Thomas Kroc

Boron neutron capture in prostate cancer cells.

A modified enhanced thermal neutron beam (METNB) assembly at Fermilab was used to irradiate borylphenylalanine (BPA) treated human prostate cancer cells, DU 145. Acceptable cellular uptake levels of BPA and no BPA cytotoxicity were observed. In the absence of BPA, the relative biological effectiveness (RBE) of the METNB was determined to be 2.3-4.8 times greater than gamma rays. An additional 1.2 or 1.4 fold relative enhancement from boron neutron capture (RE(BNC)) was observed for METNB irradiated DU 145 cells treated with 4.9 or 12mM BPA, respectively. The additional cell killing of the BPA loaded DU 145 cells by the METNB at Fermilab is evidence for a BNC enhanced cell killing.

Pileup correction of microdosimetric spectra

Microdosimetric spectra were measured at the Fermilab neutron therapy facility using low pressure proportional counters operated in pulse mode. The neutron beam has a very low duty cycle (<0.1%) and consequently a high instantaneous dose rate which causes distortions of the microdosimetric spectra due to pulse pileup. The determination of undistorted spectra at this facility necessitated (i) the modified operation of the proton accelerator to reduce the instantaneous dose rate and (ii) the establishment of a computational procedure to correct the measured spectra for remaining pileup distortions. In support of the latter effort, two different pileup simulation algorithms using analytical and Monte-Carlo-based approaches were developed. While the analytical algorithm allows a detailed analysis of pileup processes it only treats two-pulse and three-pulse pileup and its validity is hence restricted. A Monte-Carlo-based pileup algorithm was developed that inherently treats all degrees of pileup. This algorithm can be used in an iterative manner to correct pileup distorted spectra. The pileup simulation and correction codes compared well with experimental data. A set of pileup distorted spectra that were collected under different setup configurations at the Fermilab facility were corrected for pileup. Analysis of the spectral variations between the spectra is consistent with findings reported in the literature.

Gadolinium neutron capture in glioblastoma multiforme cells

Purpose: A proof of principle for cell killing by Gadolinium (Gd) neutron capture in Magnevist® preloaded Glioblastoma multiforme (GBM) cells is provided. Materials and methods: U87cells were pre-loaded with 5 mg/ml Magnevist® (Gd containing compound) and irradiated using an enhanced neutron beam developed at NIU Institute for Neutron Therapy at Fermilab. These experiments were possible because of an enhanced fast neutron therapy assembly designed to use the fast neutron beam at Fermilab to deliver a neutron beam containing a greater fraction of thermal neutrons and because of the development of improved calculations for dose for the enhanced neutron beam. Clonogenic response was determined. Results: U87 cell survival after γ irradiation, fast neutron irradiation and irradiation with the enhanced neutron beam in the presence or absence of Magnevist® were determined. Conclusions: U87 cells were the least sensitive to γ radiation, and increasingly sensitive to fast neutron irradiation, irradiation with the enhanced neutron beam and finally a significant enhancement in cell killing was observed for U87 cells preloaded with Magnevist®. The sensitivity of U87 cells pre-loaded with Magnevist® and then irradiated with the enhanced neutron beam can at least in part be attributed to the Auger electrons emitted by the neutron capture event.

Fermilab electron cooling project: commissioning of the 5 MeV recirculation test set-up

An important part of the Fermilabs Recycler Electron Cooling (REC) project is a recirculation test which is performed using a 5-MV electrostatic accelerator, a Pelletron, with two tubes and a simplified beam line with one 180-degree bend. The main goal of the test is to demonstrate stable operation of a 4.4-MeV, 0.5-A DC electron beam. The paper describes the set-up and the early experimental results.

Feasibility of the utilization of BNCT in the fast neutron therapy beam at Fermilab

The Neutron Therapy Facility at Fermilab has treated cancer patients since 1976. Since then more than 2,300 patients have been treated and a wealth of clinical information accumulated. The therapeutic neutron beam at Fermilab is produced by bombarding a beryllium target with 66 MeV protons. The resulting continuous neutron spectrum ranges from thermal to 66 MeV in neutron energy. It is clear that this spectrum is not well suited for the treatment of tumors with boron neutron capture therapy (BNCT) only However, since this spectrum contains thermal and epithermal components the authors are investigating whether BNCT can be used in this beam to boost the tumor dose. There are clinical scenarios in which a selective tumor dose boost of 10 - 15% could be clinically significant. For these cases the principal treatment would still be fast neutron therapy but a tumor boost could be used either to deliver a higher dose to the tumor tissue or to reduce the dose to the normal healthy tissue while maintaining the absorbed dose level in the tumor tissue.

Autophagic flux in glioblastoma cells

Abstract To establish metabolic context for radiation sensitivity by measuring autophagic flux in two different glioblastoma (GBM) cell lines. Clonogenic survival curve analysis of U87 or U251 cells exposed to γ radiation, fast neutrons, a mixed energy neutron beam (METNB) or Auger electrons from a gadolinium neutron capture (GdNC) reaction suggested other factors, beyond a defective DNA damage response, contribute to cell death of U251 cells. Altered tumor metabolism (autophagy) was hypothesized as a factor in U251 cells’ clonogenic response. Each of the four different radiation modalities induced an increase in the number of autophagosomes in both U87 and U251 cells. Changes in the number of autophagosomes can be explained by either induction of autophagy or alterations in autophagic flux so autophagic flux was assayed by p62 immunoblotting or in engineered GBM cells that stably express an autophagy marker protein, LC3B-eGFP-mCherry. Perturbations in later stages of autophagy in U251 cells corresponded with radiation sensitivity of U251 cells irradiated with 10 Gy γ rays. Establishment of altered autophagic flux is a useful biomarker for metabolic stress and provided metabolic context for radiation sensitization to 10 Gy γ rays. These results provide strong evidence for the usefulness of managing tumor cell metabolism as a tool for the enhancement of radiation therapy.

Fast Neutron Induced Autophagy Leads To Necrosis In Glioblastoma Multiforme Cells

Fast neutrons are highly effective at killing glioblastoma multiforme (GBM), U87 and U251 cells. The mode of cell death was investigated using transmission electron microscopy (TEM) to identify the fraction of irradiated U87 or U251 cells having morphological features of autophagy and/or necrosis. U87 or U251 cells were irradiated with 2 Gy fast neturons or 10 Gy γ rays. A majority of U87 and U251 cells exhibit features of cell death with autophagy after irradiation with either 10 Gy γ rays or 2 Gy fast neutrons. Very few γ irradiated cells had features of necrosis (U87 or U251 cell samples processed for TEM 1 day after 10 Gy γ irradiation). In contrast, a significant increase was observed in necrotic U87 and U251 cells irradiated with fast neutrons. These results show a greater percentage of cells exhibit morphological evidence of necrosis induced by a lower dose of fast neutron irradiation compared to γ irradiation. Also, the evidence of necrosis in fast neutron irradiated U87 and U251 cells occurs in a...

BNCEFN Optimisation with Lead Blocks Collimation and Graphite Embedding

Several authors have demonstrated the feasibility and efficiency of Boron Neutron Capture Enhancement of Fast Neutron (BNCEFN) at their facility.1, 2, 3, 4, 5 The two major difficulties of this technique are to incorporate a large amount of 10B selectively into the tumor (>100µg/g) and to optimize neutron thermalization in the tissues. Unfortunately, it has been also demonstrated that the number of thermal neutrons per fast neutron Gy (nth.Gy−1) is inversely proportional to fast neutron energy, and strongly proportional to the size of fast neutron irradiation field.3, 4, 5 Thus, a dramatic decrease of thermal neutron flux is seen when the irradiation fields are reduced to conform the target volume.