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Boron neutron capture therapy (BNCT) is a unique radiotherapy of selectively eradicating tumor cells using boron compounds (e.g., 4-borono-l-phenylalanine [BPA]) that are heterogeneously taken up at the cellular level. Such heterogenicity potentially reduces the curative efficiency. However, the effects of temporospatial heterogenicity on cell killing remain unclear. With the technical combination of radiation track detector and biophysical simulations, this study revealed the cell cycle-dependent heterogenicity of BPA uptake and subsequent biological effects of BNCT on HeLa cells expressing fluorescent ubiquitination-based cell cycle indicators, as well as the modification effects of polyvinyl alcohol (PVA). The results showed that the BPA concentration in the S/G2/M phase was higher than that in the G1/S phase and that PVA enhances the biological effects both by improving the uptake and by canceling the heterogenicity. These findings might contribute to a maximization of therapeutic efficacy when BNCT is combined with PVA and/or cell cycle-specific anticancer agents. [ABSTRACT FROM AUTHOR]

IntroductionDuctal carcinoma in situ (DCIS) is characterized by non-invasive cancerous cell growth within the breast ducts. Although radiotherapy is commonly used in the treatment of DCIS, the effect and molecular mechanism of ionizing radiation (IR) on DCIS are not well understood, and invasive recurrence following radiotherapy remains a significant clinical problem. This study investigated the effects of IR on a clinically relevant model of Akt-driven DCIS and identified possible molecular mechanisms underlying invasive progression in surviving cells.MethodsWe measured the level of phosphorylated-Akt (p-Akt) in a cohort of human DCIS specimens by immunohistochemistry (IHC) and correlated it with recurrence risk. To model human DCIS, we used Akt overexpressing human mammary epithelial cells (MCF10A-Akt) which, in three-dimensional laminin-rich extracellular matrix (lrECM) and in vivo, form organotypic DCIS-like lesions with lumina expanded by pleiomorphic cells contained within an intact basement membrane. In a population of cells that survived significant IR doses in three-dimensional lrECM, a malignant phenotype emerged creating a model for invasive recurrence.ResultsP-Akt was up-regulated in clinical DCIS specimens and was associated with recurrent disease. MCF10A-Akt cells that formed DCIS-like structures in three-dimensional lrECM showed significant apoptosis after IR, preferentially in the luminal compartment. Strikingly, when cells that survived IR were repropagated in three-dimensional lrECM, a malignant phenotype emerged, characterized by invasive activity, up-regulation of fibronectin, α5β1-integrin, matrix metalloproteinase-9 (MMP-9) and loss of E-cadherin. In addition, IR induced nuclear translocation and binding of nuclear factor-kappa B (NF-κB) to the β1-integrin promoter region, associated with up-regulation of α5β1-integrins. Inhibition of NF-κB or β1-integrin signaling abrogated emergence of the invasive activity.ConclusionsP-Akt is up-regulated in some human DCIS lesions and is possibly associated with recurrence. MCF10A-Akt cells form organotypic DCIS-like lesions in three-dimensional lrECM and in vivo, and are a plausible model for some forms of human DCIS. A population of Akt-driven DCIS-like spheroids that survive IR progresses to an invasive phenotype in three-dimensional lrECM mediated by β1-integrin and NF-κB signaling.

Background: Although flattening filter free (FFF) beams are commonly used in clinical treatment, the accuracy of dose measurements in FFF beams has been questioned. Higher dose per pulse (DPP) such as FFF beams from a linear accelerator may cause problems in dose profile measurements using an ionization chamber due to the change of the charge collection efficiency. Ionization chambers are commonly used for percent depth dose (PDD) measurements. Changes of DPP due to chamber movement during PDD measurement can vary the ion collection efficiency of ionization chambers. In the case of FF beams, the DPP fluctuation is negligible, but in the case of the FFF beams, the DPP is 2.5 ∼ 4 times larger than that of the FF beam, and the change in ion collection efficiency is larger than that of the FF beam. PDD profile normalized by maximum dose depth, 10 cm depth for example, may therefore be affected by the ion collection efficiency. Purpose: In this study, we investigate the characteristics of the ion collection efficiency change depending on the DPP of each ionization chamber in the FFF beam. We furthermore propose a method to obtain the chamber‐ independent PDD by applying a DPP‐dependent ion recombination correction. Methods: Prior to investigating the relationship between DPP and charge collection efficiency, Jaffe‐plots were generated with different DPP settings to investigate the linearity between the applied voltage and collected charge. The absolute dose measurement using eight ionization chambers under the irradiation settings of 0.148, 0.087, and 0.008 cGy/pulse were performed. Applied voltages for the Jaffe‐plots were 100, 125, 150, 200, 250, and 300 V. The ion recombination correction factor Pion was calculated by the two‐voltage analysis (TVA) method at the applied voltages of 300 and 100 V. The DPP dependency of the charge collection efficiency for each ionization chamber were evaluated from the DPP‐ Pion plot. PDD profiles for the 10 MV FFF beam were measured using Farmer type chambers (TN30013, FC65‐P, and FC65‐G) and mini‐type chambers (TN31010, TN31021, CC13, CC04, and FC23‐C). The PDD profiles were corrected with ion recombination correction at negative and positive polar applied voltages of 100 and 300 V. Results: From the DPP‐Pion relation for each ionization chamber with DPP ranging from 0.008 cGy/pulse to 0.148 cGy/pulse, all Farmer and mini‐type chambers satisfied the requirements described in AAPM TG‐51 addendum. However, Pion for the CC13 was most affected by DPP among tested chambers. The maximum deviation among PDDs using eight ionization chambers for 10 MV FFF was about 1%, but the deviation was suppressed to about 0.5% by applying ion recombination correction at each depth. Conclusions: In this study, the deviation of PDD profile among the ionization chambers was reduced by the ion recombination coefficient including the DPP dependency, especially for high DPP beams such as FFF beams. The present method is particularly effective for CC13, where the ion collection efficiency is highly DPP dependent. [ABSTRACT FROM AUTHOR]

Monte Carlo track structure simulation is a powerful method for estimating damage induced by water radiolysis products for cell killing. To investigate the influence of multiple ionization for the formation of water radiolysis products under 1H+, 4He2+, and 12C6+ ion beams, a Monte Carlo simulation based on Geant4-DNA was carried out. The G-value of H2O2 increased monotonically with increasing linear energy transfer up to 200 eV/nm. Above 200 eV/nm, the G-value of H2O2 began dropping, but only when the influence of multiple ionization was considered. This trend is in good agreement with the experimental results. Furthermore, we successfully reproduce the experimental results of G-values of HO2• + O2•−. The role of the multiple ionization in the production of H2O2, HO2•, O2•−, and O2 is also discussed. [ABSTRACT FROM AUTHOR]

Purpose: The Medical Physics Working Group of the Radiation Therapy Study Group at the Japan Clinical Oncology Group is currently developing a virtual audit system for intensity‐modulated radiation therapy dosimetry credentialing. The target dosimeters include films and array detectors, such as ArcCHECK (Sun Nuclear Corporation, Melbourne, Florida, USA) and Delta4 (ScandiDos, Uppsala, Sweden). This pilot study investigated the feasibility of our virtual audit system using previously acquired data. Methods: We analyzed 46 films (32 and 14 in the axial and coronal planes, respectively) from 29 institutions. Global gamma analysis between measured and planned dose distributions used the following settings: 3%/3 mm criteria (the dose denominator was 2 Gy), 30% threshold dose, no scaling of the datasets, and 90% tolerance level. In addition, 21 datasets from nine institutions were obtained for array evaluation. Five institutions used ArcCHECK, while the others used Delta4. Global gamma analysis was performed with 3%/2 mm criteria (the dose denominator was the maximum calculated dose), 10% threshold dose, and 95% tolerance level. The film calibration and gamma analysis were conducted with in‐house software developed using Python (version 3.9.2). Results: The means ± standard deviations of the gamma passing rates were 99.4 ± 1.5% (range, 92.8%–100%) and 99.2 ± 1.0% (range, 97.0%–100%) in the film and array evaluations, respectively. Conclusion: This pilot study demonstrated the feasibility of virtual audits. The proposed virtual audit system will contribute to more efficient, cheaper, and more rapid trial credentialing than on‐site and postal audits; however, the limitations should be considered when operating our virtual audit system. [ABSTRACT FROM AUTHOR]

In positron emission tomography (PET), parallax errors degrade spatial resolution. The depth of interaction (DOI) information provides the position in the depth of the scintillator interacting with the γ-rays, thus reducing parallax errors. A previous study developed a Peak-to-Charge discrimination (PQD), which can separate spontaneous alpha decay in LaBr3:Ce. Since decay constant of GSO:Ce depends on Ce concentration, the PQD is expected to discriminate GSO:Ce scintillators with different Ce concentration. In this study, the PQD-based DOI detector system was developed, which can be processed online and implemented in PET. A detector was composed of four layers of GSO:Ce crystals and a PS-PMT. The four crystals were obtained from both the top and bottom of ingots with a nominal Ce concentration of 0.5 mol% and 1.5 mol%. The PQD was implemented on the Xilinx Zynq-7000 SoC board with 8ch Flash ADC to gain real-time processing, flexibility, and expandability. The results showed that the mean Figure of Merits in 1D between four scintillators are 1.5, 0.99, 0.91 for layers between 1st–2nd, 2nd–3rd, and 3rd–4th respectively, and the mean Error Rate in 1D between four scintillators are 3.50%, 2.96%, 13.3%, and 1.88% for layers 1, 2, 3, and 4, respectively. In addition, the introduction of the 2D PQDs resulted in the mean Figure of Merits in 2D greater than 0.9 and the mean Error Rate in 2D less than 3% in all layers. [ABSTRACT FROM AUTHOR]

Purpose: We evaluate an SGRT device (Voxelan HEV‐600 M/RMS) installed with Radixact, with the view angle of the Voxelan's camera at 74 degrees. The accuracy of Voxelan with this steep angle was evaluated with phantom experiments and inter‐fractional setup errors of patients. Methods: In the phantom experiments, the difference between the measured values of Voxelan from the truth was evaluated for translations and rotations. The inter‐fractional setup error between the setup using skin markers with laser localizer (laser setup: LS) and the setup using Voxelan (surface setup: SS) was compared for head and neck (N = 19), chest (N = 7) and pelvis (N = 9) cases. The inter‐fractional setup error was calculated by subtracting from bone matching by megavoltage computed tomography (MVCT) as ground truth. Results: From the phantom experiments, the average difference between the measured values of Voxelan from the truth was within 1 mm and 1 degree. In all cases, inter‐fractional setup error based on MVCT was not significantly different between LS and SS by Welch's t‐test (P > 0.05). The vector offset of the LS for head and neck, chest, and pelvis were 6.5, 9.6, and 9.6 mm, respectively, and that of the SS were 5.8, 8.6, and 12.6 mm, respectively. Slight improvement was observed for the head and neck, and chest cases, however, pelvis cases were not improved because the umbilical region could not be clearly visualized as a reference. Conclusion: The results show that SS in Voxelan with an installation angle of 74 degrees is equal to or better than LS. [ABSTRACT FROM AUTHOR]

This study aimed to clarify the differences in radiotherapy dose characteristics and delivery efficiency between the supine and prone positions in patients with prostate cancer using the CyberKnife. The planning computed tomography (CT) and delineations of the prone position were obtained by rotating the supine CT images with delineations of 180° using image processing software. The optimization parameters for planning target volume (PTV) and organs at risk (OARs) were based on the prone position. The optimization parameters determined for the prone position were applied to the supine position for optimization and dose calculation. The dosimetric characteristics of the PTV and OARs, and delivery efficiency were compared between the two different patient positions. The plans in the prone position resulted in better PTV conformity index (nCI), rectum V 90%, V 80%, V 75%, V 50% and bladder V 50%. A significant difference was observed in treatment time and depth along the central axis (d CAX) between the two plans. The mean treatment time per fraction and d CAX for the supine and prone positions were 20.9 ± 1.7 min versus 19.8 ± 1.3 min (P  = 0.019) and 151.1 ± 33.6 mm versus 233.2 ± 8.8 mm (P  < 0.001), respectively. In this study the prone position was found to improve dosimetric characteristics and delivery efficiency compared with the supine position during prostate cancer treatment with the CyberKnife. [ABSTRACT FROM AUTHOR]

Accelerator-based neutron sources have been developed and installed in recent decades for boron neutron capture therapy (BNCT) in several clinical facilities. Lithium is one of the targets that can produce epithermal neutrons from the 7Li(p,n)7Be near-threshold reaction, and accelerator-based BNCT systems employing a Li target are promising for cancer treatment. The accurate evaluation of the characteristics of an accelerator-based neutron source is a key to estimating the therapeutic effects of the accelerator-based BNCT. Particle and Heavy Ion Transport code System (PHITS) is a general-purpose Monte Carlo code, which can simulate a variety of diverse particle types and nuclear reactions. The latest PHITS code enables simulating the generation of neutrons from the 7Li(p,n)7Be reactions by using the Japanese Evaluated Nuclear Data Library 4.0 high-energy file. Thus, the PHITS code can be adopted for dose estimation during treatment planning for the accelerator-based BNCT. In this study, we evaluated the neutron fluence using the PHITS code by comparing it to reference data. The subsequent neutron transport simulations were performed to evaluate the boron trifluoride detector responses and the recoiled proton fluence detected by a CR-39 plastic detector. These comparative studies confirmed that the PHITS code can accurately simulate neutrons generated from an accelerator using a Li target. The PHITS code has a significant potential for a detailed evaluation of neutron fields and for predicting the therapeutic effects of the accelerator-based BNCT. [ABSTRACT FROM AUTHOR]

The purpose of this work is to show the usefulness of a prediction method of tumor location based on partial least squares regression (PLSR) using multiple fiducial markers. The trajectory data of respiratory motion of four internal fiducial markers inserted in lungs were used for the analysis. The position of one of the four markers was assumed to be the tumor position and was predicted by other three fiducial markers. Regression coefficients for prediction of the position of the tumor-assumed marker from the fiducial markers' positions is derived by PLSR. The tracking error and the gating error were evaluated assuming two possible variations. First, the variation of the position definition of the tumor and the markers on treatment planning computed tomograhy (CT) images. Second, the intra-fractional anatomical variation which leads the distance change between the tumor and markers during the course of treatment. For comparison, rigid predictions and ordinally multiple linear regression (MLR) predictions were also evaluated. The tracking and gating errors of PLSR prediction were smaller than those of other prediction methods. Ninety-fifth percentile of tracking/gating error in all trials were 3.7/4.1 mm, respectively in PLSR prediction for superior–inferior direction. The results suggested that PLSR prediction was robust to variations, and clinically applicable accuracy could be achievable for targeting tumors. [ABSTRACT FROM AUTHOR]

Purpose: The real‐time tumor tracking radiotherapy (RTRT) system requires periodic quality assurance (QA) and quality control. The goal of this study is to propose QA procedures from the viewpoint of imaging devices in the RTRT system. Methods: Tracking by the RTRT system (equips two sets of colored image intensifiers (colored I.I.s) fluoroscopy units) for the moving gold‐marker (diameter 2.0 mm) in a rotating phantom were performed under various X‐ray conditions. To analyze the relationship between fluoroscopic image quality and precision of gold marker coordinate calculation, the standard deviation of the 3D coordinate (σ3D [mm]) of the gold marker, the mean of the pattern recognition score (PRS) and the standard deviation of the distance between rays (DBR) (σDBR [mm]) were evaluated. Results: When tracking with speed of 10‐60 mm/s, σDBR increased, though the mean PRS did not change significantly (p>0.05). On the contrary, the mean PRS increased depending on the integral noise equivalent quanta (∫NEQ) that is an indicator of image quality calculated from the modulation transfer function (MTF) as an indicator of spatial resolution and the noise power spectrum (NPS) as an indicator of noise characteristic. Conclusion: The indicators of NEQ, MTF, and NPS were useful for managing the tracking accuracy of the RTRT system. We propose observing the change of these indicators as additional QA procedures for each imaging device from the commissioning baseline. [ABSTRACT FROM AUTHOR]

Hypoxic cancer cells within solid tumours show radio-resistance, leading to malignant progression in fractionated radiotherapy. When prescribing dose to tumours under heterogeneous oxygen pressure with intensity-modulated radiation fields, intercellular signalling could have an impact on radiosensitivity between in-field and out-of-field (OF) cells. However, the impact of hypoxia on radio-sensitivity under modulated radiation intensity remains to be fully clarified. Here, we investigate the impact of hypoxia on in-field and OF radio-sensitivities using two types of cancer cells, DU145 and H1299. Using a nBIONIX hypoxic culture kit and a shielding technique to irradiate 50% of a cell culture flask, oxygen enhancement ratios for double-strand breaks (DSB) and cell death endpoints were determined. These in vitro measurements indicate that hypoxia impacts OF cells, although the hypoxic impacts on OF cells for cell survival were dose-dependent and smaller compared to those for in-field and uniformly irradiated cells. These decreased radio-sensitivities of OF cells were shown as a consistent tendency for both DSB and cell death endpoints, suggesting that radiation-induced intercellular communication is of importance in advanced radiotherapy dose-distributions such as with intensity-modulated radiotherapy. [ABSTRACT FROM AUTHOR]

Circadian disturbance of clock gene expression is a risk factor for diseases such as obesity, cancer, and sleep disorders. To study these diseases, it is necessary to monitor and analyze the expression rhythm of clock genes in the whole body for a long duration. The bioluminescent reporter enzyme firefly luciferase and its substrate d‐luciferin have been used to generate optical signals from tissues in vivo with high sensitivity. However, little information is known about the stability of d‐luciferin to detect gene expression in living animals for a long duration. In the present study, we examined the stability of a luciferin solution over 21 days. l‐Luciferin, which is synthesized using racemization of d‐luciferin, was at high concentrations after 21 days. In addition, we showed that bioluminescence of Period1 (Per1) expression in the liver was significantly decreased compared with the day 1 solution, although locomotor activity rhythm was not affected. These results showed that d‐luciferin should be applied to the mouse within, at most, 7 days to detect bioluminescence of Per1 gene expression rhythm in vivo. [ABSTRACT FROM AUTHOR]

Because the disruption of circadian clock gene is a risk factor in many diseases such as obesity and cancer, it is important to monitor and analyzed the expression of the rhythm of the clock gene throughout the body over a long period of time. Although we previously reported on a new gene expression analysis system tracking a target position on the body surface of freely moving mice, the experimental apparatus required a large space. We have therefore developed an in vivo recording system using a portable photomultiplier tube (PMT) system attached to an optical fibre. Directly connecting the target area with the device, we could easily measure the photon counts in a very small space. However, little information is known about the characteristics of optical fibres when exposed to twisting/looping in association with a moving mouse and the effect of the surface of optical fibre. In the present study, we report on the characteristics of optical fibres to detect gene expression rhythm in freely moving mice. Using this portable optical device directly connected with a target area, we were able to measure the circadian rhythm of clock gene expression over a prolonged period in freely moving mice in a small space. [ABSTRACT FROM AUTHOR]

The Japan Clinical Oncology Group – Radiation Therapy Study Group (JCOG-RTSG) has initiated several multicenter clinical trials for high-precision radiotherapy, which are presently ongoing. When conducting multi-center clinical trials, a large difference in physical quantities, such as the absolute doses to the target and the organ at risk, as well as the irradiation localization accuracy, affects the treatment outcome. Therefore, the differences in the various physical quantities used in different institutions must be within an acceptable range for conducting multicenter clinical trials, and this must be verified with medical physics consideration. In 2011, Japan's first Medical Physics Working Group (MPWG) in the JCOG-RTSG was established to perform this medical-physics-related verification for multicenter clinical trials. We have developed an auditing method to verify the accuracy of the absolute dose and the irradiation localization. Subsequently, we credentialed the participating institutions in the JCOG multicenter clinical trials that were using stereotactic body radiotherapy (SBRT) for lungs, intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) for several disease sites, and proton beam therapy (PT) for the liver. From the verification results, accuracies of the absolute dose and the irradiation localization among the participating institutions of the multicenter clinical trial were assured, and the JCOG clinical trials could be initiated. [ABSTRACT FROM AUTHOR]

In our laboratory we have confirmed that the capacitance of barium titanate-based capacitors changes due to radiation. Since a commercially available capacitor is very small and inexpensive, it may be used as a multidimensional dose meter in which a large number of capacitor elements are arranged, or may be embedded in the body and used as an in-vivo dose meter. In this study we examined the usefulness of a dosimeter using the capacitance change of a barium titanate capacitor. As a basic property, it was confirmed that the dose linearity was good. With regard to dose rate characteristics and response to fractionated irradiation, capacitance change due to aging affects measurement accuracy, but online measurement of capacitance change immediately before irradiation can be performed to correct aging effects during irradiation. By doing this, we confirmed that the dose rate characteristics and the response to fractionated radiation are improved. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: Image quality of chest radiographs is affected by tube voltage. This study aimed to clarify the relationship between tube voltage and physical image quality of pulmonary nodules on bone-suppressed chest radiographs.Materials and Methods: An anthropomorphic chest phantom and a spherical simulated nodule, with a 12-mm diameter and approximately +100 Hounsfield units were used. The lung field of the phantom was divided into three areas, based on the overlap with the ribs in the chest radiograph. Ten positions of the simulated nodule were defined in each area. One hundred and twenty chest radiographs were acquired using four tube voltages (70 kVp, 90 kVp, 110 kVp, and 130 kVp) for a total of 30 nodule positions and were processed to create bone-suppressed images. Differences in contrast and contrast-to-noise ratio (CNR) were analyzed for all pairs of the four tube voltages using a two-sided Wilcoxon signed-rank test.Results: In the area not overlapping with ribs, a statistically significant difference was observed only in contrast between tube voltage of 70 kVp and 90 kVp (p = 0.01). In the area overlapping with one or two ribs, the contrast and CNR tended to be higher at a lower tube voltage. In particular, the p values between the contrast at 70 kVp and that at the other three tube voltage settings were less than 0.01.Conclusion: For a relatively dense nodule, the contrast and CNR in the bone-suppressed chest radiograph were significantly improved with lower tube voltage in the lung field overlapping with the ribs. [ABSTRACT FROM AUTHOR]

Background: Real-time measurement of thermal neutrons in the tumor region is essential for proper evaluation of the absorbed dose in boron neutron capture therapy (BNCT) treatment. The gold wire activation method has been routinely used to measure the neutron flux distribution in BNCT irradiation, but a real-time measurement using gold wire is not possible. To overcome this issue, the scintillator with optical fiber (SOF) detector has been developed. The purpose of this study is to demonstrate the feasibility of the SOF detector as a real-time thermal neutron monitor in clinical BNCT treatment and also to report issues in the use of SOF detectors in clinical practice and their solutions.Material and Methods: Clinical measurements using the SOF detector were carried out in 16 BNCT clinical trial patients from December 2002 until end of 2006 at the Japanese Atomic Energy Agency (JAEA) and Kyoto University Research Reactor Institute (KURRI).Results: The SOF detector worked effectively as a real-time thermal neutron monitor. The neutron fluence obtained by the gold wire activation method was found to differ from that obtained by the SOF detector. The neutron fluence obtained by the SOF detector was in better agreement with the expected fluence than with gold wire activation. The estimation error for the SOF detector was small in comparison to the gold wire measurement. In addition, real-time monitoring suggested that the neutron flux distribution and intensity at the region of interest (ROI) may vary due to the reactor condition, patient motion and dislocation of the SOF detector.Conclusion: Clinical measurements using the SOF detector to measure thermal neutron flux during BNCT confirmed that SOF detectors are effective as a real-time thermal neutron monitor. To minimize the estimation error due to the displacement of the SOF probe during treatment, a loop-type SOF probe was developed. [ABSTRACT FROM AUTHOR]

Simple Summary: A cesium-bearing microparticle (Cs-BMP) is an insoluble radioactive microparticle possessing high specific radioactivity, which was discovered after the incident at the Fukushima nuclear power plant. Due to their insoluble nature, such Cs-BMPs are assumed to adhere in the long term to normal tissue, leading to chronic local exposure. However, radiation risk due to the intake of internal exposure to radioactive cesium is conventionally estimated from the organ dose given by uniform exposure to soluble cesium. As such, it is critical to clarify the normal tissue effects posed by heterogeneous exposure to Cs-BMPs. This in vitro study reports on the relationship between the inflammatory responses and DNA damage induction during local exposure to a Cs-BMP. Cesium-bearing microparticles (Cs-BMPs) can reach the human respiratory system after inhalation, resulting in chronic local internal exposure. We previously investigated the spatial distribution of DNA damage induced in areas around a Cs-BMP; however, the biological impacts have not been fully clarified due to the limited amount of data. Here, we investigated the inflammatory signaling and DNA damage responses after local exposure to a Cs-BMP in vitro. We used two normal human lung cell lines, i.e., lung fibroblast cells (WI-38) and bronchial epithelial cells (HBEC3-KT). After 24 h exposure to a Cs-BMP, inflammation was evaluated by immunofluorescent staining for nuclear factor κB (NF-κB) p65 and cyclooxygenase 2 (COX-2). The number of DNA double-strand breaks (DSBs) was also detected by means of phospholylated histone H2AX (γ-H2AX) focus formation assay. Cs-BMP exposure significantly increased NF-κB p65 and COX-2 expressions, which were related to the number of γ-H2AX foci in the cell nuclei. Compared to the uniform (external) exposure to 137Cs γ-rays, NF-κB tended to be more activated in the cells proximal to the Cs-BMP, while both NF-κB p65 and COX-2 were significantly activated in the distal cells. Experiments with chemical inhibitors for NF-κB p65 and COX-2 suggested the involvement of such inflammatory responses both in the reduced radiosensitivity of the cells proximal to Cs-BMP and the enhanced radiosensitivity of the cells distal from Cs-BMP. The data show that local exposure to Cs-BMP leads to biological effects modified by the NF-κB pathway, suggesting that the radiation risk for Cs-BMP exposure can differ from that estimated based on conventional uniform exposure to normal tissues. [ABSTRACT FROM AUTHOR]

Ionizing radiation (IR)-enhanced tumor invasiveness is emerging as a contributor to the limited benefit of radiotherapy; however, its mechanism is still unclear. We previously showed that subcloned lung adenocarcinoma A549 cells (P cells), which survived 10 Gy IR (IR cells), acquired high invasiveness in vitro. Here, we tried to identify the mechanism by which IR cells increase their invasiveness by examining altered gene expression and signaling pathways in IR cells compared with those in P cells. To simulate the microenvironment in vivo, cells were embedded in a three-dimensional (3D) collagen type I gel, in which the IR cells were elongated, while the P cells were spherical. The integrin expression pattern was surveyed, and expression levels of the integrin α2 and β1 subunits were significantly elevated in IR cells. Knockdown of α2 expression or functional blockade of integrin α2β1 resulted in a round morphology of IR cells, and abrogated their invasion in the collagen matrix, suggesting the molecule’s essential role in cell spread and invasion in 3D collagen. Epidermal growth factor receptor (EGFR) also presented enhanced expression and activation in IR cells. Treatment with EGFR tyrosine kinase inhibitor, PD168393, decreased the ratio of elongated cells and cell invasiveness. Signaling molecules, including extracellular signal-regulated kinase-1/2 (Erk1/2) and Akt, exhibited higher activation in IR cells. Inhibition of Akt activation by treating with phosphoinositide 3-kinase (PI3K) inhibitor LY294002 decreased IR cell invasion, whereas inhibition of Erk1/2 activation by mitogen-activated protein kinase kinase (MEK) inhibitor U0126 did not. Our results show that integrin α2β1 and EGFR cooperatively promote higher invasiveness of IR-survived lung cancer cells, mediated in part by the PI3K/Akt signaling pathway, and might serve as alternative targets in combination with radiotherapy. [ABSTRACT FROM AUTHOR]

Background: We performed a dosimetric comparison of spot-scanning proton therapy (SSPT) and intensitymodulated radiation therapy (IMRT) for hepatocellular carcinoma (HCC) to investigate the impact of tumor size on the risk of radiation induced liver disease (RILD). Methods: A number of alternative plans were generated for 10 patients with HCC. The gross tumor volumes (GTV) varied from 20.1 to 2194.5 cm3. Assuming all GTVs were spherical, the nominal diameter was calculated and ranged from 3.4 to 16.1 cm. The prescription dose was 60 Gy for IMRT or 60 cobalt Gy-equivalents for SSPT with 95% planning target volume (PTV) coverage. Using IMRT and SSPT techniques, extensive comparative planning was conducted. All plans were evaluated by the risk of RILD estimated using the Lyman-normal-tissue complication probability model. Results: For IMRT the risk of RILD increased drastically between 6.3-7.8 cm nominal diameter of GTV. When the nominal diameter of GTV was more than 6.3 cm, the average risk of RILD was 94.5% for IMRT and 6.2% for SSPT. Conclusions: Regarding the risk of RILD, HCC can be more safely treated with SSPT, especially if its nominal diameter is more than 6.3 cm. [ABSTRACT FROM AUTHOR]

Purpose: In accurate proton spot-scanning therapy, continuous target tracking by fluoroscopic x ray during irradiation is beneficial not only for respiratory moving tumors of lung and liver but also for relatively stationary tumors of prostate. Implanted gold markers have been used with great effect for positioning the target volume by a fluoroscopy, especially for the cases of liver and prostate with the targets surrounded by water-equivalent tissues. However, recent studies have revealed that gold markers can cause a significant underdose in proton therapy. This paper focuses on prostate cancer and explores the possibility that multiple-field irradiation improves the underdose effect by markers on tumor-control probability (TCP). Methods: A Monte Carlo simulation was performed to evaluate the dose distortion effect. A spherical gold marker was placed at several characteristic points in a water phantom. The markers were with two different diameters of 2 and 1.5 mm, both visible on fluoroscopy. Three beam arrangements of single-field uniform dose (SFUD) were examined: one lateral field, two opposite lateral fields, and three fields (two opposite lateral fields + anterior field). The relative biological effectiveness (RBE) was set to 1.1 and a dose of 74 Gy (RBE) was delivered to the target of a typical prostate size in 37 fractions. The ratios of TCP to that without the marker (TCPr) were compared with the parameters of the marker sizes, number of fields, and marker positions. To take into account the dependence of biological parameters in TCP model, α/β values of 1.5, 3, and 10 Gy (RBE) were considered. Results: It was found that the marker of 1.5 mm diameter does not affect the TCPs with all α/β values when two or more fields are used. On the other hand, if the marker diameter is 2 mm, more than two irradiation fields are required to suppress the decrease in TCP from TCPr by less than 3%. This is especially true when multiple (two or three) markers are used for alignment of a patient. Conclusions: It is recommended that 1.5-mm markers be used to avoid the reduction of TCP as well as to spare the surrounding critical organs, as long as the markers are visible on x-ray fluoroscopy. When 2-mm markers are implanted, more than two fields should be used and the markers should not be placed close to the distal edge of any of the beams. [ABSTRACT FROM AUTHOR]