Clinical Radiation Research Articles

Endogenous Retrovirus Activation as a Key Mechanism of Anti-Tumor Immune Response in Radiotherapy.

The generation of DNA double-strand breaks has historically been taught as the mechanism through which radiotherapy kills cancer cells. Recently, radiation-induced cytosolic DNA release and activation of the cGAS/STING pathway, with ensuing induction of interferon secretion and immune activation, have been recognized as important mechanisms for radiation-mediated anti-tumor efficacy. Here we demonstrate that radiation-induced activation of endogenous retroviruses (ERVs) also plays a major role in regulating the anti-tumor immune response during irradiation. Radiation-induced ERV-associated dsRNA transcription and subsequent activation of the innate antiviral MDA5/MAVS/TBK1 pathway led to downstream transcription of interferon-stimulated genes. Additionally, genetic knockout of KAP1, a chromatin modulator responsible for suppressing ERV transcription sites within the genome, enhanced the effect of radiation-induced anti-tumor response in vivo in two different tumor models. This anti-tumor response was immune-mediated and required an intact host immune system. Our findings indicate that radiation-induced ERV-dsRNA expression and subsequent immune response play critical roles in clinical radiotherapy, and manipulation of epigenetic regulators and the dsRNA-sensing innate immunity pathway could be promising targets to enhance the efficacy of radiotherapy and cancer immunotherapy.

Generalized Multi-Hit Model of Radiation-Induced Cell Survival with a Closed-Form Solution: An Alternative Method for Determining Isoeffect Doses in Practical Radiotherapy.

The standard linear-quadratic (LQ) model is currently the preferred model for describing the ionizing radiation-induced cell survival curves and tissue responses. And the LQ model is also widely used to calculate isoeffect doses for comparing different fractionated schemes in clinical radiotherapy. Despite its ubiquity, because the actual dose-response curve may appear linear at high doses in the semilogarithmic plot, the application of the LQ model is greatly challenged in the high-dose region, while the dose employed in stereotactic body radiotherapy (SBRT) is often in this area. Alternatively, the biophysical models of radiation-induced effects with a linear-quadratic-linear (LQL) characteristic can well fit the dose-survival curve of cells in vitro. However, most of these LQL models are phenomenological and have not fully considered the biophysical mechanism of radiation-induced damage and repair, and the fitting quality decreases in some high-dose ranges. In this work, to provide an alternative model to describe the cell survival curves in high-dose ranges and predict the biologically effective dose (BED) for SBRT, we propose a novel generalized multi-hit model with a closed-form solution by considering an upper bound on the number of lethal damages induced by radiation that can be repaired in a cell. This model has a clear biophysical basis and a simple expression, and also has the LQL characteristic under low- and high-dose approximate conditions. The experimental data fitting indicated that compared to the standard LQ model and our previously generalized target model, the current model can better fit the radiation-induced cell survival curves in the high-dose ranges (P < 0.05). The current model parameters and parameter ratios were determined from the fits in different kinds of cell lines irradiated with various dose rates and linear energy transfer (LET), which indicates that the model parameters significantly depend on the dose rate and LET. Based on the current model, we derived two equivalence formulae for the BED calculations in the low- and high-dose ranges, and then calculated the BED for the clinical data of SBRT from 17 selected studies. The correlation analysis showed that there were significant linear correlations between the BED at isocenter and planning target volume (PTV) edge calculated by this model and the LQ model (R > 0.86, P < 0.001). In conclusion, the generalized multi-hit model proposed in this work can be used as an alternative tool to handle in vitro radiation-induced cell survival curves in high-dose ranges, and calculate the in vivo BED for comparing the dose fractionation schemes in clinical radiotherapy.

Targeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss.

Clinical radiotherapy treats life-threatening cancers, but the radiation often affects neighboring normal tissues including bone. Acute effects of ionizing radiation include oxidative stress, DNA damage, and cellular apoptosis. We show in this study that a large proportion of bone marrow cells, osteoblasts, and matrix-embedded osteocytes recover from these insults only to attain a senescent profile. Bone analyses of senescence-associated genes, senescence-associated beta-galactosidase (SA-β-gal) activity, and presence of telomere dysfunction-induced foci (TIF) at 1, 7, 14, 21, and 42 days post-focal radiation treatment (FRT) in C57BL/6 male mice confirmed the development of senescent cells and the senescence-associated secretory phenotype (SASP). Accumulation of senescent cells and SASP markers were correlated with a significant reduction in bone architecture at 42 days post-FRT. To test if senolytic drugs, which clear senescent cells, alleviate FRT-related bone damage, we administered the senolytic agents, dasatinib (D), quercetin (Q), fisetin (F), and a cocktail of D and Q (D+Q). We found moderate alleviation of radiation-induced bone damage with D and Q as stand-alone compounds, but no such improvement was seen with F. However, the senolytic cocktail of D+Q reduced senescent cell burden as assessed by TIF+ osteoblasts and osteocytes, markers of senescence (p16 Ink4a and p21), and key SASP factors, resulting in significant recovery in the bone architecture of radiated femurs. In summary, this study provides proof of concept that senescent cells play a role in radiotherapy-associated bone damage, and that reduction in senescent cell burden by senolytic agents is a potential therapeutic option for alleviating radiotherapy-related bone deterioration. © 2020 American Society for Bone and Mineral Research.

An artificial neural network to model response of a radiotherapy beam monitoring system.

The integral quality monitor (IQM) is a real-time radiotherapy beam monitoring system, which consists of a spatially sensitive large-area ion chamber, mounted at the collimator of the linear accelerator (linac), and a calculation algorithm to predict the detector signal for each beam segment. By comparing the measured and predicted signals the system validates the beam delivery. The current commercial version of IQM uses an analytic method to predict the signal, which requires a semi-empirical approach to determine and optimize various calculation parameters. The process of developing the calculation model is complex and time consuming, and moreover, the model cannot be easily generalized across various beam delivery platforms with different combinations of beam energy, beam flattening, beam shaping elements, and Linac models. Therefore, as an alternative solution, we investigated the feasibility of developing a machine learning (ML) method, using an artificial neural network (ANN), to predict the ion chamber signal. In developing an ANN, it is not necessary to explicitly account for each of the elements of beam interactions with various structures in the beam path to the ion chamber. The ANN was designed with multilayer perceptron (MLP). The input layer consisted of multiple features, derived from the geometrical characteristics of beam segments. Gradient descent error backpropagation technique was used to train the ANN. The combined training dataset included 270 rectangular fields, and 801 clinical IMRT fields delivered using 6 MV beams on Varian TrueBeamTM and Elekta InfinityTM . Each of 12 different ANN configurations (3 different sets of input features×4 different sets of number of hidden nodes) was simulated 10 times with randomly selected 80% of data for training and the remaining data for validation. Artificial neural networks with one hidden layer, consisting of 10 nodes, and 10 input features provided optimum results. Once the feature sets were extracted, the time required for the network training was on the order of a few minutes, and the time required to perform an output calculation per field was only fraction of a second. More than 95% of clinical intensity-modulated radiation therapy (IMRT) segments were calculated within±3.0% modeling error for Varian Truebeam (90% and ±3.3% for Elekta Infinity). A total of 3320 volumetric-modulated arc therapy (VMAT) segments from Truebeam were calculated using the ANN trained with IMRT fields. More than 95% of the cumulative VMAT beam segments were within 3.6% modeling error, similar to the performance for IMRT segments. In general the modeling error was found to be inversely proportional to the size and intensity of the beam segment. A prototype ANN has been developed for predicting the signals of the IQM system, with substantially less efforts compared to the analytic model. The performance of the ANN was found to be at least equivalent to that of the analytic method, in terms of average and maximum error, for 6 MV beams on both Varian TrueBeam and Elekta Infinity platforms.

Estimation of the effects of radiotherapy treatment delays on tumour responses: A review

Background: The effects of radiotherapy treatment delays vary considerably depending on several factors, including tumour type, tumour characteristics, extent of delay and the radiation schedule. Both delays during treatment and delays in starting treatment may have an impact on tumour outcomes. In developing countries, particularly, budget constraints and overwhelming patient numbers may contribute to long waiting lists that may affect treatment efficacy. Empirical evidence on which to base treatment decisions and to motivate for additional resources is important. Aim: The aim of this study was to review the evidence that radiotherapy treatment delays may affect tumour response in several common tumour types and to determine, where reported, estimates of specific, commonly applied parameters to incorporate time and proliferation. Setting: Clinical radiotherapy of solid tumours. Methods: A review of the literature from an online database and search engine using terms associated with treatment delays or interruptions for a range of common tumour types was conducted. Results: There is evidence in several of the tumour types reviewed, including those of the head and neck, breast, cervix, prostate, lung, colorectal, anus, brain and bladder, that delays in radiotherapy can affect treatment outcomes. While, in most cases, delays in treatment are detrimental, there are certain examples cited where delays between other modalities and radiotherapy may be beneficial. Conclusion: While levels of evidence vary, failure to take note of proliferative effects of tumours because of extensions in treatment may in many cases result in avoidable treatment failures. It is thus prudent for radiation oncology departments to have clear policies for avoiding and dealing with treatment delays.

Effect of the rotation errors on the γ pass rate of volume-modulated arc therapy plan in rectal cancer.

To study the effect of rotation errors on the γ pass rate of volume-modulated arc therapy (VMAT) plan in rectal cancer based on the ArcCheck phantom. CT data from 20 rectal cancer patients underwent VMRT were selected randomly for this study. Targeting areas were selected, and clinical radiotherapy and validation plans were formulated. ArcCheck model was selected to validate the radiotherapy plans. The effect of the rotation errors on the dosimetric verification for VMAT in rectal cancer was simulated and analyzed with ArcCheck model software. When there was no rotation errors, the γ pass rate of VMRT plans was more than 95%. When the absolute rotation angle was less than or equal to 1°, the γ pass rate of VMAT plans was more than 90%, meeting the clinical requirements. When the absolute rotation angle was greater than 1°, the γ pass rate was less than 90%, which did not meet clinical requirements. The rotation errors affect the γ pass rate of VMAT plans. The larger the rotation angle, the lower the γ pass rate. It meets clinical requirements when the rotation error is less than or equal to 1°.

The Role of Autophagy in Cancer Radiotherapy.

Autophagy, a pathway for lysosomal-mediated cellular degradation, is a catabolic process that recycles intracellular components to maintain metabolism and survival. It is classified into three major types: macroautophagy, microautophagy, and the chaperone-mediated autophagy (CMA). Autophagy is a dynamic and multistep process that includes four stages: nucleation, elongation, autophagosome formation, and fusion. Interestingly, the influence of autophagy in cancer development is complex and paradoxical, suppressive, or promotive in different contexts. Autophagy in cancer has been demonstrated to serve as both a tumour suppressor and promoter. Radiotherapy is a powerful and common strategy for many different types of cancer and can induce autophagy, which has been shown to modulate sensitivity of cancer to radiotherapy. However, the role of autophagy in radiation treatment is controversial. Some reports showed that the upregulation of autophagy was cytoprotective for cancer cells. Others, in contrast, showed that the induction of autophagy was advantageous. Here, we reviewed recent studies and attempted to discuss the various aspects of autophagy in response to radiotherapy of cancer. Thus, we could decrease the viability of cancer cell and increase the sensibility of cancer cells to radiation, providing a new basis for the application of autophagy in clinical tumor radiotherapy.

MRI-Based Upper Abdominal Organs-at-Risk Atlas for Radiation Oncology

The purpose of our study was to provide a guide for identification and contouring of upper abdominal organs-at-risk (OARs) in the setting of online magnetic resonance imaging (MRI)-guided radiation treatment planning and delivery. After a needs assessment survey, it was determined that an upper abdominal MRI-based atlas of normal OARs would be of benefit to radiation oncologists and radiation therapists. An anonymized diagnostic 1.5T MRI from a patient with typical upper abdominal anatomy was used for atlas development. Two MRI sequences were selected for contouring, a T1-weighted gadoxetic acid contrast-enhanced MRI acquired in the hepatobiliary phase and axial fast imaging with balanced steady-state precession. Two additional clinical MRI sequences from commercial online MRI-guided radiation therapy systems were selected for contouring and were included in the final atlas. Contours from each data set were completed and reviewed by radiation oncologists, along with a radiologist who specializes in upper abdominal imaging, to generate a consensus upper abdominal MRI-based OAR atlas. A normal OAR atlas was developed, including recommendations for contouring. The atlas and contouring guidance are described, and high-resolution MRI images and contours are displayed. OARs, such as the bile duct and biliary tree, which may be better seen on MRI than on computed tomography, are highlighted. The full DICOM/DICOM-RT MRI images from both the diagnostic and clinical online MRI-guided radiation therapy systems data sets have been made freely available, for educational purposes, at econtour.org. This MRI contouring atlas for upper abdominal OARs should provide a useful reference for contouring and education. Its routine use may help to improve uniformity in contouring in radiation oncology planning and OAR dose calculation. Full DICOM/DICOM-RT images are available online and provide a valuable educational resource for upper abdominal MRI-based radiation therapy planning and delivery.

Targeting Specific Sites in Biological Systems with Synchrotron X-Ray Microbeams for Radiobiological Studies at the Photon Factory

X-ray microbeams have been used to explore radiobiological effects induced by targeting a specific site in living systems. Synchrotron radiation from the Photon Factory, Japan, with high brilliance and highly parallel directionality is a source suitable for delivering a particular beam size or shape, which can be changed according to target morphology by using a simple metal slit system (beam size from 5 μm to several millimeters). Studies have examined the non-targeted effects, called bystander cellular responses, which are thought to be fundamental mechanisms of low-dose or low-dose-rate effects in practical radiation risk research. Narrow microbeams several tens of micrometers or less in their size targeted both the cell nucleus and the cytoplasm. Our method combined with live-cell imaging techniques has challenged the traditional radiobiological dogma that DNA damage is the only major cause of radiation-induced genetic alterations and is gradually revealing the role of organelles, such as mitochondria, in these biological effects. Furthermore, three-dimensionally cultured cell systems have been used as microbeam targets to mimic organs. Combining the spatial fractionation of X-ray microbeams and a unique ex vivo testes organ culture technique revealed that the tissue-sparing effect was induced in response to the non-uniform radiation fields. Spatially fractionated X-ray beams may be a promising tool in clinical radiation therapy.

Evaluation of a pixelated large format CMOS sensor for x-ray microbeam radiotherapy.

PurposeCurrent techniques and procedures for dosimetry in microbeams typically rely on radiochromic film or small volume ionization chambers for validation and quality assurance in 2D and 1D, respectively. Whilst well characterized for clinical and preclinical radiotherapy, these methods are noninstantaneous and do not provide real time profile information. The objective of this work is to determine the suitability of the newly developed vM1212 detector, a pixelated CMOS (complementary metal‐oxide‐semiconductor) imaging sensor, for in situ and in vivo verification of x‐ray microbeams.MethodsExperiments were carried out on the vM1212 detector using a 220 kVp small animal radiation research platform (SARRP) at the Helmholtz Centre Munich. A 3 x 3 cm2 square piece of EBT3 film was placed on top of a marked nonfibrous card overlaying the sensitive silicon of the sensor. One centimeter of water equivalent bolus material was placed on top of the film for build‐up. The response of the detector was compared to an Epson Expression 10000XL flatbed scanner using FilmQA Pro with triple channel dosimetry. This was also compared to a separate exposure using 450 µm of silicon as a surrogate for the detector and a Zeiss Axio Imager 2 microscope using an optical microscopy method of dosimetry. Microbeam collimator slits with range of nominal widths of 25, 50, 75, and 100 µm were used to compare beam profiles and determine sensitivity of the detector and both film measurements to different microbeams.ResultsThe detector was able to measure peak and valley profiles in real‐time, a significant reduction from the 24 hr self‐development required by the EBT3 film. Observed full width at half maximum (FWHM) values were larger than the nominal slit widths, ranging from 130 to 190 µm due to divergence. Agreement between the methods was found for peak‐to‐valley dose ratio (PVDR), peak to peak separation and FWHM, but a difference in relative intensity of the microbeams was observed between the detectors.ConclusionsThe investigation demonstrated that pixelated CMOS sensors could be applied to microbeam radiotherapy for real‐time dosimetry in the future, however the relatively large pixel pitch of the vM1212 detector limit the immediate application of the results.

A Series of 62 Skull Base Chordomas in Pediatric and Adolescent Patients: Clinical Characteristics, Treatments, and Outcomes.

Skull base chordomas in pediatric and adolescent patients are rare and challenging for surgeons. Well-specified diagnosis and treatment are of great value for the long-term control of chordoma. This study summarizes well-followed pediatric and adolescent chordoma (PAC) patients treated in a single Asian center. PAC patients were enrolled. Data collected included clinical presentation, tumor volume, texture, surgical approach, pathology, complications, adjuvant radiotherapy (RT), and long-term outcomes. Sixty-two patients were identified from a total of 516 skull base chordoma patients (12%). Diplopia was the most prominent complaint (30%). The craniocervical junction area was the most common location (41.8%) and had the highest proportion of large tumors. The gross total resection (GTR) rate was 20.3%. The GTR rate was lowest for tumors located in the craniocervical junction area. Thirty-eight cases experienced surgical complications. Of note, there was a significant difference in the complication rate between endoscopic approaches (22.7%) and open approaches (57.9%) (P = 0.005). The mean follow-up was 66.5 months. The GTR group showed better survival compared with the non-GTR group (P = 0.043). Metastases were found in two cases. No significant difference in the overall survival (OS) time was found between the group with RT and the group without RT (P = 0.559). A higher proportion of PAC patients than previously reported exist in the population in Asia, and the metastatic rate is lower. GTR predicts excellent long-term control of the disease. RT should be considered on an individual basis.

Comparison between the american joint committee on cancer (ajcc) anatomic and prognostic stages for breast cancer

Introduction: The knowledge regarding the biology of breast cancer has grown substantially and resulted in the identification of different breast cancer subtypes based on their molecular profile, which led to an important change in treatment, from a standardized therapy to a personalized one. A panel of experts and AJCC representatives were responsible for preparing the most recent Cancer Staging Manual. The panel recognized the clinical usefulness of biological factors such as histological grade, expression of hormone receptors (HR; estrogen and progesterone) and overexpression and/or amplification of the human epidermal growth factor receptor 2 (HER2) in predicting patient survival7 and incorporated data regarding these biomarkers in the new staging system. In addition, for eligible cases, the ‘Recurrence score’ was also incorporated, generated by the analysis of OncotypeDx (genomic test). The new manual, therefore, started to use 3 stagings. Anatomical staging – based on the classic TNM; clinical prognostic staging and pathological prognosis – association of TNM with prognostic biomarkers (using clinical data in the first and data after surgical treatment in the second). Objective: To verify the agreement between anatomical staging from the 7th edition of the AJCC manual and the prognosis from its 8th edition in a cohort of breast cancer patients at the Hospital do Servidor Público Estadual de São Paulo. Methodology: Observational and cross-sectional study, which evaluated patients undergoing surgical treatment at Hospital do Servidor Público Estadual from March, 2014 to March, 2019. Information was collected regarding age, menopausal status, tumor characteristics, anatomical and clinical staging, neoadjuvant chemotherapy, adjuvant chemotherapy and radiotherapy, and type of surgery performed. Patients were staged using the digital platform “TNM8 Breast Cancer Calculator”. Results: 805 patients were included in the analysis. All patients were females aged between 29 and 97 years, mostly in the post-menopausal period (78.88%). 74.04% of cases were positive for ER, 66.21% PR-positive, and 88.07% HER2-negative. Prognostic staging downgraded a total of 285 out of 805 patients (35.4%). Almost all of the cases that decreased in staging were ER and/or PR+ (283 of 285). Most of those who went up were Triple Negatives (100 out of 111). Conclusion: Prognostic Staging changes the staging in almost half of the cases and there was a greater number of decreased staging in total and an association of increased staging with tumors considered to have a worse prognosis, which is in agreement with several studies already carried out since the new manual came out.

15. Quantitative Evaluation and Associated Uncertainties in Clinical Radiation Therapy Technology

15. Quantitative Evaluation and Associated Uncertainties in Clinical Radiation Therapy Technology

Inhibition of the Spectraplakin Protein Microtubule Actin Crosslinking Factor 1 Sensitizes Glioblastomas to Radiation.

BackgroundMicrotubule actin crosslinking factor 1 (MACF1) is a spectraplakin cytoskeletal crosslinking protein whose function and role in cancer biology has lacked investigation. Recent studies have identified MACF1 as a novel target in glioblastomas expressed in tissue from tumor patient explants but not normal brain tissue and when silenced has an antitumorigenic impact on these tumors. Radiation as a single agent therapy to treat glioblastomas has been used for decades and has done little to improve survival of individuals diagnosed with this disease. However, contemporary clinical radiotherapy protocols have provided evidence that combinatorial radiotherapy approaches confer a therapeutic benefit in glioblastoma patients. In this study MACF1 was investigated as a radiosensitization target in glioblastomas.MethodsTo provide context of MACF1 in glioblastomas, The Cancer Genome Atlas expression analyses were performed in conjunction with genes associated with glioblastoma evolution, while a genetic inhibitory approach, cell migratory assays, and immunofluorescence procedures were used to evaluate responses to MACF1 suppression with radiation. Additionally, expression analyses were conducted to assess co-expression of mTOR signaling pathway regulators and MACF1 in glioblastoma patient samples.ResultsOur amalgamation approach demonstrated that negative regulation of MACF1, which was positively correlated with epidermal growth factor receptor and p70s6k expression, enhanced the sensitivity of glioblastoma cells to radiation as a consequence of reducing glioblastoma cell viability and migration. Mechanistically, the antitumorigenic effects on glioblastoma cell behaviors after radiation and impairing MACF1 function were associated with decreased expression of ribosomal protein S6, a downstream effector of p70s6k.ConclusionMACF1 represents a diagnostic marker with target specificity in glioblastomas that can enhance the efficacy of radiation while minimizing normal tissue toxicity. This approach could potentially expand combinatorial radiation strategies for glioblastoma treatments via impairment of translational regulatory processes that contribute to poor patient survival.

Initial assessment of 3D magnetic resonance fingerprinting (MRF) towards quantitative brain imaging for radiation therapy.

Magnetic resonance fingerprinting (MRF) provides quantitative T1/T2 maps, enabling applications in clinical radiotherapy such as large-scale, multi-center clinical trials for longitudinal assessment of therapy response. We evaluated the feasibility of a quantitative three-dimensional-MRF (3D-MRF) towards its radiotherapy applications of primary brain tumors. A fast whole-brain 3D-MRF sequence initially developed for diagnostic radiology was optimized using flexible body coils, which is the typical MR imaging setup for radiotherapy treatment planning and for MR imaging (MRI)-guided treatment delivery. Optimization criteria included the accuracy and the precision of T1/T2 quantifications of polyvinylpyrrolidone (PVP) solutions, compared to those from the 3D-MRF using a 32-channel head coil. The accuracy of T1/T2 quantifications from the optimized MRF was first examined in healthy volunteers with two different coil setups. The intra- and inter-scanner variations of image intensity from the optimized sequence were quantified by longitudinal scans of the PVP solutions on two 3T scanners. Using a 3D-printed MRI geometry phantom, susceptibility-induced distortion with the optimized 3D-MRF was quantified as the Dice coefficient of phantom contours, compared to those from CT images. By introducing intentional head motion during 10% of the scan, the robustness of the optimized 3D-MRF towards motion was evaluated through visual inspection of motion artifacts and through quantitative analysis of image sharpness in brain MRF maps. The optimized sequence acquired whole-brain T1, T2 and proton density maps and with a resolution of 1.2×1.2×3mm3 in 10min, similar to the total acquisition time of 3D T1- and T2-weighted images of the same resolution. In vivo T1 and T2 values of the white and gray matter were consistent with literature. The intra- and inter-scanner variability of the intensity-normalized MRF T1 was 1.0%±0.7% and 2.3%±1.0% respectively, in contrast to 5.3%±3.8% and 3.2%±1.6% from the normalized T1-weighted MRI. Repeatability and reproducibility of MRF T1 were independent of intensity normalization. Both phantom and human data demonstrated that the optimized 3D-MRF is more robust to subject motion and artifacts from subject-specific susceptibility difference. Compared to CT contours, the Dice coefficient of phantom contours from 3D-MRF was 0.93, improved from 0.87 from the T1-weighted MRI. Compared to conventional MRI, the optimized 3D-MRF demonstrated improved repeatability across time points and reproducibility across scanners for better tissue quantification, as well as improved robustness to subject-specific susceptibility and motion artifacts under a typical MR imaging setup for radiotherapy. More importantly, quantitative MRF T1/T2 measurements lead to promising potentials towards longitudinal quantitative assessment of treatment response for better adaptive therapy and for large-scale, multi-center clinical trials.

Characterization of positional accuracy of a double-focused and double-stack multileaf collimator on an MR-guided radiotherapy (MRgRT) Linac using an IC-profiler array.

With advance magnetic resonance (MR)-guided online adaptive radiotherapy (MRgoART) relying on calculation-based intensity-modulated radiation therapy (IMRT) quality assurance (QA), accurate and sensitive QA of the multileaf collimator (MLC) becomes an increasingly essential component for routine machine QA. As such, it is important to assure compliance with the AAPM TG142 guidelines to supplement calculation-based QA methods for an online adaptive radiotherapy program. We have developed and implemented an efficient and highly sensitive QA procedure using an ionization chamber profiler (ICP) array to enable real-time characterization of the positional accuracy of a double-focused and double-stacked MLC on a clinical MR-guided radiotherapy (MRgRT) system and to supplement calculation-based QA for an MRgoART program. An in-house MR-compatible jig was used to position the ICP (detector resolution 5mm on X/Y axis) at an extended SDD of 108.4cm to enable each MLC leaf (8.3mm leaf width at isocenter) to be uniquely determined by two neighboring ion chambers. The MRgRT linac system utilizes a novel jawless, double-focused, and double-stacked MLC design such that the upper bank (MLC1) and lower bank (MLC2) are offset by half a leaf width. Positional accuracy was characterized by three methods: single bank half-beam block (HBB) at central axis, forward slash diagonal (FSD), and backslash diagonal (BSD) at off-axis. Measurements were performed for each bank in which each leaf occludes half of a detector. A corresponding reference field with the MLC retracted from occlusion was measured. The sensitivities of HBB, FSD, and BSD were evaluated by introducing 0.5-2.5mm of known errors in 0.5mm increments, in both positive and negative directions. The relationship between detector response and MLC error was established. Over a 6-month longitudinal assessment, we have evaluated MLC performance with weekly QA of HBB among cardinal angles, and monthly QA of FSD and BSD. A strong correlation was found between detector response of percentage dose difference and MLC positional error introduced (N=350 introduced errors) for both HBB and FSD/BSD with coefficient of determination of 0.999 and 0.977, respectively. The relationship between detector response to MLC positional change was found to be 20.65%/mm for HBB and 11.14%/mm for FSD and BSD. At baseline, the mean MLC positional accuracy averaged across all leaves was 0.06±0.27mm (HBB), 0.04±0.52mm (FSD), -0.06±0.51mm (BSD). The mean MLC positional accuracy relative to baseline over the 6-month assessment was found to be highly reproducible at 0.00±0.12mm (HBB; N=28weeks), -0.02±0.19mm (FSD; N=6months), -0.03±0.19mm (BSD; N=6months). Positional accuracy of a novel jawless, double-focused, double-stacked MLC has been characterized and monitored over 6 months with an efficient, highly sensitive, and robust method using an ICP array. This routine QA method supplements calculation-based IMRT QA for an online adaptive radiotherapy program. Longitudinal assessment demonstrated no-drift in the MLC calibration. A highly reproducible jig setup allowed the validation of MLC positional accuracy to be within TG142 criteria of ±1mm for 99% of measurements (i.e., 100% HBB, 95% BSD, 95% FSD) over the 6-month assessment.

Clinical Radiotherapy Physics with MATLAB: A Problem‐Solving Approach. PavelDvorak. Series in Medical Physics and Biomedical Engineering – Series Editor: John G. Webster, E. Russell Ritenour, Slavik Tabakov, and Kwan‐Hoong Ng. CRC Press Taylors &amp; Francis, Boca Raton, 2018. Hardback: 244 pp. Price: $129.95, ISBN: 9781498754996.

Medical PhysicsVolume 47, Issue 3 p. 1412-1412 Book Review Clinical Radiotherapy Physics with MATLAB: A Problem-Solving Approach. Pavel Dvorak. Series in Medical Physics and Biomedical Engineering – Series Editor: John G. Webster, E. Russell Ritenour, Slavik Tabakov, and Kwan-Hoong Ng. CRC Press Taylors & Francis, Boca Raton, 2018. Hardback: 244 pp. Price: $129.95, ISBN: 9781498754996. Kenneth Bernstein M.S, Kenneth Bernstein M.SSearch for more papers by this author Kenneth Bernstein M.S, Kenneth Bernstein M.SSearch for more papers by this author First published: 23 August 2019 https://doi.org/10.1002/mp.13775Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, Issue3March 2020Pages 1412-1412 RelatedInformation

In vivo surface dosimetry with a scintillating fiber dosimeter in preclinical image-guided radiotherapy.

New preclinical image-guided irradiators and treatment planning systems represent a huge progress in radiobiology. Nevertheless, quality control of preclinical treatments is not as advanced as in clinical radiotherapy and in vivo dosimetry is less developed. In this study, we evaluate the use of a scintillating fiber dosimeter called DosiRat to verify the agreement between the doses planned with SmART-Plan and the measured doses during small animal irradiations. In vivo dosimetry was first evaluated with DosiRat through dose measurements performed at the surface of a 3×9×3cm3 phantom. Measured and planned doses were compared for different irradiation conditions (prescription point, anterior, and posterior beams, 5mm and 10mm irradiation fields). In a second phase, measured and planned doses were compared for rat brain irradiations performed with anterior beams, with DosiRat positioned at the beam entrance. Comparisons were performed for different tube currents (1.3 and 13mA), collimations (5, 10 and 25mm diameter), and planned doses (0.1, 0.5, 2, and 10Gy). In the case of the phantom irradiations, planned and measured doses showed discrepancies smaller than the 5% accuracy of the TPS, except in cases in which the dosimeter was not centered in the irradiation field. The differences were larger for animal irradiations (from -3.3% to 8.8%) because of variations of the beam energy spectrum and the nonequivalence between materials at medium and low energy. This study highlighted the complexity to implement one-dimension in vivo dosimetry in orthovoltage millimetric beams. Nevertheless, DosiRat is well adapted to in vivo dosimetry because of its small volume and its direct reading and allowed in vivo control of planned doses for anterior beams down to 5mm diameter.

LncRNA ANRIL target miR-195 experimental study of radiation sensitivity of HCT116 cells and nude mouse transplant tumors

Objective To investigate the effect and mechanism of LncRNA ANRIL on the radiosensitivity of HCT116 cells line and nude mouse transplant tumors. Methods The expression of LncRNA ANRIL in colorectal cancer cells was detected by qPCR. The negative control siRNA, ANRIL siRNA, miR-NC mimic, miR-195 mimic, miR-NC inhibitor and miR-195 inhibitor were transfected into HCT116 cells, and marked as negative control group, silencing ANRIL group, overexpressing miR-NC group, overexpressing miR-195 group, inhibiting miR-NC group and inhibiting miR-195 group, and the HCT116 cells without any treatment were marked as the blank control group. The clone formation assay was used to detect radiosensitivity of colorectal cancer cells, flow cytometry was used to detect apoptosis. The web site, StarBase, was used to predict the downstream miRNAs of ANRIL and dual luciferase reporter gene assay was used to further verify. Subcutaneous tumor transplantation assay was used to detect the effect of ANRIL on the growth of colorectal cancer cells after irradiation. Results After irradiation with 2, 4, 6 and 8 Gy, the cell survival fraction of silencing ANRIL group was significantly decreased when compared with that of negative control group (P<0.05), and the radiosensitivity ratio was 1.52. The apoptosis rate of the silencing ANRIL+ 4 Gy group was significantly higher than that of the negative control+ 4 Gy group ((27.86±2.78)% vs. (12.06±1.46)%, P<0.05). The results of the experiment on nude mouse transplant tumors showed that the tumor volume in the negative control group was lower than that of the silent ANRIL group on days 13, 16, 19, 22 and 25 ((234±66) mm3, (273±63) mm3, (296±72) mm3, (321±85) mm3 and (403±94) mm3vs. (357±79) mm3, (485±124) mm3, (617±143) mm3, (764±174) mm3 and (985±221) mm3P<0.05). MiR-195 is a target gene of ANRIL, and inhibition of miR-195 can reverse the inhibitory effect of silencing ANRIL on radiosensitivity, apoptosis and xenografts of HCT116 cells. Conclusions LncRNA ANRIL regulates the radiosensitivity of colorectal cancer cells by miR-195, which may provide a new sensitizing target for clinical colorectal cancer radiotherapy. Key words: ANRIL gene; miR-195 gene; HCT116 cell line; Nude mouse transplant tumors; Radiosensitivity

A sparse orthogonal collimator for small animal intensity-modulated radiation therapy part I: Planning system development and commissioning.

To achieve more translatable preclinical research results, small animal irradiation needs to more closely simulate human radiotherapy. Although the clinical gold standard is intensity-modulated radiation therapy (IMRT), the direct translation of this method for small animals is impractical. In this study we describe the treatment planning system for a novel dose modulation device to address this challenge. Using delineated target and avoidance structures, a rectangular aperture optimization (RAO) problem was formulated to penalize deviations from a desired dose distribution and limit the number of selected rectangular apertures. RAO was used to create IMRT plans with highly concave targets in the mouse brain, and the plan quality was compared to that using a hypothetical miniaturized multileaf collimator (MLC). RAO plans were also created for a realistic application of mouse whole liver irradiation and for a highly complex two-dimensional (2D) dose distribution as a proof-of-principle. Beam commissioning data, including output and off-axis factors and percent depth dose (PDD) curves, were acquired for our small animal irradiation system and incorporated into the treatment planning system. A plan post-processing step was implemented for aperture size-specific dose recalculation and aperture weighting reoptimization. The first RAO test case achieved highly conformal doses to concave targets in the brain, with substantially better dose gradient, conformity, and target dose homogeneity than the hypothetical miniaturized MLC plans. In the second test case, a highly conformal dose to the liver was achieved with significant sparing of the kidneys. RAO also successfully replicated a complex 2D dose distribution with three prescription dose levels. Energy spectra for field sizes 1 to 20mm were calculated to match the measured PDD curves, with maximum and mean dose deviations of 4.47±0.30% and 1.71±0.18%. The final reoptimization of aperture weightings for the complex RAO test plan was able to reduce the maximum and mean dose deviations between the optimized and recalculated dose distributions from 10.3% to 6.6% and 4.0% to 2.8%, respectively. Using the advanced optimization techniques, complex IMRT plans were achieved using a simple dose modulation device. Beam commissioning data were incorporated into the treatment planning process to more accurately predict the resulting dose distribution. This platform substantially reduces the gap in treatment plan quality between clinical and preclinical radiotherapy, potentially increasing the value and flexibility of small animal studies.