Calculating an unknown source activity using modeled and experimental results.

A method is presented that provides a way to calculate the unknown activity of a source by using experimental exposure rate measurements from an ion chamber and exposure rates calculated using the MCNP radiation transport code. The method consists of fitting experimental data to MCNP results with both data sets in the form of (Equation is included in full-text article.)where r is the distance from the source at which the measurement was taken, X˙ is the exposure rate, and An is an assumed nominal activity of the source. The fit is done by calculating a correction factor for the nominal activity that shifts the experimental data to match the MCNP results. The actual activity of the source in question is found by multiplying the assumed nominal activity by the activity correction factor. The method was used to calculate the activities of the three Cs sources used in the Ohio Emergency Management Agency's instrument calibration range. It was found that the activities were less than the decay-corrected nominal activities by factors ranging from 3% to 10%.

A Comparison of Measurements and Calculations of the Effects of Scattered Radiation on Dosimeter Calibration in a Calibration Range.

The method presented provides an alternative to the shadow shield method for experimentally measuring the contribution due to scattering radiation in a calibration range. Scattering of 0.6616 MeV photons from a Cs irradiator in a calibration range does not only occur due to the walls and floor of the range. It also occurs due to the source material itself, its encapsulation, the brass cup that holds the source, the two stainless tubes that surround the source capsule and the brass cup, and the irradiator structure that surrounds the aforementioned objects. The shadow shield method underestimates this scattering radiation that originates in the irradiator. By measuring the uncollided effective activity using a CZT detector and a total effective activity using a survey meter, the contribution of scattered radiation (including all of the abovementioned sources of scatter) to the effective source activity is able to be measured. In this paper, the measured mean effective source activities for a Cs irradiator in a calibration range are reported for a CZT detector and a survey meter. The measured activities are compared among themselves and with the results of MCNP calculations. From these comparisons, the new alternative method for measuring the scatter contribution was validated by agreement in both the MCNP calculations and experimental measurements that scattering contributed about 28% to the overall effective activity of the range.

Evaluation of the effects of scattered radiation on dosimeter calibration in a calibration range.

ISO standard 4037 specifies limits for scattered radiation for "gamma reference radiation" for the calibration of "protection-level dosemeters and rate dosemeters." More specifically, it specifies that scattered radiation should contribute less than 5% to the total exposure rate for source-center-to-dosimeter-center distances (henceforth called downrange distances) over which dosimeters are calibrated. In a previous paper by the authors, the results of an MCNP analysis of a calibration range with a Cs irradiator (henceforth called Cs calibration range) were reported. In that paper, simulations of the singly differential photon fluence rate (i.e., flux) energy spectra (henceforth called photon flux energy spectra) from the Cs (an ISO standard 4037 gamma reference radiation) irradiator were reported. In that paper, the spectra were examined to determine the contribution of scattered photons to the exposure rate in the Cs calibration range for various downrange distances. In this paper, the simulations of the photon flux energy spectra for the Cs irradiator photons for various downrange distances are convolved with response functions, creating an ideal exposure meter and two commercially available ion chamber survey meters, in order to predict the meters' response rates versus downrange distance. The simulated response rates indicate that the Cs calibration range satisfies an operational check of the contribution of scattered radiation to the exposure rate that is specified in the ISO standard 4037, although as shown in the previous paper by the authors, the Cs calibration range does not satisfy the ISO standard 4037 specification that scattered radiation should contribute less than 5% to the total exposure rate for downrange distances over which dosimeters are calibrated. The ISO standard 4037 operational check is that the measured exposure rate varies from an inverse square dependence by less than 5% for the downrange distances over which dosimeters are calibrated.

Evaluation of scattered radiation in a calibration range using exposure rate energy spectra.

ISO standard 4037 specifies that for calibrating protection level dosimeters, scattered radiation should contribute less than 5% of the exposure. In previous work, the authors reported the results of an MCNP analysis of the shadow shield technique that was performed for a calibration range with a Cs irradiator. This paper examines the energy distribution of the photons contributing to the exposure percent scatter (S%) and the detailed origin of the scatter that originates in the irradiator. In summary, it reports that: 1) the majority of S% is due to photons with energies that are significantly below the source energy, 2) a significant percentage of S% is due to photons that scatter within the source and source capsule walls, and 3) S% due to scatter within the irradiator is even more significant than previously reported.

Evaluation of the shadow shield technique for the measurement of scattered radiation.

ISO standard 4037 specifies the characteristics and production methods of x-ray and gamma-ray reference radiation for calibrating protection-level dosimeters and rate dosimeters. The standard limits scattered radiation to 5%. The shadow shield technique is a widely accepted test used to determine scatter contribution. Using an MCNP model, an analysis of the shadow shield technique was performed. It was found that the shadow shield technique is accurate in predicting the scatter due to the walls and floor for source-to-detector distances (R) less than 6 m. For R greater than 6 m for the modeled irradiator and calibration range, the shadow shield blocks photons that scatter upbeam from the detector, which causes the shadow shield method to under-predict the scatter percentage. Moreover, the shadow shield blocks scatter that originates from the irradiator, which causes the shadow shield method to under-predict the scatter percentage by as much as 10 percentage units for the irradiator and calibration range that were modeled.

Molecular targeting and treatment of an epidermal growth factor receptor-positive glioma using boronated cetuximab.

PURPOSE: The purpose of the present study was to evaluate the anti-epidermal growth factor monoclonal antibody (mAb) cetuximab (IMC-C225) as a delivery agent for boron neutron capture therapy (BNCT) of a human epidermal growth factor receptor (EGFR) gene-transfected rat glioma, designated as F98(EGFR). EXPERIMENTAL DESIGN: A heavily boronated polyamidoamine dendrimer was chemically linked to cetuximab by means of the heterobifunctional reagents N-succinimidyl 3-(2-pyridyldithio)-propionate and N-(k-maleimido undecanoic acid)-hydrazide. The bioconjugate, designated as BD-C225, was specifically taken up by F98(EGFR) glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.8 versus 9.1 microg/g). For in vivo biodistribution studies, F98(EGFR) cells were implanted stereotactically into the brains of Fischer rats, and 14 days later, BD-C225 was given intracerebrally by either convection enhanced delivery (CED) or direct intratumoral (i.t.) injection. RESULTS: The amount of boron retained by F98(EGFR) gliomas 24 h following CED or i.t. injection was 77.2 and 50.8 microg/g, respectively, with normal brain and blood boron values <0.05 mug/g. Boron neutron capture therapy was carried out at the Massachusetts Institute of Technology Research Reactor 24 h after CED of BD-C225, either alone or in combination with i.v. boronophenylalanine (BPA). The corresponding mean survival times (MST) were 54.5 and 70.9 days (P = 0.017), respectively, with one long-term survivor (more than 180 days). In contrast, the MSTs of irradiated and untreated controls, respectively, were 30.3 and 26.3 days. In a second study, the combination of BD-C225 and BPA plus sodium borocaptate, given by either i.v. or intracarotid injection, was evaluated and the MSTs were equivalent to that obtained with BD-C225 plus i.v. BPA. CONCLUSIONS: The survival data obtained with BD-C225 are comparable with those recently reported by us using boronated mAb L8A4 as the delivery agent. This mAb recognizes the mutant receptor, EGFRvIII. Taken together, these data convincingly show the therapeutic efficacy of molecular targeting of EGFR using a boronated mAb either alone or in combination with BPA and provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.

Boron neutron capture therapy of cancer: current status and future prospects.

BACKGROUND: Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas and either cutaneous primaries or cerebral metastases of melanoma, most recently, head and neck and liver cancer. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, several European countries, and Argentina. Accelerators also can be used to produce epithermal neutrons and these are being developed in several countries, but none are currently being used for BNCT. BORON DELIVERY AGENTS: Two boron drugs have been used clinically, sodium borocaptate (Na(2)B(12)H(11)SH) and a dihydroxyboryl derivative of phenylalanine called boronophenylalanine. The major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations ( approximately 20 microg/g tumor) sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. Over the past 20 years, other classes of boron-containing compounds have been designed and synthesized that include boron-containing amino acids, biochemical precursors of nucleic acids, DNA-binding molecules, and porphyrin derivatives. High molecular weight delivery agents include monoclonal antibodies and their fragments, which can recognize a tumor-associated epitope, such as epidermal growth factor, and liposomes. However, it is unlikely that any single agent will target all or even most of the tumor cells, and most likely, combinations of agents will be required and their delivery will have to be optimized. CLINICAL TRIALS: Current or recently completed clinical trials have been carried out in Japan, Europe, and the United States. The vast majority of patients have had high-grade gliomas. Treatment has consisted first of "debulking" surgery to remove as much of the tumor as possible, followed by BNCT at varying times after surgery. Sodium borocaptate and boronophenylalanine administered i.v. have been used as the boron delivery agents. The best survival data from these studies are at least comparable with those obtained by current standard therapy for glioblastoma multiforme, and the safety of the procedure has been established. CONCLUSIONS: Critical issues that must be addressed include the need for more selective and effective boron delivery agents, the development of methods to provide semiquantitative estimates of tumor boron content before treatment, improvements in clinical implementation of BNCT, and a need for randomized clinical trials with an unequivocal demonstration of therapeutic efficacy. If these issues are adequately addressed, then BNCT could move forward as a treatment modality.

Accelerator-based epithermal neutron sources for boron neutron capture therapy of brain tumors.

This paper reviews the development of low-energy light ion accelerator-based neutron sources (ABNSs) for the treatment of brain tumors through an intact scalp and skull using boron neutron capture therapy (BNCT). A major advantage of an ABNS for BNCT over reactor-based neutron sources is the potential for siting within a hospital. Consequently, light-ion accelerators that are injectors to larger machines in high-energy physics facilities are not considered. An ABNS for BNCT is composed of: (1) the accelerator hardware for producing a high current charged particle beam, (2) an appropriate neutron-producing target and target heat removal system (HRS), and (3) a moderator/reflector assembly to render the flux energy spectrum of neutrons produced in the target suitable for patient irradiation. As a consequence of the efforts of researchers throughout the world, progress has been made on the design, manufacture, and testing of these three major components. Although an ABNS facility has not yet been built that has optimally assembled these three components, the feasibility of clinically useful ABNSs has been clearly established. Both electrostatic and radio frequency linear accelerators of reasonable cost (approximately 1.5 M dollars) appear to be capable of producing charged particle beams, with combinations of accelerated particle energy (a few MeV) and beam currents (approximately 10 mA) that are suitable for a hospital-based ABNS for BNCT. The specific accelerator performance requirements depend upon the charged particle reaction by which neutrons are produced in the target and the clinical requirements for neutron field quality and intensity. The accelerator performance requirements are more demanding for beryllium than for lithium as a target. However, beryllium targets are more easily cooled. The accelerator performance requirements are also more demanding for greater neutron field quality and intensity. Target HRSs that are based on submerged-jet impingement and the use of microchannels have emerged as viable target cooling options. Neutron fields for reactor-based neutron sources provide an obvious basis of comparison for ABNS field quality. This paper compares Monte Carlo calculations of neutron field quality for an ABNS and an idealized standard reactor neutron field (ISRNF). The comparison shows that with lithium as a target, an ABNS can create a neutron field with a field quality that is significantly better (by a factor of approximately 1.2, as judged by the relative biological effectiveness (RBE)-dose that can be delivered to a tumor at a depth of 6cm) than that for the ISRNF. Also, for a beam current of 10 mA, the treatment time is calculated to be reasonable (approximately 30 min) for the boron concentrations that have been assumed.

Synthesis of a small library of 3-(carboranylalkyl)thymidines and their biological evaluation as substrates for human thymidine kinases 1 and 2.

A small library consisting of two series of thymidine derivatives containing o-carboranylalkyl groups at the N-3 position was prepared. In both series, alkyl spacers of 2-7 methylene units were placed between the o-carborane cage and the thymidine scaffold. In one series, an additional dihydroxypropyl substituent was introduced at the second carbon atom of the carborane cage. In the series of N-3-substituted carboranyl thymidines without additional dihydroxypropyl substituent, three steps were required to obtain the target compounds in overall yields as high as 75%, while in the series of N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituent, 9-10 steps were necessary with significantly lower overall yield. All target compounds were good substrates of human cytosolic thymidine kinase 1 while they were, if at all, poor substrates of the mitochondrial thymidine kinase 2. There was only a minor difference in phosphorylation rates between N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituents with thymidine kinase 1 (range: 13-49% relative to thymidine) and their counterparts lacking this group (range: 11-57% relative to thymidine). Tether lengths of two and five methylene groups in both series gave the highest enzyme activities in the present study. A hypothesis for this result is presented.