Susan L. Kraft

A review: CNS effects and normal tissue tolerance in dogs.

Large animal studies have been utilized to definetolerance of normal brain to irradiation and verifytreatment planning programs with two recently installed epithermalneutron beams.The normal brain tolerance studies utilized two biologicalendpoints, magnetic resonance visible damage only and neurologicsigns progressing to death. The studies focused ondefining the proton RBE for the contaminant fastneutrons, and from nitrogen capture of thermal neutronsand boron capture reaction biologic effect. The protonRBE was approximately 3.0 to 6.7, depending onwhether a dose reduction factor for the lowgamma dose rate was employed.The microscopic distribution of the boron compounds, coupledwith the extremely short length of the fissionfragments from thermal neutron capture by 10B yieldsan observed biologic effect much less than wouldbe expected from such high LET irradiation. Thisobserved biologic effect, which is a product ofthe microdistribution of the boron atom and therelative biologic effect of the fission fragments hasbeen termed compound factor. The compound factor wasbased on the calculated physical dose from thefission fragment in blood based on measured blood10B concentration. The approximate compound factor for BSHwas studied at the two institutions and itranged from 0.27 to 0.55, depending on thesite and the endpoint chosen. The mean compoundfactor for BPA was only studied at onesite and was found to be 1.1 forboth endpoints. The increase in the compound factorfor BPA is in keeping with previous calculationsbased on the differences in compound distribution. Resultsof these studies has helped the initiation ofphase I and phase II clinical trials atBrookhaven National Laboratory and the planned European clinicaltrials at Petten, The Netherlands.

Large animal normal tissue tolerance with boron neutron capture

PURPOSE Normal tissue tolerance of boron neutron capture irradiation using borocaptate sodium (NA2B12H11SH) in an epithermal neutron beam was studied. METHODS AND MATERIALS Large retriever-type dogs were used and the irradiations were performed by single dose, 5 x 10 dorsal portal. Fourteen dogs were irradiated with the epithermal neutron beam alone and 35 dogs were irradiated following intravenous administration of borocaptate sodium. RESULTS Total body irradiation effect could be seen from the decreased leukocytes and platelets following irradiation. Most values returned to normal within 40 days postirradiation. Severe dermal necrosis occurred in animals given 15 Gy epithermal neutrons alone and in animals irradiated to a total peak physical dose greater than 64 Gy in animals following borocaptate sodium infusion. Lethal brain necrosis was seen in animals receiving between 27 and 39 Gy. Lethal brain necrosis occurred at 22-36 weeks postirradiation. A total peak physical dose of approximately 27 Gy and blood-boron concentrations of 25-50 ppm resulted in abnormal magnetic resonance imaging results in 6 months postexamination. Seven of eight of these animals remained normal and the lesions were not detected at the 12-month postirradiation examination. CONCLUSION The bimodal therapy presents a complex challenge in attempting to achieve dose response assays. The resultant total radiation dose is a composite of low and high LET components. The short track length of the boron fission fragments and the geometric effect of the vessels causes much of the intravascular dose to miss the presumed critical target of the endothelial cells. The results indicate a large dose-sparing effect from the boron capture reactions within the blood.

Large Animal Model Studies of Normal Tissue Tolerance Using an Epithermal Neutron Beam and Borocaptate Sodium

Epithermal neutron beams are being developed for potential boron neutron capture therapy (BNCT) to allow treatment of deep seated tumors, like glioblastoma multiforme, through the intact skin. The neutron capture cross-sections for elements in normal tissue are several orders of magnitude lower than that for boron but due to the relatively high concentrations of hydrogen and nitrogen in normal tissue, their capture through the 1H(n,γ)2H and the 14N(n,p)14C reactions respectively contribute significantly to the total radiation absorbed dose. Additional sources which contribute to the absorbed radiation dose are incident gamma-radiation and fast neutrons, i.e. components in the epithermal neutron beam.

DIAGNOSIS AND TREATMENT OF A CEREBRAL INFARCT IN A CHIMPANZEE (PAN TROGLODYTES)

Abstract A 29-yr-old chimpanzee (Pan troglodytes) presented after an acute onset of right facial and forearm paresis that progressed to paralysis within 24 hr, with subsequent development of right leg paresis. Magnetic resonance imaging (MRI) of the head revealed an abnormal region of increased signal intensity in the left frontal, parietal, and temporal cerebral hemispheres, corresponding to the vascular territory of the middle cerebral artery, with resultant compression of the left lateral ventricle. The findings were consistent with a cerebral infarct (stroke). MRI is the most sensitive test for early detection of cerebral changes due to ischemia and was essential in obtaining a diagnosis in this case. The chimpanzee responded well to treatment with long-term anticoagulant aspirin and a short, tapered course of prednisone and regained full gross motor function.

Large Animal Studies on the Use of BNCT for the Treatment of Brain Tumors

Animal models are useful to study the relative effects of BNCT on normal tissues and tumors. True efficacy studies of the modality on glioblastoma or other human malignancies requires human clinical trials. The use of large animals, primarily dogs, to study the effects of BNCT has been and continues to be of major interest. The use of large animals permits the study of normal tissue tolerance of the tissues of the head at an acceptable total body dose. These studies have been extended from normal dogs to dogs with induced and spontaneous tumors. While induced tumors in rodents are often used to study tumor response, the total body dose accompanying BNCT severely limits their use for normal tissue tolerance studies, especially with the epithermal-neutron beams.

Boron Neutron Capture Therapy of Spontaneous Intracranial Tumors in Dogs

Normal tissue tolerance studies have been extended to 23 dogs with spontaneously occurring tumors. All animals were treated with a single 10×10 cm dorsal portal following the infusion of borocaptate sodium. Blood-boron concentrations at the time of radiation have varied between 20 and 100 μg/g. Objective tumor response was seen in some animals. Radiation brain necrosis was seen in 3 dogs. The bimodal therapy presents a complex challenge in attempting to achieve dose response assays. The results indicate a large dose-sparing effect from the boron capture reactions within the blood.