Citations

Abstract Background: Endometrial cancer is highly curable when detected early, but clinical symptoms are often missed. Most cancers arise in women with abnormal postmenopausal bleeding (PMB). However, PMB is not specific for endometrial cancers. In previous reports, the prevalence of endometrial cancer in women with PMB was reported to range from 3-25%. Because of the importance for guiding clinical management and endometrial cancer risk prediction, we conducted a systematic review and meta-analysis to obtain precise prevalence estimates of endometrial cancer in women with PMB. Methods: A systematic review and meta-analysis summarized all peer-reviewed studies reporting endometrial cancer prevalence in women with PMB, published before Sept. 1, 2016. We calculated a pooled prevalence estimate and 95% confidence interval (CI) using a random-effects model, and quantified heterogeneity across studies using the I2 statistic. Subgroup meta-analyses were performed to investigate sources of variability according to selection criteria for endometrial thickness (ET) and hormone replacement therapy (HRT). We also stratified by study location to determine whether prevalence estimates varied by country or region if ≤5 studies included per country. Results: 105 studies were included, contributing data for 37,000 women with PMB and 3,028 with cancer from 34 countries. Overall, the pooled prevalence of endometrial cancer in women with PMB was 11% (95% CI 10-12%), with I2 =94.3%. Among studies that selected women with a minimum ET (≥ 4mm; n=14), the pooled prevalence of endometrial cancer was 17% (95% CI 14-20%) compared with studies that did not select for ET (10%, 95% CI 9-11%). In studies that excluded women using HRT (n=34), the pooled prevalence of endometrial cancer was 15% (95% CI 12-17%) compared with studies that did not exclude women using HRT (9%, 95% CI 8-10%). Stratification by study location revealed variation in prevalence estimates. For example, in the United States (n=9) and the United Kingdom (n=16), prevalence of endometrial cancer was 4% (95% CI 2-7%) and 5% (95% CI 4-6%), respectively, whereas in Italy (n=14), the prevalence was 11% (95% 8-14%). Regional differences were also observed, ranging from 8% (95% CI 3-14%) in South Central Asia (n=5) to 18% (95% CI 12-23%) in Southern Europe (n=11). Conclusions: The overall prevalence of endometrial cancer among unselected women with PMB is approximately 10% with substantial heterogeneity across studies. Marked geographic differences in the prevalence endometrial cancer were observed. Factors related to selection for ET and/or HRT use may partially contribute to this variability. Risk prediction models depend on precise prevalence estimates for accurate prediction and utility in clinical management. More research is needed to test the applicability of endometrial cancer risk prediction models in high-risk subgroups and in study populations from diverse geographic regions. Citation Format: Megan A. Clarke, Beverly J. Long, Arena Del Mar Morillo, Jamie N. Bakkum-Gamez, Nicolas Wentzensen. The prevalence of endometrial cancer in women with postmenopausal bleeding: a systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 275. doi:10.1158/1538-7445.AM2017-275

Objective Genome‐wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger‐onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age‐at‐onset informed GWAS meta‐analysis, including a large younger‐onset SVS population, to identify novel associations with stroke. Methods We used a three‐stage age‐at‐onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10 −9 ). The lead single‐nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10 −5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues ( p = 9.4 × 10 −7 ) and DNA methylation at probe cg16596957 in whole blood ( p = 5.3 × 10 −6 ). Interpretation 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394

ObjectiveIn observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL‐C; as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH.MethodsWe performed 2 candidate‐gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL‐C as well as ICH risk.ResultsTwelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10−4) with no heterogeneity across studies (I2 = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL‐C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10−6).InterpretationGenetic variants in CETP associated with increased HDL‐C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL‐raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730–740

Purpose Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. Patients and Methods Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). Results The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). Conclusion The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.

ABSTRACTNeither breakpoints (BPs) nor epidemiological cutoff values (ECVs) have been established forCandidaspp. with anidulafungin, caspofungin, and micafungin when using the Sensititre YeastOne (SYO) broth dilution colorimetric method. In addition, reference caspofungin MICs have so far proven to be unreliable.Candidaspecies wild-type (WT) MIC distributions (for microorganisms in a species/drug combination with no detectable phenotypic resistance) were established for 6,007Candida albicans, 186C. dubliniensis, 3,188C. glabratacomplex, 119C. guilliermondii, 493C. krusei, 205C. lusitaniae, 3,136C. parapsilosiscomplex, and 1,016C. tropicalisisolates. SYO MIC data gathered from 38 laboratories in Australia, Canada, Europe, Mexico, New Zealand, South Africa, and the United States were pooled to statistically define SYO ECVs. ECVs for anidulafungin, caspofungin, and micafungin encompassing ≥97.5% of the statistically modeled population were, respectively, 0.12, 0.25, and 0.06 μg/ml forC. albicans, 0.12, 0.25, and 0.03 μg/ml forC. glabratacomplex, 4, 2, and 4 μg/ml forC. parapsilosiscomplex, 0.5, 0.25, and 0.06 μg/ml forC. tropicalis, 0.25, 1, and 0.25 μg/ml forC. krusei, 0.25, 1, and 0.12 μg/ml forC. lusitaniae, 4, 2, and 2 μg/ml forC. guilliermondii, and 0.25, 0.25, and 0.12 μg/ml forC. dubliniensis. Species-specific SYO ECVs for anidulafungin, caspofungin, and micafungin correctly classified 72 (88.9%), 74 (91.4%), 76 (93.8%), respectively, of 81Candidaisolates with identifiedfksmutations. SYO ECVs may aid in detecting non-WT isolates with reduced susceptibility to anidulafungin, micafungin, and especially caspofungin, since testing the susceptibilities ofCandidaspp. to caspofungin by reference methodologies is not recommended.

Background and Purpose— NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Methods— Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. Results— The distribution of pathogenic categories varied by study, age, sex, and race ( P <0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69–0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70–0.75). Conclusions— This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.