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Biomedical subjects

E L Gillette

Publications and source records attributed to E L Gillette.

At least 55 records · Page 3Linked to original sources
PubMed1989

Peripheral neuropathies following experimental intraoperative radiation therapy (IORT).

Injury to peripheral nerves in the lumbar para-aortic region was evaluated in beagle dogs 2 years following fractionated irradiation (EBRT), intraoperative irradiation (IORT), or a combination of IORT and EBRT. Time to onset of peripheral neuropathy was determined by means of serially completed neurological and electrophysiological examinations. Peripheral neuropathies were seen beginning as early as 6 months following 35 Gy (or greater) IORT only and 35 Gy plus 50 Gy EBRT. The incidence of peripheral neuropathies increased with increasing IORT doses beginning at 15 Gy. Onsets of peripheral neuropathies following IORT alone were clustered between 6 and 18 months, with onset in some dogs occurring as late as 24 months. The combination of IORT and EBRT resulted in an incidence and latency to onset of neuropathies similar to that seen with IORT alone. Neuropathies were not seen with EBRT alone at doses from 50 Gy to 80 Gy. Recovery of nerve function did not occur in affected dogs. Histological studies of nerves 2 years following irradiation demonstrated loss of axons and myelin, with a corresponding increase in endoneurial, perineurial, and epineurial connective tissue. Percentage of axon and myelin decreased to about 60% of normal at 15 Gy IORT, and additionally at higher doses. An insignificant decrease in percentage of axon and myelin was seen following EBRT alone. A significant lesion occurring in and around nerves at most IORT doses was necrosis and hyalinization of the media of small arteries and arterioles. The dose for a 50% probability for causing severe vessel lesions in the 2-year study was 19.5 Gy IORT only and 18.7 Gy when IORT was combined with EBRT. These lesions were not seen with any EBRT only dose. These studies suggest that peripheral nerve is a dose limiting normal tissue in IORT. Neuropathies appear to result from direct effects of irradiation on nerve and secondary effects to nerve resulting from damage to regional vasculature.

Animals↗
PubMed1989

Response of aorta and branch arteries to experimental intraoperative irradiation.

Injury to the aorta was evaluated in dogs 2 and 5 years after fractionated irradiation (EBRT), intraoperative irradiation (IORT) or a combination. Doses greater than 20 Gy IORT combined with 50 Gy EBRT given in 2 Gy fractions or 30 Gy IORT alone were accompanied by a significant risk of aneurysms or large thrombi as determined at necropsy 4 to 5 years following irradiation. Narrowing of the aorta as detected by aortography occurred at 5 years but was not detected earlier. The ED50 for aortic narrowing was 38.8 Gy IORT and 31 Gy IORT plus 50 Gy EBRT. The ED50 for branch artery injury was 24.8 Gy IORT alone and 19.4 Gy IORT plus 50 Gy EBRT. The difference in ED50s for IORT alone and IORT plus EBRT indicates that the contribution of the EBRT dose in terms of an IORT dose for aortic narrowing was 7.8 Gy and for branch artery injury was 5.4 Gy. The ED50 for incidence of small thrombi in the aorta was about 29 Gy for IORT alone and 23.5 Gy for IORT combined with EBRT. Fibrous thickening of the adventitia was measured and the effect of the 50 Gy EBRT component of a combination of EBRT and IORT was determined to be equivalent to 10 to 12 Gy IORT. Based on the various estimates, IORT doses of 10-15 Gy have an effect of 5 times or greater the amount given in 2 Gy fractions. At all EBRT doses and at lower IORT doses the intima was greatly thickened. At IORT doses of 20 Gy or above there was a dose related decrease in intimal thickness to near normal values. This was probably due to cell killing or inhibition of intimal proliferation that predominated at higher doses. Although the risk of serious vascular complications appears low following IORT of humans, this may be due to short observation times and the fact that IORT doses currently used are usually 20 Gy or less; this may be near the tolerance for late response of larger arteries. Only one dog in this study had complete rupture of the aorta causing death. Five other dogs at high IORT doses had near ruptures of the aorta but were clinically normal.

Aortic Dissection↗
PubMed1988

Exocrine pancreatic function following intraoperative irradiation of the canine pancreas.

Twenty-four beagles received intraoperative irradiation (IORT) with 6 meV electrons to the pancreas and the duodenum. Intraoperative irradiation doses of 17.5 to 40 Gy were given. Billroth II gastrojejunostomy was done to bypass the irradiated duodenum. Six control dogs received only the Billroth II surgery. Two weeks postoperatively, irradiated dogs were given 50 Gy of 6 MV X radiation (external-beam radiation [EBRT]) to the pancreas and duodenum in 2 Gy fractions over a 5-week period. Dogs were monitored clinically and exocrine pancreatic function was evaluated using an N-benzoyl-l-tyrosyl-para-aminobenzoic acid (BT-PABA) test between 3 and 135 days postoperatively. Necropsies were performed on the dogs at 135 days postoperatively. The degree of gross pancreatic atrophy in the irradiated group was dose related. The mean percentage of normal acinar cells correlated with IORT doses and para-aminobenzoic acid (PABA) values (P less than 0.1). Weight loss was significantly greater in the irradiated dogs compared to the control (P less than 0.05) and the mean percentage of body weight loss correlated with the mean PABA values (P less than 0.01). In this study, the use of the BT-PABA test to evaluate progressive exocrine pancreatic function following IORT and EBRT showed an expected trend. A progressive decrease in exocrine pancreatic function in the irradiated dogs as indicated by plasma PABA levels may have been partly due to late radiation damage to acinar cells, secondary to vascular and ductular damage. At 135 days postoperatively none of the dogs showed clinical signs of exocrine pancreatic insufficiency and the plasma PABA levels were within the normal presurgical range. The progressive decrease in plasma PABA levels indicated a potential for the late development of exocrine pancreatic insufficiency. The BT-PABA test could be useful for evaluating the progressive decrease in exocrine pancreatic function and residual radiation injury to the pancreas. Because the exocrine deficiency can be managed with replacement therapy, pancreatic injury may not be a serious complication after doses of less than 30 Gy IORT with 50 Gy EBRT. Data from this study are in agreement with previous clinical and experimental reports that the duodenum is dose-limiting for IORT. Doses of 20 Gy IORT or less plus 50 Gy EBRT for treatment of carcinoma of the pancreas may not result in serious long-term complications due to radiation injury of the duodenum.

Adenocarcinoma↗
PubMed1988

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.

Animals↗
PubMed1988

Aortic wall injury following intraoperative irradiation.

The type, extent, and probability of vasculopathy in canine abdominal aortas were determined 5 years after large single radiation doses given intraoperatively (IORT) either alone or with fractionated doses of external beam irradiation (EBRT) to compare with the response following EBRT only. Young adult beagle dogs were used. For IORT, a 5 x 8 cm electron applicator was used to deliver 6 MeV electrons to the paraaortic region. For EBRT of the paraaortic region, 6 MV photons were given in variable total doses in 30 fractions in 6 weeks. For the combination, variable IORT doses were given following an EBRT dose of 50 Gy given in 2 Gy fractions in 5 weeks. Necropsies were performed 4 to 5 years after irradiation. Transverse sections of the aorta were examined for lesions. Probit analyses were done to determine the dose with a 50% probability to cause severe lesions of the aorta 5 years after treatment. The most severe lesions were variably organized thrombi which occupied at least a third of the luminal area or intimal surface of the aorta. Six dogs with thrombi had dissecting aneurysms. That occurred at doses as low as 25 Gy IORT plus 50 Gy EBRT (1 of 4 dogs). The doses with a 50% probability for causing aneurysms and/or severe thromboses of the aorta were 35 Gy IORT (95% C.I., 29 to 46 Gy) and 27 Gy IORT plus 50 Gy EBRT (95% C.I., 20-40 Gy). No large thrombi or aneurysms were observed 5 years after EBRT to doses as high as 80 Gy. Comparison of the ED50s for IORT alone to that of IORT combined with EBRT indicated that 50 Gy given in 25 fractions had the impact of about 8 Gy IORT. Based on the response of younger adult dogs it appears that IORT doses greater than 30 Gy alone or 20 Gy IORT combined with 50 Gy EBRT would be accompanied by a significant risk of life threatening lesions of the aorta. This is in contrast with several earlier reports indicating that the tolerance dose of canine aorta was 50 Gy IORT.

Animals↗
PubMed1988

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.

Animals↗
PubMed1988

Pathologic response of the pancreas and duodenum to experimental intraoperative irradiation.

The pancreas and duodenum of 24 beagle dogs were given intraoperative irradiation (IORT) with 6 MeV electrons. The dose range was 17.5 Gy to 40 Gy. Billroth II gastrojejunostomy was performed on all dogs prior to irradiation. Six control dogs received only Billroth II surgery. Starting 2 weeks after surgery, dogs in the irradiation groups were given 50 Gy 6 MV X rays external beam radiation therapy (EBRT) to the pancreas and duodenum. The total dose of 50 Gy was given in 2 Gy fractions over 5 weeks. Dogs were monitored for 135 days then necropsied. Gross and histopathologic changes in the pancreas and duodenum were evaluated and quantitative analysis of pancreatic lesions done. Duodenal ulcers were found following 32.5 Gy and 40 Gy IORT. The pancreases were atrophic in irradiated dogs and exocrine pancreatic insufficiency occurred in one dog given 25 Gy. Gross pancreatic atrophy correlated with IORT dose. Histopathologic evidence of radiation damage to the pancreas was observed in acinar cells. Islet cell lesions were not apparent. There was pancreatic fibrosis and damage to blood vessels and ducts. Dose-response relationships were observed for the index of damage to the pancreas as a whole, for pancreatic fibrosis and a decrease in normal acinar cells. Although 25 Gy IORT plus 50 Gy EBRT was tolerated by the duodenum to 135 days, these doses may cause later pancreatic injury as an expression of damage to blood vessels and ducts. Exocrine pancreatic insufficiency and diabetes mellitus may thus represent potential late complications of IORT following 25 Gy or higher doses.

Animals↗
PubMed1988

In vitro susceptibility of canine tumor stem cells to doxorubicin.

Thirty-four canine tumor specimens (13 sarcomas and 21 carcinomas) were grown in soft agar gel. Susceptibility after continuous exposure to doxorubicin at concentrations of 1, 5, and 10 micrograms/ml was compared with that of control cultures. Plating efficiency averaged 0.096%. Doxorubicin at a concentration of 1 microgram/ml was found to result in greater than 70% inhibition of colony formation in 3 of 13 sarcomas and 1 of 21 carcinomas tested, and greater than 50%, but less than 70%, inhibition in 3 carcinomas and 1 sarcoma. Twenty-six tumors had less than 50% reduction in colony formation and were considered resistant. Minor differences in responses to drug in primary and metastatic locations were observed and attributed to tumor heterogeneity and test variability.

Animals↗
PubMed1988

Radiation-induced cardiomyopathy in the dog.

Sequential necropsies and histologic evaluations of young adult beagle dogs were performed after irradiation of the thorax. Total doses to the heart were 36, 44, or 52 Gy given in 4-Gy fractions in 4 weeks. One month after irradiation there was little histologic evidence of damage visible by light microscopy. However, ventricular and septal weights were increased, probably due to edema. At 3 months damage to endothelial and mesothelial cells was evident. By 12 months the myocardium was thinned and focal degeneration and loss of muscle cells and Purkinje fibers were observed. There was extensive subendocardial and epicardial fibrosis as well as intimal proliferation in coronary arteries. Morphometric analyses were performed on the myocardium, pericardium, atria, and aorta. There was a slight increase in perivascular connective tissue in the myocardium. The pericardium was increased in thickness and the ratio of smooth muscle to elastin was decreased in the aorta. Severe fibrosis occurred only in the right atrium. At 1 year there was no clinical evidence of heart failure; however, evidence of myocardial damage was present histologically and functionally. Additional stress and continued aging are likely to enhance the damage and lead to serious complications. The interactions of irradiated lung and heart require further investigation.

Animals↗
PubMed1987

Ophthalmic complications following megavoltage irradiation of the nasal and paranasal cavities in dogs.

Megavoltage x-radiation was used to treat orbital nasal, and paranasal cavity malignant neoplasia in 29 dogs. In each instance, the globe and adnexal tissues were within the treatment portals (entry and/or exit). Doses administered to tumors ranged from 3,680 to 5,000 cGy. Ocular reactions after irradiation were classified as mild in 5 of 29 cases (17.2%) and severe in 17 of 29 cases (58.6%). No ocular complications were noticed in 7 of 29 cases (24.1%). Complications frequently noticed included severe keratitis (41%), mild conjunctivitis (34%), severe conjunctivitis (28%), cataract (28%), and keratoconjunctivitis sicca (24%). Ocular complications that developed were not life threatening, but posed a threat to visual function and patient quality of life. Treatment for the complications included control of bacterial infection, reduction of tissue inflammation, and ocular surface protection when tear film deficiencies were noticed. Mild complications represented acute effects of irradiation, and typically resolved. Severe complications developed both acutely and as late irradiation effects. Those attributed to late irradiation effects were more vision threatening and altered the quality of life more than did the early effects.

Animals↗
PubMed1987

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.

Animals↗
PubMed1987

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.

Abdominal Neoplasms↗
PubMed1987

Response of canine oral carcinomas to heat and radiation.

Thermal enhancement of radiation response improved the probability for local tumor control without increasing the risk for late complications in this study of relatively advanced stage tumors. Thirty-eight dogs with naturally occurring oral carcinomas were randomized to two radiation dose response groups to receive radiation alone or combined with local hyperthermia. Radiation was delivered in 10 fractions over 22 days. Heating was done 3 hours after seven of the radiation doses. The objective was to maintain a minimum tumor temperature of 42 degrees C and a maximum normal tissue temperature of 40 degrees C for 30 minutes. Normal tissue temperatures were usually 40 degrees C or less but there was great heterogeneity in tumor temperatures. Temperatures at tumor margins never exceeded 41.5 degrees C. The TCD50 for radiation was 38 Gy (32-46 Gy, 95% C.I.) and for radiation and heat it was 33 Gy (30-36 Gy, 95% C.I.). The slope of the dose response was much steeper for radiation and heat than for radiation alone indicating that the heterogeneity of tumor response was decreased with heat. All tumors were controlled at 40 and 45 Gy with heat whereas only 57% and 75% were controlled with 40 and 45 Gy radiation only. There were no late necroses for radiation and heat. The tumor control enhancement might be improved with different sequences, number of heatings or other time temperature relationships. It is not possible to predict the optimum treatment scheme because of the lack of knowledge of the influence of hyperthermia on subsequent heat or radiation treatments. That influence could be affected greatly by changes in tumor microcirculation, pH, and oxygenation as well as development and decay of thermotolerance in tumor and normal tissue.

Animals↗
PubMed1986

Use of radiotherapy for the treatment of intranasal tumors in cats: six cases (1980-1985).

Six cats with intranasal neoplasia treated with radiotherapy were evaluated. The mean survival time from the initiation of radiotherapy was 19 months, with 2 cats still known to be alive. Two cats died for reasons unrelated to the primary tumor. One cat had no clinical evidence of nasal tumor 41 months after treatment, but was lost to further follow-up evaluation.

Adenocarcinoma↗
PubMed1986

Influence of WR 2721 on radiation response of canine soft tissue sarcomas.

Seventy-three dogs with soft tissue sarcomas were randomized to 2 dose response assays to receive irradiation alone or with the radioprotector WR-2721. Nausea and vomiting were the major side effects of WR-2721 administration although one death occurred because of cardiac and respiratory failure which may have been caused by the WR-2721. There was no change in blood counts or serum chemistry values. The TCD50/lyr was 52 Gy delivered in 10 fractions for both groups. However, there was an indication of tumor protection at lower doses because at all comparable dose levels the percentage tumor control was lower in dogs given WR-2721. There was no decrease in acute skin reactions of dogs treated with WR-2721 and little, if any, protection against fibrosis, soft tissue necrosis or bone necrosis. The lack of protection of normal tissues may have been caused by fractionation. The agent may be more useful combined with large single doses such as given in intraoperative radiotherapy.

Amifostine↗