Robert Emery

Neutron exposures in human cells: bystander effect and relative biological effectiveness.

Bystander effects have been observed repeatedly in mammalian cells following photon and alpha particle irradiation. However, few studies have been performed to investigate bystander effects arising from neutron irradiation. Here we asked whether neutrons also induce a bystander effect in two normal human lymphoblastoid cell lines. These cells were exposed to fast neutrons produced by targeting a near-monoenergetic 50.5 MeV proton beam at a Be target (17 MeV average neutron energy), and irradiated-cell conditioned media (ICCM) was transferred to unirradiated cells. The cytokinesis-block micronucleus assay was used to quantify genetic damage in radiation-naïve cells exposed to ICCM from cultures that received 0 (control), 0.5, 1, 1.5, 2, 3 or 4 Gy neutrons. Cells grown in ICCM from irradiated cells showed no significant increase in the frequencies of micronuclei or nucleoplasmic bridges compared to cells grown in ICCM from sham irradiated cells for either cell line. However, the neutron beam has a photon dose-contamination of 5%, which may modulate a neutron-induced bystander effect. To determine whether these low doses of contaminating photons can induce a bystander effect, cells were irradiated with cobalt-60 at doses equivalent to the percent contamination for each neutron dose. No significant increase in the frequencies of micronuclei or bridges was observed at these doses of photons for either cell line when cultured in ICCM. As expected, high doses of photons induced a clear bystander effect in both cell lines for micronuclei and bridges (p<0.0001). These data indicate that neutrons do not induce a bystander effect in these cells. Finally, neutrons had a relative biological effectiveness of 2.0±0.13 for micronuclei and 5.8±2.9 for bridges compared to cobalt-60. These results may be relevant to radiation therapy with fast neutrons and for regulatory agencies setting standards for neutron radiation protection and safety.

An image-guided precision proton radiation platform for preclinical in vivo research

There are many unknowns in the radiobiology of proton beams and other particle beams. We describe the development and testing of an image-guided low-energy proton system optimized for radiobiological research applications. A 50 MeV proton beam from an existing cyclotron was modified to produce collimated beams (as small as 2 mm in diameter). Ionization chamber and radiochromic film measurements were performed and benchmarked with Monte Carlo simulations (TOPAS). The proton beam was aligned with a commercially-available CT image-guided x-ray irradiator device (SARRP, Xstrahl Inc.). To examine the alternative possibility of adapting a clinical proton therapy system, we performed Monte Carlo simulations of a range-shifted 100 MeV clinical beam. The proton beam exhibits a pristine Bragg Peak at a depth of 21 mm in water with a dose rate of 8.4 Gy min-1 (3 mm depth). The energy of the incident beam can be modulated to lower energies while preserving the Bragg peak. The LET was: 2.0 keV µm-1 (water surface), 16 keV µm-1 (Bragg peak), 27 keV µm-1 (10% peak dose). Alignment of the proton beam with the SARRP system isocenter was measured at 0.24 mm agreement. The width of the beam changes very little with depth. Monte Carlo-based calculations of dose using the CT image data set as input demonstrate in vivo use. Monte Carlo simulations of the modulated 100 MeV clinical proton beam show a significantly reduced Bragg peak. We demonstrate the feasibility of a proton beam integrated with a commercial x-ray image-guidance system for preclinical in vivo studies. To our knowledge this is the first description of an experimental image-guided proton beam for preclinical radiobiology research. It will enable in vivo investigations of radiobiological effects in proton beams.

Deuteron irradiation of W and WO3 for production of high specific activity 186Re: Challenges associated with thick target preparation

This investigation evaluated target fabrication and beam parameters for scale-up production of high specific activity (186)Re using deuteron irradiation of enriched (186)W via the (186)W(d,2n)(186)Re reaction. Thick W and WO3 targets were prepared, characterized and evaluated in deuteron irradiations. Full-thickness targets, as determined using SRIM, were prepared by uniaxially pressing powdered natural abundance W and WO3, or 96.86% enriched (186)W, into Al target supports. Alternatively, thick targets were prepared by pressing (186)W between two layers of graphite powder or by placing pre-sintered (1105°C, 12h) natural abundance WO3 pellets into an Al target support. Assessments of structural integrity were made on each target prepared. Prior to irradiation, material composition analyses were conducted using SEM, XRD, and Raman spectroscopy. Within a minimum of 24h post irradiation, gamma-ray spectroscopy was performed on all targets to assess production yields and radionuclidic byproducts. Problems were encountered with the structural integrity of some pressed W and WO3 pellets before and during irradiation, and target material characterization results could be correlated with the structural integrity of the pressed target pellets. Under the conditions studied, the findings suggest that all WO3 targets prepared and studied were unacceptable. By contrast, (186)W metal was found to be a viable target material for (186)Re production. Thick targets prepared with powdered (186)W pressed between layers of graphite provided a particularly robust target configuration.

Biological and dosimetric characterisation of spatially fractionated proton minibeams

The biological effectiveness of proton beams varies with depth, spot size and lateral distance from the beam central axis. The aim of this work is to incorporate proton relative biological effectiveness (RBE) and equivalent uniform dose (EUD) considerations into comparisons of broad beam and highly modulated proton minibeams. A Monte Carlo model of a small animal proton beamline is presented. Dose and variable RBE is calculated on a per-voxel basis for a range of energies (30-109 MeV). For an open beam, the RBE values at the beam entrance ranged from 1.02-1.04, at the Bragg peak (BP) from 1.3 to 1.6, and at the distal end of the BP from 1.4 to 2.0. For a 50 MeV proton beam, a minibeam collimator designed to produce uniform dose at the depth of the BP peak, had minimal impact on the open beam RBE values at depth. RBE changes were observed near the surface when the collimator was placed flush with the irradiated object, due to a higher neutron contribution derived from proton interactions with the collimator. For proton minibeams, the relative mean RBE weighted entrance dose (RWD) was ~25% lower than the physical mean dose. A strong dependency of the EUD with fraction size was observed. For 20 Gy fractions, the EUD varied widely depending on the radiosensitivity of the cells. For radiosensitive cells, the difference was up to ~50% in mean dose and ~40% in mean RWD and the EUD trended towards the valley dose rather than the mean dose. For comparative studies of uniform dose with spatially fractionated proton minibeams, EUD derived from a per-voxel RWD distribution is recommended for biological assessments of reproductive cell survival and related endpoints.

SU‐E‐T‐470: Monte Carlo Simulation of Fast Neutron Treatments for Head and Neck Cancers

Purpose: To quantify the physical characteristics of a therapeutic fast neutron beam at the University of Washington (UW) using a Monte Carlo model validated against measured percentage depth‐dose (PDD) and lateral profiles. Methods: MCNPX modeling and simulation of the UW neutron therapy systems treatment head is divided into three stages. In Stage I, 50.5 MeV protons are directed at a Be target. Neutrons produced in the target pass through the primary collimator and flattening filter; photons and neutrons produced in Stage I are saved to a 100×100 cm2 phase space file located just below the flattening filter. In Stage II, neutrons and photons are transported through the MLC and saved to a second phase space file. Automatic adjustment of the 40 individual MLC to create regular or irregular field shapes with or without a wedge is controlled by an in‐house developed python script. In Stage III, neutral particles are transported from the phase space file at the bottom of the MLC into a 40×40×40 cm3 water phantom (150 cm source to surface distance). PDD curves and lateral dose profiles are computed from dose tallies in rectangular (0.1 cm3) volumes. Results: PDD simulation for an open 10.4×10.3 cm2 field agrees with measurement to within 4% up to 17 cm and within 8% up to 30 cm. A lateral dose profile at a depth of 1.7 cm matches well the overall shape of the profile. A representative simulation (1011 source particles) requires about 150 hours of CPU time on a dual, 2.4 GHz 8‐core Intel Xeon server. Conclusion: The developed MCNPX model is capable of reproducing measured data with sufficient accuracy for clinical applications. Efforts to improve agreement in the penumbra of lateral profiles are underway as well as tests of the model for various sizes of open and wedged fields.

University of Washington Clinical Neutron Facility: Report on 26 Years of Operation

Particle radiotherapy facilities are highly capital intensive and must operate over decades to recoup the original investment. We describe the successful, long‐term operation of a neutron radiotherapy center at the University of Washington, which has been operating continuously since September 1984. To date, 2836 patients have received neutron radiotherapy. The mission of the facility has also evolved to include the production of unique radioisotopes that cannot be made with the low‐energy cyclotrons more commonly found in nuclear medicine departments. The facility is also used for neutron damage testing for industrial devices. In this paper, we describe the challenges of operating such a facility over an extended time period, including a planned maintenance and upgrade program serving diverse user groups, and summarize the major clinical results in terms of tumor control and normal tissue toxicity. Over time, the mix of patients being treated has shifted from common tumors such as prostate cancer, lung c...

Dosimetric characteristics of the University of Washington Clinical Neutron Therapy System

The University of Washington (UW) Clinical Neutron Therapy System (CNTS), which generates high linear energy transfer fast neutrons through interactions of 50.5 MeV protons incident on a Be target, has depth-dose characteristics similar to 6 MV x-rays. In contrast to the fixed beam angles and primitive blocking used in early clinical trials of neutron therapy, the CNTS has a gantry with a full 360° of rotation, internal wedges, and a multi-leaf collimator (MLC). Since October of 1984, over 3178 patients have received conformal neutron therapy treatments using the UW CNTS. In this work, the physical and dosimetric characteristics of the CNTS are documented through comparisons of measurements and Monte Carlo simulations. A high resolution computed tomography scan of the model 17 ionization chamber (IC-17) has also been used to improve the accuracy of simulations of the absolute calibration geometry. The response of the IC-17 approximates well the kinetic energy released per unit mass (KERMA) in water for neutrons and photons for energies from a few tens of keV up to about 20 MeV. Above 20 MeV, the simulated model 17 ion chamber response is 20%-30% higher than the neutron KERMA in water. For CNTS neutrons, simulated on- and off-axis output factors in water match measured values within ~2%  ±  2% for rectangular and irregularly shaped field with equivalent square areas ranging in a side dimension from 2.8 cm to 30.7 cm. Wedge factors vary by less than 1.9% of the measured dose in water for clinically relevant field sizes. Simulated tissue maximum ratios in water match measured values within 3.3% at depths up to 20 cm. Although the absorbed dose for water and adipose tissue are within 2% at a depth of 1.7 cm, the absorbed dose in muscle and bone can be as much as 12 to 40% lower than the absorbed dose in water. The reported studies are significant from a historical perspective and as additional validation of a new tool for patient quality assurance and as an aid in ongoing efforts to clinically implement advanced treatment techniques, such as intensity modulated neutron therapy, at the UW.

cGMP production of astatine-211-labeled anti-CD45 antibodies for use in allogeneic hematopoietic cell transplantation for treatment of advanced hematopoietic malignancies

The objective of this study was to translate reaction conditions and quality control methods used for production of an astatine-211(211At)-labeled anti-CD45 monoclonal antibody (MAb) conjugate, 211At-BC8-B10, from the laboratory setting to cGMP production. Five separate materials were produced in the preparation of 211At-BC8-B10: (1) p-isothiocyanato-phenethyl-closo-decaborate(2-) (B10-NCS), (2) anti-CD45 MAb, BC8, (3) BC8-B10 MAb conjugate, (4) [211At]NaAt, and (5) 211At-BC8-B10. The 211At-labeling reagent, B10-NCS, was synthesized as previously reported. BC8 was produced, then conjugated with B10-NCS under cGMP conditions to form BC8-B10. [211At]NaAt was produced by α-irradiation of Bi targets, followed by isolation of the 211At using a “wet chemistry” method. The clinical product, 211At-BC8-B10, was prepared by reacting [211At]NaAt with BC8-B10 in NH4OAc buffer (pH 5.5) for 2 min at room temperature, followed by size-exclusion chromatography purification. Quality control tests conducted on the 211At-BC8-B10 included evaluations for purity and identity, as well as pyrogen and sterility tests. Stability of the 211At-BC8-B10 in 25 mg/mL sodium ascorbate solution was evaluated at 1, 2, 4, 6 and 21 h post isolation. For qualification, three consecutive 211At-BC8-B10 clinical preparations were successfully conducted in the cGMP suite, and an additional cGMP clinical preparation was carried out to validate each step required to deliver 211At-BC8-B10 to a patient. These cGMP preparations provided 0.80–1.28 Gbq (21.5–34.5 mCi) of 211At-BC8-B10 with radiochemical purity of >97%. The preparations were found to be sterile and have a pyrogen level <0.50 EU/mL. Cell binding was retained by the 211At-BC8-B10. 211At-BC8-B10 in ascorbic acid solution demonstrated a radiochemical stability of >95% for up to 21 h at room temperature. The experiments conducted have defined conditions for translation of 211At-BC8-B10 production from the laboratory to cGMP suite. This study has allowed the initiation of a phase I/II clinical trial using 211At-BC8-B10 (NCT03128034).

Scale-up of high specific activity 186gRe production using graphite-encased thick 186W targets and demonstration of an efficient target recycling process

Abstract Production of high specific activity 186gRe is of interest for development of theranostic radiopharmaceuticals. Previous studies have shown that high specific activity 186gRe can be obtained by cyclotron irradiation of enriched 186W via the 186W(d,2n)186gRe reaction, but most irradiations were conducted at low beam currents and for short durations. In this investigation, enriched 186W metal targets were irradiated at high incident deuteron beam currents to demonstrate production rates and contaminants produced when using thick targets. Full-stopping thick targets, as determined using SRIM, were prepared by uniaxial pressing of powdered natural abundance W metal or 96.86% enriched 186W metal encased between two layers of graphite flakes for target material stabilization. An assessment of structural integrity was made on each target preparation. To assess the performance of graphite-encased thick 186W metal targets, along with the impact of encasing on the separation chemistry, targets were first irradiated using a 22 MeV deuteron beam for 10 min at 10, 20, and 27 μA, with an estimated nominal deuteron energy of 18.7 MeV on the 186W target material (after energy degradation correction from top graphite layer). Gamma-ray spectrometry was performed post EOB on all targets to assess production yields and radionuclidic byproducts. The investigation also evaluated a method to recover and recycle enriched target material from a column isolation procedure. Material composition analyses of target materials, pass-through/wash solutions and recycling process isolates were conducted with SEM, FTIR, XRD, EDS and ICP-MS spectrometry. To demonstrate scaled-up production, a graphite-encased 186W target made from recycled 186W was irradiated for ~2 h with 18.7 MeV deuterons at a beam current of 27 μA to provide 0.90 GBq (24.3 mCi) of 186gRe, decay-corrected to the end of bombardment. ICP-MS analysis of the isolated 186gRe solution provided data that indicated the specific activity of 186gRe in this scaled-up production run was 2.6±0.5 GBq/μg (70±10 Ci/mg).

Routine operation of the University of Washington fast neutron therapy facility and plans for improvements

The fast neutron therapy facility in Seattle is based on a cyclotron, which produces a 50.5 MeV proton beam. Neutrons are produced in a beryllium target installed in an isocentric gantry equipped with a multi-leaf collimator. The system has been in routine operation for 14 years and over 1800 patients have been treated. Downtime has been minimal, over the past 10 years less than 1.5% of the scheduled daily treatment sessions could not be delivered for equipment related reasons. Fast neutron therapy has been shown to be highly effective for the treatment of salivary gland tumors, sarcomas of bone and soft tissues and for certain prostate cancers. In addition there are situations such as non-small cell lung cancer, where results are promising, but success is limited by normal tissue complications. A relatively small selective increase in the tumor dose might lead to a significant clinical improvement in these situations. The use of a boron neutron capture (BNC) boost, utilizing the moderated slow neutrons n...