Response of canine mast cell tumors to radiation.

Twenty-three dogs completed a fractionated course of ionizing radiation therapy for mast cell tumors. In 10 dogs the response was satisfactory, and the tumors were considered controlled 12 months after completion of the prescribed course of therapy. Treatment was considered unsatisfactory for the remaining 13 dogs due to failure to control the tumor locally, generalized metastasis, or both. A dose effect was noted in the response of the tumors to radiation. Of 6 dogs, 5 responded satisfactorily when the tumor dose was 4,000 rads or greater. When the tumor dose was less than 4,000 rads, 5 of 17 dogs responded satisfactorily. The dose calculated to control 50% of the meat cell tumors was 3,625 rads (95% confidence interval: 3,265-4,024 rads). Adverse normal tissue reactions, which consisted of moist desquamation in 10 animals and necrosis in 4, were recorded. The dose calculated to cause desquamation in 50% of the dogs was 3,750 rads (95% confidence interval: 3,348-4,200 rads).

Radiotherapy of spontaneous fibrous connective-tissue sarcomas in animals.

The clinical records and follow-up data obtained over 13 years on the results of radiotherapy of spontaneous fibrous connective-tissue sarcomas in dogs, cats, and horses were reviewed. The results obtained from the treatment of fibrosarcomas and sarcoids of horses indicated that radiation administered with 60Co is important in the medical and surgical management of these tumors. Fibrous connective-tissue sarcomas in horses were radioresponsive. When radiotherapy was applied postoperatively, the probability of a 2-year cure approached 50% for all prescribed radiation doses of less than 2,000 to greater than 4,000 rads. If radiation doses of 4,500-6,000 rads were used, a 2-year cure rate may approach or exceed 60%.

Large animal studies of hyperthermia and irradiation.

Investigators who have studied hyperthermic response of spontaneous animal tumors have reported complete remission for variable periods of 15 to 38% of tumors treated. Normal tissue complications were minimal. Long-term control appears more likely if irradiation is combined with hyperthermia, but information is lacking to date to confirm this. Dose-response assays of radiation alone have been done which would make comparisons with hyperthermia and radiation more meaningful. Probabilities for increasing tumor control without significantly increasing normal tissue response can be estimated better from such assays. Spontaneous tumors in companion animals have advantages over rodent tumor systems of relatively larger treatment fields; longer follow-up times are possible, and serial monitoring of a variety of clinical data can be done. Experience of investigators using these tumors has shown that animal owners and referring veterinarians are most cooperative in reasonable, humane approaches to experimental cancer therapy.

Clinical use of thermal enhancement and therapeutic gain for hyperthermia combined with radiation or drugs.

Values for thermal enhancement and therapeutic gain are useful for deciding future directions of hyperthermia combined with other cancer therapy modalities. Evidence of thermal enhancement of effects on normal tissues is important as it indicates the need for dose modification. Specific values cannot be used generally to determine the degree of dose modification for clinical applications. A range of values accounting for many variables, including method of dose delivery for heat and the other modalities and knowledge of the normal tissues at risk, would be required for such specific application. There is frequently hyperthermic enhancement of radiation damage to acutely responding tissues. That may be avoided if tumors can be selectively heated, but extensive temperature monitoring is necessary to avoid hot spots. Irradiation and heating of spontaneous canine tumors resulted in an increased probability for tumor control with no apparent increase in late complications. Human clinical studies have shown that, with care, tumor response can be enhanced without significantly increasing normal tissue damage and that a therapeutic gain can be achieved. Caution must be exercised because, with few exceptions, follow-up was not long, and the tissues at risk were limited. Most human studies have been of relatively superficial tumors of small volume. Little information is available on whole-body or regional hyperthermia for assessment of thermal enhancement or therapeutic gain. Also, there is little information about chemotherapy combined with heat, although studies of heat with perfusion chemotherapy for malignant melanomas of the extremity have shown significantly increased survival rates.

Ploidy and DNA distribution analysis of spontaneous dog tumors by flow cytometry.

Ploidy and DNA content distributions were measured for 68 biopsy specimens of spontaneous (solid) dog tumors using flow cytometry analysis of mithramycin-stained cells. The tumor ploidy (i.e., DNA index values) ranged from 1.0 to 4.0 (diploid = 1.0), with a mean of 1.4. More than 80% of the tumors had elevated G0-G1 peak DNA contents and were classified heteroploid, similar to human solid tumors. Six mammary carcinomas and osteosarcomas had bimodal G0-G1 peaks. Based on flow cytometric data and pathology criteria, it was observed that: (a) the percentage of tumor S-phase cells tended to increase with increasing DNA index; and (b) for a given DNA index, the percentage of S-phase cells was lower for well-differentiated tumors and higher for poorly differentiated tumors. The inherent scattering of the DNA content and DNA distribution data between different tumor types limited the usefulness of these data for classifying tumors. The results suggest that improved classification of cytologically different tumors and tumor subsets might be achieved by simultaneous flow measurement of DNA content and DNA distribution information with an additional parameter that detects the cytological differentiation state.

Radiation-induced osteosarcoma in dogs after external beam or intraoperative radiation therapy.

This report describes radiation-induced osteosarcomas in two groups of dogs. One group was given radiation therapy for spontaneous tumors and the second group of normal adult beagle dogs was given experimental intraoperative radiation therapy. Secondary tumors developed between 1.7 to 5 years after irradiation. Three of 87 spontaneous tumor-bearing dogs or 3.4% of dogs treated for soft tissue sarcomas developed osteosarcoma within the field of irradiation. Twenty-two dogs or 25% of dogs treated for soft tissue sarcomas survived 20 months. This high incidence may be due to the use of fractions in excess of 3.5 Gy. These dogs received 10 fractions in 3 weeks with fractions ranging from 3.5 to 5.0 Gy. Tumor induction may be included in the late effects of irradiation which are worsened by the use of coarse fractionation. There appeared to be a dose relationship for tumors induced after single intraoperative radiation doses combined with fractionated external beam irradiation. Seven of 27 dogs given this treatment and surviving at least 4 years developed osteosarcomas in the field of irradiation. One of 26 dogs given intraoperative radiation alone developed a tumor between 4 and 5 years. The lower incidence after intraoperative radiation alone may have been due to the lower total dose. However, the sequence of a course of fractionated irradiation followed by a large single dose seemed to enhance carcinogenicity.

Physiological studies of whole-body hyperthermia of dogs.

Whole body hyperthermia to 42 degrees C was induced in five normal beagles, using a humidity- and temperature-controlled chamber. Core temperatures of 41.2-43.0 degrees C were achieved in 50 min and maintained for 60 min. Cardiopulmonary responses included marked tachypnea and tachycardia. Blood gases underwent progressive drops in both PO2 (mean, 117 torr) and PCO2 (mean, 22 torr), suggesting the possibility of the development of a diffusion barrier during heating. Increased anion gaps in the face of respiratory alkalosis indicated that a metabolic acidosis developed in the heated dogs. Transient but significant drops in serum potassium and phosphorus were also observed during hyperthermia. Other physiological data, including serum chemistries, complete blood count, colony-forming units, and urine electrolyte excretion, did not change significantly.

Impact of heterogeneity in the predictive value of kinetic parameters in canine osteosarcoma.

Intratumoral heterogeneity has been identified as a potential problem in the efficacy of predictive assays. Canine osteosarcoma is an extremely heterogeneous solid tumor that has been shown to be an excellent model for the human disease. Intratumoral heterogeneity of kinetic parameters and the effect of heterogeneity on predicting outcome of treatment (time until metastasis) were studied in dogs with naturally occurring osteosarcoma. Dogs were treated with amputation or tumor excision and limb-sparing followed by chemotherapy with cisplatin. Kinetic parameters evaluated included v, duration of DNA synthesis (Ts), and potential doubling time (Tpot), determined using in vivo labeling with bromodeoxyuridine and flow cytometry. In 30 tumors, multiple samples were obtained and evaluated. There was significantly more variation between tumors from different dogs than intratumoral variation of v, Ts, and Tpo. Variations in v, Ts, and Tpot within a tumor were associated with both sample location and tumor subpopulation. Time to metastasis was determined in 51 dogs with tumors sampled for kinetics. Multiple samples were available from 25 of these tumors. Cox proportional hazard analysis was performed using either the fastest or slowest Tpot from each sample. The fastest available Tpots were highly significant (P < 0.001) for prediction of outcome. The slowest available Tpots were also significant predictors, although the statistical strength was compromised (P = 0.024). Obtaining at least two samples in large tumors known to be heterogeneous is recommended to improve the predictive ability of Tpot. v is a more limited predictor but can useful when Tpot is not available. In canine osteosarcoma, an extremely heterogeneous tumor, kinetic parameters were shown to be predictors of outcome.

Unexpected toxicity associated with use of body surface area for dosing melphalan in the dog.

A multiinstitutional Phase I study using i.v. melphalan was conducted in dogs with spontaneously occurring neoplasia. Melphalan was administered at 7.5, 10, 11.25, 12.5, and 20 mg/m2 of body surface area. Disproportionately greater toxicity was observed in small dogs. Seven of the eight dogs (88%) weighing less than 14 kg experienced severe myelosuppression (neutropenia, less than 1500/mm3; and/or thrombocytopenia, less than 80,000/mm3), whereas only three of 13 dogs (23%) weighing greater than 14 kg developed severe myelosuppression (P = 0.016). We concluded that small dogs are at greater risk of developing bone marrow toxicity from i.v. melphalan than large dogs if body surface area is used to calculate the dose. Although both body surface area and weight were found to be significantly correlated with severity of toxicity, melphalan-induced toxicity in dogs can be more accurately estimated by body weight than by surface area, P = 0.008 versus P = 0.022, respectively. It may be necessary to prescribe antineoplastic agents that are eliminated by processes not primarily under metabolic influence or that produce side effects on tissue not correlated to basal metabolic rate on a parameter other than body surface area. In dogs, melphalan should be dosed on a weight basis, and treatment groups should be stratified by weight in randomized clinical studies, particularly when the weight range of treated subjects is great.

Comparison of DNA aneuploidy of primary and metastatic spontaneous canine osteosarcomas.

Spontaneous canine osteosarcomas were analyzed for DNA aneuploidy and percentage of S phase cells using flow cytometry. Forty-eight dogs were studied in which both a primary tumor and subsequent metastases were available. The DNA index distributions for the primary tumors and the metastases were quite similar. However, when individual primary tumors and metastases derived from them were compared, many of the cases had different ploidy values. The tumor cells were also analyzed for percentage of S phase. The diploid metastases had less than 17% S phase cells, whereas the aneuploid metastases had up to 40% S phase cells. There was a direct correlation between the DNA index and the percentage of S phase in the metastases.

Sealants for Preventing and Arresting Pit-and-fissure Occlusal Caries in Primary and Permanent Molars.

BACKGROUND: National Health and Nutrition Examination Survey 2011-2012 data indicated that, in the United States, nearly onefourth of children and over one-half of adolescents experienced dental caries in their permanent teeth. The purpose of this review was to summarize the available clinical evidence regarding the effect of dental sealants for the prevention and management of pit-and-fissure occlusal carious lesions in primary and permanent molars, compared with a control without sealants, with fluoride varnishes, or with other head-to head comparisons. TYPE OF STUDIES REVIEWED: The authors included parallel and split-mouth randomized controlled trials that included at least 2 years of follow-up, which they identified using MEDLINE (via PubMed), Embase, LILACS, the Cochrane Central Register of Controlled Trials, and registers of ongoing trials. Pairs of reviewers independently conducted the selection of studies, data extraction, risk of bias assessments, and quality of the evidence assessments by using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Of 2,869 records screened, the authors determined that 24 articles (representing 23 studies) proved eligible. Moderate-quality evidence suggested that participants who received sealants had a reduced risk of developing carious lesions in occlusal surfaces of permanent molars compared with those who did not receive sealants (odds ratio [OR], 0.15; 95% confidence interval [CI], 0.08-0.27) after 7 or more years of follow-up. When the authors compared studies whose investigators had compared sealants with fluoride varnishes, they found that sealants reduced the incidence of carious lesions after 7 or more years of follow-up (OR, 0.19; 95% CI, 0.07-0.51); however, this finding was supported by low-quality evidence. On the basis of the evidence, the authors could not provide a hierarchy of effectiveness among the studies whose investigators had conducted head-to-head comparisons. The investigators of 2 trials provided information about adverse events, but they did not report any adverse events. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Available evidence suggests that sealants are effective and safe to prevent or arrest the progression of noncavitated carious lesions compared with a control without sealants or fluoride varnishes. Further research is needed to provide information about the relative merits of the different types of sealant materials.

Sealants for preventing and arresting pit-and-fissure occlusal caries in primary and permanent molars: A systematic review of randomized controlled trials-a report of the American Dental Association and the American Academy of Pediatric Dentistry.

BACKGROUND: National Health and Nutrition Examination Survey 2011-2012 data indicated that, in the United States, nearly one-fourth of children and over one-half of adolescents experienced dental caries in their permanent teeth. The purpose of this review was to summarize the available clinical evidence regarding the effect of dental sealants for the prevention and management of pit-and-fissure occlusal carious lesions in primary and permanent molars, compared with a control without sealants, with fluoride varnishes, or with other head-to head comparisons. TYPE OF STUDIES REVIEWED: The authors included parallel and split-mouth randomized controlled trials that included at least 2 years of follow-up, which they identified using MEDLINE (via PubMed), Embase, LILACS, the Cochrane Central Register of Controlled Trials, and registers of ongoing trials. Pairs of reviewers independently conducted the selection of studies, data extraction, risk of bias assessments, and quality of the evidence assessments by using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Of 2,869 records screened, the authors determined that 24 articles (representing 23 studies) proved eligible. Moderate-quality evidence suggested that participants who received sealants had a reduced risk of developing carious lesions in occlusal surfaces of permanent molars compared with those who did not receive sealants (odds ratio [OR], 0.15; 95% confidence interval [CI], 0.08-0.27) after 7 or more years of follow-up. When the authors compared studies whose investigators had compared sealants with fluoride varnishes, they found that sealants reduced the incidence of carious lesions after 7 or more years of follow-up (OR, 0.19; 95% CI, 0.07-0.51); however, this finding was supported by low-quality evidence. On the basis of the evidence, the authors could not provide a hierarchy of effectiveness among the studies whose investigators had conducted head-to-head comparisons. The investigators of 2 trials provided information about adverse events, but they did not report any adverse events. CONCLUSIONS AND PRACTICAL IMPLICATIONS: Available evidence suggests that sealants are effective and safe to prevent or arrest the progression of noncavitated carious lesions compared with a control without sealants or fluoride varnishes. Further research is needed to provide information about the relative merits of the different types of sealant materials.

Evidence-based clinical practice guideline for the use of pit-and-fissure sealants: A report of the American Dental Association and the American Academy of Pediatric Dentistry.

BACKGROUND: This article presents evidence-based clinical recommendations for the use of pit-and-fissure sealants on the occlusal surfaces of primary and permanent molars in children and adolescents. A guideline panel convened by the American Dental Association (ADA) Council on Scientific Affairs and the American Academy of Pediatric Dentistry conducted a systematic review and formulated recommendations to address clinical questions in relation to the efficacy, retention, and potential side effects of sealants to prevent dental caries; their efficacy compared with fluoride varnishes; and a head-to-head comparison of the different types of sealant material used to prevent caries on pits and fissures of occlusal surfaces. TYPES OF STUDIES REVIEWED: This is an update of the ADA 2008 recommendations on the use of pit-and-fissure sealants on the occlusal surfaces of primary and permanent molars. The authors conducted a systematic search in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and other sources to identify randomized controlled trials reporting on the effect of sealants (available on the US market) when applied to the occlusal surfaces of primary and permanent molars. The authors used the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the quality of the evidence and to move from the evidence to the decisions. RESULTS: The guideline panel formulated 3 main recommendations. They concluded that sealants are effective in preventing and arresting pit-and-fissure occlusal carious lesions of primary and permanent molars in children and adolescents compared with the nonuse of sealants or use of fluoride varnishes. They also concluded that sealants could minimize the progression of noncavitated occlusal carious lesions (also referred to as initial lesions) that receive a sealant. Finally, based on the available limited evidence, the panel was unable to provide specific recommendations on the relative merits of 1 type of sealant material over the others. CONCLUSIONS AND PRACTICAL IMPLICATIONS: These recommendations are designed to inform practitioners during the clinical decision-making process in relation to the prevention of occlusal carious lesions in children and adolescents. Clinicians are encouraged to discuss the information in this guideline with patients or the parents of patients. The authors recommend that clinicians reorient their efforts toward increasing the use of sealants on the occlusal surfaces of primary and permanent molars in children and adolescents.

Hyperthermic treatment of malignant diseases: current status and a view toward the future.

New studies in hyperthermia at the basic science, engineering, and clinical level have stimulated renewed enthusiasm for re-investigating its potential as an anticancer therapy. This article reviews the salient features of these recent results and points out areas for additional investigation. Highlighting these new results is the publication of several positive phase III trials for thermoradiotherapy compared to radiotherapy alone. Important highlights are the encouraging results using magnetic resonance imaging for noninvasive thermometry. If this technology is successfully implemented with real time power control it will revolutionize the clinical application of hyperthermia.

Effect of heat, radiation and pH on mouse mammary tumor cells.

Experiments were done in vitro with cells derived from a C3H mouse mammary adenocarcinoma (MADCAP-37) to determine the influence of pH and sequencing on hyperthermia induced radiosensitization. The heat treatment was one hour at 42.5 degrees C in a precision controlled water bath. The heat treatment did not significantly reduce cell survival. Five Gy of x radiation was given at variable intervals from two hours before to two hours following heating. Survival curves under acid pH (6.4-6.7) and alkaline pH (7.2-7.4) were obtained for selected intervals, corresponding to points of interest in the sequencing study. Survival was greater for irradiation alone at acid pH than at alkaline pH. The greatest cell killing occurred when irradiation and hyperthermia were given simultaneously at either alkaline or acid pH. At alkaline pH, survival increased as the interval increased between heating and irradiation. At acid pH, radiation survival remained low for as much as two hours following heating. If tumors are at acid pH, the greatest differential effect should be obtained for irradiation following heating because cells at alkaline pH (normal) had approximately 10 times greater survival. Vascular changes caused by heating might alter that response.

Intraoperative irradiation of the canine abdominal aorta and vena cava.

The canine abdominal aorta and vena cava were examined 6 months after single doses of intraoperatively delivered electrons (IORT), fractionated external beam X rays, or a combination. The predominant pathologic change in aortas given fractionated doses was a segmental thickening of the subendothelial region of the tunica intima which was due to fibroelastic proliferation. In severe cases, the intimal proliferation caused significant narrowing of the aortic lumen. The greatest proliferation and lumen narrowing resulted from 80 Gy given in 30 fractions, whereas 60 Gy produced little response. In contrast, IORT alone or combined with fractionated doses resulted in mild subendothelial intimal proliferation at all doses. In some aortas there was focal aortic wall thinning after IORT alone or combined with fractionated doses. This response may be explained by increased intimal cell death and lost or delayed proliferative capability caused by large single doses. These studies suggest that large single doses produce structural alterations in the walls of large blood vessels that are clinically undetectable at early post-irradiation times. If these changes progress in severity they could lead to late effects such as rupture, fissure, or aneurysm that are clinically more significant than the marked intimal proliferation and lumen narrowing changes seen after fractionated doses. The aortic cell responsible for intimal fibroelastic proliferation appears to be a pluripotential stem cell capable of producing fibrous, elastic, and possibly smooth muscle tissue. There were no significant alterations in any of the irradiated vena cavas.

Late radiation response of the canine trachea with change in dose per fraction.

Seventy-two dogs were given 36 to 74 Gy to the trachea in either 2, 3, or 4 Gy per fraction. Tracheal sections were histologically and morphometrically evaluated 6 months after irradiation to determine the relative percentage of goblet cells, submucosal glands, connective tissue and blood vessels. The percent of each tissue component was plotted against total dose, regression lines calculated and isoeffective doses obtained for construction of isoeffect curves. Probit analysis for probability of surface ulceration also was done. Another group of 32 dogs received either 36, 44, or 52 Gy in 4 Gy fractions and tracheas were similarly analyzed at 1, 3, and 12 months after irradiation. Goblet cells and submucosal glands decreased with increasing total dose in each of the dose per fraction groups while connective tissue increased. Lower doses per fraction had more shallow dose response curves and higher total doses were required to produce an isoeffect. The alpha/beta ratios for tissues at 6 months after irradiation were 3.5 Gy for decrease in goblet cells, 4.7 Gy for probability for surface ulceration, 4.5 Gy for decrease in submucosal glands and 1.8 Gy for increase in connective tissue. Goblet cells and submucosal gland numbers decreased within 1 month and remained significantly decreased at higher doses at 12 months. Although there was no dose response for vasculature volume at 6 months, significant perivascular and intimal fibrosis was observed. This study revealed significant damage to the trachea at high total doses and large doses per fraction. The relatively low alpha/beta ratios obtained indicates that these adverse effects are late effects. Significant sparing of the adverse late effects was present at lower doses per fraction. These results indicate that coarser fractionation schemes that include the trachea in the treatment volume could be potentially dangerous.

Canine cardiomyopathy after whole heart and partial lung irradiation.

The late radiation response of the heart is of concern because of many reports of heart disease following radiation therapy of thoracic tumors. This study was done because of the clinical relevance of the pathophysiology of cardiopulmonary irradiation and because the heart is a good model for late effects of vasculoconnective tissue due to its lack of acutely responding parenchymal cells. Thoracic irradiation of adult beagle dogs including the heart and one third of the lung volume produced an early response in the heart at 1 and 3 months which consisted of an increase in left ventricle and septal wall thickness, decreased left ventricle ejection fraction, increased heart rates, intraventricular conduction disturbances and a high probability for pericardial effusion at 3 months. Radiation doses were 36, 44, or 52 Gy given in 4 Gy fractions in 4 weeks. Premature atrial contractions, paroxysmal atrial tachycardia, sustained atrial tachycardia and atrial fibrillation occurred at all dose levels. Evidence suggests that both early and late responses were due, at least in part, to direct injury to the cardiac microvasculature. The later effects appeared to be enhanced by injury to the lung. The early response appeared to resolve in 6 to 9 months, after which there was thinning of the myocardium at higher doses and resolution of pericardial effusions. At 12 months, elevations in right atrial pressure, but not pulmonary wedge pressure, were suggestive of right-sided congestive heart failure. Pulmonary hypertension was also present at 12 months presumably due to partial lung irradiations, and may have exacerbated right-sided congestive heart failure. The radiation injury may continue to increase with time leading to serious deficits in cardiopulmonary function. The functional studies may aid in predicting late effects and evaluating residual injury.

Long-term adverse effects of radiation inhibition of restenosis: radiation injury to the aorta and branch arteries in a canine model.

PURPOSE: To determine the long-term effects of irradiation on large arteries in view of the possible use of radiation to prevent restenosis after angioplasty. METHODS AND MATERIALS: Groups of dogs received 10-55 Gy single-dose alone, or in combination with 50 Gy in 2-Gy fractions, or 50-80 Gy in 2-2.7-Gy fractions to an 8-cm length of aorta and branch arteries. Single doses were delivered intraoperatively. Two or 5 years after irradiation, aortas and branch arteries were evaluated histomorphometrically to determine areas of intima, media, and adventitia, and qualitatively to determine other adverse effects. RESULTS: Intimal area increased at single doses < 20 Gy and after all fractionated doses, but was normal at doses > 20 Gy 2 years after irradiation. Intimal area was greater at 5 years than at 2 years after irradiation. Adventitial area increased with increasing dose at 2 and 5 years after irradiation. Thrombosis of the aorta and branch arteries occurred at 4-5 years after irradiation with ED50s of 29.7 Gy and about 25 Gy, respectively, but did not occur after fractionated irradiation. CONCLUSION: Intimal proliferation is inhibited at single doses > 20 Gy, but may be stimulated at single doses of < 20 Gy or after fractionated irradiation. Adventitial fibrosis increases with increasing dose and could contribute to adverse late vascular remodeling. Severe adverse effects were not evident until 4-5 years after irradiation at does of > 20 Gy to an 8-cm vessel length.

Response of the canine lung to fractionated irradiation: pathologic changes and isoeffect curves.

Canine lungs were irradiated with a range of total doses given in 2, 3, or 4 Gy per fraction. Sequential histopathologic evaluations were done at 1, 3, 6, and 12 months. Pathologic changes in canine lungs were found to be similar to those found in other species demonstrating a clinically latent period, a pneumonitis phase, and late fibrosis and vascular damage. The relative impact of endothelial cell and pneumocyte injury on either early or late radiation injury of the lung is difficult to resolve. Therefore, it is not possible to define a target cell for lung injury at this time. The alpha/beta ratios determined in this study indicate that the target cell or cells associated with lung consolidation are slowly proliferating and represent late responding tissues. Lungs were evaluated histomorphometrically for alveolar air space and radiographically for alveolar consolidation at 6 months after irradiation. Alpha/beta ratios of 3 Gy and 4 Gy were calculated respectively. Both assays demonstrated an increasing effect on lung damage with increasing fraction size from 2 to 4 Gy. Application of the LQ model and use of alpha/beta ratios for calculation of dose adjustments remains theoretical. Clinical data are insufficient to define specific alpha/beta ratios for the various normal tissues at risk in radiation therapy. The data are sufficient to demonstrate the sparing effects of decreasing size of dose per fraction for late responding tissue. Results of this study suggest caution against the use of large doses per fraction for radiation therapy fields which include large lung volumes.