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Refereed/Peer-reviewed Purpose: Proton therapy (PT) is broadly accepted as the gold standard of care for pediatric patients with cranial cancer. The superior dose distribution of PT compared to photon radiotherapy reduces normal tissue complication probability (NTCP) for organs at risk. As NTCPs for pediatric organs are not well understood, clinics generally base radiation response on adult data. However, there is evidence that radiation response strongly depends on the age and even sex of a patient. Furthermore, questions surround the influence of individual intrinsic radiosensitivity (α/β ratio) on pediatric NTCP. While the clinical pediatric NTCP data is scarce, radiobiological modeling and sensitivity analyses can be used to investigate the NTCP trends and its dependence on individual modeling parameters. The purpose of this study was to perform sensitivity analyses of NTCP models to ascertain the dependence of radiosensitivity, sex, and age of a child and predict cranial side-effects following intensity-modulated proton therapy (IMPT) and intensity-modulated radiotherapy (IMRT). Methods: Previously, six sex-matched pediatric cranial datasets (5, 9, and 13 years old) were planned in Varian Eclipse treatment planning system (13.7). Up to 108 scanning beam IMPT plans and 108 IMRT plans were retrospectively optimized for a range of simulated target volumes and locations. In this work, dose-volume histograms were extracted and imported into BioSuite Software for radiobiological modeling. Relative-Seriality and Lyman-Kutcher-Burman models were used to calculate NTCP values for toxicity endpoints, where TD50, (based on reported adult clinical data) was varied to simulate sex dependence of NTCP. Plausible parameter ranges, based on published literature for adults, were used in modeling. In addition to sensitivity analyses, a 20% difference in TD50 was used to represent the radiosensitivity between the sexes (with females considered more radiosensitive) for ease of data comparison as a function of parameters such as α/β ratio. Results: IMPT plans resulted in lower NTCP compared to IMRT across all models (p < 0.0001). For medulloblastoma treatment, the risk of brainstem necrosis (> 10%) and cochlea tinnitus (> 20%) among females could potentially be underestimated considering a lower TD50 value for females. Sensitivity analyses show that the difference in NTCP between sexes was significant (p < 0.0001). Similarly, both brainstem necrosis and cochlea tinnitus NTCP varied significantly (p < 0.0001) across tested α/β as a function of TD50 values (assumption being that TD50 values are 20% lower in females). If the true α/β of these pediatric tissues is higher than expected (α/β ∼ 3), the risk of tinnitus for IMRT can significantly increase (p < 0.0001). Conclusion: Due to the scarcity of pediatric NTCP data available, sensitivity analyses were performed using plausible ranges based on published adult data. In the clinical scenario where, if female pediatric patients were 20% more radiosensitive (lower TD50 value), they could be up to twice as likely to experience side-effects of brainstem necrosis and cochlea tinnitus compared to males, highlighting the need for considering the sex in NTCP models. Based on our sensitivity analyses, age and sex of a pediatric patient could significantly affect the resultant NTCP from cranial radiotherapy, especially at higher α/β values.

Background: Superior treatment responses by patients with human papillomavirus (HPV) positive head and neck squamous cell carcinoma (HNSCC),compared to patients with HNSCC from other causes, drive biomarker research to optimize treatment. Most HNSCC patients receive radiation therapy delivered as a fractionated course. Changing HPV status in HNSCC from apositive prognostic marker to a predictive one requires biomarkers that capture cellular radiation response to cumulative dose.Methods: Nuclear enlargement, γH2AX expression and micronuclei count,were studied in six HNSCC cell lines after 4 Gy fractionated X-irradiation. Results: All HNSCC cell lines displayed altered cellular responses, indicating increasing inability to repair radiation damage with subsequent radiation fractions.Increases in nuclear area were significantly greater among HPV positive cell lines(207% and 67% for the HPV positive and HPV negative groups, respectively). Conclusions: A different character of DNA repair dysfunction in the HPV positive group suggests greater chromosomal translocation with accumulated radiation dose. Refereed/Peer-reviewed

Refereed/Peer-reviewed

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 Refereed/Peer-reviewed

Head and neck squamous cell carcinomas (HNSCC) resulting from oncogenic transformations following human papillomavirus (HPV) infection consistently demonstrate better treatment outcomes than HNSCC from other aetiologies. Squamous cell carcinoma of the oropharynx (OPSCC) shows the highest prevalence of HPV involvement at around 70–80%. While strongly prognostic, HPV status alone is not sufficient to predict therapy response or any potential dose de-escalation. Cancer stem cell (CSC) populations within these tumour types represent the most therapy-resistant cells and are the source of recurrence and metastases, setting a benchmark for tumour control. This review examines clinical and preclinical evidence of differences in response to treatment by the HPV statuses of HNSCC and the role played by CSCs in treatment resistance and their repopulation from non-CSCs. Evidence was collated from literature searches of PubMed, Scopus and Ovid for differential treatment response by HPV status and contribution by critical biomarkers including CSC fractions and chemo-radio sensitivity.While HPV and CSC are yet to fulfil promise as biomarkers of treatment response, understanding how HPV positive and negative aetiologies affect CSC response to treatment and tumour plasticity will facilitate their use for greater treatment individualisation. Refereed/Peer-reviewed

The aim of this article is to offer a view of the current status of women in medical physics and biomedical engineering, while focusing on solutions towards gender balance and providing examples of current activities carried out at national and international levels. The International Union of Physical and Engineering Scientists in Medicine is committed to advancing women in science and health and has several initiatives overseen by the Women in Medical Physics and Biomedical Engineering Task Group. Some of the main strategies proposed by the Task Group to attain gender balance are: (a) identify and promote female role models that achieve successful work-life balance, (b) establish programs to develop female leaders, (c) create opportunities for females to increase the international visibility within the scientific community, and (d) establish archives and databases of women in STEM Refereed/Peer-reviewed

Purpose: Intrinsic radioresistance and increased proliferation rates in head and neck cancers (HNCs) are associated with negative radiotherapy (RT) treatment responses. The use of gold nanoparticles (AuNPs) as radiosensitisers could enable total radiation dose reduction and lowered radiation‐toxicity. AuNP radiosensitisation may overcome hypoxia‐induced radioresistence and treatment‐induced accelerated repopulation of cancer cells in HNCs, improving radiotherapy outcomes. Methods: Tumour control was determined by considering individual cancer cell responses in probabilistic computational simulations using HYP‐RT software for clinical radiotherapy doses and fractionation schedules along with 3 different nanoparticle administration schedules. Antagonistic tumour hypoxia and rapid tumour regrowth due to accelerated repopulation of cancers cells were taken into consideration. Results: Simulations indicate that tumours that are conventionally uncontrollable can be controlled with AuNP radiosensitisation. In simulations where the absence of AuNPs required radiotherapy doses above standard clinical prescriptions, reoccurring AuNP administration allowed for radiation‐dose reductions below standard clinical dose prescriptions. For example, considering a 2 Gy per fraction radiotherapy schedule, tumour control was achieved with 57.2 ± 5.1 Gy (p =

FLASH radiotherapy, or the administration of ultra-high dose rate radiotherapy, is a new radiation delivery method that aims to widen the therapeutic window in radiotherapy. Thus far, most in vitro and in vivo results show a real potential of FLASH to offer superior normal tissue sparing compared to conventionally delivered radiation. While there are several postulations behind the differential behaviour among normal and cancer cells under FLASH, the full spectra of radiobiological mechanisms are yet to be clarified. Currently the number of devices delivering FLASH dose rate is few and is mainly limited to experimental and modified linear accelerators. Nevertheless, FLASH research is increasing with new developments in all the main areas: Radiobiology, technology and clinical research. This paper presents the current status of FLASH radiotherapy with the aforementioned aspects in mind, but also to highlight the existing challenges and future prospects to overcome them. Refereed/Peer-reviewed

usc Research into machine learning (ML) for clinical vascular analysis, such as those useful for stroke and coronary artery disease, varies greatly between imaging modalities and vascular regions. Limited accessibility to large diverse patient imaging datasets, as well as a lack of transparency in specific methods, are obstacles to further development. This paper reviews the current status of quantitative vascular ML, identifying advantages and disadvantages common to all imaging modalities. Literature from the past 8 years was systematically collected from MEDLINE® and Scopus database searches in January 2021. Papers satisfying all search criteria, including a minimum of 50 patients, were further analysed and extracted of relevant data, for a total of 47 publications. Current ML image segmentation, disease risk prediction, and pathology quantitation methods have shown sensitivities and specificities over 70%, compared to expert manual analysis or invasive quantitation. Despite this, inconsistencies in methodology and the reporting of results have prevented inter-model comparison, impeding the identification of approaches with the greatest potential. The clinical potential of this technology has been well demonstrated in Computed Tomography of coronary artery disease, but remains practically limited in other modalities and body regions, particularly due to a lack of routine invasive reference measurements and patient datasets. Refereed/Peer-reviewed

In recent years, artificial intelligence (AI) has increased its prevalence in society with the potential to transform many aspects of our lives. AI is considered to be not just one but a number of technologies. Based on a combination of machine learning, neural networks, deep learning and natural language processing, AI has been demonstrated to perform better than humans in certain circumstances. With the increase in size and complexity of available data, the application of AI and related technologies specifically to medicine and healthcare provides possibilities for contributing to significant improvements in patient outcomes with regards to diagnosis and treatments. Questions remain however as to the extent to which human beings will be replaced by AI. With its potential to be transformation in medicine and healthcare, in this topical debate Lois Holloway and Eva Bezak debate the important evolving field of AI. Refereed/Peer-reviewed

Improvements in the prognosis of pancreatic ductal adenocarcinoma (PDAC) rely on the development of effective treatments to target advanced disease. Mucin 1 (MUC1) is a transmembrane glycoprotein which is involved in the metastatic progression of PDAC and is a receptor-of-interest for targeted radionuclide therapy. The aim of this study was to determine the feasibility of MUC1-based targeted radionuclide therapy for PDAC, by evaluating the expression profile of MUC1 in different pancreatic cells and tissues using the C595 antibody. MUC1 expression was evaluated in four PDAC cell lines (PANC-1, BxPC-3, CAPAN-1 and AsPC-1) using flow cytometry and immunocytochemistry. Immunohistochemistry was performed on primary and metastatic PDAC, pancreatitis, pancreatic intra-epithelial neoplasia and normal pancreatic tissue samples to identify potential changes in C595-reactive MUC1 expression across different disease groups. C595-reactive MUC1 expression was found to varying degrees in the cell lines (11.5&ndash, 93.1%). A pixel analysis of the immunohistochemical staining demonstrated highest MUC1 expression in primary PDAC tissue (mean pixel value of 205.4), followed by other pancreatic cancer types (204.9), pancreatic intra-epithelial neoplasia (203.8), metastatic PDAC (201.5), chronic pancreatitis (198.1) and normal pancreatic tissue (191.4). The increased expression in malignant tissues and reduced expression in benign tissues indicate that C595-reactive MUC1 is a potential target for targeted radionuclide therapy of PDAC.

In the current pandemic times, medical physicists may not be aware that there is an interesting story on two significant discoveries related to the coronavirus. One is the invention of the polymerase chain reaction (PCR) and the other is the first electron microscopic observation and identification of the coronavirus. Both of them were disregarded by the reviewers and major journals declined to publish these discoveries. These days, PCR, for example, is a widespread method for analyzing DNA, having a profound effect on healthcare, especially now during the Covid-19 pandemic. Prejudice or perhaps ignorance prevail in every aspect of our society, and there is no exception in scientific research. We need to, however, learn from these two stories and be open-minded about novel discoveries and findings – as they may be just disruptive in the “right” way to lead to an unexpected breakthrough.

Head and neck squamous cell carcinomas (HNSCC) resulting from human papillomavirus (HPV) are increasing in incidence but demonstrate significantly better treatment response than HNSCC from other causes such as tobacco and alcohol. This study sought to identify differences in HNSCC, intrinsic to HPV status, in their response to radiation dose. Previously unexamined changes in radio-responsiveness following fractionated X-ray irradiation were compared between HPV positive and negative statuses of HNSCC. Six HNSCC cell lines, 3 of each HPV status, were investigated for radiosensitivity by clonogenic assay and modelled by response as a function of dose. Generational cultures of each cell line were developed to follow changes in radiosensitivity after repeated irradiations simulating fractionated radiation therapy. As a group, the HPV positive cell lines were more radiosensitive, but with changes following repeated fractions of dose, and modelling of response as a function of dose, both statuses displayed large radiobiological heterogeneity. These findings challenge current radiobiological assumptions of head and neck cancers as early responding tissue to radiation and may go some way in explaining difficulties reaching consensus in stratification of treatment by HPV status. Consequently, results from this study do not support stratifying radiation therapy by HPV status. Refereed/Peer-reviewed

Pancreatic ductal adenocarcinoma (PDAC) has long been associated with low survival rates. A lack of accurate diagnostic tests and limited treatment options contribute to the poor prognosis of PDAC. Radioimmunotherapy using α- or β-emitting radionuclides has been identified as a potential treatment for PDAC. By harnessing the cytotoxicity of α or β particles, radioimmunotherapy may overcome the anatomic and physiological factors which traditionally make PDAC resistant to most conventional treatments. Appropriate selection of target receptors and the development of selective and cytotoxic radioimmunoconjugates are needed to achieve the desired results of radioimmunotherapy. The aim of this review is to examine the growing preclinical and clinical trial evidence regarding the application of α and β radioimmunotherapy for the treatment of PDAC. A systematic search of MEDLINE® and Scopus databases was performed to identify 34 relevant studies conducted on α or β radioimmunotherapy of PDAC. Preclinical results demonstrated α and β radioimmunotherapy provided effective tumour control. Clinical studies were limited to investigating β radioimmunotherapy only. Phase I and II trials observed disease control rates of 11.2%−57.9%, with synergistic effects noted for combination therapies. Further developments and optimisation of treatment regimens are needed to improve the clinical relevance of α and β radioimmunotherapy in PDAC.

With the current developments in medical physics and radiotherapy, there is a renewed interest in novel microdosimetry detectors. The Timepix detector, developed at CERN as an extension of the Medipix2 detector, represents such a microdosimeter. It can be used for experiments with photons, electrons and heavy particles and in a wide range of applications in spectroscopy, space physics, nuclear physics, radiotherapy physics, medical imaging and radiation protection.This paper reviews some of the published works utilizing Timepix as a radiation detector, as a spectroscope or as a camera for photons and charged particles. We describe specific applications of Timepix that may be of interest to physicists and the industry. We show that more investigations are still required to gain the full benefit of Timepix applications in the fields of radiation therapy and imaging to utilize the potential of this detector fully. More specifically, the application of Timepix to targeted radiotherapies remains limited despite the main advantage of Timepix, which is energy deposition tracking at a micron level. Refereed/Peer-reviewed

usc Gold nanoparticle (GNP) enhanced proton therapy is a promising treatment concept offering increased therapeutic effect. It has been demonstrated in experiments which provided indications that reactive species play a major role. Simulations of the radiolysis yield from GNPs within a cell model were performed using the Geant4 toolkit. The effect of GNP cluster size, distribution and number, cell and nuclear membrane absorption and intercellular yields were evaluated. It was found that clusters distributed near the nucleus increased the nucleus yield by 91% while reducing the cytoplasm yield by 7% relative to a disperse distribution. Smaller cluster sizes increased the yield, 200 nm clusters had nucleus and cytoplasm yields 117% and 35% greater than 500 nm clusters. Nuclear membrane absorption reduced the cytoplasm and nucleus yields by 8% and 35% respectively to a permeable membrane. Intercellular enhancement was negligible. Smaller GNP clusters delivered near sub-cellular targets maximise radiosensitisation. Nuclear membrane absorption reduces the nucleus yield, but can damage the membrane providing another potential pathway for biological effect. The minimal effect on adjacent cells demonstrates that GNPs provide a targeted enhancement for proton therapy, only effecting cells with GNPs internalised. The provided quantitative data will aid further experiments and clinical trials. Refereed/Peer-reviewed

Individuals do not react to radiation in a homogeneous manner. Recent radiogenomic research has proven that individual polymorphisms can correlate with treatment response most likely due to variation in the ability to recognise and repair DNA breaks. The difference in radiosensitivity between genders has been well documented, yet most radiotherapeutic guidelines are based solely on population averages rather than demographic subgroups such as age, race and gender. This paper is a review of the burgeoning literature available on the differences in efficacy and outcome of radiotherapy between genders. The work examines the effect of radiation on gender both from a tumour control as well as normal tissue toxicity perspective. While the literature reporting such findings is limited, the results show a small but significant difference in response to radiotherapy between sexes. Prospective and retrospective studies for evaluating these gender-specific differences are encouraged as a next step in personalised medicine. Refereed/Peer-reviewed

Introduction: Despite improvements in radiation therapy, chemotherapy and surgical procedures over the last 30 years, pancreatic cancer 5-year survival rate remains at 9%. Reduced stroma permeability and heterogeneous blood supply to the tumour prevent chemoradiation from making a meaningful impact on overall survival. Hypoxia-activated prodrugs are the latest strategy to reintroduce oxygenation to radioresistant cells harbouring in pancreatic cancer. This paper reviews the current status of photon and particle radiation therapy for pancreatic cancer in combination with systemic therapies and hypoxia activators. Methods: The current effectiveness of management of pancreatic cancer was systematically evaluated from MEDLINE® database search in April 2019. Results: Limited published data suggest pancreatic cancer patients undergoing carbon ion therapy and proton therapy achieve a comparable median survival time (25.1 months and 25.6 months, respectively) and 1-year overall survival rate (84% and 77.8%). Inconsistencies in methodology, recording parameters and protocols have prevented the safety and technical aspects of particle therapy to be fully defined yet. Conclusion: There is an increasing requirement to tackle unmet clinical demands of pancreatic cancer, particularly the lack of synergistic therapies in the advancing space of radiation oncology. Refereed/Peer-reviewed

Background: The use of gold nanoparticles (AuNPs) as radiosensitizers may offer a new approach in the treatment of head and neck cancers; minimizing treatment-associated toxicities and improving patient outcomes. AuNPs promote localized dose deposition; permitting improved local control and/or dose reduction. Aim: This work aimed to address the theoretical optimization of radiation doses, fractionation and nanoparticle injection schedules to maximize therapeutic benefits. Materials & methods: Probabilistic nanoparticle sensitization factors were incorporated into the individual cell-based HYP-RT computer model of tumor growth and radiotherapy. Results: Total dose outcomes across all radiation therapy treatment regimens were found to be significantly reduced with the presence of AuNPs, with bi-weekly injections showing the most decrease. Conclusion: Outcomes suggest the need for regular AuNP administration to permit effective radiosensitization.

Introduction. Lung cancer is a disease which, despite the advancements in treatment, still has a very poor 5-year survival rate. Stereotactic ablative radiation therapy (SABR) is a highly advanced, sophisticated, and safe treatment which allows patients with early stage lung cancer to be treated effectively without invasive procedures and with excellent clinical outcomes. Avoiding surgery minimises morbidity and recovery time, bettering patients’ quality of life. Furthermore, SABR allows patients unsuitable for surgery to still undergo curative treatment. Methods. We aimed to review SABR-related normal tissue toxicities reported in the literature. While many studies assess safety, clinical efficacy, and disease control of SABR for lung cancer, the number of comprehensive reviews that analyse SABR-related side-effects is scarce. This integrative review summarises the toxicities reported in literature based on published clinical trials and tumour location (central or peripheral tumours) for available SABR techniques. Given that the majority of the clinical studies did not report on the statistical significance (e.g., p-values and confidence intervals) of the toxicities experienced by patients, statistical analyses cannot be performed. As a result, adverse events are compiled from clinical reports; however, due to various techniques and nonstandard toxicity reports, no meta-analysis is possible at the current stage of reported data. Results. When comparing lobectomy and SABR in phase III trials, surgery resulted in increased procedure-related morbidity. In phase II trials, very few studies showed high grade toxicities/fatalities as a result of SABR for lung cancer. Gross target volume size was a significant predictor of toxicity. An ipsilateral mean lung dose larger than 9 Gy was significantly associated with radiation pneumonitis. Conclusions. Based on the studies reviewed SABR is a safe treatment technique for lung cancer; however, further well-designed phase III randomised clinical trials are required to produce timely conclusive results and to enable their comparison and statistical analysis.

The use of gold nanoparticle (GNP) and other metal nanoparticle (MNP) radiosensitisers to enhance radiotherapy offers the potential of improved treatment outcomes. Originally intended for use with X-ray therapy, the possibility of enhanced hadron therapy is desirable due to the superior sparing of healthy tissue in hadron therapy compared to conventional X-ray therapy. While MNPs were not expected to be effective radiosensitisers for hadron therapy due to the limited Z dependence of interactions, recent experimental measurements have contradicted this expectation. Key experimental measurements and Monte Carlo simulations of MNP radiosensitisation for hadron irradiation are reviewed in the current work. Numerous experimental measurements have found a large radiosensitisation effect due to MNPs for proton and carbon ion irradiation. Experiments have also indicated that the radiosensitisation is due in large part to enhanced reactive oxygen species (ROS) production. Simulations have found a large radial dose and ROS enhancement on the nanoscale around a single MNP. However, the short range of the dose enhancement is insufficient for a large macroscale dose enhancement or enhanced biological effect in a cell model considering dose to the nucleus from GNPs in the cytoplasm (a distribution observed in most experiments). Refereed/Peer-reviewed

Background: Proton radiotherapy (PT) is used increasingly for paediatric brain cancer patients. However, as demonstrated here, the knowledge on normal tissue dose constraints, to minimize side-effects, for this cohort is limited. Methods: A search strategy was systematically conducted on MEDLINE® database. 65 papers were evaluated ranging from 2013 to 2021. Results: Large variations in normal tissue tolerance and toxicity reporting across PT studies makes estimation of normal tissue dose constraints difficult, with the potential for significant late effects to go unmeasured. Mean dose delivered to the pituitary gland varies from 20 to 30 Gy across literature. Similarly, the hypothalamic dose delivery ranges from 20 to 54.6 Gy for paediatric patients. Conclusion: There is a significant lack of radiobiological data for paediatric brain cancer patients undergoing proton therapy, often using data from x-ray radiotherapy and adult populations. The way forward is through standardisation of reporting in order to validate relevant dose constraints. Refereed/Peer-reviewed

Glioblastoma multiforme (GBM) or grade IV astrocytoma is the most diagnosed form of primary brain tumours in adults. Radioimmunotherapy (RIT), mostly in combination with conventional therapies, is presented in the current review as a therapeutic strategy of high potential in the management of GBM. A systematic literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) to identify clinical studies that employed a form of radioimmunotherapy using alpha- or beta-emitting radioisotopes. The available literature on RIT in GBM and high-grade gliomas is presented and discussed. The results suggest that this promising treatment approach merits further investigation in future clinical studies. Refereed/Peer-reviewed

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.

Nanoparticle radiosensitization has been demonstrated well to enhance the effects of radiotherapy,motivate the improvement of therapeutic ratios, and decrease morbidity in cancer treatment. A significant challenge existsin optimizing formulations and translation due to insufficient knowledge of the associated mechanisms, which have historically been limited to physical concepts. Here, we investigated a concept for the role of biological mechanisms.The mere presence of gold nanoparticles led to a down regulation of thymidylate synthase, important for DNA damage repair in the radioresistant S-phase cells. By developing a cross-correlative methodology to reveal probabilistic gold nanoparticle uptake by cell sub-populations and the associated sensitization as a function of the uptake, a number of revealing observations have been achieved.Surprisingly, for low numbers of nanoparticles, a desensitization action was observed. Sensitization was discovered to preferentially impact S-phase cells, in which impairment of the DNA damage response by the homologous recombination pathway dominates. This small but radio resistant cell population correlates with much greater proliferative ability. Thus, aparadigm is presented whereby enhanced DNA damage is not necessarily due to an increase in the number of DNA double-strand breaks (DSBs) created but can be from a nanoparticle-induced impairment of the damage response by down-regulating repair proteins such as thymidylate synthase. Refereed/Peer-reviewed

Objective: Head and neck carcinomas are clinically challenging malignancies because of tumor heterogeneities and resilient tumor subvolumes that require individualized treatment planning and delivery for an improved outcome. Although current approaches to diagnosis and therapy have boosted locoregional control, the long-term survival in this patient group remains unchanged over the last decades. A new approach to head and neck cancer management is therefore needed to better identify patient subgroups that are responsive to specific therapies. The aim of this article is to review the current status of knowledge and practice utilizing big data toward personalized therapy in head and neck cancers based on CT and PET imaging modalities. Methods: Literature published in English since 2000 was searched using Medline. Additional articles were retrieved via pearling of identified literature. Publications were reviewed and summarized in tabulated format. Results: Studies based on big data in head and neck cancer are limited; however, the field of radiomics is under continuous development and provides valuable input for personalized treatment. Using PET/PET CT biomarkers for patient treatment individualization and response prediction seems promising, especially in regard to detection of hypoxia and clonogenic cancer stem cells. Literature shows that macroscopic changes in medical images (whether structural or functional) are correlated with biologic and biochemical changes within a tumor. Conclusion: Current trends in data science suggest that the ideal model for decision support in head and neck cancers should be based on human-machine collaboration, namely, on (1) software-based algorithms, (2) physician innovation collaboratives, and (3) clinician mix optimization. Refereed/Peer-reviewed

Background: Several studies have investigated cardiac dose reduction when utilizing the deep inspiration breath hold (DIBH) technique in patients undergoing radiotherapy for left-sided breast cancer. This paper aims to recommend potential selection criteria based on a retrospective single institute study of free breathing (FB) and DIBH computed tomography (CT) simulation planning scans. Methods: Dosimetric comparisons were performed retrospectively for 20 patients correlating the dose reduction and patient anatomical factors (anatomical variation of chest shape, chest wall separation, total lung volume (TLV) and others). Results: Paired t-tests demonstrated significant cardiac dose reduction for most patients but not all. Minimal cardiac dose reduction was observed for three patients using their DIBH plan, with one patient receiving a higher dose. Linear regression analysis identified a positive correlation between the patient’s TLV (on the FB CT simulation scan) and the magnitude of dosimetric benefit received (0.4045 R2). Conclusion: The TLV measured on a FB plan could potentially be utilised to predict cardiac exposure and assist with patient selection for DIBH. This is important in resource allocation, as DIBH may be unnecessarily recommended for some patients with little dosimetric benefit.

Background: While medical imaging plays a key role in diagnostic and treatment guidance, evidence shows that the number of investigations using ionizing radiation has greatly increased over the last decades, which could be a concern among paediatric patients. Repeated imaging, as required for certain congenital conditions is of particular interest in regard to cumulative dose and the associated risk of cancer. In this context, the aim of the current work is to systematically collate and evaluate the findings reported in the literature over the last 10 years, based on the imaged anatomical area, in order to identify trends, consensus and/or discrepancies in reported risks. Methods and findings: Two databases (MEDLINE, and Scopus) were systematically searched for literature published between 2010 until July 2020. Randomized clinical trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies, and case series (with ≥10 cases) were sought. Forty-five studies met eligibility criteria for inclusion in the review, with all studies achieving good-to-high-quality ratings based on the Critical Appraisal Skills Programme (CASP) assessment. The eligible articles were divided into different groups, according to the irradiated anatomy, considering that anatomy-specific assessment has important implications for future study designs, by accounting for the physiological and radiobiological particularities of a specific organ or tissue. Conclusions: Although majority of the reports present certain limitations concerning the study design or data analysis, there is a general agreement regarding paediatric exposure that require a number of key measures to reduce long-term effects, such as: dose reduction by employing non-ionizing imaging modalities, whenever possible, or plain radiographs; use of CT imaging selectively rather than routinely; use of dedicated scan protocols for each imaging modality and device; recording of specific exposure parameters for each patient during the procedure for more accurate dose calculations; creation of dose registries for paediatric exposure; cumulative dose monitoring for long-term risk analysis; and comparative dose-risk analysis among various imaging modalities for different conditions in order to evaluate the most optimal choice for each situation. Refereed/Peer-reviewed

Background: Proton radiotherapy produces superior dose distributions compared to photon radiotherapy, reducing side effects. Differences between the two modalities are not fully quantified in paediatric patients for various intracranial tumour sites or age. Understanding these differences may help clinicians estimate the benefit and improve referral across available centres. Our aim was to compare intensity-modulated proton therapy (IMPT) and intensity-modulated photon radiotherapy (IMRT) radiation doses for select paediatric intracranial tumours. Methods: IMPT and IMRT dose distributions for gender-matched paediatric cranial CT-datasets (ages 5, 9 and 13 years) were retrospectively calculated to simulate irradiation of supratentorial (ependymoma) and infratentorial (medulloblastoma) target volumes diameters (1&ndash, 3 cm) and position (central and 1&ndash, 2 cm shifts). Results: Clinical dosimetric objectives were achieved for all 216 treatment plans. Whilst infratentorial IMPT plans achieved greater maximum dose sparing to optic structures (4.8&ndash, 12.6 Gy optic chiasm), brainstem sparing was limited (~0.5 Gy). Mean dose difference for optic chiasm was associated with medulloblastoma target position (p &lt, 0.0197). Supratentorial IMPT plans demonstrated greater dose reduction for the youngest patients (pituitary gland p &lt, 0.001). Conclusions: Normal tissue sparing was achieved regardless of patient age for infratentorial tumours. However, for supratentorial tumours, there was a dosimetric advantage of IMPT across 9 vs. 13-year-old patients.

Clinical implementation of proton therapy demonstrated its potential to overcome some limitations of the more traditional, photon-based radiotherapy, due to physical and radiobiological advantages of protons. However, questions concerning the long-term effects of protons on paediatric patients need outcome analysis of the reported literature in order to be answered. The current paper has analysed the available clinical trials and comparative studies (protons vs photons) for paediatric cancers of the central nervous system (CNS) analysing the reported outcomes and follow-up times in order to evaluate the safety of proton therapy for this patient group. Based on the literature analysis, proton therapy for treatment of paediatric cancers of the CNS was found to provide survival and tumour control outcomes comparable, and frequently superior, to photon therapy. Furthermore, the use of protons was shown to decrease the incidence of severe acute and late toxicities, including reduced severity of endocrine, neurological, IQ and QoL deficits. Most commonly, the reported median follow-up time was up to 5 years. Only a few studies reported promising, longer follow-up results. Considering that these patients are likely to survive many of the malignancies reported on, the incidence of long term sequellae impacting growth, development and quality of life into adulthood, should be viewed longitudinally for completeness. The evidence surrounding proton therapy in paediatric tumour management supports its effectiveness and potential benefits in reducing the incidence of late-onset toxicities and second malignancies. For stronger evidence, it is highly desired for future studies to improve current reporting by (1) highlighting the paediatric patient cohort's outcome (in mixed patient groups), (2) reporting the follow-up time, (3) clearly indicating the toxicity criteria used in their evaluation, and (4) identifying the risk group. With this suggested clarity of future reporting, meaningful data to support treatment choice may then be available. Refereed/Peer-reviewed

Purpose: Improvements in personalized therapy are made possible by the advances in molecular biology that led to developments in molecular imaging, allowing highly specific in vivo imaging of biological processes. Positron emission tomography (PET) is the most specific and sensitive imaging technique for in vivo molecular targets and pathways, offering quantification and evaluation of functional properties of the targeted anatomy. Materials and Methods: This work is an integrative research review that summarizes and evaluates the accumulated current status of knowledge of recent advances in PET imaging for cancer diagnosis and treatment, concentrating on novel radiotracers and evaluating their advantages and disadvantages in cancer characterization. Medline search was conducted, limited to English publications from 2007 onward. Identified manuscripts were evaluated for most recent developments in PET imaging of cancer hypoxia, angiogenesis, proliferation, and clonogenic cancer stem cells (CSC). Results: There is an expansion observed from purely metabolic-based PET imaging toward antibody-based PET to achieve more information on cancer characteristics to identify hypoxia, proangiogenic factors, CSC, and others. 64Cu-ATSM, for example, can be used both as a hypoxia and a CSC marker. Conclusions: Progress in the field of functional imaging will possibly lead to more specific tumor targeting and personalized treatment, increasing tumor control and improving quality of life. Refereed/Peer-reviewed

Head and neck cancers (HNCs) are aggressive epithelial tumours frequently treated using radiation. HNC biology shows distinctions dependent on the oncologic involvement of the human papilloma virus (HPV). Clinically, HPV positive HNCs respond better to radiotherapy but few in vitro data demonstrate radiobiological differences explaining differences in clinical outcomes. This pilot study examined radiobiological responses to irradiation and subsequent regeneration in two HNC cell lines (HPV positive and negative). A novel approach was taken to develop generational cultures of HNC cell lines, UM-SCC-1 (HPV negative) and UM-SCC-47 (HPV positive). MTT assays were used to determine surviving metabolic activity as a function of dose following 6 MV X-ray irradiation. Parallel cultures surviving 4 Gy irradiation (not analysed) were re-cultured and passaged to develop subsequent generations which were re-irradiated and analysed for generational change in radiation response. Second and 3rd generations of UM-SCC-1 showed decreasing metabolic activity with dose but little difference was evident in surviving fractions between these generations. Significantly lower metabolic activity in the 3rd generation at

Targeted therapy for cancer is a rapidly expanding and successful approach to the management of many intractable cancers. However, many immunotherapies fail in the longer term and there continues to be a need for improved targeted cancer cell toxicity, which can be achieved by radiolabelling the targeting vector with a radioisotope. Such constructs are successful in using a gamma ray emitter for imaging. However, traditionally, a beta emitter is used for therapeutic applications. The new approach is to use the short range and highly cytotoxic alpha radiation from alpha emitters to achieve improved efficacy and therapeutic gain. This paper sets out to review all experimental and theoretical comparisons of efficacy and therapeutic gain for alpha and beta emitters labelling the same targeting vector. The overall conclusion is that targeted alpha therapy is superior to targeted beta therapy, such that the use of alpha therapy in clinical settings should be expanded. Refereed/Peer-reviewed

Stereotactic ablative radiation therapy for lung cancer is an advanced technique where tumours are ablated with hypofractionated radiation doses, with a high degree of accuracy. The aim of this paper is to review the available literature and to discuss the SABR-induced toxicities for lung malignancies as a function of radiation delivery technique.A Medline search was conducted to identify the appropriate literature to fulfil the aim of this review and data from all applicable papers were collated and analysed.The most common techniques of SABR delivery employ linear accelerators, CyberKnife robotic radiosurgery system, TomoTherapy and the Novalis beam surgery system. Linear accelerator-based treatments give rise to a variety of toxicities that are strongly dependent on both patient-related factors and planning/dosimetry-related factors. The limited number of studies using CyberKnife reported low grade toxicities. Grade three toxicities mainly include fatigue and chest pain, usually in less than 10% of patients.All treatment techniques presented show efficiency in SABR delivery with various toxicities which, at this stage, cannot render one technique better than the other. For more conclusive results, well-designed phase three randomised clinical trials are required with better patient selection criteria, including dose and fractionation,treatment machine and technique, along with the consistent selection of a common toxicity grading criterion. Refereed/Peer-reviewed

Introduction Endometriosis is a common, chronic gynaecological condition affecting as many as 1 in 10 women (approximately 700,000 Australians)[1]. The current consensus produced by the World Endometriosis Society (WES) suggests women with severe disease should be managed in centralised highly specialised endometriosis centres[2]. In order to facilitate accurate triage of patients to such centres, a reliable and accurate method of diagnosis is needed[3] however, we are still currently at the point where TVS for endometriosis is a highly specialised niche modality available in only a few selected centres. In Australia, our expansive geography means some women will be forced to travel extraordinary distances to access just to obtain an initial diagnosis. This literature review aims to determine the current accuracy of TVS for endometriosis as performed by sonographers. Methods A review of the literature was performed to determine the current reported accuracy of TVS in the diagnosis of deep infiltrating endometriosis (DIE). A search of four databases was performed following a PICO (MEDLINE, EMBASE, EMCARE and Google Scholar). 31 papers were included in the final review. Results Overall accuracy of TVS as compared to laparoscopy is reported to be very good by many authors with sensitives and specificities of up to 100% reported depending on location. Most of the published data has come from specialised endometriosis centres around the world (or specialised gynaecological pain clinics) leaving a gap in the literature for evidence affirming the accuracy of TVS outside of these centres. Heterogenicity exists within the literature as to the qualifications and training of those performing TVS with few authors reporting this. Reports of a sonographer (rather than a gynaecologist) performing the TVS are rare. Conclusion TVS is a reliable and accurate tool in the assessment of DIE prior to surgery. More studies are required to validate these findings outside of specialised endometriosis centres particularly utilising sonographers rather than gynaecologists to perform the scanning. Without evidence to support TVS being accurate in a generalised setting, diagnosis of endometriosis via TVS will remain a specialised and restricted service for Australian women.

Peripheral photon and neutron doses from external beam radiotherapy (EBRT) are associated with increased risk of carcinogenes is in the out-of-field organs; thus, dose estimations of secondary radiation are imperative. Peripheral photon and neutron doses from EBRT of prostate carcinoma were measured in Rando phantom. 6LiF:Mg,Cu,P and 7LiF:Mg,Cu,P glass-rod thermoluminescence dosemeters (TLDs) were inserted in slices of a Rando phantom followed by exposure to 80 Gy with 18-MV photon fourfield 3D-CRT technique. The TLDs were calibrated using 6- and 18-MV X-ray beam. Neutron dose equivalents measured with CR-39 etch-track detectors were used to derive readout-to-neutron dose conversion factor for 6LiF:Mg,Cu,P TLDs. Average neutron dose equivalents per 1 Gy of isocentre dose were 3.8±0.9 mSv Gy-1 for thyroid and 7.0±5.4 mSv Gy-1 for colon. For photons, the average dose equivalents per 1 Gy of isocentre dose were 0.2+0.1 mSv Gy21 for thyroid and 8.1+9.7 mSv Gy21 for colon. Paired 6LiF:Mg,Cu,P and 7LiF:Mg,Cu,P TLDs can be used to measure photon and neutron doses simultaneously. Organs in close proximity to target received larger doses from photons than those from neutrons whereas distally located organs received higher neutron versus photon dose. Refereed/Peer-reviewed

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.

Oesophageal cancer is a relatively uncommon malignancy, but with poor prognosis. Despite several treatment options that are available, the 5-year survival rates rarely exceed 40%. This review discusses the main challenges of oesophageal cancer, the available treatment options, and the most effective treatment in terms of overall survival. The outcomes of clinical trials show that neo-adjuvant chemo-radiotherapy using cisplatin and 5-fluorouracil followed by oesophagectomy results in the greatest survival. However, the optimal chemotherapy and radiotherapy schedule remains unclear. There is no satisfactory treatment to date, particularly for patients with co-morbidities or advanced tumours. Refereed/Peer-reviewed

Evidence of cancer cells that bear attributes analogous to those of normal stem cells has developed a hierarchical model of cancer's architecture and progression. This subset of cancer stem cells (CSCs) drives the progression and therapy resistance of cancers. Research to identify the phenotypes of these CSCs presents evidence of a subpopulation that is more resistant to therapy and may proliferate in response. Literature shows that CSCs typically represent around 1%-10% of cell populations in head and neck cancer but this proportion may increase in response to a therapeutic radiation dose. This is shown to be not just as a result of preferential killing, but also their capacity to alter divisional dynamics and enlist the support of a complicit microenvironment in therapy resistance and proliferation. The CSCs represent the apex of a hierarchy in the heterogeneity of cancer cells and may be seen as the agents of treatment failure, metastasis, and tumor recurrence, the principal cause of mortality in head and neck cancers. Greater than 90% of head and neck cancers are squamous cell carcinomas (HNSCCs), and among these an increasing incidence of the involvement of the human papillomavirus (HPV) is reported. Chemoradiotherapy along with surgical resection are the interventions of choice for control and cure of HNSCC, but given CSCs therapy resistance and proliferative responses to radiation, the identification and understanding of the radiobiology of this subpopulation is critical to their targeted elimination. This article reviews the current evidence on CSC generally and in HNSCC specifically to identify their phenotype, evaluate their responses to radiotherapy, and evaluate the defensive mechanisms used to resist therapeutic control. Refereed/Peer-reviewed

Introduction: Some head and neck squamous cell carcinomas (HNSCC) have a distinct aetiology, which depends on the presence of oncogenic human papilloma virus (HPV). Also, HNSCC contains cancer stem cells (CSCs) that have greater radio resistance and capacity to change replication dynamics in response to irradiation compared to non-clonogenic cells. Since there is limited data on CSCs in HNSCC as a function of HPV status, better understanding of their radiobiology may enable improved treatment outcome. Methods: Baseline and post-irradiation changes in CSC proportions were investigated by flow cytometry in a HPV-negative (UM-SCC-1) and a HPV-positive (UM-SCC-47) HNSCC cell line, using fluorescent staining with CD44/ALDH markers. CSC proportions in both irradiated and unirradiated cultures were compared for the two cell lines at various times post-irradiation. To assess repopulation of CSCs, untreated cultures were depleted of CD44+/ALDH+ cells and re-cultured for 3 weeks before flow cytometry analysis. Results: CSC proportions in untreated cell lines were 0.57% (UM-SCC-1) and 2.87% (UM-SCC-47). Untreated cell lines depleted of CD44+/ALDH+ repopulated this phenotype to a mean of 0.15% (UM-SCC-1) and 6.76% (UM-SCC-47). All UM-SCC-47 generations showed elevated CSC proportions after irradiation, with the most significant increase at 2 days post-irradiation. The highest elevation in UM-SCC-1 CSCs was observed at 1 day post-irradiation in the 2nd generation and at 3 days after irradiation in the 3rd generation. When measured after 10 days, only the 3rd generation of UM-SCC-1 showed elevated CSCs. Conclusions: CSC proportions in both cell lines were elevated after exposure and varied with time post irradiation. UM-SCC-47 displayed significant plasticity in repopulating the CSC phenotype in depleted cultures, which was not seen in UM-SCC-1. Refereed/Peer-reviewed

Background: The worldwide incidence of esophageal cancer has greatly increased over the past few decades making it the sixth deadliest cancer. The disease is often detected in advanced stages when surgery is no longer an option. The standard treatment in these situations is combined chemoradiotherapy, by employing drug cocktails that lead to optimal treatment outcomes both from the perspective of tumor control and normal tissue toxicity. Methods: The aim of this work was to collate the existing trials and clinical studies reported on non-operable esophageal cancer and to analyze the results based on treatment outcomes after various drug combinations. Results: Of all drug combinations, cisplatin/5-FU is the most well established chemotherapy regimen for esophageal cancer as both neoadjuvant therapy, an alternative option to surgery, and for palliative purposes. Although this regimen is associated with the most toxicity, it also appears to have the best survival benefit and relief of symptoms. Conclusions: More research is warranted to further increase the therapeutic ratio in non-operable esophageal cancers.

Radiotherapy is widely used in cancer treatment, however the benefits can be limited by radiation-induced damage to neighboring normal tissues. Parthenolide (PTL) exhibits anti-inflammatory and anti-tumor properties and selectively induces radiosensitivity in prostate cancer cell lines, while protecting primary prostate epithelial cell lines from radiation-induced damage. Low doses of radiation have also been shown to protect from subsequent high-dose-radiation-induced apoptosis as well as DNA damage. These properties of PTL and low-dose radiation could be used to improve radiotherapy by killing more tumor cells and less normal cells. Sixteen-week-old male Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) and C57BL/6J mice were treated with PTL (40 mg/kg), dimethylaminoparthenolide (DMAPT, a PTL analogue with increased bioavailability) (100 mg/kg), or vehicle control three times over one week prior to combinations of low (10 mGy) and high (6 Gy) doses of whole-body X-irradiation. Tissues were analyzed for apoptosis at a range of time points up to 72 h postirradiation. Both PTL and DMAPT protected normal tissues, but not prostate tumor tissues, from a significant proportion of high-dose-radiation-induced apoptosis. DMAPT provided superior protection compared to PTL in normal dorsolateral prostate (71.7% reduction, P = 0.026), spleen (48.2% reduction, P = 0.0001) and colorectal tissue (38.0% reduction, P = 0.0002), and doubled radiation-induced apoptosis in TRAMP prostate tumor tissue (101.3% increase, P = 0.039). Both drugs induced the greatest radiosensitivity in TRAMP prostate tissue in areas with higher grade prostatic intraepithelial neoplasia (PIN) lesions. A 10 mGy dose delivered 3 h prior to a 6 Gy dose induced a radioadaptive apoptosis response in normal C57Bl/6J prostate (28.4% reduction, P = 0.045) and normal TRAMP spleen (13.6% reduction, P = 0.047), however the low-dose-adaptive radioprotection did not significantly add to the PTL/DMAPT-induced protection in normal tissues, nor did it affect tumor kill. These results support the use of the more bioavailable DMAPT and low-dose radiation, alone or in combination as useful radioprotectors of normal tissues to alleviate radiotherapy-induced side-effects in patients. The enhanced radiosensitisation in prostate tissues displaying high-grade PIN suggests that DMAPT also holds promise for targeted therapy of advanced prostate cancer, which may go on to become metastatic. The redox mechanisms involved in the differential radioprotection observed here suggest that increased radiotherapy efficacy by DMAPT is more broadly applicable to a range of cancer types. Refereed/Peer-reviewed

Background: Out-of-field organs can be affected by secondary radiations originating from high energy linear accelerators, leading to an increased risk of carcinogenesis. The aim of this work was to determine the risk of second primary cancers (SPC) in the organs distal to the prostate during 3D conformal radiotherapy. Materials and methods: Based on previously measured peripheral photon and neutron doses in a Rando phantom using an 18. MV photon beam, SPC risks in the out-of-field organs were estimated using the linear-no-threshold and the competitive risk models. Whole body as well as organ specific risk coefficients were used to calculate the SPC risks in order to estimate upper and lower risk limits, given the uncertainties associated with the coefficients. Results: The corresponding estimated average SPC risks ranged from 1.5. ±. 0.3% for thyroid to 4.5. ±. 4.2% for colon using whole body risk coefficients and 0.12. ±. 0.03% and 1.45. ±. 1.34%, respectively, using organ specific risk coefficients. The linear-no-threshold and the competitive risk models resulted in the same risk estimates (within the estimated errors) in the dose range received by out-of-field organs (≤1. Gy). Distally located organs such as lungs, oesophagus, and thyroid received higher neutron versus photon dose. Conclusions: The findings have important radiation protection implications when using high energy linear accelerators, as radiation protective measures could be employed to minimize the secondary out-of-field radiation for patients undergoing high energy external beam irradiation of the prostate. Refereed/Peer-reviewed

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. Refereed/Peer-reviewed

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. Refereed/Peer-reviewed

Aims: There is evidence towards the induction of second primary cancers (SPCs) after breast radiotherapy (RT). Organs, such as the lungs and the esophagus, have been identified as common sites for SPC formation. As a result, the current study investigated the risk of secondary carcinogenesis associated with particular RT techniques for breast cancer; including whole breast, segmented breast, partial breast and mammosite brachytherapy. Methods: In this study, seven breast cancer patients had all major organs contoured on their planning computed tomography (CT) images. Whole breast, segmented breast, accelerated partial breast irradiation (APBI) and mammosite boost treatment plans were generated for each patient using Pinnacle3 treatment planning system. Differential dose-volume histograms were generated for a number of critical structures: bladder, brain and central nervous system (CNS), breast, colon, liver, lung, mouth and pharynx, esophagus, ovary, salivary gland, small intestine, stomach, and uterus. The lifetime attributed risk (LAR) of cancer induction was estimated using the Schneider et al. excess absolute risk models and dose-volume histograms for the above organs. Results: The sites with the highest LAR estimates were the ipsilateral and contralateral lungs, and contralateral breast for all treatment techniques. For all sites, the LAR estimates for the segmented breast and mammosite treatments were lower than those for the whole breast and APBI treatments. For right-sided target volumes the liver also resulted in high LAR estimates, with all techniques having a LAR greater than 20 per 10 000 person-years (PY), except for mammosite with a mean LAR estimate of 13.2 per 10 000 PY. For left-sided target volumes the stomach also resulted in high LAR estimates, with both whole breast and APBI having a LAR greater than 20 per 10 000 PY, and mammosite the lowest with a LAR of 8.3 per 10 000 PY. Conclusion: It is concluded that the lungs and contralateral breast showed high LAR estimates. Refereed/Peer-reviewed

The in vivo mouse transgenic pKZ1 chromosomal inversion assay is a sensitive assay that responds to very low doses of DNA-damaging agents. pKZ1 inversions are measured as the frequency of cells expressing E. coli bgalactosidase protein, which can only be produced from an inverted pKZ1 transgene. In previous studies we reported that a single whole-body low dose of 0.01 mGy X rays alone caused an increase in pKZ1 chromosomal inversions in spleen when analyzed 3 days postirradiation, and yet this same dose could protect from high-dose-induced inversions when delivered as a conditioning dose 4 h before or after a 1 Gy challenge dose. In an attempt to explain these results, we performed temporal studies over a wide radiation dose range to determine if the inversion response was temporally different at different doses. pKZ1 mice were irradiated with a single whole-body X-ray dose of 0.01 mGy, 1 mGy or 1 Gy, and spleen sections were then analyzed for pKZ1 inversions at 7 h, 1 day or 7 days after exposure. No change in inversion frequency was observed at the 7 h time point at any dose. At day 1, an increase in inversions was observed in response to the 0.01 mGy dose, whereas a decrease in inversions below sham-treated frequency was observed for the 1 mGy dose. Inversion frequency for both doses returned to sham-treated inversion frequency by day 7. To our knowledge, this is the first reported study to examine the temporal nature of a radiation response spanning a wide dose range, including doses relevant to occupational exposure, and the results are dynamic and dose specific. The results suggest that inversions induced after low-dose irradiation are removed by homeostatic mechanisms within a short time frame, and underscore the importance of studying responses over a period of time when interpreting radiation effects. Refereed/Peer-reviewed

Purpose To simulate stereotactic ablative radiation therapy on hypoxic and well-oxygenated in silico tumors, incorporating probabilistic parameter distributions and linear-quadratic versus linear-quadratic-cubic methodology and the evaluation of optimal fractionation schemes using biological effective dose (BEDα/β=10 or 3) comparisons. Methods and Materials A temporal tumor growth and radiation therapy algorithm simulated high-dose external beam radiation therapy using stochastic methods. Realistic biological proliferative cellular hierarchy and pO2 histograms were incorporated into the 108-cell tumor model, with randomized radiation therapy applied during continual cell proliferation and volume-based gradual tumor reoxygenation. Dose fractions ranged from 6-35 Gy, with predictive outcomes presented in terms of the total doses (converted to BED) required to eliminate all cells that could potentially regenerate the tumor. Results Well-oxygenated tumor control BED10 outcomes were not significantly different for high-dose versus conventional radiation therapy (BED10: 79-84 Gy; Equivalent Dose in 2 Gy fractions with α/β of 10: 66-70 Gy); however, total treatment times decreased from 7 down to 1-3 weeks. For hypoxic tumors, an additional 28 Gy (51 Gy BED10) was required, with BED10 increasing with dose per fraction due to wasted dose in the final fraction. Fractions of 9 Gy compromised well for total treatment time and BED, with BED10:BED3 of 84:176 Gy for oxic and 132:278 Gy for non-reoxygenating hypoxic tumors. Initial doses of 12 Gy followed by 6 Gy further increased the therapeutic ratio. When delivering ≥9 Gy per fraction, applying reoxygenation and/or linear-quadratic-cubic cell survival both affected tumor control doses by a significant 1-2 fractions. Conclusions The complex temporal dynamics of tumor oxygenation combined with probabilistic cell kinetics in the modeling of radiation therapy requires sophisticated stochastic modeling to predict tumor cell kill. For stereotactic ablative radiation therapy, high doses in the first week followed by doses that are more moderate may be beneficial because a high percentage of hypoxic cells could be eradicated early while keeping the required BED10 relatively low and BED3 toxicity to tolerable levels. Conclusions: The complex temporal dynamics of tumor oxygenation combined with probabilistic cell kinetics in the modeling of radiation therapy requires sophisticated stochastic modeling to predict tumor cell kill. For stereotactic ablative radiation therapy, high doses in the first week followed by doses that are more moderate may be beneficial because a high percentage of hypoxic cells could be eradicated early while keeping the required BED10 relatively low and BED3 toxicity to tolerable levels. Refereed/Peer-reviewed

Introduction. Evidence exists that exposure of non-irradiated cells to Irradiated Cell Conditioned Medium (ICCM) can cause effects similar to those resulting from direct radiation damage. This study attempts to validate the stochastic model, relating absorbed dose to the emission and processing of cell death signals by non-irradiated cells, in vitro in PC3 human prostate cancer cell line. Methods. The recipient cell survival was measured after exposure of cells to ICMM derived from donor cells: a) exposed to radiation doses from 2 Gy to 8 Gy and b) of concentrations varying from 2 x102 to 6 x106 irradiated with 2 Gy. Results. Exposure to ICCM, irradiated with doses between 2–8 Gy, resulted in a significant (p < 0.001) decrease in clonogenic survival of non-irradiated recipient cells compared to the control group. However, dose dependency above 2 Gy was not observed, indicating that any dose threshold was below 2 Gy. A significant (p < 0.001) decrease in survival was found in recipient cells exposed to the ICCM, derived from different concentrations of donor cells exposed to 2 Gy, compared to the control group. The recipient cell survival following exposure to ICCM derived from 2 x 102 cells was significantly higher (p < 0.5) compared to the rest of donor cell concentrations, indicating that the toxicity of ICCM depends on the cellular concentration of donor cells. Non-linear regression data fitting provided reasonable agreement with the microdosimetric model for the induction of cell killing through medium-borne signals. Conclusion. For the given cell line and given experimental conditions, significant decreases in cell survival were observed in non-irradiated cells exposed to ICCM derived from donor cells of various concentrations and irradiated with different doses. Refereed/Peer-reviewed

Objective: A temporal Monte Carlo tumour growth and radiotherapy effect model (HYP-RT) simulating hypoxia in head and neck cancer has been developed and used to analyse parameters influencing cell kill during conventionally fractionated radiotherapy. The model was designed to simulate individual cell division up to 108 cells, while incorporating radiobiological effects, including accelerated repopulation and reoxygenation during treatment.Method: Reoxygenation of hypoxic tumours has been modelled using randomised increments of oxygen to tumour cells after each treatment fraction. The process of accelerated repopulation has been modelled by increasing the symmetrical stem cell division probability. Both phenomena were onset immediately or after a number of weeks of simulated treatment. Results: The extra dose required to control (total cell kill) hypoxic vs oxic tumours was 15–25% (8–20 Gy for 5×2 Gy per week) depending on the timing of accelerated repopulation onset. Reoxygenation of hypoxic tumours resulted in resensitisation and reduction in total dose required by approximately 10%, depending on the time of onset. When modelled simultaneously, accelerated repopulation and reoxygenation affected cell kill in hypoxic tumours in a similar manner to when the phenomena were modelled individually; however, the degree was altered, with non-additive results. Simulation results were in good agreement with standard linear quadratic theory; however, differed for more complex comparisons where hypoxia, reoxygenation as well as accelerated repopulation effects were considered.Conclusion: Simulations have quantitatively confirmed the need for patient individualisation in radiotherapy for hypoxic head and neck tumours, and have shown the benefits of modelling complex and dynamic processes using Monte Carlo methods. Refereed/Peer-reviewed