Publications by authors named "Paul Harnett"

92 Publications

Policies are Needed to Increase the Reach and Impact of Evidence-Based Parenting Supports: A Call for a Population-Based Approach to Supporting Parents, Children, and Families.

Child Psychiatry Hum Dev 2022 Jan 6. Epub 2022 Jan 6.

Parenting and Family Support Centre, School of Psychology, The University of Queensland, Brisbane, QLD, Australia.

Parents can be essential change-agents in their children's lives. To support parents in their parenting role, a range of programs have been developed and evaluated. In this paper, we provide an overview of the evidence for the effectiveness of parenting interventions for parents and children across a range of outcomes, including child and adolescent mental and physical health, child and adolescent competencies and academic outcomes, parental skills and competencies, parental wellbeing and mental health, and prevention of child maltreatment and family violence. Although there is extensive research showing the effectiveness of evidence-based parenting programs, these are not yet widely available at a population level and many parents are unable to access support. We outline how to achieve increased reach of evidence-based parenting supports, highlighting the policy imperative to adequately support the use of these supports as a way to address high priority mental health, physical health, and social problems.
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http://dx.doi.org/10.1007/s10578-021-01309-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733919PMC
January 2022

Validated biomarker assays confirm ARID1A loss is confounded with MMR deficiency, CD8 TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas.

J Pathol 2021 Dec 13. Epub 2021 Dec 13.

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

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1,623 endometriosis-associated ovarian carcinomas, including 1,078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumour-infiltrating lymphocytes (CD8+ TIL), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOC and 25% of ENOC. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p = 0.012), and associated with MMRd (p < 0.001), and presence of CD8+ TIL (p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOC we also observed an association between ARID1A loss-of-function mutation as a result of small indels (p = 0.035, versus single nucleotide variants). In ENOC, the association between ARID1A loss, CD8+ TIL, and age, appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/path.5849DOI Listing
December 2021

Impact of the EndoPredict genomic assay on treatment decisions for oestrogen receptor-positive early breast cancer patients: benefits of physician selective testing.

Breast Cancer Res Treat 2021 Dec 1. Epub 2021 Dec 1.

Westmead Breast Cancer Institute, Westmead, NSW, 2145, Australia.

Purpose: Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application.

Methods: Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team.

Results: 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p < 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p < 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p < 0.001) were the strongest discriminators of risk.

Conclusion: Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.
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http://dx.doi.org/10.1007/s10549-021-06456-5DOI Listing
December 2021

MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma.

Virchows Arch 2021 Nov 15. Epub 2021 Nov 15.

Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
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http://dx.doi.org/10.1007/s00428-021-03232-0DOI Listing
November 2021

Developing a maturity model for cancer multidisciplinary teams.

Int J Med Inform 2021 12 4;156:104610. Epub 2021 Oct 4.

Sydney West Translational Cancer Research Centre, Western Sydney Local Health District, Westmead NSW 2145, Australia; Western Sydney Local Health District, Westmead NSW 2145, Australia. Electronic address:

Background: Multidisciplinary teams (MDTs) are considered the "gold standard" of care for patients with cancer but how well they function and the role they play in decision making varies widely. Although several observational tools have been developed to evaluate MDT performance, they are resource intensive and only assess MDT performance at a static point in time. The aim of this study was to develop a validated maturity model as a self-assessment instrument for MDTs to evaluate their performance and monitor improvement over time.

Methods: The authors used a three-phase methodology to develop a maturity model. In the first phase, using a modified Delphi technique, we identified 20 indicators (within five components), each having five levels of maturity [1]. In the second phase, further Delphi iterations were undertaken to refine the content and structure of the model. By the end of the second phase six components and 17 indicators had been established. In the third phase, the refined model was distributed to members from 11 MDTs to test for validity and reliability. 101 valid responses were received. Principal Component Analysis was used to determine the optimal number of components that fit the indicators. Factors with eigenvalue greater than one were extracted. Cronbach's alpha (α) was used to measure the internal consistency of components. Bivariate correlation analysis, measuring pair-wise relationships between indicators (r), was undertaken to assess convergent and discriminant validity.

Results: Five factors were extracted from Principal Component Analysis. For the factors extracted, 16 out of 17 indicators showed loadings greater than the 0.4 threshold. All components demonstrated good levels of internal consistency (α > 0.8) and convergent validity (r > 0.6). Discriminant validity cannot be established. Ratings for ease of use (3.6/5) and usefulness (3.4/5) were considered acceptable.

Conclusions: Further work is required to establish discriminant validity and refine the components and indicators. Once further refinement and validation are completed, the maturity model should be a simple tool for MDTs to measure their performance and monitor improvement over time.
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http://dx.doi.org/10.1016/j.ijmedinf.2021.104610DOI Listing
December 2021

New therapeutic opportunities for women with low-grade serous ovarian cancer.

Endocr Relat Cancer 2021 Nov 11;29(1):R1-R16. Epub 2021 Nov 11.

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

Low-grade serous ovarian cancer (LGSC) is a morphologically and molecularly distinct subtype of ovarian cancer, accounting for ~10% of serous carcinomas. Women typically present at a younger age and have a protracted clinical course compared with the more common, high-grade serous ovarian cancer. Currently, the primary treatment of LGSC is the same as other epithelial ovarian cancer subtypes, with treatment for most patients comprised of debulking surgery and platinum/taxane chemotherapy. Primary surgical cytoreduction to no visible residual disease remains a key prognostic factor; however, the use of platinum-based chemotherapy in both upfront and relapsed setting is being questioned due to low response rates in LGSC. Most LGSC expresses steroid hormone receptors, and selected patients may benefit from endocrine maintenance therapy following chemotherapy, in particular, those with evidence of residual disease at completion of surgery. In the recurrent setting, while hormonal therapies may offer disease stabilisation with relatively low toxicity, objective response rates remain low. Strategies to increase response rates, including combining with CDK4/6 inhibitors, are being investigated. LGSC has a high prevalence of activating somatic mutations in mitogen-activated protein kinase pathway genes, most commonly in KRAS, BRAF and NRAS. Trametinib, a MEK inhibitor, has shown efficacy over chemotherapy and endocrine therapy. The use of combination targeted therapies, immunotherapy and anti-angiogenic agents, remain active areas of investigation for the treatment of LGSC.
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http://dx.doi.org/10.1530/ERC-21-0191DOI Listing
November 2021

The impact of posttraumatic stress disorder on the psychological distress, positivity, and well-being of Australian police officers.

Psychol Trauma 2021 Sep 30. Epub 2021 Sep 30.

National Centre for Youth Substance Use Research.

Objective: Police officers experience many traumatic events over the course of their career, often resulting in posttraumatic stress disorder (PTSD) and associated psychological distress. Studies have investigated the efficacy of interventions aimed at reducing symptoms of PTSD experienced by police officers, but lacking are studies investigating the impact of PTSD on positivity, a construct we define as a latent variable estimated using self-report measures of optimism, gratitude, self-compassion, and mindfulness. The present study carried out a path analysis of a model testing the hypothesis that PTSD would be associated with increased psychological distress and decreased positivity, both of which influence well-being. The model also evaluated associations between constructs that could be modified through interventions to increase well-being-associations between posttraumatic growth, social support, physical activity and psychological distress, positivity, and well-being.

Method: Police officers ( = 506) completed an online survey that included self-report measures of the constructs included in the model being tested.

Results: The model tested produced fit indices of root mean square error of approximation (RMSEA) = .089; comparative fit index (CFI) = .960; Tucker-Lewis index (TLI) = .93; standardized root mean square residual (SRMR) = .041 and ² = .79. Results found that neither PTSD or psychological distress had a direct effect on well-being. Psychological distress indirectly influenced well-being by lowering levels of positivity, while positivity was associated with higher scores on the measure of well-being.

Conclusions: The implication of the results is that interventions aimed at enhancing positivity could be expected to improve well-being in police officers and offering traditional therapies together with positivity enhancing therapies may have additional benefits over either alone. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/tra0001136DOI Listing
September 2021

Maximum Tolerated Dose and Anti-Tumor Activity of Intraperitoneal Cantrixil (TRX-E-002-1) in Patients with Persistent or Recurrent Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer: Phase I Study Results.

Cancers (Basel) 2021 Jun 26;13(13). Epub 2021 Jun 26.

Lifespan Cancer Institute, Providence, RI 02913, USA.

Survival outcomes in ovarian cancer are poor. The aims of this Phase I progressive design study (NCT02903771) were to evaluate the maximum tolerated dose (MTD), tolerability, and antitumor activity of Cantrixil-a novel third-generation benzopyran molecule-in patients ( = 25) with advanced, recurrent/persistent epithelial ovarian, primary peritoneal, or fallopian tube cancer. All had completed ≥ 2 prior regimens; 3 (12%) had platinum-refractory disease, and 17 (68%) had platinum-resistant disease. Following intraperitoneal (IP) port placement, patients received weekly IP Cantrixil in 3-week cycles as monotherapy (Cycles 1-2), and then in combination with intravenous (IV) chemotherapy (Cycles 3-8). Part A (dose escalation) enrolled 11 patients in 6 dose-level cohorts. An MTD of 5 mg/kg was established with dose-limiting toxicity of ileus. Most treatment-related adverse events were gastrointestinal. Across Parts A and B (dose expansion), 16 (64%) patients received ≥ 1 3-week Cantrixil cycle, and had ≥ 1 post-baseline efficacy measurement available. The results show promising anti-tumor activity in monotherapy (stable disease rate of 56%) and in combination with IV chemotherapy (objective response rate of 19%, disease control rate of 56%, and median progression-free survival of 13.1 weeks). The molecular target and mechanism of action of Cantrixil are yet to be confirmed. Preliminary analysis of stem cell markers suggests that IP Cantrixil might induce ovarian cancer stem cell death and sensitize cells to standard chemotherapy, warranting further evaluation.
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http://dx.doi.org/10.3390/cancers13133196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268018PMC
June 2021

Moderators and mediators of outcomes of parents with substance use problems: further evaluation of the Parents under Pressure programme.

Addiction 2021 11 7;116(11):3206-3218. Epub 2021 Jun 7.

Department of Social Policy and Intervention, University of Oxford, Oxford, UK.

Background And Aims: Family-focused interventions can improve family functioning when parents have substance use problems. However, there has been little focus upon potential predictors of change and analysis of mechanisms of change. This study aims to identify mediators and moderators of change in a pragmatic, multi-site, randomized controlled trial of the Parents under Pressure (PuP) programme, a family-focused intervention for parents with substance use and other problems, and treatment-as-usual (TAU).

Design: Secondary analysis of data: multi-level modelling was used to investigate moderators of treatment outcome; mediation was tested with cross-lagged models.

Setting: Community-based family support services in the United Kingdom.

Participants: Parents (n = 100) attending community-based addiction services with children aged 2.5 years or younger.

Measurements: Predictors of the primary outcome, child abuse potential, were: baseline child age and gender, composite family risk score, parental substance use and parental emotional dysregulation. Mediation was tested across three time-points with the observed variables parental emotion dysregulation and child abuse potential.

Findings: Increased child age [Z = 2.14, 95% confidence interval (CI) = 0.01, 0.33] at baseline was associated with greater reductions in child abuse potential for PuP programme participants compared with TAU. Poorer parental emotional regulation (Z = 2.48, 95% CI = -2.76, -0.32) was associated with greater reductions in child abuse potential for all participants. Parental substance use (either recent use or primary substance of concern) did not alter any treatment effects on child abuse potential. The mediation analysis showed that PuP produced greater improvements in emotional regulation at post-treatment (P < 0.001) compared with TAU, which predicted lower child abuse potential at 6-month follow up (P < 0.05).

Conclusions: For UK parents enrolled in a family-focused intervention, baseline measurements of higher child age appear to be associated with greater reductions in child abuse potential at 6-month follow-up in PuP participants compared with treatment as usual (TAU). Poorer parental emotional regulation and, potentially, higher family risk, appears to be associated with greater reductions in child abuse potential at 6-month follow-up in PuP and TAU. Emotional regulation appeared to act as a mediator as improvements in parental emotional regulation post-treatment appeared to be associated with greater reductions in child abuse potential at 6-month follow up. Notably, participation in the PuP programme led to better parental emotional regulation compared with TAU.
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http://dx.doi.org/10.1111/add.15579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518422PMC
November 2021

Improving Cancer MDT performance in Western Sydney - three years' experience.

BMC Health Serv Res 2021 Mar 6;21(1):203. Epub 2021 Mar 6.

Sydney West - Translational Cancer Research Centre, Western Sydney Local Health District, PO Box 533 Wentworthville, Sydney, NSW, 2145, Australia.

Background: While multidisciplinary teams (MDTs) are now considered an essential part of cancer care decision-making, how they perform varies widely. The authors hypothesised that a comprehensive, multipronged improvement program, and associated annual member survey, could strengthen MDT performance across a whole cancer service.

Methods: The study comprised the introduction of a structured program, the Tumour Program Strengthening Initiative (TPSI) linked with an annual survey of member's perceptions of their performance. Three iterations of the survey have been completed (2017, 2018 and 2019). Generalised estimating equations (GEEs) were used to test for a difference in the proportion of positive survey responses between 2017 and 2019 adjusted for team clustering.

Results: Twelve teams participated in TPSI. One hundred twenty-nine, 118 and 146 members completed the survey in 2017, 2018 and 2019, respectively. Of the 17 questions that were asked in all three years, nine showed significant improvement and, of these, five were highly significant. Documenting consensus, developing Terms of Reference (TORs), establishing referral criteria and referring to clinical practice guidelines showed most improvement. Questions related to patient considerations, professional development and quality improvement (QI) activities showed no significant change.

Conclusions: TPSI resulted in sustained and significant improvement. The MDT survey not only allowed MDT members to identify their strengths and weaknesses but also provided insights for management to flag priority areas for further support. Overall program improvement reflected the strengthening of the weakest teams as well as further improvement in highly performing MDTs. Importantly, the initiative has the potential to achieve behaviour change amongst clinicians.
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http://dx.doi.org/10.1186/s12913-021-06203-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937192PMC
March 2021

Developing an Intranet-Based Lymphedema Dashboard for Breast Cancer Multidisciplinary Teams: Design Research Study.

J Med Internet Res 2020 04 21;22(4):e13188. Epub 2020 Apr 21.

Research in Implementation Science and eHealth Group, Faculty of Health Sciences, The University of Sydney, Sydney, Australia.

Background: A large quantity of data is collected during the delivery of cancer care. However, once collected, these data are difficult for health professionals to access to support clinical decision making and performance review. There is a need for innovative tools that make clinical data more accessible to support health professionals in these activities. One approach for providing health professionals with access to clinical data is to create the infrastructure and interface for a clinical dashboard to make data accessible in a timely and relevant manner.

Objective: This study aimed to develop and evaluate 2 prototype dashboards for displaying data on the identification and management of lymphedema.

Methods: The study used a co-design framework to develop 2 prototype dashboards for use by health professionals delivering breast cancer care. The key feature of these dashboards was an approach for visualizing lymphedema patient cohort and individual patient data. This project began with 2 focus group sessions conducted with members of a breast cancer multidisciplinary team (n=33) and a breast cancer consumer (n=1) to establish clinically relevant and appropriate data for presentation and the visualization requirements for a dashboard. A series of fortnightly meetings over 6 months with an Advisory Committee (n=10) occurred to inform and refine the development of a static mock-up dashboard. This mock-up was then presented to representatives of the multidisciplinary team (n=3) to get preliminary feedback about the design and use of such dashboards. Feedback from these presentations was reviewed and used to inform the development of the interactive prototypes. A structured evaluation was conducted on the prototypes, using Think Aloud Protocol and semistructured interviews with representatives of the multidisciplinary team (n=5).

Results: Lymphedema was selected as a clinically relevant area for the prototype dashboards. A qualitative evaluation is reported for 5 health professionals. These participants were selected from 3 specialties: surgery (n=1), radiation oncology (n=2), and occupational therapy (n=2). Participants were able to complete the majority of tasks on the dashboard. Semistructured interview themes were categorized into engagement or enthusiasm for the dashboard, user experience, and data quality and completeness.

Conclusions: Findings from this study constitute the first report of a co-design process for creating a lymphedema dashboard for breast cancer health professionals. Health professionals are interested in the use of data visualization tools to make routinely collected clinical data more accessible. To be used effectively, dashboards need to be reliable and sourced from accurate and comprehensive data sets. While the co-design process used to develop the visualization tool proved effective for designing an individual patient dashboard, the complexity and accessibility of the data required for a cohort dashboard remained a challenge.
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http://dx.doi.org/10.2196/13188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201315PMC
April 2020

Bilateral acetabular fractures induced by an epileptic seizure in a paediatric patient: a unique case and its management.

BMJ Case Rep 2019 Aug 21;12(8). Epub 2019 Aug 21.

Trauma & Orthopaedic Surgery, King's College Hospital NHS Foundation Trust, London, UK.

Bilateral acetabular fractures following epileptic seizures are a rare but known occurrence in adults, with an 18.5% mortality rate. These fractures occurring post epileptic seizures have not been previously documented in children. We report a case of a 13-year-old boy who presented to hospital via ambulance following two violent generalised tonic-clonic seizures in a postictal state, metabolically acidotic and a low haemoglobin. Acute abdomen was suspected and the patient underwent a CT scan which showed bilateral acetabular fractures with central dislocations of both femoral heads and free fluid in the abdomen. The patient underwent initial damage control intervention with insertion of bilateral distal femur skeletal traction. Definitive fixation of the acetabular fractures occurred 1 week later with an open reduction internal fixation with novel supra-pectineal plates using a Pfannenstiel incision. We use this report to increase awareness of significant pelvic injuries in paediatric patients post epileptic seizures.
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http://dx.doi.org/10.1136/bcr-2019-230143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720713PMC
August 2019

Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial.

Lancet Oncol 2019 09 1;20(9):1306-1315. Epub 2019 Aug 1.

Westmead Hospital, Sydney, NSW, Australia.

Background: Rationale exists for combined treatment with immune checkpoint inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors in a variety of solid tumours. This study aimed to investigate the safety and antitumour effects of pamiparib, an oral PARP 1/2 inhibitor, combined with tislelizumab, a humanised anti-PD-1 monoclonal antibody, in patients with advanced solid tumours and to determine the optimum doses for further evaluation.

Methods: We did a multicentre, open-label, phase 1a/b study at five academic sites or community oncology centres in Australia. We recruited adults (aged ≥18 years) with advanced solid tumours who had received one or more previous lines of therapy, with an Eastern Cooperative Oncology Group performance score of 1 or less, and a life expectancy of 12 weeks or more. Patients were enrolled into one of five dose-escalation cohorts, with dose-escalation done in a 3 + 3 design. Cohorts 1-3 received intravenous tislelizumab 2 mg/kg every 3 weeks plus 20, 40, or 60 mg oral pamiparib twice daily, respectively; cohorts 4 and 5 received 200 mg intravenous tislelizumab every 3 weeks plus 40 or 60 mg oral pamiparib twice daily, respectively. The primary endpoints of the phase 1a dose-escalation part of the study were safety and tolerability, including the occurrence of dose-limiting toxicities and determination of the maximum tolerated dose and recommended phase 2 dose. All primary endpoints were analysed in the safety analysis set, which included all patients who received at least one dose of tislelizumab or pamiparib, with the exception of the occurrence of dose-limiting toxicities, which was analysed in the dose-limiting toxicity analysis set, which included all patients who received at least 90% of the first scheduled tislelizumab dose and at least 75% of scheduled pamiparib doses, or who had a dose-limiting toxicity event during cycle 1. Reported here are results of the phase 1a dose-escalation stage of the trial. This trial is registered with ClinicalTrials.gov, number NCT02660034, and is ongoing.

Findings: Between Jan 22, 2016, and May 16, 2017, we enrolled 49 patients (median age 63 years [IQR 55-67]), all of whom received at least one dose of pamiparib or tiselzumab. Four patients had dose-limiting toxicities (intractable grade 2 nausea [n=1] and grade 3 rash [n=1] in cohort 4, and grade 2 nausea and vomiting [n=1] and grade 4 immune-mediated hepatitis [n=1] in cohort 5). The recommended phase 2 dose was tislelizumab 200 mg every 3 weeks plus pamiparib 40 mg twice daily (the dose given in cohort 4). The most common treatment-emergent adverse events were nausea (in 31 [63%] of 49 patients), fatigue (26 [53%]), diarrhoea (17 [35%]), and vomiting (15 [31%]). 23 (47%) of 49 patients had immune-related adverse events, of whom nine (39%) had asymptomatic grade 3-4 hepatic immune-related adverse events, which were reversible with corticosteroid treatment. The most common adverse event of grade 3 or worse severity was anaemia (in six [12%] patients) and no grade 5 adverse events were reported. Hepatitis or autoimmune hepatitis was the only serious adverse event to occur in two or more patients (in four [8%] patients). At a median follow-up of 8·3 months (IQR 4·8-12·8), ten (20%) of 49 patients achieved an objective response according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, including two complete responses and eight partial responses.

Interpretation: Pamiparib with tislelizumab was generally well tolerated and associated with antitumour responses and clinical benefit in patients with advanced solid tumours supporting further investigation of the combination of pamiparib with tislelizumab.

Funding: BeiGene.
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http://dx.doi.org/10.1016/S1470-2045(19)30396-1DOI Listing
September 2019

A tool to improve the performance of multidisciplinary teams in cancer care.

BMJ Open Qual 2019 31;8(2):e000435. Epub 2019 May 31.

Western Sydney Local Health District, Sydney West Cancer Network, Sydney, New South Wales, Australia.

Introduction: While multidisciplinary teams (MDTs) are well established in many healthcare institutions, both how they function and their role in decision-making vary widely. This study adopted an innovative methodology to assess multidisciplinary team performance and engage teams in performance improvement strategies.

Methods: The study comprised a survey to evaluate MDT members' perceptions of their team's performance before the implementation of the programme and annually thereafter, and a maturity matrix designed as a self-assessment tool. Each MDT used the matrix to collectively assess its performance and identify areas for improvement.

Results: In the first cycle, 180 member surveys from 19 MDTs were completed. This provided insights into team members' perceptions of performance. 12 of these teams continued with the study and all 12 completed the matrix. Most teams rated themselves at level one or two (low) on a scale of five for most items.

Conclusions: The MDT survey and maturity matrix have the potential to be useful for cancer care teams to identify their strengths and weaknesses and monitor performance over time and also for management to review its performance against standard criteria and to identify priority areas for improvement and further support.
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http://dx.doi.org/10.1136/bmjoq-2018-000435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567949PMC
June 2020

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207534PMC
December 2019

An Investigation of the Impact of Childhood Trauma on Quality of Caregiving in High Risk Mothers: Does Maternal Substance Misuse Confer Additional Risk?

Child Psychiatry Hum Dev 2019 10;50(5):835-845

School of Applied Psychology, Griffith University, Mt Gravatt Campus, 176 Messines Ridge Road, Brisbane, QLD, 4122, Australia.

The quality of caregiving is often compromised when mothers have co-occurring difficulties such as substance misuse and problems associated with extreme emotional dysregulation. These, in turn, are associated with poor child outcomes. The aim of the current study was twofold. First, to investigate the potential differences in risk factors associated with poor child outcome by comparing three groups: substance misusing mothers (Substance Misusing Mothers; SMM); mothers matched on demographic characteristics (Matched Comparison Mothers; MCM) and mothers recruited from the community (Matched Control Comparison; MCC). Second, to investigate the underlying mechanisms which are associated with poor child outcome by testing a mediated moderation model to ascertain (i) whether environmental risk and borderline psychopathology was a mediator between maternal childhood trauma and quality of caregiving and (ii) maternal substance misuse status moderated outcome. There were no significant differences found between the SMM and MCM groups on the key variables, but significant differences on all variables for both SMM and MCM compared to CCM. The moderated mediation analysis found that while there was significant mediation of environmental risk and borderline pathology between maternal childhood trauma and child outcome, this was not moderated by maternal substance abuse status. The importance of environmental-risk as a mechanism leading to reduced caregiving quality suggest treatment programs need to consider targeting these factors in high risk families.
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http://dx.doi.org/10.1007/s10578-019-00886-5DOI Listing
October 2019

Attitudes of health professionals to using routinely collected clinical data for performance feedback and personalised professional development.

Med J Aust 2019 04;210 Suppl 6:S17-S21

Westmead Hospital, Sydney, NSW.

Objectives: To learn the attitudes of health professionals, health informaticians and information communication technology professionals to using data in electronic health records (eHRs) for performance feedback and professional development.

Design: Qualitative research in a co-design framework. Health professionals' perceptions of the accessibility of data in eHRs, and barriers to and enablers of using these data in performance feedback and professional development were explored in co-design workshops. Audio recordings of the workshops were transcribed, de-identified, and thematically analysed.

Setting, Participants: A total of nine co-design workshops were held in two major public hospitals in Sydney: three for nursing staff (ten participants), three for doctors (15 participants), and one each for information communication technology professionals (six participants), health informaticians (four participants), and allied health professionals (13 participants).

Main Outcome Measures: Key themes related to attitudes of participants to the secondary use of eHR data for improving health care practice.

Results: Six themes emerged from the discussions in the workshops: enthusiasm for feeding back clinical data; formative rather than punitive use; peer comparison, benchmarking, and collaborative learning; data access and use; capturing complex clinical narratives; and system design challenges. Barriers to secondary use of eHR data included access to information, measuring performance on the basis of eHR data, and technical questions.

Conclusions: Our findings will inform the development of programs designed to utilise routinely collected eHR data for performance feedback and professional development.
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http://dx.doi.org/10.5694/mja2.50022DOI Listing
April 2019

Testing the biosocial cognitive model of substance use in cannabis users referred to treatment.

Drug Alcohol Depend 2019 01 6;194:216-224. Epub 2018 Nov 6.

Centre for Youth Substance Abuse Research, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; Alcohol and Drug Assessment Unit, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia. Electronic address:

Background: The bioSocial Cognitive Theory (bSCT) hypothesizes two pathways linking dimensions of impulsivity to substance use. The first predicts that the association between reward sensitivity and substance use is mediated by positive outcome expectancies. The second predicts that the relationship between rash impulsiveness and substance use is mediated by refusal self-efficacy. This model has received empirical support in studies of alcohol use. The present research provides the first application of bSCT to a cannabis treatment population and aims to extend its utility to understanding cannabis use and severity of dependence.

Design: 273 patients referred for cannabis treatment completed a clinical assessment that contained measures of interest.

Setting: A public hospital alcohol and drug clinic.

Measurements: The Sensitivity to Reward Scale, Dysfunctional Impulsivity Scale, Cannabis Expectancy Questionnaire, Cannabis Refusal Self-Efficacy Questionnaire and Severity of Dependence Scale-Cannabis were completed, along with measures of cannabis consumption.

Findings: The bSCT model provided a good fit to the data for cannabis use and severity of dependence outcomes. The association between reward sensitivity and each cannabis outcome was fully mediated by positive cannabis expectancies and cannabis refusal self-efficacy. The relationship between rash impulsiveness and each cannabis outcome was fully mediated by cannabis refusal self-efficacy.

Conclusions: Findings support the application of the bSCT model to cannabis use and dependence severity and highlight the important role of social cognitive mechanisms in understanding the association between impulsivity traits and these outcomes. The differential association of impulsivity traits to social cognition may assist targeted treatment efforts.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.09.032DOI Listing
January 2019

A randomized controlled trial and economic evaluation of the Parents Under Pressure program for parents in substance abuse treatment.

Drug Alcohol Depend 2019 01 3;194:184-194. Epub 2018 Nov 3.

School of Applied Psychology, Griffith University, Brisbane, Australia. Electronic address:

Background: There is growing interest in the provision of parenting support to substance misusing parents.

Methods: This pragmatic, multi-center randomized controlled trial compared an intensive one-to-one parenting program (Parents under Pressure, PuP) with Treatment as Usual (TAU) in the UK. Parents were engaged in community-based substance misuse services and were primary caregivers of children less than 2.5 years of age. The primary outcome was child abuse potential, and secondary outcomes included measures of parental emotional regulation assessed at baseline, 6 and 12-months. A prospective economic evaluation was also conducted.

Results: Of 127 eligible parents, 115 met the inclusion criteria, and subsequently parents were randomly assigned to receive PuP (n = 48) or TAU (n = 52). Child abuse potential was significantly improved in those receiving the PuP program while those in TAU showed a deterioration across time in both intent-to-treat (p < 0.03) and per-protocol analyses (p < 0.01). There was also significant reliable change (recovery/improvement) in 30.6% of the PuP group compared with 10.3% of the TAU group (p < 0.02), and deterioration in 3% compared with 18% (p < 0.02). The probability that the program is cost-effective was approximately 51.8% if decision-makers are willing to pay £1000 for a unit improvement in the primary outcome, increasing to 98.0% at a £20,000 cost-effectiveness threshold for this measure.

Conclusions: Up to one-third of substance dependent parents of children under 3-years of age can be supported to improve their parenting, using a modular, one-to-one parenting program. Further research is needed.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.08.044DOI Listing
January 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

Multidisciplinary teams and ICT: a qualitative study exploring the use of technology and its impact on multidisciplinary team meetings.

BMC Health Serv Res 2018 06 13;18(1):444. Epub 2018 Jun 13.

Faculty of Health Sciences, Charles Perkins Centre, The University of Sydney, Level 2, Charles Perkins Centre D17, Camperdown, NSW, Australia.

Background: Multidisciplinary teams (MDTs) are an integral component in the delivery of health care. This is particularly evident in the delivery of cancer care, where multidisciplinary teams are internationally recognized as the preferred method for service delivery. The use of health information systems and technology are key enabling factors for building the capacity of MDTs to engage in improvement and implementation projects but there is scant research on how MDTs make use of technology and information systems or the kinds of systems needed for them to undertake improvement and implementation research. This paper reports findings on how seven MDTs in cancer care utilized technological and information systems and the barriers and enabling factors that impacted on their uptake.

Methods: Seven multidisciplinary teams from two large metropolitan hospitals participated in the study. Qualitative methods including structured observations and semi structured interviews that explored how teams engaged in research and improvement activities were utilized. Participants were also observed and interviewed in relation to their use of data and health information systems. Findings were subject to content analysis and key themes were identified. Interviews were transcribed and de-identified and key themes were subsequently discussed with participants to allow for member checking and further clarification of findings.

Results: A total of 43 MDT meetings across seven tumor streams were observed. Of these, observation notes from 13 meetings contained direct references to emerging technologies and health information systems. Findings from 15 semi-structured interviews were also analyzed in relation to how MDTs used technology in weekly meetings, and the perceived impact of technology. Three broad themes emerged: (1) methods for data collection and use by MDTs, (2) the impact of technology on the MDT meeting environment, and (3) the impact of technology and information systems on clinical decision making.

Conclusion: The study demonstrates that real time data collection and imaging may improve patient centered care coordination. However, ICTs can be used sub-optimally by teams. We therefore urge additional research to identify the enabling factors that support better collection and use of outcome data from ICT.
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http://dx.doi.org/10.1186/s12913-018-3242-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001028PMC
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

Physiological self-regulation and mindfulness in children with a diagnosis of fetal alcohol spectrum disorder.

Dev Neurorehabil 2019 May 10;22(4):228-233. Epub 2018 Apr 10.

a School of Applied Psychology, Menzies Health Institute Queensland , Griffith University , Mt Gravatt , Queensland , Australia.

Objective: To explore the differences in baseline respiratory sinus arrhythmia (RSA) between children with fetal alcohol spectrum disorder (FASD) and typically developing children (TDC) and to investigate whether children with FASD have the capacity to engage in a brief mindfulness exercise.

Methods: Participants were 14 children with FASD and 20 TDC. RSA was measured at baseline, during, and following a mindfulness exercise. A mindfulness compliance checklist was completed to ascertain if children could follow the task instructions.

Results: Both groups obtained high scores on the mindfulness compliance checklist. There was a trend for children with FASD to have lower baseline RSA compared to TDC. Children in both groups demonstrated an increase in RSA during the mindfulness task.

Conclusions: Children with FASD could engage in a mindfulness task, and both groups showed an increase in RSA. Further research is needed to establish whether prolonged mindfulness practice could be beneficial.
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http://dx.doi.org/10.1080/17518423.2018.1461948DOI Listing
May 2019

Transducin-Like Enhancer of Split 3 (TLE3) Expression Is Associated with Taxane Sensitivity in Nonserous Ovarian Carcinoma in a Three-Cohort Study.

Cancer Epidemiol Biomarkers Prev 2018 06 12;27(6):680-688. Epub 2018 Mar 12.

Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland.

Chemoresistance is a major challenge in ovarian cancer treatment, resulting in poor survival rates. Identifying markers of treatment response is imperative for improving outcome while minimizing unnecessary side effects. We have previously demonstrated that expression of transducin-like enhancer of split 3 (TLE3) is associated with favorable progression-free survival in taxane-treated ovarian cancer patients with nonserous histology. The purpose of this study was to perform an independent evaluation of the association of TLE3 expression with response to taxane-based chemotherapy in nonserous ovarian cancer, to validate its role as a potential therapeutic response marker for taxane-based chemotherapy. We performed immunohistochemical staining of TLE3 on ovarian cancer specimens from the Australian Ovarian Cancer Study, the Westmead Gynaecological Oncology Biobank, and Memorial Sloan Kettering Cancer Center. Progression-free survival and overall survival were assessed to validate an association between TLE3 expression and response to taxane therapy that we previously observed in a smaller study. Expression of TLE3 was associated with favorable outcome only in patients who had received paclitaxel as part of their treatment regimen for both 3-year progression-free survival ( = 160; HR, 0.56; = 0.03) and 5-year overall survival (HR, 0.53; = 0.04). Further analysis revealed that the predictive association between TLE3 expression and outcome was strongest in tumors with clear cell histology. The association between high TLE3 expression and a favorable response to taxane-containing chemotherapy regimens was validated in patients with nonserous ovarian cancer. TLE3 expression may serve as a marker of chemosensitivity in taxane-treated patients with nonserous histologies. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-1101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984690PMC
June 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

Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss Are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer.

Clin Cancer Res 2018 02 23;24(3):569-580. Epub 2017 Oct 23.

Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Women with epithelial ovarian cancer generally have a poor prognosis; however, a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths. We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing. Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8 tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR deficiency and RB1 loss were correlated, and co-occurrence was significantly associated with prolonged survival. There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1621DOI Listing
February 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

A biosocial cognitive model of cannabis use in emerging adulthood.

Addict Behav 2018 Jan 18;76:229-235. Epub 2017 Aug 18.

Centre for Youth Substance Abuse Research, Faculty of Health Sciences, The University of Queensland, Brisbane, QLD 4029, Australia; Alcohol and Drug Assessment Unit, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia. Electronic address:

Objectives: The aim of this study was to test a new theoretical model of cannabis use incorporating biologically-based personality traits and social cognition. This biosocial cognitive theory (bSCT) has robust support in alcohol studies, but has not been applied to cannabis. The model proposes two pathways linking dimensions of impulsivity to cannabis use. The first predicts that the association between Reward Sensitivity (SR) and cannabis use is mediated by positive outcome expectancies. The second predicts that the relationship between Rash Impulsiveness (RI) and cannabis use is mediated by cannabis refusal self-efficacy. An extended version of this model was also tested and included a third pathway linking Punishment Sensitivity (SP) to cannabis use via higher negative outcome expectancies.

Method: Participants were 252 18-to-21-year-olds who completed questionnaires assessing cannabis use, personality and social cognition. Theoretical models were tested using structural equation modeling.

Results: The bSCT model provided a good fit to the data (CFI=0.95; RMSEA=0.07; SRMR=0.06). Positive cannabis expectancies and refusal self-efficacy partially mediated the association between SR and cannabis use (p<0.05). Cannabis refusal self-efficacy fully mediated the relationship between RI and cannabis use (p<0.05). The addition of a third SP pathway did not improve model fit.

Conclusions: Consistent with alcohol studies, the association between impulsivity and cannabis use is largely mediated by social cognition. The bSCT may provide novel insights to inform prevention and treatment of problematic cannabis use.
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http://dx.doi.org/10.1016/j.addbeh.2017.08.011DOI Listing
January 2018

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
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