Sir Peter MacCallum Department of Oncology - Research Publications
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ItemEstrogen Receptor β Activation Impairs Prostatic Regeneration by Inducing Apoptosis in Murine and Human Stem/Progenitor Enriched Cell Populations(PUBLIC LIBRARY SCIENCE, 2012-07-10)Androgen depletion is the primary treatment for prostate disease; however, it fails to target residual castrate-resistant cells that are regenerative and cells of origin of prostate cancer. Estrogens, like androgens, regulate survival in prostatic cells, and the goal of this study was to determine the advantages of selective activation of estrogen receptor β (ERβ) to induce cell death in stem cells that are castrate-resistant. Here we show two cycles of short-term ERβ agonist (8β-VE2) administration this treatment impairs regeneration, causing cystic atrophy that correlates with sustained depletion of p63+ basal cells. Furthermore, agonist treatment attenuates clonogenicity and self-renewal of murine prostatic stem/progenitor cells and depletes both murine (Lin(-)Sca1(+)CD49f(hi)) and human (CD49f(hi)Trop2(hi)) prostatic basal cells. Finally, we demonstrate the combined added benefits of selective stimulation of ERβ, including the induction of cell death in quiescent post-castration tissues. Subsequent to castration ERβ-induces further apoptosis in basal, luminal and intermediate cells. Our results reveal a novel benefit of ERβ activation for prostate disease and suggest that combining selective activation of ERβ with androgen-deprivation may be a feasible strategy to target stem cells implicated in the origin of prostatic disease.
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ItemComparing women pharmacy consumers' experiences with weight loss treatment in Victoria and Nottingham: a cross-sectional study.(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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ItemExploiting the noise: improving biomarkers with ensembles of data analysis methodologies(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.
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ItemParaneoplastic leukocytoclastic vasculitis as an initial presentation of malignant pleural mesothelioma: a case report.(Springer Science and Business Media LLC, 2012-08-31)INTRODUCTION: Vasculitis has been associated with malignancies, more commonly hematological rather than solid malignancies. Due to the rarity of these conditions and the lack of a temporal association, the relationship between vasculitis and malignancy remains unclear. Paraneoplastic vasculitis as a phenomenon of lung cancer has been described in the literature. To the best of our knowledge, this is the first case report of leukocytoclastic vasculitis being an initial presentation of malignant pleural mesothelioma. CASE PRESENTATION: We report the case of an 84-year old Greek man who presented to our facility with an erythematous, pruritic and purpuric rash affecting his limbs. This was biopsy-proven to be leukocytoclastic vasculitis and treated conservatively with topical corticosteroids as well as oral prednisolone, with good results. Six months later, he was diagnosed as having malignant pleural mesothelioma. As he remained asymptomatic from his malignancy, no systemic chemotherapy was instituted. He had a recurrence of biopsy-proven leukocytoclastic vasculitis two months after he was diagnosed as having mesothelioma, which again settled with conservative measures. CONCLUSIONS: It is important to remain vigilant with regard to the association between leukocytoclastic vasculitis and malignancies. A diagnosis of vasculitis requires a search for malignancies as well as other possible etiologies. This is particularly of relevance when the vasculitis becomes chronic, recurrent or treatment is no longer effective. Should our patient have experienced refractory vasculitis, we would have instituted systemic chemotherapy to treat the underlying malignancy.
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ItemScreening participation for people at increased risk of colorectal cancer due to family history: a systematic review and meta-analysis(SPRINGER, 2013-09)We conducted a systematic review and a meta-analysis of observational studies to identify and summarise the level of colorectal cancer (CRC) screening participation for people at increased risk due to family history of the disease. Medline, Cinhal, Embase and PsychInfo databases were comprehensively searched between January 1995 and May 2012 to identify relevant articles. To be included, studies had to report on screening for people who had at least one first-degree relative with CRC and no previous personal diagnosis of the disease. Pooled screening participation levels were calculated for each screening modality. Seventeen studies, accounting for a total of 13,269 subjects with a family history of CRC met the inclusion criteria. Seven studies, including a total of 6,901 subjects had a pooled faecal occult blood testing screening participation (at least once) of 25 % (95 % CI 12-38). Five studies including a total of 5,091 subjects had a pooled sigmoidoscopy-based screening participation (at least once) of 16 % (95 % CI 7-27). Seven studies including a total of 9,965 subjects had pooled participation colonoscopy-based screening (at least once) of 40 % (95 % CI 26-54). There was a significant level of screening heterogeneity between studies. This review identified a substantial underuse of CRC screening for people at increased risk of developing the disease. It highlights the potential opportunity that exists for increasing screening participation among this segment of the population and the need to adjust the current CRC screening policies towards that objective.
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ItemSuboptimal health literacy in patients with lung cancer or head and neck cancer(SPRINGER, 2013-08)BACKGROUND: Health literacy is the capacity to seek, understand and utilise health information to make informed health decisions. Suboptimal health literacy has been linked to poor health outcomes. This study assessed health literacy in patients treated for head and neck or lung cancer and associations between health literacy and demographic factors and distress levels. METHODS: Consecutive English-speaking patients were approached at Peter MacCallum Cancer Centre. Face-to-face interviews were conducted. Health literacy was assessed using the Shortened Test of Functional Health Literacy in Adults (S-TOFHLA) and Health Literacy Management Scale (HeLMS). Distress was assessed by the Distress Thermometer. RESULTS: Response rate was 73 % (n = 93). Using S-TOFHLA, prevalence of inadequate and marginal health literacy was 5.4 and 6.5 % respectively, and both groups were associated with older age (p = 0.043) and low education level (p = 0.009). Specific assessment of S-TOFHLA revealed that 70 % could not interpret prescription labels. HeLMS reported that 17 % had health literacy difficulties. Low scores on domains of HeLMS were associated with lower education level (p < 0.05) but younger age (p < 0.05). Distress was not associated with S-TOFHLA scores but related to low scores in two domains of HeLMS (p < 0.05). CONCLUSION: Using two different measures, a substantial proportion of patients have poor health literacy abilities and may experience difficulties in accessing health services.
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ItemOntogeny of small RNA in the regulation of mammalian brain development(BIOMED CENTRAL LTD, 2014-09-09)BACKGROUND: MicroRNAs (miRNAs) play a pivotal role in coordinating messenger RNA (mRNA) transcription and stability in almost all known biological processes, including the development of the central nervous system. Despite our broad understanding of their involvement, we still have a very sparse understanding of specifically how miRNA contribute to the strict regional and temporal regulation of brain development. Accordingly, in the current study we have examined the contribution of miRNA in the developing rat telencephalon and mesencephalon from just after neural tube closure till birth using a genome-wide microarray strategy. RESULTS: We identified temporally distinct expression patterns in both the telencephalon and mesencephalon for both miRNAs and their target genes. We demonstrate direct miRNA targeting of several genes involved with the migration, differentiation and maturation of neurons. CONCLUSIONS: Our findings suggest that miRNA have significant implications for the development of neural structure and support important mechanisms that if disrupted, may contribute to or drive neurodevelopmental disorders.
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ItemThe Australian Clinical Dosimetry Service: a commentary on the first 18 months(SPRINGER, 2012-12)
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ItemAssessing HER2 amplification in breast cancer: findings from the Australian In Situ Hybridization Program(SPRINGER, 2012-07)In August 2006, the Australian government approved subsidized trastuzumab therapy for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, and it was mandated that HER2 testing should be performed using in situ hybridization (ISH) rather than immunohistochemistry (IHC). Here we review results of the first regulated, nationwide program to provide HER2 ISH testing for all newly diagnosed breast cancer patients, with a particular emphasis on cases where IHC and ISH results were discordant. Data from all laboratories participating in the program were collated. Cases with an equivocal ISH test result [by chromogenic ISH (CISH) or silver ISH (SISH)] were tested centrally by fluorescence ISH. Most laboratories also performed HER2 IHC, and 200 cases with discordant IHC and ISH results were selected for further analysis in a central laboratory. A total of 26 laboratories were involved and 53,402 tests were reported. Over a 4-year period the HER2 positivity rate decreased for primary cancers from 23.8 to 14.6 %, but remained relatively constant for samples from metastases. Average ISH reporting times were <5 days for all yearly reporting periods. Test-repeat rates decreased for CISH (8.9-3.6 %) and SISH (13.7-8.4 %). Only 12 of 196 cases remained discordant after retesting in a central laboratory. These findings demonstrate the successful implementation of a regulated, national program that continues to collect data on HER2 status. The results also highlight the differences in IHC interpretation between local laboratories and a central, more experienced, laboratory. This model could be used to establish future biomarker-testing programs in other countries.
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ItemA phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575)(SPRINGER, 2014-04)PURPOSE: To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. METHODS: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). RESULTS: A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). CONCLUSIONS: RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified.