Radiobiology and Microdosimetry

@article{decunha_patient-specific_2021,

title = {Patient-specific microdosimetry: a proof of concept},

author = {Joseph M. DeCunha and Fernanda Villegas and Martin Vallières and Jose Torres and Sophie Camilleri-Broët and Shirin A. Enger},

doi = {10.1088/1361-6560/ac1d1e},

issn = {1361-6560},

year  = {2021},

date = {2021-08-01},

journal = {Physics in Medicine and Biology},

abstract = {Microscopic energy deposition distributions from ionizing radiation are used to predict the biological effects of an irradiation and vary depending on biological target size. Ionizing radiation is thought to kill cells or inhibit cell cycling mainly by damaging DNA in the cell nucleus. The size of cells and nuclei depends on tissue type, cell cycle, and malignancy, all of which vary between patients. The aim of this study was to develop methods to perform patient-specific microdosimetry, that being, determining microdosimetric quantities in volumes that correspond to the sizes of cells and nuclei observed in a patient's tissue. A histopathological sample extracted from a stage I lung adenocarcinoma patient was analyzed. A pouring simulation was used to generate a three-dimensional tissue model from cell and nucleus size information determined from the histopathological sample. Microdosimetric distributions including f(y) and d(y) were determined for Co-60,Ir-192,Yb-169 and I-125 in a patient-specific model containing a distribution of cell and nucleus sizes. Fixed radius models and a summation method (where f(y) from many fixed radii models are summed) were compared to the full patient-specific model to evaluate their suitability for fast determination of patient-specific microdosimetric parameters. Fixed radius models do not provide a close approximation of the full patient-specific model y ̅_f or y ̅_d for the lower energy sources investigated, Yb-169 and I-125. The higher energy sources investigated, Co-60 and Ir-192 are less sensitive to target size variation than Yb-169 and I-125. A summation method yields the most accurate approximation of the full model d(y) for all radioisotopes investigated. A summation method allows for the computation of patient-specific microdosimetric distributions with the computing power of a personal computer. With appropriate biological inputs the microdosimetric distributions computed using these methods can yield a patient-specific relative biological effectiveness as part of a multiscale treatment planning approach.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{decunha_development_2021,

title = {Development of patient-specific 3D models from histopathological samples for applications in radiation therapy},

author = {Joseph M. DeCunha and Christopher M. Poole and Martin Vallières and Jose Torres and Sophie Camilleri-Broët and Roni F. Rayes and Jonathan D. Spicer and Shirin A. Enger},

doi = {10.1016/j.ejmp.2020.12.009},

issn = {1724-191X},

year  = {2021},

date = {2021-01-01},

journal = {Physica medica: PM: an international journal devoted to the applications of physics to medicine and biology: official journal of the Italian Association of Biomedical Physics (AIFB)},

volume = {81},

pages = {162--169},

abstract = {The biological effects of ionizing radiation depend on the tissue, tumor type, radiation quality, and patient-specific factors. Inter-patient variation in cell/nucleus size may influence patient-specific dose response. However, this variability in dose response is not well investigated due to lack of available cell/nucleus size data. The aim of this study was to develop methods to derive cell/nucleus size distributions from digital images of 2D histopathological samples and use them to build digital 3D models for use in cellular dosimetry. Nineteen of sixty hematoxylin and eosin stained lung adenocarcinoma samples investigated passed exclusion criterion to be analyzed in the study. A difference of gaussians blob detection algorithm was used to identify nucleus centers and quantify cell spacing. Hematoxylin content was measured to determine nucleus radius. Pouring simulations were conducted to generate one-hundred 3D models containing volumes of equivalent cell spacing and nuclei radius to those in histopathological samples. The nuclei radius distributions of non-tumoral and cancerous regions appearing in the same slide were significantly different (p textless 0.01) in all samples analyzed. The median nuclear-cytoplasmic ratio was 0.36 for non-tumoral cells and 0.50 for cancerous cells. The average cellular and nucleus packing densities in the 3D models generated were 65.9% (SD: 1.5%) and 13.3% (SD: 0.3%) respectively. Software to determine cell spacing and nuclei radius from histopathological samples was developed. 3D digital tissue models containing volumes with equivalent cell spacing, nucleus radius, and packing density to cancerous tissues were generated.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{decunha_patient-specific_2021b,

title = {Patient-specific microdosimetry: a proof of concept},

author = {Joseph M. DeCunha and Fernanda Villegas and Martin Vallières and Jose Torres and Sophie Camilleri-Broët and Shirin A. Enger},

url = {http://iopscience.iop.org/article/10.1088/1361-6560/ac1d1e},

doi = {10.1088/1361-6560/ac1d1e},

issn = {0031-9155},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Physics in Medicine & Biology},

abstract = {Microscopic energy deposition distributions from ionizing radiation are used to predict the biological effects of an irradiation and vary depending on biological target size. Ionizing radiation is thought to kill cells or inhibit cell cycling mainly by damaging DNA in the cell nucleus. The size of cells and nuclei depends on tissue type, cell cycle, and malignancy, all of which vary between patients. The aim of this study was to develop methods to perform patient-specific microdosimetry, that being, determining microdosimetric quantities in volumes that correspond to the sizes of cells and nuclei observed in a patient’s tissue. A histopathological sample extracted from a stage I lung adenocarcinoma patient was analyzed. A pouring simulation was used to generate a three-dimensional tissue model from cell and nucleus size information determined from the histopathological sample. Microdosimetric distributions including f(y) and d(y) were determined for Co-60,Ir-192,Yb-169 and I-125 in a patient-specific model containing a distribution of cell and nucleus sizes. Fixed radius models and a summation method (where f(y) from many fixed radii models are summed) were compared to the full patient-specific model to evaluate their suitability for fast determination of patient-specific microdosimetric parameters. Fixed radius models do not provide a close approximation of the full patient-specific model y ̅_f or y ̅_d for the lower energy sources investigated, Yb-169 and I-125. The higher energy sources investigated, Co-60 and Ir-192 are less sensitive to target size variation than Yb-169 and I-125. A summation method yields the most accurate approximation of the full model d(y) for all radioisotopes investigated. A summation method allows for the computation of patient-specific microdosimetric distributions with the computing power of a personal computer. With appropriate biological inputs the microdosimetric distributions computed using these methods can yield a patient-specific relative biological effectiveness as part of a multiscale treatment planning approach.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{famulari_rapidbrachymctps_2018,

title = {RapidBrachyMCTPS: a Monte Carlo-based treatment planning system for brachytherapy applications},

author = {Gabriel Famulari and Marc-André Renaud and Christopher M. Poole and Michael D. C. Evans and Jan Seuntjens and Shirin A. Enger},

doi = {10.1088/1361-6560/aad97a},

issn = {1361-6560},

year  = {2018},

date = {2018-08-01},

journal = {Physics in Medicine and Biology},

volume = {63},

number = {17},

pages = {175007},

abstract = {Despite being considered the gold standard for brachytherapy dosimetry, Monte Carlo (MC) has yet to be implemented into a software for brachytherapy treatment planning. The purpose of this work is to present RapidBrachyMCTPS, a novel treatment planning system (TPS) for brachytherapy applications equipped with a graphical user interface (GUI), optimization tools and a Geant4-based MC dose calculation engine, RapidBrachyMC. Brachytherapy sources and applicators were implemented in RapidBrachyMC and made available to the user via a source and applicator library in the GUI. To benchmark RapidBrachyMC, TG-43 parameters were calculated for the microSelectron v2 (192Ir) and SelectSeed (125I) source models and were compared against previously validated MC brachytherapy codes. The performance of RapidBrachyMC was evaluated for a prostate high dose rate case. To assess the accuracy of RapidBrachyMC in a heterogeneous setup, dose distributions with a cylindrical shielded/unshielded applicator were validated against film measurements in a Solid WaterTM phantom. TG-43 parameters calculated using RapidBrachyMC generally agreed within 1%-2% of the results obtained in previously published work. For the prostate case, clinical dosimetric indices showed general agreement with Oncentra TPS within 1%. Simulation times were on the order of minutes on a single core to achieve uncertainties below 2% in voxels within the prostate. The calculation time was decreased further using the multithreading features of Geant4. In the comparison between MC-calculated and film-measured dose distributions, at least 95% of points passed the 3%/3 mm gamma index criteria in all but one case. RapidBrachyMCTPS can be used as a post-implant dosimetry toolkit, as well as for MC-based brachytherapy treatment planning. This software is especially well suited for the development of new source and applicator models.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{decunha_new_2018,

title = {A new delivery system to resolve dosimetric issues in intravascular brachytherapy},

author = {Joseph M. DeCunha and Shirin A. Enger},

doi = {10.1016/j.brachy.2018.01.012},

issn = {1873-1449},

year  = {2018},

date = {2018-06-01},

journal = {Brachytherapy},

volume = {17},

number = {3},

pages = {634--643},

abstract = {PURPOSE: Renewed interest is being expressed in intravascular brachytherapy (IVBT). A number of unresolved issues exist in the discipline. Providing a homogeneous and adequate dose to the target remains difficult in IVBT. The guidewire that delivers the device to the target, arterial plaques, and stent struts are all known to reduce the dose delivered to target. The viability and efficacy of a proposed IVBT delivery system designed to resolve the issue of guidewire attenuation is evaluated and compared to that of a popular and commercially available IVBT device. 

METHODS AND MATERIALS: Monte Carlo simulations are conducted to determine distributions of absorbed dose around an existing and proposed IVBT delivery system. 

RESULTS: For the Novoste Beta-Cath 3.5F (TeamBest®), dose in water varies by 10% as a function of angle in the plane perpendicular to the delivery catheter due to off-centering of seeds in the catheter. Dose is reduced by 52% behind a stainless steel guidewire and 64% behind a guidewire, arterial plaque, and stent strut for the Novoste Beta-Cath 3.5F. Dose is not perturbed by the presence of a guidewire for the proposed device and is reduced by 46% by an arterial plaque and stent strut. 

CONCLUSIONS: Dose attenuation by guidewire is likely the single greatest source of dose attenuation in IVBT in terms of absolute dose reduction and is greater than previously reported for the Novoste Beta-Cath 3.5F. The Novoste Beta-Cath 3.5F delivers an inhomogeneous dose to target. A delivery system is proposed, which resolves the issue of guidewire attenuation in IVBT and should reduce treatment times.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{famulari_microdosimetric_2018,

title = {Microdosimetric Evaluation of Current and Alternative Brachytherapy Sources-A Geant4-DNA Simulation Study},

author = {Gabriel Famulari and Piotr Pater and Shirin A. Enger},

doi = {10.1016/j.ijrobp.2017.09.040},

issn = {1879-355X},

year  = {2018},

date = {2018-01-01},

journal = {International Journal of Radiation Oncology, Biology, Physics},

volume = {100},

number = {1},

pages = {270--277},

abstract = {PURPOSE: Radioisotopes such as 75Se, 169Yb, and 153Gd have photon energy spectra and half-lives that make them excellent candidates as alternatives to 192Ir for high-dose-rate brachytherapy. The aim of the present study was to evaluate the relative biological effectiveness (RBE) of current (192Ir, 125I, 103Pd) and alternative (75Se, 169Yb, 153Gd) brachytherapy radionuclides using Monte Carlo simulations of lineal energy distributions. 

METHODS AND MATERIALS: Brachytherapy sources (microSelectron v2 [192Ir, 75Se, 169Yb, 153Gd], SelectSeed [125I], and TheraSeed [103Pd]) were placed in the center of a spherical water phantom with a radius of 40 cm using the Geant4 Monte Carlo simulation toolkit. The kinetic energy of all primary, scattered, and fluorescence photons interacting in a scoring volume were tallied at various depths from the source. Electron tracks were generated by sampling the photon interaction spectrum and tracking all the interactions down to 10 eV using the event-by-event capabilities of the Geant4-DNA models. The dose mean lineal energy (y¯D) values were obtained through random sampling of transfer points and overlaying spherical scoring volumes within the associated volume of the tracks. The scoring volume diameter was determined by fitting the y¯D ratio for 125I to its observed RBE. 

RESULTS: y¯D increased with the increasing distance from the source for 192Ir, 75Se, and 169Yb, remained constant for 153Gd and 125I, and decreased for 103Pd. The diameter at which the y¯D ratio coincided with the RBE of 1.15 to 1.20 for 125I was ∼25 to 40 nm. The RBE (reference 1 MeV photons) at high doses and dose rates for 192Ir, 75Se, 169Yb, 153Gd, 125I, and 103Pd was 1.028 to 1.034, 1.05 to 1.07, 1.12 to 1.15, 1.16 to 1.21, 1.15 to 1.20, and 1.17 to 1.22, respectively. 

CONCLUSIONS: The radiation quality of the radionuclides under investigation was greater than that of high-energy photons. The present study has provided a set of values to modify the prescription doses for brachytherapy to account for the variation in radiation quality among radionuclides.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{famulari_microdosimetry_2017,

title = {Microdosimetry calculations for monoenergetic electrons using Geant4-DNA combined with a weighted track sampling algorithm},

author = {Gabriel Famulari and Piotr Pater and Shirin A. Enger},

doi = {10.1088/1361-6560/aa71f6},

issn = {1361-6560},

year  = {2017},

date = {2017-07-01},

journal = {Physics in Medicine and Biology},

volume = {62},

number = {13},

pages = {5495--5508},

abstract = {The aim of this study was to calculate microdosimetric distributions for low energy electrons simulated using the Monte Carlo track structure code Geant4-DNA. Tracks for monoenergetic electrons with kinetic energies ranging from 100 eV to 1 MeV were simulated in an infinite spherical water phantom using the Geant4-DNA extension included in Geant4 toolkit version 10.2 (patch 02). The microdosimetric distributions were obtained through random sampling of transfer points and overlaying scoring volumes within the associated volume of the tracks. Relative frequency distributions of energy deposition f(textgreaterE)/f(textgreater0) and dose mean lineal energy ([Formula: see text]) values were calculated in nanometer-sized spherical and cylindrical targets. The effects of scoring volume and scoring techniques were examined. The results were compared with published data generated using MOCA8B and KURBUC. Geant4-DNA produces a lower frequency of higher energy deposits than MOCA8B. The [Formula: see text] values calculated with Geant4-DNA are smaller than those calculated using MOCA8B and KURBUC. The differences are mainly due to the lower ionization and excitation cross sections of Geant4-DNA for low energy electrons. To a lesser extent, discrepancies can also be attributed to the implementation in this study of a new and fast scoring technique that differs from that used in previous studies. For the same mean chord length ([Formula: see text]), the [Formula: see text] calculated in cylindrical volumes are larger than those calculated in spherical volumes. The discrepancies due to cross sections and scoring geometries increase with decreasing scoring site dimensions. A new set of [Formula: see text] values has been presented for monoenergetic electrons using a fast track sampling algorithm and the most recent physics models implemented in Geant4-DNA. This dataset can be combined with primary electron spectra to predict the radiation quality of photon and electron beams.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{decunha_investigation_2017,

title = {Investigation of a New Device to Improve Dosimetric Outcomes in Intravascular Brachytherapy},

author = {Joseph M. DeCunha and Shirin A. Enger},

url = {https://www.brachyjournal.com/article/S1538-4721(17)30207-6/abstract},

doi = {10.1016/j.brachy.2017.04.146},

issn = {1538-4721, 1873-1449},

year  = {2017},

date = {2017-05-01},

urldate = {2017-05-01},

journal = {Brachytherapy},

volume = {16},

number = {3},

pages = {S80},

abstract = {Coronary artery disease is amongst the main causes of death in developed countries. 

Percutaneous Transluminal Coronary Angioplasty (PTCA or angioplasty) is a procedure 

used to open stenoted (narrowed) arteries. Restenosis (renarrowing) of the treated 

vessel is a major complication of PTCA. A metal mesh tube (stent) is expanded inside 

the vessel to prevent restenosis. Tissue stress incurred during angioplasty and stenting 

can provoke rapid proliferation of neointimal cells leading to in stent restenosis 

(ISR).},

note = {Publisher: Elsevier},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{decunha_retrospective_2017,

title = {A retrospective analysis of catheter-based sources in intravascular brachytherapy},

author = {Joseph M. DeCunha and Christian Janicki and Shirin A. Enger},

url = {https://www.sciencedirect.com/science/article/pii/S1538472117300077},

doi = {10.1016/j.brachy.2017.01.004},

issn = {1538-4721},

year  = {2017},

date = {2017-05-01},

urldate = {2017-05-01},

journal = {Brachytherapy},

volume = {16},

number = {3},

pages = {586--596},

abstract = {Purpose 

Coronary artery disease involves the deposition of plaque along the walls of a coronary artery leading to narrowed or blocked vessels (stenosis) and is one of the main causes of death in developed countries. Percutaneous transluminal coronary angioplasty (PTCA) is used to reverse stenosis. Restenosis (renarrowing) of the treated vessel is a major complication of PTCA. A metal mesh tube (stent) can be placed inside the vessel to prevent restenosis. Tissue stress incurred during PTCA and stenting can provoke neointimal cell proliferation leading to in-stent restenosis (ISR). Intravascular brachytherapy (IVBT), a form of internal radiotherapy, is used to treat ISR. Renewed interest in IVBT is being expressed as a treatment for patients with ISR in drug-eluting stents. Current treatment planning (TP) of IVBT is extremely limited and assumes human tissue can be approximated by water. The interactions of arterial plaque, guidewires, and the stent have been shown to attenuate radiation significantly but are ignored in TP. Other models have determined the degree of attenuation by each factor in isolation. For the first time, we create a model with several inhomogenities present to determine whether attenuation by multiple inhomogenities combines linearly or if a larger dose reduction than anticipated is realized. We are also able to evaluate a spatial distribution of dose around the source and in arterial walls. 

Methods and Materials 

A dosimetric analysis of two commercially available IVBT systems was performed in a Monte Carlo–based particle simulation (Geant4). Absorbed dose was calculated using a model of a human coronary artery with a calcified plaque and stent. Dose delivered in water was also calculated to evaluate the accuracy of a water approximation. 

Results 

Dose as a function of θ shows significant variation around IVBT sources. For the Guidant Galileo, dose is reduced by 20% behind stent struts and as much as 66% in a region occluded by the guidewire, plaque, and stent. For the Novoste Beta Cath device, delivered dose is reduced by 19% and 58%, respectively, in the same regions. 

Conclusions 

Our findings show that the water approximation used in clinical practice to calculate dose is inaccurate when inhomogeneities are present. Methods proposed for calculating dose perturbations in IVBT may underestimate the magnitude of dose reduction. Increasing source dwell time seems unlikely to resolve dosimetric issues in IVBT. The effectiveness of currently existing β-emitting devices may be reduced in patients with complex lesions at the treatment site. Investigation of new radioisotopes and off-centering devices should be considered to improve dose outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pater_proton_2016b,

title = {Proton and light ion RBE for the induction of direct DNA double strand breaks},

author = {Piotr Pater and Gloria Bäckstöm and Fernanda Villegas and Anders Ahnesjö and Shirin A. Enger and Jan Seuntjens and Issam El Naqa},

url = {https://aapm.onlinelibrary.wiley.com/doi/abs/10.1118/1.4944870},

doi = {10.1118/1.4944870},

issn = {2473-4209},

year  = {2016},

date = {2016-01-01},

urldate = {2021-09-07},

journal = {Medical Physics},

volume = {43},

number = {5},

pages = {2131--2140},

abstract = {Purpose: To present and characterize a Monte Carlo (MC) tool for the simulation of the relative biological effectiveness for the induction of direct DNA double strand breaks () for protons and light ions. Methods: The MC tool uses a pregenerated event-by-event tracks library of protons and light ions that are overlaid on a cell nucleus model. The cell nucleus model is a cylindrical arrangement of nucleosome structures consisting of 198 DNA base pairs. An algorithm relying on k-dimensional trees and cylindrical symmetries is used to search coincidences of energy deposition sites with volumes corresponding to the sugar–phosphate backbone of the DNA molecule. Strand breaks (SBs) are scored when energy higher than a threshold is reached in these volumes. Based on the number of affected strands, they are categorized into either single strand break (SSB) or double strand break (DSB) lesions. The number of SBs composing each lesion (i.e., its size) is also recorded. is obtained by taking the ratio of DSB yields of a given radiation field to a 60Co field. The MC tool was used to obtain SSB yields, DSB yields, and as a function of linear energy transfer (LET) for protons (1H+), 4He2+, 7Li3+, and 12C6+ ions. Results: For protons, the SSB yields decreased and the DSB yields increased with LET. At ≈24.5 keV μm−1, protons generated 15% more DSBs than 12C6+ ions. The varied between 1.24 and 1.77 for proton fields between 8.5 and 30.2 keV μm−1, and it was higher for iso-LET ions with lowest atomic number. The SSB and DSB lesion sizes showed significant differences for all radiation fields. Generally, the yields of SSB lesions of sizes ≥2 and the yields of DSB lesions of sizes ≥3 increased with LET and increased for iso-LET ions of lower atomic number. On the other hand, the ratios of SSB to DSB lesions of sizes 2–4 did not show variability with LET nor projectile atomic number, suggesting that these metrics are independent of the radiation quality. Finally, a variance of up to 8% in the DSB yields was observed as a function of the particle incidence angle on the cell nucleus. This simulation effect is due to the preferential alignment of ion tracks with the DNA nucleosomes at specific angles. Conclusions: The MC tool can predict SSB and DSB yields for light ions of various LET and estimate . In addition, it can calculate the frequencies of different DNA lesion sizes, which is of interest in the context of biologically relevant absolute dosimetry of particle beams.},

note = {_eprint: https://aapm.onlinelibrary.wiley.com/doi/pdf/10.1118/1.4944870},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{poole_determination_2015,

title = {Determination of subcellular compartment sizes for estimating dose variations in radiotherapy},

author = {Christopher M. Poole and Anders Ahnesjö and Shirin A. Enger},

doi = {10.1093/rpd/ncv305},

issn = {1742-3406},

year  = {2015},

date = {2015-09-01},

journal = {Radiation Protection Dosimetry},

volume = {166},

number = {1-4},

pages = {361--364},

abstract = {The variation in specific energy absorbed to different cell compartments caused by variations in size and chemical composition is poorly investigated in radiotherapy. The aim of this study was to develop an algorithm to derive cell and cell nuclei size distributions from 2D histology samples, and build 3D cellular geometries to provide Monte Carlo (MC)-based dose calculation engines with a morphologically relevant input geometry. Stained and unstained regions of the histology samples are segmented using a Gaussian mixture model, and individual cell nuclei are identified via thresholding. Delaunay triangulation is applied to determine the distribution of distances between the centroids of nearest neighbour cells. A pouring simulation is used to build a 3D virtual tissue sample, with cell radii randomised according to the cell size distribution determined from the histology samples. A slice with the same thickness as the histology sample is cut through the 3D data and characterised in the same way as the measured histology. The comparison between this virtual slice and the measured histology is used to adjust the initial cell size distribution into the pouring simulation. This iterative approach of a pouring simulation with adjustments guided by comparison is continued until an input cell size distribution is found that yields a distribution in the sliced geometry that agrees with the measured histology samples. The thus obtained morphologically realistic 3D cellular geometry can be used as input to MC-based dose calculation programs for studies of dose response due to variations in morphology and size of tumour/healthy tissue cells/nuclei, and extracellular material.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}