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Possible immunological aspects of radiation pneumonitis: Experimental investigations
320
Radiation Oncology, Biology, Physics Volume 30, Supplement 1
I+sults: HPLC and SDS-PAGE analysis show >95% purity of modified fragment. Tumor accumulation of modified fragment is significantly hrgher (p< 0.01) than that of unmodified fragment at all time points and teaches a maximum at 24 hr postinjection. The retention of radioactivity in liver is approximately two-fold higher @< 0.001) for modified fragment than for unmodified fragment. Kidney uptake of modified fragment is lower (~~0.01) than unmodified fragment. Blood radioactivity clears rapidly and does not show any substantial difference between the two fragments. Whole-body retention of unmodified fragment is of shorter duration than that of modified fragment. The biological half-lives of unmodified and modified fragments were calculated to be 27 and 42 hr, respectively. Radioimmunoscintigrams of animals injected with llllnlabeled unmodified and modified F(ab’)2 fragments reflected the biodistribution data obtained in other animals. Co!+sions: Modified fragment delivers higher radiation dose and stays longer in tumor. It clears from the circulation rapidly hence causes less tzhauon to other organs. Modified fragment is expected to have a higherthexapeutic valuein radioimmunotherapy. This work was supported by NIH grants CA-S 1161 and CA 4379 1.
1139 CLINICAL TOXICITY OF PERIPHERAL NERVE TO INTRAOPERATIVE
RADIOTHERAPY
IN A CANINE MODEL
Johnstone, P. A. I.*, DeLuca, A.M. ‘, Bather, J,D.‘, Hampshire, V.A. 3, Terrill, R.E. 4, Kinsella, T.J. I, Sindelar,W.F.
’
’ Radiation Oncology and 5 Surgery Branches, and the ’ Office of Laboratory Animal Science, National Cancer Institute; the 3 Veterinary Resources Program, National Center for Research Resources, National Institutes of Health, Bethesda, MD; and the * Radiation Oncology Division, Naval Medical Center San Diego, CA. Gbiective: The clinical late effects of intraoperative radiotherapy on peripheral nerve were investigated in a foxhound model. Methods and Materials: Between 1982 and 1987, 40 animals underwent laparotomy with intraoperative radiotherapy of doses from 0 - 7.5 Gy administered to the right lumbosacral plexus. Subsequently, all animals were monitored closely and sacrificed to assess treatment effects on peripheral nerve. This analysis examines clinical results, with follow-up to 8.9 years postoperatively. Results: All animals treated with > 25 Gy developed ipsilateral paralysis. An inverse relationship was noted between IORT dose and time to neuropathy, with a crude TD m,sof 18 Gy. One of the animals treated with 15 Gy IORT developed paralysis, after a much longer latency than the other animals. Conclusions: Doses of 15 Gy delivered intraoperatively may be accompanied by peripheral neuropathy with long-term followup. This dose threshhold is less than that previously reported by our group, with shorter follow-up. The value of TD,,, determined here is in keeping with data from other researchers in animal models and clinical triais.
1140 POSSIBLE IMMUNOLOGICAL ASPECTS OF RADIATION PNEUMONITIS: EXPERIMENTAL INVESTIGATIONS P Mahler, D Vail, G MacEwen, L Forrest, T Kinsella University of Wisconsin School of Medicine, School of Veterinary Medicine
The intensity of radiation therapy and combined radiationchemotherapy is being increased in Purpose/Objective: attempts to improve control rates of thoracic malignancies, particularly lung cancer and esophageal cancer. These increases in treatment intensity are constrained by increases in normal tissue toxicity, most notably pneumonitis. We are in the process of characterizing a large animal model of pneumonitis utilizing bronchoalveolar lavage (BAL) to study acute lung processes. We anticipate this will aid in understanding the basic pathophysiological mechanisms of the pneumonitic process. Materials 81 Methods: Male Beagle dogs (14) where exposed to OGy (3), 12Gy (3), 15Gy (4) or 1BGy (4) right hemithorax irradiation in a single fraction, using a DV-VD parallel opposed field technique ,80 cm SAD, employing 6OCo gamma rays. Prior to irradiation and at multiple times from 1 to 13 weeks after irradiation all dogs had chest radiographs, chest CT scans, and underwent BAL using 3 aliquots of normal saline, 25 ml each. Both the nonirradiated left lung and the right lung were lavaged in each animal. Fluid and cells recovered from the BAL are being analyzed for differential cell counts, and for selected cytokine levels. In particular, activation of pulmonary macrophages was determined by measurement of TNF production. Results: Macrophage activity in the irradiated lungs showed a statistically significant increase compared to preirradiation levels in all irradiated groups at 1 and 2 weeks post irradiation. This is well before any increase in lung density was seen on chest radiographs or on CT scans. Macrophage activation then decreased until a second, lesser increase in macrophage activation was seen at seven weeks post irradiation. By this time marked changes were seen on chest CT scans, and detectable changes were seen on chest radiographs. BAL in this large animal model of treatment pneumonitis provides earlier indication of impending Conclusion: pneumonttis than do conventional imaging studies. The fact the macrophages show significant activation suggests that intervention in the activation process either by modulation of the activating signal(s) or by attenuation of the macrophage effect may be of benefit in increasing lung tolerance to radiation. Additional data on other cytokines will be presented.
Radiation Oncology, Biology, Physics Volume 30, Supplement 1
I+sults: HPLC and SDS-PAGE analysis show >95% purity of modified fragment. Tumor accumulation of modified fragment is significantly hrgher (p< 0.01) than that of unmodified fragment at all time points and teaches a maximum at 24 hr postinjection. The retention of radioactivity in liver is approximately two-fold higher @< 0.001) for modified fragment than for unmodified fragment. Kidney uptake of modified fragment is lower (~~0.01) than unmodified fragment. Blood radioactivity clears rapidly and does not show any substantial difference between the two fragments. Whole-body retention of unmodified fragment is of shorter duration than that of modified fragment. The biological half-lives of unmodified and modified fragments were calculated to be 27 and 42 hr, respectively. Radioimmunoscintigrams of animals injected with llllnlabeled unmodified and modified F(ab’)2 fragments reflected the biodistribution data obtained in other animals. Co!+sions: Modified fragment delivers higher radiation dose and stays longer in tumor. It clears from the circulation rapidly hence causes less tzhauon to other organs. Modified fragment is expected to have a higherthexapeutic valuein radioimmunotherapy. This work was supported by NIH grants CA-S 1161 and CA 4379 1.
1139 CLINICAL TOXICITY OF PERIPHERAL NERVE TO INTRAOPERATIVE
RADIOTHERAPY
IN A CANINE MODEL
Johnstone, P. A. I.*, DeLuca, A.M. ‘, Bather, J,D.‘, Hampshire, V.A. 3, Terrill, R.E. 4, Kinsella, T.J. I, Sindelar,W.F.
’
’ Radiation Oncology and 5 Surgery Branches, and the ’ Office of Laboratory Animal Science, National Cancer Institute; the 3 Veterinary Resources Program, National Center for Research Resources, National Institutes of Health, Bethesda, MD; and the * Radiation Oncology Division, Naval Medical Center San Diego, CA. Gbiective: The clinical late effects of intraoperative radiotherapy on peripheral nerve were investigated in a foxhound model. Methods and Materials: Between 1982 and 1987, 40 animals underwent laparotomy with intraoperative radiotherapy of doses from 0 - 7.5 Gy administered to the right lumbosacral plexus. Subsequently, all animals were monitored closely and sacrificed to assess treatment effects on peripheral nerve. This analysis examines clinical results, with follow-up to 8.9 years postoperatively. Results: All animals treated with > 25 Gy developed ipsilateral paralysis. An inverse relationship was noted between IORT dose and time to neuropathy, with a crude TD m,sof 18 Gy. One of the animals treated with 15 Gy IORT developed paralysis, after a much longer latency than the other animals. Conclusions: Doses of 15 Gy delivered intraoperatively may be accompanied by peripheral neuropathy with long-term followup. This dose threshhold is less than that previously reported by our group, with shorter follow-up. The value of TD,,, determined here is in keeping with data from other researchers in animal models and clinical triais.
1140 POSSIBLE IMMUNOLOGICAL ASPECTS OF RADIATION PNEUMONITIS: EXPERIMENTAL INVESTIGATIONS P Mahler, D Vail, G MacEwen, L Forrest, T Kinsella University of Wisconsin School of Medicine, School of Veterinary Medicine
The intensity of radiation therapy and combined radiationchemotherapy is being increased in Purpose/Objective: attempts to improve control rates of thoracic malignancies, particularly lung cancer and esophageal cancer. These increases in treatment intensity are constrained by increases in normal tissue toxicity, most notably pneumonitis. We are in the process of characterizing a large animal model of pneumonitis utilizing bronchoalveolar lavage (BAL) to study acute lung processes. We anticipate this will aid in understanding the basic pathophysiological mechanisms of the pneumonitic process. Materials 81 Methods: Male Beagle dogs (14) where exposed to OGy (3), 12Gy (3), 15Gy (4) or 1BGy (4) right hemithorax irradiation in a single fraction, using a DV-VD parallel opposed field technique ,80 cm SAD, employing 6OCo gamma rays. Prior to irradiation and at multiple times from 1 to 13 weeks after irradiation all dogs had chest radiographs, chest CT scans, and underwent BAL using 3 aliquots of normal saline, 25 ml each. Both the nonirradiated left lung and the right lung were lavaged in each animal. Fluid and cells recovered from the BAL are being analyzed for differential cell counts, and for selected cytokine levels. In particular, activation of pulmonary macrophages was determined by measurement of TNF production. Results: Macrophage activity in the irradiated lungs showed a statistically significant increase compared to preirradiation levels in all irradiated groups at 1 and 2 weeks post irradiation. This is well before any increase in lung density was seen on chest radiographs or on CT scans. Macrophage activation then decreased until a second, lesser increase in macrophage activation was seen at seven weeks post irradiation. By this time marked changes were seen on chest CT scans, and detectable changes were seen on chest radiographs. BAL in this large animal model of treatment pneumonitis provides earlier indication of impending Conclusion: pneumonttis than do conventional imaging studies. The fact the macrophages show significant activation suggests that intervention in the activation process either by modulation of the activating signal(s) or by attenuation of the macrophage effect may be of benefit in increasing lung tolerance to radiation. Additional data on other cytokines will be presented.