The parenteral administration of iron-dextran complex to gerbils caused hepatic hemosiderosis and fibrosis after 6 wk. Type I and III collagen synthesis in the liver developed from perisinusoidal stellate cells that are often referred to as myofibroblasts. Immunohistologically these cells were shown to have large intracellular deposits of ferritin. The hepatic fibrosis appeared to be associated with aggregates of these cells rather than the aggregates of Kupffer cells, which also occur in hemosiderosis in the liver. No appreciable necrosis of hepatocytes to trigger the fibrotic response was found, so that the fibrosis appeared to be related to the accumulation of ferritin in the perisinusoidal stellate cells. In contrast, rats and mice did not accumulate ferritin in their perisinusoidal cells or develop hepatic fibrosis in response to parenterally administered iron, although they accumulated similar or greater amounts of total iron in their livers. The rapid induction of hepatic fibrosis in gerbils in response to parenterally administered iron will provide a model to investigate the mechanism of induction of collagen deposition in response to iron overload and a means of quickly evaluating therapeutic treatments for iron overload-induced fibrosis in vivo using iron-chelating drugs.

The aim of this paper is the retrospective comparison of accelerated/hypofractionated radiotherapy regimen (AHFX) with standard fractionation regimen (SFX) for patients with early glottic carcinoma. One hundred and forty-five patients with T(1)-T(2) glottic cancer between 1986 and 1998 were eligible. Before 1992, patients received 60-66 Gy in 30-33 fractions over 6-6.5 weeks (SFX) with (60)Co and 6-MV beams. After 1992, patients received 52.5-55 Gy in 20 fractions over 4 weeks (AHFX) using 6-MV beams. The end-points were overall survival, laryngectomy-free survival (LFS), loco-regional control and toxicity. One hundred and two were stage T(1)N(0); 43 were stage T(2)N(0). Median follow up was 4.9 years. The 5-year overall survival was 78%. Five-year loco-regional control in T(1)N(0) patients was higher in AHFX than in SFX group (95 vs 75%, P = 0.002). Loco-regional control in T(2)N(0) patients was similar for AHFX and SFX (81 vs 80%, P = 0.813). Overall LFS was 88%. T(1)N(0) AHFX patients had 5-year LFS of 95% compared with 75% for SFX (P = 0.003). For T(2)N(0) AHFX patients, overall LFS was 92% compared with 80% for the SFX group (P = 0.291). No grade 4 or 5 late toxicity occurred. One AHFX patient developed grade 3 toxicity; two of 51 SFX patients developed grade 2 toxicity versus five of 94 AHFX patients. AHFX using 6-MV beams for treatment of early glottic cancer resulted in equivalent LFS and toxicity when compared with SFX.

Gerbils administered iron dextran are the only animal species which have been shown to develop hemochromatosis of the liver and heart in the same manner as transfusion dependent homozygous thalassemics. The iron chelating hydroxypyridinone, CP94, has been administered prophylactically to iron overloaded gerbils in a dosing regime which favors the formation of bidentate chelated iron, to examine the possibility of additional toxicity being caused to the liver and heart by the bidentate chelated iron complex. Hepatic iron accumulation was inhibited by CP94 administration for up to 6 weeks, but not after 20 weeks. Iron accumulation in the heart was increased significantly after 6 and 20 weeks of chelator treatment. Pathological changes in both organs were markedly more severe after 20 weeks in chelator treated animals. There was a higher incidence of cardiofibrosis and more extensive liver fibrosis in iron overloaded, chelator treated animals after 20 weeks.