• Humans
• Neoplasms/radiotherapy
• Models, Theoretical
• Radiotherapy Planning, Computer-Assisted/methods
• Radiosurgery/methods
• Precision Medicine
• Radiotherapy/methods

• Artificial intelligence
• Normal tissue complication probability
• Radiotherapy
• Treatment response
• Tumour control probability

• Humans
• Artificial Intelligence
• Precision Medicine/methods
• Radiation Oncology/methods
• Neoplasms/radiotherapy
• Radiotherapy Planning, Computer-Assisted/methods

• Deutsches Krebsforschungszentrum (DKFZ) (1052)

• DNA repair
• Monte Carlo
• cell death
• modelling
• radiobiology

• Neoplasms/genetics
• Neoplasms/radiotherapy
• Humans
• Radiobiology
• Radiotherapy/adverse effects
• Radiotherapy/standards
• Radiation Injuries/genetics
• Dose-Response Relationship, Radiation
• Radiation Tolerance
• Models, Biological
• DNA Damage

• Hopf bifurcation
• Oncolytic virus
• Reaction diffusion system
• Spatial viral distribution
• Travelling wave
• Tumor control probability

• Oncolytic Virotherapy/methods
• Oncolytic Viruses/physiology
• Mathematical Concepts
• Models, Biological
• Humans
• Neoplasms/therapy
• Neoplasms/virology
• Computer Simulation

• NA UAEU College of Science

• Cell death
• Clonogenic survival
• DNA damage
• Ionizing radiation

• Algorithmic approach
• Anatomical parameters
• Intensity-modulated radiotherapy
• Prostate cancer
• Radiobiology

Deterministic particle transport codes usually take into account scattered photons with correct attenuation laws and application of buildup factor to incident beam. Transmission buildup factors for adipose, bone, muscle, and skin human tissues, as well as for various combinations of these media for point isotropic photon source with energies of .15, 1.5 and 15 MeV, for different thickness of layers, were carried out using Geant4 (version 10.5) simulation toolkit. Also, we performed the analysis of existing multilayered shield fitting models (Lin and Jiang, Kalos, Burke and Beck) of buildup factor and the proposition of a new model. We found that the model combining those of Burke and Beck, for low atomic number (Z) followed by high Z materials and Kalos 1 for high Z followed by low Z materials, accurately reproduces simulation results with approximated deviation of 3 ± 3%, 2 ± 2%, and 3 ± 2% for 2, 3, and 4 layers, respectively. Since buildup factors are the key parameter for point kernel calculations, a correct study can be of great interest to the large community of radiation physicists, in general, and to medical imaging and radiotreatment physicists, especially.

The preferred radiotherapy treatment for medulloblastoma is craniospinal irradiation (CSI). With the aim of developing the potential to reduce normal tissue dose and associated post-treatment complications with photon and proton radiotherapy techniques for CSI. This report aims to carefully compare and rank treatment planning and dosimetric outcomes for pediatric medulloblastoma patients using normal tissue complication probability (NTCP) formalism between photon (three-dimensional conformal radiotherapy, intensity-modulated radiotherapy [IMRT], volumetric-modulated arc therapy [VMAT], and HT) and proton CSI.

The treatment data of eight pediatric patients who typically received CSI treatment were used in this study. The patients were 7 years of age on average, with ages ranging from 3 to 11 years. A prescription dose of 3600 cGy was delivered in 20 fractions by the established planning methods. The Niemierko's and Lyman–Kutcher–Burman models were followed to carefully estimate NTCP and compare different treatment plans.

The NTCP of VMAT plans in upper and middle thoracic volumes was relatively high compared to helical tomotherapy (HT) and pencil beam scanning (PBS) (all P < 0.05). PBS rather than IMRT and VMAT in the middle thoracic region (P < 0.06) could significantly reduce the NTCP of the heart. PBS significantly reduced NTCP of the lungs and liver (all P < 0.05).

The NTCP and tumor control probability (TCP) model-based plan ranking along with dosimetric indices will help the clinical practitioner or medical physicists to choose the best treatment plan for each patient based on their anatomical or clinical challenges.

• Craniospinal irradiation
• normal tissue complication probability
• radiobiological model
• radiotherapy
• tumor control probability

• cell culture
• in silico modeling
• mouse model
• organoids
• preclinical models
• proton RBE
• proton therapy
• tissue slice culture
• toxicity
• zebrafish

• n.a. Alois Hirdt-Erben und Wieland-Stiftung

• TCP
• hypofractionation
• hypoxia
• linear-quadratic model
• tumor volume

• outcomes
• predictive modeling
• radiogenomics
• radiomics
• radiotherapy

• R01 CA233487 NCI NIH HHS
• R41 CA243722 NCI NIH HHS
• 75N92022D00018 NHLBI NIH HHS
• P30 CA008748 NCI NIH HHS
• 75N99020D00018 ORFDO NIH HHS
• R37 CA222215 NCI NIH HHS
• 75N94020D00018 NICHD NIH HHS
• 75N92023D00018 NHLBI NIH HHS

• Breast Neoplasms
• Radiotherapy
• Radiotherapy, Conformal
• Respiratory Gated Radiotherapy
• Tumor Tracking

Radiotherapy can effectively kill malignant cells, but the doses required to cure cancer patients may inflict severe collateral damage to adjacent healthy tissues. Recent technological advances in the clinical application has revitalized hyperthermia treatment (HT) as an option to improve radiotherapy (RT) outcomes. Understanding the synergistic effect of simultaneous thermoradiotherapy via mathematical modelling is essential for treatment planning. We here propose a theoretical model in which the thermal enhancement ratio (TER) relates to the cell fraction being radiosensitised by the infliction of sublethal damage through HT. Further damage finally kills the cell or abrogates its proliferative capacity in a non-reversible process. We suggest the TER to be proportional to the energy invested in the sensitisation, which is modelled as a simple rate process. Assuming protein denaturation as the main driver of HT-induced sublethal damage and considering the temperature dependence of the heat capacity of cellular proteins, the sensitisation rates were found to depend exponentially on temperature; in agreement with previous empirical observations. Our findings point towards an improved definition of thermal dose in concordance with the thermodynamics of protein denaturation. Our predictions well reproduce experimental in vitro and in vivo data, explaining the thermal modulation of cellular radioresponse for simultaneous thermoradiotherapy.

• Gillespie algorithm
• Random fluctuations
• Stochastic model
• Tumor control probability

To examine general dose–volume characteristics in Gamma Knife (GK) plans which may be associated with higher tumor control probability (TCP) and equivalent uniform dose (EUD) using characteristic curve sets.

Two sets of dose–volume histograms (DVHs) were exported alongside an analytical purpose‐generated DVH: (a) single‐shot large collimator (8 or 16 mm) emulated with multiple shots of 4 mm collimator. (b) shot‐within‐shot (SWS) technique with isodose lines (IDLs) of 40–75%. TCP, average dose, EUD in single‐fraction (EUD_T) and 2 Gy fractionated regimens (EUD_R) were examined for trends with cumulative DVH (cDVH) shape as calculated using a linear‐quadratic cell survival model (α/β = 10.0 Gy, N₀ = 1 × 10⁶) with both α = 0.20 Gy⁻¹ and α = 0.23 Gy⁻¹.

Using α = 0.20 Gy⁻¹ (α = 0.23 Gy⁻¹), plans in the analytical set with higher shoulder regions had TCP, EUD_T, EUD_R increased by 180%, 5.9%, 10.7% (11.2%, 6.3%, 10.0%), respectively. With α = 0.20 Gy⁻¹ (α = 0.23 Gy⁻¹), plans with higher heels had TCP, EUD_T, EUD_R increased by 4.0%, <1%, <1% (0.6%, <1%, <1%), respectively. In emulating a 16 (8) mm collimator, 64 (12) shots of the small collimators were used. Plans based on small collimators had higher shoulder regions and, with α = 0.20 Gy⁻¹ (α = 0.23 Gy⁻¹), TCP, EUD_T, EUD_R was increased up to 351.4%, 5.0%, 8.8% (270.4%, 5.0%, 6.8%) compared with the single‐shot large collimator. Delivery times ranged from 10.2 to 130.3 min. The SWS technique used 16:8 mm collimator weightings ranging from 1:2 to 9.2:1 for 40–75% IDL. With α = 0.20 Gy⁻¹ (α = 0.23 Gy⁻¹), the 40% IDL plan had the highest shoulder with increased TCP, EUD_T, EUD_R by 130.7%, 9.6%, 17.1% (12.9%, 9.1%, 16.4%) over the 75% IDL plan. Delivery times ranged 6.9–13.8 min.

The magnitude of the shoulder region characteristic to GK cDVHs may be used to rapidly identify superior plan among candidates. Practical issues such as delivery time may require further consideration.

• Gamma Knife
• dose-volume histogram
• equivalent uniform dose
• radiosurgery
• tumor control probability

Radiation therapy is one of the main methods of treating patients with non-small cell lung cancer (NSCLC). However, the resistance of tumor cells to exposure remains the main factor that limits successful therapeutic outcome. To study the molecular/cellular mechanisms of increased resistance of NSCLC to ionizing radiation (IR) exposure, we compared A549 (p53 wild-type) and H1299 (p53-deficient) cells, the two NSCLC cell lines. Using fractionated X-ray irradiation of these cells at a total dose of 60 Gy, we obtained the survived populations and named them A549IR and H1299IR, respectively. Further characterization of these cells showed multiple alterations compared to parental NSCLC cells. The additional 2 Gy exposure led to significant changes in the kinetics of γH2AX and phosphorylated ataxia telangiectasia mutated (pATM) foci numbers in A549IR and H1299IR compared to parental NSCLC cells. Whereas A549, A549IR, and H1299 cells demonstrated clear two-component kinetics of DNA double-strand break (DSB) repair, H1299IR showed slower kinetics of γH2AX foci disappearance with the presence of around 50% of the foci 8 h post-IR. The character of H2AX phosphorylation in these cells was pATM-independent. A decrease of residual γH2AX/53BP1 foci number was observed in both A549IR and H1299IR compared to parental cells post-IR at extra doses of 2, 4, and 6 Gy. This process was accompanied with the changes in the proliferation, cell cycle, apoptosis, and the expression of ATP-binding cassette sub-family G member 2 (ABCG2, also designated as CDw338 and the breast cancer resistance protein (BCRP)) protein. Our study provides strong evidence that different DNA repair mechanisms are activated by multifraction radiotherapy (MFR), as well as single-dose IR, and that the enhanced cellular survival after MFR is reliant on both p53 and 53BP1 signaling along with non-homologous end-joining (NHEJ). Our results are of clinical significance as they can guide the choice of the most effective IR regimen by analyzing the expression status of the p53–53BP1 pathway in tumors and thereby maximize therapeutic benefits for the patients while minimizing collateral damage to normal tissue.

• DNA repair
• ionizing radiation
• non-small cell lung cancer
• p53
• radioresistance

• breast cancer
• miR-122
• microRNAs
• radioresistance

• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Breast Neoplasms/radiotherapy
• Female
• Gene Expression Regulation, Neoplastic/radiation effects
• Genes, Tumor Suppressor
• Humans
• MCF-7 Cells
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• Neoplasm Proteins
• RNA, Neoplasm/biosynthesis
• RNA, Neoplasm/genetics
• Radiation Tolerance
• Up-Regulation/radiation effects

Personalized medicine for patients receiving radiation therapy remains an elusive goal due, in part, to the limits in our understanding of the underlying mechanisms governing tumor response to radiation. The purpose of this study was to develop a kinetic model, in the context of locally advanced lung cancer, connecting cancer cell subpopulations with tumor volumes measured during the course of radiation treatment for understanding treatment outcome for individual patients.

The kinetic model consists of three cell compartments: cancer stem-like cells (CSCs), non-stem tumor cells (TCs) and dead cells (DCs). A set of ordinary differential equations were developed to describe the time evolution of each compartment, and the analytic solution of these equations was iterated to be aligned with the day-to-day tumor volume changes during the course of radiation treatment. A least squares fitting method was used to estimate the parameters of the model that include the proportion of CSCs and their radio-sensitivities. This model was applied to five patients with stage III lung cancer, and tumor volumes were measured from 33 cone-beam computed tomography (CBCT) images for each of these patients. The analytical solution of these differential equations was compared with numerically simulated results.

For the five patients with late stage lung cancer, the derived proportions of CSCs are 0.3 on average, the average probability of the symmetry division is 0.057 and the average surviving fractions of CSCs is 0.967, respectively. The derived parameters are comparable to the results from literature and our experiments. The preliminary results suggest that the CSC self-renewal rate is relatively small, compared to the proportion of CSCs for locally advanced lung cancers.

A novel mathematical model has been developed to connect the population of cancer stem-like cells with tumor volumes measured from a sequence of CBCT images. This model may help improve our understanding of tumor response to radiation therapy, and is valuable for development of new treatment regimens for patients with locally advanced lung cancer.

• Cancer stem-like cells
• Kinetic model
• Lung cancer
• Radiation therapy
• Tumor regression

• Tumor control probability (TCP)
• radiobiological parameter setting
• radiotherapy

• Doppler
• LQ model
• cervical cancer
• mathematical model
• radiosensitivity
• radiotherapy
• ultrasound

• Radiotherapy
• Stochastic modeling
• Tumor heterogeneity

• Humans
• Models, Theoretical
• Neoplasms/genetics
• Neoplasms/therapy
• Stochastic Processes

• Directorate for Engineering

• big data
• data mining
• machine learning
• radiotherapy
• systems radiobiology

• Machine learning
• Outcomes modeling
• Prostate cancer
• Radiotherapy

Intratumoural heterogeneity is known to contribute to poor therapeutic response. Variations in oxygen tension in particular have been correlated with changes in radiation response in vitro and at the clinical scale with overall survival. Heterogeneity at the microscopic scale in tumour blood vessel architecture has been described, and is one source of the underlying variations in oxygen tension. We seek to determine whether histologic scale measures of the erratic distribution of blood vessels within a tumour can be used to predict differing radiation response. Using a two-dimensional hybrid cellular automaton model of tumour growth, we evaluate the effect of vessel distribution on cell survival outcomes of simulated radiation therapy. Using the standard equations for the oxygen enhancement ratio for cell survival probability under differing oxygen tensions, we calculate average radiation effect over a range of different vessel densities and organisations. We go on to quantify the vessel distribution heterogeneity and measure spatial organization using Ripley’s L function, a measure designed to detect deviations from complete spatial randomness. We find that under differing regimes of vessel density the correlation coefficient between the measure of spatial organization and radiation effect changes sign. This provides not only a useful way to understand the differences seen in radiation effect for tissues based on vessel architecture, but also an alternate explanation for the vessel normalization hypothesis.

In this paper we use a mathematical model, called a hybrid cellular automaton, to study the effect of different vessel distributions on radiation therapy outcomes at the cellular level. We show that the correlation between radiation outcome and spatial organization of vessels changes signs between relatively low and high vessel density. Specifically, that for relatively low vessel density, radiation efficacy is decreased when vessels are more homogeneously distributed, and the opposite is true, that radiation efficacy is improved, when vessel organisation is normalised in high densities. This result suggests an alteration to the vessel normalization hypothesis which states that normalisation of vascular beds should improve radio- and chemo-therapeutic response, but has failed to be validated in clinical studies. In this alteration, we show that Ripley’s L function allows discrimination between vascular architectures in different density regimes in which the standard hypothesis holds and does not hold. Further, we find that this information can be used to augment quantitative histologic analysis of tumours to aid radiation dose personalisation.

AIM: To explore the potential correlation between insulin-like growth factor receptor-1 (IGF-1R) expression and rectal cancer radiosensitivity.

METHODS: Eighty-seven rectal cancer patients (cTNM I-III) treated in our department between January 2011 and December 2012 were enrolled. All subjects were treated with preoperative radiotherapy and radical resection of rectal carcinoma. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were performed to detect IGF-1R expression in pre-treatment and postoperative colorectal cancer specimens. Radiosensitivity for rectal cancer specimens was evaluated by observing rectal carcinoma mass regression combined with fibrosis on HE staining, degree of necrosis and quantity of remaining tumor cells. The relative IGF-1R expression was evaluated for association with tumor radiosensitivity.

RESULTS: Immunohistochemistry showed diffuse IGF-1R staining on rectal cancer cells with various degrees of signal density. IGF-1R expression was significantly correlated with cTNM staging (P = 0.012) while no significant association was observed with age, sex, tumor size and degree of differentiation (P = 0.424, 0.969, 0.604, 0.642). According to the Rectal Cancer Regression Grades (RCRG), there were 31 cases of RCRG1 (radiation sensitive), 28 cases of RCRG2 and 28 cases of RCRG3 (radiation resistance) in 87 rectal cancer subjects. IGF-1R protein hyper-expression was significantly correlated with a poor response to radiotherapy (P < 0.001, r = 0.401). RT-PCR results from pre-radiation biopsy specimens also showed that IGF-1R mRNA negative group exhibited a higher radiation sensitivity (P < 0.001, r = 0.497). Compared with the pre-radiation biopsy specimens, the paired post-operative specimens showed a significantly increased IGF-1R protein and mRNA expression in the residual cancer cells (P < 0.001, respectively).

CONCLUSION: IGF-1R expression level may serve as a predictive biomarker for radiosensitivity of rectal cancer before preoperative radiotherapy.

• Insulin-like growth factor-1 receptor
• Rectal carcinoma
• Preoperative radiotherapy
• Immunohistochemistry
• Reverse transcription-polymerase chain reaction

• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Biopsy
• Carcinoma/chemistry
• Carcinoma/pathology
• Carcinoma/radiotherapy
• Carcinoma/surgery
• Female
• Fibrosis
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Necrosis
• Neoadjuvant Therapy
• Neoplasm Staging
• RNA, Messenger/metabolism
• Radiation Tolerance
• Radiotherapy, Adjuvant
• Radiotherapy, Intensity-Modulated
• Receptor, IGF Type 1
• Receptors, Somatomedin/genetics
• Receptors, Somatomedin/metabolism
• Rectal Neoplasms/genetics
• Rectal Neoplasms/metabolism
• Rectal Neoplasms/pathology
• Rectal Neoplasms/radiotherapy
• Rectal Neoplasms/surgery
• Retrospective Studies
• Reverse Transcriptase Polymerase Chain Reaction
• Time Factors
• Treatment Outcome
• Up-Regulation

The tumour control probability (TCP) is a formalism derived to compare various treatment regimens of radiation therapy, defined as the probability that given a prescribed dose of radiation, a tumour has been eradicated or controlled. In the traditional view of cancer, all cells share the ability to divide without limit and thus have the potential to generate a malignant tumour. However, an emerging notion is that only a sub-population of cells, the so-called cancer stem cells (CSCs), are responsible for the initiation and maintenance of the tumour. A key implication of the CSC hypothesis is that these cells must be eradicated to achieve cures, thus we define TCP_S as the probability of eradicating CSCs for a given dose of radiation. A cell surface protein expression profile, such as CD44high/CD24low for breast cancer or CD133 for glioma, is often used as a biomarker to monitor CSCs enrichment. However, it is increasingly recognized that not all cells bearing this expression profile are necessarily CSCs, and in particular early generations of progenitor cells may share the same phenotype. Thus, due to the lack of a perfect biomarker for CSCs, we also define a novel measurable TCP_CD+, that is the probability of eliminating or controlling biomarker positive cells. Based on these definitions, we use stochastic methods and numerical simulations parameterized for the case of gliomas, to compare the theoretical TCP_S and the measurable TCP_CD+. We also use the measurable TCP to compare the effect of various radiation protocols.

• Biomarkers, Tumor/metabolism
• Gene Expression Regulation, Neoplastic/radiation effects
• Humans
• Models, Theoretical
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Neoplastic Stem Cells/radiation effects
• Tumor Cells, Cultured

• Adult
• Aged
• Cell Proliferation/radiation effects
• Cohort Studies
• Female
• Glioblastoma/diagnosis
• Glioblastoma/pathology
• Glioblastoma/radiotherapy
• Humans
• Male
• Middle Aged
• Models, Biological
• Neoplasm Invasiveness
• Precision Medicine/methods
• Prognosis
• Radiotherapy Dosage
• Radiotherapy Planning, Computer-Assisted/methods
• Radiotherapy, Intensity-Modulated/methods
• Treatment Outcome

• R01 NS060752 NINDS NIH HHS
• R01 CA16437 NCI NIH HHS

• 5-FU
• 5-fluorouracil
• AFP
• AJCC
• American Joint Committee on Cancer
• BCLC
• Barcelona Clinic Liver Cancer
• CRC
• CapeOx
• DEB
• DEBIRI
• EASL
• EGFR
• European Association for Study of the Liver
• FOLFIRI
• FOLFOX
• HCC
• IRE
• NCCN
• NCI
• NET
• NSCLC
• National Cancer Institute
• National Comprehensive Cancer Network
• PV
• RF
• RT
• VEGFR
• capecitabine/oxaliplatin
• colorectal cancer
• drug-eluting bead
• drug-eluting beads with irinotecan
• epidermal growth factor receptor
• hepatocellular carcinoma
• irinotecan/5-fluorouracil/leucovorin
• irreversible electroporation
• neuroendocrine tumor
• non–small-cell lung cancer
• oxaliplatin/5-fluorouracil/leucovorin
• portal vein
• radiation therapy
• radiofrequency
• vascular endothelial growth factor receptor
• α-fetoprotein

• Ablation Techniques
• Catheterization
• Endovascular Procedures
• Evidence-Based Medicine
• Humans
• Medical Oncology/methods
• Neoplasms/diagnostic imaging
• Neoplasms/pathology
• Neoplasms/therapy
• Practice Guidelines as Topic
• Radiography, Interventional
• Treatment Outcome

• R01 CA126809 NCI NIH HHS
• CA126809 NCI NIH HHS

Preoperative chemoradiotherapy represents the standard treatment for patients with locally advanced rectal cancer. Unfortunately, the response of individual tumors to multimodal treatment is not uniform and ranges from complete response to complete resistance. This poses a particular problem for patients with a priori resistant tumors because they may be exposed to irradiation and chemotherapy, treatment regimens that are both expensive and at times toxic, without benefit. Accordingly, there is a strong need to establish molecular biomarkers that predict the response of an individual patient’s tumor to multimodal treatment and that indicate treatment-associated toxicities prior to therapy. Such biomarkers may guide clinicians in choosing the best possible treatment for each individual patient. In addition, these biomarkers could be used to identify novel molecular targets and thereby assist in implementing novel strategies to sensitize a priori resistant tumors to multimodal treatment regimens.

The aim of this review is to summarize recent findings about the molecular basis of treatment resistance and treatment toxicity in patients with rectal cancer. Whole-genome, as well as single-biomarker or multibiomarker, analyses and their potential implications will be highlighted. At the end, we will outline a future vision of rectal cancer treatment in the era of personalized medicine.

• Biomarkers, Tumor/genetics
• Chemoradiotherapy/adverse effects
• Chemoradiotherapy/methods
• Combined Modality Therapy
• DNA Damage/drug effects
• DNA Damage/radiation effects
• DNA Repair/drug effects
• DNA Repair/radiation effects
• Drug Resistance, Neoplasm/genetics
• Gene Expression Profiling
• Genetic Variation/genetics
• Humans
• Neoadjuvant Therapy/methods
• Precision Medicine
• Prognosis
• Radiation Tolerance/genetics
• Rectal Neoplasms/genetics
• Rectal Neoplasms/mortality
• Rectal Neoplasms/pathology
• Rectal Neoplasms/therapy
• Survival Rate