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Dimensionality dependence of the Rayleigh-Taylor and Richtmyer-Meshkov instability late-time scaling laws

The late-time nonlinear evolution of the three-dimensional (3D) Rayleigh–Taylor (RT) and Richtmyer–Meshkov (RM) instabilities for random initial perturbations is investigated. Using full 3D numerical simulations, a statistical mechanics bubble-competition model, and a Layzer-type drag-buoyancy model, it is shown that the RT scaling parameters, αB and αS, are similar in two and three dimensions, but the RM exponents, θB and θS are lower by a factor of 2 in three dimensions. The similarity parameter hB/〈λ〉 is higher by a factor of 3 in the 3D case compared to the 2D case, in very good agreement with recent Linear Electric Motor (LEM) experiments. A simple drag-buoyancy model, similar to that proposed by Youngs [see J. C. V. Hanson et al., Laser Part. Beams 8, 51 (1990)], but using the coefficients from the A=1 Layzer model, rather than phenomenological ones, is introduced.

Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters

A new method utilizing alpha particles to treat solid tumors is presented. Tumors are treated with interstitial radioactive sources which continually release short-lived alpha emitting atoms from their surface. The atoms disperse inside the tumor, delivering a high dose through their alpha decays. We implement this scheme using thin wire sources impregnated with (224)Ra, which release by recoil (220)Rn, (216)Po and (212)Pb atoms. This work aims to demonstrate the feasibility of our method by measuring the activity patterns of the released radionuclides in experimental tumors. Sources carrying (224)Ra activities in the range 10-130 kBq were used in experiments on murine squamous cell carcinoma tumors. These included gamma spectroscopy of the dissected tumors and major organs, Fuji-plate autoradiography of histological tumor sections and tissue damage detection by Hematoxylin-Eosin staining. The measurements focused on (212)Pb and (212)Bi. The (220)Rn/(216)Po distribution was treated theoretically using a simple diffusion model. A simplified scheme was used to convert measured (212)Pb activities to absorbed dose estimates. Both physical and histological measurements confirmed the formation of a 5-7 mm diameter necrotic region receiving a therapeutic alpha-particle dose around the source. The necrotic regions shape closely corresponded to the measured activity patterns. (212)Pb was found to leave the tumor through the blood at a rate which decreased with tumor mass. Our results suggest that the proposed method, termed DART (diffusing alpha-emitters radiation therapy), may potentially be useful for the treatment of human patients.

Growth retardation and destruction of experimental squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms.

In the present study, we examined the antitumoral effects caused by the release of alpha emitting radioisotopes into solid squamous cell carcinoma (SCC) tumors. Using a novel method termed DART (Diffusing Alpha‐emitters Radiation Therapy), we assessed the efficacy of short‐lived daughters of 224Ra releasing alpha particles, dispersing in the malignant tissue, to cause tumor growth retardation and destruction. It was carried out using specially designed wires loaded with 224Ra activities in the range of 7–42 kBq in a set of experiments performed on BALB/c and nude mice bearing metastatic SCC tumors derived from either mouse SQ2 or human CAL27 cell lines. The insertion of a DART wire to the center of 6–7 mm primary tumors, retarded tumor growth, reduced lung metastatic load, prolonged life expectancy and in some cases caused tumor eradication. These effects were enhanced either when treating smaller tumors or treating identical tumors with 2 DART wires. Similar experiments on human‐derived SCC tumors in nude mice were consistent with the outcomes of the murine model. Histological assessments revealed the tissue damage pattern, and indicated a role for the tumor vasculature in the dispersion of the atoms and the propagation of the damage. Our findings indicate that Diffusing Alpha‐emitting Radiation Therapy is effective in a model system using SCC primary tumors. The in situ destruction of primary solid tumors by DART is evidently a necessary step toward curing cancer and might be augmented by chemotherapy and other modalities such as immunotherapy or antigrowth factors agents.

A general buoyancy-drag model for the evolution of the Rayleigh-Taylor and Richtmyer-Meshkov instabilities

The growth of a single-mode perturbation is described by a buoyancy-drag equation, which describes all instability stages (linear, nonlinear and asymptotic) at time-dependent Atwood number and acceleration profile. The evolution of a multimode spectrum of perturbations from a short wavelength random noise is described using a single characteristic wavelength. The temporal evolution of this wavelength allows the description of both the linear stage and the late time self-similar behavior. Model results are compared to full two-dimensional numerical simulations and shock-tube experiments of random perturbations, studying the various stages of the evolution. Extensions to the model for more complicated flows are suggested.

Local Control of Lung Derived Tumors by Diffusing Alpha-Emitting Atoms Released From Intratumoral Wires Loaded With Radium-224

PURPOSE Diffusing alpha-emitters radiation therapy (DART) is a new form of brachytherapy enabling the treatment of solid tumors with alpha radiation. The present study examines the antitumoral effects resulting from the release of alpha emitting radioisotopes into solid lung carcinoma (LL2, A427, and NCI-H520). METHODS AND MATERIALS An in vitro setup tested the dose-dependent killing of tumor cells exposed to alpha particles. In in vivo studies, radioactive wires (0.3 mm diameter, 5 mm long) with (224)Ra activities in the range of 21-38 kBq were inserted into LL/2 tumors in C57BL/6 mice and into human-derived A427 or NCI-H520 tumors in athymic mice. The efficacy of the short-lived daughters of (224)Ra to produce tumor growth retardation and prolong life was assessed, and the spread of radioisotopes inside tumors was measured using autoradiography. RESULTS The insertion of a single DART wire into the center of 6- to 7-mm tumors had a pronounced retardation effect on tumor growth, leading to a significant inhibition of 49% (LL2) and 93% (A427) in tumor development and prolongations of 48% (LL2) in life expectancy. In the human model, more than 80% of the treated tumors disappeared or shrunk. Autoradiographic analysis of the treated sectioned tissue revealed the intratumoral distribution of the radioisotopes, and histological analysis showed corresponding areas of necrosis. In vitro experiments demonstrated a dose-dependent killing of tumors cells exposed to alpha particles. CONCLUSIONS Short-lived diffusing alpha-emitters produced tumor growth retardation and increased survival in mice bearing lung tumor implants. These results justify further investigations with improved dose distributions.

Local control of experimental malignant pancreatic tumors by treatment with a combination of chemotherapy and intratumoral 224Radium-loaded wires releasing alpha-emitting atoms

We developed (224)Ra-loaded wires that when inserted into solid tumors, release radioactive atoms that spread in the tumor and irradiate it effectively with alpha particles (diffusing alpha-emitters radiation therapy [DaRT]). In this study, we tested the ability of intratumoral (224)Ra-loaded wires to control the local growth of pancreatic tumors and the enhancement of this effect by chemotherapy. Pancreatic mouse tumors (Panc02) were treated with (224)Ra-loaded wire(s) with or without gemcitabine. The tumor size and survival were monitored, and autoradiography was performed to evaluate the spread of radioactive atoms inside the tumor. Mouse and human pancreatic cancer cells, irradiated in vitro by alpha particles with or without chemotherapy, were evaluated for cell growth inhibition. The insertion of (224)Ra-loaded wires into pancreatic tumors in combination with gemcitabine achieved significant local control and was superior to each treatment alone. A dosimetric analysis showed the spread of radioactive atoms in the tumor around the wires. Alpha particles combined with gemcitabine or 5-FU killed mouse and human cells in vitro better than each treatment alone. DaRT in combination with gemcitabine was proven effective against pancreatic tumors in vivo and in vitro, and the process may be applicable as a palliative treatment for patients with pancreatic cancer.

Interstitial wires releasing diffusing alpha emitters combined with chemotherapy improved local tumor control and survival in squamous cell carcinoma-bearing mice.

The objective of this study was to examine the combined effect of diffusing alpha‐emitter radiation therapy (DART) together with the chemotherapeutic agent cisplatin on tumor development.

Scaling laws of nonlinear Rayleigh-Taylor and Richtmyer-Meshkov instabilities in two and three dimensions

Abstract The late-time nonlinear evolution of the Rayleigh-Taylor (RT) and Richtmyer-Meshkov (RM) instabilities for random initial perturbations is investigated using a statistical mechanics model based on single-mode and bubble-competition physics at all Atwood numbers ( A ) and full numerical simulations in two and three dimensions. It is shown that the RT mixing zone bubble and spike fronts evolve as h ∼ α · A · gt 2 with different values of α for the bubble and spike fronts. The RM mixing zone fronts evolve as h ∼ t θ with different values of θ for bubbles and spikes. Similar analysis yields a linear growth with time of the Kelvin–Helmholtz mixing zone. The dependence of the RT and RM scaling parameters on A and the dimensionality will be discussed. The 3D predictions are found to be in good agreement with recent Linear Electric Motor (LEM) experiments.

Comparative In Vitro Microdosimetric Study of Murine- and Human-Derived Cancer Cells Exposed to Alpha Particles

Diffusing alpha-emitter radiation therapy (DaRT) is a proposed new form of brachytherapy using α particles to treat solid tumors. The method relies on implantable 224Ra-loaded sources that continually release short-lived α-particle-emitting atoms that spread inside the tumor over a few millimeters. This treatment was demonstrated to have a significant effect on tumor growth in murine and human-derived models, but the degree of tumor response varied across cell lines. Tumor response was found to correlate with the degree of radionuclide spread inside the tumor. In this work we examined the radiosensitivity of individual cells to determine its relationship to tumor response. Cells were irradiated in vitro by α particles using a 228Th irradiator, with the mean lethal dose, D0, estimated from survival curves generated by standard methods. The results were further analyzed by microdosimetric tools to calculate z0, the specific energy resulting in a survival probability of 1/e for a single cell, which is considered to better represent the intrinsic radiosensitivity of individual cells. The results of the study demonstrate that, as a rule, tumors that respond more favorably to the DaRT treatment are also characterized by higher intrinsic cellular radiosensitivities, with D0 ranging from 0.7 Gy to 1.5 Gy for the extreme cases and z0 following the same trend.

The treatment of solid tumors by alpha emitters released from 224Ra-loaded sources—internal dosimetry analysis

Diffusing alpha-emitters radiation therapy (DART) is a proposed new form of brachytherapy, allowing the treatment of solid tumors by alpha particles. DART utilizes implantable sources carrying small activities of radium-224, which continually release into the tumor radon-220, polonium-216 and lead-212 atoms, while radium-224 itself remains fixed to the source. The released atoms disperse inside the tumor by diffusive and convective processes, creating, through their alpha emissions, a high-dose region measuring several mm in diameter about each source. The efficacy of DART has been demonstrated in preclinical studies on mice-borne squamous cell carcinoma and lung tumors and the method is now being developed toward clinical trials. This work studies DART safety with respect to the dose delivered to distant organs as a result of lead-212 leakage from the tumor through the blood, relying on a biokinetic calculation coupled to internal dose assessments. It is found that the dose-limiting organs are the kidneys and red bone marrow. Assuming a typical source spacing of approximately 5 mm and a typical radium-224 activity density of 0.4-0.8 MBq g(-1) of tumor tissue, it is predicted that tumors weighing up to several hundred grams may be treated without reaching the tolerance dose in any organ.