Comparing the DNA-damage RBE of intraoperative and conventional electron beams using a hybrid simulation approach.

PURPOSE: Employing electron beam for radiotherapy purposes now has been established as one of the standard cancer treatment modalities. Both dedicated intraoperative and conventional electron beams can be employed in patient irradiation. Due to the differences between accelerating structure and electron beam delivery of dedicated intraoperative radiotherapy (IORT) machines and conventional ones, the initial energy spectra of the produced electron beam by these machines may be different. Accordingly, this study aims to evaluate whether these spectral differences can affect the relevant relative biological effectiveness (RBE) values of intraoperative and conventional electron beams. MATERIALS AND METHODS: A hybrid Monte Carlo simulation approach was considered. At first, the head LIAC12 machine (as an IORT accelerator) and Varian 2100C/D (as a conventional accelerator) were simulated by MCNPX code and electron energy spectra at different depths and off-axis distances were scored for two nominal electron energies of 6 and 12 MeV at the field sizes of 6 and 10 cm. Then, the calculated spectra were imported to MCDS code to estimate the induced DNA-damage RBE values. Finally, the obtained RBE values for intraoperative and conventional electron beams were compared together. RESULTS: The results showed that the RBE values of the intraoperative electron beam are superior to those obtained for conventional electron beam at the same energy/field size combination. Variations of the depth can regularly affect the RBE value for both conventional and intraoperative electron beams, while no ordered variation trend was observed for RBE with changing the off-axis distance. Variations of electron energy and field size can also influence the RBE value for both types of studied electron beams. CONCLUSIONS: From the results, it can be concluded the structural differences between the dedicated IORT and conventional Linacs can lead to distinct initial electron energy spectra for intraoperative and conventional electron beams. These physical differences can finally lead to different RBE values for intraoperative and conventional electron beams at the same energy and field size.

Establishment and validation of a calibration curve for dicentric chromosome induced by 6MV X-ray.

Radiation during radiotherapy and nuclear accidents is currently one of the biggest concerns for the international community. Biological dosimetry examines the amount of damage caused by radiation at the cellular level by quantifying a radiation biomarker. In particular, the dicentric chromosome assay is a biodosimetric technique that can quantify radiation damage by correlating radiation dose exposure with the frequency of dicentric chromosomes in the peripheral lymphocytes extracted from exposed individuals. This study aims to present of the reference dose-response calibration curve for biodosimetry laboratory of Mashhad University of Medical Sciences (north-east of Iran). In all, 40 samples of peripheral blood from four healthy volunteers were irradiated at doses of 0-5 Gray in a customised water phantom using a 6 MV X-rays at dose rate of 2 Gy/min from a linear accelerator. The irradiated samples were cultured and analysed according to the International Atomic Energy Agency Cytogenetic Dosimetry Protocol (2011) with some modifications. Linear-quadratic model curve fitting and further statistical analysis were done using Chromosome Aberration Calculation Software Version 2.0 and Dose Estimate (Version 5.2). The curve equation obtained was ${Y}_{dic}=0.0533{D}^2+0.0231D+0.0001$ and was in the range of other studies. Validation of the calibration curve was done by estimating the dose of blind samples.

7-geranyloxycoumarin enhanced radiotherapy effects on human gastric adenocarcinoma cells.

Background: Gastric adenocarcinoma (GA) is a serious malignancy with growing incidence and mortality rate worldwide. The objective of the present study was to determine whether 7-geranyloxycoumarin, a natural monoterpene coumarin, could induce anticancer effects, in single use and/or in combination with anticancer drugs and ionizing radiation, on GA cells. Materials and Methods: 7-geranyloxycoumarin was synthesized by a reaction between 7-hydroxycoumarin and transgeranyl bromide. MKN45 cells were treated with 7-geranyloxycoumarin, and the viability of cells was determined by resazurin. Apoptosis was then evaluated by flow cytometric analysis using annexin V and propidium iodide, and the expression of P53 and BCL2 was analyzed by quantitative polymerase chain reaction (qPCR). Combinatorial effects of 7-geranyloxycoumarin with 5-fluorouracil (5-FU), cisplatin (CDDP), and X radiation were also evaluated. Results: Assessment of cell viability indicated that 7-geranyloxycoumarin induced its toxic effects in a time- and dose-dependent manner. This was confirmed by the detection of apoptotic cells, and qPCR results revealed a significant downregulation in BCL2 expression. Although combinatorial use of 7-geranyloxycoumarin + 5-FU or + CDDP did not improve cytotoxicity of anticancer drugs, significant increase in the effectiveness of applied radiations was detected upon pretreatment with 7-geranyloxycoumarin. Conclusion: Our findings provide valuable insights into single and combinatorial effects of 7-geranyloxycoumarin on the GA cells.

Optimizing the Radiation Treatment Planning of Brain Tumors by Integration of Functional MRI and White Matter Tractography.

Background: Diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) present the ability to selectively protect functional regions and fiber tracts of the brain when brain tumors are treated with radiotherapy. Objective: This study aimed to assess whether the incorporation of fMRI and DTI data into the radiation treatment planning process of brain tumors could prevent the neurological parts of the brain from high doses of radiation. Material and Methods: In this investigational theoretical study, the fMRI and DTI data were obtained from eight glioma patients. This patient-specific fMRI and DTI data were attained based on tumor location, the patient's general conditions, and the importance of the functional and fiber tract areas. The functional regions, fiber tracts, anatomical organs at risk, and the tumor were contoured for radiation treatment planning. Finally, the radiation treatment planning with and without fMRI & DTI information was obtained and compared. Results: The mean dose to the functional areas and the maximum doses were reduced by 25.36% and 18.57% on fMRI & DTI plans compared with the anatomical plans. In addition, 15.59% and 20.84% reductions were achieved in the mean and maximum doses of the fiber tracts, respectively. Conclusion: This study demonstrated the feasibility of using fMRI and DTI data in radiation treatment planning to maximize radiation protection of the functional cortex and fiber tracts. The mean and maximum doses significantly decreased to neurologically relevant brain regions, resulting in reducing the neuro-cognitive complications and improving the patient's quality of life.

7-Geranyloxcycoumarin enhances radio sensitivity in human prostate cancer cells.

BACKGROUND: Prostate cancer is the second most prevalent and the fifth deadliest cancer among men worldwide. To improve radiotherapy outcome, we investigated the effects of 7-geranyloxycoumarin, also known as auraptene (AUR), on radiation response of prostate cancer cells. METHODS AND RESULTS: PC3 cells were pretreated with 20 and 40 µM AUR for 24, 48 and 72 h, followed by X-ray exposure (2, 4 and 6 Gy). After 72 h recovery, cell viability was determined by alamar Blue assay. Flow cytometric analysis was performed to assess apoptosis induction, clonogenic assay was carried out to investigate clonogenic survival, and the expression of P53, BAX, BCL2, CCND1 and GATA6 was analyzed by quantitative polymerase chain reaction (qPCR). Cell viability assay indicated that toxic effects of radiation was enhanced by AUR, which was also confirmed by increased numbers of apoptotic cells and reduced amount of survival fraction. The qPCR results demonstrated significant induction of P53 and BAX, while the expression of BCL2, GATA6, and CCND1 was significantly downregulated. CONCLUSION: The findings of the present study indicated, for the first time, that AUR improved radio sensitivity in prostate cancer cells, and thus, has the potential to be used in future clinical trials.

Gold-containing liposomes and glucose-coated gold nanoparticles enhances the radiosensitivity of B16F0 melanoma cells via increasing apoptosis and ROS production.

AIM: To increase the effectiveness of radiation therapy, metals with high Z number are used as radiosensitizers. In this regard, the effectiveness of various gold nanoparticles as radiosensitizer has been proven. Therefore, this study aimed to evaluate the effects of liposomes containing gold ions (Gold-Lips) and glucose-coated gold nanoparticles (Glu-GNPs) on radiation sensitivity of B16F0 melanoma cells. MAIN METHODS: Naked GNPs, Glu-GNPs and Gold-Lips were synthesized and their physicochemical properties were evaluated using DLS. The cytotoxicity and sensitivity of the nanoparticles to radiation were evaluated using MTT and colony formation assay, respectively. Flow cytometry was performed to evaluate the apoptotic effect of nanoparticles on B16F0 cells. The intracellular ROS levels and mRNA expression of Bax, Bcl-2, p53, Caspase-3, and Caspase-7 genes were also evaluated. Finally, caspase 3/7 activity was determined using a luminescence assay kit. KEY FINDINGS: The results revealed that GNPs, Glu-GNPs, and Gold-Lips had a desired size and zeta potential. Results from the colony assay showed that the all non-toxic concentrations of Gold-Lips significantly increased cell death in B16F0 cells compared with the Glu-GNPs (p > 0.05). Flow cytometry and Caspase-3/-7 activity confirmed the results of the colony assay and showed that increasing the sensitivity of cells to radiation increases apoptosis. Moreover, we found that Gold-Lips increased the mRNA expression of p53, Bax, and Caspase-3/-7, and decreased the Bcl-2 mRNA expression. SIGNIFICANCE: Overall, both Gold-Lips and Glu-GNPs enhanced the radiosensitivity of B16F0 cells, however, Gold-Lips had better effects, which could make them a promising tools in cancer radiotherapy.

Evaluation of dose distribution of an intraoperative radiotherapy device using thermoluminescent dosimeters and radiographic films.

Background: To investigate dose distribution of the 5cm spherical applicator of the INTRABEAM™ intraoperative radiation therapy (IORT) device via thermoluminescence dosimeters (TLDs) and Radiographic films. Independent dose distribution assessment of IORT devices is considered important. Several methods are described for this purpose, including TLDs and films. However, Radiographic films are not routinely used. Materials and methods: Twenty TLDs were used for depth dose measuring and evaluating the isotropy in water. Additionally, the isotropy was assessed separately via Radiographic films in air by drawing isodose curves. Results: TLD measurements showed a steep dose decline which the relative average dose of 0.94 at the applicator surface reduced to 0.32, 0.13, and 0.07 at 1, 2, and 3 cm depths in water, respectively. Some remarkable isodose curves prepared using Radiographic films showed forward anisotropy of the 5 cm applicator. Conclusion: A very steep dose decline and approximately isotropic dose distribution of the 5 cm applicator were observed via TLD measurements. Radiographic films showed acceptable potential for drawing dose distribution maps. However, they should be applied in more various radiation setups to be implemented more confidently.

Radiation Response of Human Leukemia/Lymphoma Cells was Improved by 7-Geranyloxycoumarin.

Objectives: Adult T-cell leukemia/lymphoma (ATLL) is a blood neoplasm with specific geographic distribution. Although radiotherapy is a palliative treatment that provides long-term local control, single use of radiation leads to complications for patients. To introduce a novel multimodal approach against ATLL, we investigated combinatorial effects of 7-geranyloxycoumarin and radiation in vitro. Methods: Viability of MT-2 cells was determined by resazurin assay upon administration of 7-geranyloxycoumarin alone and followed by radiation. Then, apoptosis was detected by annexin V and propidium iodide, and the expression of candidate genes was analyzed by qPCR. Results: Findings revealed significant (P<.0001) improvement in radiation effects upon 7-geranyloxycoumarin pretreatment, most notably when cells were pretreated with 5 µg/ml 7-geranyloxycoumarin for 96 h, exposed to 6 Gy radiation and recovered for 48 h. These results were confirmed by flow cytometry, as the percentage of early and late apoptotic cells was increased after combinatorial treatment. In addition, significant (P< .0001) changes in CD44, c-MYC, cFLIPL, BMI-1, NF-κB (Rel A), and P53 expression was induced by 7-geranyloxycoumarin and radiation. Conclusions: Current research indicated, for the first time, that combinatorial use of 7-geranyloxycoumarin and ionizing radiation could be considered as an effective therapeutic modality for ATLL.

Urolithins increased anticancer effects of chemical drugs, ionizing radiation and hyperthermia on human esophageal carcinoma cells in vitro.

Despite progress in diagnosis and treatment of esophageal cancer (EC), it is still considered as a serious malignancy with very poor prognosis. Urolithins are colonic microbiota metabolites with a wide range of pharmacological properties including chemopreventive, anti-inflammatory and anticancer activities. In this study, we hypothesized that urolithins might possess the potential to improve the efficacy of chemical drugs, ionizing radiation (IR) and/or hyperthermia on EC cells. After synthesis of urolithin A (UA), methylurolithin A (mUA) and urolithin B (UB), KYSE30 esophageal cancer cells were treated with urolithins + paclitaxel (PTX), + cisplatin (DDP), + different doses of IR or + heat-shock. Viability of cells was then determined by alamarBlue assay. To further elucidate the effects of UA, we used flow cytometry for investigation of induced apoptosis, and qRT-PCR for evaluating changes in the expression of HSP27, CCND1 and BCL2. Assessment of cell viability demonstrated that mUA increased the toxicity of PTX and DDP (up to 22.4 % and 20 %, respectively) and improved the effects of 6 Gy IR (26.5 %). Our main results achieved after UA treatment were improved toxicity of PTX and 6 Gy IR, beside enhanced effects of hyperthermia (37.3 %), which was confirmed by flow cytometry analysis and downregulation of HSP27, CCND1 and BCL2 expression. Taken together, our findings suggest that UA and mUA could be used as promising agents in combination with therapeutic modalities to improve the clinical outcomes of EC treatment.

Comparing two radiotherapy techniques of whole central nervous system tumors, considering tumor and critical organs' dose provided by treatment planning system and direct measurement.

AIMS: In central nervous system (CNS) tumors, surgery combined with radiotherapy may cure many tumors. The basic technique in conventional radiotherapy is craniospinal radiotherapy; in this technique, spinal cord can be treated with electron or photon beams. This study was aimed to compare two radiotherapy techniques in craniospinal radiotherapy, (a) treatment of spine with a single photon beam and (b) with a combination of photon and electron beams. MATERIALS AND METHODS: The two techniques were planned. In the first technique, both brain and spine were irradiated with 6 MV photon beams. In the second technique, brain was irradiated with 6 MV photon and spine with 18 MeV electron beams. To compensate the dose deficiency in lumbar area, an anterior field of 15 MV photon beam was also applied in the second technique. The dose to target volume and organ at risks (OARs) were measured by thermoluminescent dosimeter and compared with the corresponding values calculated by Isogray treatment planning system. RESULTS: OARs including heart, mandible, thyroid, and lungs received lower dose from technique 2 compared with technique 1; kidneys were exceptions which received higher dose in the technique 2. CONCLUSIONS: The dose to thyroid, mandible, heart, and lungs were lower in technique 2, while kidneys received higher dose in technique 2. This was caused by using the anterior 15 MV photon beam. Based on these results, for children, instead of photon beam for treatment of spinal cord, it is wiser to use electron beam.

Evaluation of the heart and lung dosimetric parameters in deep inspiration breath hold using 3D Slicer.

PURPOSE: The present study was conducted to compare dosimetric parameters for the heart and left lung between free breathing (FB) and deep inspiration breath hold (DIBH) and determine the most important potential factors associated with increasing the lung dose for left-sided breast radiotherapy using image analysis with 3D Slicer software. MATERIALS AND METHODS: Computed tomography-simulation scans in FB and DIBH were obtained from 17 patients with left-sided breast cancer. After contouring, three-dimensional conformal plans were generated for them. The prescribed dose was 50 Gy to the clinical target volume. In addition to the dosimetric parameters, the irradiated volumes and both displacement magnitudes and vectors for the heart and left lung were assessed using 3D Slicer software. RESULTS: The average of the heart mean dose (Dmean) decreased from 5.97 to 3.83 Gy and V25 from 7.60% to 3.29% using DIBH (p < 0.001). Furthermore, the average of Dmean for the left lung was changed from 8.67 to 8.95 Gy (p = 0.389) and V20 from 14.84% to 15.44% (p = 0.387). Both of the absolute and relative irradiated heart volumes decreased from 42.12 to 15.82 mL and 8.16% to 3.17%, respectively (p < 0.001); however, these parameters for the left lung increased from 124.32 to 223.27 mL (p < 0.001) and 13.33% to 13.99% (p = 0.350). In addition, the average of heart and left lung displacement magnitudes were calculated at 7.32 and 20.91 mm, respectively. CONCLUSION: The DIBH is an effective technique in the reduction of the heart dose for tangentially treated left sided-breast cancer patients, without a detrimental effect on the left lung.

Evaluation of application of EPID for rapid QC testing of linear accelerator.

AIM: Evaluation of application of EPID for rapid QC testing of linear accelerator. BACKGROUND: Quality control of a linear accelerator device is a time and energy intensive process. In this study, attempts have been made to perform the linear accelerator quality control using electronic portal imaging device (EPID), which is mounted on most accelerators. MATERIALS AND METHODS: First, quality control and dosimetry parameters of the device were determined and measured based on standard protocols to ensure full calibration of the accelerator. Then, various features of EPID including spatial resolution and contrast resolution, the effect of buildup region, dose response and image uniformity were evaluated. In the next step, consistent with the parameters of linear accelerator quality control including field size, field flatness and symmetry, the light field coincidence with X-ray field, mechanical stability and multileaf collimator position accuracy test, the output images of device were obtained.After feeding images to the MATLAB software, their pixel content was analyzed. All measurements of the three photon beams were repeated three times. RESULTS: The EPID image had a desirable resolution, contrast and uniformity and displayed high sensitivity to dose changes with linear dose response. Seven qualitative parameters of the linear accelerator were then controlled by EPID. CONCLUSIONS: The results of the linear accelerator quality control using the EPID were consistent with practice. Quality control using the EPID was more convenient and faster than conventional methods.

Monte Carlo Simulation of a 6 MV X-Ray Beam for Open and Wedge Radiation Fields, Using GATE Code.

The aim of this study is to provide a control software system, based on Monte Carlo simulation, and calculations of dosimetric parameters of standard and wedge radiation fields, using a Monte Carlo method. GATE version 6.1 (OpenGATE Collaboration), was used to simulate a compact 6 MV linear accelerator system. In order to accelerate the calculations, the phase-space technique and cluster computing (Condor version 7.2.4, Condor Team, University of Wisconsin-Madison) were used. Dosimetric parameters used in treatment planning systems for the standard and wedge radiation fields (10 cm × 10 cm to 30 cm × 30 cm and a 60° wedge), including the percentage depth dose and dose profiles, were measured by both computational and experimental methods. Gamma index was applied to compare calculated and measured results with 3%/3 mm criteria. Gamma index was applied to compare calculated and measured results. Almost all calculated data points have satisfied gamma index criteria of 3% to 3 mm. Based on the good agreement between calculated and measured results obtained for various radiation fields in this study, GATE may be used as a useful tool for quality control or pretreatment verification procedures in radiotherapy.

A Monte Carlo study on electron and neutron contamination caused by the presence of hip prosthesis in photon mode of a 15 MV Siemens PRIMUS linac.

Several investigators have pointed out that electron and neutron contamination from high-energy photon beams are clinically important. The aim of this study is to assess electron and neutron contamination production by various prostheses in a high-energy photon beam of a medical linac. A 15 MV Siemens PRIMUS linac was simulated by MCNPX Monte Carlo (MC) code and the results of percentage depth dose (PDD) and dose profile values were compared with the measured data. Electron and neutron contaminations were calculated on the beam's central axis for Co-Cr-Mo, stainless steel, Ti-alloy, and Ti hip prostheses through MC simulations. Dose increase factor (DIF) was calculated as the ratio of electron (neutron) dose at a point for 10 × 10 cm² field size in presence of prosthesis to that at the same point in absence of prosthesis. DIF was estimated at different depths in a water phantom. Our MC-calculated PDD and dose profile data are in good agreement with the corresponding measured values. Maximum dose increase factor for electron contamination for Co-Cr-Mo, stainless steel, Ti-alloy, and Ti prostheses were equal to 1.18, 1.16, 1.16, and 1.14, respectively. The corresponding values for neutron contamination were respectively equal to: 184.55, 137.33, 40.66, and 43.17. Titanium-based prostheses are recommended for the orthopedic practice of hip junction replacement. When treatment planning for a patient with hip prosthesis is performed for a high-energy photon beam, attempt should be made to ensure that the prosthesis is not exposed to primary photons.