ORCID Profile
0000-0002-5790-0208
Current Organisation
Illawarra Shoalhaven Local Health District
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Publisher: CSIRO Publishing
Date: 1989
DOI: 10.1071/RD9890357
Abstract: The oxidative metabolic capability of mature boar spermatozoa has been determined in vitro. The high rate of oxidation of fructose, glucose, glycerol, glycerol-3-phosphate and lactate to CO2 and the optimization of incubation conditions indicates that these cells could constitute a model system for investigating the anti-glycolytic activity of potential male anti-fertility agents. The effects of several chemical agents on the oxidative metabolism of boar spermatozoa are reported.
Publisher: Elsevier BV
Date: 07-2012
Publisher: Springer Science and Business Media LLC
Date: 21-11-2014
DOI: 10.1038/BJC.2013.722
Publisher: Springer Science and Business Media LLC
Date: 24-02-2016
DOI: 10.1038/NATURE16965
Abstract: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous (2) pancreatic progenitor (3) immunogenic and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2017
DOI: 10.1038/NATURE21063
Abstract: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
Publisher: Wiley
Date: 14-10-2014
DOI: 10.1002/CNCR.28863
Abstract: Inherited predisposition to pancreatic cancer contributes significantly to its incidence and presents an opportunity for the development of early detection strategies. The genetic basis of predisposition remains unexplained in a high proportion of patients with familial PC (FPC). Clinicopathologic features were assessed in a cohort of 766 patients who had been diagnosed with pancreatic ductal adenocarcinoma (PC). Patients were classified with FPC if they had ≥1 affected first-degree relatives otherwise, they were classified with sporadic PC (SPC). The prevalence of FPC in this cohort was 8.9%. In FPC families with an affected parent-child pair, 71% in the subsequent generation were 12.3 years younger at diagnosis. Patients with FPC had more first-degree relatives who had an extrapancreatic malignancy (EPM) (42.6% vs 21.2 P 2 years) was associated with poor survival in both groups. FPC represents 9% of PC, and the risk of malignancy in kindred does not appear to be confined to the pancreas. Patients with FPC have more precursor lesions and include fewer active smokers, but other clinicopathologic factors and outcome are similar to those in patients with SPC. Furthermore, some FPC kindreds may exhibit anticipation. A better understanding of the clinical features of PC will facilitate efforts to uncover novel susceptibility genes and the development of early detection strategies.
Publisher: Springer Science and Business Media LLC
Date: 25-02-2015
DOI: 10.1038/NATURE14169
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.CRITREVONC.2015.05.003
Abstract: Locally advanced rectal cancer is regularly treated with trimodality therapy consisting of neoadjuvant chemoradiation, surgery and adjuvant chemotherapy. There is a need for biomarkers to assess treatment response, and aid in stratification of patient risk to adapt and personalise components of the therapy. Currently, pathological stage and tumour regression grade are used to assess response. Experimental markers include proteins involved in cell proliferation, apoptosis, angiogenesis, the epithelial to mesenchymal transition and microsatellite instability. As yet, no single marker is sufficiently robust to have clinical utility. Microarrays that screen a tumour for multiple promising candidate markers, gene expression and microRNA profiling will likely have higher yield and it is expected that a combination or panel of markers would prove most useful. Moving forward, utilising serial s les of circulating tumour cells or circulating nucleic acids can potentially allow us to demonstrate tumour heterogeneity, document mutational changes and subsequently measure treatment response.
Publisher: American Association for Cancer Research (AACR)
Date: 30-04-2015
DOI: 10.1158/1078-0432.CCR-15-0426
Abstract: Purpose: Personalized medicine strategies using genomic profiling are particularly pertinent for pancreas cancer. The In idualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was initially designed to exploit results from genome sequencing of pancreatic cancer under the auspices of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed small subsets of patients with aberrations in their tumor genome that could be targeted with currently available therapies. Experimental Design: The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumor specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable timeframe. We screened for three molecular targets: HER2 lification KRAS wild-type and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). Results: Tumor biopsy and archived tumor s les were collected from 93 patients and 76 were screened. To date 22 candidate cases have been identified: 14 KRAS wild-type, 5 cases of HER2 lification, 2 mutations in BRCA2, and 1 ATM mutation. Median time from consent to the return of validated results was 21.5 days. An inability to obtain a biopsy or insufficient tumor content in the available specimen were common reasons for patient exclusion from molecular analysis while deteriorating performance status prohibited a number of patients from proceeding in the study. Conclusions: Documenting the feasibility of acquiring and screening biospecimens for actionable molecular targets in real time will aid other groups embarking on similar trials. Key elements include the need to better prescreen patients, screen more patients, and offer more attractive clinical trial options. Clin Cancer Res 21(9) 2029–37. ©2015 AACR.
Publisher: Elsevier BV
Date: 08-2011
Abstract: Bevacizumab is an antiangiogenic mAb with efficacy against several cancers, but it is associated with risk of arterial thromboembolism (ATE). Further data are needed to determine the safety of bevacizumab. We recorded grade 3, 4, or 5 ATE events and other data (including age, baseline cardiovascular risk factors, history of ATE, and aspirin use) from 471 patients with metastatic colorectal cancer in the MAX (Mitomycin, Avastin, Xeloda) trial of capecitabine monotherapy versus capecitabine with bevacizumab with or without mitomycin C. Bevacizumab-treated patients had 12 grade 3, 4, or 5 ATEs (3.8% incidence). ATEs occurred in 2.1% of patients >65 years, 5% of those with a history of ATE, and 5% of those with cardiac risk factors. Age, history of ATE, or vascular risk factors did not increase risk. Aspirin users had a higher incidence than nonusers (8.9% versus 2.7%) but had higher rates of vascular risk factors. Bevacizumab was associated with a modestly higher risk of ATE, but safety was not significantly worse in older patients or patients with a history of ATE or vascular risk factors. The effect of aspirin in preventing ATE in patients receiving bevacizumab could not be determined from this study.
Publisher: Informa UK Limited
Date: 28-08-2017
DOI: 10.1080/14737140.2017.1369882
Abstract: Despite recent progress, the outlook for most patients with pancreatic cancer remains poor. There is variation in how patients are managed globally due to differing interpretations of the evidence, partly because studies in this disease are challenging to undertake. This article collates the evidence upon which current best practice is based and offers an expert opinion from an international faculty on how latest developments should influence current treatment paradigms. Areas covered: Optimal chemotherapy for first and subsequent lines of therapy optimal management of locally advanced, non-metastatic cancer including the role of neoadjuvant chemo(radio)therapy, current evidence for adjuvant chemotherapy, major advances in pancreatic cancer genomics and challenges in supportive care particularly relevant to patients with pancreatic cancer. For each section, literature was reviewed by comprehensive search techniques, including clinical trial websites and abstracts from international cancer meetings. Expert commentary: For each section, a commentary is provided. Overall the challenges identified were: difficulties in diagnosing pancreatic cancer early, challenges for performing randomised clinical trials in all stages of the disease, some progress in systemic therapy with new agents and in identifying molecular subtypes that may be clinically relevant and move towards personalized therapy, but still, pancreatic cancer remains a very poor prognosis cancer with significant palliative care needs.
Publisher: Spandidos Publications
Date: 30-03-2015
DOI: 10.3892/MCO.2015.533
Publisher: Springer Science and Business Media LLC
Date: 24-10-2012
DOI: 10.1038/NATURE11547
Publisher: American Society of Clinical Oncology (ASCO)
Date: 07-2016
Abstract: RAS mutations predict lack of response to epidermal growth factor receptor monoclonal antibody therapy in patients with metastatic colorectal cancer (mCRC), but preclinical studies and retrospective clinical data suggest that patients with tumors harboring the exon 2 KRAS G13D mutation may benefit from cetuximab. We aimed to assess cetuximab monotherapy and cetuximab plus irinotecan in patients with molecularly selected (G13D mutation) chemotherapy-refractory mCRC in a randomized phase II trial of this rare molecular subtype. Patients with chemotherapy-refractory KRAS G13D mutation–positive mCRC who had progressed within 6 months of irinotecan therapy were randomly assigned to cetuximab 400 mg/m 2 loading dose and then 250 mg/m 2 once per week with or without irinotecan 180 mg/m 2 once every 2 weeks. The primary end point was 6-month progression-free survival secondary end points were response rate, overall survival, quality of life, and toxicity. Fifty-one of 53 patients recruited over 2 years were eligible. The 6-month progression-free survival rate was 10% (95% CI, 2% to 26%) for cetuximab versus 23% (95% CI, 9% to 40%) for cetuximab plus irinotecan with a hazard ratio of 0.74 (95% CI, 0.42 to 1.32). Response and stable disease rates were 0% and 58% for monotherapy versus 9% and 70% for combination treatment, respectively. Overall survival and quality of life were similar toxicities were higher with combination therapy. In patients with G13D-mutated chemotherapy-refractory mCRC, there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan. No responses were seen with single-agent cetuximab. The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity. The ICECREAM (Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Among Patients with a G13D Mutation) study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2013
Abstract: In iduals with adenocarcinoma of the ulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ulla of Vater. Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34 95% CI, 1.69 to 6.62 P .001) and both validation cohorts (HR, 5.65 95% CI, 2.77 to 11.5 P .001 and HR, 2.78 95% CI, 1.25 to 7.17 P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.
Publisher: Wiley
Date: 06-2018
DOI: 10.1111/IMJ.13810
Abstract: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a lethal disease with a poor 5-year survival. Systemic treatments can be used to control symptoms and prolong life. Cytotoxic chemotherapies are commonly administered, with combination treatments, such as fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine showing the largest clinical benefits. Newer genomic classifications of PDAC may provide a rationale for targeted therapies or immunotherapies, although at present these remain largely experimental. This review discusses the evidence behind the currently used regimens, while introducing the potential future of pancreatic cancer care.
Publisher: Bentham Science Publishers Ltd.
Date: 05-08-2015
DOI: 10.2174/1568009615666150512102957
Abstract: Sirtuin 1 is a protein deacetylase that regulates a large number of proteins often functionally implicated in tumor development and progression. Its pleiotropic function has turned SIRT1 into an attractive chemotherapeutic target, underscored by very promising preclinical results with SIRT1 inhibitors in the treatment of chronic myeloid leukemia. Here, we revisit the studies on SIRT1 as an emerging target for therapy in pancreatic cancer, a tumor with dismal outcomes for which currently few therapeutic options are available. We highlight those potential SIRT1 target genes that are commonly affected in pancreatic cancer according to recent genomic analyses.
Publisher: Bioscientifica
Date: 1992
Abstract: Mature boar spermatozoa oxidized glycerol to carbon dioxide in the absence of any detectable activity of glycerol kinase. With triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase inhibited by the presence of 3-chloro-1-hydroxypropanone (CHOP), dihydroxyacetone phosphate accumulated in incubates when glycerol-3-phosphate was the substrate, but not when it was glycerol. Both dihydroxyacetone and glyceraldehyde could be used as substrates in the presence of CHOP, dihydroxyacetone phosphate and fructose-1,6-bisphosphate accumulated when dihydroxyacetone was the substrate, but not when it was glyceraldehyde. The metabolic pathways glycerol----glyceraldehyde----glyceraldehyde 3-phosphate and dihydroxyacetone----dihydroxyacetone phosphate have been shown to operate in these cells.
Publisher: Springer Science and Business Media LLC
Date: 27-09-2017
DOI: 10.1038/NATURE24026
Abstract: This corrects the article DOI: 10.1038/nature21063.
Publisher: Springer Science and Business Media LLC
Date: 31-05-2016
Publisher: BMJ
Date: 28-10-2017
DOI: 10.1136/GUTJNL-2017-315144
Abstract: Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts ( specimens). Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.
Publisher: Springer Science and Business Media LLC
Date: 11-2017
DOI: 10.1038/NATURE24462
Publisher: Wiley
Date: 20-03-2018
Publisher: Baishideng Publishing Group Inc.
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/GM482
Publisher: Wiley
Date: 09-09-1992
Abstract: The polymerase chain reaction (PCR) was used to investigate the prevalence and distribution of human papillomavirus (HPV)-16 DNA in paraffin sections of all pelvic lymph nodes removed from 14 patients with Stage Ib-cervical cancer at the time of resection of their primary tumours. The results were compared with those obtained from 8 women with no known history of cervical abnormality. In all, 22 cervical biopsies and 40 I lymph nodes (296 paraffin blocks) were examined. Nine of the 14 cervical cancer patients had primary tumours that were positive for HPV-16 DNA: only 3 of these had lymph nodes with histological evidence of metastasis, and HPV 16 DNA was detected in each of the corresponding paraffin blocks. HPV 16 DNA was also detected in varying proportions (8%-92%) of the histologically-negative lymph nodes from these women. There was no correlation between the HPV DNA-positive lymph nodes and their proximity to the primary tumour. HPV-16 DNA was not identified in any of the lymph nodes from the 5 women whose cancers were not HPV-16-related, or in those of women with no evidence of cervical abnormality. This preliminary survey suggests that HPV DNA is frequently transported from HPV-16-related cervical tumours to regional lymph nodes. However, its practical significance will not be clear until sufficient time has elapsed for correlation of the results with the clinical outcome.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2017
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.CANLET.2013.08.015
Abstract: Chronic pancreatitis predisposes to pancreatic cancer development and both diseases share a common etiology. A central role has been proposed for the digestive enzyme-secreting acinar cell that can undergo ductal metaplasia in the inflammatory environment of pancreatitis. This metaplastic change is now a recognised precursor of pancreatic cancer. Inflammatory molecules also foster tumour growth through autocrine and paracrine effects in the epithelium and the stroma. These insights have raised new opportunities such as the manipulation of inflammation as a preventive and/or therapeutic strategy for pancreatic cancer. Finally, we address the need for an in-depth study of the pancreatic acinar cells.
No related grants have been discovered for Lorraine Chantrill.