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The purpose of this study was to investigate the in vivo combined effects of pulsed focused ultrasound (pFUS) and radiation (RT) for prostate cancer treatment. An animal prostate tumor model was developed by implanting human LNCaP tumor cells in the prostates of nude mice. Tumor-bearing mice were treated with pFUS, RT or both (pFUS + RT) and compared with a control group. Non-thermal pFUS treatment was delivered by keeping the body temperature below 42 °C as measured real-time by MR thermometry and using a pFUS protocol (1 MHz, 25 W focused ultrasound; 1 Hz pulse rate with a 10% duty cycle for 60 sec for each sonication). Each tumor was covered entirely using 4–8 sonication spots. RT treatment with a dose of 2 Gy was delivered using an external beam (6 MV photon energy with dose rate 300MU/min). Following the treatment, mice were scanned weekly with MRI for tumor volume measurement. The results showed that the tumor volume in the control group increased exponentially to 142 ± 6%, 205 ± 12%, 286 ± 22% and 410 ± 33% at 1, 2, 3 and 4 weeks after treatment, respectively. In contrast, the pFUS group was 29% (p < 0.05), 24% (p < 0.05), 8% and 9% smaller, the RT group was 7%, 10%, 12% and 18% smaller, and the pFUS + RT group was 32%, 39%, 41% and 44% (all with p < 0.05) smaller than the control group at 1, 2, 3, and 4 weeks post treatment, respectively. Tumors treated by pFUS showed an early response (i.e. the first 2 weeks), while the RT group showed a late response. The combined pFUS + RT treatment showed consistent response throughout the post-treatment weeks. These results suggest that RT combined with non-thermal pFUS can significantly delay the tumor growth. The mechanism of tumor cell killing between pFUS and RT may be different. Pulsed FUS shows early tumor growth delay, while RT contributes to the late effect on tumor growth delay. The addition of pFUS to RT significantly enhanced the therapeutic effect for prostate cancer treatment. [ABSTRACT FROM AUTHOR]

This paper examines the views of Hong Kong community leaders on the underlying issues that affect family health, happiness and harmony (3Hs) in Hong Kong. Using a community reconnaissance method, a series of individual in-depth interviews with 26 leaders that represent neighbourhoods of diverse socio-economic status (SES) from June to August 2008 were conducted. Participants considered that changing family structure, economic situation and strong work ethic are the most salient factors that affect family 3Hs. The deprived comprehensive social security assistance recipients, single-parent families and migrant women were considered to be the most vulnerable groups to breakdown in family 3Hs and particularly, they lack family resources. Families from different SES have to overcome different challenges in order to achieve and sustain family 3Hs. Leaders from low SES neighbourhood were concerned more about providing tangible help such as child care facilities to improve family resources, whereas leaders from high SES neighbourhood focused more on preventive interventions such as education on relationship skills to achieve better family well-being. The findings offer insights in designing effective social marketing education campaigns and family-friendly workplace policy to promote social harmony through the maintenance of 3Hs families.

Cell death is one of the inevitable life activities of cells during the growth and development of the body. Regulated cell death (RCD) is a type of cell death mode that can be regulated and depends on specific molecular mechanisms which play an essential role in various pathophysiological environments. Pyrolysis is a newly discovered method of programmed cell death mediated by members of the Gasdermin protein family which is characterized by the activation of inflammatory factors and the formation of cell membrane pores. The specific manifestations are the swelling of cells, the appearance of plasma membrane bullae and the release of cell contents after cell rupture. A cascade of inflammation occurs after cell death. Activation of inflammasomes activates the classic pyrolysis pathway depending on caspase-1 or the non-classical pyrolysis pathway depending on Caspase-4/5/11 and the subsequent inflammation reaction, excessive immune response caused by microbial infection and danger signals can lead to a variety of inflammatory diseases. In the inflammatory response, large numbers of inflammasomes activate the substrate protein GSDMD. GSDMD mediates pyrolysis by forming pores in the plasma membrane and mitochondria. Many studies have shown that pyrolysis plays an essential role in inflammatory bowel disease and other inflammatory diseases. This article aims to elaborate on the molecular mechanisms of pyroptosis in ulcerative colitis (UC) pathogenesis and provide new therapeutic ideas for UC. [ABSTRACT FROM AUTHOR]

To provide accurate and fast 3-D dose verification for hypofractionated stereotactic radiotherapy (SRT/SBRT) of small and multi targets calculated with a Varian Eclipse treatment planning system (TPS) delivered on a Varian accelerator. Ten brain and lung hypofractionated SRT/ SBRT linac-based and CyberKnife plans were generated by the Eclipse system for delivery on the accelerator with the Millenium-120 leaf multileaf collimator (MLC) and Multiplan for the CyberKnife machine. These clinical SRT/SBRT plans required accurate quality assurance measurements to obtain absolute point dose and 3-D dose distributions due to the low number of fractions and high fraction doses. For small-field and multi-target plans, the EGS4/MCSIM code was used to calculate the dose distribution. A 0.125 cc ion chamber, a 0.016 cc pin-point chamber and Kodak EDR2 film were used for the measurements and the results were compared with Monte Carlo (MC) calculations. The dosimetry for small-field and multi-target treatment plans is challenging due to the comparable range of secondary electrons and the field sizes defined by SRT/SBRT MLC segments. Our MC simulations can accurately reproduce the linac dose distributions (within 1%/1 mm) three dimensionally. For the clinical SRT/SBRT plans investigated in this work, the MC doses agreed within 3% with ion chamber measurements and within 2%/2 mm with film measurements. The doses calculated by the Eclipse AAA algorithm and Multiplan differed by no more than 5% from MC calculations for small (4-40 cc) Planning Target Volumes (PTVs). MC dose calculation provides accurate and fast 3-D dose verification for hypofractionated SRT for small and multi-target treatment plans generated by a Varian Eclipse TPS on a Varian accelerator and Multiplan treatment planning on the CyberKnife System. [ABSTRACT FROM AUTHOR]

Photodynamic therapy has been clinically proven to be effective, but its effect is limited to relatively shallow tumors because of its use of visible light. Radiodynamic therapy (RDT) has therefore been investigated as a means to treat deep-seated tumors. In this study, the treatment effect of a novel form of RDT consisting of radiation combined with 5-aminolevulinic acid (5-ALA) and carbamide peroxide was investigated using a mouse model. Male nude mice were injected bilaterally and subcutaneously with human prostate cancer (PC-3) cells and randomized into 8 treatment groups, consisting of various combinations of 15-MV radiotherapy (RT), 5-ALA, and carbamide peroxide. The treatment effect of a single fraction of treatment was measured by calculating tumor growth delay, monitored using weekly MR scans. The ability of the drugs to be delivered to the tumors was qualitatively measured using 18 F-FDG PET/CT scans. RDT was shown to significantly delay the tumor growth for the mouse model and tumor cell line investigated in this work. Tumors treated with RDT showed a decrease in tumor growth of 24 ± 9% and 21 ± 8% at one and two weeks post-treatment, respectively. Peroxide and 5-ALA did not contribute significantly to tumor growth delay when administered alone or separately with RT. Blood perfusion was shown to be able to deliver agents to the tumors investigated in this work, although uptake of 18 F-FDG was shown to be non-uniform. [ABSTRACT FROM AUTHOR]

Linac calibration is done in water, but patients are comprised primarily of soft tissue. Conceptually, and specified in NRG/RTOG trials, dose should be reported as dose‐to‐muscle to describe the dose to the patient. Historically, the dose‐to‐water of the linac calibration was often converted to dose‐to‐muscle for patient calculations through manual application of a 0.99 dose‐to‐water to dose‐to‐muscle correction factor, applied during the linac clinical reference calibration. However, many current treatment planning system (TPS) dose calculation algorithms approximately provide dose‐to‐muscle (tissue), making application of a manual scaling unnecessary. There is little guidance on when application of a scaling factor is appropriate, resulting in highly inconsistent application of this scaling by the community. In this report we provide guidance on the steps necessary to go from the linac absorbed dose‐to‐water calibration to dose‐to‐muscle in patient, for various commercial TPS algorithms. If the TPS does not account for the difference between dose‐to‐water and dose‐to‐muscle, then TPS reference dose scaling is warranted. We have tabulated the major vendors' TPS in terms of whether they approximate dose‐to‐muscle or calculate dose‐to‐water and recommend the correction factor required to report dose‐to‐muscle directly from the TPS algorithm. Physicists should use this report to determine the applicable correction required for specifying the reference dose in their TPS to achieve this goal and should remain attentive to possible changes to their dose calculation algorithm in the future. [ABSTRACT FROM AUTHOR]

Purpose: The directional planar palladium‐103 LDR device (CivaSheetTM) may be used for intraoperative implantation at the interface between the tumor site and healthy tissue. Its dosimetric properties have been studied in the ideal case of application on a flat surface. The dosimetric impact of implanting this highly directional device on a curved surface that may be encountered in clinical treatments is analyzed. Methods: CivaSheet is designed as an array of directional palladium‐103 sources (CivaDots). From the postoperative computed tomography (CT) scans of three patients, the shape of each implanted CivaSheet was reconstructed. In order to obtain a realistic estimate of the distribution of curvatures, the mean radius of curvature at the location of each CivaDot was calculated. A Monte Carlo simulation (FLUKA) of a single CivaDot was designed, based upon published geometry and material specifications. Both the radial dose function analog and the two‐dimensional anisotropy function analog for the CivaDot were validated in comparison with film measurements and benchmarked to published Monte Carlo data. A value for the dose‐rate constant Λ = 0.587(19) cGy/h/U for a CivaDot source in water was calculated as well. Knowledge of the dose distribution in the vicinity of each source allowed the dose at any point around CivaSheets of different curvatures and orientations to be calculated. Results: The local radius of curvature was found to be primarily between 2 and 8 cm in all three patient implants. On the unshielded side of an inward‐facing curved CivaSheet implant of radius 2 cm, the calculated dose at 0.5 cm depth exceeded the prescribed dose by ∼20%, while on the shielded side the dose increased by a factor of two, thus compromising the shielding efficiency of the original design. On the unshielded side of an outward‐facing curved implant, the dose at 0.5 cm depth decreased by ∼20%. Conclusions: When tumor bed curvature can be estimated from the preplanning CT scan, the results from this study provide quantitative guide for modifying the source strength to achieve the desired clinical results. In many intraoperative cases, however, accurate preplanning based on surface curvature may not be practical. In such situations, knowledge of the dosimetric impact of the surface curvature provides motivation for avoiding implantation geometries that can lead to either over/underdosing the target, or excess dose to healthy tissue. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Two different respiratory monitoring systems (Varian's Real‐Time Position Management (RPM) System and Siemens’ ANZAI belt Respiratory Gating System) are compared in the context of respiratory signals and 4D CT images that are accordingly reconstructed. This study aims to evaluate the feasibility of combined use of RPM and ANZAI systems for 4DCT simulation and gated radiotherapy treatment, respectively. Methods: The RPM infrared reflecting marker and the ANZAI belt pressure sensor were both placed on the patient's abdomen during 4DCT scans. The respiratory signal collected by the two systems was synchronized. Fifteen patients were enrolled for respiratory signal collection and analysis. The discrepancies between the RPM and ANZAI traces can be characterized by phase shift and shape distortion. To reveal the impact of the changes in respiratory signals on 4D images, two sets of 4D images based on the same patient's raw data were reconstructed using the RPM and ANZAI data for phase sorting, respectively. The volume of whole lung and the position of diaphragm apex were measured and compared for each respiratory phase. Results: The mean phase shift was measured as 0.2 ± 0.1 s averaged over 15 patients. The shape of the breathing trace was found to be in disagreement. For all the patients, the ANZAI trace had a steeper falloff in exhalation than RPM. The inhalation curve, however, was matched for nine patients, steeper in ANZAI for five patients and steeper in RPM for one patient. For 4D image comparison, the difference in whole‐lung volume was about −4% to +4% and the difference in diaphragm position was about −5 mm to +4 mm, compared in each individual phase and averaged over seven patients. Conclusions: Combined use of one system for 4D CT simulation and the other for gated treatment should be avoided as the resultant gating window would not fully match with each other due to the remarkable discrepancy in breathing traces acquired by the two different surrogate systems. [ABSTRACT FROM AUTHOR]

The correct equation should be 2 HT ht where ( I W i / I e i ) SB air sb is the average energy expended per unit charge of ionization produced in dry air, having the value 33.97 J/C, and (1 - I g i ) corrects for the effect of radiative losses (mainly due to bremsstrahlung emission) by the secondary charged particles, and I g i is less than 0.1% for photons below 300 keV in air. Erratum: "AAPM protocol for 40-300 kV x-ray beam dosimetry in radiotherapy and radiobiology". [Extracted from the article]

The fruit body ofLasiosphaera fenzliiwas found to show cytotoxicity on cancer cells during a preliminary screening. Repeated column chromatography of the fungal methanol extract resulted in the isolation of six compounds identified as 5α,8α-epidioxy-ergosta-6,22-dien-3β-ol (1), 5α,8α-epidioxy-ergosta-6,9(11),22-trien-3β-ol (2), 5α-ergosta-7,22-dien-3β-ol (3), 5α-ergosta-7,22-dien-3-one (4), ergosta-7,22-dien-3β,5α,6β-triol (5) and 6-dihydroxy-2,3-dihydro-1H-isoindol-1-one (6). The two peroxide compounds,1and2, showed cytotoxic activity and compound1was selectively cytotoxic to cancer cells. Furthermore, compound1synergised the cytotoxicity of paclitaxel on Hela cells by increasing intracellular accumulation of paclitaxel in cancer cells but not in normal cells. [ABSTRACT FROM PUBLISHER]

The purpose of this study is to evaluate the treatment plan adequacy and delivery efficiency among volumetric-modulated arc therapy (VMAT) with one or two arcs and the conventional static-field dynamic multileaf collimator (dMLC) intensity-modulated radiation therapy (IMRT) in patients undergoing oropharyngeal carcinoma. Fifteen patient cases were included in this investigation. Each of the cases was planned using step-and-shoot IMRT, VMAT with a single arc (Arc1) and VMAT with double arcs (Arc2). A two-dose level prescription for planning target volumes (PTVs) was delivered with 70 Gy/56 Gy in 30 fractions. Comparisons were performed of the dose-volume histograms (DVH) for PTVs, the DVH for organs at risk (OARs), the monitor units per fraction (MU/fx), and delivery time. IMRT and Arc2 achieved similar target coverage, but superior to Arc1. Apart from the oral cavity, Arc1 showed no advantage in sparing of OARs compared with IMRT, while Arc2 obtained equivalent or better sparing of OARs among the three techniques. VMAT reduced MU/fx and shortened delivery time remarkably compared with IMRT. Our results demonstrated that for oropharyngeal cases, Arc2 can achieve superior target coverage and normal tissue sparing, as well as a significant reduction in treatment time. [ABSTRACT FROM AUTHOR]

Purpose: High-intensity focused ultrasound (HIFU) has been investigated for ablative therapy and drug enhancement for gene therapy and chemotherapy. The aim of this work is to explore the feasibility of pulsed focused ultrasound (pFUS) for cancer therapy using an in vivo animal model. Methods: A clinical HIFU system (InSightec ExAblate 2000) integrated with a 1.5 T GE MR scanner was used in this study. Suitable ultrasound parameters were investigated to perform nonthermal soni-cations, keeping the temperature elevation below 4 °C as measured in real time by MR thermometry. LNCaP cells (106) were injected into the prostates of male mice (n = 20). When tumors reached a diameter of about 5 mm in 3D as measured on magnetic resonance imaging (MRI), the tumor-bearing mice (n = 8) were treated with pFUS (1 MHz frequency; 25 W acoustic power; 0.1 duty cycle; 60 s duration). A total of 4-6 sonications were used to cover the entire tumor volume under MR image guidance. The animals were allowed to survive for 4 weeks after the treatment. The tumor growth was monitored on high-resolution (0.2 mm) MRI weekly post treatment and was compared with that of the control group (n = 12). Results: Significant tumor growth delay was observed in the tumor-bearing mice treated with pFUS. The mean tumor volume for the pFUS treated mice remained the same 1 week after the treatment while the mean tumor volume of the control mice grew 42% over the same time. Two weeks after the pFUS treatment, the control group had a mean tumor volume 40% greater than that of the treated group. There was a greater variation in tumor volume at 4 weeks post treatment for both treated and control mice and a slightly faster tumor growth for the pFUS treated mice Conclusions: The authors' results demonstrated that pFUS may have a great potential for cancer therapy. Further experiments are warranted to understand the predominantly nonthermal cell killing mechanisms of pFUS and to derive optimal ultrasound parameters and fractionation schemes to maximize the therapeutic effect of pFUS. [ABSTRACT FROM AUTHOR]

The turbulent nature of wind significantly complicates the airflow-exchange process at single openings that function as both inlets and outlets simultaneously. For such flow problems, describing the ventilation rate using a constant value is insufficient if the fluctuating intensity is too large. This paper uses a large eddy simulation (LES) model combined with the tracer gas concentration decay method to investigate fluctuating ventilation characteristics through a single opening under various approaching wind directions. The numerical method is validated against a field measurement of single-sided ventilation rates. Results show that wind direction (which characterizes the external airflow pattern) greatly influences the airflow exchange at a single opening. The ventilation rate is relatively steady for a windward opening and shows more unsteadiness for a lateral and a leeward opening. The airflow-exchange process is mainly driven by the mean flow at the windward opening and is dominated by the turbulent flow at the lateral opening. The findings from this study imply that the turbulence-induced component of single-sided ventilation rates should always be considered, especially for non-windward openings. [ABSTRACT FROM AUTHOR]

It has been known for about sixty years that proton and heavy ion therapy is a very powerful radiation procedure for treating tumors. It has an innate ability to irradiate tumors with greater doses and spatial selectivity compared with electron and photon therapy and, hence, is a tissue sparing procedure. For more than twenty years, powerful lasers have generated high energy beams of protons and heavy ions and it has, therefore, frequently been speculated that lasers could be used as an alternative to radiofrequency (RF) accelerators to produce the particle beams necessary for cancer therapy. The present paper reviews the progress made towards laser driven hadron cancer therapy and what has still to be accomplished to realize its inherent enormous potential. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the association between polymorphic variants of DNA repair genes with the susceptibility of acute oral mucositis (OM) in nasopharyngeal carcinoma (NPC) patients treated with radiotherapy. Materials and methods: The study population consisted of 120 NPC patients treated with intensity-modulated radiation therapy (IMRT). Among them 70 patients also received concurrent chemotherapy. Genotypes in DNA repair genes Ku70 c.-1310C>G (rs2267437), Ku70 c.1781G> T (rs132788), Ku80 c.2099-2408G> A (rs3835), Ku80 c.*841G> A (rs2440) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) c.2888 + 713C> T (rs2213178) were determined by polymerase chain reaction combined with the restriction fragment length polymorphism (PCR-RFLP) technique. Mucositis was scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into the CTC0-2 group (CTC toxicity grade 0, 1 and 2) and the CTC3 + group (CTC toxicity grade 3 and above). Odd ratios (OR) and 95% confidence intervals (CI) were calculated using the multivariate logistic regression analysis. Results: A significant difference in Ku70 c.1781G> T genotype distribution was observed between the CTC0-2 and CTC3 + groups for the 120 patients analyzed. The GG carriers were at higher risks for severe OM (CTC3+) compared with the TT homozygotes (OR = 3.000, 95% CI = 1.287-6.994, p = 0.011). No association was found between Ku70 (c.-1310C> G), Ku80 (c.2099-2408G> A, c.*841G> A), DNA-PKcs (c.2888 + 713 C > T) and the development of severe oral mucositis. Stratification analyses for the 50 patients treated with radiation alone further confirmed the association between the variant genotype of GG and severe OM (OR = 5.128, 95% CI = 1.183-22.238, p = 0.029). Concurrent radiochemotherapy increased the risk of severe OM for both the TT homozygotes and GG genotypes. Conclusions: Our study suggests that the Ku70 c.1781G> T polymorphism may be a susceptibility factor for radiation-induced oral mucositis in Chinese nasopharyngeal carcinoma patients. [ABSTRACT FROM AUTHOR]

Electron beam therapy has been an important radiation therapy modality for many decades. Studies have been conducted recently for more efficient and advanced delivery of electron beam radiation therapy. X-ray contamination is a common problem that exists with all of the advanced electron beam therapy techniques such as Bolus Electron conformal therapy, segmented electron conformal therapy, and modulated electron arc therapy. X-ray contamination could add some limitations to the advancement and clinical utility of those electron modalities. It was previously shown in the literature that the scattering foil is one of the major accelerator parts contributing to the generation of bremsstrahlung photons. Thus, in this work we investigate the dosimetric characteristics of scattering foil free (SFF) electron beams and the feasibility of using those beams for breast cancer boosts. The SFF electron beams were modeled and simulated using the Monte Carlo method. CT scans of six previously treated breast patients were used for the treatment plan generation utilizing our in-house Monte Carlo-based treatment planning system. Electron boost plans with conventional beams and the SFF beams were generated, respectively, for all patients. A significant reduction of the photon component was observed with the removal of the primary scattering foil for beam energies higher than 12 MeV. Flatness was greatly affected but the difference in flatness between conventional and SFF beams was much reduced for small cone sizes, which were often used clinically for breast boosts. It was found that the SFF electron beams could deliver high-quality dose distributions as conventional electron beams for boost treatments of the breast with an added advantage of a further reduced dose to the lung and the heart. [ABSTRACT FROM AUTHOR]

Many tumor cells demonstrate hyperradiosensitivity at doses below ∼50 cGy. Together with the increased normal tissue repair under low dose rate, the pulsed low dose rate radiotherapy (PLDR), which separates a daily fractional dose of 200 cGy into 10 pulses with 3 min interval between pulses (∼20 cGy/pulse and effective dose rate 6.7 cGy min−1), potentially reduces late normal tissue toxicity while still providing significant tumor control for re-irradiation treatments. This work investigates the dosimetric and technical feasibilities of intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT)-based PLDR treatments using Varian Linacs. Twenty one cases (12 real re-irradiation cases) including treatment sites of pancreas, prostate, pelvis, lung, head-and-neck, and breast were recruited for this study. The lowest machine operation dose rate (100 MU min−1) was employed in the plan delivery. Ten-field step-and-shoot IMRT and dual-arc VMAT plans were generated using the Eclipse TPS with routine planning strategies. The dual-arc plans were delivered five times to achieve a 200 cGy daily dose (∼20 cGy arc−1). The resulting plan quality was evaluated according to the heterogeneity and conformity indexes (HI and CI) of the planning target volume (PTV). The dosimetric feasibility of retaining the hyperradiosensitivity for PLDR was assessed based on the minimum and maximum dose in the target volume from each pulse. The delivery accuracy of VMAT and IMRT at the 100 MU min−1 machine operation dose rate was verified using a 2D diode array and ion chamber measurements. The delivery reproducibility was further investigated by analyzing the Dynalog files of repeated deliveries. A comparable plan quality was achieved by the IMRT (CI 1.10–1.38; HI 1.04–1.10) and the VMAT (CI 1.08–1.26; HI 1.05–1.10) techniques. The minimum/maximum PTV dose per pulse is 7.9 ± 5.1 cGy/33.7 ± 6.9 cGy for the IMRT and 12.3 ± 4.1 cGy/29.2 ± 4.7 cGy for the VMAT. Six out of the 186 IMRT pulses (fields) were found to exceed 50 cGy maximum PTV dose per pulse while the maximum PTV dose per pulse was within 40 cGy for all the VMAT pulses (arcs). However, for VMAT plans, the dosimetric quality of the entire treatment plan was less superior for the breast cases and large irregular targets. The gamma passing rates for both techniques at the 100 MU min−1 dose rate were at least 94.1% (3%/3 mm) and the point dose measurements agreed with the planned values to within 2.2%. The average root mean square error of the leaf position was 0.93 ± 0.83 mm for IMRT and 0.53 ± 0.48 mm for VMAT based on the Dynalog file analysis. The RMS error of the leaf position was nearly identical for the repeated deliveries of the same plans. In general, both techniques are feasible for PLDR treatments. VMAT was more advantageous for PLDR with more uniform target dose per pulse, especially for centrally located tumors. However, for large, irregular and/or peripheral tumors, IMRT could produce more favorable PLDR plans. By taking the biological benefit of PLDR delivery and the dosimetric benefit of IMRT and VMAT, the proposed methods have a great potential for those previously-irradiated recurrent patients. [ABSTRACT FROM AUTHOR]

Purpose: Sorafenib, an oral multikinase inhibitor, is the first agent that has demonstrated an improved overall survival benefit in advanced hepatocellular carcinoma, setting a new standard for first-line treatment. However, the association between radiosensitivity and sorafenib remains unclear. The purpose of this study was to investigate whether sorafenib could enhance radiosensitivity and the possible mechanisms of sorafenib-mediated radiosensitization in human hepatocellular carcinoma cell line SMMC-7721. Experimental design: The cell viability of human hepatocellular carcinoma cell line SMMC-7721 was determined by the 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. The radiosensitization of sorafenib in SMMC-7721 cells was evaluated by clonogenic assays, and immunofluorescence for DNA double-strand break detection, and Western blotting for protein detection. Results: The MTT results clearly showed that sorafenib affected cell viability in human hepatocellular cell line SMMC-7721. Sorafenib administered 1 h before the radiation treatment resulted in radiosensitization with a sensitivity enhancement ratio (SER) of 1.65 as shown by clonogenic assays. Furthermore, sorafenib pretreatment led to decreased phosphorylation levels of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) in SMMC-7721 cells. Interestingly, pretreatment of mitogen-activated protein kinase kinases/extracellular signal-regulated kinase (MEK/ERK) signaling inhibitor U0126 had a similar effect as that of sorafenib pretreatment in hepatocellular carcinoma cells, whereas pretreatment of phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling inhibitor LY294002 in the same cells had no effect on radiosensitization. The group treated with sorafenib and radiation was more sensitive to irradiation alone as demonstrated by the results of the DNA double-strand break detection. Conclusions: The combination of sorafenib and radiation affected cell viability more effectively than radiation alone. Sorafenib significantly enhanced the sensitivity of SMMC-7721 cells to radiation showing significantly reduced repair of DNA double-strand breaks. The MEK/ERK signaling pathway may be a pathway responsible for the radiosensitivity enhancement of sorafenib. Our data provided experimental support for the possible combination of sorafenib with radiation for the treatment of hepatocellular carcinoma and other cancers. [ABSTRACT FROM AUTHOR]

A motorized electron multileaf collimator (eMLC) was developed as an add-on device to the Varian linac for delivery of advanced electron beam therapy. It has previously been shown that electron beams collimated by an eMLC have very similar penumbra to those collimated by applicators and cutouts. Thus, manufacturing patient specific cutouts would no longer be necessary, resulting in the reduction of time taken in the cutout fabrication process. Moreover, cutout construction involves handling of toxic materials and exposure to toxic fumes that are usually generated during the process, while the eMLC will be a pollution-free device. However, undulation of the isodose lines is expected due to the finite size of the eMLC. Hence, the provided planned target volume (PTV) shape will not exactly follow the beam's-eye-view of the PTV, but instead will make a stepped approximation to the PTV shape. This may be a problem when the field edge is close to a critical structure. Therefore, in this study the capability of the eMLC to achieve the same clinical outcome as an applicator/cutout combination was investigated based on real patient computed tomographies (CTs). An in-house Monte Carlo based treatment planning system was used for dose calculation using ten patient CTs. For each patient, two plans were generated; one with electron beams collimated using the applicator/cutout combination; and the other plan with beams collimated by the eMLC. Treatment plan quality was compared for each patient based on dose distribution and dose-volume histogram. In order to determine the optimal position of the leaves, the impact of the different leaf positioning strategies was investigated. All plans with both eMLC and cutouts were generated such that 100% of the target volume receives at least 90% of the prescribed dose. Then the percentage difference in dose between both delivery techniques was calculated for all the cases. The difference in the dose received by 10% of the volume of the target was showing a mean percentage difference of 1.57%±1.65, while the difference in the dose received by 99% of the volume was showing a mean percentage difference of 1.08%±0.78. The mean percentage volume of Lung receiving a percentage dose equal to or greater than 20% of the prescribed dose was found to be 8.55%±7.3 and 8.67%±7 for the eMLC and applicator/cutout combination delivery methods respectively. Results have shown that target coverage and critical structure sparing can be effectively achieved by electron beams collimated with the eMLC. Positioning the eMLC leaves in such a way to avoids shielding any part of the projected treatment volume is most conservative and would be the recommended method to define the actual leaf position for the eMLC defined field. More optimal leaf positions can be achieved in shaping the same treatment field through the interplay of different leaf positioning strategies. We concluded that the eMLC represents an effective time saving and pollution-free device that can completely replace patient specific cutouts. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to develop an EPID-guided 4D patient dose reconstruction framework and to investigate its feasibility for lung SBRT treatment validation. Methods: Both the beam apertures and tumor movements were detected based on the continuously acquired EPID images during the treatment. Instead of directly using the transit photon fluence measured by the EPID, this method reconstructed the entrance fluence with the measured beam apertures and the delivered MUs. The entrance fluence distributions were sorted into their corresponding phases based on the detected tumor motion pattern and then accumulated for each phase. Together with the in-room 4DCT taken before every treatment to consider the interfractional-motion, the entrance fluence was then used for the patient dose calculation. Deformable registration was performed to sum up the phase doses for final treatment assessment. The feasibility of using the transit EPID images for entrance fluence reconstruction was evaluated against EPID in-air measurements. The accuracy of 3D- and 4D-dose reconstruction was validated by experiments with a motor-driven cylindrical diode array for six clinical-SBRT plans. Results: The average difference between the measured and reconstructed fluence maps was within 0.16%. The reconstructed 3D-dose showed a less than 1.4% difference for the CAX-dose and at least a 98.3% gamma-passing-rate (2%/2 mm) for the peripheral dose. Distorted dose distributions were observed in the measurement with the moving phantom. The comparison between the measured and the reconstructed 4D-dose without considering temporal information failed the gamma-evaluation for most cases. In contrast, when temporal information was considered, the dose distortion phenomena were successfully represented in the reconstructed dose (97.6%-99.7% gamma-passing rate). Conclusions: The proposed method considered uncertainties of the beam delivery system, the interfractional- and intrafractional-motion, and the interplay effect. The experimental validation demonstrates that this method is practical and accurate for online or offline SBRT patient dose verification. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the potential of MR-guided pulsed focused ultrasound (pFUS) for the enhancement of drug uptake in prostate tumors in vivo using doxorubicin (Dox). Methods: An antitumor drug Dox, an orthotopic animal prostate tumor model using human prostate cancer, LNCaP cell line, and a clinical FUS treatment system (InSightec ExAblate 2000) with a 1.5T GE MR scanner were used in this study. First, experiments on a tissue mimic phantom to determine the optimal acoustic power and exposure durations with a 10% duty cycle and a 1 Hz pulse rate were performed. The temperature variation was monitored using real-time MR thermometry. Second, tumor-bearing animals were treated with pFUS. There were three groups (n = 8/group): group 1 received pFUS + Dox (10 mg/kg i.v. injection immediately after pFUS exposure), group 2 received Dox only (10 mg/kg i.v. injection), and group 3 was a control. Animals were euthanized 2 h after the pFUS treatment. The Dox concentration in the treated tumors was measured by quantifying fluorescent tracers using a fluorometer. Third, the histological changes of tumors with and without pFUS treatments were evaluated. Finally, experiments were performed to study the spatial drug distribution in tumors after the pFUS treatment, in which two animals received pFUS + Dox, two animals received Dox only, and one animal was used as control. Two hours following the treatment, animals were euthanized and processed. The Dox distribution was determined using a fluorescence microscope. Results: Parametric measurements using a tissue phantom showed that the temperature increased with an increasing acoustic power (from 10 to 50 W) or sonication duration (from 10 to 60 s) with a given acoustic frequency of 1 MHz, duty cycle 10%, and pulse rate 1 Hz. A set of ultrasound parameters was identified with which the temperature elevation was less than 5 °C, which was used for nonthermal pFUS sonication. Increased Dox concentration (14.9 ± 2.5 μg/g) was measured in the pFUS-treated group compared to the Dox-only group (9.5 ± 1.6 μg/g), indicating an approximate 60% increase with p = 0.05. The results were consistent with the increased spatial drug distributions by fluorescence imaging. Histological analysis showed increased extravasation in pFUS-treated prostate tumors suggesting increased drug delivery with pFUS. Conclusions: The results showed that pFUS-enhanced drug uptake in prostate tumors was significant. This increased uptake may be due to increased extravasation by pFUS. Optimal pFUS parameters may exist to maximize the drug uptake, and this study using Dox demonstrated a quantitative method for such systematic parametric studies. In addition, this study may provide useful data for the potential application of pFUS-mediated Dox delivery for prostate tumor therapy. [ABSTRACT FROM AUTHOR]

Purpose: To commission Monte Carlo beam models for five Varian megavoltage photon beams (4, 6, 10, 15, and 18 MV). The goal is to closely match measured dose distributions in water for a wide range of field sizes (from 2×2 to 35×35 cm2). The second objective is to reinvestigate the sensitivity of the calculated dose distributions to variations in the primary electron beam parameters. Methods: The GEPTS Monte Carlo code is used for photon beam simulations and dose calculations. The linear accelerator geometric models are based on (i) manufacturer specifications, (ii) corrections made by Chibani and Ma ['On the discrepancies between Monte Carlo dose calculations and measurements for the 18 MV Varian photon beam,' Med. Phys. 34, 1206-1216 (2007)], and (iii) more recent drawings. Measurements were performed using pinpoint and Farmer ionization chambers, depending on the field size. Phase space calculations for small fields were performed with and without angle-based photon splitting. In addition to the three commonly used primary electron beam parameters (EAV is the mean energy, FWHM is the energy spectrum broadening, and R is the beam radius), the angular divergence (θ) of primary electrons is also considered. Results: The calculated and measured dose distributions agreed to within 1% local difference at any depth beyond 1 cm for different energies and for field sizes varying from 2×2 to 35×35 cm2. In the penumbra regions, the distance to agreement is better than 0.5 mm, except for 15 MV (0.4-1 mm). The measured and calculated output factors agreed to within 1.2%. The 6, 10, and 18 MV beam models use θ=0°, while the 4 and 15 MV beam models require θ=0.5° and 0.6°, respectively. The parameter sensitivity study shows that varying the beam parameters around the solution can lead to 5% differences with measurements for small (e.g., 2×2 cm2) and large (e.g., 35×35 cm2) fields, while a perfect agreement is maintained for the 10×10 cm2 field. The influence of R on the central-axis depth dose and the strong influence of θ on the lateral dose profiles are demonstrated. Conclusions: Dose distributions for very small and very large fields were proved to be more sensitive to variations in EAV, R, and θ in comparison with the 10×10 cm2 field. Monte Carlo beam models need to be validated for a wide range of field sizes including small field sizes (e.g., 2×2 cm2). [ABSTRACT FROM AUTHOR]