A Comparison of 2 Disease Burden Assessment Methods (3D Volume Versus the Number of Lesions) for Prognostication of Survival in Metastatic Melanoma: Implications for the Characterization of Oligometastatic Disease.

PURPOSE: Oligometastatic disease (OMD), generally defined by the presence of ≤5 metastatic lesions, represents an intermediate state between localized and widespread metastatic disease. This study aimed to question the conventional definition of OMD and assess the significance of the total volume and loci of metastases in characterizing OMD using an unselected metastatic melanoma cohort. METHODS AND MATERIALS: We identified 86 consecutive patients with metastatic melanoma who received pembrolizumab monotherapy from 2015 to 2020. We retrospectively contoured the gross tumor volumes of all metastatic lesions on baseline and follow-up imaging. The number, total volume, and loci information of metastases was collected. The primary endpoint was overall survival. A density histogram plot was used for tumor characteristic descriptions, and classification analysis using the decision tree and random forest methods was performed to determine the optimal combination of prognostic factors in the clinical setting. RESULTS: A total of 2728 gross tumor volumes were delineated. On baseline imaging, the median number and total volume of metastases was 7 (interquartile range, 3-17) and 28.4 cc (interquartile range, 8.4-88.78), respectively. The lymph node was the most common metastatic site (n = 46, 54%), followed by the lungs (n = 32, 37%), liver (n = 23, 27%), and bones (n = 21, 24%). Two-year overall survival rates of patients with 1 to 5, 6 to 10, 11 to 20, and >20 metastases were 58%, 47%, 31%, and 14%, respectively, and with ≤10, 11 to 30, 31 to 130, and >130 cc of metastatic volume were 64%, 43%, 33%, and 25%, respectively. K-adaptive partitioning revealed that the optimal cutoff was 20 and 37.9 cc. Decision tree and random forest analyses revealed that volume and loci (brain and liver metastases) were the most important factors (Harrell's C-index, 0.78). CONCLUSIONS: The OMD state could represent a continuous spectrum of disease burden instead of a binary phenomenon. We propose integrating the volumetric and spatial information of metastases into the characterization of OMD and the stratification tool of clinical trials in the metastatic setting, although external validation studies are needed.

Microdosimetric-Kinetic Model for Radio-enhancement of Gold Nanoparticles: Comparison with LEM.

Numerous studies have strongly supported the application of gold nanoparticles (GNPs) as radio-enhanced agents. In our previous study, the local effect model (LEM I) was adopted to predict the cell survival for MDA-MB-231 cells exposed to 150 kVp X rays after 500 µg/ml GNPs treatment. However, microdosimetric quantities could not be obtained, which were correlated with biological effects on cells. Thus, we developed microdosimetric kinetic model (MKM) for GNP radio-enhancement (GNP-MKM), which uses the microdosimetric quantities such as dose-mean lineal energy with subcellular domain size. Using the Monte Carlo simulation tool Geant4, we estimated the dose-mean lineal energy with secondary radiations from GNPs and absorbed dose in the nucleus. The variations in MKM parameters for different domain sizes, and GNP concentrations, were calculated to compare the survival fractions predicted by both models. With a domain radius of 500 nm and a threshold dose of 20 Gy, the sensitizer enhancement ratio predicted by GNP-MKM and GNP-LEM was 1.41 and 1.29, respectively. The GNP-MKM predictions were much more strongly dependent on the domain size than were the GNP-LEM on the threshold dose. These findings provide another method to predict survival fraction for the GNP radio-enhancement.

Measuring radioenhancement by gold nanofilms: Comparison with analytical calculations.

PURPOSE: To measure radioenhancement by gold nanoparticles (GNPs) using gold nanofilms (GNFs). METHODS: GNFs of 20-100 nm thicknesses were prepared. The GNF attached to radiochromic film (RCF) was irradiated using 50, 220 kVp, and 6 MV X-rays. The radiation doses to the active layer of RCF with and without GNF were measured using an optical flatbed scanner and Raman spectrometer to estimate the dose enhancement factor (DEF). For verification, analytical calculations of DEF within the thickness of active layer and the ranges of secondary electrons were carried out. RESULTS: The DEFs for GNFs of 20 to 100 nm thicknesses measured by an optical scanner ranged from 2.1 to 6.1 at 50 kVp and 1.6 to 4.9 at 220 kVp. Similarly, the DEFs measured by Raman spectroscopy ranged from 2.6 to 4.6 at 50 kVp and 2.2 to 4.8 at 220 kVp. The calculated DEFs ranged from 1.5 to 3.6 at 50 kVp and from 1.7 to 4.7 at 220 kVp. Almost no dose enhancement was observed in 6 MV X-ray. The analytical DEFs seemed to be underestimated by averaging local enhancement over the entire active layer. However, analytical DEFs within the ranges of secondary electrons was much higher than the measured macroscopic DEFs. CONCLUSIONS: The experimental and analytical approaches developed in this study could quantitatively estimate radioenhancement by GNPs. Due to a short range of low-energy electrons emitted from gold, the microscopic radioenhancement within the ranges of low-energy electrons would be particularly important in a cell.

The microdosimetric extension in TOPAS: development and comparison with published data.

Microdosimetric energy depositions have been suggested as a key variable for the modeling of the relative biological effectiveness (RBE) in proton and ion radiation therapy. However, microdosimetry has been underutilized in radiation therapy. Recent advances in detector technology allow the design of new mico- and nano-dosimeters. At the same time Monte Carlo (MC) simulations have become more widely used in radiation therapy. In order to address the growing interest in the field, a microdosimetric extension was developed in TOPAS. The extension provides users with the functionality to simulate microdosimetric spectra as well as the contribution of secondary particles to the spectra, calculate microdosimetric parameters, and determine RBE with a biological weighting function approach or with the microdosimetric kinetic (MK) model. Simulations were conducted with the extension and the results were compared with published experimental data and other simulation results for three types of microdosimeters, a spherical tissue equivalent proportional counter (TEPC), a cylindrical TEPC and a solid state microdosimeter. The corresponding microdosimetric spectra obtained with TOPAS from the plateau region to the distal tail of the Bragg curve generally show good agreement with the published data.

Computational Modeling and Clonogenic Assay for Radioenhancement of Gold Nanoparticles Using 3D Live Cell Images.

Radioenhancement of gold nanoparticles (GNPs) has shown great potential for increasing the therapeutic efficiency of radiotherapy. Here we report on a computational model of radiation response, which was developed to predict the survival curves of breast cancer cells incubated with GNPs. The amount of GNP uptake was estimated using inductively coupled plasma-mass spectroscopy, and the three-dimensional (3D) intracellular distribution of GNPs was obtained using optical diffraction tomography. The developed computational model utilized the 3D live cell imaging and recent Monte Carlo techniques to calculate microscopic dose distributions within the cell. Clonogenic assays with and without GNPs were performed to estimate the radioenhancement for 150 kVp X rays in terms of cell survival fractions. Measured cell survival fractions were comparable with the computational model.

Energy optimization in gold nanoparticle enhanced radiation therapy.

Gold nanoparticles (GNPs) have been demonstrated as radiation dose enhancing agents. Kilovoltage external photon beams have been shown to yield the largest enhancement due to the high interaction probability with gold. While orthovoltage irradiations are feasible and promising, they suffer from a reduced tissue penetrating power. This study quantifies the effect of varying photon beam energies on various beam arrangements, body, tumor, and cellular GNP uptake geometries. Cell survival was modeled based on our previously developed GNP-local effect model with radial doses calculated using the TOPAS-nBio Monte Carlo code. Cell survival curves calculated for tumor sites with GNPs were used to calculate the relative biological effectiveness (RBE)-weighted dose. In order to evaluate the plan quality, the ratio of the mean dose between the tumor and normal tissue for 50-250 kVp beams with GNPs was compared to the standard of care using 6 MV photon beams without GNPs for breast and brain tumors. For breast using a single photon beam, kV + GNP was found to yield up to 2.73 times higher mean RBE-weighted dose to the tumor than two tangential megavoltage beams while delivering the same dose to healthy tissue. For irradiation of brain tumors using multiple photon beams, the GNP dose enhancement was found to be effective for energies above 50 keV. A small tumor at shallow depths was found to be the most effective treatment conditions for GNP enhanced radiation therapy. GNP uptake distributions in the cell (with or without nuclear uptake) and the beam arrangement were found to be important factors in determining the optimal photon beam energy.

Pinhole X-ray fluorescence imaging of gadolinium and gold nanoparticles using polychromatic X-rays: a Monte Carlo study.

This work aims to develop a Monte Carlo (MC) model for pinhole K-shell X-ray fluorescence (XRF) imaging of metal nanoparticles using polychromatic X-rays. The MC model consisted of two-dimensional (2D) position-sensitive detectors and fan-beam X-rays used to stimulate the emission of XRF photons from gadolinium (Gd) or gold (Au) nanoparticles. Four cylindrical columns containing different concentrations of nanoparticles ranging from 0.01% to 0.09% by weight (wt%) were placed in a 5 cm diameter cylindrical water phantom. The images of the columns had detectable contrast-to-noise ratios (CNRs) of 5.7 and 4.3 for 0.01 wt% Gd and for 0.03 wt% Au, respectively. Higher concentrations of nanoparticles yielded higher CNR. For 1×1011 incident particles, the radiation dose to the phantom was 19.9 mGy for 110 kVp X-rays (Gd imaging) and 26.1 mGy for 140 kVp X-rays (Au imaging). The MC model of a pinhole XRF can acquire direct 2D slice images of the object without image reconstruction. The MC model demonstrated that the pinhole XRF imaging system could be a potential bioimaging modality for nanomedicine.

Monte Carlo simulation for scanning technique with scattering foil free electron beam: A proof of concept study.

This study investigated the potential of a newly proposed scattering foil free (SFF) electron beam scanning technique for the treatment of skin cancer on the irregular patient surfaces using Monte Carlo (MC) simulation. After benchmarking of the MC simulations, we removed the scattering foil to generate SFF electron beams. Cylindrical and spherical phantoms with 1 cm boluses were generated and the target volume was defined from the surface to 5 mm depth. The SFF scanning technique with 6 MeV electrons was simulated using those phantoms. For comparison, volumetric modulated arc therapy (VMAT) plans were also generated with two full arcs and 6 MV photon beams. When the scanning resolution resulted in a larger separation between beams than the field size, the plan qualities were worsened. In the cylindrical phantom with a radius of 10 cm, the conformity indices, homogeneity indices and body mean doses of the SFF plans (scanning resolution = 1°) vs. VMAT plans were 1.04 vs. 1.54, 1.10 vs. 1.12 and 5 Gy vs. 14 Gy, respectively. Those of the spherical phantom were 1.04 vs. 1.83, 1.08 vs. 1.09 and 7 Gy vs. 26 Gy, respectively. The proposed SFF plans showed superior dose distributions compared to the VMAT plans.

Evaluation of the microscopic dose enhancement for nanoparticle-enhanced Auger therapy.

The aim of this study is to investigate the dosimetric characteristics of nanoparticle-enhanced Auger therapy. Monte Carlo (MC) simulations were performed to assess electron energy spectra and dose enhancement distributions around a nanoparticle. In the simulations, two types of nanoparticle structures were considered: nanoshell and nanosphere, both of which were assumed to be made of one of five elements (Fe, Ag, Gd, Au, and Pt) in various sizes (2-100 nm). Auger-electron emitting radionuclides (I-125, In-111, and Tc-99m) were simulated within a nanoshell or on the surface of a nanosphere. For the most promising combination of Au and I-125, the maximum dose enhancement was up to 1.3 and 3.6 for the nanoshell and the nanosphere, respectively. The dose enhancement regions were restricted within 20-100 nm and 0-30 nm distances from the surface of Au nanoshell and nanosphere, respectively. The dose enhancement distributions varied with sizes of nanoparticles, nano-elements, and radionuclides and thus should be carefully taken into account for biological modeling. If the nanoparticles are accumulated in close proximity to the biological target, this new type of treatment can deliver an enhanced microscopic dose to the target (e.g. DNA). Therefore, we conclude that Auger therapy combined with nanoparticles could have the potential to provide a better therapeutic effect than conventional Auger therapy alone.

Dosimetric perturbations due to an implanted cardiac pacemaker in MammoSite(®) treatment.

PURPOSE: To investigate dose perturbations for pacemaker-implanted patients in partial breast irradiation using high dose rate (HDR) balloon brachytherapy. METHODS: Monte Carlo (MC) simulations were performed to calculate dose distributions involving a pacemaker in Ir-192 HDR balloon brachytherapy. Dose perturbations by varying balloon-to-pacemaker distances (BPD = 50 or 100 mm) and concentrations of iodine contrast medium (2.5%, 5.0%, 7.5%, and 10.0% by volume) in the balloon were investigated for separate parts of the pacemaker (i.e., battery and substrate). Relative measurements using an ion-chamber were also performed to confirm MC results. RESULTS: The MC and measured results in homogeneous media without a pacemaker agreed with published data within 2% from the balloon surface to 100 mm BPD. Further their dose distributions with a pacemaker were in a comparable agreement. The MC results showed that doses over the battery were increased by a factor of 3, compared to doses without a pacemaker. However, there was no significant dose perturbation in the middle of substrate but up to 70% dose increase in the substrate interface with the titanium capsule. The attenuation by iodine contrast medium lessened doses delivered to the pacemaker by up to 9%. CONCLUSIONS: Due to inhomogeneity of pacemaker and contrast medium as well as low-energy photons in Ir-192 HDR balloon brachytherapy, the actual dose received in a pacemaker is different from the homogeneous medium-based dose and the external beam-based dose. Therefore, the dose perturbations should be considered for pacemaker-implanted patients when evaluating a safe clinical distance between the balloon and pacemaker.