Local hypoxia in oral mucosa (mouse) during daily fractionated irradiation - Effect of pentoxifylline.

PURPOSE: A significant reduction of radiation-induced oral mucositis by systemic application of pentoxifylline has been demonstrated in a mouse tongue model. However, the underlying mechanisms remain unclear. The present study focuses on the development of local hypoxia in mouse tongue during daily fractionated irradiation and a potential modulation by pentoxifylline. MATERIALS AND METHODS: Daily fractionated irradiation with 5×3Gy/week (days 0-4, 7-11) was given to the snouts of mice. Groups of 3 animals per day were sacrificed between day 0 and 14. Pentoxifylline (15mg/kg, s.c.) was administered daily from day -5 to the day before the mice were sacrificed. The expression of intrinsic hypoxia markers HIF-1α and GLUT1 in the epithelium of the lower tongue surface was analysed by immunohistochemistry in 3 animals per day; the percentage of positive epithelial cells and the staining intensity were analysed as endpoints. RESULTS: Compared to untreated control tissue, fractionated irradiation resulted in a progressive increase in the expression of both hypoxia markers. This effect was significantly reduced by pentoxifylline. CONCLUSION: An early onset of local hypoxia occurs during fractionated irradiation in mouse tongue epithelium. The effect is markedly reduced by the mucoprotective agent pentoxifylline, suggesting a mucositis-promoting role of hypoxia; this, however, deserves further investigation.

Modulation of radiation-induced oral mucositis by pentoxifylline: preclinical studies.

BACKGROUND AND PURPOSE: Oral mucositis is a frequent early side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is accompanied by inflammatory reactions; their interaction with epithelial processes remains unclear. The aim of the present study was to investigate the effect of pentoxifylline (PTX) on the oral mucosal radiation response in the mouse tongue model. MATERIALS AND METHODS: Irradiation comprised fractionation (5 fractions of 3 Gy/week) over 1 (days 0-4) or 2 weeks (days 0-4, 7-11), followed by graded local top-up doses (day 7/14), in order to generate complete dose-effect curves. PTX (15 mg/kg subcutaneously) was applied once daily over varying time intervals. Ulceration of mouse tongue epithelium, corresponding to confluent mucositis, was analyzed as the clinically relevant endpoint. RESULTS: With fractionated irradiation over 1 week, PTX administration significantly reduced the incidence of mucosal reactions when initiated before (day-5) the onset of fractionation; a trend was observed for start of PTX treatment on day 0. Similarly, PTX treatment combined with 2 weeks of fractionation had a significant effect on ulcer incidence in all but one experiment. This clearly illustrates the potential of PTX to ameliorate oral mucositis during daily fractionated irradiation. CONCLUSION: PTX resulted in a significant reduction of oral mucositis during fractionated irradiation, which may be attributed to stimulation of mucosal repopulation processes. The biological basis of this effect, however, needs to be clarified in further, detailed mechanistic studies.

Effect of selective inhibitors of inflammation on oral mucositis: preclinical studies.

OBJECTIVE: Oral mucositis is a severe, dose-limiting side effect of radio(chemo)therapy for head and neck tumors. The epithelial radiation response (ulceration) is accompanied by inflammatory changes. Their interaction with the epithelial processes remains unclear. The present study was initiated to determine the effect of inhibition of TNF-alpha or COX-2 on the epithelial radiation response in the mouse tongue model. METHODS: Daily fractionated irradiation was given with 5 x 3 Gy/week over one (days 0-4) or two weeks (days 0-4, 7-11). Each protocol was terminated by graded test doses (5 dose groups, 10 animals each) to a defined area of the lower tongue surface to generate full dose-effect curves for mucosal ulceration. A TNF-alpha inhibiting antibody (Infliximab) or a COX-2 inhibitor (Celecoxib) was administered. RESULTS: No effect of Infliximab or Celecoxib was found in any of the protocols. Isoeffective doses for ulcer induction were unchanged. Also, the time course of the response was largely unaffected. CONCLUSIONS: Inhibition of TNF-alpha or COX-2, two dominating inflammatory pathways, did not result in modulation of the response of oral epithelium during fractionated irradiation. This suggests that the inflammatory changes mediated through TNF-alpha or COX-2 are not relevant for the epithelial radiation response of oral mucosa.

Rabies in a 10-week-old puppy.

A 10-week-old, male, border collie-cross puppy was examined for an acute onset of unilateral vestibular signs. Neurologic deterioration was rapid over the next 12 hours and the puppy was euthanized. Rabies was diagnosed by histopathologic and immunohistochemical examination.

Endoscopic ultrasound of the canine abdomen.

The aim of this study was to develop a standardized procedure for examination of the canine abdomen using endoscopic ultrasound and to describe the organs and structures that could be identified transgastrically. The abdomen of four healthy dogs and two cadavers were examined with endoscopic ultrasound. Five anatomic landmarks were used for standardized imaging of the cranial abdomen. These were the portal vein, splenic head and body, duodenum, left kidney, and aorta. High-resolution images of the following organs and structures could be made: distal esophagus, gastric wall from the cardia to the pylorus, liver, caudal vena cava, hepatic lymph nodes, liver hilus, and associated vessels, trifurcation of the celiac artery as well as the path of its branches and the left pancreatic limb and body. Structures that were more difficult to image were the distal duodenum and right pancreatic limb, the entire jejunum, ileum, and cecum as well as the tail of the spleen. Endoscopic ultrasound allowed excellent visualization of the gastric wall and regional structures without interference with gas artefacts. Centrally located organs such as the pancreas could be well examined transgastrically with endoscopic ultrasound without interference by overlying intestinal segments as is common with transabdominal ultrasound.