Early effects of exogenous arginine after the implantation of prosthetic material into the rat abdominal wall.

We have investigated the effects of high arginine (Arg) levels (7.5 mg/100 g body weight per hour) on the early integration of biocompatible mesh grafts into the rat abdominal wall. Studies were performed over implantation intervals of 6, 12, 24 or 48 hours (n=12, each). Arginine and related compounds were quantified in plasma, wound fluids and multiple tissues. Plasma nitric oxide (NO) production was studied. Strips were taken from the polypropylene fiber-host tissue interfaces (PTIs) for optical microscopic analysis and for immunohistochemical analysis using rat-specific antibodies against type I and type III collagens. Exogenous Arg was metabolized at the peripheral tissues but reliably reached the wound space. High amounts of Arg and ornithine (Orn) were detected in the specimens considered. No changes on citrulline (Ctr) or NO concentrations were observed, overall suggesting that, during the period studied, the arginase pathway predominated. The acute scarring response differed significantly in the two placements considered. The P-SS interface evidenced more extensive new tissue growth than the P-DS interface. Forty-eight hours after mesh implantation cellular infiltration, fibroblast proliferation, and mesh-surrounding angiogenesis were higher in the arginine-treated rats. Type III collagen staining was related to arginine treatment, being higher (++) in the study group. In conclusion, and independently of the site of mesh placement, supplemental Arg seemed to favorably affect early local collagen deposition. This could be potentially helpful to ameliorate the integration of biomaterials into the tissues and, consequently, to allow for the design of more selective therapeutic strategies to prevent hernia recurrence rates.

Fluorouracil and high-dose leucovorin with radiotherapy as adjuvant therapy for rectal cancer. Results of a phase II study.

The purpose of this phase II study was to evaluate the efficacy and toxicity of fluorouracil and high-dose leucovorin (5-FU/LV) with pelvic irradiation as adjuvant therapy for patients with macroscopical resected rectal or recto-sigmoid cancer. Following surgery for stages II-III primary (52) or recurrent rectal cancer (4), 56 patients received 8 cycles of 5-FU/LV and pelvic irradiation. 5-FU doses were 200 mgr/m2 for cycles 2-3 and 300 mgr/m2 for cycles 1 and 4-8. LV doses remained fixed at 200 mgr/m2. Pelvic radiation was started in the third week, between the first and second cycle. The total dose was 50.4 Gy. No severe complications had been recorded. The incidence of grade 3 diarrhea was 19%. Three patients presented leukopenia grade 3 (5%). In 44 patients (78%) the planned treatment could be administered. The median follow-up was 40 months (range 22-66). Seven patients had a local relapse (13%) and 6 developed distant metastasis (10%). The 3-year disease-free survival was 72% and the overall survival was 76%. These preliminary results show that combined post-operative 5-FU/LV and pelvic radiotherapy are well tolerated and present a reasonable local control and survival rates. This adjuvant treatment should be evaluated in randomized trials.

Sequential combination of methotrexate (MTX), 5-fluorouracil (FU), and high-dose folinic acid (FA) in advanced colorectal cancer: double biochemical modulation?

Thirty evaluable patients were treated with methotrexate (MTX) 200 mg/m2, i.v. infusion over 60 minutes, 24 hours prior to the administration of 5-fluorouracil 600 mg/m2, and folinic acid 200 mg/m2, i.v. infusion over 60 minutes, every 2 weeks. A partial or complete response was achieved in 12 patients (40%), and disease stable in 10 patients (33%). Median actuarial survival was 18 months. Side effects, which were within acceptable limits, included 11 cases of stomatitis (5 Grade 3), 3 cases of leukopenia (Grade 2) and 12 cases of mild nausea and vomiting. We conclude that the present combination is active in metastatic colorectal cancer with mild toxicity. These results are being confirmed and a randomized trial is being carried out to prove that this combination holds therapeutic advantage.