Publications by authors named "Sarah J Lord"

86 Publications

Prognostic nomogram for progression-free survival in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer on maintenance olaparib therapy following response to chemotherapy.

Eur J Cancer 2021 Sep 19;154:190-200. Epub 2021 Jul 19.

National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, NSW 2050, Australia; Department of Medical Oncology, St George Hospital, Kogarah, NSW 2217, Australia; Australia New Zealand Gynecological Oncology Group, Camperdown, New South Wales, Australia.

Background: The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients.

Methods: The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib.

Results: The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3-11.3), 5.4 (4.8-5.8) and 2.9 (2.8-4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1-22.4) and 8.3 (7.1-10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot).

Conclusions: This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.06.024DOI Listing
September 2021

Trastuzumab emtansine for HER2-positive metastatic breast cancer: Outcomes from a whole-of-population Australian cohort.

Breast 2021 Aug 7;58:106-112. Epub 2021 May 7.

Medicines Policy Research Unit, Centre for Big Data Research in Health, UNSW, Sydney, Australia.

Purpose: We aim to describe the treatment patterns and overall survival (OS) outcomes in patients receiving trastuzumab emtansine (T-DM1) for HER2-positive metastatic breast cancer (HER2+MBC) in routine clinical care.

Methods: Retrospective, whole-of-population cohort study of people initiating T-DM1 for HER2+MBC between October 2015 and May 2019 in Australia. We used dispensing claims to estimate time-to-T-DM1 initiation, duration of treatment, and treatments administered prior to and following T-DM1 therapy. We estimated OS from T-DM1 initiation and stratified results based on whether patients received first- or second-line T-DM1 treatment. We benchmarked outcomes to those reported in the pivotal, EMILIA trial.

Results: 345 patients initiated T-DM1: 309 as second-line therapy for HER2+MBC and 36 as first-line therapy. 51% of patients had received endocrine therapy and 98% of second-line patients received pertuzumab prior to starting T-DM1. The median age was 57 years (53 in EMILIA); median time-to-T-DM1 initiation from start of HER2-targeted therapy for HER2+MBC was 11.6 months (IQR: 7.9-16.6); median duration of T-DM1 treatment was 6.5 months (3.1-13.5; 7.6 months in EMILIA), and median OS was 19.3 months (7.9-29.5; 29.9 months in EMILIA).

Conclusions: Our findings highlight differences in patient characteristics (older, more previous pertuzumab therapy) and outcomes (shorter OS) from the T-DM1 pivotal trial and provide real-world estimates that can inform patient, clinician and policy, decisions around the use of HER2-targeted therapies in routine clinical care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.breast.2021.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138859PMC
August 2021

Reporting the trajectories of adverse events over the entire treatment course in patients with recurrent platinum-sensitive ovarian cancer treated with platinum-based combination chemotherapy regimens: A graphical approach to trial adverse event reporting.

Eur J Cancer 2021 May 20;148:251-259. Epub 2021 Mar 20.

National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, NSW, 2050, Australia; Department of Medical Oncology, St George Hospital, Kogarah, NSW, 2217, Australia.

Background: Clinical trials report adverse events (AEs) in a dense table focusing on the frequency of 'worst grade' AEs experienced over the duration of treatment. There is usually no granular information provided on the timing and trajectory of AEs or whether they are likely to worsen, improve, or remain constant over time.

Patients And Methods: Non-hematologic (NH) AE data was extracted from the CALYPSO trial comparing carboplatin with pegylated liposomal doxorubicin (CD) to carboplatin with paclitaxel (CP) in recurrent ovarian cancer (ROC). Generalised estimating equations (GEE) were used to assess the risk and trajectory of combined Grade 2 or higher (G2+) AE and of each specific AE. The risk of G2+AE was also compared between treatment arms.

Results: The study included 976 patients and AE were reported for the duration of treatment. Most patients experienced at least one G2+NHAE (CP:CD, 96.0%:80.6%). Risk of combined G2+AE increased with CP (4.1% per-cycle) but decreased with CD (0.8%, P <0.01). When alopecia and sensory neuropathy were excluded, risk of G2+ AE decreased by 2.7% per-cycle, with no significant difference between treatment arms. G2+ nausea improved (15.2% per-cycle, P <0.01). G2+ sensory neuropathy worsened (29.3% per-cycle, P <0.01). Fatigue was stable (17% per-cycle, P =0.06) whilst G2+ pain decreased over time (13.4% per-cycle, P <0.01), with no difference between treatment arms.

Conclusion: Existing trial data can be used to provide AE trajectories as illustrated here for ROC. These trajectories have utility in guiding treatment choice and potentially optimising AE management with novel therapies and treatment combinations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.02.006DOI Listing
May 2021

Performance of Long-Term CT and PET/CT Surveillance for Detection of Distant Recurrence in Patients with Resected Stage IIIA-D Melanoma.

Ann Surg Oncol 2021 Aug 3;28(8):4561-4569. Epub 2021 Jan 3.

NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.

Background: Follow-up for patients with resected stage IIIA-D melanoma may include computed tomography (CT) or positron emission tomography (PET)/CT imaging to identify distant metastases. The aim of this study was to evaluate the test performance over follow-up time, of structured 6- and 12-monthly follow-up imaging schedules in these patients.

Methods: We conducted a retrospective analysis of consecutive resected stage IIIA-D melanoma patients from Melanoma Institute Australia (2000-2017). Patients were followed until a confirmed diagnosis of distant metastasis, end of follow-up schedule, or death. Test accuracy was evaluated by cross-classifying the results of the test against a composite reference standard of histopathology, cytology, radiologic imaging, and/or clinical follow-up, and then quantified longitudinally using logistic regression models with random effects.

Results: In total, 1373 imaging tests were performed among 332 patients. Distant metastases were detected in 110 (33%) patients during a median follow-up of 61 months (interquartile range 38-86), and first detected by imaging in 86 (78%) patients. 152 (68%) patients had at least one false-positive result. Sensitivity of the schedule over 5 years was 79% [95% confidence interval (CI) 70-86%] and specificity was 88% (95% CI 86-90%). There was no evidence of a significant difference in test performance over follow-up time or by American Joint Committee on Cancer (AJCC) substage. The positive predictive value ranged between 33 and 48% over follow-up time, reflecting a ratio of 1:2 false-positives per true-positive finding.

Conclusions: Regular 6- or 12-monthly surveillance imaging using CT or PET/CT has reasonable and consistent sensitivity and specificity over 5-year follow-up for resected stage IIIA-D melanoma patients. These data are useful when discussing the risks and benefits of long-term follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09270-3DOI Listing
August 2021

Setting minimum clinical performance specifications for tests based on disease prevalence and minimum acceptable positive and negative predictive values: Practical considerations applied to COVID-19 testing.

Clin Biochem 2021 Feb 20;88:18-22. Epub 2020 Nov 20.

Department of Clinical Chemistry, New South Wales Health Pathology, Prince of Wales Hospital, Sydney, Australia. Electronic address:

Objectives: Several guidelines for the evaluation of laboratory tests for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection have recommended establishing an a priori definition of minimum clinical performance specifications before test selection and method evaluation.

Methods: Using positive (PPV) and negative predictive values (NPV), we constructed a spreadsheet tool for determining the minimum clinical specificity (conditional on NPV or PPV, sensitivity and prevalence) and minimum clinical sensitivity (conditional on NPV or PPV, specificity and prevalence) of tests.

Results: At a prevalence of 1%, there are no minimum sensitivity requirements to achieve a desired NPV of 60%-95% for a given clinical specificity above 20%. It is not possible to achieve 60-95% PPV even with 100% clinical sensitivity, except when the clinical specificity is near 100%. The opposite trend is seen in high prevalence settings (60%), where a relatively low minimum clinical sensitivity is required to achieve a desired PPV for a given clinical specificity, and a higher minimum clinical specificity is required to achieve a desired NPV for a given clinical sensitivity.

Discussion: The selection of laboratory tests and the testing strategy for SARS-CoV-2 involves delicate trade-offs between NPV and PPV based on prevalence and clinical sensitivity and clinical specificity. Practitioners and health authorities should carefully consider the clinical scenarios under which the test result will be used and select the most appropriate testing strategy that fulfils the a priori defined clinical performance specification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinbiochem.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678449PMC
February 2021

Cost-effectiveness analysis of PET/CT surveillance imaging to detect systemic recurrence in resected stage III melanoma: study protocol.

BMJ Open 2020 11 5;10(11):e037857. Epub 2020 Nov 5.

NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia.

Introduction: In the new era of effective systemic therapies for advanced melanoma, early detection of lower volume recurrent disease using surveillance imaging can improve survival. However, intensive imaging follow-up strategies are likely to increase costs to health systems and may pose risks to patients. The objective of this study is to estimate from the Australian health system perspective the cost-effectiveness of four follow-up strategies in resected stage III melanoma over a 5-year period following surgical treatment with curative intent.

Methods And Analysis: A decision-analytic model will be built to estimate the costs and benefits of (1) 12 monthly, (2) 6 monthly, (3) 3-4 monthly positron emission tomography/CT imaging for 5 years, compared with (4) no imaging follow-up. The model will be populated with probabilities of disease recurrence, test performance measures using data from >1000 consecutive resected stage III melanoma patients from Melanoma Institute Australia diagnosed between 2000 and 2017. Healthcare resource use, including surveillance imaging, doctor's visits, subsequent tests and procedures to investigate suspicious findings, will be quantified from detailed patient records and valued using Australian reference pricing. Economic outcomes include cost per new distant melanoma recurrence detected and cost per diagnostic error avoided, for no imaging compared with the other strategies.Deterministic sensitivity analyses will examine the robustness of model results.

Ethics And Dissemination: This study was approved by the Sydney Local Health District, Sydney Local Health District Ethics Review Committee (RPAH Zone), AU/1/830638 and the Australian Institute of Health and Welfare (EO2019-1-454). The results of this study will be published in peer-reviewed medical and health economics journals and will inform melanoma management guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-037857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646332PMC
November 2020

Concordance between CA-125 and RECIST progression in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer treated in the SOLO2 trial with olaparib as maintenance therapy after response to chemotherapy.

Eur J Cancer 2020 11 23;139:59-67. Epub 2020 Sep 23.

Université Paris Descartes, Paris, France; ARCAGY-GINECO, France.

Background: Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo.

Methods: We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV).

Results: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90-99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45-59%). Within treatment arms, PPV was similar (olaparib: 95% [84-99%], placebo: 97% [87-100%]) but NPV was lower in patients on placebo (olaparib: 60% [52-68%], placebo: 30% [20-44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST.

Conclusions: Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.08.021DOI Listing
November 2020

The AEDUCATE Collaboration. Comprehensive antenatal education birth preparation programmes to reduce the rates of caesarean section in nulliparous women. Protocol for an individual participant data prospective meta-analysis.

BMJ Open 2020 09 23;10(9):e037175. Epub 2020 Sep 23.

NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, New South Wales, Australia.

Introduction: Rates of medical interventions in normal labour and birth are increasing. This prospective meta-analysis (PMA) proposes to assess whether the addition of a comprehensive multicomponent birth preparation programme reduces caesarean section (CS) in nulliparous women compared with standard hospital care. Additionally, do participant characteristics, intervention components or hospital characteristics modify the effectiveness of the programme? METHODS AND ANALYSIS: : women with singleton vertex pregnancies, no planned caesarean section (CS) or epidural.: in addition to hospital-based standard care, a comprehensive antenatal education programme that includes multiple components for birth preparation, addressing the three objectives: preparing women and their birth partner/support person for childbirth through education on physiological/hormonal birth (knowledge and understanding); building women's confidence through psychological preparation (positive mindset) and support their ability to birth without pain relief using evidence-based tools (tools and techniques). The intervention could occur in a hospital-based or community setting.: standard care alone in hospital-based maternity units.

Outcomes: : CS.: epidural analgesia, mode of birth, perineal trauma, postpartum haemorrhage, newborn resuscitation, psychosocial well-being.: parity, model of care, maternal risk status, maternal education, maternal socio-economic status, intervention components.

Study Design: An individual participant data (IPD) prospective meta-analysis (PMA) of randomised controlled trials, including cluster design. Each trial is conducted independently but share core protocol elements to contribute data to the PMA. Participating trials are deemed eligible for the PMA if their results are not yet known outside their Data Monitoring Committees.

Ethics And Dissemination: Participants in the individual trials will consent to participation, with respective trials receiving ethical approval by their local Human Research Ethics Committees. Individual datasets remain the property of trialists, and can be published prior to the publication of final PMA results. The overall data for meta-analysis will be held, analysed and published by the collaborative group, led by the Cochrane PMA group.

Trial Registration Number: CRD42020103857.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-037175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513601PMC
September 2020

Development and temporal validation of a prognostic model for 1-year clinical outcome after decompression surgery for lumbar disc herniation.

Eur Spine J 2020 07 27;29(7):1742-1751. Epub 2020 Feb 27.

Schulthess Klinik, Spine Center, Zurich, Switzerland.

Purpose: Surgeons need tools to provide individualised estimates of surgical outcomes and the uncertainty surrounding these, to convey realistic expectations to the patient. This study developed and validated prognostic models for patients undergoing surgical treatment of lumbar disc herniation, to predict outcomes 1 year after surgery, and implemented these models in an online prediction tool.

Methods: Using the data of 1244 patients from a large spine unit, LASSO and linear regression models were fitted with 90% upper prediction limits, to predict scores on the Core Outcome Measures Index, and back and leg pain. Candidate predictors included sociodemographic factors, baseline symptoms, medical history, and surgeon characteristics. Temporal validation was conducted on 364 more recent patients at the same unit, by examining the proportion of observed outcomes exceeding the threshold of the 90% upper prediction limit (UPL), and by calculating mean bias and other calibration measures.

Results: Poorer outcome was predicted by obesity, previous spine surgery, and having basic obligatory (rather than private) insurance. In the validation data, fewer than 12% of outcomes were above the 90% UPL. Calibration plots for the model validation showed values for mean bias < 0.5 score points and regression slopes close to 1.

Conclusion: While the model accuracy was good overall, the prediction intervals indicated considerable predictive uncertainty on the individual level. Implementation studies will assess the clinical usefulness of the online tool. Updating the models with additional predictors may improve the accuracy and precision of outcome predictions. These slides can be retrieved under Electronic Supplementary Material.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00586-020-06351-5DOI Listing
July 2020

Prediction of pre-eclampsia in nulliparous women using routinely collected maternal characteristics: a model development and validation study.

BMC Pregnancy Childbirth 2020 Jan 6;20(1):23. Epub 2020 Jan 6.

School of Medicine, The University of Notre Dame Australia, 160 Oxford Street, Darlinghurst, NSW, 2010, Australia.

Background: Guidelines recommend identifying in early pregnancy women at elevated risk of pre-eclampsia. The aim of this study was to develop and validate a pre-eclampsia risk prediction model for nulliparous women attending routine antenatal care "the Western Sydney (WS) model"; and to compare its performance with the National Institute of Health and Care Excellence (NICE) risk factor-list approach for classifying women as high-risk.

Methods: This retrospective cohort study included all nulliparous women who gave birth in three public hospitals in the Western-Sydney-Local-Health-District, Australia 2011-2014. Using births from 2011 to 2012, multivariable logistic regression incorporated established maternal risk factors to develop and internally validate the WS model. The WS model was then externally validated using births from 2013 to 2014, assessing its discrimination and calibration. We fitted the final WS model for all births from 2011 to 2014, and compared its accuracy in predicting pre-eclampsia with the NICE approach.

Results: Among 12,395 births to nulliparous women in 2011-2014, there were 293 (2.4%) pre-eclampsia events. The WS model included: maternal age, body mass index, ethnicity, multiple pregnancy, family history of pre-eclampsia, autoimmune disease, chronic hypertension and chronic renal disease. In the validation sample (6201 births), the model c-statistic was 0.70 (95% confidence interval 0.65-0.75). The observed:expected ratio for pre-eclampsia was 0.91, with a Hosmer-Lemeshow goodness-of-fit test p-value of 0.20. In the entire study sample of 12,395 births, 374 (3.0%) women had a WS model-estimated pre-eclampsia risk ≥8%, the pre-specified risk-threshold for considering aspirin prophylaxis. Of these, 54 (14.4%) developed pre-eclampsia (sensitivity 18% (14-23), specificity 97% (97-98)). Using the NICE approach, 1173 (9.5%) women were classified as high-risk, of which 107 (9.1%) developed pre-eclampsia (sensitivity 37% (31-42), specificity 91% (91-92)). The final model showed similar accuracy to the NICE approach when using lower risk-threshold of ≥4% to classify women as high-risk for pre-eclampsia.

Conclusion: The WS risk model that combines readily-available maternal characteristics achieved modest performance for prediction of pre-eclampsia in nulliparous women. The model did not outperform the NICE approach, but has the advantage of providing individualised absolute risk estimates, to assist with counselling, inform decisions for further testing, and consideration of aspirin prophylaxis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12884-019-2712-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945640PMC
January 2020

The association between ethnicity and pre-eclampsia in Australia: A multicentre retrospective cohort study.

Aust N Z J Obstet Gynaecol 2020 06 3;60(3):396-404. Epub 2019 Oct 3.

School of Medicine, The University of Notre Dame Australia, Sydney, New South Wales, Australia.

Background: Rates of pre-eclampsia vary between countries and certain ethnic groups. However, there is limited evidence about the impact of ethnicity on risk of pre-eclampsia, beyond established clinical risk factors.

Aims: To assess the association between ethnicity and pre-eclampsia in Australia's diverse multi-ethnic population.

Materials And Methods: We conducted a retrospective cohort study using the ObstetriX database. We included all women with a birth between January 2011 and December 2014, at Auburn, Blacktown/Mount-Druitt and Westmead Hospitals in the Western Sydney Local Health District. We estimated the pre-eclampsia rate overall, and by maternal ethnic group, defined by country of birth and primary language. We developed multivariable logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CIs) for pre-eclampsia, adjusting for maternal age, body mass index, autoimmune disease, chronic hypertension, chronic renal disease, diabetes mellitus (type 1 or 2), and multiple pregnancy. A secondary analysis was restricted to nulliparous women.

Results: There were 40 824 women evaluated, including 12 743 nulliparous women. Of these, 1448 (3.5%) developed pre-eclampsia (range: Australian/New Zealand-born English speakers 735/15 422 (4.8%); North-East Asian women 51/4470 (1.1%)). Relative to Australian/New Zealand-born English speakers, immigrants had a lower risk of pre-eclampsia overall (adjusted OR 0.67; 95% CI 0.60-0.75); as did the three largest immigrant groups examined: Southern Asian (0.73; 0.62-0.85), Middle-Eastern/African (0.55; 0.47-0.66) and North-East Asian (0.33; 0.25-0.45) women. Findings were similar for nulliparous women.

Conclusions: Certain immigrant groups are at lower risk of pre-eclampsia than Australian/New Zealand-born English-speaking women. Understanding why this is so may lead to better screening and preventive strategies in higher-risk women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajo.13069DOI Listing
June 2020

The impact of neutrophil-lymphocyte ratio on risk reclassification of patients with advanced renal cell cancer to guide risk-directed therapy.

Acta Oncol 2020 Jan 29;59(1):20-27. Epub 2019 Aug 29.

National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, Australia.

An elevated neutrophil-lymphocyte ratio (NLR) is associated with poor prognosis in advanced renal cell carcinoma (RCC). We examined whether the addition of NLR improves the risk reclassification of advanced RCC using current prognostic tools from the Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Using randomised data from the COMPARZ trial of first-line pazopanib vs. sunitinib in advanced RCC, we constructed multivariable models containing MSKCC and IMDC predictor variables with and without NLR. We evaluated model discrimination using the concordance index (C-index). We computed net reclassification improvement to quantify patient reclassification into low/intermediate/poor risk groups with the addition of NLR. Of 1102 patients, NLR ≥ 5 (16%) was associated with shorter survival adjusting for MSKCC variables (adjusted HR 1.89, < .001). Adding NLR to MSKCC variables increased the C-index by 0.01. Among patients who died before 24 months ( = 415), adding NLR reclassified 8% and 2% to a higher and lower risk category, respectively. Among those alive at 24 months ( = 636), adding NLR reclassified 4% and 1% to a higher and lower risk category, respectively. This finding translates to a net benefit of eight additional patients who die within 24 months correctly identified as poor risk per 1000 patients tested. We obtained similar results when evaluating NLR with IMDC variables. NLR does not substantially improve risk reclassification over pre-existing prognostic tools. MSKCC and IMDC classifications remain the standard for guiding risk-directed therapy and trial stratification of patients with advanced RCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/0284186X.2019.1656342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577380PMC
January 2020

Setting clinical performance specifications to develop and evaluate biomarkers for clinical use.

Ann Clin Biochem 2019 09 16;56(5):527-535. Epub 2019 Apr 16.

14 Department of Clinical Chemistry & Endocrinology, Prince of Wales Hospital, New South Wales Health Pathology and School of Medical Sciences, University of New South Wales, Randwick, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0004563219842265DOI Listing
September 2019

Metastatic breast cancer incidence, site and survival in Australia, 2001-2016: a population-based health record linkage study protocol.

BMJ Open 2019 02 1;9(2):e026414. Epub 2019 Feb 1.

Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales, Australia.

Introduction: Advances in systemic therapy for early and metastatic breast cancer (BC) over the last two decades have improved patients' survival, but their impact on metastatic disease outcomes at a population level is not well described. The aim of this study is to investigate changes in the incidence, site and survival of metastatic disease for women with a first diagnosis of BC in 2001-2002 vs 2006-2007.

Methods And Analysis: Population-based retrospective cohort study of women with first primary invasive BC registered in the New South Wales (NSW) Cancer Registry in 2001-2002 and 2006-2007. We will use linked records from NSW hospitals, dispensed medicines, outpatient services and death registrations to determine: women's demographic and tumour characteristics; treatments received; time to first distant metastasis; site of first metastasis and survival. We will use the Kaplan-Meier method to estimate cumulative incidence of distant metastasis, distant recurrence-free interval and postmetastasis survival by extent of disease at initial diagnosis, site of metastasis and treatment-defined tumour receptor type (hormone receptor-positive, human epidermal growth factor receptor-2-positive, triple negative). We will use Cox proportional hazards regression to estimate the relative effects of prognostic factors, and we will compare systemic therapy patterns by area-of-residence and area-level socioeconomic status to examine equity of access to healthcare.

Ethics And Dissemination: Research ethics committee approval was granted by the Australian Institute of Health and Welfare (#EO2017/2/255), NSW Population and Health Services (#HREC/17/CIPHS/19) and University of Notre Dame Australia (#0 17 144S). We will disseminate research findings to oncology, BC consumer and epidemiology audiences through national and international conference presentations, lay summaries to BC consumer groups and publications in international peer-reviewed oncology and cancer epidemiology journals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2018-026414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367965PMC
February 2019

Assessment of NICE and USPSTF guidelines for identifying women at high risk of pre-eclampsia for tailoring aspirin prophylaxis in pregnancy: An individual participant data meta-analysis.

Eur J Obstet Gynecol Reprod Biol 2018 Oct 2;229:159-166. Epub 2018 Sep 2.

School of Medicine, The University of Notre Dame Australia, Sydney, NSW, Australia; NHMRC Clinical Trial Centre, University of Sydney, Sydney, NSW, Australia. Electronic address:

Objective: To assess the accuracy of the National Institute of Health and Care Excellence (NICE) and United States Preventive Services Task Force (USPSTF) guidelines for predicting pre-eclampsia in pregnancy to guide aspirin prophylaxis.

Study Design: We conducted an individual participant data meta-analysis using the Perinatal Antiplatelet Review of International Studies (PARIS) dataset. This dataset includes randomised controlled trials (RCTs) of antiplatelet therapy for primary prevention of pre-eclampsia conducted in international antenatal care settings. RCTs were eligible if they enrolled pregnant women up to 28 weeks'gestation, reported risk factors, and assessed pre-eclampsia. Women assigned to the control arm (no antiplatelet agent) were included. Both guidelines recommend aspirin if ≥1 high-risk factors or ≥2 moderate-risk factors. Two moderate-risk factors (body mass index and pregnancy interval) were unavailable. Pre-eclampsia was the primary outcome. The secondary outcomes were pre-eclampsia defined by gestational age at delivery (<37 weeks versus ≥37 weeks; <34 weeks versus ≥34 weeks). We assessed the performance of the NICE and USPSTF approaches for parous and nulliparous women by estimating sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for predicting pre-eclampsia, the number-needed-to-screen (NNS) and the number-needed-to-treat (NNT) to prevent one pre-eclampsia event.

Results: Three RCTs were eligible (4524 women, 221 pre-eclampsia cases). Using the NICE guidelines, 9.4% of 1020 parous women were classified as screen-positive with a sensitivity of 26.4% (95% confidence interval 16.4-39.6%), specificity 91.5% (89.6-93.1%), PPV 14.6% (8.9-23.0%) and NPV 95.8% (94.3-96.9%). The NNS was 729 and NNT 69. For 3504 nulliparous women, 3% were classified as screen-positive with a sensitivity of 8.9% (5.5-14.4%), specificity 97.2% (96.6-97.8%), PPV 14.2% (8.7-21.9%), NPV 95.5% (94.8-96.1%). The NNS was 2336 and NNT 71. The USPSTF approach demonstrated similar performance.

Conclusion: The NICE and USPSTF guidelines offer a simple and specific approach for recommending aspirin prophylaxis for women at high-risk of pre-eclampsia where more advanced screening methods are not available. However, the low detection rate limits its value in clinical practice, in particular for nulliparous women, and raises the need for development of an improved simple risk prediction tool.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejogrb.2018.08.587DOI Listing
October 2018

Progression-free survival as a surrogate endpoint for overall survival in modern ovarian cancer trials: a meta-analysis.

Ther Adv Med Oncol 2018 6;10:1758835918788500. Epub 2018 Aug 6.

NHMRC Clinical Trials Centre, Australia New Zealand Gynaecological Oncology Group, University of Sydney, Camperdown, Australia.

Background: Progression-free survival (PFS) has been adopted as the primary endpoint in many randomized controlled trials, and can be determined much earlier than overall survival (OS). We investigated whether PFS is a good surrogate endpoint for OS in trials of first-line treatment for epithelial ovarian cancer (EOC), and whether this relationship has changed with the introduction of new treatment types.

Methods: In a meta-analysis, we identified summary data [hazard ratio (HR) and median time] from published randomized controlled trials. Linear regression was used to assess the association between treatment effects on PFS and OS overall, and for subgroups defined by treatment type, postprogression survival (PPS) and established prognostic factors.

Results: Correlation between HRs for PFS and OS, in 26 trials with 30 treatment comparisons comprising 24,870 patients, was modest ( = 0.52, weighted by trial sample size). The correlation diminished with recency: preplatinum/paclitaxel era, 0.66; platinum/paclitaxel, 0.44; triplet combinations, 0.22; biologicals, 0.30. The median PPS increased over time for the experimental ( = 0.03) and control arms ( = 0.003). The difference in median PPS between treatment arms strongly correlated with the difference in median OS ( = 0.83). In trials where the control therapy had median PPS of less than 18 months, correlation between PFS and OS was stronger ( = 0.64) than where the median PPS was longer ( = 0.48).

Conclusions: In EOC, correlation in the relative treatment effect between PFS and OS in first-line platinum-based chemotherapy randomized controlled trials is moderate and has weakened with increasing availability of effective salvage therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1758835918788500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080081PMC
August 2018

Practical guide for identifying unmet clinical needs for biomarkers.

EJIFCC 2018 Jul 11;29(2):129-137. Epub 2018 Jul 11.

New South Wales Health Pathology, Department of Clinical Chemistry and Endocrinology, Prince of Wales Hospital and School of Medical Sciences, University of New South Wales, Australia.

The development and evaluation of novel biomarkers and testing strategies requires a close examination of existing clinical pathways, including mapping of current pathways and identifying areas of unmet need. This approach enables early recognition of analytical and clinical performance criteria to guide evaluation studies, in a cyclical and iterative manner, all the time keeping the clinical pathway and patient health outcomes as the key drivers in the process. The Test Evaluation Working Group of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM TE-WG) https://www.eflm.eu/site/page/a/1158 has published a conceptual framework of the test evaluation cycle which is driven by the clinical pathway, inherent to which is the test purpose and role within the pathway that are defined by clinical need. To supplement this framework, the EFLM TE-WG has also published an interactive checklist for identifying unmet clinical needs for new biomarkers; a practical tool that laboratories, clinicians, researchers and industry can equally use in a consistent manner when new tests are developed and before they are released to the market. It is hoped that these practical tools will provide consistent and appropriate terminology in this diverse field and offer a platform that facilitates greater consultation and collaboration between all stakeholders. The checklist should assist the work of all colleagues involved in the discovery of novel biomarkers and implementation of new medical tests. The tool is aligned with the IOM recommendations and the FDA and CE regulating body's requirements.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053814PMC
July 2018

Adherence to prescribing restrictions for HER2-positive metastatic breast cancer in Australia: A national population-based observational study (2001-2016).

PLoS One 2018 26;13(7):e0198152. Epub 2018 Jul 26.

Medicines Policy Research Unit, Centre for Big Data Research in Health, UNSW, Sydney, Australia.

Background: Targeted cancer therapy is often complex, involving multiple agents and chemotherapeutic partners. In Australia, prescribing restrictions are put in place to reflect existing evidence of cost-effectiveness of these medicines. As therapeutic options continue to expand, these restrictions may not be perceived to align with best practice and it is not known if their use in the real-world clinic adheres to these restrictions. We examined the treatment of women receiving trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) to determine the extent to which treatment adhered to national prescribing restrictions.

Patients And Methods: Our population-based, retrospective cohort study used dispensing records for every Australian woman initiating publicly-subsidised trastuzumab for HER2+MBC between 2001-2013, followed through 2016. We used group-based trajectory models (GBTMs) to cluster patients, first on their patterns of trastuzumab exposure, and then on their patterns of lapatinib and chemotherapy exposure. We described the characteristics of patients within each cluster, and examined their treatments and combinations of treatments to determine restriction adherence.

Results: Of 5,052 patients initiating trastuzumab, 1,795 (36%) received at least one non-adherent HER2-targeted treatment. The most common non-adherent treatments were trastuzumab combinations involving vinorelbine (24% of non-adherent treatments); capecitabine (24%); and anthracyclines (10%). Non-adherent lapatinib use was observed in 4% of patients. GBTM identified three trastuzumab exposure clusters, each containing three further sub-clusters. The largest proportions of non-adherent treatments were in sub-clusters with longer trastuzumab exposure and more non-taxane chemotherapy. Patients in these sub-clusters were younger than those in sub-clusters with less non-adherent treatment.

Conclusions: Our study highlights that, even during the relatively simpler treatment era of our study period, a substantial amount of treatment did not adhere to prescribing restrictions. As more trials are conducted exploring pertuzumab and T-DM1 in combination with different chemotherapies and other HER2-targeted therapies, the regulation and funding of HER2-targeted treatment will become more challenging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198152PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061975PMC
December 2018

Performance of four published risk models to predict sentinel lymph-node involvement in Australian women with early breast cancer.

Breast 2018 Oct 26;41:82-88. Epub 2018 Jun 26.

Department of Surgery, The University of Adelaide, Adelaide, South Australia, Australia. Electronic address:

Background: Sentinel lymph-node biopsy has reduced the need for extensive axillary surgery for staging. It still exposes women to associated morbidity. Risk models that use clinical and pathology information of the primary tumour to predict sentinel lymph-node metastasis may allow further improvements in care. This study assessed the performance of four published risk models for predicting sentinel lymph-node metastasis in Australian women with early breast cancer; including one model developed in an Australian population.

Methods: The Sentinel Node Biopsy Versus Axillary Clearance (SNAC) trial dataset was used to assess model discrimination by calculating the area under the receiver-operating-characteristic curve (AUC) and the false-negative rate for sentinel lymph-node metastasis using model-predicted risk cut-points of 10%, 20%, 30%, and calibration using Hosmer-Lemeshow tests and calibration plots.

Results: The sentinel node was positive in 248 of 982 (25.2%) women (158 macrometastasis, 90 micrometastasis). The AUCs of risk models ranged from 0.70 to 0.74 for prediction of any sentinel-node metastasis; 0.72 to 0.75 for macrometastasis. Calibration was poor for the three models developed outside of Australia (lack-of-fit statistics, P < 0.001). For women with a model-predicted risk of sentinel lymph-node metastasis ≤10%, observed risk was 0-13% (three models <10%), false-negative rate 0-9%; 1-17% of women were classified in this range.

Conclusion: All four models showed good discrimination for predicting sentinel lymph-node metastasis, in particular for macrometastasis. With further development such risk models could have a role in the provision of reassurance to low risk women with normal nodes sonographicaally for whom no axillary surgery is contemplated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.breast.2018.05.011DOI Listing
October 2018

Long-term survival in trastuzumab-treated patients with HER2-positive metastatic breast cancer: real-world outcomes and treatment patterns in a whole-of-population Australian cohort (2001-2016).

Breast Cancer Res Treat 2018 Aug 7;171(1):151-159. Epub 2018 May 7.

Medicines Policy Research Unit, Centre for Big Data Research in Health, UNSW, Sydney, Australia.

Purpose: Patients treated with trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) are living longer, but there is little information on their outcomes and treatment experience beyond the median survival from clinical trials and real-world observational studies. We aim to describe the real-world treatment patterns and overall survival (OS) for women surviving five or more years from initiation of trastuzumab for HER2+MBC.

Methods: This is a retrospective, whole-of-population cohort study of women initiating trastuzumab for HER2+MBC between 2001 and 2011, followed to 2016. We defined long-term survivors (LTS) as those patients surviving ≥ 5 years from trastuzumab initiation. We used dispensing claims to describe timing of cancer treatments used by LTS and to estimate time on and off HER2-targeted therapies, and OS from trastuzumab initiation for HER2+MBC.

Results: Of 4177 women initiating trastuzumab for HER2+MBC, 1082 (26%) survived ≥ 5 years. Median age for LTS was 54 years (IQR 46-63). At a median follow-up of 9.4 years, 36% of LTS died; their conditional probability of surviving an additional 5 years was 55%. Median time on trastuzumab and all HER2-targeted therapy was 58.9 months (27.6-88.1) and 69.1 months (35.6-124.5), respectively. 85% of LTS had a period off HER2 therapy, lasting a median of 30.4 months (8.2-NR).

Conclusions: LTS generally receive HER2-targeted therapies for periods of time longer than in clinical trials, but most LTS also had breaks in treatment. More research is needed to understand the effects of long-term treatment and to identify patients who may be able to safely discontinue HER2-targeted therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-018-4804-0DOI Listing
August 2018

Total Hip Arthroplasty by the Direct Anterior Approach Using a Neck-preserving Stem: Safety, efficacy and learning curve.

Indian J Orthop 2018 Mar-Apr;52(2):124-132

Department of Research, School of Medicine, University of Notre Dame, Fremantle, New South Wales, Australia.

Background: The concept of femoral neck preservation in total hip replacement (THR) was introduced in 1993. It is postulated that retaining cortical bone of the femoral neck offers triplanar stability, uniform stress distribution, and accommodates physiological anteversion. However, data on safety, efficacy and learning curve are lacking.

Materials And Methods: We prospectively assessed all patients who were operated for a THR with a short neck preserving stem (MiniHip) between 2012 and 2014. The safety and learning curve were assessed by recording operative time; stem size; and adverse events including periprosthetic fracture; paresthesia; and limb length discrepancy (LLD). The cohort was divided into equal groups to assess the learning curve effect, and the cumulative sums (CUSUM) test was performed to monitor intraoperative neck fractures. For assessment of efficacy, Oxford Hip Score (OHS) and Short Form-36 (SF-36) scores were compared preoperatively and postoperatively.

Results: 138 patients with median age 62 years (range 35-82 years) were included with a median followup of 42 months (range 30-56 months). The minimum followup was 2.5 years. The OHS, SF-36 (physical and mental component) scores improved by a mean score of 26, 28, and 27 points, respectively. All patients had LLD of <10 mm (1.9 mm ± 1.3). Adverse events included intraoperative neck fracture ( = 6), subsidence ( = 1), periprosthetic fracture ( = 1), paresthesia ( = 12), and trochanteric bursitis ( = 2). After early modification of the technique to use a smaller finishing broach, the CUSUM test demonstrated acceptable intraoperative neck fracture risk. The second surgery group had a reduced risk of intraoperative neck fracture (5/69 vs. 1/69 = 0.2), reduced operative time (66 vs. 61 min, = 0.06), and increased stem size (5 vs. 6, = 0.09) although these differences were not statistically significant.

Conclusions: The MiniHip stem is safe alternative to standard THR with good functional outcomes but with a learning curve for the surgical technique, implants sizing, and the risk of intraoperative neck fractures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/ortho.IJOrtho_314_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858205PMC
March 2018

Trastuzumab for metastatic breast cancer: Real world outcomes from an Australian whole-of-population cohort (2001-2016).

Breast 2018 Apr 21;38:7-13. Epub 2017 Nov 21.

Medicines Policy Research Unit, Centre for Big Data Research in Health, UNSW, Sydney, Australia.

Purpose: Outcomes for patients treated in clinical trials may not reflect the experience in routine clinical care. We aim to describe the real-world treatment patterns and overall survival (OS) for women receiving trastuzumab for metastatic breast cancer (MBC).

Methods: Retrospective, whole-of-population cohort study using demographic, dispensing, and medical services data for women in the Herceptin Program for HER2+MBC. We estimated time on trastuzumab and OS from first dispensing of trastuzumab for MBC and rates of cardiac monitoring prior to and during treatment. We stratified outcomes by two groups based on year of initiation: 2001-2008 and 2009-2015. We benchmarked outcomes to two key trastuzumab clinical trials: H0648g (median OS 25 months) and CLEOPATRA (control group median OS 41 months).

Results: Median age of the 5899 women at first trastuzumab dispensing was 57 years (interquartile range [IQR]: 48-66). Median time on trastuzumab increased from 15 months (7-33) in Group One to 18 months (8-42) in Group Two. Median OS increased from 27 months (12-57) in Group One to 38 months (16-83) in Group Two. Rates of cardiac monitoring increased at baseline (52%-76%), and on-treatment (47%-67%), in Group One and Two, respectively.

Conclusions: OS, duration of trastuzumab, and frequency of cardiac monitoring increased over the study period. Outcomes for trastuzumab in this heterogeneous real world population were reassuringly comparable to those from clinical trials, with the median OS > 3 years in Group Two and 25% of patients living 7 years or longer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.breast.2017.11.007DOI Listing
April 2018

Survival outcomes for Australian women receiving trastuzumab for HER2-positive metastatic breast cancer following (neo)adjuvant trastuzumab: a national population-based observational study (2006-2014).

Br J Cancer 2018 02 14;118(3):441-447. Epub 2017 Nov 14.

Medicines Policy Research Unit, Centre for Big Data Research in Health, University of New South Wales, Sydney, NSW 2052, Australia.

Background: Patients treated with (neo)adjuvant trastuzumab who relapse and receive trastuzumab for metastatic breast cancer (MBC) are a growing population with little outcome data given their exclusion from most clinical trials. We aim to estimate survival outcomes for this trastuzumab 'pre-treated' population.

Methods: Population-based study of Australian women receiving trastuzumab for HER2-positive MBC between 2006 and 2014, who also received (neo)adjuvant trastuzumab. We used Kaplan-Meier methods to estimate the following: overall survival (OS) from initiation of trastuzumab for MBC; duration of trastuzumab for MBC; and time from last (neo)adjuvant trastuzumab to first trastuzumab for MBC.

Results: Of 3199 patients dispensed trastuzumab for MBC, 634 (20%) had received (neo)adjuvant traztuzumab. Pre-treated patients had a median (interquartile range) OS of 21.8 months (10.9-51.6), trastuzumab duration of 12.8 months (4.7-17.5), and time from last (neo)adjuvant trastuzumab to first trastuzumab for MBC of 15.6 months (6.5-28.6). Median OS for patients initiating trastuzumab <12 months and ⩾12 months from their last (neo)adjuvant trastuzumab were 17.1 months and 24.8 months, respectively.

Conclusions: Patients starting trastuzumab for MBC following (neo)adjuvant trastuzumab had a median treatment duration of 1 year and OS of almost 2 years. These data help inform clinical practice and service planning for this under-researched population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/bjc.2017.405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808025PMC
February 2018

How will transitioning from cytology to HPV testing change the balance between the benefits and harms of cervical cancer screening? Estimates of the impact on cervical cancer, treatment rates and adverse obstetric outcomes in Australia, a high vaccination coverage country.

Int J Cancer 2017 12 5;141(12):2410-2422. Epub 2017 Oct 5.

Cancer Research Division, Cancer Council NSW, Australia.

Primary HPV screening enables earlier diagnosis of cervical lesions compared to cytology, however, its effect on the risk of treatment and adverse obstetric outcomes has not been extensively investigated. We estimated the cumulative lifetime risk (CLR) of cervical cancer and excisional treatment, and change in adverse obstetric outcomes in HPV unvaccinated women and cohorts offered vaccination (>70% coverage in 12-13 years) for the Australian cervical screening program. Two-yearly cytology screening (ages 18-69 years) was compared to 5-yearly primary HPV screening with partial genotyping for HPV16/18 (ages 25-74 years). A dynamic model of HPV transmission, vaccination, cervical screening and treatment for precancerous lesions was coupled with an individual-based simulation of obstetric complications. For cytology screening, the CLR of cervical cancer diagnosis, death and treatment was estimated to be 0.649%, 0.198% and 13.4% without vaccination and 0.182%, 0.056% and 6.8%, in vaccinated women, respectively. For HPV screening, relative reductions of 33% and 22% in cancer risk for unvaccinated and vaccinated women are predicted, respectively, compared to cytology. Without the implementation of vaccination, a 4% increase in treatment risk for HPV versus cytology screening would have been expected, implying a possible increase in pre-term delivery (PTD) and low birth weight (LBW) events of 19 to 35 and 14 to 37, respectively, per 100,000 unvaccinated women. However, in vaccinated women, treatment risk will decrease by 13%, potentially leading to 4 to 41 fewer PTD events and from 2 more to 52 fewer LBW events per 100,000 vaccinated women. In unvaccinated women in cohorts offered vaccination as 12-13 year olds, no change to lifetime treatment risk is expected with HPV screening. In unvaccinated women in cohorts offered vaccination as 12-13 year olds, no change to lifetime treatment risk is expected with HPV screening. HPV screening starting at age 25 in populations with high vaccination coverage, is therefore expected to both improve the benefits (further decrease risk of cervical cancer) and reduce the harms (reduce treatments and possible obstetric complications) associated with cervical cancer screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.30926DOI Listing
December 2017

Rapid Rule-out of Acute Myocardial Infarction With a Single High-Sensitivity Cardiac Troponin T Measurement Below the Limit of Detection: A Collaborative Meta-analysis.

Ann Intern Med 2017 05 18;166(10):715-724. Epub 2017 Apr 18.

From Christchurch Hospital, University of Otago Christchurch, and Christchurch Heart Institute, Christchurch, New Zealand; Queensland University of Technology and Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; Medical Centre Leeuwarden, Leeuwarden, the Netherlands; Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, Manchester, United Kingdom; Southmead Hospital, North Bristol NHS Trust, Bristol, United Kingdom; St. George's University Hospitals NHS Foundation Trust and St. George's University of London, London, United Kingdom; Hôpital Lapeyronie, Montpellier, France; Skåne University Hospital, Lund, Sweden; Uppsala University, Uppsala, Sweden; Sorbonne Université and Assistance Publique-Hôpitaux de Paris, Paris, France; University of Sheffield, Sheffield, United Kingdom; Mayo Clinic, Rochester, Minnesota; University of Notre Dame Australia, Darlinghurst, New South Wales, Australia; Universitätsspital Basel, Basel, Switzerland; Nelson Hospital, Nelson, New Zealand; Baylor College of Medicine, Houston, Texas; National University of Singapore, Singapore; Universidad de Valencia, CIBERCV, Hospital Clínico Universitario, Valencia, Spain; and University of Sydney, Camperdown, New South Wales, Australia.

Background: High-sensitivity assays for cardiac troponin T (hs-cTnT) are sometimes used to rapidly rule out acute myocardial infarction (AMI).

Purpose: To estimate the ability of a single hs-cTnT concentration below the limit of detection (<0.005 µg/L) and a nonischemic electrocardiogram (ECG) to rule out AMI in adults presenting to the emergency department (ED) with chest pain.

Data Sources: EMBASE and MEDLINE without language restrictions (1 January 2008 to 14 December 2016).

Study Selection: Cohort studies involving adults presenting to the ED with possible acute coronary syndrome in whom an ECG and hs-cTnT measurements were obtained and AMI outcomes adjudicated during initial hospitalization.

Data Extraction: Investigators of studies provided data on the number of low-risk patients (no new ischemia on ECG and hs-cTnT measurements <0.005 µg/L) and the number who had AMI during hospitalization (primary outcome) or a major adverse cardiac event (MACE) or death within 30 days (secondary outcomes), by risk classification (low or not low risk). Two independent epidemiologists rated risk of bias of studies.

Data Synthesis: Of 9241 patients in 11 cohort studies, 2825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day MACEs ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died.

Limitation: Few studies, variation in timing and methods of reference standard troponin tests, and heterogeneity of risk and prevalence of AMI across studies.

Conclusion: A single hs-cTnT concentration below the limit of detection in combination with a nonischemic ECG may successfully rule out AMI in patients presenting to EDs with possible emergency acute coronary syndrome.

Primary Funding Source: Emergency Care Foundation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/M16-2562DOI Listing
May 2017

Changes in gene expression of neo-squamous mucosa after endoscopic treatment for dysplastic Barrett's esophagus and intramucosal adenocarcinoma.

United European Gastroenterol J 2017 Feb 7;5(1):13-20. Epub 2016 Jul 7.

Gastroesophageal Cancer Research Program, St Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia; School of Medicine, University of Notre Dame, Sydney, NSW, Australia; Diagnostic Endoscopy Centre, St Vincent's Clinic, Sydney, NSW, Australia.

Background: Endoscopic therapy, including by radiofrequency ablation (RFA) or endoscopic mucosal resection (EMR), is first line treatment for Barrett's esophagus (BE) with high-grade dysplasia (HGD) or intramucosal cancer (IMC) and may be appropriate for some patients with low-grade dysplasia (LGD).

Objective: The purpose of this study was to investigate the molecular effects of endotherapy.

Methods: mRNA expression of 16 genes significantly associated with different BE stages was measured in paired pre-treatment BE tissues and post-treatment neo-squamous biopsies from 36 patients treated by RFA (19 patients, 3 IMC, 4 HGD, 12 LGD) or EMR (17 patients, 4 IMC, 13 HGD). EMR was performed prior to RFA in eight patients. Normal squamous esophageal tissues were from 20 control individuals.

Results: Endoscopic therapy resulted in significant change towards the normal squamous expression profile for all genes. The neo-squamous expression profile was significantly different to the normal control profile for 11 of 16 genes.

Conclusion: Endotherapy results in marked changes in mRNA expression, with replacement of the disordered BE dysplasia or IMC profile with a more "normal" profile. The neo-squamous mucosa was significantly different to the normal control squamous mucosa for most genes. The significance of this finding is uncertain but it may support continued endoscopic surveillance after successful endotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2050640616650794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384557PMC
February 2017

Reversibility of nerve root sedimentation sign in lumbar spinal stenosis patients after decompression surgery.

Eur Spine J 2017 10 4;26(10):2573-2580. Epub 2017 Feb 4.

Department of Orthopaedic Surgery, Asklepios Klinikum Uckermark, Auguststr. 23, 16303, Schwedt, Germany.

Purpose: The nerve root sedimentation sign (SedSign) is a magnetic resonance imaging (MRI) sign for the diagnosis of lumbar spinal stenosis (LSS). It is included in the assessment of LSS to help determine whether decompression surgery is indicated. Assessment of the reversibility of the SedSign after surgery may also have clinical implications for the decision about whether or not a secondary operation or revision is needed. This study investigated if lumbar decompression leads to a reversal of the SedSign in patients with LSS and a positive SedSign pre-operatively; and if a reversal is associated with more favourable clinical outcomes. If reversal of the SedSign is usual after sufficient decompression surgery, a new positive SedSign could be used as an indicator of new stenosis in previously operated patients.

Methods: A prospective cohort study of 30 LSS patients with a positive pre-operative SedSign undergoing decompression surgery with or without instrumented fusion was undertaken to assess the presence of nerve root sedimentation (=negative SedSign) on MRI at 3 months post-operation. Functional limitation (Oswestry Disability Index, ODI), back and leg pain (Visual Analogue Scale, VAS), and treadmill walking distance were also compared pre- and 3 months post-operatively. The short follow-up period was chosen to exclude adjacent segment disease and the potential influence of surgical technique on clinical outcomes at longer follow-up times.

Results: 30 patients [median age 73 years (interquartile range (IQR) 65-79), 16 males] showed a median pre-operative ODI of 66 (IQR 52-78), a median VAS of 8 (IQR 7-9), and a median walking distance of 0 m (IQR 0-100). Three months post-operation 27 patients had a negative SedSign. In this group, we found improved clinical outcomes at follow-up: median post-operative ODI of 21 (IQR 12-26), median VAS of 2 (IQR 2-4), and median walking distance of 1000 m (IQR 500-1000). These changes were all statistically significant (p < 0.001). Three patients had a positive SedSign at 3-month follow-up due to epidural fat (n = 2) or a dural cyst following an intra-operative dural tear (n = 1), but also showed improvements in clinical outcomes for ODI, VAS and walking distance.

Conclusion: The reversibility of a pre-operative positive SedSign was demonstrated after decompression of the affected segmental level and associated with an improved clinical outcome. A persisting positive SedSign could be the result of incomplete decompression or surgical complications. A new positive SedSign after sufficient decompression surgery could be used as an indicator of new stenosis in previously operated patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00586-017-4962-5DOI Listing
October 2017

Use and outcomes of targeted therapies in early and metastatic HER2-positive breast cancer in Australia: protocol detailing observations in a whole of population cohort.

BMJ Open 2017 01 24;7(1):e014439. Epub 2017 Jan 24.

Medicines Policy Research Unit, Centre for Big Data Research in Health, UNSW, Sydney, New South Wales, Australia.

Background: The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has changed dramatically with the introduction and widespread use of HER2-targeted therapies. However, there is relatively limited real-world information on patterns of use, effectiveness and safety in whole of population cohorts. The research programme detailed in this protocol will generate evidence on the prescribing patterns, safety monitoring and outcomes of patients with BC treated with HER2-targeted therapies in Australia.

Methods/design: Our ongoing research programme will involve a series of retrospective cohort studies that include every patient accessing Commonwealth-funded HER2-targeted therapies for the treatment of early BC and advanced BC in Australia. At the time of writing, our cohorts consist of 11 406 patients with early BC and 5631 with advanced BC who accessed trastuzumab and lapatinib between 2001 and 2014. Pertuzumab and trastuzumab emtansine were publicly funded for metastatic BC in 2015, and future data updates will include patients accessing these medicines. We will use dispensing claims for cancer and other medicines, medical service claims and demographics data for each patient accessing HER2-targeted therapies to undertake this research.

Ethics And Dissemination: Ethics approval has been granted by the Population Health Service Research Ethics Committee and data access approval has been granted by the Australian Department of Human Services (DHS) External Review Evaluation Committee. Our findings will be reported in peer-reviewed publications, conference presentations and policy forums. By providing detailed information on the use and outcomes associated with HER2-targeted therapies in a national cohort treated in routine clinical care, our research programme will better inform clinicians and patients about the real-world use of these treatments and will assist third-party payers to better understand the use and economic costs of these treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2016-014439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278255PMC
January 2017
-->