. Only 11 patients (27%) completed the six cycles of treatment, but more than 50% received three or more cycles. Dose intensity was 89.56% for gemcitabine and 87.36% for tegafur. Efficacy ORR was 22.5% (CI 95%, 6–37%). TTP was 3.87 months (CI 95%, 2.1–5.6), time to treatment failure was 2.97 months (CI 95%, 2.43–4.67) and OS 6.3 months (CI 95%, 4–7). The chemotherapeutic combination was well accepted; most haematologic and non-haematologic toxicities were grade 1 or 2. The most prevalent grade 3/4 toxicities were asthenia (30%), liver biochemistry disorders (25%), diarrhoea (15%) and stomatitis (12%).

Conclusions

The administration of gemcitabine, associated with oral tegafur and leucovorin, has activity against advanced pancreatic cancer, with an adequate toxicity profile.     

Inflammatory bowel disease: current therapeutic options

Medical management of inflammatory bowel diseases (IBD) includes two treatment strategies: induction and maintenance of remission. 5-Aminosalicylates are mostly used for mild active IBD and for maintenance treatment in ulcerative colitis (UC). Glucocorticoids remain, despite their frequent (and occasionally severe) side effects, as the mainstay for induction of remission in moderate to severe active IBD, both UC and Crohn's disease (CD). Cyclosporine and infliximab have emerged as the main, rapid-acting, alternatives in steroid-refractory UC and CD, respectively. Thiopurines (azathioprine and 6-mercaptopurine) are the most efficient and used immunomodulators in IBD; steroid refractoriness, steroid dependency, and long-term maintenance of remission for both UC and CD are their main indications. Methotrexate and infliximab may be used in the same clinical settings as thiopurines in CD, but not in UC; however, these drugs are a second-line treatment because of safety profile and economic costs.