Judit Benczik

Late radiation effects in the dog brain: correlation of MRI and histological changes

PURPOSE To determine the correlation between sequential changes in the brain of dogs after irradiation, as detected by magnetic resonance imaging (MRI), with the eventual appearance of histological lesions. Histology was performed 77-115 weeks after irradiation. MATERIALS AND METHODS Groups of five beagle dogs were irradiated to the brain with single doses of 10, 12, 14 or 16 Gy of 6 MV photons, at the 100% iso-dose. Sequential MRIs were taken to detect changes in the brain for 77-115 weeks after irradiation. Dose-effect relationships were established for changes in the brain as detected by MRI, computerized tomography (CT), gross morphology and histology. The doses that caused a specified response in 50% of the animals (ED(50)+/-SE) were calculated from these dose-effect relationships for each endpoint. RESULTS The ED50 values (+/-SE) for focal and diffuse changes on T2-weighted MR images were 11.0+/-1.1 and 10.8+/-0.9 Gy, respectively. The ED50 values (+/-SE) for contrast enhancement on T1-weighted MR images and on CT were 13.4+/-0.6 and 13.0+/-0.6 Gy, respectively. It was 11.4+/-0.6 Gy for any type of histological lesion (haemorrhage, reactive change or glial scar) 77-115 weeks after irradiation. For a macroscopic lesion the ED50 (+/-SE) value was 13.0+/-1.1 Gy. CONCLUSIONS The presence of focal or diffuse changes on T2-weighted MR images was the best indicator for the eventual appearance of any type of histological lesion in the dog brain after irradiation with single doses of photons. The ED50 for any histological lesion did not differ significantly from the ED50 for a focal (P>0.35) or diffuse (P=0.3) change on T2-weighted MR images.

Dose planning with comparison to in vivo dosimetry for epithermal neutron irradiation of the dog brain.

Boron neutron capture therapy (BNCT) is an experimental type of radiotherapy, presently being used to treat glioblastoma and melanoma. To improve patient safety and to determine the radiobiological characteristics of the epithermal neutron beam of Finnish BNCT facility (FiR 1) dose-response studies were carried on the brain of dogs before starting the clinical trials. A dose planning procedure was developed and uncertainties of the epithermal neutron-induced doses were estimated. The accuracy of the method of computing physical doses was assessed by comparing with in vivo dosimetry. Individual radiation dose plans were computed using magnetic resonance images of the heads of 15 Beagle dogs and the computational model of the FiR 1 epithermal neutron beam. For in vivo dosimetry, the thermal neutron fluences were measured using Mn activation foils and the gamma-ray doses with MCP-7s type thermoluminescent detectors placed both on the skin surface of the head and in the oral cavity. The degree of uncertainty of the reference doses at the thermal neutron maximum was estimated using a dose-planning program. The estimated uncertainty (+/-1 standard deviation) in the total physical reference dose was +/-8.9%. The calculated and the measured dose values agreed within the uncertainties at the point of beam entry. The conclusion is that the dose delivery to the tissue can be verified in a practical and reliable fashion by placing an activation dosimeter and a TL detector at the beam entry point on the skin surface with homogeneous tissues below. However, the point doses cannot be calculated correctly in the inhomogeneous area near air cavities of the head model with this type of dose-planning program. This calls for attention in dose planning in human clinical trials in the corresponding areas.

In Vivo Dosimetry of the Dog Irradiations at the Finnish BNCT Facility

A healthy tissue tolerance study1,2 with Beagle dogs was carried out at the Finnish BNCT facility FiR 1 during February-March 1998. Three dose groups of dogs without boron carrier, each comprising five Beagles, and one dose group with BPA-F infusion were irradiated. Individual dose plans1 were done for each dog. The absorbed doses, which were actually delivered to healthy tissues, were monitored in vivo by placing the dosimeters on the shaved skin of the dogs or in the accessible cavities. In this study, absorbed gamma doses were monitored with thermoluminescent (TL) dosimeters, and neutron fluences were determined with activation foils. The obtained results were compared to the calculated values.

Compartmental and Non-Compartmental Methods in Studying the Kinetics of Boron-10 after Boronophenylalanine Fructose Complex (BPA-F)-Infusion in Dogs

One of the essential requirements for optimising BNC-treatment is to know the boron-10 concentration in tissues under irradiation. A model which describes the kinetics of boron-10 in the patient would be valuable. The primary aim of the present study was to create a model for the pharmacokinetics of boron-10 in dogs after 4-dihydroxy-borylphenylalanine fructose complex (BPA-F) infusion so that we could predict the boron-10 concentration in blood during the irradiation.1 In addition we wanted to clarify if it is possible to design a simple compartmental model which could be used in defining the kinetic behaviour of boron-10 in the blood circulation.

Large Animal Model for Healthy Tissue Tolerance Study in BNCT

In radiotherapy where normal brain tissue is in the treatment field there is a risk of developing late radiation side effects. Consequently, evaluation of normal tissue tolerance is critical for the application of safe and effective treatment. The biological effectiveness of the calculated physical doses must be estimated before boron neutron capture therapy (BNCT) is applied clinically. Relative biological effectiveness (RBE) is a function of the energy of particles. As a consequence of the difference in neutron spec-trums in different BNCT facilities the RBE of each beam may be different. The aim of the healthy tissue tolerance study at the Finnish Research Reactor (FiR 1) was to obtain a complete dose effect curve for beam characterisation as part of the safety studies. The effects of high linear energy transfer (LET) radiation from the 10B(n,α)7Li reaction were compared with the effects of the beam-only irradiation. A large animal model (the dog brain) was used for the estimation of the probability of late radiation reactions as a function of dose. The endpoint of the study was visible magnetic resonance image (MRI) changes in the brain.

At the Threshold of Clinical Trials

The aim of the Finnish BNCT-project is to start BNC-treatments of malignant brain tumors. The first clinical trial is planned to start in early 1999 at the treatment facility of the 250kW FiR 1 TRIGA research reactor. Excellent patient treatment facilities have been built at the reactor which is located only 5 km from the Helsinki University Central Hospital making the treatment facility very easy to reach.

Quantitative MRI in Assessing Irradiation Effect in Dog Brain

The effect of radiation to the central nervous system has been studied frequently.1, 2, 3, 4, 5 Early delayed injury occurs a few weeks to 3 months after therapy. Late radiation injury, which is observed a few months to 10 or more years after radiotherapy, is often irreversible, progressive, and is seen as focal injury or diffuse white matter injury. The degree of lesion and its characteristics depend upon the radiation dose, the time within which this dose is delivered, and the type of the target cell. The radiation response of normal brain has been investigated in a variety of animal models. Available data suggest that non-human primates and dogs are the best models of the human brain, with similar dose requirements to induce damage, and similar radiographic and histopathologic changes.6

Irradiation of Dog Brain with Single Doses of X-Rays

It is not possible to selectively irradiate a single hemisphere of the dog brain with epithermal neutrons. Therefore, a whole brain irradiation study with photons was carried out to establish adequate controls for the normal tissue tolerance studies with boron neutron capture irradiation at the Finnish Research Reactor.1 The primary objective of the study was to obtain a radiation-induced dose effect curve for visible changes on computerised tomography after photon irradiation and to calculate the ED50 to this change. Computerised tomography (CT), with contrast enhancement, was used to detect the changes in the brain, induced by radiation, after 20 months follow up. A secondary objective of the present study was to estimate possible differences in response between half brain and whole brain irradiation. The results of whole brain irradiation in dogs in the present study were compared to those obtained by Fike using half brain irradiation.2,3 For immobilisation of the dogs during high-energy photon irradiation an anaesthetic agent that does not suppress the arterial oxygen saturation (SpO2) is needed. In this study we used general anaesthesia accomplished with intravenous (iv.) propofol as the induction agent and isoflu-rane as the maintenance agent to ensure the oxygen saturation of haemoglobin.

A Large Animal Model Study Investigating Potential BNCT Retreatment Using BSH

Boron neutron capture therapy (BNCT) treatments utilizing epithermal neutron beams and available boron compounds result in a mixed irradiation field of low and high linear energy components (LET). Previous studies attempting to measure the repair of the low LET component, comparing a multifraction study to single fraction study failed to identify sufficient repair in normal tissue tolerance studies of the dog brain utilizing borocaptate sodium (BSH) and epithermal neutron irradiation.1 Many current patients in clinical trials relapse approximately 6 months after their initial BNCT treatment. Many have considered the possibility of retreatment due to the theoretical dose localization in BNCT. A six-month interval would not be sufficient to allow retreatment of a full course of conventional irradiation. Therefore, a study was undertaken to give purpose-bred laboratory dogs an initial BNCT to near tolerance levels followed in six-month by a second identical dose.