Citations

Context.— The College of American Pathologists (CAP) developed proficiency testing for platelet function assays by using blood collected by the participant added to challenge tubes containing either saline (normal) or tirofiban (abnormal). Objective.— To analyze platelet function proficiency testing for Platelet Function Analyzer PFA-100, platelet aggregation, PlateletWorks, and PlateletMapping. Design.— Proficiency testing data from 2012–2016 were analyzed. Results.— For PFA-100, a total of 1200 laboratories participated; the coefficient variation (CV) of cartridge closure times was 22% (saline); 44,952 of 45,616 survey responses (99%) provided an interpretation, and 42,934 of 44,952 (96%) were correct. For optical platelet aggregation, 190 laboratories participated; the CV was 17% (saline), 7444 of 7813 survey responses (95%) provided an interpretation, and 7015 of 7444 (94%) were correct. For PlateletWorks, 60 laboratories participated; the CV was 3% to 11% (saline); 2412 of 2454 survey responses (98%) provided an interpretation, and 1207 of 1276 (95%) were correct for adenosine diphosphate (ADP) and 936 of 1136 (82%) for collagen. For PlateletMapping, 200 laboratories participated. For ADP, 1128 of 2697 survey responses (42%) provided an interpretation, but only 927 of 1128 (82%) were correct. For arachidonic acid, 1139 of 2604 survey responses (44%) provided an interpretation and 964 of 1139 (85%) were correct. Conclusions.— CAP is the first to provide proficiency testing for platelet aggregation, PlateletWorks, and PlateletMapping. Platelet aggregation, PFA-100, and PlateletWorks using ADP as an agonist performed well with more than 90% of laboratories providing an interpretation and a similar number providing correct results. PlateletWorks using collagen and PlateletMapping showed worse interpretive accuracy than the other methods.

Abstract Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. Significance: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene. See related commentary by Choi and Brown, p. 439

Abstract Background: The GALAD score is a serum biomarker–based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison with liver ultrasound for detection of HCC. Methods: A single-center cohort of 111 HCC patients and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) phase II HCC Study were analyzed. Results: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI), 0.93–97], which was higher than the AUC of ultrasound (0.82, P <0.01). At a cutoff of −0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early-stage HCC detection remained high at 0.92 (95% CI, 0.88–0.96; cutoff −1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85–0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single-center cohort, achieving an AUC of 0.98 (95% CI, 0.96–0.99; cutoff −0.18, sensitivity 95%, specificity 91%). Conclusions: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score. Impact: The GALAD score was validated in the United States.

AbstractBackground/AimsHypothyroidism has been associated with hepatocellular carcinoma (HCC) incidence; however, the relationship between hypothyroidism and HCC patient outcomes is unclear. We investigated the impact of hypothyroidism on outcomes after liver transplantation for HCC.Materials and MethodsWe retrospectively studied HCC patients transplanted between January 2000 and December 2015. Hypothyroidism was defined as a thyroid‐stimulating hormone (TSH) level continuously greater than 5 mIU/L, a documented history of hypothyroidism, or treatment with thyroid hormone replacement therapy. Multivariate Cox regression was used to assess the impact of hypothyroidism on overall survival (OS) and recurrence‐free survival (RFS) adjusting for potential confounders. Subgroup analyses and interaction tests were conducted to compare the impact of hypothyroidism in different subgroups and assess for possible synergistic effects. Sensitivity analyses were performed among different cohorts to verify the stability of the results.ResultsA total of 343 HCC patients who underwent liver transplantation were included in the analysis. The primary analysis was conducted among 288 patients diagnosed with HCC prior to transplantation. Hypothyroidism was independently associated with worse OS and RFS, as was elevated TSH. The adjusted hazard ratio (AHR) of hypothyroidism was 2.45 (95% confidence interval [CI], 1.44‐4.18) for OS and 5.54 (2.36, 13.01) for RFS. The AHR of TSH for OS was 1.05 (1.02, 1.09) and 1.08 (1.03, 1.13) for RFS. No interaction was found among different subgroups categorized by etiology and comorbidity. The results were stable to sensitivity analyses.ConclusionHypothyroidism is associated with poorer overall and recurrence‐free survival of HCC patients receiving liver transplantation. These results require validation.

SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss‐of‐function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation‐positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow‐growing hypothalamo‐pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.