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The use of magnetic fluids and magnetic particles in combinatorial hyperthermia therapy for cancer treatment is reviewed. The investigation approach adopted for producing thermoregulating particles and tissue model studies for studying particle retention and heating characteristics is discussed.
Studies of the structure of particle tracks have led to models of track effects based on radial dose and radiobiological target theory that have been very successful in describing and predicting track effects in physical, chemical, and biological systems. For describing mammalian cellular inactivation two inactivation modes are required, called gamma-kill and ion-kill, the first due to synergistic effects of delta rays from adjacent ion paths thus resembling the effects from gamma rays, and the second to the effects of single ion transits through a cell nucleus. The ion-kill effect is more severe, where the fraction of cells experiencing ion kill is responsible for a decrease in the oxygen enhancement ratio, and an increase in relative biological effectiveness, but these are accompanied by loss of repair, hence to a reduction in the efficiency of fractionation in high LET therapy, as shown by our calculations for radiobiological effects in the "spread out Bragg Peak".
Monte Carlo transport codes like FLUKA are useful for many purposes, and one of those is the simulation of the effects of radiation traversing the human body. In particular, radiation has been used in cancer therapy for a long time, and recently this has been extended to include heavy ion particle beams. The advent of this particular type of therapy has led to the need for increased capabilities in the transport codes used to simulate the detailed nature of the treatment doses to the Y ~ ~ O U S tissues that are encountered. This capability is also of interest to NASA because of the nature of the radiation environment in space.[l] While in space, the crew members bodies are continually being traversed by virtually all forms of radiation. In assessing the risk that this exposure causes, heavy ions are of primary importance. These arise both from the primary external space radiation itself, as well as fragments that result from interactions during the traversal of that radiation through any intervening material including intervening body tissue itself. Thus the capability to characterize the details of the radiation field accurately within a human body subjected to such external 'beams" is of critical importance.
Alpha particle and proton beams in radiation therapy of pituitary gland tumors and adenoma
The particles and energies commonly used for hadron therapy overlap the low end of the charge and energy range of greatest interest for space radiation applications, Z=1-26 and approximately 100-1000 MeV/nucleon. It has been known for some time that the nuclear interactions of the incident ions must be taken into account both in treatment planning and in understanding and addressing the effects of galactic cosmic ray ions on humans in space. Until relatively recently, most of the studies of nuclear fragmentation and transport in matter were driven by the interests of the nuclear physics and later, the hadron therapy communities. However, the experimental and theoretical methods and the accelerator facilities developed for use in heavy ion nuclear physics are directly applicable to radiotherapy and space radiation studies. I will briefly review relevant data taken recently at various accelerators, and discuss the implications of the measurements for radiotherapy, radiobiology and space radiation research.
The transport of heavy ion beams in extended materials is a problem of interest in accelerator and space shielding, radiation therapy, and astrophysical and radiobiological studies. The beam particles change their energy and direction of motion through atomic/molecular collisions and undergo occasional radical transformation in nuclear collision. In health physics applications, a heavy ion beam of initially well defined radiation quality is transformed into a complex mixture of diverse quality components after passing through a modest amount of material. This transformation of radiation quality must be understood to adequately explain the biological response of tissue to heavy ion radiation. A theoretical/experimental program to define an ion beam and its products in extended matter is described.
Retrospective and ongoing analyses of clinical records from 347 primary intraocular melanoman patients treated with helium ions at Lawrence Berkeley Laboratory (LBL) will allow examination of the exposure-response data for human cataract; which is a complication of the therapy from incidental exposure of the lens. Direct particle beam traversal of at least a portion of the lens usually is unavoidable in treatment of posterior intraocular tumors. The precise treatment planned for each patient permits quantitative assessment of the lenticular dose and its radiation quality. We are reporting our preliminary results on the development of helium-ion-induced lens opacifications and cataracts in 54 of these patients who had 10% or less of their lens in the treatment field. We believe these studies will be relevant to estimating the human risk for cataract in space flight.
FLUKA is a multipurpose Monte Carlo code which can transport a variety of particles over a wide energy range in complex geometries. The code is a joint project of INFN and CERN: part of its development is also supported by the University of Houston and NASA. FLUKA is successfully applied in several fields, including but not only, particle physics, cosmic ray physics, dosimetry, radioprotection, hadron therapy, space radiation, accelerator design and neutronics. The code is the standard tool used at CERN for dosimetry, radioprotection and beam-machine interaction studies. Here we give a glimpse into the code physics models with a particular emphasis to the hadronic and nuclear sector.
This report describes the development of two radiation monitors (RADMON's) for use in detecting total radiation dose and high-energy particles. These radiation detectors are chip-size devices fabricated in 1.2 micrometer CMOS and have flown in space on both experimental and commercial spacecraft. They have been used to characterize protons and electrons in the Earth's radiation belts, particles from the Sun, and protons used for medical therapy. Having proven useful in a variety of applications, the detector is now being readied for commercialization.
Hyperthermia is a well known cancer therapy and consists of heating a tumor region to the elevated temperatures in the range of 40-45 C for an extended period of time (2-8 hours). This leads to thermal inactivation of cell regulatory and growth processes with resulting widespread necrosis, carbonization and coagulation. Moreover, heat boosts the tumor response to other treatments such as radiation, chemotherapy or immunotherapy. Of particular importance is careful control of generated heat in the treated region and keeping it localized. Higher heating, to about 56 C can lead to tissue thermo-ablation. With accurate temperature control, hyperthermia has the advantage of having minimal side effects. Several heating techniques are utilized for this purpose, such as whole body hyperthermia, radio-frequency (RF) hyperthermia, ultrasound technique, inductive microwave antenna hyperthermia, inductive needles (thermoseeds), and magnetic fluid hyperthermia (MFH).MFH offers many advantages as targeting capability by applying magnets. However, this technology still suffers significant inefficiencies due to lack of thermal control. This paper will provide a review of the topic and outline the ongoing work in this area. The main emphasis is in devising ways to overcome the technical difficulty in hyperthermia breast therapy of achieving a uniform therapeutic temperature over the required region of the body and holding it steady for an extended period (2-3 hours). The basic shortcomings of the presently utilized heating methods stem from the non-uniform thermal properties of the tissue and the point heating characteristics of the techniques without any thermal control. Our approach is to develop a novel class of magnetic fluids, which have inherent thermoregulating properties. We have identified a few magnetic alloys which can serve as suitable nano to micron-size particle material. The objective is to synthesize, characterize and evaluate the efficacy of Thermo Regulating Magnetic Fluids (TRMF) for hyperthermia therapy. The development of a tissue model and testing the fluid dynamics of particle motion, settling, distribution in the tissue matrix and heat generation will be discussed.
Hyperthermia is a well known cancer therapy and consists of heating a tumor region to the elevated temperatures in the range of 40-45 C for an extended period of time (2-8 hours). This leads to thermal inactivation of cell regulatory and growth processes with resulting widespread necrosis, carbonization and coagulation. Moreover, heat boosts the tumor response to other treatments such as radiation, chemotherapy or immunotherapy. Of particular importance is careful control of generated heat in the treated region and keeping it localized. Higher heating, to about 56 C can lead to tissue thermo-ablation. With accurate temperature control, hyperthermia has the advantage of having minimal side effects. Several heating techniques are utilized for this purpose, such as whole body hyperthermia, radio-frequency (RF) hyperthermia, ultrasound technique, inductive microwave antenna hyperthermia, inductive needles (thermoseeds), and magnetic fluid hyperthermia (MFH).MFH offers many advantages as targeting capability by applying magnets. However, this technology still suffers significant inefficiencies due to lack of thermal control. This paper will provide a review of the topic and outline the ongoing work in this area. The main emphasis is in devising ways to overcome the technical difficulty in hyperthermia therapy of achieving a uniform therapeutic temperature over the required region of the body and holding it steady. The basic obstacle of the present heating methods are non-uniform thermal properties of the tissue. Our approach is to develop a novel class of magnetic fluids which have inherent thermoregulating properties. We have identified a few magnetic alloys which can serve as a suitable nano-particle material. The objective is to synthesize, characterize and evaluate the efficacy of TRMF for hyperthermia therapy.
Two conflicting phenomena, bystander effect and adaptive response, are important in determining the biological responses at low doses of radiation and have the potential to impact the shape of the dose-response relationship. Using the Columbia University charged-particle microbeam and the highly sensitive AL cell mutagenic assay, we show here that non-irradiated cells acquire mutagenesis through direct contact with cells whose nuclei have been traversed with a single alpha particle each. Pretreatment of cells with a low dose of X-rays four hours before alpha particle irradiation significantly decreased this bystander mutagenic response. Results from the present study address some of the fundamental issues regarding both the actual target and radiation dose effect and can contribute to our current understanding in radiation risk assessment. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.
This paper develops a deterministic model of frequency distributions for energy imparted (total energy deposition) in small volumes similar to DNA molecules from high-energy ions of interest for space radiation protection and cancer therapy. Frequency distributions for energy imparted are useful for considering radiation quality and for modeling biological damage produced by ionizing radiation. For high-energy ions, secondary electron (delta-ray) tracks originating from a primary ion track make dominant contributions to energy deposition events in small volumes. Our method uses the distribution of electrons produced about an ion's path and incorporates results from Monte Carlo simulation of electron tracks to predict frequency distributions for ions, including their dependence on radial distance. The contribution from primary ion events is treated using an impact parameter formalism of spatially restricted linear energy transfer (LET) and energy-transfer straggling. We validate our model by comparing it directly to results from Monte Carlo simulations for proton and alpha-particle tracks. We show for the first time frequency distributions of energy imparted in DNA structures by several high-energy ions such as cosmic-ray iron ions. Our comparison with results from Monte Carlo simulations at low energies indicates the accuracy of the method.
Painting of interphase chromosomes can be useful for biodosimetric purposes in particular cases such as radiation therapy, accidental exposure to very high radiation doses and exposure to densely ionizing radiation, for example during space missions. Biodosimetry of charged-particle radiation is analyzed in the present paper. Target cells were human peripheral blood lymphocytes irradiated in vitro with gamma rays, protons and iron ions. After exposure, lymphocytes were incubated for different times to allow repair of radiation-induced damage and then fused to mitotic hamster cells to promote premature condensation in the interphase chromosomes. Chromosome spreads were then hybridized with whole-chromosome DNA probes labeled with fluorescent stains. Dose-response curves for the induction of chromatin fragments shortly after exposure, as well as the kinetics of rejoining and misrejoining, were not markedly dependent on linear energy transfer. However, after exposure to heavy ions, more aberrations were scored in the interphase cells after incubation for repair than in metaphase samples harvested at the first postirradiation mitosis. On the other hand, no significant differences were observed in the two samples after exposure to sparsely ionizing radiation. These results suggest that interphase chromosome painting can be a useful tool for biodosimetry of particle radiation.
By virtue of the highly energetic particles released when they annihilate in matter, antiprotons have a variety of potentially important applications. Among others, these include remote 3-D density and composition imaging of the human body and also of thick, dense materials, cancer therapy, and spacecraft propulsion. Except for spacecraft propulsion, the required numbers of low energy antiprotons can be produced, stored, and transported through reliance on current or near term technology. Paramount to these applications and to fundamental research involving antiprotons is knowledge of how antiprotons interact with matter. The basic annihilation process is fairly well understood, but the antiproton annihilation and energy loss rates in matter depend in complex ways on a number of atomic processes. The rates, and the corresponding cross sections, were measured or are accurately predictable only for limited combinations of antiproton kinetic energy and material species.
A proposed radiation-detecting apparatus would provide information on the kinetic energies, directions, and electric charges of highly energetic incident subatomic particles. The apparatus was originally intended for use in measuring properties of cosmic rays in outer space, but could also be adapted to terrestrial uses -- for example, radiation dosimetry aboard high-altitude aircraft and in proton radiation therapy for treatment of tumors.
The Strategic Defense Initiative's (SDI) investment in particle accelerator technology for its directed energy weapons program has produced breakthroughs in the size and power of new accelerators. These accelerators, in turn, have produced spinoffs in several areas: the radio frequency quadrupole linear accelerator (RFQ linac) was recently incorporated into the design of a cancer therapy unit at the Loma Linda University Medical Center, an SDI-sponsored compact induction linear accelerator may replace Cobalt-60 radiation and hazardous ethylene-oxide as a method for sterilizing medical products, and other SDIO-funded accelerators may be used to produce the radioactive isotopes oxygen-15, nitrogen-13, carbon-11, and fluorine-18 for positron emission tomography (PET). Other applications of these accelerators include bomb detection, non-destructive inspection, decomposing toxic substances in contaminated ground water, and eliminating nuclear waste.
This software describes the transport and energy deposition of the passage of galactic cosmic rays in astronaut tissues during space travel, or heavy ion beams in patients in cancer therapy. Space radiation risk is a probability distribution, and time-dependent biological events must be accounted for physical description of space radiation transport in tissues and cells. A stochastic model can calculate the probability density directly without unverified assumptions about shape of probability density function. The prior art of transport codes calculates the average flux and dose of particles behind spacecraft and tissue shielding. Because of the signaling times for activation and relaxation in the cell and tissue, transport code must describe temporal and microspatial density of functions to correlate DNA and oxidative damage with non-targeted effects of signals, bystander, etc. These are absolutely ignored or impossible in the prior art. The GERM code provides scientists data interpretation of experiments; modeling of beam line, shielding of target samples, and sample holders; and estimation of basic physical and biological outputs of their experiments. For mono-energetic ion beams, basic physical and biological properties are calculated for a selected ion type, such as kinetic energy, mass, charge number, absorbed dose, or fluence. Evaluated quantities are linear energy transfer (LET), range (R), absorption and fragmentation cross-sections, and the probability of nuclear interactions after 1 or 5 cm of water equivalent material. In addition, a set of biophysical properties is evaluated, such as the Poisson distribution for a specified cellular area, cell survival curves, and DNA damage yields per cell. Also, the GERM code calculates the radiation transport of the beam line for either a fixed number of user-specified depths or at multiple positions along the Bragg curve of the particle in a selected material. The GERM code makes the numerical estimates of basic physical and biophysical quantities of high-energy protons and heavy ions that have been studied at the NASA Space Radiation Laboratory (NSRL) for the purpose of simulating space radiation biological effects. In the first option, properties of monoenergetic beams are treated. In the second option, the transport of beams in different materials is treated. Similar biophysical properties as in the first option are evaluated for the primary ion and its secondary particles. Additional properties related to the nuclear fragmentation of the beam are evaluated. The GERM code is a computationally efficient Monte-Carlo heavy-ion-beam model. It includes accurate models of LET, range, residual energy, and straggling, and the quantum multiple scattering fragmentation (QMSGRG) nuclear database.