Radiation-induced morphologic changes in the rhesus monkey (Macaca mulatta) brain.

The right cerebral hemisphere of 24 rhesus monkeys scheduled for necropsy at the completion of another project were studied histopathologically 1-30 days after a single dose of 60Co-irradiation. Histopathologically, inflammation and gliosis consistently occurred at specific time points but varied in severity between individuals. Multifocal hemorrhage, edema, and an acute neutrophilic inflammatory response were observed initially whereas perivascular accumulations of lymphocytes were observed in specimens at the end of the study. Microglia/macrophages were most prominent during the first week after irradiation, whereas astrocytes were reactive throughout the observation period. The early clinical manifestations of the central nervous system (CNS), because of brain irradiation in humans, correspond temporally with acute vascular responses, acute and subacute inflammatory cell responses, and subacute demyelination and reactive astrocytic and microglial responses observed in the rhesus monkey. Initial responses of the CNS to gamma-irradiation may have potential implications for the development of radiation-induced late injury of the CNS.

Comparison of kidney weight and volume to selected anatomical parameters in the adult female rhesus monkey (Macaca mulatta).

In this study, the normal distribution of renal weight and volume was determined and the correlation between the weight and volume and various skeletal measurements taken from radiographs and at necropsy was assessed. Values from 136 female monkeys with complete data (including all bone, radiographic, and kidney measurements) were analyzed. The mean kidney weight was 13 g with a standard deviation (SD) of 2 g. The mean kidney volume was 12 ml, SD 2 ml. The estimation of kidney weight and volume from bone length, age, or body weight was not reliable according to statistical analysis of our data. We did find that all apparently normal adult female rhesus monkeys typically have similar sized kidneys. This information is useful in that it reduces concerns about consistency in experimental subjects.

Reliable establishment of human sarcoma xenografts in the nude rat.

Purpose. The ability to establish consistent human tumor xenografts in experimental animals is a crucial part of preclinical investigations.The goal of this study was to develop a method of establishing a human tumor xenograft in the leg of a nude rat for evaluation of new surgical and molecular methods of treatments of human extremity sarcoma.Methods and results. Initial attempts to produce sarcoma nodules by subcutaneous injection of a human leiomyosarcoma tumor cell suspension (SKLMS-1) resulted in tumor nodule formation in only four of 10 sites (40%).The xenograft method was modified to include younger nude rats of a different source and substrain (HSD:rnu/rnu, 5-9 weeks old), treated with 500 cGy whole-body irradiation, and the transplantation of tumor cells or small tumor fragments which had been embedded in Matrigel.These changes improved the tumor take rate per site to 52/52 (100%).Tumor nodules demonstrated rapid and progressive growth and histological features consistent with the original human sarcoma.Discussion. Successful human leiomyosarcoma establishment in these nude rats permits the investigation of sarcoma biology and treatment with surgical procedures for which a mouse model would be inadequate. In this study we identified modifications in technique which enhanced the xenografting of a leiomyosarcoma cell line in nude rats; these techniques may increase tumor take rates for other tumor types as well.

Postirradiation sarcomas in Sprague-Dawley rats.

A series of radiation-induced neoplasms occurred in Sprague-Dawley rats 4-8 months after irradiation of a single hind leg with 60Co gamma rays. The rats were exposed to fractionated cumulative doses that ranged from 0 to 106 Gy. Osteosarcomas, malignant fibrous histiocytomas and fibrosarcomas developed in the radiation fields of a number of the rats in the higher-dose groups. Tumors did not develop throughout an 8-month observation period in rats that received doses of only 0 or 46 Gy. The most common postirradiation sarcomas in humans are osteosarcoma, malignant fibrous histiocytoma and fibrosarcoma. The Sprague-Dawley rat may serve as a good animal model in studying the development of sarcoma in humans after regional radiotherapy.

The effects of preoperative irradiation on peripheral nerve regeneration.

The purpose of this study was to evaluate the effects of preoperative external cobalt60 beam irradiation on nerve regeneration. Ninety 250-g male Sprague-Dawley rats were studied. Peripheral nerve regeneration was measured by walking track analysis and histomorphology of the proximal, grafted, and distal nerve segments. Ninety animals were randomly assigned to one of five treatment groups, receiving a total fractionated dose of 30, 50, 70, and 90 Gy. Each animal received a 15-mm interposition nerve graft into the right posterior tibial nerve 6 weeks following completion of radiation therapy. The left leg served as a control. The remaining 10 animals received a nerve isograft subjected to a single dose of 30 Gy prior to placement (group 5). Walking track analysis was performed monthly through 8 months. At the conclusion of 120 and 240 days, sections of the proximal, grafted, and distal nerve were harvested, stained, and examined histomorphologically. Evaluation of the print length index demonstrated no statistical difference between our previously established nonirradiated controls, the irradiated groups, and the irradiated isograft group (group 5). The total number of axons per square millimeter was significantly decreased in the distal segment of all irradiated groups when compared with the controls. No statistical difference in number of axons per square millimeter was noted in the irradiated isograft group. Furthermore, no statistical difference was noted in the nerve fiber density between the control group, the preoperative irradiated groups, or the irradiated isograft group (group 5). Despite the reduction in myelinated regenerating fibers, no reduction in function was observed as measured by walking track analysis. Thus, immediate reconstruction of peripheral nerve defects in the face of preoperative irradiation may not be contraindicated.

Peripheral nerve regeneration: the effects of postoperative irradiation.

The purpose of this study was to evaluate the effects of postoperative external cobalt-60 beam irradiation on nerve regeneration. Sixty-five 250-gm male Sprague-Dawley rats were studied. Peripheral nerve regeneration was measured by walking track analysis and histomorphology of the proximal, graft, and distal nerve segments. These 65 animals underwent a 1.5-cm interpositional nerve graft into the right posterior tibial nerve. The left leg served as a control. Each animal was then randomly allocated into one of four groups. Group 1 served as control. Groups 2 through 4 were subjected to external cobalt-60 gamma-ray irradiation through a 2.5-cm circular portal for a total fractionated dose of 30, 50, and 70 Gy beginning on postoperative day 3. Radiation was administered in 2-Gy fractions, 5 fractions per week, with a top-up dose of 16 Gy given at the end of the fractionated irradiation. Walking track analysis was performed at 30, 60, 90, and 120 days after nerve grafting. At the conclusion of 120 days, sections of the proximal, grafted, and distal nerve were harvested, stained, and examined histomorphologically. Hematoxylin and eosin stains also were obtained. Evaluation of the print-length index demonstrated no statistical difference between the unirradiated controls and the irradiated groups. The total number of axons per square millimeter and nerve fiber density per square millimeter were significantly decreased in the distal segment of all the irradiated groups when compared with controls. Despite the reduction in myelinated regenerating fibers, no reduction in function was observed, as measured by walking track analysis. We would therefore recommend immediate reconstruction of peripheral nerve defects in the face of postoperative irradiation.

Laparoscopically guided bipolar radiofrequency ablation of areas of porcine liver.

BACKGROUND: Bipolar radiofrequency ablation (BRFA) is a promising technique with which to treat unresectable primary and metastatic liver tumors. Its effects on normal liver tissue and postoperative liver function, however, are unknown. We performed this study to determine (1) the feasibility of using laparoscopic ultrasound to guide placement of BRFA needle electrodes in the liver and (2) the histopathologic, hepatic biochemical, and systemic hemodynamic responses to BRFA. METHODS: Two BRFA lesions were created in the liver of adult domestic pigs to ablate 8-10% of the normal liver volume. Laparoscopic ultrasound was used to guide creation of one peripheral liver lesion and one central liver lesion (with a major hepatic or portal venous vein branch in the center of the BRFA lesions) in each animal. BRFA of liver tissue was performed by passing 12 W of RF power for 16 min across two 16-gauge active-needle electrodes placed 3 cm apart. RESULTS: All animals survived the procedure without significant hemodynamic alterations during or after BRFA. All animals had a transient elevation in serum transaminase levels that returned to normal within 1 week of the BRFA of liver tissue. Gross and microscopic histopathology of the BRFA lesions revealed 2.0-2.5-cm zones of complete coagulative necrosis around and between the BRFA needle tracks without destruction of major blood vessel walls. CONCLUSIONS: This study demonstrates (1) that laparoscopic ultrasound can be used to guide placement of BRFA needles in the liver and (2) that BRFA produces focal destruction of liver without significant systemic hemodynamic responses or alterations in liver function. Further studies of this technique to ablate malignant liver tumors are ongoing.

Stenosing colonic adenocarcinoma in a female rhesus monkey.

Laparoscopic surgery was performed on a 16 year-old female rhesus monkey presenting with chronic lethargy and inappetence. The procedure revealed a "napkin-ring" stricture located in the ascending large colon. Histologic evaluation of the colonic lesion exhibited large numbers of irregular acini lined by a single layer of well-differentiated neoplastic epithelial cells. Based on the gross and histopathologic findings a diagnosis of adenocarcinoma of the proximal colon was made.

Glioblastoma multiforme arising in the irradiated spinal cord of a rhesus monkey (Macaca mulatta).

An adult female rhesus monkey that had received 44.0 Gy of cobalt 60 radiation to 8 cm of the cervical and upper thoracic spinal cord approximately 2.8 years postirradiation developed a sudden onset of self-mutilation and loss of function of the right arm followed progressively by loss of function of the left arm and terminally bilateral paresis of the legs. Histopathologic examination of the cervical spinal cord revealed a glioblastoma multiforme that extended from the cervical medullary junction to the sixth cervical vertebrae. Because of the infrequent occurrence of spontaneous neoplasia in rhesus monkeys and the location in the radiation field, the glioblastoma is believed to be radiation induced.