Vitamin D deficiency induces Th2 skewing and eosinophilia in neonatal allergic airways disease.

BACKGROUND: Associations between vitamin D status and childhood asthma are increasingly reported, but direct causation and mechanisms underlying an effect remain unknown. We investigated the effect of early-life vitamin D deficiency on the development of murine neonatal allergic airways disease (AAD). METHODS: In utero and early-life vitamin D deficiency was achieved using a vitamin D-deficient diet for female mice during the third trimester of pregnancy and lactation. Offspring were weaned onto a vitamin D-deficient or vitamin D-replete diet, and exposure to intranasal house dust mite (HDM) or saline was commenced from day 3 of life for up to 6 weeks, when airway hyper-responsiveness (AHR), airway inflammation and remodelling were assessed. RESULTS: Neonatal mice that had in utero and early-life vitamin D deficiency had significantly increased pulmonary CD3(+) CD4(+) T1ST2(+) cells and reduced CD4(+) IL-10(+) cells. This effect was enhanced following HDM exposure. AHR in HDM-exposed mice was unaffected by vitamin D status. Introduction of vitamin D into the diet at weaning resulted in a significant reduction in serum IgE levels, reduced pulmonary eosinophilia and peri-bronchiolar collagen deposition. CONCLUSION: Peri-natal vitamin D deficiency alone has immunomodulatory effects including Th2 skewing and reduced IL-10-secreting T regulatory cells, exaggerated with additional allergen exposure. Vitamin D deficiency in early life does not affect AHR, but contributes to disease severity with worse eosinophilic inflammation and airway remodelling. Importantly, supplementation with vitamin D improves both of these pathological abnormalities.

Leucovorin and fluorouracil vs levamisole and fluorouracil as adjuvant chemotherapy in rectal cancer.

The aim of this study was to evaluate the effectiveness of 6-month therapy with leucovorin (LV) + 5-fluorouracil (5-FU) vs 12 months of therapy with levamisole (LVZ) + 5-FU, as adjuvant chemotherapy in patients with completely resected Dukes' stage B2 or C rectal cancer. One hundred and fifty patients with surgically resected rectal carcinoma, were enrolled in the present study; Dukes' stage B2 (n=70) or C (n=80), were randomly assigned to chemotherapy with 5-FU + LV x 6 months or 5-FU + LVZ x 12 months. Patient characteristics were equally balanced between the examined groups. Adjuvant CT consisted of LV 20 mg/m(2) intravenously (i.v.) plus 5-FU 450 mg/m(2) i.v., on days 1-5 every 4 weeks for 6 cycles or 5-FU 450 mg/m(2) i.v. every week plus LVZ 50 mg t.i.d x 3 days for 1 year. All patients received radiotherapy with a three-field technique to a total dose of 45 Gy, over 5 weeks. After a median follow-up of 7.4 years there were no significant differences between the two treatment groups with respect to the recurrence rates (P=0.821). Moreover, there was no difference in disease-free survival for patients stage Dukes' B2 (log-rank p=0.73); median for LV group 90 (8-131) months, and for LVZ group 86.5 (3-129) months. No difference was noted in disease-free survival for patients stage Dukes' C (log-rank p=0.73); median for LV group 60 (17-128) months, and for LVZ group 64 (2-123) months. There was no difference in overall survival for patients stage Dukes' B2 (log-rank p=0.75); median for LV group 90 (22-131) months, and for LVZ group 86 (10-129) months. For stage Dukes' C (log-rank p=0.73); median for LV group 67 (17-128) months, and for LVZ group 64 (5-123) months. Toxicities were as follows in the 5-FU + LVZ vs 5-FU + LV group; myelosuppression (leucopenia grade 3, 12% vs 4%, p<0.04), diarrhea (grade 0, 60% vs 76%, p<0.02), and liver toxicity (increase of transaminases >3-fold, 12 patients vs 2, p<0.03), were more frequent in LVZ group. None of the patients stopped chemotherapy because of the toxicity, and there were no toxicity-related deaths. In conclusion, adjuvant chemotherapy in RC with LV + 5-FU for 6 months is equally effective and less toxic than LVZ + 5-FU for 12 months.

Surgical adjuvant therapy of rectal carcinoma: a controlled evaluation of leucovorin, 5-fluorouracil and radiation therapy with or without interferon-alpha2b.

BACKGROUND: The aim of this study was to determine whether the efficacy of the combination of 5-fluorouracil (5-FU), leucovorin (LV) and radiation therapy (RT) could be improved by the addition of interferon-alpha2b (IFN-alpha) in patients who have had a 'curative' resection, for rectal adenocarcinoma (Dukes' B2/C; T3 N0, T4 N0, N1-3). PATIENTS AND METHODS: A total of 207 eligible patients with a performance status of 0 or 1 were randomized postoperatively between days 21 and 70 to one of the two treatment groups: group A, LV 20 mg/m2 i.v. bolus and 5-FU 425 mg/m2 i.v. days 1-5 and 29-33, LV 20 mg/m2 and 5-FU 400 mg/m2 days 57-60 and 85-88, LV 20 mg/m2 and 5-FU 380 mg/m2 days 1-5 and 29-33 with the second day 1 occurring 28 days after the completion of RT (45 Gy); group B, LV, 5-FU and RT as in group A, and IFN-alpha 5 x 10(6) IU s.c. three times during each week chemotherapy is given. RESULTS: 104 patients were randomized into group A and 103 into group B. There was no statistically significant difference in either disease-free survival or overall survival between the two groups. Toxicity was also the same, except for the flu-like syndrome associated with the IFN-alpha administration. CONCLUSIONS: There was no difference in efficacy between the two combinations. Toxicity was greater with the LV + 5-FU + IFN-alpha regimen because of the flu-like syndrome.