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Sharpley C.F.,University of New England of Australia | Bitsika V.,Bond University | Denham J.W.,Calvary Materials Newcastle Hospital | Denham J.W.,University of Newcastle
Psycho-Oncology | Year: 2014

Objectives To identify the factors underlying prostate cancer (PCa) patients' depression-anxiety, sexual problems, urinary dysfunction and androgen deprivation therapy (ADT)-linked breast changes and hot flushes, and test these as predictors of loss of masculinity (LoM) over 36months following diagnosis. Methods One thousand seventy patients from the TROG 03.04 (RADAR) trial the EORTC QLQ C-30 and PR 25 questionnaires, and the International Prostate Cancer Symptom Score of the American Urological Association at baseline, 3, 7, 12, 18, 24 and 36months. Selected items from these scales were factor-analysed to identify a four-component solution for responses at 18 and 36months, and these components were regressed against a single-item measuring LoM. Results Depression-anxiety factor was the most powerful predictor of LoM at both time points, followed by sexual problems of ADT side effects (breast changes and hot flushes). Urinary dysfunction was not a consistent predictor of LoM. Depression-anxiety was also the most significant factor distinguishing between those men who reported LoM and those who did not. Conclusions Although LoM is often reported as arising from ADT, the relative power of depression-anxiety in predicting LoM, both at the selected time points and using a time-lagged analysis, plus the finding that depression-anxiety was the most consistent difference between men who reported LoM and those who did not, argues for the presence of adverse mood states as being the key ingredient in deciding if PCa patients experience loss of their feelings of masculinity. Copyright © 2013 John Wiley & Sons, Ltd. Copyright © 2013 John Wiley & Sons, Ltd.

Von Kleist L.,Free University of Berlin | Stahlschmidt W.,Free University of Berlin | Bulut H.,Free University of Berlin | Gromova K.,Free University of Berlin | And 17 more authors.
Cell | Year: 2011

Clathrin-mediated endocytosis (CME) regulates many cell physiological processes such as the internalization of growth factors and receptors, entry of pathogens, and synaptic transmission. Within the endocytic network, clathrin functions as a central organizing platform for coated pit assembly and dissociation via its terminal domain (TD). We report the design and synthesis of two compounds named pitstops that selectively block endocytic ligand association with the clathrin TD as confirmed by X-ray crystallography. Pitstop-induced inhibition of clathrin TD function acutely interferes with receptor-mediated endocytosis, entry of HIV, and synaptic vesicle recycling. Endocytosis inhibition is caused by a dramatic increase in the lifetimes of clathrin coat components, including FCHo, clathrin, and dynamin, suggesting that the clathrin TD regulates coated pit dynamics. Pitstops provide new tools to address clathrin function in cell physiology with potential applications as inhibitors of virus and pathogen entry and as modulators of cell signaling. © 2011 Elsevier Inc.

Isbister G.K.,Calvary Materials Newcastle Hospital | Isbister G.K.,University of Newcastle | Balit C.R.,Childrens Hospital at Westmead | MacLeod D.,Austin Repatriation Hospital | Duffull S.B.,University of Otago
Journal of Clinical Psychopharmacology | Year: 2010

This study aimed to describe the effects of the antipsychotic amisulpride in overdose, including the frequency of QT prolongation and torsades de pointes. Cases of amisulpride overdose (>1 g) were recruited from 2 state poison centers and a tertiary toxicology unit over 5 years. A 1-page clinical research form was used to collect clinical information. Copies of all electrocardiograms were obtained. Electrocardiogram parameters (QRS and QT intervals) were manually measured as previously described, and plots of QT-heart rate (HR) pairs were compared with the QT nomogram. There were 83 patients with amisulpride overdoses with a median age of 29 years (interquartile range [IQR], 23-40 years), and 42 (51%) were female. The median dose ingested was 6 g (IQR, 3-13 g, range, 1.2-120 g). The median HR was 66 beats/min (IQR, 60-81 beats/min). Bradycardia occurred in 20 cases (24%), and hypotension in 19 (23%). From 440 electrocardiograms (average of 5 per case; range, 1-15), an abnormal QT-HR pair occurred in 61 cases (73%). Torsades de pointes developed in 6 cases (7%), with doses of 4, 4.6, 18, 24, 32, and 80 g. The patient taking 32 g died after a cardiac arrest. Widened QRS did not occur except transient rate-dependent bundle-branch block in 3 cases. There were significant associations of bradycardia, hypokalemia, and hypocalcaemia, with QT prolongation and torsades de pointes. Central nervous system effects were uncommon with coma in 7 cases, seizures in 2, and dystonic reactions in 2. Amisulpride overdose commonly causes QT prolongation, bradycardia, and hypotension. Torsades de pointes occurred commonly enough to suggest that amisulpride is highly cardiotoxic in overdose. © 2010 Lippincott Williams & Wilkins.

Rowshanfarzad P.,University of Newcastle | Sabet M.,University of Newcastle | O'Connor D.J.,University of Newcastle | Greer P.B.,University of Newcastle | Greer P.B.,Calvary Materials Newcastle Hospital
Medical Physics | Year: 2011

Purpose:Verification of the mechanical isocenter position is required as part of comprehensive quality assurance programs for stereotactic radiosurgery/radiotherapy (SRS/SRT) treatments. Several techniques have been proposed for this purpose but each of them has certain drawbacks. In this paper, a new efficient and more comprehensive method using cine-EPID images has been introduced for automatic verification of the isocenter with sufficient accuracy for stereotactic applications.Methods: Using a circular collimator fixed to the gantry head to define the field, EPID images of a Winston-Lutz phantom were acquired in cine-imaging mode during 360° gantry rotations. A robust matlab code was developed to analyze the data by finding the center of the field and the center of the ball bearing shadow in each image with sub-pixel accuracy. The distance between these two centers was determined for every image. The method was evaluated by comparison to results of a mechanical pointer and also by detection of a manual shift applied to the phantom position. The repeatability and reproducibility of the method were tested and it was also applied to detect couch and collimator wobble during rotation.Results:The accuracy of the algorithm was 0.03 ± 0.02 mm. The repeatability was less than 3 μm and the reproducibility was less than 86 μm. The time elapsed for the analysis of more than 100 cine images of Varian aS1000 and aS500 EPIDs were ∼65 and 20 s, respectively. Processing of images taken in integrated mode took 0.1 s. The output of the analysis software is printable and shows the isocenter shifts as a function of angle in both in-plane and cross-plane directions. It gives warning messages where the shifts exceed the criteria for SRS/SRT and provides useful data for the necessary adjustments in the system including bearing system and/or room lasers.Conclusions: The comprehensive method introduced in this study uses cine-images, is highly accurate, fast, and independent of the observer. It tests all gantry angles and is suitable for pretreatment QA of the isocenter for stereotactic treatments. © 2011 American Association of Physicists in Medicine.

Tarleton M.,University of Newcastle | Gilbert J.,Calvary Materials Newcastle Hospital | Sakoff J.A.,Calvary Materials Newcastle Hospital | McCluskey A.,University of Newcastle
European Journal of Medicinal Chemistry | Year: 2012

Cantharidin (1) and norcantharidin (2) display high levels of anticancer activity against a broad range of tumour cell lines. Synthetic manipulation of norcantharidin yields (3S,3aR,4S,7R,7aS)-3-hydroxyhexahydro-4,7- epoxyisobenzofuran-1(3H)-one (3), which also displays a high level of anticancer activity against tumour cells but interestingly, shows selectivity towards HT29 (colon; GI50 = 14 μM) and SJ-G2 (glioblastoma; GI50 = 15 μM) cell lines. Substitution at the hydroxyl group of the cyclic lactone within (3) produces a diasteromeric pair of products that have no difference in cytotoxicity over the cell lines tested. Incorporation of an isopropyl tail at this position (16) produced the most promising compound of this series to date, with strong selectivity towards HT29 (colon; GI50 = 19 μM) and SJ-G2 (glioblastoma; GI50 = 21 μM) cell lines but completely void of any activity against the remaining tumour cell lines (GI50 > 100 μM), as per the parent molecule. We also discovered that the introduction of a terminal phosphate moiety (28) at the same position produced a different trend in cytotoxicity with strong activity in BE2-C (neuroblastoma; GI 50 = 9 μM) cells; suggestive of an alternate mode of action. © 2012 Elsevier Masson SAS. All rights reserved.

King B.W.,University of Newcastle | Morf D.,Varian Medical Systems | Greer P.B.,University of Newcastle | Greer P.B.,Calvary Materials Newcastle Hospital
Medical Physics | Year: 2012

Purpose: To investigate the properties of a modified backscatter shielded electronic portal imaging device (BSS-EPID) and to develop a dose model to convert BSS-EPID images to dose in water as part of an improved system for dosimetry using EPIDs. Methods: The effectiveness of the shielding of the BSS-EPID was studied by comparing images measured with the BSS-EPID mounted on the support arm to images measured with the BSS-EPID removed from the support arm. A dose model was developed and optimized to reconstruct dose in water at different depths from measured BSS-EPID images. The accuracy of the dose model was studied using BSS-EPID images of 28 IMRT fields to reconstruct dose in water at depths of 2, 5, 10, and 20 cm and comparing to measured dose in water from a two-dimensional diode array at the same depths. The ability of the BSS-EPID system to operate independently of detector position was demonstrated by comparing the dose reconstruction of a 10 × 10 cm2 field using different detector offsets to that measured by a two-dimensional diode array. Results: The shielding of the BSS-EPID was found to be effective, with more than 99 of pixels showing less than 0.5 change due to the presence of the support arm and at most a 0.2 effect on the central axis for 2 × 2 cm2 fields to fully open 30 × 40 cm2 images. The dose model was shown to accurately reconstruct measurements of dose in water using BSS-EPID images with average γ pass rates (2, 2 mm criteria) of 92.5, 98.7, 97.4, and 97.2 at depths of 2, 5, 10, and 20 cm, respectively, when compared to two-dimensional diode array measurements. When using 3, 3 mm γ criteria, the average pass rate was greater than 97 at all depths. Reconstructed dose in water for a 10 × 10 cm2 field measured with detector offsets as large as 10 cm agreed with each other and two-dimensional diode array measurements within 0.9. Conclusions: The modified BSS-EPID and associated dose model provide an improved system for dosimetry measurements using EPIDs. Several important limitations of the current hardware and software are addressed by this system. © 2012 American Association of Physicists in Medicine.

Rowshanfarzad P.,University of Newcastle | Sabet M.,University of Manitoba | O'Connor D.J.,CancerCare Manitoba | McCowan P.M.,University of Manitoba | And 2 more authors.
Medical Physics | Year: 2012

Purpose: Electronic portal imaging devices (EPIDs) have been studied and used for pretreatment and in-vivo dosimetry applications for many years. The application of EPIDs for dosimetry in arc treatments requires accurate characterization of the mechanical sag of the EPID and gantry during rotation. Several studies have investigated the effects of gravity on the sag of these systems but each have limitations. In this study, an easy experiment setup and accurate algorithm have been introduced to characterize and correct for the effect of EPID and gantry sag during arc delivery. Methods: Three metallic ball bearings were used as markers in the beam: two of them fixed to the gantry head and the third positioned at the isocenter. EPID images were acquired during a 360 gantry rotation in cine imaging mode. The markers were tracked in EPID images and a robust in-house developed MATLAB code was used to analyse the images and find the EPID sag in three directions as well as the EPID gantry sag by comparison to the reference gantry zero image. The algorithm results were then tested against independent methods. The method was applied to compare the effect in clockwise and counter clockwise gantry rotations and different source-to-detector distances (SDDs). The results were monitored for one linear accelerator over a course of 15 months and six other linear-accelerators from two treatment centers were also investigated using this method. The generalized shift patterns were derived from the data and used in an image registration algorithm to correct for the effect of the mechanical sag in the system. The Gamma evaluation (3, 3 mm) technique was used to investigate the improvement in alignment of cine EPID images of a fixed field, by comparing both individual images and the sum of images in a series with the reference gantry zero image. Results: The mechanical sag during gantry rotation was dependent on the gantry angle and was larger in the in-plane direction, although the patterns were not identical for various linear-accelerators. The reproducibility of measurements was within 0.2 mm over a period of 15 months. The direction of gantry rotation and SDD did not affect the results by more than 0.3 mm. Results of independent tests agreed with the algorithm within the accuracy of the measurement tools. When comparing summed images, the percentage of points with Gamma index 1 increased from 85.4 to 94.1 after correcting for the EPID sag, and to 99.3 after correction for gantry EPID sag. Conclusions: The measurement method and algorithms introduced in this study use cine-images, are highly accurate, simple, fast, and reproducible. It tests all gantry angles and provides a suitable automatic analysis and correction tool to improve EPID dosimetry and perform comprehensive linac QA for arc treatments. © 2012 American Association of Physicists in Medicine.

Upanal N.,Calvary Materials Newcastle Hospital | Enjeti A.,Calvary Materials Newcastle Hospital
Australian and New Zealand Journal of Obstetrics and Gynaecology | Year: 2011

Primary lymphoma of the uterus and cervix is rarely encountered. We present two cases of diffuse large B-cell lymphoma of the cervix and uterus that were treated with R-CHOP chemotherapy followed by pelvic radiotherapy. The women are disease free 20 and 19 months after the diagnosis respectively. Seventy-two cases of primary uterine and cervical lymphoma reported in the English literature in the last 10 years from 2000 to 2010 are reviewed. © 2011 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology.

Ansbacher W.,BC Cancer Agency | Swift C.-L.,BC Cancer Agency | Greer P.B.,Calvary Materials Newcastle Hospital
Journal of Physics: Conference Series | Year: 2010

We investigated cine-mode portal imaging on a Varian Trilogy accelerator and found that the linearity and other dosimetric properties are sufficient for 3D dose reconstruction as used in patient-specific quality assurance for VMAT (RapidArc) treatments. We also evaluated the gantry angle label in the portal image file header as a surrogate for the true imaged angle. The precision is only just adequate for the 3D evaluation method chosen, as discrepancies of 2° were observed. © 2010 IOP Publishing Ltd.

Dempsey C.,Calvary Materials Newcastle Hospital
Australasian Physical and Engineering Sciences in Medicine | Year: 2010

To describe the steps undertaken to commission a 3D high dose rate (HDR) brachytherapy treatment planning system (TPS). Emphasis was placed on validating previously published recommendations, in addition to checking 3D parameters such as treatment optimization and dose volume histogram (DVH) analysis. Commissioning was performed of the brachytherapy module of the Nucletron Oncentra MasterPlan treatment planning system (version 3.2). Commissioning test results were compared to an independent external beam TPS (Varian Eclipse v 8.6) and the previously commissioned Nucletron Plato (V 14.3.7) brachytherapy treatment planning system, with point doses also independently verified using the brachytherapy module in RadCalc (v 6.0) independent point dose calculation software. Tests were divided into eight categories: (i) Image import accuracy, (ii) Reconstruction accuracy, (iii) Source configuration data check, (iv) Dose calculation accuracy, (v) Treatment optimization validation, (vi) DVH reproducibility, (vii) Treatment export check and (viii) Printout consistency. Point dose agreement between Oncentra, Plato and RadCalc was better than 5% with source data and dose calculation protocols following the American Association of Physicists in Medicine (AAPM) guidelines. Testing of image accuracy (import and reconstruction), along with validation of automated treatment optimization and DVH analysis generated a more comprehensive set of testing procedures than previously listed in published recommendations. © Australasian College of Physical Scientists and Engineers in Medicine 2010.

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