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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.
Abstract Objective. Proton Radiography can be used in conjunction with proton therapy for patient positioning, real-time estimates of stopping power, and adaptive therapy in regions with motion. The modeling capability shown here can be used to evaluate lens-based radiography as an instantaneous proton-based radiographic technique. The utilization of user-friendly Monte Carlo program TOPAS enables collaborators and other users to easily conduct medical- and therapy- based simulations of the Los Alamos Neutron Science Center (LANSCE). The resulting transport model is an open-source Monte Carlo package for simulations of proton and heavy ion therapy treatments and concurrent particle imaging. Approach. The four-quadrupole, magnetic lens system of the 800-MeV proton beamline at LANSCE is modeled in TOPAS. Several imaging and contrast objects were modelled to assess transmission at energies from 230–930 MeV and different levels of particle collimation. At different proton energies, the strength of the magnetic field was scaled according to βγ, the inverse product of particle relativistic velocity and particle momentum. Main results. Materials with high atomic number, Z, (gold, gallium, bone-equivalent) generated more contrast than materials with low-Z (water, lung-equivalent, adipose-equivalent). A 5-mrad collimator was beneficial for tissue-to-contrast agent contrast, while a 10-mrad collimator was best to distinguish between different high-Z materials. Assessment with a step-wedge phantom showed water-equivalent path length did not scale directly according to predicted values but could be mapped more accurately with calibration. Poor image quality was observed at low energies (230 MeV), but improved as proton energy increased, with sub-mm resolution at 630 MeV. Significance. Proton radiography becomes viable for shallow bone structures at 330 MeV, and for deeper structures at 630 MeV. Visibility improves with use of high-Z contrast agents. This modality may be particularly viable at carbon therapy centers with accelerators capable of delivering high energy protons and could be performed with carbon therapy.
PIConGPU, Particle In Cell on GPUs, is an open source simulations framework for plasma and laser-plasma physics used to develop advanced particle accelerators for radiation therapy of cancer, high energy physics and photon science. While PIConGPU has been optimized for at least 5 years to run well on NVIDIA GPU-based clusters, there has been limited exploration by the development team of potential scalability bottlenecks using recently updated and new tools including NVIDIA’s NVProf tool and the brand-new NVIDIA NSight Suite (Systems and Compute) tools. PIConGPU is a highly optimized application that runs production jobs at scale on a system Oak Ridge Leadership Facility’s (OLCF) Summit supercomputer (using the full machine at 4600 nodes; at 98% of GPU utilization on all ~28000 NVIDIA Volta GPUs). PIConGPU has been selected as one of the the eight applications for OLCF’s coveted Center for Accelerated Application Readiness (CAAR) program aimed at the facility’s Frontier supercomputer (OLCF’s first exascale system to launch in 2021), to partner with our vendors (primary vendors: AMD and Cray/HPE) ensuring that Frontier will be able to perform large-scale science when it opens to users in 2022. To this effect, performance engineers on the PIConGPU team wanted to dive deep into the application to understand at the finest granularity, which portions of the code could be further optimized to exploit the hardware on Summit at it’s maximum potential and also to elucidate which key kernels should be tracked and optimized for the CAAR effort to port this code to Frontier. Any bottlenecks that are observed via performance profiling on Summit are likely to also impact scalability on the Frontier-dev system and the Frontier Early Access (EA) system. Additionally, the engineers wanted to take a closer look at the newest NVIDIA profiling tools which allows us to identify the most useful features on these tools and will provide an opportunity to compare it to new AMD and Cray’s performance analysis tool releases and provide feedback to our vendor partners on what features are most important and mission critical for CAAR efforts. The primary goal of this report is to focus on the evaluation of PIConGPU’s most time-intensive kernels using NVProf and NSight Suite. Three kernels, Current Deposition (also known as Compute Current), Particle Push (Move and Mark), and Shift Particles are known to be some of the most time-consuming kernels in PIConGPU. The Current xi Deposition kernel and Particle Push kernel both set up the particle attributes for running any physics simulation with PIConGPU, so it is crucial to improve the performance of these two kernels. In this report, we measure single GPU metrics for the three kernels, offer high level takeaways from the conducted analysis, and compare the profiling data from NSight Compute to that of NVProf. This analysis was performed using a grid size of 240 x 272 x 224, and 10 time steps with the Mid-November Figure of Merit (FOM) run setup. The Traveling Wave Electron Acceleration (TWEAC) science case used in this run is a representative science case for PIConGPU. This execution can also be used for baseline analysis on AMD MI50/ MI60 systems. As of the time of writing, the PIConGPU application has limited use for features of NSight Systems, so this report will mainly focus on insights garnered from NSight Compute. For this analysis, we run the “full” metric set available in NSight Compute version 2020.1.2 and use NSight Systems version 2020.3.1 to generate the application timeline.
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".
Acoustic holograms have promising applications in sound-field reconstruction, particle manipulation, ultrasonic haptics, and therapy. This study reports on the theoretical, numerical, and experimental investigation of multiplexed acoustic holograms at both audio and ultrasonic frequencies via a rationally designed transmission-type acoustic metamaterial. The proposed metahologram is composed of two Fabry–Pérot resonant channels per unit cell, which enables the simultaneous modulation of the transmitted amplitude and phase at two desired frequencies. In contrast to conventional acoustic metamaterial-based holograms, the design strategy proposed here provides a new degree of freedom (frequency) that can actively tailor holograms that are otherwise completely passive and significantly enhances the information encoded in acoustic metamaterials. To demonstrate the multiplexed acoustic metamaterial, the projection of two different high-quality metaholograms is first shown at 14 and 17 kHz, with the patterns of the letters N and S. Then, two-channel ultrasound focusing and annular beams generation for the incident ultrasonic frequencies of 35 and 42.5 kHz are demonstrated. Furthermore, these multiplexed acoustic metaholograms offer a technical advance to tackle the rising challenges in the fields of acoustic metamaterials, architectural acoustics, and medical ultrasound.
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.
The general concept of radiation therapy used in conventional cancer treatment is to increase the therapeutic index by creating a physical dose differential between tumors and normal tissues through precision dose targeting, image guidance, and radiation beams that deliver a radiation dose with high conformality, e.g., protons and ions. However, the treatment and cure are still limited by normal tissue radiation toxicity, with the corresponding side effects. A fundamentally different paradigm for increasing the therapeutic index of radiation therapy has emerged recently, supported by preclinical research, and based on the FLASH radiation effect. FLASH radiation therapy (FLASH-RT) is an ultra-high-dose-rate delivery of a therapeutic radiation dose within a fraction of a second. Experimental studies have shown that normal tissues seem to be universally spared at these high dose rates, whereas tumors are not. While dose delivery conditions to achieve a FLASH effect are not yet fully characterized, it is currently estimated that doses delivered in less than 200 ms produce normal-tissue-sparing effects, yet effectively kill tumor cells. Despite a great opportunity, there are many technical challenges for the accelerator community to create the required dose rates with novel compact accelerators to ensure the safe delivery of FLASH radiation beams.
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.
We report one of the main challenges in targeted alpha therapy is assuring delivery of the α-particle dose to the targeted cells. Thus, it is critical to identify ligands for α-emitting radiometals that will form complexes that are very stable, both in vitro and in vivo. In this investigation, thorium-227 (t 1/2 = 18.70 days) chelation of ligands containing hydroxypyridinonate (HOPO) or picolinic acid (pa) moieties and the stability of the resultant complexes were studied. Chelation reactions were followed by reversed-phased HPLC and gamma spectroscopy. Studies revealed that high 227 Th chelation yields could be obtained within 2.5 h or less with ligands containing four Me-3,2-HOPO moieties, 1 (83%) and 2 (65%), and also with ligands containing pa moieties, H 4 octapa 3 (65%) and H 4 py4pa 6 (87%). No reaction occurred with H 4 neunpa-p-Bn-NO 2 4, and the chelation reaction with another pa ligand H 4 pypa 5 gave inconsistent yields with a very broad radio-HPLC peak. The ligands spermine-(Me-3,2-HOPO) 4 1, H 4 octapa 3, and H 4 py4pa 6 had high stability (i.e., 87% of 227 Th still bound to the ligand) in phosphate-buffered saline at room temperature over a 6-day period. Preliminary studies with ligand 6 demonstrated efficient chelation of thorium-226 (t 1/2 = 30.57 min) when heated to 80°C for 5 min.
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.
Particle radiobiology has contributed new understanding of radiation safety and underlying mechanisms of action to radiation oncology for the treatment of cancer, and to planning of radiation protection for space travel. This manuscript will highlight the significance of precise physical and biologically effective dosimetry to this translational research for the benefit of human health. This review provides a brief snapshot of the evolving scientific basis for, and the complex current global status, and remaining challenges of hadron therapy for the treatment of cancer. The need for particle radiobiology for risk planning in return missions to the Moon, and exploratory deep-space missions to Mars and beyond are also discussed.
Low Gain Avalanche Diodes, also known as LGADs, are widely considered for fast-timing applications in high energy physics, nuclear physics, space science, medical imaging, and precision measurements of rare processes. Such devices are silicon-based and feature an intrinsic gain due to a p + -doped layer that allows the production of a controlled avalanche of carriers, with multiplication on the order of 10–100. This technology can provide time resolution on the order of 20–30 ps, and variants of this technology can provide precision tracking too. The characterization of LGAD performance has so far primarily been focused on the interaction of minimum ionizing particles for high energy and nuclear physics applications. This article expands the study of LGAD performance to highly-ionizing particles, such as 28-MeV protons, which are relevant for several future scientific applications, e.g. in biology and medical physics, among others. These studies were performed with a beam of 28-MeV protons from a tandem Van de Graaff accelerator at Brookhaven National Laboratory and beta particles from a ^90Sr source; these were used to characterize the response and the gain of an LGAD as a function of bias voltage and collected charge. Here, the experimental results are also compared to TCAD simulations.
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.
This article first gives the authors' perspectives on how the field of plasma-based acceleration (PBA) developed and how the current experiments, theory, and simulations are motivated by long term applications of PBA to a future linear collider and an x-ray free electron laser. Here, we then focus on some early applications that will likely emerge from PBA research such as electron beam radiotherapy, directional but incoherent x-ray beams for science and technology, near single cycle continuously tunable infrared pulses for spectroscopy, and non-perturbative quantum electrodynamics enabled by PBA electron beams. In our opinion, these near term applications could be developed within the next decade with a concerted effort by the community.
Targeted α therapy (TAT) of soft-tissue cancers using the α particle-emitting radionuclide 223 Ra holds great potential because of its favorable nuclear properties, adequate availability, and established clinical use for treating metastatic prostate cancer of the bone. Despite these advantages, the use of 223 Ra has been largely overshadowed by other α emitters due to its challenging chelation chemistry. A key criterion that needs to be met for a radionuclide to be used in TAT is its stable attachment to a targeting vector via a bifunctional chelator. The low charge density of Ra 2+ arising from its large ionic radius weakens its electrostatic binding interactions with chelators, leading to insufficient complex stability in vivo. In this study, we synthesized and evaluated macropa-XL as a novel chelator for 223 Ra. It bears a large 21-crown-7 macrocyclic core and two picolinate pendent groups, which we hypothesized would effectively saturate the large coordination sphere of the Ra 2+ ion. The structural chemistry of macropa-XL was first established with the nonradioactive Ba 2+ ion using X-ray diffraction and X-ray absorption spectroscopy, which revealed the formation of an 11-coordinate complex in a rare anti pendent-arm configuration. Subsequently, the stability constant of the [Ra(macropa-XL)] complex was determined via competitive cation exchange with 223 Ra and 224 Ra radiotracers and compared with that of macropa, the current state-of-the-art chelator for Ra 2+ . A moderate log K ML value of 8.12 was measured for [Ra(macropa-XL)], which is approximately 1.5 log K units lower than the stability constant of [Ra(macropa)]. This relative decrease in Ra 2+ complex stability for macropa-XL versus macropa was further probed using density functional theory calculations. Additionally, macropa-XL was radiolabeled with 223 Ra, and the kinetic stability of the resulting complex was evaluated in human serum. Furthermore, although macropa-XL could effectively bind 223 Ra under mild conditions, the complex appeared to be unstable to transchelation. Collectively, this study sheds additional light on the chelation chemistry of the exotic Ra 2+ ion and contributes to the small, but growing, number of chelator development efforts for 223 Ra-based TAT.