Publications by authors named "Paul R Harnett"

25 Publications

  • Page 1 of 1

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Mod Pathol 2019 12 25;32(12):1834-1846. Epub 2019 Jun 25.

Department of Obstetrics and Gynecology, Sahlgrenska Cancer Center, Inst Clinical Scienses, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7/CK20/CDX2/PAX8. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.
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http://dx.doi.org/10.1038/s41379-019-0302-0DOI Listing
December 2019

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

J Pathol Clin Res 2018 10 21;4(4):250-261. Epub 2018 Sep 21.

Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
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http://dx.doi.org/10.1002/cjp2.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174617PMC
October 2018

Improved ovarian cancer EMT-CTC isolation by immunomagnetic targeting of epithelial EpCAM and mesenchymal N-cadherin.

J Circ Biomark 2018 Jan-Dec;7:1849454418782617. Epub 2018 Jun 24.

Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.

Epithelial cell adhesion molecule (EpCAM)-targeted capture remains the most common isolation strategy for circulating tumor cells (CTCs). However, epithelial-to-mesenchymal transition (EMT) leads to decreased epithelial EpCAM expression affecting the optimal CTC capture. In this study, we tested a cohort of ovarian cancer cell lines using flow cytometry to identify N-cadherin as the additional immunomagnetic cell surface target for ovarian cancer cell isolation. Combined immunomagnetic targeting of mesenchymal N-cadherin and epithelial EpCAM enriched CTCs from advanced ovarian cancer patient blood approximately three times more efficiently than targeting of EpCAM alone. We also show that more EMT-phenotype CTCs are captured by including N-cadherin targeting into CTC isolation protocols. However, after N-cadherin-based CTC isolation, in some blood samples of healthy individuals, we also observed the presence of cells expressing markers common to CTCs. Our data show that these "false positives" can be largely distinguished from CTCs as circulating endothelial cells (CECs) by vascular endothelial-cadherin co-staining. CEC counts are highly variable in patients and healthy controls. Our data demonstrate that a combination of EpCAM with N-cadherin-targeted isolation can improve CTC detection and widen the EMT-phenotype spectrum of captured CTCs.
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http://dx.doi.org/10.1177/1849454418782617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043919PMC
June 2018

Response rates to second-line platinum-based therapy in ovarian cancer patients challenge the clinical definition of platinum resistance.

Gynecol Oncol 2018 08 26;150(2):239-246. Epub 2018 May 26.

Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia. Electronic address:

Objective: The aim of this study was to compare response rates and survival in women with "platinum resistant" epithelial ovarian cancer (EOC) who received further platinum-based or non‑platinum chemotherapy for treatment at first relapse.

Methods: Patients with high-grade EOC (including fallopian tube and peritoneal cancer) of all histologies recruited to the Australian Ovarian Cancer Study (AOCS) and treated with platinum-based primary chemotherapy were included. Response to second-line chemotherapy, overall survival (OS) and survival after treatment for first progression (OS2) were determined in all histologies and separately in women with high-grade serous tumors.

Results: Of the 341 patients classified as platinum-resistant by the 6-month threshold, 243 (71%) were treated with chemotherapy at relapse. CA-125 response rates to platinum-based chemotherapy were significantly higher compared to non‑platinum chemotherapy (51% vs 21%, P < 0.001). Among patients with a platinum-free interval (PFI) of 3-6 months, OS2 in patients treated with platinum was significantly longer compared to individuals receiving non‑platinum-based treatment (median 17.67 months, 95% CI: 14.79-20.75 vs. 10.62 months, 95% CI: 8.02-12.72, P = 0.022). The patterns were similar when restricted to patients with high-grade serous histology. In patients with PFI <3 months, there was no significant difference in response or survival according to type of second-line treatment.

Conclusions: Our findings further question the use of a 6-month PFI as an arbitrary threshold for subsequent treatment decision-making. Some patients considered "platinum resistant" still derive clinical benefit from platinum-based chemotherapy. Biomarkers of platinum sensitivity are needed in clinical practice to identify potential responders who should be offered re-treatment with platinum.
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http://dx.doi.org/10.1016/j.ygyno.2018.05.020DOI Listing
August 2018

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

Mayo Clin Proc 2018 03;93(3):307-320

Department of Medical Oncology, Mayo Clinic, Rochester, MN.

Objective: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.

Patients And Methods: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong).

Results: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively).

Conclusion: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.
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http://dx.doi.org/10.1016/j.mayocp.2017.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870793PMC
March 2018

Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer.

Sci Rep 2018 01 24;8(1):1508. Epub 2018 Jan 24.

Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia.

Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 10, empirical P = 1.4 × 10), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10, empirical P = 1.3 × 10). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.
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http://dx.doi.org/10.1038/s41598-018-19590-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784122PMC
January 2018

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.

JAMA Oncol 2017 12;3(12):e173290

Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Germany and Institute of Pathology, University of Heidelberg, Heidelberg, Germany

Importance: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.

Objective: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer.

Design, Setting, And Participants: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.

Exposures: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.

Main Outcomes And Measures: Overall survival time.

Results: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.

Conclusions And Relevance: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.
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http://dx.doi.org/10.1001/jamaoncol.2017.3290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744673PMC
December 2017

and Mutations Co-occur and Cooperate in Low-Grade Serous Ovarian Carcinomas.

Cancer Res 2017 08 23;77(16):4268-4278. Epub 2017 Jun 23.

Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia.

Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator and in , and RAS pathway mutations were mutually exclusive; however, we found significant co-occurrence of mutations in and Missense mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant and proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2224DOI Listing
August 2017

Our Faustian pact with the digital world.

Lancet Oncol 2017 02;18(2):171-172

Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Crown Princess Mary Cancer Centre, Westmead, NSW, Australia.

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http://dx.doi.org/10.1016/S1470-2045(17)30005-0DOI Listing
February 2017

Serous ovarian and primary peritoneal cancers: A comparative analysis of clinico-pathological features, molecular subtypes and treatment outcome.

Gynecol Oncol 2016 Sep 18;142(3):458-64. Epub 2016 Jul 18.

The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia; Department of Gynecological Oncology, Westmead Hospital, Sydney, NSW, Australia. Electronic address:

Objective: Primary peritoneal cancer is rare and considered equivalent to stage III/IV ovarian cancer, but questions remain concerning its underlying biology, prognosis and optimal management.

Methods: Clinico-pathological and treatment details of primary peritoneal (n=120) and ovarian cancer (n=635) were obtained on women recruited to the Australian Ovarian Cancer Study. Log-rank test was used to compare survival and cox proportional hazards models were fitted to obtain hazard ratios and 95% confidence intervals, both unadjusted and adjusted for age, grade, FIGO stage, residual disease and treatment with neoadjuvant chemotherapy. Molecular subtype was determined by gene expression profiling using published data.

Results: Compared with advanced serous ovarian cancer, primary peritoneal cancer patients were older (mean age 65.5 vs. 60.2years, p<0.001), more often treated with neoadjuvant chemotherapy (38.4% vs. 11.4%, p<0.001). Gene expression profiling classified a substantially higher proportion of primary peritoneal carcinomas as C1 (mesenchymal, reactive stromal infiltration) subtype (70.6% vs. 32.1%, p=0.029), which was associated with lower complete surgical resection rate. Women with primary peritoneal cancer had significantly shorter progression-free (11.6 vs. 13.6months, p=0.007) and overall survival (31.7 vs. 39.8months, p=0.012). In multivariate analysis, residual disease and neoadjuvant chemotherapy were both independently associated with increased risk of progression and death.

Conclusions: Primary peritoneal cancer patients were more frequently treated with neoadjuvant chemotherapy and had inferior survival. Different tumor biology characterized by activated stromal fibrosis in primary peritoneal cancer may underlie the differences in treatment and clinical outcome.
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http://dx.doi.org/10.1016/j.ygyno.2016.06.023DOI Listing
September 2016

Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver.

Clin Cancer Res 2014 Dec 14;20(24):6618-30. Epub 2014 Oct 14.

Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia. Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. University of Sydney, Westmead Hospital, Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia.

Purpose: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies.

Experimental Design: We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling.

Results: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC.

Conclusion: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-1292DOI Listing
December 2014

Successful carboplatin desensitization by using omalizumab and paradoxical diminution of total IgE levels.

J Allergy Clin Immunol Pract 2014 Jan-Feb;2(1):105-6. Epub 2013 Oct 17.

Department of Immunology and Immunopathology, Institute for Clinical Pathology and Medical Research, Westmead Hospital, Westmead, Sydney, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2013.08.009DOI Listing
April 2014

Left ventricular systolic function in HER2/neu negative breast cancer patients treated with anthracycline chemotherapy: a comparative analysis of left ventricular ejection fraction and myocardial strain imaging over 12 months.

Eur J Cancer 2013 Nov 9;49(16):3396-403. Epub 2013 Aug 9.

Faculty of Health Science, University of Sydney, Lidcombe, NSW, Australia. Electronic address:

Aim: Anthracycline agents are undermined by their cardiotoxicity. As life expectancy following treatment is greatly improved, techniques that ensure early detection and timely management of cardiotoxicity are essential. The aim of the present study was to evaluate left ventricular (LV) systolic function with LV ejection fraction (LVEF) and two-dimensional myocardial strain up to 12 months after anthracycline chemotherapy, specifically in HER2/neu negative breast cancer patients.

Methods: Seventy-eight consecutive anthracycline naïve breast cancer patients were studied before and immediately after anthracycline chemotherapy. Fifty HER2/neu negative patients were studied over 12 months with serial echocardiograms at four time points. All patients were treated with standard regimens containing anthracyclines.

Results: Global systolic strain was significantly reduced immediately after, and 6 months after anthracyclines (-19.0 ± 2.3% to -17.5 ± 2.3% (P<0.001) and -18.2 ± 2.2% (P=0.01) respectively). A non-uniform reduction in strain was observed each time with relative sparing of the LV apex. LVEF remained largely unchanged at both time points. Global strain normalised by 12 months in the majority of patients. Persistently reduced strain was observed in 16% (n=8); these patients had a greater reduction in strain at 6 months (≤ -17.2%), and had received higher cumulative anthracycline doses.

Conclusion: Myocardial strain imaging is more sensitive than LVEF for the early detection and intermediate term monitoring of LV systolic function following anthracycline chemotherapy in HER2/neu negative breast cancer patients, and may aid in the development of improved monitoring protocols.
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http://dx.doi.org/10.1016/j.ejca.2013.06.046DOI Listing
November 2013

LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin.

Cancer Res 2012 Aug;72(16):4060-73

Cancer Genomics and Genetics Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-0203DOI Listing
August 2012

Altered left ventricular longitudinal diastolic function correlates with reduced systolic function immediately after anthracycline chemotherapy.

Eur Heart J Cardiovasc Imaging 2013 Mar 10;14(3):228-34. Epub 2012 Jul 10.

Faculty of Health Science, University of Sydney, Lidcombe, NSW, Australia.

Aims: The benefits from anthracycline chemotherapy are undermined by potentially life-threatening cardiotoxicity. Transthoracic echocardiography is the most commonly used method for monitoring cardiotoxicity, and centres on the measurement of left ventricular systolic function. The aim of this study was to utilize two-dimensional speckle tracking echocardiography (2DSTE) at baseline and immediately after anthracycline chemotherapy to investigate whether patients with significant changes in systolic function after anthracycline therapy would also develop alterations in diastolic parameters.

Methods And Results: Fifty-two women with histologically confirmed breast cancer were prospectively recruited. Echocardiograms were performed 1 week prior to and 1 week following chemotherapy (always before adjuvant trastuzumab or thoracic radiotherapy). Conventional Doppler, tissue velocity imaging (TVI), and 2DSTE were used to measure diastolic function. 2DSTE measurements included longitudinal diastolic strain, early (E-Sr), and late (A-Sr) myocardial strain rate. 2DSTE and left ventricular ejection fraction (LVEF) were used to measure longitudinal systolic function. Altered LV diastolic function (including E-Sr) was observed in the entire cohort after chemotherapy, with a differential reduction in participants with a post therapy LVEF <55%. Pre-chemotherapy systolic strain was found to predict reduced E-Sr post therapy (P = 0.04). Univariate predictors of E-Sr were LVEF post therapy (P = 0.049) and systolic strain post-therapy (P = 0.01). In a multivariate analysis, systolic strain after chemotherapy was the strongest independent predictor (P = 0.001).

Conclusion: Altered LV diastolic function was observed immediately after the administration of therapeutic doses of anthracycline chemotherapy. Furthermore, our analysis indicates that the changes in diastolic function are associated with reduced systolic function.
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http://dx.doi.org/10.1093/ehjci/jes139DOI Listing
March 2013

Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy.

Eur J Echocardiogr 2011 Dec 1;12(12):945-52. Epub 2011 Oct 1.

Faculty of Health Science, University of Sydney, Lidcombe Campus, 75 East Street, Lidcombe, NSW 2141, Australia.

Aims: The efficacy of anthracyclines is undermined by potential life-threatening cardiotoxicity. Cardiotoxicity is dependent upon several factors and the timing to its development is variable. Moreover, as adjuvant therapy with trastuzumab often follows, a close monitoring of cardiac function in those treated with anthracyclines is mandatory. Left ventricular ejection fraction (LVEF) by echocardiography is currently used for monitoring cardiotoxicity; however, LVEF has numerous limitations. Two-dimensional strain imaging may provide a more sensitive measure of altered LV systolic function, so the aim of the present study was to compare LVEF and LV systolic strain before and after anthracyclines.

Methods And Results: Fifty-two women with histologically confirmed breast cancer were prospectively studied. Echocardiographic LVEF (by Simpson's method), global and regional peak longitudinal, radial, and circumferential 2D systolic strain were measured 1 week before and 1 week after chemotherapy. Global and regional longitudinal LV systolic strain was significantly reduced after treatment; global longitudinal strain decreased from -17.7 to -16.3% (P < 0.01) with 48% of global measurements reduced by >10%. Global and regional radial LV systolic strain after treatment was also significantly reduced; global radial strain dropped from 40.5 to 34.5% (P < 0.01) with 59% of global measurements reduced by >10%. In contrast, no reduction in LVEF >10% after chemotherapy was observed.

Conclusion: Reduced LV systolic strain immediately after anthracycline treatment may indicate early impairment of myocardial function before detectable change in LVEF.
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http://dx.doi.org/10.1093/ejechocard/jer187DOI Listing
December 2011

Comparison of expression profiles in ovarian epithelium in vivo and ovarian cancer identifies novel candidate genes involved in disease pathogenesis.

PLoS One 2011 Mar 15;6(3):e17617. Epub 2011 Mar 15.

Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia.

Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute to the development of ovarian cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017617PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057977PMC
March 2011

Ankyrin repeat domain 1, ANKRD1, a novel determinant of cisplatin sensitivity expressed in ovarian cancer.

Clin Cancer Res 2008 Nov;14(21):6924-32

Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Australia.

Purpose: The standard of care for ovarian cancer includes platinum-based chemotherapy. It is not possible, however, to predict clinical platinum sensitivity or to design rational strategies to overcome resistance. We used a novel approach to identify altered gene expression associated with high sensitivity to cisplatin, to define novel targets to sensitize tumor cells to platins and ultimately improve the effectiveness of this widely used class of chemotherapeutics.

Experimental Design: Using differential display PCR, we identified genes differentially expressed in a mutagenized cell line with unusual sensitivity to cisplatin. The most highly differentially expressed gene was selected, and its role in determining cisplatin sensitivity was validated by gene transfection and small interfering RNA (siRNA) approaches, by association of expression levels with cisplatin sensitivity in cell lines, and by association of tumor expression levels with survival in a retrospective cohort of 71 patients with serous ovarian adenocarcinoma.

Results: The most highly differently expressed gene identified was ANKRD1, ankyrin repeat domain 1 (cardiac muscle). ANKRD1 mRNA levels were correlated with platinum sensitivity in cell lines, and most significantly, decreasing ANKRD1 using siRNA increased cisplatin sensitivity >2-fold. ANKRD1 was expressed in the majority of ovarian adenocarcinomas tested (62/71, 87%), and higher tumor levels of ANKRD1 were found in patients with worse outcome (overall survival, P=0.013).

Conclusions: These findings suggest that ANKRD1, a gene not previously associated with ovarian cancer or with response to chemotherapy, is associated with treatment outcome, and decreasing ANKRD1 expression, or function, is a potential strategy to sensitize tumors to platinum-based drugs.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-5189DOI Listing
November 2008

ABCB1 (MDR 1) polymorphisms and progression-free survival among women with ovarian cancer following paclitaxel/carboplatin chemotherapy.

Clin Cancer Res 2008 Sep;14(17):5594-601

Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

Purpose: The human ABCB1 gene encodes P-glycoprotein, which transports a broad range of anticancer drugs, including paclitaxel. Although the functional consequences of ABCB1 polymorphisms have been the subject of numerous studies, few have assessed the association with clinical outcome.

Experimental Design: We assessed the association between the 2677G>T/A, 3435C>T, and 1236C>T ABCB1 polymorphisms and progression-free and overall survival in 309 patients from the Australian Ovarian Cancer Study treated with paclitaxel/carboplatin and subsequently tested significant observations in an independent validation set.

Results: Women who carried the minor T/A alleles at the 2677G>T/A polymorphism were significantly less likely to relapse following treatment compared with homozygote GG carriers (P(Log-rank)=0.001) in the Australian Ovarian Cancer Study cohort. Subgroup analyses showed that this effect was limited to cases with residual disease 1 cm (P(Log-rank)=0.3). This effect was not confirmed in an independent validation set of carboplatin/paclitaxel-treated patients (n=278) using a higher residual disease cut point (
Conclusion: Our findings indicate that there is an effect of the 2677G>T/A polymorphism on progression-free survival in ovarian cancer patients who are treated with a taxane/carboplatin, which is dependent on the extent of residual disease, with a better prognosis for patients with the 2677T/A allele and minimal residual disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-0606DOI Listing
September 2008

Rupture of the intra-articular portion of the long head of the biceps associated with a symptomatic os acromiale.

Int J Shoulder Surg 2008 Jul;2(3):56-8

Department of Orthopaedics, Royal Free Hampstead NHS, London, UK.

We report the case of a 45-year-old male who presented with a 5-year history of shoulder pain following an injury. Clinical and radiological investigations revealed a ruptured long head of the biceps and a meso-os acromiale. We performed an arthroscopic resection of the intra-articular stump of the long head of the biceps, followed by internal fixation of the mobile os acromiale using a tension band technique. Rupture of the long head of the biceps associated with a symptomatic os acromiale has not been previously described. This case reinforces the importance of routine shoulder arthroscopy in the treatment of symptomatic os acromiale.
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http://dx.doi.org/10.4103/0973-6042.42578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840822PMC
July 2008

Managing quality in cancer services: why improvement isn't easy.

Aust Health Rev 2005 Nov;29(4):406-15

Centre for Health Services Management, University of Technology, PO Box 123, Broadway, Sydney, NSW.

Optimising the quality of care is an imperative for health services worldwide, including in Australia. Recognition that poor quality often has its roots in system failures is beginning to shift strategies for improvement to the systems of care, although the tendency remains to focus on eliminating the practice variations of individual clinicians. In those instances where systems improvement is addressed, strategies tend to be generic and technical, and often unrelated to the context in which they are applied. This paper reports an interim evaluation of a quality management program in cancer services implemented in a Sydney metropolitan teaching hospital dispersed across multiple campuses. The paper aims to inform the debate on quality improvement by reporting not only on what was achieved, but why change seems to be so hard. We found that organisational and social factors that influence the quality of health services were not sufficiently addressed, compared with technical factors. We conclude that service quality needs to be repositioned as an organisational goal, and implemented via a structured process that addresses organisational and social factors, as well as technical factors.
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http://dx.doi.org/10.1071/ah050406DOI Listing
November 2005

MRP2 (ABCC2) and cisplatin sensitivity in hepatocytes and human ovarian carcinoma.

Gynecol Oncol 2006 Feb 5;100(2):239-46. Epub 2005 Oct 5.

Department of Gynaecological Oncology, Westmead Hospital, University of Sydney at Westmead Millennium Institute, WESTMEAD, NSW 2145, Australia.

Objective: The ABC transporter MRP2 (ABCC2) can mediate cisplatin efflux, and over-expression of MRP2 has been associated with cisplatin resistance in cancer cell lines. The aim of this study was to determine the role of MRP2 in modulating cisplatin cytotoxicity in normal cells as well as the relationship between MRP2 expression and clinical response to platinum-based agents in ovarian cancer.

Methods: The effect of absence of MRP2 expression on cisplatin sensitivity was investigated using primary hepatocyte cultures from the TR- rat strain, which is deficient in Mrp2. We also examined MRP2 expression immunohistochemically in human ovarian tumors exhibiting extremes of clinical response to platinum-based chemotherapy, either absolute platin resistance or patients with residual disease after surgery who experienced extremely long complete response to primary platinum-based chemotherapy.

Results: Primary hepatocyte cultures from Mrp2-deficient TR- rats were over threefold more sensitive to cisplatin and accumulated a twofold greater amount of platinum on DNA that wild-type rat hepatocytes. In human ovarian carcinomas, MRP2 was detected by immunohistochemistry in 3/13 (23%) tumors from patients with absolute platin resistance compared with 5/9 (56%) tumors from patients with prolonged survival following treatment including a platinum-based agent.

Conclusion: These studies indicate that MRP2 may play an important role in modulating normal tissue response to cisplatin. However, MRP2 expression occurred only in a subset of primary ovarian cancers, was frequently aberrant in location and was not correlated with clinical response to platinum-based chemotherapy.
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http://dx.doi.org/10.1016/j.ygyno.2005.08.046DOI Listing
February 2006

Expression of progesterone receptor A and B isoforms in low-grade endometrial stromal sarcoma.

Int J Gynecol Pathol 2004 Apr;23(2):138-44

Translational Oncology Westmead and Nepean Hospitals, Westmead, Australia.

The progesterone receptor (PR) exists as two isoforms, PRA and PRB. In vitro studies have shown that these proteins are functionally distinct, suggesting that their relative expression can influence progesterone response. Low-grade endometrial stromal sarcoma (LGESS) is an uncommon tumor that usually expresses PR. In normal endometrial stroma, both PR isoforms are present with PRA predominant throughout the menstrual cycle. The relative expression of PRA and PRB in LGESS has not been previously reported. All nine cases of primary LGESS (seven uterine, two extrauterine) expressed PRB. Eight tumors also contained PRA and it was the predominant isoform in seven cases. These tumors had similar histopathologic appearances, whereas a case with approximately equal PR isoform expression showed features of sex cord or smooth muscle differentiation. An extrauterine tumor expressing only PRB had myxoid stroma. Recurrent tumor in two cases, which expressed predominantly PRA in the primary, contained reduced levels of PR consisting predominantly or entirely of PRB after prolonged interval progestin therapy. Most primary LGESSs showed PR isoform expression similar to normal endometrial stroma, consistent with the highly differentiated phenotype of this tumor. Variant differentiation or disease recurrence was accompanied by an altered PR isoform profile that could impact on hormone response.
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http://dx.doi.org/10.1097/00004347-200404000-00008DOI Listing
April 2004

"But doctor, what have I got to lose...?".

J Clin Oncol 2003 May;21(9 Suppl):27s-29s

Department of Medical Oncology and Palliative Care, Westmead Hospital, Westmead, New South Wales, Australia.

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http://dx.doi.org/10.1200/JCO.2003.01.161DOI Listing
May 2003

Scientists and clinicians test their metal-back to the future with platinum compounds.

Lancet Oncol 2002 May;3(5):312-8

Department of Medical Oncology and Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead Hospital, NSW 2145, Australia.

After more than two decades of extensive use, drugs based on platinum continue to have a major role in cancer treatment. Although systematic approaches to the development of new analogues have produced agents with less toxicity and novel mechanisms of action, to date such approaches have not achieved more cures than can be achieved with the parent compound, cisplatin. Greater gains might be expected from accumulating knowledge about what makes cancer cells sensitive or resistant to platinum-based chemotherapy. Recent information on drug-efflux pathways, including expression of multidrug-resistance protein 2, and on how tumour cells behave when their DNA is distorted by a platinum adduct, suggests new avenues for translational research. The prospects include modulation of cellular handling of platinum compounds and individualised therapy based on expression of molecules that determine platinum sensitivity.
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http://dx.doi.org/10.1016/s1470-2045(02)00733-7DOI Listing
May 2002