Modeling the effect of daughter migration on dosimetry estimates for unlabeled actinium-225.

BACKGROUND: Actinium-225 (225 Ac) is an alpha emitting radionuclide which has demonstrated promising results in Targeted Alpha Therapy (TAT). A concern with 225 Ac is that the decay energy can break the bond to the targeting vehicle, resulting in the release of free alpha-emitting daughter radionuclides in the body. PURPOSE: The aim of this work is to develop a compartment model to describe the movement of unlabeled 225 Ac in a human where the daughter isotopes of 225 Ac have unique biokinetics. METHOD: The ICRP Occupational Intake of Radionuclides reports were used to construct a compartment model for the 225 Ac decay chain where the daughter isotopes of 225 Ac are assigned their own unique transfer coefficients (TCs) between compartments. Computer simulations were performed for unlabeled 225 Ac uniformly placed in the plasma and only the dose from alpha particles was considered. Absorbed doses to normal organs were determined for the liver, kidneys, bone, soft tissue, active marrow, and blood. Simulations were performed for the case when: (1) the daughters have unique biokinetics and (2) the daughters decay at the site of 225 Ac. RESULTS: When the daughters have unique biokinetics, the organs that receive the highest absorbed dose are the liver (male: 1466.6 mGy/MBq, female: 1885.7 mGy/MBq), bone (male: 293.6 mGy/MBq, female: 403.6 mGy/MBq) and kidneys (male: 260.8 mGy/MBq, female: 294.0 mGy/MBq). These doses were compared to the case when the daughters of 225 Ac decay at the site of 225 Ac. There was a 13.5% increase in kidney dose, a 0.8% decrease in liver dose, and <0.1% decrease in bone dose calculations when the daughters have unique biokinetics compared to assuming the daughters decay at the site of 225 Ac. CONCLUSIONS: The kidneys received a large dose estimate (260-295 mGy/MBq) as well as a considerable change in dose of +13.5% when the daughters have unique biokinetics compared to assuming the daughters decay at the site of 225 Ac. Therefore, to accurately determine the kidney dose from unlabeled 225 Ac in a human, the biokinetics of the daughter isotopes should be considered.

Exceeding radiation thresholds for cataract induction in diagnostic imaging: a paediatric case report.

This case report investigates the radiation dose received by a paediatric patient with a ventricular assist device who underwent four non-contrast brain computed tomography (CT) scans, two brain perfusion CT scans and two head angiographic CT scans. The total estimated absorbed dose to the lens of the eye is above the 500 mGy radiation-induced cataract threshold. It is recommended that this patient and those with similar imaging histories have routine follow-up with an ophthalmologist. It is also recommended that radiation dose tracking and an electronic medical alert program be implemented to allow the identification of patients who may exceed tissue reaction thresholds.

Close contact restriction periods for patients who have received iodine-131 therapy for differentiated thyroid cancer.

Patients treated with radionuclide therapy usually require restrictions on certain activities for a period of time following treatment to optimise protection of the public and ensure the legal dose limit is not exceeded. Software may be used to calculate necessary restriction periods for an individual based on longitudinal dose rate measurements from the time of radiopharmaceutical administration. A spreadsheet program has been used for this purpose in Australian hospitals for the last two decades. However, this spreadsheet has a limitation in that it uses an approximation in the calculation of dose from a contact pattern, which affects the calculated restriction period. A computer program called Dorn was developed that provides the same functionality as the spreadsheet but without this approximation. Proffered radiation safety advice from Dorn and the spreadsheet were compared. Advice from the spreadsheet and Dorn were compared for 55 patients who underwent iodine-131 therapy for differentiated thyroid cancer. The restriction periods for caring for infants, close contact with children and sleeping with a partner were typically about 13 h longer in Dorn than in the spreadsheet, but in some cases were over a week shorter or a month longer. If the Dorn program is used clinically in place of the spreadsheet, some patients will enjoy shorter restriction periods and the therapy provider can be more confident in their compliance with regulatory requirements and best practice. Dorn is freely available fromhttps://doi.org/jg5f.

Dosimetry in targeted alpha therapy. A systematic review: current findings and what is needed.

Objective. A systematic review of dosimetry in Targeted Alpha Therapy (TAT) has been performed, identifying the common issues.Approach. The systematic review was performed in accordance with the PRISMA guidelines, and the literature was searched using the Scopus and PubMed databases.Main results. From the systematic review, three key points should be considered when performing dosimetry in TAT. (1) Biodistribution/Biokinetics: the accuracy of the biodistribution data is a limit to accurate dosimetry in TAT. The biodistribution of alpha-emitting radionuclides throughout the body is difficult to image directly, with surrogate radionuclide imaging, blood/faecal sampling, and animal studies able to provide information. (2) Daughter radionuclides: the decay energy of the alpha-emissions is sufficient to break the bond to the targeting vector, resulting in a release of free daughter radionuclides in the body. Accounting for daughter radionuclide migration is essential. (3) Small-scale dosimetry and microdosimetry: due to the short path length and heterogeneous distribution of alpha-emitters at the target site, small-scale/microdosimetry are important to account for the non-uniform dose distribution in a target region, organ or cell and for assessing the biological effect of alpha-particle radiation.Significance. TAT is a form of cancer treatment capable of delivering a highly localised dose to the tumour environment while sparing the surrounding healthy tissue. Dosimetry is an important part of treatment planning and follow up. Being able to accurately predict the radiation dose to the target region and healthy organs could guide the optimal prescribed activity. Detailed dosimetry models accounting for the three points mentioned above will help give confidence in and guide the clinical application of alpha-emitting radionuclides in targeted cancer therapy.

Stochastic multicellular modeling of x-ray irradiation, DNA damage induction, DNA free-end misrejoining and cell death.

The repair or misrepair of DNA double-strand breaks (DSBs) largely determines whether a cell will survive radiation insult or die. A new computational model of multicellular, track structure-based and pO2-dependent radiation-induced cell death was developed and used to investigate the contribution to cell killing by the mechanism of DNA free-end misrejoining for low-LET radiation. A simulated tumor of 1224 squamous cells was irradiated with 6 MV x-rays using the Monte Carlo toolkit Geant4 with low-energy Geant4-DNA physics and chemistry modules up to a uniform dose of 1 Gy. DNA damage including DSBs were simulated from ionizations, excitations and hydroxyl radical interactions along track segments through cell nuclei, with a higher cellular pO2 enhancing the conversion of DNA radicals to strand breaks. DNA free-ends produced by complex DSBs (cDSBs) were able to misrejoin and produce exchange-type chromosome aberrations, some of which were asymmetric and lethal. A sensitivity analysis was performed and conditions of full oxia and anoxia were simulated. The linear component of cell killing from misrejoining was consistently small compared to values in the literature for the linear component of cell killing for head and neck squamous cell carcinoma (HNSCC). This indicated that misrejoinings involving DSBs from the same x-ray (including all associated secondary electrons) were rare and that other mechanisms (e.g. unrejoined ends) may be important. Ignoring the contribution by the indirect effect toward DNA damage caused the DSB yield to drop to a third of its original value and the cDSB yield to drop to a tenth of its original value. Track structure-based cell killing was simulated in all 135306 viable cells of a 1 mm3 hypoxic HNSCC tumor for a uniform dose of 1 Gy.

Approaches to combat hypoxia in cancer therapy and the potential for in silico models in their evaluation.

AIM: The negative impact of tumour hypoxia on cancer treatment outcome has been long-known, yet there has been little success combating it. This paper investigates the potential role of in silico modelling to help test emerging hypoxia-targeting treatments in cancer therapy. METHODS: A Medline search was undertaken on the current landscape of in silico models that simulate cancer therapy and evaluate their ability to test hypoxia-targeting treatments. Techniques and treatments to combat tumour hypoxia and their current challenges are also presented. RESULTS: Hypoxia-targeting treatments include tumour reoxygenation, hypoxic cell radiosensitization with nitroimidazoles, hypoxia-activated prodrugs and molecular targeting. Their main challenges are toxicity and not achieving adequate delivery to hypoxic regions of the tumour. There is promising research toward combining two or more of these techniques. Different types of in silico therapy models have been developed ranging from temporal to spatial and from stochastic to deterministic models. Numerous models have compared the effectiveness of different radiotherapy fractionation schedules for controlling hypoxic tumours. Similarly, models could help identify and optimize new treatments for overcoming hypoxia that utilize novel hypoxia-targeting technology. CONCLUSION: Current therapy models should attempt to incorporate more sophisticated modelling of tumour angiogenesis/vasculature and vessel perfusion in order to become more useful for testing hypoxia-targeting treatments, which typically rely upon the tumour vasculature for delivery of additional oxygen, (pro)drugs and nanoparticles.

The Potential Role of Radiomics and Radiogenomics in Patient Stratification by Tumor Hypoxia Status.

BACKGROUND: Despite the clinical knowledge accumulated over a century about tumor hypoxia, this biologic parameter remains a major challenge in cancer treatment. Patients presenting with hypoxic tumors are more resistant to radiotherapy and often poor responders to chemotherapy. Treatment failure because of hypoxia is, therefore, very common. Several methods have been trialed to measure and quantify tumor hypoxia, with varied success. Over the last couple of decades, hypoxia-specific functional imaging has started to play an important role in personalized treatment planning and delivery. Yet, there are no gold standards in place, owing to inter- and intrapatient phenotypic variations that further complicate the overall picture. The aim of the current article is to analyze, through the review of the literature, the potential role of radiomics and radiogenomics in patient stratification by tumor hypoxia status. METHODS: Search of literature published in English since 2000 was conducted using Medline. Additional articles were retrieved via pearling of identified literature. Publications were reviewed and summarized in text and in a tabulated format. RESULTS: Although still an immature area of science, radiomics has shown its potential in the quantification of hypoxia within the heterogeneous tumor, quantification of changes regarding the degree of hypoxia after radiotherapy and drug delivery, monitoring tumor response to anti-angiogenic therapy, and assisting with patient stratification and outcome prediction based on the hypoxic status. CONCLUSIONS: The lack of technique standardization to measure and quantify tumor hypoxia presents an opportunity for data mining and machine learning in radiogenomics.

Monte Carlo Simulation of the Oxygen Effect in DNA Damage Induction by Ionizing Radiation.

DNA damage induced by ionizing radiation exposure is enhanced in the presence of oxygen (the "oxygen effect"). Despite its practical importance in radiotherapy, the oxygen effect has largely been excluded from models that predict DNA damage from radiation tracks. A Monte Carlo-based algorithm was developed in MATLAB software to predict DNA damage from physical and chemical tracks through a cell nucleus simulated in Geant4-DNA, taking into account the effects of cellular oxygenation (pO2) on DNA radical chemistry processes. An initial spatial distribution of DNA base and sugar radicals was determined by spatially clustering direct events (that deposited at least 10.79 eV) and hydroxyl radical (•OH) interactions. The oxygen effect was modeled by increasing the efficiency with which sugar radicals from direct-type effects were converted to strand breaks from 0.6 to 1, the efficiency with which sugar radicals from the indirect effect were converted to strand breaks from 0.28 to 1 and the efficiency of base-to-sugar radical transfer from •OH-mediated base radicals from 0 to 0.03 with increasing pO2 from 0 to 760 mmHg. The DNA damage induction algorithm was applied to tracks from electrons, protons and alphas with LET values from 0.2 to 150 keV/µm under different pO2 conditions. The oxygen enhancement ratio for double-strand break induction was 3.0 for low-LET radiation up to approximately 15 keV/µm, after which it gradually decreased to a value of 1.3 at 150 keV/µm. These values were consistent with a range of experimental data published in the literature. The DNA damage yields were verified using experimental data in the literature and results from other theoretical models. The spatial clustering approach developed in this work has low memory requirements and may be suitable for particle tracking simulations with a large number of cells.

Simulation of head and neck cancer oxygenation and doubling time in a 4D cellular model with angiogenesis.

Tumor oxygenation has been correlated with treatment outcome for radiotherapy. In this work, the dependence of tumor oxygenation on tumor vascularity and blood oxygenation was determined quantitatively in a 4D stochastic computational model of head and neck squamous cell carcinoma (HNSCC) tumor growth and angiogenesis. Additionally, the impacts of the tumor oxygenation and the cancer stem cell (CSC) symmetric division probability on the tumor volume doubling time and the proportion of CSCs in the tumor were also quantified. Clinically relevant vascularities and blood oxygenations for HNSCC yielded tumor oxygenations in agreement with clinical data for HNSCC. The doubling time varied by a factor of 3 from well oxygenated tumors to the most severely hypoxic tumors of HNSCC. To obtain the doubling times and CSC proportions clinically observed in HNSCC, the model predicts a CSC symmetric division probability of approximately 2% before treatment. To obtain the doubling times clinically observed during treatment when accelerated repopulation is occurring, the model predicts a CSC symmetric division probability of approximately 50%, which also results in CSC proportions of 30-35% during this time.

A review of the development of tumor vasculature and its effects on the tumor microenvironment.

BACKGROUND: The imbalance of angiogenic regulators in tumors drives tumor angiogenesis and causes the vasculature to develop much differently in tumors than in normal tissue. There are several cancer therapy techniques currently being used and developed that target the tumor vasculature for the treatment of solid tumors. This article reviews the aspects of the tumor vasculature that are relevant to most cancer therapies but particularly to vascular targeting techniques. MATERIALS AND METHODS: We conducted a review of identified experiments in which tumors were transplanted into animals to study the development of the tumor vasculature with tumor growth. Quantitative vasculature morphology data for spontaneous human head and neck cancers are reviewed. Parameters assessed include the highest microvascular density (h-MVD) and the relative vascular volume (RVV). The effects of the vasculature on the tumor microenvironment are discussed, including the distributions of hypoxia and proliferation. RESULTS: Data for the h-MVD and RVV in head and neck cancers are highly varied, partly due to methodological differences. However, it is clear that the cancers are typically more vascularized than the corresponding normal tissue. The commonly observed chronic hypoxia and acute hypoxia in these tumors are due to high intratumor heterogeneity in MVD and lower than normal blood oxygenation levels through the abnormally developed tumor vasculature. Hypoxic regions are associated with decreased cell proliferation. CONCLUSION: The morphology of the vasculature strongly influences the tumor microenvironment, with important implications for tumor response to medical intervention such as radiotherapy. Quantitative vasculature morphology data herein may be used to inform computational models that simulate the spatial tumor vasculature. Such models may play an important role in exploring and optimizing vascular targeting cancer therapies.

Development of an in silico stochastic 4D model of tumor growth with angiogenesis.

PURPOSE: A stochastic computer model of tumour growth with spatial and temporal components that includes tumour angiogenesis was developed. In the current work it was used to simulate head and neck tumour growth. The model also provides the foundation for a 4D cellular radiotherapy simulation tool. METHODS: The model, developed in Matlab, contains cell positions randomised in 3D space without overlap. Blood vessels are represented by strings of blood vessel units which branch outwards to achieve the desired tumour relative vascular volume. Hypoxic cells have an increased cell cycle time and become quiescent at oxygen tensions less than 1 mmHg. Necrotic cells are resorbed. A hierarchy of stem cells, transit cells and differentiated cells is considered along with differentiated cell loss. Model parameters include the relative vascular volume (2-10%), blood oxygenation (20-100 mmHg), distance from vessels to the onset of necrosis (80-300 µm) and probability for stem cells to undergo symmetric division (2%). Simulations were performed to observe the effects of hypoxia on tumour growth rate for head and neck cancers. Simulations were run on a supercomputer with eligible parts running in parallel on 12 cores. RESULTS: Using biologically plausible model parameters for head and neck cancers, the tumour volume doubling time varied from 45 ± 5 days (n = 3) for well oxygenated tumours to 87 ± 5 days (n = 3) for severely hypoxic tumours. CONCLUSIONS: The main achievements of the current model were randomised cell positions and the connected vasculature structure between the cells. These developments will also be beneficial when irradiating the simulated tumours using Monte Carlo track structure methods.