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

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

Detection of a possible superluminous supernova in the epoch of reionization

An interesting transient has been detected in one of our three Dark Energy Camera deep fields. Observations of these deep fields take advantage of the high red sensitivity of DECam on the Cerro Tololo Interamerican Observatory Blanco telescope. The survey includes the Y band with rest wavelength 1430{\AA} at z = 6. Survey fields (the Prime field 0555-6130, the 16hr field 1600-75 and the SUDSS New Southern Field) are deeper in Y than other infrared surveys. They are circumpolar, allowing all night to be used efficiently, exploiting the moon tolerance of 1 micron observations to minimize conflict with the Dark Energy Survey. As an i-band dropout (meaning that the flux decrement shortward of Lyman alpha is in the i bandpass), the transient we report here is a supernova candidate with z ~ 6, with a luminosity comparable to the brightest known current epoch superluminous supernova (i.e., ~ 2 x 10^11 solar luminosities).Comment: Reference adde

Ovarian cancer symptoms, routes to diagnosis and survival – population cohort study in the ‘no screen’ arm of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Objective: There are widespread efforts to increase symptom awareness of ‘pelvic/abdominal pain, increased abdominal size/bloating, difficulty eating/feeling full and urinary frequency/urgency’ in an attempt to diagnose ovarian cancer earlier. Long-term survival of women with these symptoms adjusted for known prognostic factors is yet to be determined. This study explored the association of symptoms, routes and interval to diagnosis and long-term survival in a population-based cohort of postmenopausal women diagnosed with invasive epithelial tubo-ovarian cancer (iEOC) in the ‘no screen’ (control) UKCTOCS arm. Methods: Of 101,299 women in the control arm, 574 were confirmed on outcome review to have iEOC between randomisation (2001–2005) and 31 December 2014. Data was extracted from medical notes and electronic records. A multivariable model was fitted for individual symptoms, time interval from symptom onset to diagnosis, route to diagnosis, speciality, morphological Type, age at diagnosis, year of diagnosis (period effect), stage, primary treatment, and residual disease. Results: Women presenting with symptoms listed in the NICE guidelines (HR1.48, 95%CI1.16–1.89, p = 0.001) or the modified Goff Index (HR1·68, 95%CI1·32–2.13, p < 0.0001) had significantly worse survival than those who did not. Each additional presenting symptom decreased survival (HR1·20, 95%CI1·12–1·28, p < 0.0001). In multivariable analysis, in addition to advanced stage, increasing residual disease and inadequate primary treatment, abdominal pain and loss of appetite/feeling full were significantly associated with increased mortality. Conclusions: The ovarian cancer symptom indices identify postmenopausal women with a poorer prognosis. This study however cannot exclude the possibility of better outcomes in those who are aware and act on their symptoms

Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development

Background: Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. Methods and Findings: Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. Conclusions: HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies.publishedVersio

The WID-EC test for the detection and risk prediction of endometrial cancer

The incidence of endometrial cancer is rising. Measures to identify women at risk and to detect endometrial cancer earlier are required to reduce the morbidity triggered by the aggressive treatment required for advanced endometrial cancer. We developed the WID-EC (Women's cancer risk IDentification-Endometrial Cancer) test, which is based on DNA methylation at 500 CpG sites, in a discovery set of cervical liquid-based cytology samples from 1,086 women with and without an endometrial cancer (217 cancer cases and 869 healthy controls) with a worse prognosis (grade 3 or ≥stage IB). We validated the WID-EC test in an independent external validation set of 64 endometrial cancer cases and 225 controls. We further validated the test in 150 healthy women (prospective set) who provided a cervical sample as part of the routine Swedish cervical screening programme, 54 of whom developed endometrial cancer within three years of sample collection. The WID-EC test identified women with endometrial cancer with a receiver operator characteristic area under the curve (AUC) of 0.92 (95% CI: 0.88-0.97) in the external set and of 0.82 (95% CI: 0.74-0.89) in the prospective validation set. Using an optimal cutoff, cancer cases were detected with a sensitivity of 86% and a specificity of 90% in the external validation set, and a sensitivity and specificity of 52% and 98% respectively in the prospective validation set. The WID-EC test can identify women with or at risk of endometrial cancer

The SAURON project. II. Sample and early results

Early results are reported from the SAURON survey of the kinematics and stellar populations of a representative sample of nearby E, S0 and Sa galaxies. The survey is aimed at determining the intrinsic shape of the galaxies, their orbital structure, the mass-to-light ratio as a function of radius, the age and metallicity of the stellar populations, and the frequency of kinematically decoupled cores and nuclear black holes. The construction of the representative sample is described, and its properties are illustrated. A comparison with long-slit spectroscopic data establishes that the SAURON measurements are comparable to, or better than, the highest-quality determinations. Comparisons are presented for NGC 3384 and NGC 4365 where stellar velocities and velocity dispersions are determined to a precision of 6 km/s, and the h3 and h4 parameters of the line-of-sight velocity distribution to a precision of better than 0.02. Extraction of accurate gas emission-line intensities, velocities and line widths from the datacubes is illustrated for NGC 5813. Comparisons with published line-strengths for NGC 3384 and NGC 5813 reveal uncertainties of < 0.1 A on the measurements of the Hbeta, Mgb and Fe5270 indices. Integral-field mapping uniquely connects measurements of the kinematics and stellar populations to the galaxy morphology. The maps presented here illustrate the rich stellar kinematics, gaseous kinematics, and line-strength distributions of early-type galaxies. The results include the discovery of a thin, edge-on, disk in NGC 3623, confirm the axisymmetric shape of the central region of M32, illustrate the LINER nucleus and surrounding counter-rotating star-forming ring in NGC 7742, and suggest a uniform stellar population in the decoupled core galaxy NGC 5813.Comment: 20 pages, 17 figures. To be published in MNRAS. Version with full resolution images available at http://www.strw.leidenuniv.nl/~dynamics/Instruments/Sauron/pub_list.htm

The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

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) versus 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 versus 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. Conclusions: 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 to 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

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

Background Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the eff ect of early detection by screening on ovarian cancer mortality. Methods In this randomised controlled trial, we recruited postmenopausal women aged 50–74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computergenerated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. Findings Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202 638 women: 50 640 (25·0%) to MMS, 50 639 (25·0%) to USS, and 101 359 (50·0%) to no screening. 202 546 (>99·9%) women were eligible for analysis: 50 624 (>99·9%) women in the MMS group, 50 623 (>99·9%) in the USS group, and 101 299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345 570 MMS and 327 775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0–12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0–14 of 15% (95% CI –3 to 30; p=0·10) with MMS and 11% (–7 to 27; p=0·21) with USS. The Royston-Parmar fl exible parametric model showed that in the MMS group, this mortality eff ect was made up of 8% (–20 to 31) in years 0–7 and 23% (1–46) in years 7–14, and in the USS group, of 2% (–27 to 26) in years 0–7 and 21% (–2 to 42) in years 7–14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly diff erent death rates (p=0·021), with an overall average mortality reduction of 20% (–2 to 40) and a reduction of 8% (–27 to 43) in years 0–7 and 28% (–3 to 49) in years 7–14 in favour of MMS. Interpretation Although the mortality reduction was not signifi cant in the primary analysis, we noted a signifi cant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7–14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-eff ectiveness of ovarian cancer screening

Performance characteristics of the ultrasound strategy during incidence screening in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Randomised controlled trials of ovarian cancer (OC) screening have not yet demonstrated an impact on disease mortality. Meanwhile, the screening data from clinical trials represents a rich resource to understand the performance of modalities used. We report here on incidence screening in the ultrasound arm of UKCTOCS. 44,799 of the 50,639 women who were randomised to annual screening with transvaginal ultrasound attended annual incidence screening between 28 April 2002 and 31 December 2011. Transvaginal ultrasound was used both as the first and the second line test. Participants were followed up through electronic health record linkage and postal questionnaires. Out of 280,534 annual incidence screens, 960 women underwent screen-positive surgery. 113 had ovarian/tubal cancer (80 invasive epithelial). Of the screen-detected invasive epithelial cancers, 37.5% (95%CI: 26.9–49.0) were Stage I/II. An additional 52 (50 invasive epithelial) were diagnosed within one year of their last screen. Of the 50 interval epithelial cancers, 6.0% (95%CI: 1.3–16.5) were Stage I/II. For detection of all ovarian/tubal cancers diagnosed within one year of screen, the sensitivity, specificity, and positive predictive values were 68.5% (95%CI: 60.8–75.5), 99.7% (95%CI: 99.7–99.7), and 11.8% (95%CI: 9.8–14) respectively. When the analysis was restricted to invasive epithelial cancers, sensitivity, specificity and positive predictive values were 61.5% (95%CI: 52.6–69.9); 99.7% (95%CI: 99.7–99.7) and 8.3% (95%CI: 6.7–10.3), with 12 surgeries per screen positive. The low sensitivity coupled with the advanced stage of interval cancers suggests that ultrasound scanning as the first line test might not be suitable for population screening for ovarian cancer. Trial registration: ISRCTN22488978. Registered on 6 April 2000