Sir Peter MacCallum Department of Oncology - Research Publications

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    Streamlined genetic education is effective in preparing women newly diagnosed with breast cancer for decision making about treatment-focused genetic testing: a randomized controlled noninferiority trial
    Quinn, VF ; Meiser, B ; Kirk, J ; Tucker, KM ; Watts, KJ ; Rahman, B ; Peate, M ; Saunders, C ; Geelhoed, E ; Gleeson, M ; Barlow-Stewart, K ; Field, M ; Harris, M ; Antill, YC ; Cicciarelli, L ; Crowe, K ; Bowen, MT ; Mitchell, G (NATURE PUBLISHING GROUP, 2017-04-01)
    PURPOSE: Increasingly, women newly diagnosed with breast cancer are being offered treatment-focused genetic testing (TFGT). As the demand for TFGT increases, streamlined methods of genetic education are needed. METHODS: In this noninferiority trial, women aged <50 years with either a strong family history (FH+) or other features suggestive of a germ-line mutation (FH-) were randomized before definitive breast cancer surgery to receive TFGT education either as brief written materials (intervention group (IG)) or during a genetic counseling session at a familial cancer clinic (usual-care group (UCG)). Women completed self-report questionnaires at four time points over 12 months. RESULTS: A total of 135 women were included in the analysis, all of whom opted for TFGT. Decisional conflict about TFGT choice (primary outcome) was not inferior in the IG compared with the UCG (noninferiority margin of -10; mean difference = 2.45; 95% confidence interval -2.87-7.76; P = 0.36). Costs per woman counseled in the IG were significantly lower (AUD$89) compared with the UCG (AUD$173; t(115) = 6.02; P < 0.001). CONCLUSION: A streamlined model of educating women newly diagnosed with breast cancer about TFGT seems to be a cost-effective way of delivering education while ensuring that women feel informed and supported in their decision making, thus freeing resources for other women to access TFGT.Genet Med 19 4, 448-456.
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    Pheo-Type: A Diagnostic Gene-expression Assay for the Classification of Pheochromocytoma and Paraganglioma
    Flynn, A ; Dwight, T ; Harris, J ; Benn, D ; Zhou, L ; Hogg, A ; Catchpoole, D ; James, P ; Duncan, EL ; Trainer, A ; Gill, AJ ; Clifton-Bligh, R ; Hicks, RJ ; Tothill, RW (ENDOCRINE SOC, 2016-03-01)
    CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are heritable neoplasms that can be classified into gene-expression subtypes corresponding to their underlying specific genetic drivers. OBJECTIVE: This study aimed to develop a diagnostic and research tool (Pheo-type) capable of classifying PPGL tumors into gene-expression subtypes that could be used to guide and interpret genetic testing, determine surveillance programs, and aid in elucidation of PPGL biology. DESIGN: A compendium of published microarray data representing 205 PPGL tumors was used for the selection of subtype-specific genes that were then translated to the Nanostring gene-expression platform. A support vector machine was trained on the microarray dataset and then tested on an independent Nanostring dataset representing 38 familial and sporadic cases of PPGL of known genotype (RET, NF1, TMEM127, MAX, HRAS, VHL, and SDHx). Different classifier models involving between three and six subtypes were compared for their discrimination potential. RESULTS: A gene set of 46 genes and six endogenous controls was selected representing six known PPGL subtypes; RTK1-3 (RET, NF1, TMEM127, and HRAS), MAX-like, VHL, and SDHx. Of 38 test cases, 34 (90%) were correctly predicted to six subtypes based on the known genotype to gene-expression subtype association. Removal of the RTK2 subtype from training, characterized by an admixture of tumor and normal adrenal cortex, improved the classification accuracy (35/38). Consolidation of RTK and pseudohypoxic PPGL subtypes to four- and then three-class architectures improved the classification accuracy for clinical application. CONCLUSIONS: The Pheo-type gene-expression assay is a reliable method for predicting PPGL genotype using routine diagnostic tumor samples.
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    TERT structural rearrangements in metastatic pheochromocytomas
    Dwight, T ; Flynn, A ; Amarasinghe, K ; Benn, DE ; Lupat, R ; Li, J ; Cameron, DL ; Hogg, A ; Balachander, S ; Candiloro, ILM ; Wong, SQ ; Robinson, BG ; Papenfuss, AT ; Gill, AJ ; Dobrovic, A ; Hicks, RJ ; Clifton-Bligh, RJ ; Tothill, RW (BIOSCIENTIFICA LTD, 2018-01-01)
    Pheochromocytomas (PC) and paragangliomas (PGL) are endocrine tumors for which the genetic and clinicopathological features of metastatic progression remain incompletely understood. As a result, the risk of metastasis from a primary tumor cannot be predicted. Early diagnosis of individuals at high risk of developing metastases is clinically important and the identification of new biomarkers that are predictive of metastatic potential is of high value. Activation of TERT has been associated with a number of malignant tumors, including PC/PGL. However, the mechanism of TERT activation in the majority of PC/PGL remains unclear. As TERT promoter mutations occur rarely in PC/PGL, we hypothesized that other mechanisms - such as structural variations - may underlie TERT activation in these tumors. From 35 PC and four PGL, we identified three primary PCs that developed metastases with elevated TERT expression, each of which lacked TERT promoter mutations and promoter DNA methylation. Using whole genome sequencing, we identified somatic structural alterations proximal to the TERT locus in two of these tumors. In both tumors, the genomic rearrangements led to the positioning of super-enhancers proximal to the TERT promoter, that are likely responsible for the activation of the normally tightly repressed TERT expression in chromaffin cells.
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    Prefrontal cortical control of a brainstem social behavior circuit
    Franklin, TB ; Silva, BA ; Perova, Z ; Marrone, L ; Masferrer, ME ; Zhan, Y ; Kaplan, A ; Greetham, L ; Verrechia, V ; Halman, A ; Pagella, S ; Vyssotski, AL ; Illarionova, A ; Grinevich, V ; Branco, T ; Gross, CT (NATURE PUBLISHING GROUP, 2017-02-01)
    The prefrontal cortex helps adjust an organism's behavior to its environment. In particular, numerous studies have implicated the prefrontal cortex in the control of social behavior, but the neural circuits that mediate these effects remain unknown. Here we investigated behavioral adaptation to social defeat in mice and uncovered a critical contribution of neural projections from the medial prefrontal cortex to the dorsal periaqueductal gray, a brainstem area vital for defensive responses. Social defeat caused a weakening of functional connectivity between these two areas, and selective inhibition of these projections mimicked the behavioral effects of social defeat. These findings define a specific neural projection by which the prefrontal cortex can control and adapt social behavior.
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    Comparing women pharmacy consumers' experiences with weight loss treatment in Victoria and Nottingham: a cross-sectional study.
    Fakih, S ; Marriott, JL ; Boardman, H ; Anderson, C ; Hussainy, SY (Springer Science and Business Media LLC, 2014-06-28)
    BACKGROUND: There has been a recent increase in weight management services available in pharmacies across Australia and England. The aim of this study was to determine the following between women in Victoria and Nottingham: similarities and differences of what weight management options are preferred by women pharmacy consumers; how they feel about pharmacists providing advice in this area; and what they desire in a weight management program. METHOD: Women pharmacy consumers were randomly approached by a researcher in community pharmacies in Victoria and Nottingham and asked to complete a questionnaire regarding their own weight management experiences. The questionnaire was self-completed or researcher-administered and was comprised of four main sections that focused on the participant's general health, previous weight loss experiences, their ideal weight management program and their demographics. Data was entered in SPSS 19 and logistic regression was used to identify any differences in weight loss experiences between women. RESULTS: The participant rates were high: 86% (n = 395/460) in Victoria and 98% in Nottingham (n = 215/220). Overall, women in Victoria and Nottingham were similar with comparable demographics. Approximately 50% (250/507) of women were in the overweight or obese body mass index category, with over 70% (n = 436/610) of women having attempted to lose weight in the past. The majority of women (n = 334/436) felt comfortable receiving advice from pharmacists. In the logistic regression analysis women in Nottingham were found to be significantly less likely to have utilised a pharmacy weight management program in the last five years (OR: 0.23 CI: 0.08, 0.63) and were significantly less likely to want an ideal weight management program located in a pharmacy (OR: 0.49 CI: 0.30, 0.82) compared to women in Victoria. No significant associations between location and feeling comfortable with a pharmacist advising on weight loss or wanting a pharmacist in an ideal weight management program were seen. CONCLUSION: Results from this study have provided information on possible ideal pharmacy weight management programs in both Victoria and Nottingham. Although differences were seen between the two populations, similarities between ideal weight management programs and comfort level with pharmacist interaction were noted.
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    Knowledge, attitudes and practices of health professionals and women towards medication use in breastfeeding: A review.
    Hussainy, SY ; Dermele, N (Springer Science and Business Media LLC, 2011-08-26)
    Many breastfeeding women require and regularly take medicines, especially those available over-the-counter, and the safe use of these is dependent on the advice provided by health professionals such as general practitioners and pharmacists. The primary aim of this review therefore, was to investigate the literature relating to health professionals' and women's knowledge, attitudes and practices towards medication use and safety in breastfeeding. The limited literature that was uncovered identified that general practitioners and pharmacists have poor knowledge, but positive attitudes, and variable practices that are mostly guided by personal experience. They tend to make decisions about the use of a medicine whilst breastfeeding based on the potential 'risk' that it poses to the infant in terms of possible adverse reactions, rather than its 'compatibility' with breast milk. The decision-making process between health professionals and women is usually not a negotiated process, and women are often asked to stop breastfeeding whilst taking a medicine. Women, in turn, are left dissatisfied with the advice received, many choosing not to initiate therapy or not to continue breastfeeding. Some directions for future research have been suggested to address the issues identified in this critical area. This review is important from a societal perspective because many breastfeeding women require and regularly take medications, especially those available without prescription, and the safe use of these is dependent on the advice provided by health professionals, which is ultimately influenced by their knowledge, attitudes and practices. However, there is an absence of high quality evidence from randomised controlled trials on the safety of medications taken during breastfeeding, which naturally would hinder health professionals from appropriately advising women. It is equally important to know about women's experiences of advice received from health professionals, and whether there is consistency between recommendations made across resources on medication safety in breastfeeding, in order to gain a full understanding of the issues prevalent in this area of practice.
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    Piloting the role of a pharmacist in a community palliative care multidisciplinary team: an Australian experience.
    Hussainy, SY ; Box, M ; Scholes, S (Springer Science and Business Media LLC, 2011-10-31)
    BACKGROUND: While the home is the most common setting for the provision of palliative care in Australia, a common problem encountered here is the inability of patient/carers to manage medications, which can lead to misadventure and hospitalisation. This can be averted through detection and resolution of drug related problems (DRPs) by a pharmacist; however, they are rarely included as members of the palliative care team. The aim of this study was to pilot a model of care that supports the role of a pharmacist in a community palliative care team. A component of the study was to develop a cost-effective model for continuing the inclusion of a pharmacist within a community palliative care service. METHODS: The study was undertaken (February March 2009-June 2010) in three phases. Development (Phase 1) involved a literature review; scoping the pharmacist's role; creating tools for recording DRPs and interventions, a communication and education strategy, a care pathway and evidence based patient information. These were then implemented in Phase 2. Evaluation (Phase 3) of the impact of the pharmacist's role from the perspectives of team members was undertaken using an online survey and focus group. Impact on clinical outcomes was determined by the number of patients screened to assess their risk of medication misadventure, as well as the number of medication reviews and interventions performed to resolve DRPs. RESULTS: The pharmacist screened most patients (88.4%, 373/422) referred to the palliative care service to assess their risk of medication misadventure, and undertook 52 home visits. Medication reviews were commonly conducted at the majority of home visits (88%, 46/52), and a variety of DRPs (113) were detected at this point, the most common being "patient requests drug information" (25%, 28/113) and "condition not adequately treated" (22%, 25/113). The pharmacist made 120 recommendations in relation to her interventions.Fifty percent of online survey respondents (10/20) had interacted 10 or more times with the pharmacist for advice. All felt that the pharmacist's role was helpful, improving their knowledge of the different medications used in palliative care. The six team members who participated in the focus group indicated that there were several benefits of the pharmacist's contributions towards medication screening and review. CONCLUSIONS: The inclusion of a pharmacist in a community palliative care team lead to an increase in the medication-related knowledge and skills of its members, improved patients' medication management, and minimised related errors. The model of care created can potentially be duplicated by other palliative care services, although its cost-effectiveness was unable to be accurately tested within the study.
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    Sustainable Syntheses of (-)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site
    Smedley, CJ ; Stanley, PA ; Qazzaz, ME ; Prota, AE ; Olieric, N ; Collins, H ; Eastman, H ; Barrow, AS ; Lim, K-H ; Kam, T-S ; Smith, BJ ; Duivenvoorden, HM ; Parker, BS ; Bradshaw, TD ; Steinmetz, MO ; Moses, JE (NATURE PORTFOLIO, 2018-07-13)
    The jerantinine family of Aspidosperma indole alkaloids from Tabernaemontana corymbosa are potent microtubule-targeting agents with broad spectrum anticancer activity. The natural supply of these precious metabolites has been significantly disrupted due to the inclusion of T. corymbosa on the endangered list of threatened species by the International Union for Conservation of Nature. This report describes the asymmetric syntheses of (-)-jerantinines A and E from sustainably sourced (-)-tabersonine, using a straight-forward and robust biomimetic approach. Biological investigations of synthetic (-)-jerantinine A, along with molecular modelling and X-ray crystallography studies of the tubulin-(-)-jerantinine B acetate complex, advocate an anticancer mode of action of the jerantinines operating via microtubule disruption resulting from binding at the colchicine site. This work lays the foundation for accessing useful quantities of enantiomerically pure jerantinine alkaloids for future development.
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    Characterisation and validation of Mel38; A multi-tissue microRNA signature of cutaneous melanoma
    Van Laar, R ; Lincoln, M ; Fereday, S ; Ahmad, A (PUBLIC LIBRARY SCIENCE, 2019-02-05)
    BACKGROUND: Histopathologic examination of melanocytic neoplasms can be challenging and subjective, with no specific circulating or tissue-based biomarkers currently available. Recently, a circulating 38-microRNA profile of melanoma (Mel38) was described. In this study, Mel38 expression and its impact on downstream mRNA regulation in solid tissue is examined. METHODS: Mel38 was applied to archival, clinically-annotated, solid-tissue genomic datasets representing benign naevi, primary and metastatic melanoma. Statistical analysis of the signature in relation to disease status, patient outcome and molecular pathways was performed. RESULTS: Mel38 is able to stratify genomic data from solid tissue biopsies on the basis of disease status and differences in melanoma-specific survival. Experimentally-verified messenger-RNA targets of Mel38 also exhibit prognostic expression patterns and represent key molecular pathways and events in melanoma development and progression. CONCLUSION: The Mel38 microRNA profile may have diagnostic and prognostic utility in solid tissue as well as being a robust circulating biomarker of melanoma.
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    Exploiting the noise: improving biomarkers with ensembles of data analysis methodologies
    Starmans, MHW ; Pintilie, M ; John, T ; Der, SD ; Shepherd, FA ; Jurisica, I ; Lambin, P ; Tsao, M-S ; Boutros, PC (BMC, 2012-11-12)
    BACKGROUND: The advent of personalized medicine requires robust, reproducible biomarkers that indicate which treatment will maximize therapeutic benefit while minimizing side effects and costs. Numerous molecular signatures have been developed over the past decade to fill this need, but their validation and up-take into clinical settings has been poor. Here, we investigate the technical reasons underlying reported failures in biomarker validation for non-small cell lung cancer (NSCLC). METHODS: We evaluated two published prognostic multi-gene biomarkers for NSCLC in an independent 442-patient dataset. We then systematically assessed how technical factors influenced validation success. RESULTS: Both biomarkers validated successfully (biomarker #1: hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.21 to 2.19, P = 0.001; biomarker #2: HR 1.42, 95% CI 1.03 to 1.96, P = 0.030). Further, despite being underpowered for stage-specific analyses, both biomarkers successfully stratified stage II patients and biomarker #1 also stratified stage IB patients. We then systematically evaluated reasons for reported validation failures and find they can be directly attributed to technical challenges in data analysis. By examining 24 separate pre-processing techniques we show that minor alterations in pre-processing can change a successful prognostic biomarker (HR 1.85, 95% CI 1.37 to 2.50, P < 0.001) into one indistinguishable from random chance (HR 1.15, 95% CI 0.86 to 1.54, P = 0.348). Finally, we develop a new method, based on ensembles of analysis methodologies, to exploit this technical variability to improve biomarker robustness and to provide an independent confidence metric. CONCLUSIONS: Biomarkers comprise a fundamental component of personalized medicine. We first validated two NSCLC prognostic biomarkers in an independent patient cohort. Power analyses demonstrate that even this large, 442-patient cohort is under-powered for stage-specific analyses. We then use these results to discover an unexpected sensitivity of validation to subtle data analysis decisions. Finally, we develop a novel algorithmic approach to exploit this sensitivity to improve biomarker robustness.