ObjectiveEstimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance.DesignWe undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene.Results1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian.ConclusionsThe four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

BackgroundMost patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

ObjectiveToday most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers?DesignInformation was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants.Results1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%).ConclusionsRelative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94–1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.

IntroductionThe COVID-19 pandemic is ongoing, yet, due to the lack of a COVID-19-specific tool, clinicians must use pre-existing illness severity scores for initial prognostication. However, the validity of such scores in COVID-19 is unknown.MethodsThe North West Collaborative Organisation for Respiratory Research performed a multicentre prospective evaluation of adult patients admitted to the hospital with confirmed COVID-19 during a 2-week period in April 2020. Clinical variables measured as part of usual care at presentation to the hospital were recorded, including the Confusion, Urea, Respiratory Rate, Blood Pressure and Age Above or Below 65 Years (CURB-65), National Early Warning Score 2 (NEWS2) and Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) scores. The primary outcome of interest was 30-day mortality.ResultsData were collected for 830 people with COVID-19 admitted across seven hospitals. By 30 days, a total of 300 (36.1%) had died and 142 (17.1%) had been in the intensive care unit. All scores underestimated mortality compared with pre-COVID-19 cohorts, and overall prognostic performance was generally poor. Among the ‘low-risk’ categories (CURB-65 score<2, NEWS2<5 and qSOFA score<2), 30-day mortality was 16.7%, 32.9% and 21.4%, respectively. NEWS2≥5 had a negative predictive value of 98% for early mortality. Multivariable logistic regression identified features of respiratory compromise rather than circulatory collapse as most relevant prognostic variables.ConclusionIn the setting of COVID-19, existing prognostic scores underestimated risk. The design of new prognostic tools should focus on features of respiratory compromise rather than circulatory collapse. We provide a baseline set of variables which are relevant to COVID-19 outcomes and may be used as a basis for developing a bespoke COVID-19 prognostication tool.

In most medical research, treatment effectiveness is assessed using the Average Treatment Effect (ATE) or some version of subgroup analysis. The practice of individualized or precision medicine, however, requires new approaches that predict how an individual will respond to treatment, rather than relying on aggregate measures of effect. In this study, we present a conceptual framework for estimating individual treatment effects, referred to as Predicted Individual Treatment Effects (PITE). We first apply the PITE approach to a randomized controlled trial designed to improve behavioral and physical symptoms. Despite trivial average effects of the intervention, we show substantial heterogeneity in predicted individual treatment response using the PITE approach. The PITEs can be used to predict individuals for whom the intervention may be most effective (or harmful). Next, we conduct a Monte Carlo simulation study to evaluate the accuracy of Predicted Individual Treatment Effects. We compare the performance of two methods used to obtain predictions: multiple imputation and non-parametric random decision trees (RDT). Results showed that, on average, both predictive methods produced accurate estimates at the individual level; however, the RDT tended to underestimate the PITE for people at the extreme and showed more variability in predictions across repetitions compared to the imputation approach. Limitations and future directions are discussed.

BackgroundWe have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy.MethodsThe cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence.ResultsCumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05).ConclusionsThe hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.Electronic supplementary materialThe online version of this article (10.1186/s13053-017-0078-5) contains supplementary material, which is available to authorized users.

Objectives To assess the achievability and effect of attaining low disease activity (LDA) or remission in childhood (cSLE). Methods Attainment of three adult-SLE derived definitions of LDA (LLDAS, LA, Toronto-LDA), and four definitions of remission (clinical-SLEDAI-defined remission on/off treatment, pBILAG-defined remission on/off treatment) was assessed in UK JSLE Cohort Study patients longitudinally. Prentice-Williams-Petersen-GAP recurrent event models assessed the impact of LDA/remission attainment on severe flare/new damage. Results LLDAS, LA and Toronto-LDA targets were reached in 67%, 73% and 32% of patients, after a median of 18, 15 or 17 months, respectively. Cumulatively, LLDAS, LA and Toronto-LDA was attained for a median of 23%, 31% and 19% of total follow-up-time, respectively. Remission on-treatment was more common (61% cSLEDAI-defined, 42% pBILAG-defined) than remission off-treatment (31% cSLEDAI-defined, 21% pBILAG-defined). Attainment of all target states, and disease duration (&gt;1 year), significantly reduced the hazard of severe flare (p&lt; 0.001). As cumulative time in each target increased, hazard of severe flare progressively reduced. LLDAS attainment reduced the hazard of severe flare more than LA or Toronto-LDA (p&lt; 0.001). Attainment of LLDAS and all remission definitions led to a statistically comparable reduction in the hazards of severe flare (p&gt; 0.05). Attainment of all targets reduced the hazards of new damage (p&lt; 0.05). Conclusions This is the first study demonstrating that adult-SLE-derived definitions of LDA/remission are achievable in cSLE, significantly reducing risk of severe flare/new damage. Of the LDA definitions, LLDAS performed best, leading to a statistically comparable reduction in the hazards of severe flare to attainment of clinical-remission.

BackgroundThe addition of annual MRI screening to mammography has heightened optimism that intensive screening along with improved treatments may substantially improve life expectancy of women at high risk of breast cancer. However, survival data from BRCA2 mutation carriers undergoing intensive combined breast screening are scarce.MethodsWe have collated the results of screening with either annual mammography or mammography with MRI in female BRCA2 mutation carriers in Manchester and Oslo and use a Manchester control group of BRCA2 mutation carriers who had their first breast cancer diagnosed without intensive screening.ResultsEighty-seven BRCA2 mutation carriers had undergone combined (n = 34) or mammography (n = 53) screening compared to 274 without such intensive screening. Ten year breast cancer specific survival was 100 % in the combined group (95 % CI 82.5–100 %) and 85.5 % (95 % CI 72.6–98.4 %) in the mammography group compared to 74.6 % (95 % CI 66.6–82.6 %) in the control group. Better survival was driven by lymph node status (negative in 67 % of screened vs 39 % of unscreened women; p < 0.001) and a significantly greater proportion of intensively screened women had invasive breast cancers <2 cm at diagnosis (74.6 % vs 50.4 %; p = 0.002).ConclusionIntensive combined breast cancer screening with annual MRI and mammography appears to improve survival from breast cancer in BRCA2 mutation carriers. Data from larger groups are required to confirm the effectiveness of combined screening in BRCA2 carriers.