C. E. DeHaan

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.

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.

Quantitative 123I IMP and 99mTc HMPAO imaging in the dog following cocaine administration

SPECT and associated imaging procedures were used in beagle dogs to (1) evaluate the uptake, distribution, and clearance properties of i.v.-injected 123I IMP (IMP) and 99mTc HMPAO (HMPAO) in the brain, lungs, liver, and kidneys; (2) quantify the acute effects (after 15 sec) of very low doses (0.5 or 1.0 mg/kg) cocaine on the kinetics and localization properties of IMP and HMPAO; and (3) evaluate comparative imaging properties of IMP and HMPAO for measuring regional cerebral blood flow (rCBF). Regional and global uptake and localization of IMP or HMPAO were evaluated in control studies using dynamic planar (0-30 min) and SPECT imaging (at 35 min). The regional distribution properties of IMP and HMPAO in the brain were estimated from regions of interest (ROIs) drawn around anatomic structures on MR slices and manually registered with corresponding SPECT slices. Cocaine significantly reduced the 30-min IMP uptake in the brain and lungs by approximately 15%, but only slightly changed HMPAO uptake in the brain and other organs. In the control studies, the respective uptakes of IMP in the brain and lungs were 9 and 39% greater (p < 0.01) than those of HMPAO. In control SPECT studies, the highest uptake of IMP was observed in the thalamus and progressively less activity was observed in the parietal lobe, frontal lobe, cerebellum, occipital lobe, and entire brain; activity in the olfactory bulb was lower than in all other regions. Cocaine reduced IMP uptake in the cerebellum (p < 0.01), occipital lobe (p < 0.01), and entire brain (p < 0.05). IMP uptake (cpm/pixel-mCi) in the different brain regions was 1.3 to 2.1 times greater than that of HMPAO (p < 0.001). HMPAO uptake was more homogeneous throughout the gray matter of the brain; no significant uptake differences were observed among flagged regions. Results indicate that single, acute doses of cocaine, 0.5 and 1.0 mg/kg, significantly altered the uptake and localization properties of IMP in the dogs brain, lungs, liver, and kidneys. Variations in regional uptake of IMP in the parietal, frontal, and occipital lobes, cerebellum, and thalamus were greater than with HMPAO.

Spontaneous Canine Oral Melanoma: A Large Animal Model for BNCT

Spontaneous tumors, in comparison to transplantable tumors, in animals offer several advantages for investigating new therapeutic modalities prior to human clinical trials. The main advantages are “typical” tumor vasculature, normal anatomical sites, slow growth rates and long cell-cycle times, and a nonimmunogenic nature.

Acute and Late Reactions Following Boron Neutron Capture Epithermal-Neutron Therapy in Dogs with Spontaneous Brain Tumors

Dogs have a relatively high incidence of primary tumors of the central nervous system and have proven to be good models for new therapeutic investigation.1 The pharmacokinetics of borocaptate sodium have been well documented in the dog.2 Preliminary investigations of the normal tissue tolerance to boron neutron capture therapy have been performed utilizing normal laboratory dogs. This study was an extension of the normal tissue tolerance and was designed to ensure a therapeutic margin was present for the dogs with spontaneous tumors; i.e., a measurable effect could be had on the tumor at doses considered safe for the normal tissues.

The Biodistribution of Boron in Normal Canine Tissues Following Borocaptate Sodium Administration and the Effect of Plasma Exchange

Normal tissue tolerance establishes the dose limitations for any form of radiation therapy. The complexity of the mixed form of radiation from Boron Neutron Capture Therapy (BNCT) makes it difficult to predict normal tissue tolerance. A premise for BNCT is that the ideal boron compound should result in minimal boron concentrations in normal tissues and blood and high concentrations in tumor tissue.(1)

Regional and Total Body Dose Following BNCT Epithermal Head Irradiation: Biologic and Dosimetric Evaluation

Normal laboratory dogs received epithermal-neutron irradiation to the right cerebrum via a dorsal portal using a 5×10 cm incident field. The Brookhaven Medical Research Reactor (BMRR) power was 3 MW. Significant regional and total body radiation effects were noted. The reactions were of sufficient magnitude to reveal the need for additional shielding or other efforts to reduce these effects.