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Skates, Steven

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Skates, Steven
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    The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)
    (Nature Publishing Group, 2017) Menon, Usha; McGuire, Alistair J; Raikou, Maria; Ryan, Andy; Davies, Susan K; Burnell, Matthew; Gentry-Maharaj, Aleksandra; Kalsi, Jatinderpal K; Singh, Naveena; Amso, Nazar N; Cruickshank, Derek; Dobbs, Stephen; Godfrey, Keith; Herod, Jonathan; Leeson, Simon; Mould, Tim; Murdoch, John; Oram, David; Scott, Ian; Seif, Mourad W; Williamson, Karin; Woolas, Robert; Fallowfield, Lesley; Campbell, Stuart; Skates, Steven; Parmar, Mahesh; Jacobs, Ian J
    Background: To assess the within-trial cost-effectiveness of an NHS ovarian cancer screening (OCS) programme using data from UKCTOCS and extrapolate results based on average life expectancy. Methods: Within-trial economic evaluation of no screening (C) vs either (1) an annual OCS programme using transvaginal ultrasound (USS) or (2) an annual ovarian cancer multimodal screening programme with serum CA125 interpreted using a risk algorithm (ROCA) and transvaginal ultrasound as a second-line test (MMS), plus comparison of lifetime extrapolation of the no screening arm and the MMS programme using both a predictive and a Markov model. Results: Using a CA125–ROCA cost of £20, the within-trial results show USS to be strictly dominated by MMS, with the MMS vs C comparison returning an incremental cost-effectiveness ratio (ICER) of £91 452 per life year gained (LYG). If the CA125–ROCA unit cost is reduced to £15, the ICER becomes £77 818 per LYG. Predictive extrapolation over the expected lifetime of the UKCTOCS women returns an ICER of £30 033 per LYG, while Markov modelling produces an ICER of £46 922 per QALY. Conclusion: Analysis suggests that, after accounting for the lead time required to establish full mortality benefits, a national OCS programme based on the MMS strategy quickly approaches the current NICE thresholds for cost-effectiveness when extrapolated out to lifetime as compared with the within-trial ICER estimates. Whether MMS could be recommended on economic grounds would depend on the confirmation and size of the mortality benefit at the end of an ongoing follow-up of the UKCTOCS cohort.
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    Evidence of Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom Familial Ovarian Cancer Screening Study
    (American Society of Clinical Oncology, 2017) Rosenthal, Adam N.; Fraser, Lindsay S.M.; Philpott, Susan; Manchanda, Ranjit; Burnell, Matthew; Badman, Philip; Hadwin, Richard; Rizzuto, Ivana; Benjamin, Elizabeth; Singh, Naveena; Evans, D. Gareth; Eccles, Diana M.; Ryan, Andy; Liston, Robert; Dawnay, Anne; Ford, Jeremy; Gunu, Richard; Mackay, James; Skates, Steven; Menon, Usha; Jacobs, Ian J.
    Purpose To establish the performance of screening with serum cancer antigen 125 (CA-125), interpreted using the risk of ovarian cancer algorithm (ROCA), and transvaginal sonography (TVS) for women at high risk of ovarian cancer (OC) or fallopian tube cancer (FTC). Patients and Methods Women whose estimated lifetime risk of OC/FTC was ≥ 10% were recruited at 42 centers in the United Kingdom and underwent ROCA screening every 4 months. TVS occurred annually if ROCA results were normal or within 2 months of an abnormal ROCA result. Risk-reducing salpingo-oophorectomy (RRSO) was encouraged throughout the study. Participants were observed via cancer registries, questionnaires, and notification by centers. Performance was calculated after censoring 365 days after prior screen, with modeling of occult cancers detected at RRSO. Results: Between June 14, 2007, and May 15, 2012, 4,348 women underwent 13,728 women-years of screening. The median follow-up time was 4.8 years. Nineteen patients were diagnosed with invasive OC/FTC within 1 year of prior screening (13 diagnoses were screen-detected and six were occult at RRSO). No symptomatic interval cancers occurred. Ten (52.6%) of the total 19 diagnoses were stage I to II OC/FTC (CI, 28.9% to 75.6%). Of the 13 screen-detected cancers, five (38.5%) were stage I to II (CI, 13.9% to 68.4%). Of the six occult cancers, five (83.3%) were stage I to II (CI, 35.9% to 99.6%). Modeled sensitivity, positive predictive value, and negative predictive value for OC/FTC detection within 1 year were 94.7% (CI, 74.0% to 99.9%), 10.8% (6.5% to 16.5%), and 100% (CI, 100% to 100%), respectively. Seven (36.8%) of the 19 cancers diagnosed < 1 year after prior screen were stage IIIb to IV (CI, 16.3% to 61.6%) compared with 17 (94.4%) of 18 cancers diagnosed > 1 year after screening ended (CI, 72.7% to 99.9%; P < .001). Eighteen (94.8%) of 19 cancers diagnosed < 1 year after prior screen had zero residual disease (with lower surgical complexity, P = .16) (CI, 74.0% to 99.9%) compared with 13 (72.2%) of 18 cancers subsequently diagnosed (CI, 46.5% to 90.3%; P = .09). Conclusion: ROCA-based screening is an option for women at high risk of OC/FTC who defer or decline RRSO, given its high sensitivity and significant stage shift. However, it remains unknown whether this strategy would improve survival in screened high-risk women.
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    Pleural Fluid Mesothelin as an Adjunct to the Diagnosis of Pleural Malignant Mesothelioma
    (Hindawi Publishing Corporation, 2014) Creaney, Jenette; Segal, Amanda; Olsen, Nola; Dick, Ian M.; Musk, A. W(Bill); Skates, Steven; Robinson, Bruce W.
    Rationale:. The diagnosis of pleural malignant mesothelioma (MM) by effusion cytology may be difficult and is currently controversial. Effusion mesothelin levels are increased in patients with MM but the clinical role of this test is uncertain. Objectives:. To determine the clinical value of measuring mesothelin levels in pleural effusion supernatant to aid diagnosis of MM. Methods and Measurements. Pleural effusion samples were collected prospectively from 1331 consecutive patients. Mesothelin levels were determined by commercial ELISA in effusions and their relationship to concurrent pathology reporting and final clinical diagnosis was determined. Results:. 2156 pleural effusion samples from 1331 individuals were analysed. The final clinical diagnosis was 183 MM, 436 non-MM malignancy, and 712 nonmalignant effusions. Effusion mesothelin had a sensitivity of 67% for MM at 95% specificity. Mesothelin was elevated in over 47% of MM cases in effusions obtained before definitive diagnosis of MM was established. In the setting of inconclusive effusion cytology, effusion mesothelin had a positive predictive value of 79% for MM and 94% for malignancy. Conclusions:. A mesothelin-positive pleural effusion, irrespective of the identification of malignant cells, indicates the likely presence of malignancy and adds weight to the clinical rationale for further investigation to establish a malignant diagnosis.
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    A Framework for Evaluating Biomarkers for Early Detection: Validation of Biomarker Panels for Ovarian Cancer
    (American Association for Cancer Research (AACR), 2011) Zhu, C. S.; Pinsky, P. F.; Cramer, Daniel; Ransohoff, D. F.; Hartge, P.; Pfeiffer, R. M.; Urban, N.; Mor, G.; Bast, R. C.; Moore, L. E.; Lokshin, A. E.; McIntosh, M. W.; Skates, Steven; Vitonis, A.; Zhang, Z.; Ward, D. C.; Symanowski, J. T.; Lomakin, A.; Fung, E. T.; Sluss, Patrick M.; Scholler, N.; Lu, K. H.; Marrangoni, A. M.; Patriotis, C.; Srivastava, S.; Buys, S. S.; Berg, C. D.
    A panel of biomarkers may improve predictive performance over individual markers. Although many biomarker panels have been described for ovarian cancer, few studies used pre-diagnostic samples to assess the potential of the panels for early detection. We conducted a multi-site systematic evaluation of biomarker panels using pre-diagnostic serum samples from the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening trial. Using a nested case-control design, levels of 28 biomarkers were measured laboratory-blinded in 118 serum samples obtained before cancer diagnosis and 951 serum samples from matched controls. Five predictive models, each containing 6–8 biomarkers, were evaluated according to a pre-determined analysis plan. Three sequential analyses were conducted: blinded validation of previously established models (Step 1); simultaneous split-sample discovery and validation of models (Step 2); and exploratory discovery of new models (Step 3). Sensitivity, specificity, sensitivity at 98% specificity, and AUC were computed for the models and CA125 alone among 67 cases diagnosed within one year of blood draw and 476 matched controls. In Step 1, one model showed comparable performance to CA125, with sensitivity, specificity and AUC at 69.2%, 96.6% and 0.892, respectively. Remaining models had poorer performance than CA125 alone. In Step 2, we observed a similar pattern. In Step 3, a model derived from all 28 markers failed to show improvement over CA125. Thus, biomarker panels discovered in diagnostic samples may not validate in pre-diagnostic samples; utilizing pre-diagnostic samples for discovery may be helpful in developing validated early detection panels.
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    Ovarian Cancer Biomarker Performance in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Specimens
    (American Association for Cancer Research (AACR), 2011) Cramer, Daniel; Bast, R. C.; Berg, C. D.; Diamandis, E. P.; Godwin, A. K.; Hartge, P.; Lokshin, A. E.; Lu, K. H.; McIntosh, M. W.; Mor, G.; Patriotis, C.; Pinsky, P. F.; Thornquist, M. D.; Scholler, N.; Skates, Steven; Sluss, Patrick M.; Srivastava, S.; Ward, D. C.; Zhang, Z.; Zhu, C. S.; Urban, N.
    Establishing a cancer screening biomarker’s intended performance requires “phase III” specimens obtained in asymptomatic individuals before clinical diagnosis rather than “phase II” specimens obtained from symptomatic individuals at diagnosis. We used specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to evaluate ovarian cancer biomarkers previously assessed in phase II sets. Phase II specimens from 180 ovarian cancer cases and 660 benign disease or general population controls were assembled from four Early Detection Research Network (EDRN) or Ovarian Cancer Specialized Program of Research Excellence (SPORE) sites and used to rank 49 biomarkers. Thirty-five markers, including 6 additional markers from a fifth site, were then evaluated in PLCO proximate specimens from 118 women with ovarian cancer and 474 matched controls. Top markers in phase II specimens included CA125, HE4, transthyretin, CA15.3, and CA72.4 with sensitivity at 95% specificity ranging from 0.73 to 0.40. Except for transthyretin, these markers had similar or better sensitivity when moving to phase III specimens that had been drawn within six months of the clinical diagnosis. Performance of all markers declined in phase III specimens more remote than 6 months from diagnosis. Despite many promising new markers for ovarian cancer, CA125 remains the single-best biomarker in the phase II and phase III specimens tested in this study.
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    Proteogenomics connects somatic mutations to signaling in breast cancer
    (2016) Mertins, Philipp; Mani, D. R.; Ruggles, Kelly V.; Gillette, Michael; Clauser, Karl R.; Wang, Pei; Wang, Xianlong; Qiao, Jana W.; Cao, Song; Petralia, Francesca; Kawaler, Emily; Mundt, Filip; Krug, Karsten; Tu, Zhidong; Lei, Jonathan T.; Gatza, Michael L.; Wilkerson, Matthew; Perou, Charles M.; Yellapantula, Venkata; Huang, Kuan-lin; Lin, Chenwei; McLellan, Michael D.; Yan, Ping; Davies, Sherri R.; Townsend, R. Reid; Skates, Steven; Wang, Jing; Zhang, Bing; Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry; Ding, Li; Paulovich, Amanda G.; Fenyo, David; Ellis, Matthew J.; Carr, Steven A.
    Summary Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. We describe quantitative mass spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers of which 77 provided high-quality data. Integrated analyses allowed insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. The 5q trans effects were interrogated against the Library of Integrated Network-based Cellular Signatures, thereby connecting CETN3 and SKP1 loss to elevated expression of EGFR, and SKP1 loss also to increased SRC. Global proteomic data confirmed a stromal-enriched group in addition to basal and luminal clusters and pathway analysis of the phosphoproteome identified a G Protein-coupled receptor cluster that was not readily identified at the mRNA level. Besides ERBB2, other amplicon-associated, highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.
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    Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening
    (American Society of Clinical Oncology, 2015) Menon, Usha; Ryan, Andy; Kalsi, Jatinderpal; Gentry-Maharaj, Aleksandra; Dawnay, Anne; Habib, Mariam; Apostolidou, Sophia; Singh, Naveena; Benjamin, Elizabeth; Burnell, Matthew; Davies, Susan; Sharma, Aarti; Gunu, Richard; Godfrey, Keith; Lopes, Alberto; Oram, David; Herod, Jonathan; Williamson, Karin; Seif, Mourad W.; Jenkins, Howard; Mould, Tim; Woolas, Robert; Murdoch, John B.; Dobbs, Stephen; Amso, Nazar N.; Leeson, Simon; Cruickshank, Derek; Scott, Ian; Fallowfield, Lesley; Widschwendter, Martin; Reynolds, Karina; McGuire, Alistair; Campbell, Stuart; Parmar, Mahesh; Skates, Steven; Jacobs, Ian
    Purpose Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates. Patients and Methods In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves. Results: After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869). Conclusion: Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded.
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    Impact on Mortality and Cancer Incidence Rates of Using Random Invitation from Population Registers for Recruitment to Trials
    (BioMed Central, 2011) Burnell, Matthew; Gentry-Maharaj, Aleksandra; Ryan, Andy; Apostolidou, Sophia; Habib, Mariam; Kalsi, Jatinderpal; Parmar, Mahesh; Seif, Mourad W; Amso, Nazar N; Godfrey, Keith; Oram, David; Herod, Jonathan; Williamson, Karin; Jenkins, Howard; Mould, Tim; Woolas, Robert; Murdoch, John; Dobbs, Stephen; Leeson, Simon; Cruickshank, Derek; Campbell, Stuart; Fallowfield, Lesley; Jacobs, Ian; Menon, Usha; Skates, Steven
    Background: Participants in trials evaluating preventive interventions such as screening are on average healthier than the general population. To decrease this ‘healthy volunteer effect’ (HVE) women were randomly invited from population registers to participate in the United Kingdom Collaborative Trial of Ovarian Cancer Screening(UKCTOCS) and not allowed to self refer. This report assesses the extent of the HVE still prevalent in UKCTOCS and considers how certain shortfalls in mortality and incidence can be related to differences in socioeconomic status. Methods: Between 2001 and 2005, 202 638 postmenopausal women joined the trial out of 1 243 312 women randomly invited from local health authority registers. The cohort was flagged for deaths and cancer registrations and mean follow up at censoring was 5.55 years for mortality, and 2.58 years for cancer incidence. Overall and cause-specific standardised Mortality Ratios (SMRs) and Standardised Incidence Ratios (SIRs) were calculated based on national mortality (2005) and cancer incidence (2006) statistics. The Index of Multiple Deprivation (IMD 2007) was used to assess the link between socioeconomic status and mortality/cancer incidence, and differences between the invited and recruited populations. Results: The SMR for all trial participants was 37%. By subgroup, the SMRs were higher for: younger age groups, extremes of BMI distribution and with each increasing year in trial. There was a clear trend between lower socioeconomic status and increased mortality but less pronounced with incidence. While the invited population had higher mean IMD scores (more deprived) than the national average, those who joined the trial were less deprived. Conclusions: Recruitment to screening trials through invitation from population registers does not prevent a pronounced HVE on mortality. The impact on cancer incidence is much smaller. Similar shortfalls can be expected in other screening RCTs and it maybe prudent to use the various mortality and incidence rates presented as guides for calculating event rates and power in RCTs involving women. Trial Registration: This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Medical Research Council (grant no. G990102), Cancer Research UK (grant no. C1479/A2884) and Department of Health
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    Recruitment to Multicentre Trials—Lessons from UKCTOCS: Descriptive Study
    (BMJ Publishing Group, 2008) Menon, Usha; Gentry-Maharaj, Aleksandra; Ryan, Andy; Sharma, Aarti; Burnell, Matthew; Hallett, Rachel; Lopez, Alberto; Godfrey, Keith; Oram, David; Herod, Jonathan; Williamson, Karin; Seif, Mourad; Scott, Ian; Mould, Tim; Woolas, Robert; Murdoch, John; Dobbs, Stephen; Amso, Nazar; Leeson, Simon; Cruickshank, Derek; McGuire, Ali; Campbell, Stuart; Fallowfield, Lesley; Parmar, Mahesh; Jacobs, Ian; Lewis, Sarah Catherine; Skates, Steven
    Objective: To describe the factors that contributed to successful recruitment of more than 200,000 women to the UK Collaborative Trial of Ovarian Cancer Screening, one of the largest ever randomised controlled trials. Design Descriptive study. Setting 13 NHS trusts in England, Wales, and Northern Ireland. Participants Postmenopausal women aged 50-74; exclusion criteria included ovarian malignancy, bilateral oophorectomy, increased risk of familial ovarian cancer, active non-ovarian malignancy, and participation in other ovarian cancer screening trials. Main outcome measures: Achievement of target recruitment, acceptance rates of invitation, and recruitment rates. Results: The trial was set up in 13 centres with 27 adjoining local health authorities. The coordinating centre team was led by one of the senior investigators, who was closely involved in planning and day to day trial management. Of 1,243,282 women invited, 23.2% (288,955) replied that they were eligible and would like to participate. Of those sent appointments, 73.6% (205,090) attended for recruitment. The acceptance rate varied from 19% to 33% between trial centres. Measures to ensure target recruitment included named coordinating centre staff supporting and monitoring each centre, prompt identification and resolution of logistic problems, varying the volume of invitations by centre, using local non-attendance rates to determine the size of recruitment clinics, and organising large ad hoc clinics supported by coordinating centre staff. The trial randomised 202,638 women in 4.3 years. Conclusions: Planning and trial management are as important as trial design and require equal attention from senior investigators. Successful recruitment needs constant monitoring by a committed proactive management team that is willing to explore individual solutions for different centres and use central resources to improve local recruitment. Automation of trial processes with web based trial management systems is crucial in large multicentre randomised controlled trials. Recruitment can be further enhanced by using information videos and group discussions.