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Multiple-breath nitrogen washout (MBNW) and its clinical parameter lung clearance index (LCI) are gaining increasing attention for the assessment of small airway function. Measurement of LCI relies on accurate assessment of functional residual capacity (FRC). The EasyOne Pro LAB (ndd) and Exhalyzer D (EM) are two commercially available MBNW devices. The aim of the study was to compare these two devices in vitro and in vivo in healthy subjects with regard to FRC, LCI and secondary outcome parameters and to relate FRC MBNW to FRC measured by body plethysmography (pleth) and helium dilution technique. MBNW measurements were performed using a lung model (FRC between 500 and 4000 mL) in vitro and in 38 subjects aged 6-65 years followed by helium dilution and pleth in vivo using fixed and relaxed breathing techniques. In vitro accuracy within 5% of lung model FRC was 67.3% for ndd, FRC was >5% higher for EM in all tests. In vivo , FRC pleth ranged from 1.2 to 5.6 L. Mean differences (limits of agreement) between FRC pleth and FRC MBNW were -7.0%, (-23.2 to 9.2%) and 5.7% (-11.2 to 22.6%) using ndd and EM, respectively. FRC ndd was consistently lower than FRC EM (-11.8% (-25.6 to 2%)). LCI was comparable between the two devices (-1.3% (-21.9 to 19.3%)). There was a difference of >10 % in LCI in 12 of 38 subjects. Using the most recent software updates, both devices show relevant deviations in FRC measurement both in vitro and in vivo and individual differences in LCI in a significant proportion of subjects. The devices are therefore not interchangeable., Competing Interests: Conflict of interest: A.M. Zwitserloot reports a grant from Stichting Astma Bestrijding and that ndd Medical Technologies provided the EasyOne Pro LAB MBNW device and lung model setup for this study; and money to her institution for an advisory board for GSK outside the submitted work. Conflict of interest: E.J. van den Berg has nothing to disclose. Conflict of interest: L.H.A. Raaijmakers has nothing to disclose. Conflict of interest: W.E. Stalman has nothing to disclose. Conflict of interest: M. van Smaalen has nothing to disclose. Conflict of interest: M. van den Berge reports research grants to his university from GlaxoSmithKline, TEVA, Chiesi and Novartis, outside the submitted work. Conflict of interest: M. Gappa has nothing to disclose. Conflict of interest: G.H. Koppelman reports grants from the Lung Foundation of the Netherlands during the conduct of the study, TETRI Foundation, UBBO EMMIUS Foundation, TEVA the Netherlands, VERTEX and GSK, and that he has participated in an advisory board for GSK, outside the submitted work. Conflict of interest: B.W.M. Willemse has nothing to disclose., (Copyright ©ERS 2020.)

Background: Marfan syndrome (MFS) represents a genetic disorder with variable phenotypic expression. The main cardiovascular sequelae of MFS include aortic aneurysm/dissection and cardiomyopathy. Although significant advances in the understanding of transforming growth factor beta signaling have led to promising therapeutic targets for the treatment of aortopathy, clinical studies have tempered this optimism. In particular, these studies suggest additional signaling pathways that play a significant role in disease progression. To date, studies aimed at elucidating molecular mechanisms involved in MFS-induced disease progression have been hampered by the lack of an accelerated disease model., Methods: Wild-type B6.129 mice and MFS Fbn1 C1039G/+ mice underwent subcutaneous, cervical osmotic minipump installation with sodium chloride (wild-type mice, n = 39; MFS mice, n = 12) or angiotensin II, 4.5 mg/kg daily (wild-type mice, n = 11; MFS mice; n = 35) for as long as 28 days. Hemodynamic measurements were obtained throughout the experiment. Aortas and hearts were analyzed by transthoracic echocardiography and histopathology study., Results: This accelerated murine MFS model replicates increased mortality from MFS-related maladies (20.0%, 39.3%, and 52.9% at 10, 14, and 28 days, respectively). Aortic diameters in accelerated MFS mice were significantly enlarged at 10 days after minipump implantation and correlated with a higher degree of elastin fragmentation. Accelerated MFS mice also demonstrated dilated cardiomyopathy at 14 days, even without aortic insufficiency, suggesting an intrinsic etiology., Conclusions: A novel in vivo model consisting of subcutaneously delivered angiotensin II in MFS mice reproducibly causes accelerated aortic aneurysm formation and cardiomyopathy. This model allows for better investigation of MFS sequelae by rapid experimental processes., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Multiple myeloma (MM) is characterized by the production of monoclonal protein (MP). We have shown previously that disruption of the isoprenoid biosynthetic pathway (IBP) causes a block in MP secretion through a disruption of Rab GTPase activity, leading to an enhanced unfolded protein response and subsequent apoptosis in MM cells. Autophagy is induced by cellular stressors including nutrient deprivation and ER stress. IBP inhibitors have been shown to have disparate effects on autophagy. Here we define the mechanisms underlying the differential effects of IBP inhibitors on autophagic flux in MM cells utilizing specific pharmacological inhibitors. We demonstrate that IBP inhibition induces a net increase in autophagy as a consequence of disruption of isoprenoid biosynthesis which is not recapitulated by direct geranylgeranyl transferase inhibition. IBP inhibitor-induced autophagy is a cellular defense mechanism as treatment with the autophagy inhibitor bafilomycin A1 enhances the cytotoxic effects of GGPP depletion, but not geranylgeranyl transferase inhibition. Immunofluorescence microscopy studies revealed that IBP inhibitors disrupt ER to Golgi trafficking of monoclonal light chain protein and that this protein is not a substrate for alternative degradative pathways such as aggresomes and autophagosomes. These studies support further development of specific GGTase II inhibitors as anti-myeloma agents.

The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: A beamlet based direct aperture optimization (DAO) for modulated electron radiotherapy (MERT) using photon multileaf collimator (pMLC) shaped electron fields is developed and investigated., Methods: The Swiss Monte Carlo Plan (SMCP) allows the calculation of dose distributions for pMLC shaped electron beams. SMCP is interfaced with the Eclipse TPS (Varian Medical Systems, Palo Alto, CA) which can thus be included into the inverse treatment planning process for MERT. This process starts with the import of a CT-scan into Eclipse, the contouring of the target and the organs at risk (OARs), and the choice of the initial electron beam directions. For each electron beam, the number of apertures, their energy, and initial shape are defined. Furthermore, the DAO requires dose-volume constraints for the structures contoured. In order to carry out the DAO efficiently, the initial electron beams are divided into a grid of beamlets. For each of those, the dose distribution is precalculated using a modified electron beam model, resulting in a dose list for each beamlet and energy. Then the DAO is carried out, leading to a set of optimal apertures and corresponding weights. These optimal apertures are now converted into pMLC shaped segments and the dose calculation for each segment is performed. For these dose distributions, a weight optimization process is launched in order to minimize the differences between the dose distribution using the optimal apertures and the pMLC segments. Finally, a deliverable dose distribution for the MERT plan is obtained and loaded back into Eclipse for evaluation. For an idealized water phantom geometry, a MERT treatment plan is created and compared to the plan obtained using a previously developed forward planning strategy. Further, MERT treatment plans for three clinical situations (breast, chest wall, and parotid metastasis of a squamous cell skin carcinoma) are created using the developed inverse planning strategy. The MERT plans are compared to clinical standard treatment plans using photon beams and the differences between the optimal and the deliverable dose distributions are determined., Results: For the idealized water phantom geometry, the inversely optimized MERT plan is able to obtain the same PTV coverage, but with an improved OAR sparing compared to the forwardly optimized plan. Regarding the right-sided breast case, the MERT plan is able to reduce the lung volume receiving more than 30% of the prescribed dose and the mean lung dose compared to the standard plan. However, the standard plan leads to a better homogeneity within the CTV. The results for the left-sided thorax wall are similar but also the dose to the heart is reduced comparing MERT to the standard treatment plan. For the parotid case, MERT leads to lower doses for almost all OARs but to a less homogeneous dose distribution for the PTV when compared to a standard plan. For all cases, the weight optimization successfully minimized the differences between the optimal and the deliverable dose distribution., Conclusions: A beamlet based DAO using multiple beam angles is implemented and successfully tested for an idealized water phantom geometry and clinical situations.

Purpose: The range of patient setup errors in six dimensions detected in clinical routine for cranial as well as for extracranial treatments, were analyzed while performing linear accelerator based stereotactic treatments with frameless patient setup systems. Additionally, the need for re-verification of the patient setup for situations where couch rotations are involved was analyzed for patients treated in the cranial region., Methods and Materials: A total of 2185 initial (i.e. after pre-positioning the patient with the infrared system but before image guidance) patient setup errors (1705 in the cranial and 480 in the extracranial region) obtained by using ExacTrac (BrainLAB AG, Feldkirchen, Germany) were analyzed. Additionally, the patient setup errors as a function of the couch rotation angle were obtained by analyzing 242 setup errors in the cranial region. Before the couch was rotated, the patient setup error was corrected at couch rotation angle 0° with the aid of image guidance and the six degrees of freedom (6DoF) couch. For both situations attainment rates for two different tolerances (tolerance A: ± 0.5mm, ± 0.5°; tolerance B: ± 1.0 mm, ± 1.0°) were calculated., Results: The mean (± one standard deviation) initial patient setup errors for the cranial cases were -0.24 ± 1.21°, -0.23 ± 0.91° and -0.03 ± 1.07° for the pitch, roll and couch rotation axes and 0.10 ± 1.17 mm, 0.10 ± 1.62 mm and 0.11 ± 1.29 mm for the lateral, longitudinal and vertical axes, respectively. Attainment rate (all six axes simultaneously) for tolerance A was 0.6% and 13.1% for tolerance B, respectively. For the extracranial cases the corresponding values were -0.21 ± 0.95°, -0.05 ± 1.08° and -0.14 ± 1.02° for the pitch, roll and couch rotation axes and 0.15 ± 1.77 mm, 0.62 ± 1.94 mm and -0.40 ± 2.15 mm for the lateral, longitudinal and vertical axes. Attainment rate (all six axes simultaneously) for tolerance A was 0.0% and 3.1% for tolerance B, respectively. After initial setup correction and rotation of the couch to treatment position a re-correction has to be performed in 77.4% of all cases to fulfill tolerance A and in 15.6% of all cases to fulfill tolerance B., Conclusion: The analysis of the data shows that all six axes of a 6DoF couch are used extensively for patient setup in clinical routine. In order to fulfill high patient setup accuracies (e.g. for stereotactic treatments), a 6DoF couch is recommended. Moreover, re-verification of the patient setup after rotating the couch is required in clinical routine., (Copyright © 2014. Published by Elsevier GmbH.)

When inhibitors of enzymes that utilize isoprenoid pyrophosphates are based on the natural substrates, a significant challenge can be to achieve selective inhibition of a specific enzyme. One element in the design process is the stereochemistry of the isoprenoid olefins. We recently reported preparation of a series of isoprenoid triazoles as potential inhibitors of geranylgeranyl transferase II but these compounds were obtained as a mixture of olefin isomers. We now have accomplished the stereoselective synthesis of these triazoles through the use of epoxy azides for the cycloaddition reaction followed by regeneration of the desired olefin. Both geranyl and neryl derivatives have been prepared as single olefin isomers through parallel reaction sequences. The products were assayed against multiple enzymes as well as in cell culture studies and surprisingly a Z-olefin isomer was found to be a potent and selective inhibitor of geranylgeranyl diphosphate synthase., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: This paper describes the development of a forward planning process for modulated electron radiotherapy (MERT). The approach is based on a previously developed electron beam model used to calculate dose distributions of electron beams shaped by a photon multi leaf collimator (pMLC)., Methods: As the electron beam model has already been implemented into the Swiss Monte Carlo Plan environment, the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA) can be included in the planning process for MERT. In a first step, CT data are imported into Eclipse and a pMLC shaped electron beam is set up. This initial electron beam is then divided into segments, with the electron energy in each segment chosen according to the distal depth of the planning target volume (PTV) in beam direction. In order to improve the homogeneity of the dose distribution in the PTV, a feathering process (Gaussian edge feathering) is launched, which results in a number of feathered segments. For each of these segments a dose calculation is performed employing the in-house developed electron beam model along with the macro Monte Carlo dose calculation algorithm. Finally, an automated weight optimization of all segments is carried out and the total dose distribution is read back into Eclipse for display and evaluation. One academic and two clinical situations are investigated for possible benefits of MERT treatment compared to standard treatments performed in our clinics and treatment with a bolus electron conformal (BolusECT) method., Results: The MERT treatment plan of the academic case was superior to the standard single segment electron treatment plan in terms of organs at risk (OAR) sparing. Further, a comparison between an unfeathered and a feathered MERT plan showed better PTV coverage and homogeneity for the feathered plan, with V95% increased from 90% to 96% and V107% decreased from 8% to nearly 0%. For a clinical breast boost irradiation, the MERT plan led to a similar homogeneity in the PTV compared to the standard treatment plan while the mean body dose was lower for the MERT plan. Regarding the second clinical case, a whole breast treatment, MERT resulted in a reduction of the lung volume receiving more than 45% of the prescribed dose when compared to the standard plan. On the other hand, the MERT plan leads to a larger low-dose lung volume and a degraded dose homogeneity in the PTV. For the clinical cases evaluated in this work, treatment plans using the BolusECT technique resulted in a more homogenous PTV and CTV coverage but higher doses to the OARs than the MERT plans., Conclusions: MERT treatments were successfully planned for phantom and clinical cases, applying a newly developed intuitive and efficient forward planning strategy that employs a MC based electron beam model for pMLC shaped electron beams. It is shown that MERT can lead to a dose reduction in OARs compared to other methods. The process of feathering MERT segments results in an improvement of the dose homogeneity in the PTV.

Purpose: Modulated electron radiotherapy (MERT) promises sparing of organs at risk for certain tumor sites. Any implementation of MERT treatment planning requires an accurate beam model. The aim of this work is the development of a beam model which reconstructs electron fields shaped using the Millennium photon multileaf collimator (MLC) (Varian Medical Systems, Inc., Palo Alto, CA) for a Varian linear accelerator (linac)., Methods: This beam model is divided into an analytical part (two photon and two electron sources) and a Monte Carlo (MC) transport through the MLC. For dose calculation purposes the beam model has been coupled with a macro MC dose calculation algorithm. The commissioning process requires a set of measurements and precalculated MC input. The beam model has been commissioned at a source to surface distance of 70 cm for a Clinac 23EX (Varian Medical Systems, Inc., Palo Alto, CA) and a TrueBeam linac (Varian Medical Systems, Inc., Palo Alto, CA). For validation purposes, measured and calculated depth dose curves and dose profiles are compared for four different MLC shaped electron fields and all available energies. Furthermore, a measured two-dimensional dose distribution for patched segments consisting of three 18 MeV segments, three 12 MeV segments, and a 9 MeV segment is compared with corresponding dose calculations. Finally, measured and calculated two-dimensional dose distributions are compared for a circular segment encompassed with a C-shaped segment., Results: For 15 × 34, 5 × 5, and 2 × 2 cm(2) fields differences between water phantom measurements and calculations using the beam model coupled with the macro MC dose calculation algorithm are generally within 2% of the maximal dose value or 2 mm distance to agreement (DTA) for all electron beam energies. For a more complex MLC pattern, differences between measurements and calculations are generally within 3% of the maximal dose value or 3 mm DTA for all electron beam energies. For the two-dimensional dose comparisons, the differences between calculations and measurements are generally within 2% of the maximal dose value or 2 mm DTA., Conclusions: The results of the dose comparisons suggest that the developed beam model is suitable to accurately reconstruct photon MLC shaped electron beams for a Clinac 23EX and a TrueBeam linac. Hence, in future work the beam model will be utilized to investigate the possibilities of MERT using the photon MLC to shape electron beams.

Multiple myeloma is characterized by the production of substantial quantities of monoclonal protein. We have previously demonstrated that select inhibitors of the isoprenoid biosynthetic pathway (IBP) induce apoptosis of myeloma cells via inhibition of Rab geranylgeranylation, leading to disruption of monoclonal protein trafficking and induction of the unfolded protein response (UPR) pathway. Heat-shock protein 90 (HSP90) inhibitors disrupt protein folding and are currently under clinical investigation in myeloma. The effects of combining IBP and HSP90 inhibitors on cell death, monoclonal protein trafficking, the UPR and chaperone regulation were investigated in monoclonal protein-producing cells. An enhanced induction of cell death was observed following treatment with IBP and HSP90 inhibitors, which occurred through both ER stress and non-ER stress pathways. The HSP90 inhibitor 17-AAG abrogated the effects of the IBP inhibitors on intracellular monoclonal protein levels and localization as well as induction of the UPR in myeloma cells. Disparate effects on chaperone expression were observed in myeloma vs amyloid light chain cells. Here we demonstrate that the novel strategy of targeting MP trafficking in concert with HSP90 enhances myeloma cell death via a complex modulation of ER stress, UPR, and cell death pathways.

The electron Monte Carlo (eMC) dose calculation algorithm available in the Eclipse treatment planning system (Varian Medical Systems) is based on the macro MC method and uses a beam model applicable to Varian linear accelerators. This leads to limitations in accuracy if eMC is applied to non-Varian machines. In this work eMC is generalized to also allow accurate dose calculations for electron beams from Elekta and Siemens accelerators. First, changes made in the previous study to use eMC for low electron beam energies of Varian accelerators are applied. Then, a generalized beam model is developed using a main electron source and a main photon source representing electrons and photons from the scattering foil, respectively, an edge source of electrons, a transmission source of photons and a line source of electrons and photons representing the particles from the scrapers or inserts and head scatter radiation. Regarding the macro MC dose calculation algorithm, the transport code of the secondary particles is improved. The macro MC dose calculations are validated with corresponding dose calculations using EGSnrc in homogeneous and inhomogeneous phantoms. The validation of the generalized eMC is carried out by comparing calculated and measured dose distributions in water for Varian, Elekta and Siemens machines for a variety of beam energies, applicator sizes and SSDs. The comparisons are performed in units of cGy per MU. Overall, a general agreement between calculated and measured dose distributions for all machine types and all combinations of parameters investigated is found to be within 2% or 2 mm. The results of the dose comparisons suggest that the generalized eMC is now suitable to calculate dose distributions for Varian, Elekta and Siemens linear accelerators with sufficient accuracy in the range of the investigated combinations of beam energies, applicator sizes and SSDs.

Although the Monte Carlo (MC) method allows accurate dose calculation for proton radiotherapy, its usage is limited due to long computing time. In order to gain efficiency, a new macro MC (MMC) technique for proton dose calculations has been developed. The basic principle of the MMC transport is a local to global MC approach. The local simulations using GEANT4 consist of mono-energetic proton pencil beams impinging perpendicularly on slabs of different thicknesses and different materials (water, air, lung, adipose, muscle, spongiosa, cortical bone). During the local simulation multiple scattering, ionization as well as elastic and inelastic interactions have been taken into account and the physical characteristics such as lateral displacement, direction distributions and energy loss have been scored for primary and secondary particles. The scored data from appropriate slabs is then used for the stepwise transport of the protons in the MMC simulation while calculating the energy loss along the path between entrance and exit position. Additionally, based on local simulations the radiation transport of neutrons and the generated ions are included into the MMC simulations for the dose calculations. In order to validate the MMC transport, calculated dose distributions using the MMC transport and GEANT4 have been compared for different mono-energetic proton pencil beams impinging on different phantoms including homogeneous and inhomogeneous situations as well as on a patient CT scan. The agreement of calculated integral depth dose curves is better than 1% or 1 mm for all pencil beams and phantoms considered. For the dose profiles the agreement is within 1% or 1 mm in all phantoms for all energies and depths. The comparison of the dose distribution calculated using either GEANT4 or MMC in the patient also shows an agreement of within 1% or 1 mm. The efficiency of MMC is up to 200 times higher than for GEANT4. The very good level of agreement in the dose comparisons demonstrate that the newly developed MMC transport results in very accurate and efficient dose calculations for proton beams.

A small set of triazole bisphosphonates has been prepared and tested for the ability to inhibit geranylgeranyltransferase II (GGTase II). The compounds were prepared through use of click chemistry to assemble a central triazole that links a polar head group to a hydrophobic tail. The resulting compounds were tested for their ability to inhibit GGTase II in an in vitro enzyme assay and also were tested for cytotoxic activity in an MTT assay with the human myeloma RPMI-8226 cell line. The most potent enzyme inhibitor was the triazole with a geranylgeranyl tail, which suggests that inhibitors that can access the enzyme region that holds the isoprenoid tail will display greater activity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Recently, the new high definition multileaf collimator (HD120 MLC) was commercialized by Varian Medical Systems providing high resolution in the center section of the treatment field. The aim of this work is to investigate the characteristics of the HD120 MLC using Monte Carlo (MC) methods., Methods: Based on the information of the manufacturer, the HD120 MLC was implemented into the already existing Swiss MC Plan (SMCP). The implementation has been configured by adjusting the physical density and the air gap between adjacent leaves in order to match transmission profile measurements for 6 and 15 MV beams of a Novalis TX. These measurements have been performed in water using gafchromic films and an ionization chamber at an SSD of 95 cm and a depth of 5 cm. The implementation was validated by comparing diamond measured and calculated penumbra values (80%-20%) for different field sizes and water depths. Additionally, measured and calculated dose distributions for a head and neck IMRT case using the DELTA(4) phantom have been compared. The validated HD120 MLC implementation has been used for its physical characterization. For this purpose, phase space (PS) files have been generated below the fully closed multileaf collimator (MLC) of a 40 × 22 cm(2) field size for 6 and 15 MV. The PS files have been analyzed in terms of energy spectra, mean energy, fluence, and energy fluence in the direction perpendicular to the MLC leaves and have been compared with the corresponding data using the well established Varian 80 leaf (MLC80) and Millennium M120 (M120 MLC) MLCs. Additionally, the impact of the tongue and groove design of the MLCs on dose has been characterized., Results: Calculated transmission values for the HD120 MLC are 1.25% and 1.34% in the central part of the field for the 6 and 15 MV beam, respectively. The corresponding ionization chamber measurements result in a transmission of 1.20% and 1.35%. Good agreement has been found for the comparison between transmission profiles resulting from MC simulations and film measurements. The simulated and measured values for the penumbra agreed within <0.5 mm for all field sizes, depths, and beam energies, and a good agreement has been found between the measured and the calculated dose distributions for the IMRT case. The total energy spectra are almost identical for the three MLCs. However, the mean energy, fluence and energy fluence are significantly different. Due to the different leaf widths of the MLCs, the shape of these distributions is different, each representing its leave structure. Due to the increase in width from the inner to the outer HD120 MLC leaves, the fluence and energy fluence clearly decrease below the outer leaves. The MLC80 and the M120 MLC resulted in an increase of the fluence and energy fluence compared with those resulted for the HD120 MLC. The dose reduction can exceed 20% compared with the dose of the open field due to the tongue and groove design of the HD120 MLC., Conclusions: The HD120 MLC has been successfully implemented into the SMCP. Comparisons between MC calculations and measurements show very good agreement. The SMCP is now able to calculate accurate dose distributions for treatment plans using the HD120 MLC.

Genetic and functional data support a role for angiotensinogen in blood pressure control, and many population studies have suggested that polymorphisms in the angiotensinogen gene contribute to hypertension. Two common haplotypes of the human angiotensinogen gene are -6A/235T and -6G/235M. To study their contributions to blood pressure regulation in a controlled model system, we developed triple-transgenic mice expressing either -6A/235T or -6G/235M human angiotensinogen, expressing either an overexpressed and poorly regulated (REN9) or a tightly regulated (PAC160) human renin, and all carrying a null mutation in the endogenous murine angiotensinogen gene. These humanized mice were then examined for blood pressure differences at baseline and after a high-salt diet, changes in cardiovascular organ weight, and differences in angiotensinogen and renin gene expression. Mice expressing the -6G/235M haplotype on the PAC160 background exhibited increased blood pressure and cardiac hypertrophy at baseline. In contrast, all of the mice with the REN9 background had equivalent baseline blood pressures. On the REN9 background, there was a greater increase in blood pressure in -6A/235T in response to a high-salt diet, providing evidence it may be a susceptibility allele. There were no differences in angiotensinogen expression between haplotypes on either background strain. The data suggest that the impact of angiotensinogen haplotypes on cardiovascular end points may be dependent on renin status and environmental influences, such as dietary sodium. These insights may help explain the discrepancies among observational studies that have examined roles for the -6A/235T and -6G/235M angiotensinogen haplotypes in varied human populations.

The electron Monte Carlo (eMC) dose calculation algorithm in Eclipse (Varian Medical Systems) is based on the macro MC method and is able to predict dose distributions for high energy electron beams with high accuracy. However, there are limitations for low energy electron beams. This work aims to improve the accuracy of the dose calculation using eMC for 4 and 6 MeV electron beams of Varian linear accelerators. Improvements implemented into the eMC include (1) improved determination of the initial electron energy spectrum by increased resolution of mono-energetic depth dose curves used during beam configuration; (2) inclusion of all the scrapers of the applicator in the beam model; (3) reduction of the maximum size of the sphere to be selected within the macro MC transport when the energy of the incident electron is below certain thresholds. The impact of these changes in eMC is investigated by comparing calculated dose distributions for 4 and 6 MeV electron beams at source to surface distance (SSD) of 100 and 110 cm with applicators ranging from 6 x 6 to 25 x 25 cm(2) of a Varian Clinac 2300C/D with the corresponding measurements. Dose differences between calculated and measured absolute depth dose curves are reduced from 6% to less than 1.5% for both energies and all applicators considered at SSD of 100 cm. Using the original eMC implementation, absolute dose profiles at depths of 1 cm, d(max) and R50 in water lead to dose differences of up to 8% for applicators larger than 15 x 15 cm(2) at SSD 100 cm. Those differences are now reduced to less than 2% for all dose profiles investigated when the improved version of eMC is used. At SSD of 110 cm the dose difference for the original eMC version is even more pronounced and can be larger than 10%. Those differences are reduced to within 2% or 2 mm with the improved version of eMC. In this work several enhancements were made in the eMC algorithm leading to significant improvements in the accuracy of the dose calculation for 4 and 6 MeV electron beams of Varian linear accelerators.

The problem of re-sampling spatially distributed data organized into regular or irregular grids to finer or coarser resolution is a common task in data processing. This procedure is known as 'gridding' or 're-binning'. Depending on the quantity the data represents, the gridding-algorithm has to meet different requirements. For example, histogrammed physical quantities such as mass or energy have to be re-binned in order to conserve the overall integral. Moreover, if the quantity is positive definite, negative sampling values should be avoided. The gridding process requires a re-distribution of the original data set to a user-requested grid according to a distribution function. The distribution function can be determined on the basis of the given data by interpolation methods. In general, accurate interpolation with respect to multiple boundary conditions of heavily fluctuating data requires polynomial interpolation functions of second or even higher order. However, this may result in unrealistic deviations (overshoots or undershoots) of the interpolation function from the data. Accordingly, the re-sampled data may overestimate or underestimate the given data by a significant amount. The gridding-algorithm presented in this work was developed in order to overcome these problems. Instead of a straightforward interpolation of the given data using high-order polynomials, a parametrized Hermitian interpolation curve was used to approximate the integrated data set. A single parameter is determined by which the user can control the behavior of the interpolation function, i.e. the amount of overshoot and undershoot. Furthermore, it is shown how the algorithm can be extended to multidimensional grids. The algorithm was compared to commonly used gridding-algorithms using linear and cubic interpolation functions. It is shown that such interpolation functions may overestimate or underestimate the source data by about 10-20%, while the new algorithm can be tuned to significantly reduce these interpolation errors. The accuracy of the new algorithm was tested on a series of x-ray CT-images (head and neck, lung, pelvis). The new algorithm significantly improves the accuracy of the sampled images in terms of the mean square error and a quality index introduced by Wang and Bovik (2002 IEEE Signal Process. Lett. 9 81-4).

BEAMnrc, a code for simulating medical linear accelerators based on EGSnrc, has been bench-marked and used extensively in the scientific literature and is therefore often considered to be the gold standard for Monte Carlo simulations for radiotherapy applications. However, its long computation times make it too slow for the clinical routine and often even for research purposes without a large investment in computing resources. VMC++ is a much faster code thanks to the intensive use of variance reduction techniques and a much faster implementation of the condensed history technique for charged particle transport. A research version of this code is also capable of simulating the full head of linear accelerators operated in photon mode (excluding multileaf collimators, hard and dynamic wedges). In this work, a validation of the full head simulation at 6 and 18 MV is performed, simulating with VMC++ and BEAMnrc the addition of one head component at a time and comparing the resulting phase space files. For the comparison, photon and electron fluence, photon energy fluence, mean energy, and photon spectra are considered. The largest absolute differences are found in the energy fluences. For all the simulations of the different head components, a very good agreement (differences in energy fluences between VMC++ and BEAMnrc <1%) is obtained. Only a particular case at 6 MV shows a somewhat larger energy fluence difference of 1.4%. Dosimetrically, these phase space differences imply an agreement between both codes at the <1% level, making VMC++ head module suitable for full head simulations with considerable gain in efficiency and without loss of accuracy.

Currently photon Monte Carlo treatment planning (MCTP) for a patient stored in the patient database of a treatment planning system (TPS) can usually only be performed using a cumbersome multi-step procedure where many user interactions are needed. This means automation is needed for usage in clinical routine. In addition, because of the long computing time in MCTP, optimization of the MC calculations is essential. For these purposes a new graphical user interface (GUI)-based photon MC environment has been developed resulting in a very flexible framework. By this means appropriate MC transport methods are assigned to different geometric regions by still benefiting from the features included in the TPS. In order to provide a flexible MC environment, the MC particle transport has been divided into different parts: the source, beam modifiers and the patient. The source part includes the phase-space source, source models and full MC transport through the treatment head. The beam modifier part consists of one module for each beam modifier. To simulate the radiation transport through each individual beam modifier, one out of three full MC transport codes can be selected independently. Additionally, for each beam modifier a simple or an exact geometry can be chosen. Thereby, different complexity levels of radiation transport are applied during the simulation. For the patient dose calculation, two different MC codes are available. A special plug-in in Eclipse providing all necessary information by means of Dicom streams was used to start the developed MC GUI. The implementation of this framework separates the MC transport from the geometry and the modules pass the particles in memory; hence, no files are used as the interface. The implementation is realized for 6 and 15 MV beams of a Varian Clinac 2300 C/D. Several applications demonstrate the usefulness of the framework. Apart from applications dealing with the beam modifiers, two patient cases are shown. Thereby, comparisons are performed between MC calculated dose distributions and those calculated by a pencil beam or the AAA algorithm. Interfacing this flexible and efficient MC environment with Eclipse allows a widespread use for all kinds of investigations from timing and benchmarking studies to clinical patient studies. Additionally, it is possible to add modules keeping the system highly flexible and efficient.

The purpose of this work was to study and quantify the differences in dose distributions computed with some of the newest dose calculation algorithms available in commercial planning systems. The study was done for clinical cases originally calculated with pencil beam convolution (PBC) where large density inhomogeneities were present. Three other dose algorithms were used: a pencil beam like algorithm, the anisotropic analytic algorithm (AAA), a convolution superposition algorithm, collapsed cone convolution (CCC), and a Monte Carlo program, voxel Monte Carlo (VMC++). The dose calculation algorithms were compared under static field irradiations at 6 MV and 15 MV using multileaf collimators and hard wedges where necessary. Five clinical cases were studied: three lung and two breast cases. We found that, in terms of accuracy, the CCC algorithm performed better overall than AAA compared to VMC++, but AAA remains an attractive option for routine use in the clinic due to its short computation times. Dose differences between the different algorithms and VMC++ for the median value of the planning target volume (PTV) were typically 0.4% (range: 0.0 to 1.4%) in the lung and -1.3% (range: -2.1 to -0.6%) in the breast for the few cases we analysed. As expected, PTV coverage and dose homogeneity turned out to be more critical in the lung than in the breast cases with respect to the accuracy of the dose calculation. This was observed in the dose volume histograms obtained from the Monte Carlo simulations.

Background and Purpose: Daily use of conventional electronic portal imaging devices (EPID) for organ tracking is limited due to the relatively high dose required for high quality image acquisition. We studied the use of a novel dose saving acquisition mode (RadMode) allowing to take images with one monitor unit per image in prostate cancer patients undergoing intensity-modulated radiotherapy (IMRT) and tracking of implanted fiducial gold markers., Patients and Methods: Twenty five patients underwent implantation of three fiducial gold markers prior to the planning CT. Before each treatment of a course of 37 fractions, orthogonal localization images from the antero-posterior and from the lateral direction were acquired. Portal images of both the setup procedure and the five IMRT treatment beams were analyzed., Results: On average, four localization images were needed for a correct patient setup, resulting in four monitor units extra dose per fraction. The mean extra dose delivered to the patient was thereby increased by 1.2%. The procedure was precise enough to reduce the mean displacements prior to treatment to < o =0.3 mm., Conclusions: The use of a new dose saving acquisition mode enables to perform daily EPID-based prostate tracking with a cumulative extra dose of below 1 Gy. This concept is efficiently used in IMRT-treated patients, where separation of setup beams from treatment beams is mandatory.

In external beam radiotherapy, electronic portal imaging becomes more and more an indispensable tool for the verification of the patient setup. For the safe clinical introduction of high dose conformal radiotherapy like intensity modulated radiation therapy, on-line patient setup verification is a prerequisite to ensure that the planned dosimetric coverage of the tumor volume is actually realized in the patient. Since the direction of setup fields often deviates from the direction of the treatment beams, extra dose is delivered to the patient during the acquisition of these portal images which may reach clinical relevance. The aim of this work was to develop a new acquisition mode for the PortalVision aS500 electronic portal imaging device from Varian Medical Systems that allows one to take portal images with reduced dose while keeping good image quality. The new acquisition mode, called RadMode, selectively enables and disables beam pulses during image acquisition allowing one to stop wasting valuable dose during the initial acquisition of "reset frames." Images of excellent quality can be taken with 1 MU only. This low dose per image facilitates daily setup verification with considerably reduced extra dose.

Detailed knowledge of the characteristics of the radiation field shaped by a multileaf collimator (MLC) is essential in intensity modulated radiotherapy (IMRT). A previously developed multiple source model (MSM) for a 6 MV beam was extended to a 15 MV beam and supplemented with an accurate model of an 80-leaf dynamic MLC. Using the supplemented MSM and the MC code GEANT, lateral dose distributions were calculated in a water phantom and a portal water phantom. A field which is normally used for the validation of the step and shoot technique and a field from a realistic IMRT treatment plan delivered with dynamic MLC are investigated. To assess possible spectral changes caused by the modulation of beam intensity by an MLC, the energy spectra in five portal planes were calculated for moving slits of different widths. The extension of the MSM to 15 MV was validated by analysing energy fluences, depth doses and dose profiles. In addition, the MC-calculated primary energy spectrum was verified with an energy spectrum which was reconstructed from transmission measurements. MC-calculated dose profiles using the MSM for the step and shoot case and for the dynamic MLC case are in very good agreement with the measured data from film dosimetry. The investigation of a 13 cm wide field shows an increase in mean photon energy of up to 16% for the 0.25 cm slit compared to the open beam for 6 MV and of up to 6% for 15 MV, respectively. In conclusion, the MSM supplemented with the dynamic MLC has proven to be a powerful tool for investigational and benchmarking purposes or even for dose calculations in IMRT.

A multiple source model (MSM) for the 6 MV beam of a Varian Clinac 2300 C/D was developed by simulating radiation transport through the accelerator head for a set of square fields using the GEANT Monte Carlo (MC) code. The corresponding phase space (PS) data enabled the characterization of 12 sources representing the main components of the beam defining system. By parametrizing the source characteristics and by evaluating the dependence of the parameters on field size, it was possible to extend the validity of the model to arbitrary rectangular fields which include the central 3 x 3 cm2 field without additional precalculated PS data. Finally, a sampling procedure was developed in order to reproduce the PS data. To validate the MSM, the fluence, energy fluence and mean energy distributions determined from the original and the reproduced PS data were compared and showed very good agreement. In addition, the MC calculated primary energy spectrum was verified by an energy spectrum derived from transmission measurements. Comparisons of MC calculated depth dose curves and profiles, using original and PS data reproduced by the MSM, agree within 1% and 1 mm. Deviations from measured dose distributions are within 1.5% and 1 mm. However, the real beam leads to some larger deviations outside the geometrical beam area for large fields. Calculated output factors in 10 cm water depth agree within 1.5% with experimentally determined data. In conclusion, the MSM produces accurate PS data for MC photon dose calculations for the rectangular fields specified.

Purpose: Study of behavior and influence of a multileaf collimator (MLC) on dose calculation, verification, and portal energy spectra in the case of intensity-modulated fields obtained with a step-and-shoot or a dynamic technique., Methods: The 80-leaf MLC for the Varian Clinac 2300 C/D was implemented in a previously developed Monte Carlo (MC) based multiple source model (MSM) for a 6 MV photon beam. Using this model and the MC program GEANT, dose distributions, energy fluence maps and energy spectra at different portal planes were calculated for three different MLC applications., Results: The comparison of MC-calculated dose distributions in the phantom and portal plane, with those measured with films showed an agreement within 3% and 1.5 mm for all cases studied. The deviations mainly occur in the extremes of the intensity modulation. The MC method allows to investigate, among other aspects, dose components, energy fluence maps, tongue-and-groove effects and energy spectra at portal planes., Conclusion: The MSM together with the implementation of the MLC is appropriate for a number of investigations in intensity-modulated radiation therapy (IMRT).

Monte Carlo (code GEANT) produced 6 and 15 MV phase space (PS) data were used to define several simple photon beam models. For creating the PS data the energy of starting electrons hitting the target was tuned to get correct depth dose data compared to measurements. The modeling process used the full PS information within the geometrical boundaries of the beam including all scattered radiation of the accelerator head. Scattered radiation outside the boundaries was neglected. Photons and electrons were assumed to be radiated from point sources. Four different models were investigated which involved different ways to determine the energies and locations of beam particles in the output plane. Depth dose curves, profiles, and relative output factors were calculated with these models for six field sizes from 5x5 to 40x40cm2 and compared to measurements. Model 1 uses a photon energy spectrum independent of location in the PS plane and a constant photon fluence in this plane. Model 2 takes into account the spatial particle fluence distribution in the PS plane. A constant fluence is used again in model 3, but the photon energy spectrum depends upon the off axis position. Model 4, finally uses the spatial particle fluence distribution and off axis dependent photon energy spectra in the PS plane. Depth dose curves and profiles for field sizes up to 10x10cm2 were not model sensitive. Good agreement between measured and calculated depth dose curves and profiles for all field sizes was reached for model 4. However, increasing deviations were found for increasing field sizes for models 1-3. Large deviations resulted for the profiles of models 2 and 3. This is due to the fact that these models overestimate and underestimate the energy fluence at large off axis distances. Relative output factors consistent with measurements resulted only for model 4.

Stereotactic radiosurgery stands for a high precision irradiation concept, which allows to deliver a high dose of ionizing radiation to the tumor volume. The characteristic steep dose fall-off immediately outside the target volume enables the selective destruction of small intracranial tumors while sharply minimizing the dose to the surrounding healthy tissue. This treatment modality is non-invasive and in general well tolerated with minimal side-effects. Especially for palliative concepts the short treatment time is of great importance.