Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo.

Irradiated cells induce chromosomal instability in unirradiated bystander cells in vitro. Although bystander effects are thought to be linked to radiation-induced secondary cancers, almost no studies have evaluated bystander effects in vivo. Furthermore, it has been proposed that epigenetic changes mediate bystander effects, but few studies have evaluated epigenetic factors in bystander tissues in vivo. Here, we describe studies in which mice were unilaterally exposed to X-irradiation and the levels of DNA damage, DNA methylation and protein expression were evaluated in irradiated and bystander cutaneous tissue. The data show that X-ray exposure to one side of the animal body induces DNA strand breaks and causes an increase in the levels of Rad51 in unexposed bystander tissue. In terms of epigenetic changes, unilateral radiation suppresses global methylation in directly irradiated tissue, but not in bystander tissue at given time-points studied. Intriguingly, however, we observed a significant reduction in the levels of the de novo DNA methyltransferases DNMT3a and 3b and a concurrent increase in the levels of the maintenance DNA methyltransferase DNMT1 in bystander tissues. Furthermore, the levels of two methyl-binding proteins known to be involved in transcriptional silencing, MeCP2 and MBD2, were also increased in bystander tissue. Together, these results show that irradiation induces DNA damage in bystander tissue more than a centimeter away from directly irradiated tissues, and suggests that epigenetic transcriptional regulation may be involved in the etiology of radiation-induced bystander effects.

Solid state microdosimetry in hadron therapy.

A report of recent developments in silicon microdosimetry is presented. SOI based microdosemeters have shown promise as a viable alternative to traditional tissue-equivalent proportional counters. The application of these silicon microdosemeters to such radiation therapy modalities as boron neutron capture therapy (BNCT), boron neutron capture synovectomy (BNCS), proton therapy (PT), and fast neutron therapy (FNT) has been performed. Several shortcomings of the current silicon microdosemeter were identified and will be taken into account in the design of a second-generation device.

In-phantom dosimetry for the 13C(d,n)14N reaction as a source for accelerator-based BNCT.

The use of the 13C(d,n) 14N reaction at Ed=1.5 MeV for accelerator-based boron neutron capture therapy (AB-BNCT) is investigated. Among the deuteron-induced reactions at low incident energy, the 3C(d,n)14N reaction turns out to be one of the best for AB-BNCT because of beneficial materials properties inherent to carbon and its relatively large neutron production cross section. The deuteron beam was produced by a tandem accelerator at MIT's Laboratory for Accelerator Beam Applications (LABA) and the neutron beam shaping assembly included a heavy water moderator and a lead reflector. The resulting neutron spectrum was dosimetrically evaluated at different depths inside a water-filled brain phantom using the dual ionization chamber technique for fast neutrons and photons and bare and cadmium-covered gold foils for the thermal neutron flux. The RBE doses in tumor and healthy tissue were calculated from experimental data assuming a tumor 10B concentration of 40 ppm and a healthy tissue 10B concentration of 11.4 ppm (corresponding to a reported ratio of 3.5:1). All results were simulated using the code MCNP, a general Monte Carlo radiation transport code capable of simulating electron, photon, and neutron transport. Experimental and simulated results are presented at 1, 2, 3, 4, 6, 8, and 10 cm depths along the brain phantom centerline. An advantage depth of 5.6 cm was obtained for a treatment time of 56 min assuming a 4 mA deuteron current and a maximum healthy tissue dose of 12.5 RBE Gy.

Biological dosimetry for epithermal neutron beams.

The radiobiological effectiveness of an epithermal neutron beam is described using cell survival as the end point. The M67 epithermal neutron beam at the Nuclear Reactor Laboratory, Massachusetts Institute of Technology, that was used for clinical trials of boron neutron capture therapy was used to irradiate Chinese hamster ovary cells at seven depths in a water-filled phantom that simulated healthy tissue. No boron was added to the samples. Therefore, this experiment evaluates the biological effectiveness of the neutron and photon components, which comprise 80-95% of the dose to healthy tissue. Cell survival was dependent upon the depth in the phantom, as a result of moderation and attenuation of the epithermal neutron beam components by the overlying water. The results were compared with 250 kVp X irradiations to determine relative biological effectiveness values. Cell survival as a function of the dose delivered was lowest at the most shallow depth of 0.5 cm, and increased at depths of 1.5, 3, 4, 5.6, 6.6 and 8.1 cm. The gradual increase in cell survival with increasing depth in the phantom is due to the exponential drop of the fast-neutron intensity of the beam. These results are applicable to clinical boron neutron capture therapy Phase I/II trials in which healthy tissue toxicity was an end point.

The feasibility of accelerator-based in vivo neutron activation analysis of nitrogen.

The feasibility of accelerator-based in vivo neutron activation analysis of nitrogen has been investigated. It was found that a moderated neutron flux from approximately 10 microA of 2.5 MeV protons on a 9Be target performed as well as, and possibly slightly better than the existing isotope-based approach in terms of net counts per unit subject dose. Such a system may be an attractive alternative to the widespread use of (238,239)Pu/Be or 252Cf neutron sources, since there is more flexibility in the energy spectrum generated by accelerator-based neutron sources. From a radiation safety standpoint, accelerators have the advantage in that they only produce radiation when in operation. Furthermore, an accelerator beam can be pulsed, to reduce background detected in the prompt-gamma measurement, and such a device has a wide range of additional biological and medical applications.

An investigation of the feasibility of gadolinium for neutron capture synovectomy.

Neutron capture synovectomy (NCS) has been proposed as a possible treatment modality for rheumatoid arthritis. Neutron capture synovectomy is a two-part modality, in which a compound containing an isotope with an appreciable thermal neutron capture cross section is injected directly into the joint, followed by irradiation with a neutron beam. Investigations to date for NCS have focused on boron neutron capture synovectomy (BNCS), which utilizes the 10B(n,alpha)7Li nuclear reaction to deliver a highly localized dose to the synovium. This paper examines the feasibility of gadolinium, specifically 157Gd, as an alternative to boron as a neutron capture agent for NCS. This alternative modality is termed Gadolinium Neutron Capture Synovectomy, or GNCS. Monte Carlo simulations have been used to compare 10B and 157Gd as isotopes for accelerator-based NCS. The neutron source used in these calculations was a moderated spectrum from the 9Be(p,n) reaction at a proton energy of 4 MeV. The therapy time to deliver the NCS therapeutic dose of 10000 RBE-cGy, is 27 times longer when 157Gd is used instead of 10B. The skin dose to the treated joint is 33 times larger when 157Gd is used instead of 10B. Furthermore, the impact of using 157Gd instead of 10B was examined in terms of shielded whole-body dose to the patient. The effective dose is 202 mSv for GNCS, compared to 7.6 mSv for BNCS. This is shown to be a result of the longer treatment times required for GNCS; the contribution of the high-energy photons emitted from neutron capture in gadolinium is minimal. Possible explanations as to the relative performance of 157Gd and 10B are discussed, including differences in the RBE and range of boron and gadolinium neutron capture reaction products, and the relative values of the 10B and 157Gd thermal neutron capture cross section as a function of neutron energy.

Development and construction of a neutron beam line for accelerator-based boron neutron capture synovectomy.

A potential application of the 10B(n, alpha)7Li nuclear reaction for the treatment of rheumatoid arthritis, termed Boron Neutron Capture Synovectomy (BNCS), is under investigation. In an arthritic joint, the synovial lining becomes inflamed and is a source of great pain and discomfort for the afflicted patient. The goal of BNCS is to ablate the synovium, thereby eliminating the symptoms of the arthritis. A BNCS treatment would consist of an intra-articular injection of boron followed by neutron irradiation of the joint. Monte Carlo radiation transport calculations have been used to develop an accelerator-based epithermal neutron beam line for BNCS treatments. The model includes a moderator/reflector assembly, neutron producing target, target cooling system, and arthritic joint phantom. Single and parallel opposed beam irradiations have been modeled for the human knee, human finger, and rabbit knee joints. Additional reflectors, placed to the side and back of the joint, have been added to the model and have been shown to improve treatment times and skin doses by about a factor of 2. Several neutron-producing charged particle reactions have been examined for BNCS, including the 9Be(p,n) reaction at proton energies of 4 and 3.7 MeV, the 9Be(d,n) reaction at deuteron energies of 1.5 and 2.6 MeV, and the 7Li(p,n) reaction at a proton energy of 2.5 MeV. For an accelerator beam current of 1 mA and synovial boron uptake of 1000 ppm, the time to deliver a therapy dose of 10,000 RBEcGy ranges from 3 to 48 min, depending on the treated joint and the neutron producing charged particle reaction. The whole-body effective dose that a human would incur during a knee treatment has been estimated to be 3.6 rem or 0.75 rem, for 1000 ppm or 19,000 ppm synovial boron uptake, respectively, although the shielding configuration has not yet been optimized. The Monte Carlo design process culminated in the construction, installation, and testing of a dedicated BNCS beam line on the high-current tandem electrostatic accelerator at the Laboratory for Accelerator Beam Applications at the Massachusetts Institute of Technology.

Development of a high-power water cooled beryllium target for use in accelerator-based boron neutron capture therapy.

In order for ABNCT (accelerator-based boron neutron capture therapy) to be successful, 10-16 kW or more must be dissipated from a target. Beryllium is well suited as a high-power target material. Beryllium has a thermal conductivity of 200 W/mK at 300 K which is comparable to aluminum, and it has one of the highest strength to weight ratios of any metal even at high temperatures (100 MPa at 600 degrees C). Submerged jet impingement cooling has been investigated as an effective means to remove averaged power densities on the order of 2 x 10(7) W/m2 with local power densities as high as 6 x 10(7) W/m2. Water velocities required to remove these power levels are in excess of 24 m/s with volumetric flow rates of nearly 100 GPM. Tests on a prototype target revealed that the heat transfer coefficient scaled as Re0.6. With jet-Reynolds numbers as high as 5.5 x 10(5) heat transfer coefficients of 2.6 x 10(5) W/m2K were achieved. With this type of cooling configuration 30 kW of power could be effectively removed from a beryllium target placed on the end of an accelerator. A beryllium target utilizing a proton beam of 3.7 MeV and cooled by submerged jet impingement could be used to deliver a dose of 13 RBE cGy/min mA to a tumor at a depth of 4 cm. With a beam power of 30 kW, 1500 cGy could be delivered in 14.2 min.

Initial characterization of the dosimetry and radiology of a device for administering interstitial stereotactic radiosurgery.

OBJECTIVE: We report the design and initial characterization of the dosimetry and radiobiology of a novel device for interstitial stereotactic radiosurgery. INSTRUMENTATION: The device is lightweight, handheld, and battery-powered, and it emits x-ray radiation from the tip of a probe 3 mm in diameter by 10 cm in length. METHODS: The dosimetry was characterized by two independent methods: thermoluminescent dosimeters and radiochromic film. The radiobiology was characterized by in vivo irradiation of rat liver, dog liver, and dog brain. The animals were killed at varying intervals of time, and histological examinations were performed. Heat transfer from the probe to dog brain was studied in vivo by placing thermocouple sensors around the probe tip before irradiating. RESULTS: Both dosimetric methods showed a steep dose-distance fall-off relationship (proportional to the reciprocal of the cube of the distance from the probe tip). Rats and dogs that were killed weeks to months after liver irradiation tended to have sharply demarcated lesions. Liver enzyme levels, measured serially in the dogs, did not give evidence of chronic inflammation. Histological examination of the brains of dogs that were killed acutely after irradiation did not show evidence of inflammation, edema, or hemorrhage. The tissue temperature elevation 1 cm from the tip never exceeded 0.5 degree C, thereby excluding hyperthermia as a significant contributor to the formation of lesions. CONCLUSIONS: Because this device requires relatively few supporting resources, has sharp dosimetric properties, and seems to be safe, it may be useful as a clinical tool for interstitial stereotactic radiosurgery.

Monte Carlo simulation of a miniature, radiosurgery x-ray tube using the ITS 3.0 coupled electron-photon transport code.

A miniature, interstitial x-ray generator has recently been developed and is currently undergoing clinical trials for the treatment of brain tumors. The maximum photon energy from this x-ray tube is 50 keV, although most of the initial testing has been carried out at 40 keV. Dose rates of up to 2 Gy/min in a water phantom at a distance of 10 mm from the tube tip are produced. In this paper we describe the modeling and simulation of x-ray production from this device using the ITS 3.0 Monte Carlo code. Verification of the simulation of x-ray production in the device was carried out by comparing predictions of spatial photon distribution, energy spectrum, and dose versus depth in water with experimentally obtained measurements. Agreement between the simulated results and experimental measurements was fairly good when comparing the angular distribution of photons emitted from the x-ray tube and very good when comparing dose rate versus depth in a water phantom. Discrepancies observed when comparing the calculated and measured estimates of characteristic line radiation were reduced by incorporation of a modification to the ITS code. Possible causes of the remaining discrepancy in bremsstrahlung intensity are discussed.

A new miniature x-ray source for interstitial radiosurgery: device description.

A device that generates low-energy x rays at the tip of a needle-like probe was developed for stereotactic interstitial radiosurgery. Electrons from a small thermionic gun are accelerated to a final energy of up to 40 keV and directed along a 3 mm outside diameter drift tube to a thin Au target, where the beam size is approximately 0.3 mm. All high-voltage electronics are in the probe housing, connected by low-voltage cable to a battery-operated control box. X-ray output, which is nearly isotropic, consists of a bremsstrahlung spectrum and several lines between 7 and 14 keV, with characteristic radiation contributing 15% of the total energy output. To date, 14 patients with metastatic brain tumors have been treated with this device.

Beta-particle dosimetry in radiation synovectomy.

Beta-particle dosimetry of various radionuclides used in the treatment of rheumatoid arthritis was estimated using Monte Carlo radiation transport simulation coupled with experiments using reactor-produced radionuclides and radiachromic film dosimeters inserted into joint phantoms and the knees of cadavers. Results are presented as absorbed dose factors (cGy-cm2/MBq-s) versus depth in a mathematical model of the rheumatoid joint which includes regions of bone, articular cartilage, joint capsule, and tissue (synovium) found in all synovial joints. The factors can be used to estimate absorbed dose and dose rate distributions in treated joints. In particular, guidance is provided for those interested in (a) a given radionuclide's therapeutic range, (b) the amount of radioactivity to administer on a case-by-case basis, (c) the expected therapeutic dose to synovium, and (d) the radiation dose imparted to other, nontarget components in the joint, including bone and articular cartilage.

Shielding design and dose assessment for accelerator based neutron capture therapy.

Preparations are ongoing to test the viability and usefulness of an accelerator source of epithermal neutrons for ultimate use in a clinical environment. This feasibility study is to be conducted in a shielded room located on the Massachusetts Institute of Technology campus and will not involve patient irradiations. The accelerator production of neutrons is based on the 7Li(p, n)7Be reaction, and a maximum proton beam current of 4 mA at an energy of 2.5 MeV is anticipated. The resultant 3.58 x 10(12) neutrons s-1 have a maximum energy of 800 keV and will be substantially moderated. This paper describes the Monte Carlo methods used to estimate the neutron and photon dose rates in a variety of locations in the vicinity of the accelerator, as well as the shielding configuration required when the device is run at maximum current. Results indicate that the highest absorbed dose rate to which any individual will be exposed is 3 microSv h-1 (0.3 mrem h-1). The highest possible yearly dose is 0.2 microSv (2 x 10(-2) mrem) to the general public or 0.9 mSv (90 mrem) to a radiation worker in close proximity to the accelerator facility. The shielding necessary to achieve these dose levels is also discussed.

Mixed field dosimetry of epithermal neutron beams for boron neutron capture therapy at the MITR-II research reactor.

During the past several years, there has been growing interest in Boron Neutron Capture Therapy (BNCT) using epithermal neutron beams. The dosimetry of these beams is challenging. The incident beam is comprised mostly of epithermal neutrons, but there is some contamination from photons and fast neutrons. Within the patient, the neutron spectrum changes rapidly as the incident epithermal neutrons scatter and thermalize, and a photon field is generated from neutron capture in hydrogen. In this paper, a method to determine the doses from thermal and fast neutrons, photons, and the B-10(n, alpha)Li-7 reaction is presented. The photon and fast neutron doses are measured with ionization chambers, in realistic phantoms, using the dual chamber technique. The thermal neutron flux is measured with gold foils using the cadmium difference technique, the thermal neutron and B-10 doses are determined by the kerma factor method. Representative results are presented for a unilateral irradiation of the head. Sources of error in the method as applied to BNCT dosimetry, and the uncertainties in the calculated doses are discussed.

Design of a californium-based epithermal neutron beam for neutron capture therapy.

The potential of the spontaneously fissioning isotope, 252Cf, to provide epithermal neutrons for use in boron neutron capture therapy (BNCT) has been investigated using Monte Carlo simulation. The Monte Carlo code MCNP was used to design an assembly composed of a 26 cm long, 11 cm radius cylindrical D2O moderator followed by a 64 cm long Al filter. Lithium filters are placed between the moderator and the filter and between the Al and the patient. A reflector surrounding the moderator/filter assembly is required in order to maintain adequate therapy flux at the patient position. An ellipsoidal phantom composed of skull- and brain-equivalent material was used to determine the dosimetric effect of this beam. It was found that both advantage depths and advantage ratios compare very favourably with reactor and accelerator epithermal neutron sources. The dose rate obtainable, on the other hand, is 4.1 RBE cGy min-1, based on a very large (1.0 g) source of 252Cf. This dose rate is two to five times lower than those provided by existing reactor beams and can be viewed as a drawback of using 252Cf as a neutron source. Radioisotope sources, however, do offer the advantage of in-hospital installation.

Dosimetric effects of beam size and collimation of epithermal neutrons for boron neutron capture therapy.

A series of studies of "ideal" beams has been carried out using Monte Carlo simulation with the goal of providing guidance for the design of epithermal beams for boron neutron capture therapy (BNCT). An "ideal" beam is defined as a monoenergetic, photon-free source of neutrons with user-specified size, shape and angular dependence of neutron current. The dosimetric behavior of monoenergetic neutron beams in an elliptical phantom composed of brain-equivalent material has been assessed as a function of beam diameter and neutron emission angle (beam angle), and the results are reported here. The simulation study indicates that substantial differences exist in the dosimetric behavior of small and large neutron beams (with respect to the phantom) as a function of the extent of beam collimation. With a small beam, dose uniformity increases as the beam becomes more isotropic (less collimated); the opposite is seen with large beams. The penetration of thermal neutrons is enhanced as the neutron emission angle is increased with a small beam; again the opposite trend is seen with large beams. When beam size is small, the dose delivered per neutron is very dependent on the extent of beam collimation; this does not appear to be the case with a larger beam. These trends in dose behavior are presented graphically and discussed in terms of their effect on several figures of merit, the advantage depth, the advantage ratio, and the advantage depth-dose rate. Tables giving quick summaries of these results are provided.

Calculation of beta dosimetry in radiation synovectomy using Monte Carlo simulation (EGS4).

Using the EGS4 Monte Carlo code, absorbed dose rate factors were estimated for four radionuclides of interest in radiation synovectomy, an intra-articular radiation therapy to treat rheumatoid arthritis. The treatment consists of the injection of a beta-emitting radionuclide into the joint capsule in order to eliminate diseased synovium through irradiation. The radionuclides investigated are 32P, 90Y, 165Dy, and 198Au. Calculations reveal the absorbed dose factor (cGy cm2/MBq s) as a function of distance (mm) in an EGS4 model of the rheumatic joint. The model incorporates bone, articular cartilage, joint capsule, and tissue (synovium) components found in all synovial joints, with dimensions in the model corresponding to dimensions typically found in larger joints, e.g., the knee, shoulder, or hip. Results are compared with previous, analytical approaches to beta dosimetry in radiation synovectomy. In addition, radiation backscatter due to the presence of bone is investigated and determined to have a negligible enhancement effect on absorbed dose to synovium.

Dosimetry of 252Cf sources for neutron radiotherapy with and without augmentation by boron neutron capture therapy.

Interstitial and intracavity 252Cf sources have been used to treat a number of tumor types with encouraging results. In particular these tumors include a variety of cervical, head-and-neck, and oral-cavity cancers and possible malignant gliomas. As a neutron source, 252Cf offers certain theoretical advantages over photon therapy (i.e., in treating tumors with significant hypoxic or necrotic components). With the recent availability of 10B-labeled tumor-seeking compounds, the usefulness of 252Cf may be further improved by augmenting the 252Cf dose to the tumor with an additional dose due to the fission (following thermal neutron capture) of 10B located in the tumor itself. While the high mean neutron energy permits 252Cf to deliver a high-LET, low-OER dose to the tumor on a macroscopic scale, thermalization of neutrons followed by 10B capture may augment this dose at the cellular level if adequate loading of tumor cells with 10B is possible. This paper presents results of a Monte Carlo simulation study investigating the dosimetric characteristics of linear 252Cf sources both with and without the quantitative increase in tumor dose possible with the addition of 10B. Results are displayed in the form of "along and away" tables and dose profiles in a water phantom. Comparisons of Monte Carlo results with experimental and analytical dosimetry data available in the literature are also presented.

Accelerator-based epithermal neutron beam design for neutron capture therapy.

Recent interest in the production of epithermal neutrons for use in boron neutron capture therapy (BNCT) has promoted an investigation into the feasibility of generating such neutrons with a high current proton accelerator. Energetic protons (2.5 MeV) on a 7Li target produce a spectrum of neutrons with maximum energy of roughly 800 keV. A number of combinations of D2O moderator, lead reflector, 6Li thermal neutron filtration, and D2O/6Li shielding will result in a useful epithermal flux of 1.6 x 10(8) n/s at the patient position. The neutron beam is capable of delivering 3000 RBE-cGy to a tumor at a depth of 7.5 cm in a total treatment time of 60-93 min (depending on RBE values used and based on a 24-cm diameter x 19-cm length D2O moderator). Treatment of deeper tumors with therapeutic advantage would also be possible. Maximum advantage depths (RBE weighted) of 8.2-9.2 (again depending on RBE values and precise moderator configuration) are obtained in a right-circular cylindrical phantom composed of brain-equivalent material with an advantage ratio of 4.7-6.3. A tandem cascade accelerator (TCA), designed and constructed at Science Research Laboratory (SRL) in Somerville MA, can provide the required proton beam parameters for BNCT of deep-seated tumors. An optimized configuration of materials required to shift the accelerator neutron spectrum down to therapeutically useful energies has been designed using Monte Carlo simulation in the Whitaker College Biomedical Imaging and Computation Laboratory at MIT. Actual construction of the moderator/reflector assembly is currently underway.