Medical Research Reactor Research Articles

Nano Yttrium-90 and Rhenium-188 production through medium medical cyclotron and research reactor for therapeutic usages: A Simulation study

The main goal of the coordinated project development of therapeutic radiopharmaceuticals of Y-90 and Re-188 is to exploit advancements in radionuclide production technology. Here, direct and indirect production methods with medium reactor and cyclotron are compared to evaluate derived neutron flux and production yield. First, nano-sized 186W and 89Y specimens are suspended in water in a quartz vial by FLUKA simulation. Then, the solution is irradiated for 4 days under 9E+14 n/cm2/s neutron flux of reactor. Also, a neutron activator including three layers—lead moderator, graphite reflector, and polyethylene absorbent— is simulated and tungsten target is irradiated by 60 MeV protons of cyclotron to generate induced neutrons for 188W and 90Sr production via neutron capture. As the neutron energy reduced, the flux gradually increased towards epithermal range to satisfy (n/2n,γ) reactions. The obtained specific activities at saturation were higher than the reported experimental values because the accumulated epithermal flux and nano-sized specimens influence the outcomes. The beta emitters, which are widely utilized in brachytherapy, appeal an alternative route to locally achieve a rational yield. Therefore, the proposed method via neutron activator may ascertain these broad requirements.

Dosimetry in Thermal Neutron Irradiation Facility at BMRR

Radiation dosimetry for Neutron Capture Therapy (NCT) has been performed since 1959 at Thermal Neutron Irradiation Facility (TNIF) of the three-megawatt light-water cooled Brookhaven Medical Research Reactor (BMRR). In the early 1990s when more effective drug carriers were developed for NCT, in which the eye melanoma and brain tumors in rats were irradiated in situ, extensive clinical trials of small animals began using a focused thermal neutron beam. To improve the dosimetry at irradiation facility, a series of innovative designs and major modifications made to enhance the beam intensity and to ease the experimental sampling at BMRR were performed; including (1) in-core fuel addition to increase source strength and balance flux of neutrons towards two ports, (2) out of core moderator remodeling, done by replacing thicker D2O tanks at graphite-shutter interfacial areas, to expedite neutron thermalization, (3) beam shutter upgrade to reduce strayed neutrons and gamma dose, (4) beam collimator redesign to optimize the beam flux versus dose for animal treatment, (5) beam port shielding installation around the shutter opening area (lithium-6 enriched polyester-resin in boxes, attached with polyethylene plates) to reduce prompt gamma and fast neutron doses, (6) sample holder repositioning to optimize angle versus distance for a single more » organ or whole body irradiation, and (7) holder wall buildup with neutron reflector materials to increase dose and dose rate from scattered thermal neutrons. During the facility upgrade, reactor dosimetry was conducted using thermoluminescent dosimeters TLD for gamma dose estimate, using ion chambers to confirm fast neutron and gamma dose rate, and by the activation of gold-foils with and without cadmium-covers, for fast and thermal neutron flux determination. Based on the combined effect from the size and depth of tumor cells and the location and geometry of dosimeters, the measured flux from cadmium-difference method was 4 - 7 % lower than the statistical mean derived from the Monte-Carlo modeling (5% uncertainty). The dose rate measured by ion chambers was 6 - 10 % lower than the output tallies (7% uncertainty). The detailed dosimetry that was performed at the TNIF for the NCT will be described. « less

Obama's Engagement Strategy with Iran: Limited Results

Obama's diplomacy had early success with Iran's agreement in October 2009 to ship most of its low-enriched uranium abroad in exchange for fuel rods for its medical research reactor. This agreement did not last, however, in the face of strong domestic US opposition and the Western powers' refusal to allow modifications. Obama had further success in June 2010, when the UN Security Council imposed new sanctions on Iran. In addition, the United States and the European Union imposed sanctions of their own. Whatever happens in the future, Iran does not seem ready to give up its nuclear program, although it is currently feeling the weight of new sanctions from the UN—as well as pressures from the United States and the EU.

Radiation Dosimetry in the BNCT Patient Treatment Room at the Brookhaven Medical Research Reactor

Abstract The BMRR was a 3 MW light water reactor that had an epithermal neutron beam that was used to perform clinical trials on patients with malignant brain tumors. A series of measurements and calculations had been performed in the treatment room both prior to the trials and during the trials. The details of the measurements and the Monte Carlo calculations are presented and compared.

Porphyrin-Mediated Boron Neutron Capture Therapy: A Preclinical Evaluation of the Response of the Oral Mucosa

Preclinical studies are in progress to determine the potential of boron neutron capture therapy (BNCT) for the treatment of carcinomas of the head and neck. Recently, it has been demonstrated that various boronated porphyrins can target a variety of tumor types. Of the porphyrins evaluated so far, copper tetracarboranylphenyl porphyrin (CuTCPH) is potentially a strong candidate for clinical use. In the present investigation, the response of the oral mucosa to CuTCPH-mediated boron neutron capture (BNC) irradiation was assessed using the ventral surface of the tongue of adult male Fischer 344 rats, a standard rodent model. CuTCPH was administered by intravenous infusion, at a dose of 200 mg/kg body weight, over a 48-h period. Three days after the end of the administration of CuTCPH, biodistribution studies indicated very low levels of boron (<2 microg/g) in the blood. Levels of boron in tongue tissue were 39.0 +/- 3.8 microg/g at this time. This was the time selected for irradiation with single doses of thermal neutrons from the Brookhaven Medical Research Reactor. The estimated level of boron-10 in the oral mucosa was used in the calculation of the physical radiation doses from the 10B(n,alpha)7Li reaction. This differs from the approach using the present generation of clinical boron carriers, where boron levels in blood at the time of irradiation are used for this calculation. Dose-response curves for the incidence of mucosal ulceration were fitted using probit analysis, and the doses required to produce a 50% incidence of the effect (ED50 +/- SE) were calculated. Analysis of the dose-effect data for CuTCPH-mediated BNC irradiation, compared with those for X rays and thermal neutrons alone, gave a compound biological effectiveness (CBE) factor of approximately 0.04. This very low CBE factor would suggest that there was relatively low accumulation of boron in the key target epithelial stem cells of the oral mucosa. As a consequence, with low levels of boron (<2 microg/g) in the blood, the response of the oral mucosa to CuTCPH-mediated BNCT will be governed primarily by the radiation effects of the thermal neutron beam and not from the boron neutron capture reaction [10B(n,alpha)7Li].

Progress with the NCT international dosimetry exchange

The international collaboration that was organized to undertake a dosimetry exchange for purposes of combining clinical data from different facilities conducting neutron capture therapy has continued since its founding at the 9th ISNCT symposium in October 2000. The thrust towards accumulating physical dosimetry data for comparison between different participants has broadened to include facilities in Japan and the determination of spectral descriptions of different beams. Retrospective analysis of patient data from the Brookhaven Medical Research Reactor is also being considered for incorporation into this study to increase the pool of available data. Meanwhile the next essential phase of comparing measurements of visiting dosimetry groups with treatment plan calculations from the host institutes has commenced. Host centers from Petten, Finland and the Czech Republic in Europe and MIT in the USA have applied the regular calculations and clinical calibrations from their current clinical studies, to generate treatment plans in the large standard phantom used for measurements by visiting participants. These data have been exchanged between the participants and scaling factors to relate the separate dose components between the different institutes are being determined. Preliminary normalization of measured and calculated dosimetry for patients is nearing completion to enable the physical radiation doses that comprise a treatment prescription at a host institute to be directly related to the corresponding measured doses of a visiting group. This should serve as an impetus for the direct comparison of patient data although the clinical requirements for achieving this need to be clearly defined. This may necessitate more extensive comparisons of treatment planning calculations through the solution of test problems and clarification regarding the question of dose specification from treatment calculations in general.

Optimization of the Epithermal Neutron Beam for Boron Neutron Capture Therapy at the Brookhaven Medical Research Reactor

The use of epithermal neutron beam in clinical trials of Boron Neutron Capture Therapy for patients with malignant brain tumors had been carried out for half a decade at the Brookhaven's Medical Reactor. The decision to permanently close this reactor in 2000 cut short the efforts to implement a new conceptual design to optimize this beam in preparation for use with possible new BNCT protocols. Details of the conceptual design to produce a highly intensified and focused neutron beam with less gamma and neutron contamination in tissues are presented here for their potential applicability to other reactor facilities. Neutron-photon coupled Monte Carlo calculations were used to predict the flux, current, heating, and absorbed dose produced by the proposed design. The results were benchmarked by the dose rate and flux measurements taken at the facility then in use.

Combination of boron neutron capture therapy and external beam radiotherapy for brain tumors

Purpose Boron neutron capture therapy (BNCT) has been used clinically as a single modality treatment for high-grade gliomas and melanomas metastatic to the brain. The purpose of the present study was to determine whether its efficacy could be enhanced by an X-ray boost administered after BNCT. Two brain tumor models were used, the F98 glioma as a model for primary brain tumors and the MRA 27 human melanoma as a model for metastatic brain tumors. Methods and materials For biodistribution studies, either 10 5 F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats or 10 6 MRA 27 melanoma cells were implanted intracerebrally into National Institutes of Health (NIH)-rnu nude rats. Biodistribution studies were performed 11–13 days after implantation of the F98 glioma and 20–24 days after implantation of the MRA 27 melanoma. Animals bearing the F98 glioma received a combination of two boron-containing drugs, sodium borocaptate at a dose of 30 mg/kg and boron phenylalanine (BPA) at a dose of 250 mg/kg. MRA 27 melanoma-bearing rats received BPA (500 mg/kg) containing an equivalent amount of 10B (27 mg B/kg). The drugs were administered by either intracarotid or i.v. injection. Results The tumor boron concentration after intracarotid injection was ∼50% greater in the F98 glioma and MRA 27 melanoma after intracarotid injection (20.8 and 36.8 μg/g, respectively) compared with i.v. injection (11.2 and 19.5 μg/g, respectively). BNCT was carried out at the Brookhaven National Laboratory Medical Research Reactor ∼14 days after tumor implantation of either the F98 glioma or the MRA 27 melanoma. Approximately 7–10 days after BNCT, subsets of animals were irradiated with 6-MV photons, produced by a linear accelerator at a total dose of 15 Gy, delivered in 5-Gy daily fractions. F98 glioma-bearing rats that received intracarotid or i.v. sodium borocaptate plus BPA, followed 2.5 h later by BNCT and 7–10 days later by X-rays, had similar mean survival times (61 days and 53 days, respectively, p = 0.25), and the non X-irradiated, BNCT-treated animals had a mean survival time of 52 and 40 days, respectively, for intracarotid vs. i.v. injection; the latter was equivalent to that of the irradiated animals. The corresponding survival time for MRA 27 melanoma-bearing rats that received intracarotid or i.v. BPA, followed by BNCT and then X-irradiation, was 75 and 82 days, respectively ( p = 0.5), 54 days without X-irradiation ( p = 0.0002), 37 days for X-irradiation alone, and 24 days for untreated controls. In contrast to the data obtained with the F98 glioma, MRA 27 melanoma-bearing rats that received i.v. BPA, followed by BNCT, had a highly significant difference in mean survival time compared with the irradiated controls (54 vs. 37 days, p = 0.008). Conclusion Our data are the first to suggest that a significant therapeutic gain may be obtained when BNCT is combined with an X-ray boost. Additional experimental studies are required to determine the optimal combination of X-radiation and neutron doses and whether it is more advantageous to administer the photon boost before or after BNCT.

Feasibility study on epithermal neutron field for cyclotron-based boron neutron capture therapy.

To realize the accelerator-based boron neutron capture therapy (BNCT) at the Cyclotron and Radioisotope Center of Tohoku University, the feasibility of a cyclotron-based BNCT was evaluated. This study focuses on optimizing the epithermal neutron field with an energy spectrum and intensity suitable for BNCT for various combinations of neutron-producing reactions and moderator materials. Neutrons emitted at 90 degrees from a thick (stopping-length) Ta target, bombarded by 50 MeV protons of 300 microA beam current, were selected as a neutron source, based on the measurement of angular distributions and neutron energy spectra. As assembly composed of iron, AlF3/Al/6LiF, and lead was chosen as moderators, based on the simulation trials using the MCNPX code. The depth dose distributions in a cylindrical phantom, calculated with the MCNPX code, showed that, within 1 h of therapeutic time, the best moderator assembly, which is 30-cm-thick iron, 39-cm-thick AlF3/Al/6LiF, and 1-cm-thick lead, provides an epithermal neutron flux of 0.7 x 10(9) [n cm(-2) s(-1)]. This results in a tumor dose of 20.9 Gy-eq at a depth of 8 cm in the phantom, which is 6.4 Gy-eq higher than that of the Brookhaven Medical Research Reactor at the equivalent condition of maximum normal tissue tolerance. The beam power of the cyclotron is 15 kW, which is much lower than other accelerator-based BNCT proposals.

Evaluation of the relative biological effectiveness of a clinical epithermal neutron beam using dog brain.

This investigation was designed to determine the relative biological effectiveness (RBE) of an epithermal neutron beam (FiR 1 beam) using the brains of dogs. The FiR 1 beam was developed for the treatment of patients with glioma using boron neutron capture therapy. Comparisons were made between the effects of whole-brain irradiation with epithermal neutrons and 6 MV photons. For irradiations with epithermal neutrons, three dose groups were used, 9.4 +/- 0.1, 10.2 +/- 0.1 and 11.5 +/- 0.2 Gy. These physical doses were given as a single exposure and are quoted at the 90% isodose. Four groups of five dogs were irradiated with single doses of 10, 12, 14 or 16 Gy of 6 MV photons to the 100% isodose. Different reference isodoses were used to obtain the most comparable dose distribution in the brain for the two different irradiation modalities. Sequential magnetic resonance images (MRI) were taken for 77-115 weeks after irradiation to detect changes in the brain. Dose-effect relationships were established for changes in the brain as detected either by MRI or by subsequent gross morphology and histology. The doses that caused a specified response in 50% of the animals (ED(50)) were calculated from these dose-effect curves for each end point, and these values were used to calculate the RBE values for the different end points. The RBE values for the FiR 1 beam, based on changes observed on MRI, were in the range 1.2-1.3. For microscopic and gross pathological lesions, the values were in the range 1.2-1.4. The corresponding RBE values for the MRI and pathological end points for the high-LET components (protons from nitrogen capture and recoil protons from fast neutrons) were in the ranges 3.5-4.0 and 3.4-4.4, respectively. This assumed a dose-rate reduction factor of 0.6 for the low-dose-rate gamma-ray component of this beam. Finally, a comparison was made between experimentally derived photon doses, for a specified end point, with calculated photon equivalent doses, which were obtained using the weighting factors for clinical studies on the epithermal neutron beam on the Brookhaven Medical Research Reactor (BNL) in New York. This indicated that the radiation-induced lesions seen in the present study were, on average, detected at a 12% lower photon dose than predicted by the use of the BNL clinical weighting factors. This indicates the need for caution in the extrapolation of results from one reactor-based epithermal neutron beam to another.

Porphyrin-mediated boron neutron capture therapy: evaluation of the reactions of skin and central nervous system

Purpose: Recently, various boronated porphyrins have been shown to preferentially target a variety of tumour types. Of the different porphyrins evaluated, copper tetra-phenyl-carboranyl porphyrin (CuTCPH) is a strong candidate for future preclinical evaluation. In the present study, the responses of two critical normal tissues, skin and central nervous system (CNS), to boron neutron capture (BNC) irradiation in the presence of this porphyrin were evaluated.Materials and methods: Standard models for the skin and spinal cord of adult male Fischer 344 rats were used. CuTCPH was administered by intravenous infusion at a dose of 200 mg kgm 1 body weight, over 48 h. The thermal beam at the Brookhaven Medical Research Reactor was used for the BNC irradiations. The 20-mm diameter irradiation field, for both the skin and the spinal cord, was located on the mid-dorsal line of the neck. Dose-response data were fitted using probit analysis and the doses required to produce a 50% incidence rate of early and late skin changes or myeloparesis (ED 50 - SE) were calculated from these curves.Results: Biodistribution studies indicated very low levels of boron (<3 µ;g gm 1) in the blood 3 days after the administration of CuTCPH. This was the time point selected for radiation exposure in the radiobiological studies. Levels of boron in the CNS were also low (2.8 - 0.6 µ;g gm 1) after 3 days. However, the concentration of boron in the skin was considerably higher at 22.7 - 2.6 µ;g gm 1. Single radiation exposures were carried out using a thermal neutron beam. The impact of CuTCPH-mediated BNC irradiation on the normal skin and CNS at therapeutically effective exposure times was minimal. This was primarily due to the very low blood boron levels (from CuTCPH) at the time of irradiation. Analysis of the relevant dose-effect data gave compound biological effectiveness factors of about 1.8 for skin (moist desquamation) and about 4.4 for spinal cord (myeloparesis) for CuTCPH. These values were based on the BNC radiation doses to tissues calculated using the blood boron levels at the time of irradiation.Conclusions: CuTCPH-mediated BNC irradiation will not cause significant damage to skin and CNS at clinically relevant radiation doses provided that blood boron levels are low at the time of radiation exposure.

Neutron capture therapy of intracerebral melanoma: enhanced survival and cure after blood-brain barrier opening to improve delivery of boronophenylalanine

Purpose : Multicentric cerebral metastases of melanoma represent an important clinical problem for which there currently is no satisfactory treatment. We previously developed a model for melanoma metastatic to the brain employing nude rats bearing intracerebral implants of the human MRA27 melanoma. The purpose of the present study was to determine if the efficacy of boron neutron capture therapy (BNCT) could be improved by either Cereport (RMP-7) mediated modulation of blood-brain barrier (BBB) permeability or hyperosmotic mannitol-induced BBB disruption using boronophenylalanine (BPA) as the capture agent. Methods and Materials : Biodistribution studies were carried out at 0.5, 2.5, and 4 h after intracarotid administration of Cereport (1.5 μg/kg) and intracarotid or i.v. administration of BPA (500 mg/kg). Peak tumor boron concentrations (65.4 μg/g) and the best composite tumor:brain (6.1:1) and tumor:blood (6.3:1) ratios were observed at 2.5 h after intracarotid administration. BNCT was initiated at the Brookhaven Medical Research Reactor 13–14 days after intracerebral implantation of 10 6 MRA27 cells. Results : Untreated control rats had a median survival time (MeST) of 22 days and for irradiated controls, it was 30 days. Rats that received i.v. or intracarotid BPA without Cereport followed by BNCT 2.5 h later had MeSTs of 41 days and 57 days, respectively, with 20% long-term survivors (>180 days) in the latter group. Rats that received intracarotid BPA with Cereport had an MeST of 86 days with 36% long-term survivors, which was very close to that of rats that had hyperosmotic mannitol-induced disruption of the BBB (85 days with 25% long-term survivors). When these two groups were combined, and survival times were compared, using the Wilcoxon rank sum test, to those of rats that received intracarotid BPA without blood-brain barrier disruption, these differences were significant at the level p = 0.01. Conclusions : Our data show that optimizing the delivery of BPA by means of intracarotid injection combined with opening the BBB by infusing Cereport or a hyperosmotic solution of mannitol significantly enhanced survival times and produced long-term cures of MRA27 melanoma-bearing rats. These observations are relevant to future clinical studies using BNCT for the treatment of intracerebral melanoma.

Development and calculation of an energy dependent normal brain tissue neutron RBE for evaluating neutron fields for BNCT.

In Boron Neutron Capture Therapy (BNCT) of malignant brain tumors, the energy dependence of a clinically relevant Relative Biological Effectiveness (RBE) for epithermal neutrons, RBE(En), is important in neutron field design. In the first half of this paper, we present the development of an expression for the energy dependent normal-tissue RBE, RBE(En). We then calculate a reasonable estimate for RBE(En) for adult brain tissue. In the second half of the paper, two separate RBE expressions are developed, one for the RBE of the neutrons that interact in tissue via the 14N(n,p)14C reaction, denoted RBE(N), and one for the RBE of the neutrons which interact in tissue via the 1H(n,n')1H reaction, denoted RBE(H). The absorbed-dose-averaged values of these expressions are calculated for the neutron flux spectrum in phantom for the Brookhaven Medical Research Reactor (BMRR) epithermal neutron beam. The calculated values, [RBE(norm)N] = 3.4 and [RBE(norm)H] = 3.2, are within 6% of being equal, and support the use of equal values for RBEN and RBE(H) by researchers at Brookhaven National Laboratory (BNL). Finally, values of [RBE(norm)N] and [RBE(norm)H], along with the absorbed-dose-averaged RBE for brain, [RBE(norm)b], were calculated as a function of depth along the centerline of an ellipsoidal head phantom using flux spectra calculated for our Accelerator-Based Neutron Source (ABNS). These values remained essentially constant with depth, supporting the use of constant values for RBE, as is done at BNL.

Improved survival after boron neutron capture therapy of brain tumors by Cereport-mediated blood-brain barrier modulation to enhance delivery of boronophenylalanine.

Cereport (Alkermes, Inc., Cambridge, MA), or, as it has been previously called, RMP-7 (receptor-mediated permeabilizer-7), is a bradykinin analog that has been shown to produce a transient, pharmacologically mediated opening of the blood-brain barrier. The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy (BNCT) could be enhanced by means of intracarotid (i.c.) infusion of Cereport, in combination with intravenous (i.v.) injection or i.c. infusion of boronophenylalanine (BPA) in the F98 rat glioma model. For biodistribution studies, Fischer rats bearing intracerebral implants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 microg/kg b.w. of Cereport. For therapy studies, BNCT was initiated 14 days after intracerebral implantation of 10(3) F98 cells. The i.v. or i.c. injection of BPA (500 mg/kg b.w.) was given with or without Cereport, and the animals were irradiated 2.5 hours later at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. At a BPA dose of 500 mg/kg b.w., tumor boron concentrations (mean +/- standard deviation) were 55.7 +/- 9.6 microg/g with Cereport versus 33.6 +/- 3.9 microg/g without Cereport at 2.5 hours after i.c. infusion of BPA, and concentrations were 29.4 +/- 9.9 microg/g with Cereport versus 15.4 +/- 3.5 microg/g without Cereport (P < 0.05) after i.v. injection of BPA. After i.c. administration of BPA and Cereport, the tumor-to-blood ratio was 5.4 +/- 0.6, and the tumor-to-brain ratio was 5.2 +/- 2.4. After BNCT with BPA at a dose of 500 mg/kg, the survival time was 50 +/- 16 days for i.c. administration of BPA with Cereport versus 40 +/- 6 days without Cereport (P = 0.05), 38 +/- 4 days for i.v. administration of BPA with Cereport versus 34 +/- 3 days without Cereport (P = 0.02), 28 +/- 5 days for irradiated controls, and 23 +/- 3 days for untreated controls. Compared with untreated controls, there was a 117% increase in lifespan in rats that received an i.c. infusion of Cereport and then BPA, and an 86% increase in lifespan in rats that received i.c. administration of BPA without Cereport. These studies have established that i.c. administration of Cereport can not only increase tumor uptake of BPA, but also enhance the efficacy of BNCT.

Boron neutron capture therapy of brain tumors: enhanced survival and cure following blood–brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine

Purpose: Boronophenylalanine (BPA) and sodium borocaptate (Na 2B 12H 11SH or BSH) have been used clinically for boron neutron capture therapy (BNCT) of high-grade gliomas. These drugs appear to concentrate in tumors by different mechanisms and may target different subpopulations of glioma cells. The purpose of the present study was to determine if the efficacy of BNCT could be further improved in F98-glioma-bearing rats by administering both boron compounds together and by improving their delivery by means of intracarotid (i.c.) injection with or without blood–brain barrier disruption (BBB-D). Methods and Materials: For biodistribution studies, 10 5 F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Eleven to 13 days later animals were injected intravenously (i.v.) with BPA at doses of either 250 or 500 mg/kg body weight (b.w.) in combination with BSH at doses of either 30 or 60 mg/kg b.w. or i.c. with or without BBB-D, which was accomplished by i.c. infusion of a hyperosmotic (25%) solution of mannitol. For BNCT studies, 10 3 F98 glioma cells were implanted intracerebrally, and 14 days later animals were transported to the Brookhaven National Laboratory (BNL). They received BPA (250 mg/kg b.w.) in combination with BSH (30 mg/kg b.w.) by i.v. or i.c. injection with or without BBB-D, and 2.5 hours later they were irradiated with a collimated beam of thermal neutrons at the BNL Medical Research Reactor. Results: The mean tumor boron concentration ± standard deviation (SD) at 2.5 hours after i.c. injection of BPA (250 mg/kg b.w.) and BSH (30 mg/kg b.w.) was 56.3 ± 37.8 μg/g with BBB-D compared to 20.8 ± 3.9 μg/g without BBB-D and 11.2 ± 1.8 μg/g after i.v. injection. Doubling the dose of BPA and BSH produced a twofold increase in tumor boron concentrations, but also concomitant increases in normal brain and blood levels, which could have adverse effects. For this reason, the lower boron dose was selected for BNCT studies. The median survival time was 25 days for untreated control rats, 29 days for irradiated controls, 42 days for rats that received BPA and BSH i.v., 53 days following i.c. injection, and 72 days following i.c. injection + BBB-D with subsets of long-term survivors and/or cured animals in the latter two groups. No histopathologic evidence of residual tumor was seen in the brains of cured animals. Conclusions: The combination of BPA and BSH, administered i.c. with BBB-D, yielded a 25% cure rate for the heretofore incurable F98 rat glioma with minimal late radiation-induced brain damage. These results demonstrate that using a combination of boron agents and optimizing their delivery can dramatically improve the efficacy of BNCT in glioma-bearing rats.

Neutron Beam Optimization for Boron Neutron Capture Therapy Using the D-D and D-T High-Energy Neutron Sources

A monoenergetic neutron beam simulation study is carried out to determine the most suitable neutron energy for treatment of shallow and deep-seated brain tumors in the context of boron neutron capture therapy. Two figures-of-merit—the absorbed skin dose and the absorbed tumor dose at a given depth in the brain - are used to measure the neutron beam quality. Based on the results of this study, moderators, reflectors, and delimiters are designed and optimized to moderate the high-energy neutrons from the fusion reactions 2H(d,n)3He and 3H(d,n)4He down to a suitable energy spectrum. Two different computational models (MCNP and BNCT_RTPE) have been used to study the dose distribution in the brain. With the optimal beam-shaping assembly, a 1-A mixed deuteron/triton beam of energy 150 keV accelerated onto a titanium target leads to a treatment time of 1 h. The dose near the center of the brain obtained with this configuration is >65% higher than the dose from a typical spectrum produced by the Brookhaven Medical Research Reactor and is comparable to the dose obtained by other accelerator-produced neutron beams.

Boron neutron capture therapy of brain tumors: functional and neuropathologic effects of blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine.

Sodium borocaptate (BSH) and boronophenylalanine (BPA) are two drugs that have been used clinically for boron neutron capture therapy (BNCT) of brain tumors. We previously have reported that hyperosmotic mannitol-induced disruption of the blood-brain barrier (BBB-D), followed by intracarotid (i.c.) administration of BPA or BSH, either individually or in combination, significantly enhanced tumor boron delivery and the efficacy of BNCT in F98 glioma bearing rats. The purpose of the present study was to determine the short-term neuropathologic consequences of this treatment and the long-term effects on motor and cognitive function, as well as the neuropathologic sequelae 1 year following neutron capture irradiation. BBB-D was carried out in non-tumor bearing Fischer rats by infusing a 25% solution of mannitol i.c. followed by i.c. injection of BPA or BSH, either individually or in combination, immediately thereafter. Animals were euthanized 2 days after compound administration, and their brains were processed for neuropathologic examination, which revealed sporadic, mild, focal neuronal degeneration, hemorrhage, and necrosis. To assess the long-term effects of such treatment followed by neutron capture irradiation, non-tumor bearing rats were subjected to BBB-D after which they were injected i.c. with BPA (25 mg B/kg body weight (b.w)) or BSH (30 mg B/kg b.w.) either individually or in combination (BPA 12.5 mg and BSH 14 mg B/kg b.w.). Two and a half hours later they were irradiated at the Medical Research Reactor, Brookhaven National Laboratory, Upton, NY, with the same physical radiation doses (5.79, 8.10 or 10.06 Gy), delivered to the brain, as those that previously had been used for our therapy experiments. The animals tolerated this procedure well, after which they were returned to Columbus, Ohio where their clinical status was monitored weekly. After 1 year, motor function was assessed using a sensitive and reliable locomotor rating scale for open field testing in rats and cognitive function was evaluated by their performance in the Morris water maze, the results of which were similar to those obtained with age matched controls. After functional evaluation, the rats were euthanized, their brains were removed, and then processed for neuropathologic examination. Subtle histopathologic changes were seen in the choroid plexuses of irradiated animals that had received BPA, BSH or saline. Radiation related ocular changes consisting of keratitis, blepharitis, conjunctivitis and cataract formation were seen with similar frequency in most rats in each treatment group. Based on these observations, and the previously reported significant therapeutic gain associated with BBB-D and i.c. injection of BSH and BPA, the present observations establish its safety in rats and suggest that further studies in large animals and humans are warranted.

Tolerance of the normal canine brain to epithermal neutron irradiation in the presence of p-boronophenylalanine.

Twelve normal dogs underwent brain irradiation in a mixed-radiation, mainly epithermal neutron field at the Brookhaven Medical Research Reactor following intravenous infusion of 950 mg of 10B-enriched BPA/kg as its fructose complex. The 5 x 10 cm irradiation aperture was centered over the left hemisphere. For a subgroup of dogs reported previously, we now present more detailed analyses including dose-volume relationships, longer follow-ups, MRIs, and histopathological observations. Peak doses (delivered to 1 cm3 of brain at the depth of maximum thermal neutron flux) ranged from 7.6 Gy (photon-equivalent dose: 11.8 Gy-Eq) to 11.6 Gy (17.5 Gy-Eq). The average dose to the brain ranged from 3.0 Gy (4.5 Gy-Eq) to 8.1 Gy (11.9 Gy-Eq) and to the left hemisphere, 6.6 Gy (10.1 Gy-Eq) to 10.0 Gy (15.0 Gy-Eq). Maximum tolerated 'threshold' doses were 6.7 Gy (9.8 Gy-Eq) to the whole brain and 8.2 Gy (12.3 Gy-Eq) to one hemisphere. The threshold peak brain dose was 9.5 Gy (14.3 Gy-Eq). At doses below threshold, some dogs developed subclinical MRI changes. Above threshold, all dogs developed dose-dependent MRI changes, neurological deficits, and focal brain necrosis.

The Effects of Boron Neutron Capture Irradiation on Oral Mucosa: Evaluation Using a Rat Tongue Model

The ventral surface of the tongue of male Fisher 344 rats was used to evaluate the response of oral mucosa to boron neutron capture irradiation. Three hours after i.p. injection of 700 mg/kg of the boron delivery agent p-boronophenylalanine (BPA), the boron concentrations in blood and tongue mucosal epithelium were approximately 21 and 23 microgram (10)B/g, respectively. The doses required to produce a 50% incidence of ulceration with X rays, the Brookhaven Medical Research Reactor thermal neutron beam alone, or the thermal neutron beam in the presence of BPA were 13.4 +/- 0.2, 4. 2 +/- 0.1, and 3.0 +/- 0.1 Gy, respectively. Ulceration of the tongue was evident by 6 to 7 days after irradiation, irrespective of the irradiation modality; healing was related to dose and was relatively rapid (</=19 days). Compared to 100 kVp X rays, the relative biological effectiveness factors were 3.2 for the thermal neutron beam and 4.9 for the products of the boron neutron capture reaction, (10)B(n,alpha)(7)Li. Oral mucosa is highly sensitive to BPA-mediated BNC irradiation and could be a dose-limiting normal tissue in BNCT of brain tumors, or if BPA-based BNCT is applied to the treatment of head and neck tumors.

130 Boron neutron capture therapy for glioblastoma multiforme: Results from the third contemporary clinical phase I/II dose escalation study at the Brookhaven medical research reactor

130 Boron neutron capture therapy for glioblastoma multiforme: Results from the third contemporary clinical phase I/II dose escalation study at the Brookhaven medical research reactor