Thomas B. Borak

Radiation Leukemogenesis in Mice : Loss of PU. 1 on Chromosome 2 in CBA and C57BL/6 Mice after Irradiation with 1 GeV/nucleon 56Fe Ions, X Rays or γ Rays. Part I. Experimental Observations

Abstract Peng, Y., Brown, N., Finnon, R., Warner, C. L., Liu, X., Genik, P. C., Callan, M. A., Ray, F. A., Borak, T. B., Badie, C., Bouffler, S. D., Ullrich, R. L., Bedford, J. S. and Weil, M. M. Radiation Leukemogenesis in Mice: Loss of PU.1 on Chromosome 2 in CBA and C57BL/6 Mice after Irradiation with 1 GeV/nucleon 56Fe Ions, X Rays or γ Rays. Part I. Experimental Observations. Radiat. Res. 171, 474–483 (2009). Since deletion of the PU.1 gene on chromosome 2 is a crucial acute myeloid leukemia (AML) initiating step in the mouse model, we quantified PU.1 deleted cells in the bone marrow of γ-, X- and 56Fe-ion-irradiated mice at various times postirradiation. Although 56Fe ions were initially some two to three times more effective than X or γ rays in inducing PU.1 deletions, by 1 month postirradiation, the proportions of cells with PU.1 deletions were similar for the HZE particles and the sparsely ionizing radiations. These results indicate that while 56Fe ions are more effective in inducing PU.1 deletions, they are also more effective in causing collateral damage that removes hit cells from the bone marrow. After X, γ or 56Fe-ion irradiation, AML-resistant C57BL/6 mice have fewer cells with PU.1 deletions than CBA mice, and those cells do not persist in the bone marrow of the C57B6/6 mice. Our findings suggest that quantification of PU.1 deleted bone marrow cells 1 month postirradiation can be used as surrogate for the incidence of radiation-induced AML measured in large-scale mouse studies. If so, PU.1 loss could be used to systematically assess the potential leukemogenic effects of other ions and energies in the space radiation environment.

Heavy charged particle radiobiology: Using enhanced biological effectiveness and improved beam focusing to advance cancer therapy

Ionizing radiation causes many types of DNA damage, including base damage and single- and double-strand breaks. Photons, including X-rays and γ-rays, are the most widely used type of ionizing radiation in radiobiology experiments, and in radiation cancer therapy. Charged particles, including protons and carbon ions, are seeing increased use as an alternative therapeutic modality. Although the facilities needed to produce high energy charged particle beams are more costly than photon facilities, particle therapy has shown improved cancer survival rates, reflecting more highly focused dose distributions and more severe DNA damage to tumor cells. Despite early successes of charged particle radiotherapy, there is room for further improvement, and much remains to be learned about normal and cancer cell responses to charged particle radiation.

The Response of a Spherical Tissue-Equivalent Proportional Counter to Iron Particles from 200 – 1000 MeV/nucleon

Abstract Gersey, B. B., Borak, T. B., Guetersloh, S. B., Zeitlin, C., Miller, J., Heilbronn, L., Murakami, T. and Iwata, Y. The Response of a Spherical Tissue-Equivalent Proportional Counter to Iron Particles from 200 – 1000 MeV/nucleon. Radiat. Res. 157, 350 – 360 (2002). The radiation environment on board the space shuttle and the International Space Station includes high-Z and high-energy (HZE) particles that are part of the galactic cosmic radiation (GCR) spectrum. Iron-56 particles are considered to be one of the most biologically important parts of the GCR spectrum. Tissue-equivalent proportional counters (TEPCs) are used as active dosimeters on manned space flights. These TEPCs are further used to determine the average quality factor for each space mission. A TEPC simulating a 1-μm-diameter sphere of tissue was exposed as part of a particle spectrometer to 56Fe particles at energies from 200 – 1000 MeV/nucleon. The response of TEPCs in terms of mean lineal energy, ȳF, and dose mean lineal energy, ȳD, as well as the energy deposited at different impact parameters through the detector was determined for six different incident energies of 56Fe particles in this energy range. Calculations determined that charged-particle equilibrium was achieved for each of the six experiments. Energy depositions at different impact parameters were calculated using a radial dose distribution model, and the results were compared to experimental data.

Intraoperative radiation (IORT) injury to sciatic nerve in a large animal model.

Peripheral nerve appears to be a dose-limiting normal tissue in the clinical application of intraoperative radiation therapy (IORT). To assess IORT injury to peripheral nerve, three groups of five beagle dogs received doses of 12, 20 or 28 Gy to the surgically exposed and isolated right sciatic nerve in the mid-femoral region using 6 MeV electrons. The left sciatic nerve of each dog served as its own control. As a surgical control five dogs received surgical exposure of the nerve only. Monthly neurologic exams, electromyogram and nerve conduction studies were performed following treatment for 12 months. After that dogs were euthanatized and histologic studies of nerves were done to define the degree of axon and myelin loss as well as presence of fibrosis and vascular lesions for different doses of IORT. Results showed that the threshold dose most likely related to expression of severe radiation damage to the nerve in this model is between 20 and 25 Gy. Radiation injury to peripheral nerve appears to be the result of direct radiation effects on Schwann cells and nerve vasculature and secondary effects resulting from damage to regional muscle and vasculature. A theoretical mechanism of radiation injury to peripheral nerve is proposed.

Wall effects observed in tissue-equivalent proportional counters from 1.05 GeV/nucleon iron-56 particles.

Tissue-equivalent proportional counters (TEPCs) have been used to measure energy deposition in simulated volumes of tissue ranging in diameter from 0.1 to 10 microm. There has been some concern that the wall used to define the volume of interest could influence energy deposition within the sensitive volume because it has a density significantly greater than that of the cavity gas. These effects become important for high-velocity heavy ions. Measurements of energy deposition were made for 1 GeV/nucleon iron particles in a TEPC simulating a 1-microm-diameter sphere of tissue. The TEPC was nested within a particle spectrometer that provided identification and flight path of individual particles. Energy deposition was studied as a function of pathlength through the TEPC. Approximately 30% of the energy transfer along trajectories through the center of the detector escapes the sensitive volume. The response of the TEPC, for trajectories through the detector, is always larger than calculations for energy loss in a homogeneous medium. This enhancement is greatest for trajectories near the cavity/wall interface. An integration of the response indicates that charged-particle equilibrium is essentially achieved for a wall thickness of 2.54 mm. However, estimates of the linear energy transfer for the incident particles are influenced by these wall effects.

Comparisons of LET distributions for protons with energies between 50 and 200 MeV determined using a spherical tissue-equivalent proportional counter(TEPC) and a position-sensitive silicon spectrometer (RRMD-III)

Abstract Borak, T. B., Doke, T., Fuse, T., Guetersloh, S., Heilbronn, L., Hara, K., Moyers, M., Suzuki, S., Taddei, P., Terasawa, K. and Zeitlin, C. J. Comparisons of LET Distributions for Protons with Energies between 50 and 200 MeV Determined Using a Spherical Tissue-Equivalent Proportional Counter (TEPC) and a Position-Sensitive Silicon Spectrometer (RRMD-III). Radiat. Res. 162, 687–692 (2004). Experiments have been performed to measure the response of a spherical tissue-equivalent proportional counter (TEPC) and a silicon-based LET spectrometer (RRMD-III) to protons with energies ranging from 50–200 MeV. This represents a large portion of the energy distribution for trapped protons encountered by astronauts in low-Earth orbit. The beam energies were obtained using plastic polycarbonate degraders with a monoenergetic beam that was extracted from a proton synchrotron. The LET spectrometer provided excellent agreement with the expected LET distribution emerging from the energy degraders. The TEPC cannot measure the LET distribution directly. However, the frequency mean value of lineal energy, ȳf, provided a good approximation to LET. This is in contrast to previous results for high-energy heavy ions where ȳf underestimated LET, whereas the dose-averaged lineal energy, ȳD, provided a good approximation to LET.

The response of a spherical tissue-equivalent proportional counter to different ions having similar linear energy transfer.

Abstract Guetersloh, S. B., Borak, T. B., Taddei, P. J., Zeitlin, C., Heilbronn, L., Miller, J., Murakami, T. and Iwata, Y. The Response of a Spherical Tissue-Equivalent Proportional Counter to Different Ions Having Similar LET. Radiat. Res. 161, 64–71 (2004). The response of a tissue-equivalent proportional counter (TEPC) to different ions having a similar linear energy transfer (LET) has been studied. Three ions, 14N, 20Ne and 28Si, were investigated using the HIMAC accelerator at the National Institute of Radiological Sciences at Chiba, Japan. The calculated linear energy transfer (LET∞) of all ions was 44 ± 2 keV/μm at the sensitive volume of the TEPC. A particle spectrometer was used to record the charge and position of each incident beam particle. This enabled reconstruction of the location of the track as it passed though the TEPC and ensured that the particle survived without fragmentation. The spectrum of energy deposition events in the TEPC could be evaluated as a function of trajectory through the TEPC. The data indicated that there are many events from particles that did not pass through the sensitive volume. The fraction of these events increased as the energy of the particle increased due to changes in the maximum energy of the δ rays. Even though the LET of the incident particles was nearly identical, the frequency-averaged lineal energy, ȳF, as well as the dose-averaged lineal energy, ȳD, varied with the velocity of the incident particle. However, both values were within 15% of LET in all cases.

Effects of intraoperative irradiation and intraoperative hyperthermia on canine sciatic nerve: Neurologic and electrophysiologic study

PURPOSE Late radiation injury to peripheral nerve may be the limiting factor in the clinical application of intraoperative radiation therapy (IORT). The combination of IORT with intraoperative hyperthermia (IOHT) raises specific concerns regarding the effects on certain normal tissues such as peripheral nerve, which might be included in the treatment field. The objective of this study was to compare the effect of IORT alone to the effect of IORT combined with IOHT on peripheral nerve in normal beagle dogs. METHODS AND MATERIALS Young adult beagle dogs were randomized into five groups of three to five dogs each to receive IORT doses of 16, 20, 24, 28, or 32 Gy to 5 cm of surgically exposed right sciatic nerve using 6 MeV electrons and six groups of four to five dogs each received IORT doses of 0, 12,16, 20, 24, or 28 Gy simultaneously with 44 degrees C of IOHT for 60 min. IOHT was performed using a water circulating hyperthermia device with a multichannel thermometry system on the surgically exposed sciatic nerve. Neurologic and electrophysiologic examinations were done before and monthly after treatment for 24 months. Electrophysiologic studies included electromyographic (EMG) examinations of motor function, as well as motor nerve conduction velocities studies. RESULTS Two years after treatment, the effective dose for 50% complication (ED50) for limb paresis in dogs exposed to IORT only was 22 Gy. The ED50 for paresis in dogs exposed to IORT combined with IOHT was 15 Gy. The thermal enhancement ratio (TER) was 1.5. Electrophysiologic studies showed more prominent changes such as EMG abnormalities, decrease in conduction velocity and amplitude of the action potential, and complete conduction block in dogs that received the combination of IORT and IOHT. The latency to development of peripheral neuropathies was shorter for dogs exposed to the combined treatment. CONCLUSION The probability of developing peripheral neuropathies in a large animal model was higher for IORT combined with IOHT, than for IORT alone. The dose required to produce the same level of late radiation injury to the sciatic nerve was reduced by a factor of 1.5 (TER) if IORT was combined with 44 degrees C of IOHT for 60 min.

Galactic cosmic ray simulation at the NASA Space Radiation Laboratory

Most accelerator-based space radiation experiments have been performed with single ion beams at fixed energies. However, the space radiation environment consists of a wide variety of ion species with a continuous range of energies. Due to recent developments in beam switching technology implemented at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), it is now possible to rapidly switch ion species and energies, allowing for the possibility to more realistically simulate the actual radiation environment found in space. The present paper discusses a variety of issues related to implementation of galactic cosmic ray (GCR) simulation at NSRL, especially for experiments in radiobiology. Advantages and disadvantages of different approaches to developing a GCR simulator are presented. In addition, issues common to both GCR simulation and single beam experiments are compared to issues unique to GCR simulation studies. A set of conclusions is presented as well as a discussion of the technical implementation of GCR simulation.

Effects of intraoperative hyperthermia on peripheral nerves: Neurological and electrophysiological studies

The tolerance of peripheral nerves to heat may limit the heat dose which can be applied to tumours. This may be particularly important in intraoperative hyperthermia (IOHT) for pelvic and retroperitoneal tumours. Furthermore the effects of hyperthermia alone must be known before its effects can be assessed in combination with irradiation. In this study injury to sciatic nerves was evaluated in 30 beagle dogs for 1 year following IOHT. IOHT was performed using a water circulating hyperthermia device with multichannel thermometry system. Neurological and electrophysiological examinations were done before, during and after IOHT treatment. Electrophysiological examinations showed a significant decrease in sciatic nerve conduction velocity and potential amplitude immediately after 60 min of heating for all temperatures. The greatest decrease in conduction velocity was observed for a temperature of 45 degrees C. Full recovery of nerve conduction velocity was observed 3 weeks following hyperthermia for all dogs except for those exposed to 45 degrees C. Neurological findings correlated with electrophysiological results. All five dogs which had nerve exposed to 45 degrees C for 60 min had severe neurological changes, with recovery taking place between 3 and 11 months after treatment. Based on these results it appears that temperatures to the peripheral nerve exceeding 44 degrees C for 1 h are likely to cause significant, but not necessarily permanent, nerve injury.