Effects of a Flavonoid-Rich Blackcurrant Beverage on Markers of the Gut-Brain Axis in Healthy Females: Secondary Findings From a 4-Week Randomized Crossover Control Trial.

The microbiota-gut-brain axis is a promising target to alleviate the growing burden of neurologic and mental health disorders. Dietary polyphenols act on multiple components of the microbiota-gut-brain axis, but this complex relationship requires further attention. This randomized, placebo-controlled, double-blind, crossover trial (ACTRN12622000850774) compared 4 wk of a commercially available flavonoid-rich blackcurrant beverage (FBB; 151 mg anthocyanins, 308 mg total polyphenols) with placebo in 40 healthy females (18-45 y). The primary outcome of stress reactivity was assessed by change in present feelings of stress, mood, and fatigue before and after completing a 20-min cognitive stressor [Purple multitasking framework (MTF)]. Secondary end points included cognitive performance (MTF), mood [profile of mood states (POMS)], sleep (Pittsburgh Sleep Quality Index), fecal microbiome composition and functional potential (shotgun sequencing), and blood biomarker concentrations (brain-derived neurotrophic factor, tryptophan, kynurenine, and interleukin 6). Statistical analyses were conducted on an intention-to-treat basis using linear mixed-effect models. Thirty-eight participants completed both intervention arms. There was no significant treatment effect on the primary outcome of stress reactivity. Compared with placebo, working memory (letter retrieval scores from MTF), and anxiety/tension and anger/hostility domains of the POMS improved with FBB supplementation (time × intervention interaction; P < 0.05). There were no treatment effects on gut microbiome composition or functional potential. Baseline abundances of Bifidobacterium genera and species (Bifidobacterium longum and Bifidobacterium bifidum) tended to be higher in participants with the greatest improvements in letter retrieval scores with FBB supplementation (nominally significant, P < 0.05). In conclusion, 4-wk FBB supplementation improved secondary outcomes of working memory performance during multitasking and mood outcomes in healthy adult females. These results should be confirmed in a larger cohort with a longer duration of follow-up.

Evaluating on-board kVCT- and MVCT-based dose calculation accuracy using a thorax phantom for helical tomotherapy treatments.

Purpose.To evaluate the impact of CT number calibration and imaging parameter selection on dose calculation accuracy relative to the CT planning process in thoracic treatments for on-board helical CT imaging systems used in helical tomotherapy.Methods and Materials.Direct CT number calibrations were performed with appropriate protocols for each imaging system using an electron density phantom. Large volume and SBRT treatment plans were simulated and optimized for planning CT scans of an anthropomorphic thorax phantom and transferred to registered kVCT and MVCT scans of the phantom as appropriate. Relevant DVH metrics and dose-difference maps were used to evaluate and compare dose calculation accuracy relative to the planning CT based on a variation in imaging parameters applied for the on-board systems.Results.For helical kVCT scans of the thorax phantom, median differences in DVH parameters for the large volume treatment plan were less than ±1% with dose to the target volume either over- or underestimated depending on the imaging parameters utilized for CT number calibration and thorax phantom acquisition. For the lung SBRT plan calculated on helical kVCT scans, median dose differences were up to -2.7% with a more noticeable dependence on parameter selection. For MVCT scans, median dose differences for the large volume plan were within +2% with dose to the target overestimated regardless of the imaging protocol.Conclusion.Accurate dose calculations (median errors of <±1%) using a thorax phantom simulating realistic patient geometry and scatter conditions can be achieved with images acquired with a helical kVCT system on a helical tomotherapy unit. This accuracy is considerably improved relative to that achieved with the MV-based approach. In a clinical setting, careful consideration should be made when selecting appropriate kVCT imaging parameters for this process as dose calculation accuracy was observed to vary with both parameter selection and treatment type.

Targeting the GTV in medically inoperable endometrial cancer using brachytherapy.

PURPOSE: We aimed to determine the relationship between gross tumor volume (GTV) dose and tumor control in women with medically inoperable endometrial cancer, and to demonstrate the feasibility of targeting a GTV-focused volume using imaged-guided brachytherapy. METHODS AND MATERIALS: An endometrial cancer database was used to identify patients. Treatment plans were reviewed to determine doses to GTV, clinical target volume (CTV), and OARs. Uterine recurrence-free survival was evaluated as a function of CTV and GTV doses. Brachytherapy was replanned with a goal of GTV D98 EQD2 ≥ 80 Gy, without regard for coverage of the uninvolved uterus and while respecting OAR dose constraints. RESULTS: Fifty-four patients were identified. In the delivered plans, GTV D90 EQD2 ≥ 80 Gy was achieved in 36 (81.8%) patients. Uterine recurrence-free survival was 100% in patients with GTV D90 EQD2 ≥ 80 Gy and 66.7% in patients with EQD2 < 80 Gy (p = 0.001). On GTV-only replans, GTV D98 EQD2 ≥ 80 Gy was achieved in 39 (88.6%) patients. Mean D2cc was lower for bladder (47.1 Gy vs. 73.0 Gy, p < 0.001), and sigmoid (47.0 Gy vs. 58.0 Gy, p = 0.007) on GTV-only replans compared to delivered plans. Bladder D2cc was ≥ 80 Gy in 11 (25.0%) delivered plans and four (9.1%) GTV-only replans (p = 0.043). Sigmoid D2cc was ≥ 65 Gy in 20 (45.4%) delivered plans and 10 (22.7%) GTV-only replans (p = 0.021). CONCLUSIONS: OAR dose constraints should be prioritized over CTV coverage if GTV coverage is sufficient. Prospective evaluation of image-guided brachytherapy to a reduced, GTV-focused volume is warranted.

Commissioning an Exradin W2 plastic scintillation detector for clinical use in small radiation fields.

PURPOSE: The purpose of this work is to evaluate the Standard Imaging Exradin W2 plastic scintillation detector (W2) for use in the types of fields used for stereotactic radiosurgery. METHODS: Prior to testing the W2 in small fields, the W2 was evaluated in standard large field conditions to ensure good detector performance. These tests included energy dependence, short-term repeatability, dose-response linearity, angular dependence, temperature dependence, and dose rate dependence. Next, scan settings and calibration of the W2 were optimized to ensure high quality data acquisition. Profiles of small fields shaped by cones and multi-leaf collimator (MLCs) were measured using the W2 and IBA RAZOR diode in a scanning water tank. Output factors for cones (4-17.5 mm) and MLC fields (1, 2, 3 cm) were acquired with both detectors. Finally, the dose at isocenter for seven radiosurgery plans was measured with the W2 detector. RESULTS: W2 exhibited acceptable warm-up behavior, short-term reproducibility, axial angular dependence, dose-rate linearity, and dose linearity. The detector exhibits a dependence upon energy, polar angle, and temperature. Scanning measurements taken with the W2 and RAZOR were in good agreement, with full-width half-maximum and penumbra widths agreeing to within 0.1 mm. The output factors measured by the W2 and RAZOR exhibited a maximum difference of 1.8%. For the seven point-dose measurements of radiosurgery plans, the W2 agreed well with our treatment planning system with a maximum deviation of 2.2%. The Cerenkov light ratio calibration method did not significantly impact the measurement of relative profiles, output factors, or point dose measurements. CONCLUSION: The W2 demonstrated dosimetric characteristics that are suitable for radiosurgery field measurements. The detector agreed well with the RAZOR diode for output factors and scanned profiles and showed good agreement with the treatment planning system in measurements of clinical treatment plans.

Characterization of imaging performance of a novel helical kVCT for use in image-guided and adaptive radiotherapy.

ClearRT helical kVCT imaging for the Radixact helical tomotherapy system recently received FDA approval and is available for clinical use. The system is intended to enhance image fidelity in radiation therapy treatment planning and delivery compared to the prior MV-based onboard imaging approach. The purpose of this work was to characterize the imaging performance of this system and compare this performance with that of clinical systems used in image-guided and/or adaptive radiotherapy (ART) or computed tomography (CT) simulation, including Radixact MVCT, TomoTherapy MVCT, Varian TrueBeam kV OBI CBCT, and the Siemens SOMATOM Definition Edge kVCT. A CT image quality phantom was scanned across clinically relevant acquisition modes for each system to evaluate image quality metrics, including noise, uniformity, contrast, spatial resolution, and CT number linearity. Similar noise levels were observed for ClearRT and Siemens Edge, whereas noise for the other systems was ∼1.5-5 times higher. Uniformity was best for Siemens Edge, whereas most scans for ClearRT exhibited a slight "cupping" or "capping" artifact. The ClearRT and Siemens Edge performed best for contrast metrics, which included low-contrast visibility and contrast-to-noise ratio evaluations. Spatial resolution was best for TrueBeam and Siemens Edge, whereas the three kVCT systems exhibited similar CT number linearity. Overall, these results provide an initial indication that ClearRT image quality is adequate for image guidance in radiotherapy and sufficient for delineating anatomic structures, thus enabling its use for ART. ClearRT also showed significant improvement over MVCT, which was previously the only onboard imaging modality available on Radixact. Although the acquisition of these scans does come at the cost of additional patient dose, reported CTDI values indicate a similar or generally reduced machine output for ClearRT compared to the other systems while maintaining comparable or improved image quality overall.

Radiation-induced Hounsfield unit change correlates with dynamic CT perfusion better than 4DCT-based ventilation measures in a novel-swine model.

To analyze radiation induced changes in Hounsfield units and determine their correlation with changes in perfusion and ventilation. Additionally, to compare the post-RT changes in human subjects to those measured in a swine model used to quantify perfusion changes and validate their use as a preclinical model. A cohort of 5 Wisconsin Miniature Swine (WMS) were studied. Additionally, 19 human subjects were recruited as part of an IRB approved clinical trial studying functional avoidance radiation therapy for lung cancer and were treated with SBRT. Imaging (a contrast enhanced dynamic perfusion CT in the swine and 4DCT in the humans) was performed prior to and post-RT. Jacobian elasticity maps were calculated on all 4DCT images. Contours were created from the isodose lines to discretize analysis into 10 Gy dose bins. B-spline deformable image registration allowed for voxel-by-voxel comparative analysis in these contours between timepoints. The WMS underwent a research course of 60 Gy in 5 fractions delivered locally to a target in the lung using an MRI-LINAC system. In the WMS subjects, the dose-bin contours were copied onto the contralateral lung, which received < 5 Gy for comparison. Changes in HU and changes in Jacobian were analyzed in these contours. Statistically significant (p < 0.05) changes in the mean HU value post-RT compared to pre-RT were observed in both the human and WMS groups at all timepoints analyzed. The HU increased linearly with dose for both groups. Strong linear correlation was observed between the changes seen in the swine and humans (Pearson coefficient > 0.97, p < 0.05) at all timepoints. Changes seen in the swine closely modeled the changes seen in the humans at 12 months post RT (slope = 0.95). Jacobian analysis showed between 30 and 60% of voxels were damaged post-RT. Perfusion analysis in the swine showed a statistically significant (p < 0.05) reduction in contrast inside the vasculature 3 months post-RT compared to pre-RT. The increases in contrast outside the vasculature was strongly correlated (Pearson Correlation 0.88) with the reduction in HU inside the vasculature but were not correlated with the changes in Jacobians. Radiation induces changes in pulmonary anatomy at 3 months post-RT, with a strong linear correlation with dose. The change in HU seen in the non-vessel lung parenchyma suggests this metric is a potential biomarker for change in perfusion. Finally, this work suggests that the WMS swine model is a promising pre-clinical model for analyzing radiation-induced changes in humans and poses several benefits over conventional swine models.

A multipurpose brachytherapy catheter to enable intratumoral injection.

PURPOSE: To create and test a multipurpose brachytherapy catheter prototype enabling intratumoral injection and brachytherapy after a single catheter insertion. METHODS AND MATERIALS: The design of the prototype consists of an outer tube and an inner syringe tube that can be filled with injectable agent. The outer sheath and inner syringe tube were constructed using polytetrafluoroethylene tubing, and the other components were 3D printed using dental resin and polylactic acid material. To demonstrate functionality, we injected in vitro phantoms with dyed saline. For proof of concept, we demonstrated the potential for the prototype to deliver cell therapy, enhance tumor delineation, deliver tattoo ink for pathology marking, avoid toxicity through local delivery of chemotherapy, and facilitate combination brachytherapy and immunotherapy. RESULTS: The prototype enables accurate injection in vitro and in vivo without altering dosimetry. To illustrate the potential for delivery of cell therapies, we injected luciferase-expressing splenocytes and confirmed their delivery with bioluminescence imaging. To demonstrate feasibility of radiographically visualizing injected material, we delivered iohexol contrast intratumorally and confirmed tumor retention using Faxitron x-ray imaging. In addition, we show the potential of intratumoral administration to reduce toxicity associated with cyclophosphamide compared with systemic administration. To demonstrate feasibility, we treated tumor-bearing mice with brachytherapy (192Ir source, 2 Gy to 5 mm) in combination with intratumoral injection of 375,000 U of interleukin 2 and observed no increased toxicity. CONCLUSIONS: These results demonstrate that a prototype multipurpose brachytherapy catheter enables accurate intratumoral injection and support the feasibility of combining intratumoral injection with brachytherapy.

Evaluation of a commercial deformable image registration algorithm for dual-energy CT processing.

PURPOSE: Several dual-energy computed tomography (DECT) techniques require a deformable image registration to correct for motion between the acquisition of low and high energy data. However, current DECT software does not provide tools to assess registration accuracy or allow the user to export deformed images, presenting a unique challenge for image registration quality assurance (QA). This work presents a methodology to evaluate the accuracy of DECT deformable registration and to quantify the impact of registration errors on end-product images. METHODS: The deformable algorithm implemented in Siemen Healthineers's Syngo was evaluated using a deformable abdomen phantom and a rigid phantom to mimic sliding motion in the thorax. Both phantoms were imaged using sequential 80 and 140 kVp scans with motion applied between the two scans. Since Syngo does not allow the export of the deformed images, this study focused on quantifying the accuracy of various end-product, dual-energy images resulting from processing of deformed images. RESULTS: The Syngo algorithm performed well for the abdomen phantom with a mean registration error of 0.4 mm for landmark analysis, Dice similarity coefficients (DSCs) > 0.90 for five organs contoured, and mean iodine concentrations within 0.2 mg/mL of values measured on static images. For rigid sliding motion, the algorithm performed poorer and resulted in noticeable registration errors toward the superior and inferior scan extents and DSCs as low as 0.41 for iodine rods imaged in the phantom. Additionally, local iodine concentration errors in areas of misregistration exceeded 3 mg/mL. CONCLUSIONS: This work represents the first methodology for DECT image registration QA using commercial software. Our data support the clinical use of the Syngo algorithm for abdominal sites with limited motion (i.e., pancreas and liver). However, dual-energy images generated with this algorithm should be used with caution for quantitative measurements in areas with sliding motion.

Investigating split-filter dual-energy CT for improving liver tumor visibility for radiation therapy.

PURPOSE: Accurate liver tumor delineation is crucial for radiation therapy, but liver tumor volumes are difficult to visualize with conventional single-energy CT. This work investigates the use of split-filter dual-energy CT (DECT) for liver tumor visibility by quantifying contrast and contrast-to-noise ratio (CNR). METHODS: Split-filter DECT contrast-enhanced scans of 20 liver tumors including cholangiocarcinomas, hepatocellular carcinomas, and liver metastases were acquired. Analysis was performed on the arterial and venous phases of mixed 120 kVp-equivalent images and VMIs at 57 keV and 40 keV gross target volume (GTV) contrast and CNR were calculated. RESULTS: For the arterial phase, liver GTV contrast was 12.1 ± 10.0 HU and 43.1 ± 32.3 HU (P < 0.001) for the mixed images and 40 keV VMIs. Image noise increased on average by 116% for the 40 keV VMIs compared to the mixed images. The average CNR did not change significantly (1.6 ± 1.5, 1.7 ± 1.4, 2.4 ± 1.7 for the mixed, 57 keV and 40 keV VMIs (P > 0.141)). For individual cases, however, CNR increases of up to 607% were measured for the 40 keV VMIs compared to the mixed image. Venous phase 40 keV VMIs demonstrated an average increase of 35.4 HU in GTV contrast and 121% increase in image noise. Average CNR values were also not statistically different, but for individual cases CNR increases of up to 554% were measured for the 40 keV VMIs compared to the mixed image. CONCLUSIONS: Liver tumor contrast was significantly improved using split-filter DECT 40 keV VMIs compared to mixed images. On average, there was no statistical difference in CNR between the mixed images and VMIs, but for individual cases, CNR was greatly increased for the 57 keV and 40 keV VMIs. Therefore, although not universally successful for our patient cohort, split-filter DECT VMIs may provide substantial gains in tumor visibility of certain liver cases for radiation therapy treatment planning.

Investigating a novel split-filter dual-energy CT technique for improving pancreas tumor visibility for radiation therapy.

PURPOSE: Tumor delineation using conventional CT images can be a challenge for pancreatic adenocarcinoma where contrast between the tumor and surrounding healthy tissue is low. This work investigates the ability of a split-filter dual-energy CT (DECT) system to improve pancreatic tumor contrast and contrast-to-noise ratio (CNR) for radiation therapy treatment planning. MATERIALS AND METHODS: Multiphasic scans of 20 pancreatic tumors were acquired using a split-filter DECT technique with iodinated contrast medium, OMNIPAQUETM . Analysis was performed on the pancreatic and portal venous phases for several types of DECT images. Pancreatic gross target volume (GTV) contrast and CNR were calculated and analyzed from mixed 120 kVp-equivalent images and virtual monoenergetic images (VMI) at 57 and 40 keV. The role of iterative reconstruction on DECT images was also investigated. Paired t-tests were used to assess the difference in GTV contrast and CNR among the different images. RESULTS: The VMIs at 40 keV had a 110% greater image noise compared to the mixed 120 kVp-equivalent images (P < 0.0001). VMIs at 40 keV increased GTV contrast from 15.9 ± 19.9 HU to 93.7 ± 49.6 HU and CNR from 1.37 ± 2.05 to 3.86 ± 2.78 in comparison to the mixed 120 kVp-equivalent images. The iterative reconstruction algorithm investigated decreased noise in the VMIs by about 20% and improved CNR by about 30%. CONCLUSIONS: Pancreatic tumor contrast and CNR were significantly improved using VMIs reconstructed from the split-filter DECT technique, and the use of iterative reconstruction further improved CNR. This gain in tumor contrast may lead to more accurate tumor delineation for radiation therapy treatment planning.

Novel use of ViewRay MRI guidance for high-dose-rate brachytherapy in the treatment of cervical cancer.

PURPOSE: To characterize image quality and feasibility of using ViewRay MRI (VR)-guided brachytherapy planning for cervical cancer. METHODS AND MATERIALS: Cervical cancer patients receiving intracavitary brachytherapy with tandem and ovoids, planned using 0.35T VR MRI at our institution, were included in this series. The high-risk clinical target volume (HR-CTV), visible gross tumor volume, bladder, sigmoid, bowel, and rectum contours for each fraction of brachytherapy were evaluated for dosimetric parameters. Typically, five brachytherapy treatments were planned using the T2 sequence on diagnostic MRI for the first and third fractions, and a noncontrast true fast imaging with steady-state precession sequence on VR or CT scan for the remaining fractions. Most patients received 5.5 Gy × 5 fractions using high-dose-rate Ir-192 following 45 Gy of whole-pelvis radiotherapy. The plan was initiated at 5.5 Gy to point A and subsequently optimized and prescribed to the HR-CTV. The goal equivalent dose in 2 Gy fractions for the combined external beam and brachytherapy dose was 85 Gy. Soft-tissue visualization using contrast-to-noise ratios to distinguish normal tissues from tumor at their interface was compared between diagnostic MRI, CT, and VR. RESULTS: One hundred and forty-two fractions of intracavitary brachytherapy were performed from April 2015 to January 2017 on 29 cervical cancer patients, ranging from stages IB1 to IVA. The median HR-CTV was 27.78 cc, with median D90 HR-CTV of 6.1 Gy. The median time from instrument placement to start of treatment using VR was 65 min (scan time 2 min), compared to 105 min using diagnostic MRI (scan time 11 min) (t-test, p < 0.01). The contrast-to-noise ratio of tumor to cervix in both diagnostic MRI and VR had significantly higher values compared to CT (ANOVA and t-tests, p < 0.01). CONCLUSIONS: We report the first clinical use of VR-guided brachytherapy. Time to treatment using this approach was shorter compared to diagnostic MRI. VR also provided significant advantage in visualizing the tumor and cervix compared to CT. This presents a feasible and reliable manner to image and plan gynecologic brachytherapy.

Reply to: Comment on: polarity effects and apparent ion recombination in microionization chambers [Med. Phys. 43(5) 2141-2152 (2016)].

We would like to thank Dr. Brivio et al. [Med. Phys.] for their comment on our recent paper. Miller et al. [Med. Phys. 43 (2016) 2141-2152] determined the primary cause of voltage-dependent polarity effects in microchambers to be a potential difference between the guard and collecting electrodes. In their comment, Brivio et al., offer an explanation for the cause of such potential differences. Brivio et al. attribute the potential difference to the disparity in the work functions between guard and collecting electrodes composed of different materials. However, all of the microchambers investigated in Miller et al. contained a guard and collecting electrode which were composed of the same material. Therefore, the explanation offered by Brivio et al. that "the electric potential perturbation arises from the work function difference of the disparate materials electrodes" does not explain the polarity effects exhibited by the microchambers investigated in Miller et al., all of which contain electrodes composed of the same materials.

Ion recombination and polarity corrections for small-volume ionization chambers in high-dose-rate, flattening-filter-free pulsed photon beams.

PURPOSE: To investigate ion recombination and polarity effects in scanning and microionization chambers when used with digital electrometers and high-dose-rate linac beams such as flattening-filter-free (FFF) fields, and to compare results against conventional pulsed and continuous photon beams. METHODS: Saturation curves were obtained for one Farmer-type ionization chamber and eight small-volume chamber models with volumes ranging from 0.01 to 0.13 cm3 using a Varian TrueBeam™ STx with FFF capability. Three beam modes (6 MV, 6 MV FFF, and 10 MV FFF) were investigated, with nominal dose-per-pulse values of 0.0278, 0.0648, and 0.111 cGy/pulse, respectively, at dmax . Saturation curves obtained using the Theratronics T1000 60 Co unit at the UWADCL and a conventional linear accelerator (Varian Clinac iX) were used to establish baseline behavior. Jaffé plots were fitted to obtain Pion , accounting for exponential effects such as charge multiplication. These values were compared with the two-voltage technique recommended in TG-51, and were plotted as a function of dose-per-pulse to assess the ability of small-volume chambers to meet reference-class criteria in FFF beams. RESULTS: Jaffé- and two-voltage-determined Pion values measured for high-dose-rate beams agreed within 0.1% for the Farmer-type chamber and 1% for scanning and microionization chambers, with the exception of the CC01 which agreed within 2%. With respect to ion recombination and polarity effects, the Farmer-type chamber, scanning chambers and the Exradin A26 microchamber exhibited reference-class behavior in all beams investigated, with the exception of the IBA CC04 scanning chamber, which had an initial recombination correction that varied by 0.2% with polarity. All microchambers investigated, with the exception of the A26, exhibited anomalous polarity and ion recombination behaviors that make them unsuitable for reference dosimetry in conventional and high-dose-rate photon beams. CONCLUSIONS: The results of this work demonstrate that recombination and polarity behaviors seen in conventional pulsed and continuous photon beams trend accordingly in high-dose-rate FFF linac beams. Several models of small-volume ionization chambers used with a digital electrometer have been shown to meet reference-class requirements with respect to ion recombination and polarity, even in the high-dose-rate environment. For such chambers, a two-voltage technique agreed well with more rigorous methods of determining Pion . However, the results emphasize the need for careful reference detector selection, and indicate that ionization chambers ought to be extensively tested in each beam of interest prior to their use for reference dosimetry.

Polarity effects and apparent ion recombination in microionization chambers.

PURPOSE: Microchambers demonstrate anomalous voltage-dependent polarity effects. Existing polarity and ion recombination correction factors do not account for these effects. As a result, many commercial microchamber models do not meet the specification of a reference-class ionization chamber as defined by the American Association of Physicists in Medicine. The purpose of this investigation is to determine the cause of these voltage-dependent polarity effects. METHODS: A series of microchamber prototypes were produced to isolate the source of the voltage-dependent polarity effects. Parameters including ionization-chamber collecting-volume size, stem and cable irradiation, chamber assembly, contaminants, high-Z materials, and individual chamber components were investigated. Measurements were performed with electrodes coated with graphite to isolate electrode conductivity. Chamber response was measured as the potential bias of the guard electrode was altered with respect to the collecting electrode, through the integration of additional power supplies. Ionization chamber models were also simulated using comsol Multiphysics software to investigate the effect of a potential difference between electrodes on electric field lines and collecting volume definition. RESULTS: Investigations with microchamber prototypes demonstrated that the significant source of the voltage-dependent polarity effects was a potential difference between the guard and collecting electrodes of the chambers. The voltage-dependent polarity effects for each prototype were primarily isolated to either the guard or collecting electrode. Polarity effects were reduced by coating the isolated electrode with a conductive layer of graphite. Polarity effects were increased by introducing a potential difference between the electrodes. comsol simulations further demonstrated that for a given potential difference between electrodes, the collecting volume of the chamber changed as the applied voltage was altered, producing voltage-dependent polarity effects in the chamber response. Ionization chamber measurements and comsol simulations demonstrated an inverse relationship between the chamber collecting volume size and the severity of voltage-dependent polarity effects on chamber response. The effect of a given potential difference on chamber polarity effects was roughly ten times greater for microchambers as compared to Farmer-type chambers. Stem and cable irradiations, chamber assembly, contaminants, and high-Z materials were not found to be a significant source of the voltage-dependent polarity effects. CONCLUSIONS: A potential difference between the guard and collecting electrodes was found to be the primary source of the voltage-dependent polarity effects demonstrated by microchambers. For a given potential difference between electrodes, the relative change in the collecting volume is smaller for larger-volume chambers, illustrating why these polarity effects are not seen in larger-volume chambers with similar guard and collecting electrode designs. Thus, for small-volume chambers, it is necessary to reduce the potential difference between the guard and collecting electrodes in order to reduce polarity effects for reference dosimetry measurements.

VB-111: a novel anti-vascular therapeutic for glioblastoma multiforme.

Glioblastoma multiforme (GBM) is among the most highly vascularized of solid tumors, contributing to the infiltrative nature of the disease, and conferring poor outcome. Due to the critical dependency of GBM on growth of new endothelial vasculature, we evaluated the preclinical activity of a novel adenoviral gene therapy that targets the endothelium within newly formed blood vessels for apoptosis. VB-111, currently in phase II clinical trials, consists of a non-replicating Adenovirus 5 (El deleted) carrying a proapoptotic human Fas-chimera (transgene) under the control of a modified murine promoter (PPE-1-3×) which specifically targets endothelial cells within the tumor vasculature. Here we report that a single intravenous dose of 2.5 × 10(11) or 1 × 10(11) VPs was sufficient to extend survival in nude rats bearing U87MG-luc2 or nude mice bearing U251-luc, respectively. Bioluminescence imaging of nude rats showed that VB-111 effectively inhibited tumor growth within four weeks of treatment. This was confirmed in a select group of animals by MRI. In our mouse model we observed that 3 of 10 nude mice treated with VB-111 completely lost U251 luciferase signal and were considered long term survivors. To assess the antiangiogenic effects of VB-111, we evaluated the tumor-associated microvaculature by CD31, a common marker of neovascularization, and found a significant decrease in the microvessel density by IHC. We further assessed the neovasculature by confocal microscopy and found that VB-111 inhibits vascular density in two separate mouse models bearing U251-RFP xenografts. Collectively, this study supports the clinical development of VB-111 as a treatment for GBM.

Using a mass media campaign to raise women's awareness of the link between alcohol and cancer: cross-sectional pre-intervention and post-intervention evaluation surveys.

OBJECTIVES: To evaluate the effectiveness of a population-based, statewide public health intervention designed to improve women's awareness and knowledge of the link between alcohol and cancer. DESIGN: Cross-sectional tracking surveys conducted pre-intervention and post-intervention (waves I and III of campaign). SETTING: Western Australia. PARTICIPANTS: Cross-sectional samples of Western Australian women aged 25-54 years before the campaign (n=136) and immediately after wave I (n=206) and wave III (n=155) of the campaign. INTERVENTION: The 'Alcohol and Cancer' mass media campaign ran from May 2010 to May 2011 and consisted of three waves of paid television advertising with supporting print advertisements. MAIN OUTCOME MEASURES: Campaign awareness; knowledge of drinking guidelines and the link between alcohol and cancer; intentions towards drinking. RESULTS: Prompted recognition of the campaign increased from 67% following wave I to 81% following wave III (adjusted OR (adj OR)=2.31, 95% CI 1.33 to 4.00, p=0.003). Improvements in women's knowledge that drinking alcohol on a regular basis increases cancer risk were found following wave I (adj OR=2.60, 95% CI 1.57 to 4.30, p<0.001) and wave III (adj OR=4.88, 95% CI 2.55 to 9.36, p<0.001) compared with baseline. Knowledge of the recommended number of standard drinks for low risk in the long term increased between baseline and wave I (adj OR=1.68, 95% CI 1.02 to 2.76, p=0.041), but not baseline and wave III (adj OR=1.42, 95% CI 0.84 to 2.39, p=0.191). Among women who drink alcohol, the proportion expressing intentions to reduce alcohol consumption increased significantly between baseline and wave III (adj OR=2.38, 95% CI 1.11 to 5.12, p=0.026). However, no significant reductions in recent drinking behaviour were found following the campaign. CONCLUSIONS: Results indicate a population-based mass media campaign can reach the target audience and raise awareness of links between alcohol and cancer, and knowledge of drinking guidelines. However, a single campaign may be insufficient to measurably curb drinking behaviour in a culture where pro-alcohol social norms and product marketing are pervasive.

Rhenium-186 liposomes as convection-enhanced nanoparticle brachytherapy for treatment of glioblastoma.

Although external beam radiation is an essential component to the current standard treatment of primary brain tumors, its application is limited by toxicity at doses more than 80 Gy. Recent studies have suggested that brachytherapy with liposomally encapsulated radionuclides may be of benefit, and we have reported methods to markedly increase the specific activity of rhenium-186 ((186)Re)-liposomes. To better characterize the potential delivery, toxicity, and efficacy of the highly specific activity of (186)Re-liposomes, we evaluated their intracranial application by convection-enhanced delivery in an orthotopic U87 glioma rat model. After establishing an optimal volume of 25 µL, we observed focal activity confined to the site of injection over a 96-hour period. Doses of up to 1850 Gy were administered without overt clinical or microscopic evidence of toxicity. Animals treated with (186)Re-liposomes had a median survival of 126 days (95% confidence interval [CI], 78.4-173 days), compared with 49 days (95% CI, 44-53 days) for controls. Log-rank analysis between these 2 groups was highly significant (P = .0013) and was even higher when 100 Gy was used as a cutoff (P < .0001). Noninvasive luciferase imaging as a surrogate for tumor volume showed a statistically significant separation in bioluminescence by 11 days after 100 Gy or less treatment between the experimental group and the control animals (χ(2)[1, N= 19] = 4.8; P = .029). MRI also supported this difference in tumor size. Duplication of tumor volume differences and survival benefit was possible in a more invasive U251 orthotopic model, with clear separation in bioluminescence at 6 days after treatment (χ(2)[1, N= 9] = 4.7; P = .029); median survival in treated animals was not reached at 120 days because lack of mortality, and log-rank analysis of survival was highly significant (P = .0057). Analysis of tumors by histology revealed minimal areas of necrosis and gliosis. These results support the potential efficacy of the highly specific activity of brachytherapy by (186)Re-liposomes convection-enhanced delivery in glioma.

Effect of trans8, cis10+cis9, trans11 conjugated linoleic acid mixture on lipid metabolism in 3T3-L1 cells.

Evidence suggests that minor isomers of conjugated linoleic acid (CLA), such as trans8, cis10 CLA, can elicit unique biological effects of their own. In order to determine the effect of a mixture of t8, c10+c9, t11 CLA isomers on selected aspects of lipid metabolism, 3T3-L1 preadipocytes were differentiated for 8 days in the presence of 100 microM linoleic acid (LA); t8, c10+c9, t11 CLA; t10, c12+c9, t11 CLA or purified c9, t11 CLA. Whereas supplementation with c9, t11 and t10, c12+c9, t11 CLA resulted in cellular triglyceride (TG) concentrations of 3.4 +/- 0.26 and 1.3 +/- 0.11 microg TG/microg protein, respectively (P < 0.05), TG accumulation following treatment with CLA mixture t8, c10+c9, t11 was significantly intermediate (2.5 +/- 0.22 microg TG/microg protein, P < 0.05) between the two other CLA treatments. However, these effects were not attributable to an alteration of the Delta(9) desaturation index. Adiponectin content of adipocytes treated with t8, c10+c9, t11 mixture was similar to the individual isomer c9, t11 CLA, and both the t8, c10+c9, t11 and c9, t11 CLA groups were greater (P < 0.05) than in the t10, c12+c9, t11 CLA group. Overall, these results suggest that t8, c10+c9, t11 CLA mixture affects TG accumulation in 3T3-L1 cells differently from the c9, t11 and t10, c12 isomers. Furthermore, the reductions in TG accumulation occur without adversely affecting the adiponectin content of these cells.

Conjugated linoleic acid isomers have no effect on atherosclerosis and adverse effects on lipoprotein and liver lipid metabolism in apoE-/- mice fed a high-cholesterol diet.

Dietary supplementation with conjugated linoleic acid (CLA) has been shown, in several animal models, to decrease the development of atherosclerosis. The mechanism behind the anti-atherogenic properties of CLA is not clear. The objectives of this study were to determine the effect of CLA on atherosclerosis, lipoprotein and liver lipid metabolism, and plasma adiponectin and insulin in apoE(-/-) mice fed an atherogenic (16%, w/w fat; 1.25%, w/w cholesterol) diet. Mice were fed the diet with or without supplementation of linoleic acid (LA), c-9,t-11 CLA, t-10,c-12 CLA, or a 1:1 mixture of the two CLA isomers, at a concentration of 0.5% (w/w), for 12 weeks. Relative to the LA group, CLA supplementation had no significant effect on the lesion area in either en face preparations of the aorta or in aortic root cross-sections. Plasma triacylglycerol and cholesterol concentrations were higher in the t-10,c-12 CLA group than all other treatment groups and liver weight was also increased in this group due to a three-fold increase in liver triacylglycerol. Supplementation with t-10,c-12 CLA or mixed CLA reduced plasma adiponectin levels, whereas t-10,c-12 CLA increased plasma insulin levels. Liver triglycerides correlated directly with blood glucose and plasma insulin and inversely with plasma adiponectin. We conclude that dietary supplementation with CLA does not affect atherosclerosis of the apoE(-/-) mouse on a high-cholesterol diet. Furthermore, t-10,c-12 CLA causes adverse changes in adipocyte function and plasma and liver lipid metabolism, which are partially ameliorated by the inclusion of the c-9,t-11 CLA isomer.