Citations

Objectives: Assessment of carotid disease is most commonly performed with duplex ultrasonography (DUS). Measures of plaque area and tissue composition from DUS images may identify patients at risk for future neurologic events, and may assess the effects of vascular risk-factor modification (by measuring change in plaque area and/or tissue constituents). We quantified plaque area and tissue constituents from DUS images of CREST-2 participants at baseline and correlated them with their baseline vascular risk factors. Methods: CREST-2 consists of two multicenter, randomized trials in patients with asymptomatic ≥70% carotid stenosis comparing intensive medical management (IMM) plus endarterectomy or stenting vs IMM alone. Baseline B-mode DUS images from 500 patients underwent manual plaque outlining and automatic pixel brightness assessment. Plaque area, grayscale median (GSM), Gray-Weale score for heterogeneity, and areas for intraplaque hemorrhage and lipid were the output parameters. We computed the parameter estimates (95% confidence intervals) for baseline patient characteristics (age, sex, race, diabetes, smoking, BMI, blood pressure and LDL levels) versus plaque characteristics. Results: High-risk plaque features (larger plaque area, lower GSM , lower Gray-Weale scores, or larger areas of hemorrhage and lipid) were present in older patients, males, and those with elevated diastolic blood pressure and LDL levels (Table). Conclusions: In a randomized trial of asymptomatic patients with high-grade carotid stenosis, DUS-based computation of plaque geometry and tissue composition is feasible. Elevated diastolic blood pressure and LDL levels at baseline are associated with high-risk plaque characteristics. These novel findings identify potentially modifiable targets for aggressive treatment to reduce stroke-risk in patients with carotid stenosis.

Background: The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) previously reported increased mortality in patients who sustained a periprocedural stroke or cardiac event (myocardial infarction [MI] or biomarker only) in follow-up to 4 years. We now extend these observations to 10 years. Methods and Results: CREST is a randomized controlled trial designed to compare the outcomes of carotid stenting versus carotid endarterectomy. Proportional hazards models were used to assess the association between mortality and periprocedural stroke, MI, or biomarker-only events. For 10-year follow-up, patients with periprocedural stroke were at 1.74× the risk of death compared with those without stroke (adjusted hazard ratio [HR]=1.74; 95% CI, 1.21–2.50; P <0.003). This increased risk was driven by increased early (between 0 and 90 days) mortality (adjusted HR=14.41; 95% CI, 5.33–38.94; P <0.0001), with no significant increase in late (between 91 days and 10 years) mortality (adjusted HR=1.40; 95% CI, 0.93–2.10; P =0.11). Patients with a protocol MI were at 3.61× increased risk of death compared with those without MI (adjusted HR=3.61; 95% CI, 2.28–5.73; P <0.0001), with an increased hazard both early (adjusted HR=8.20; 95% CI, 1.86–36.2; P =0.006) and late (adjusted HR=3.40; 95% CI, 2.09–5.53; P <0.0001). Patients with a biomarker-only event were at 2.04× increased risk overall (adjusted HR=2.04; 95% CI, 1.09–3.84; P =0.03) than those without MI, with an increased early hazard (adjusted HR=8.44; 95% CI, 1.09–65.5; P =0.04) and a suggestive but nonsignificant association toward higher 91-day to 10-year risk (1.88; 95% CI, 0.97–3.64; P =0.062) contributing to the increased risk. Conclusions: In the CREST trial, patients with periprocedural events demonstrate a substantial increase in future mortality to 10 years. For stroke, this risk is largely confined to an early time frame while periprocedural MI or biomarker-only events confer a continuous increased mortality for 10 years. Strategies to reduce periprocedural events and to optimize the evaluation and management of patients with cardiac events should be considered in efforts to reduce not only early but also long-term mortality. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00004732.

Background The Nepean Dyspepsia Index (NDI) has been in widespread use since its publication in 1999 and the addition of a short form in 2001. The NDI was one of the first disease-specific quality-of-life instruments created for functional dyspepsia (FD). However, its psychometric properties have never been validated in an independent sample. Aim This study aimed to evaluate the validity and reliability of the NDI in an a-priori driven approach in an independent population. Patients and methods In 289 individuals who fulfilled the Rome criteria for FD enrolled in a randomized placebo-controlled trial (FD treatment trial), we examined construct validity, convergent validity, and internal consistency. Results Construct validity was supported in its 25-item unweighted and weighted forms as well as the 10-item short form. All items in the 25-item form yielded considerable (>0.5) standardized loadings on their respective latent variables and all reached statistical significance ( P <0.0001), supporting their relationships with the hypothesized domains. Convergent validity was strongly supported, with every domain being correlated with multiple external instruments; the majority of correlations were in the range 0.3–0.5 (in absolute values). The items comprising each domain showed good internal consistency, with the lowest value of Chronbach α at 0.80. Scores based on the short form (10-item) version of the NDI correlated strongly with the full 25-item form (tension ρ =0.88, interference ρ =0.94, eat/drink ρ =0.95, knowledge ρ =0.84 and work/study ρ =0.97; all P <0.0001). Conclusion The NDI is a valid instrument that can be used to measure the disease-specific impact of FD on quality of life.

Background: In CREST2, intensive medical management of subjects’ vascular risk factors is overseen by the site Principal Investigator (PI) and implemented by a designated Medical Management Physician (MMP) and coordinator. These physicians have different specialties and experience with risk factor management. We sought to determine the relationship between risk factor control and PI and MMP specialty. Methods: Data on 613 patients with at least 1 follow-up visit from 105 CREST2 sites were used for these analyses. CREST2 sites were categorized based on both PI specialty and MMP specialty. Specialty of the site-designated primary MMP was used for sites with more than one MMP. We compared the percentage of patients in target at last follow-up visit for the primary risk factors, LDL < 70 mg/dL and SBP <140 mm Hg, among PI specialties and MMP specialties, using the chi-square test. Results: The table shows the number of patients by PI and MMP specialty, as well as their control of SBP and LDL. There were no significant differences in control of SBP or LDL by PI specialty. There was a trend toward an association between LDL control and MMP specialty, with higher rates of LDL control at sites with Internal Medicine MMP specialists and lower rates of control with Vascular Surgery MMPs. SBP control rates were not significantly different across MMP specialties. Conclusions: In this early analysis of risk factor control in the CREST2 study, site PI and MMP specialty did not have a significant effect on LDL and SBP during follow-up. This suggests that protocol care pathways are generalizable to diverse physicians.

Rationale: Asymptomatic carotid stenosis is commonly seen in medical practice. CREST-2 is a pair of concurrent two-arm multi-site randomized trials of intensive medical management versus intensive medical management in combination with revascularization by endarterectomy or stenting. It is not known how often patients entering the trials have opportunities for further risk factor reduction at study entry and whether these opportunities vary across trial centers. Methods: Baseline data on 683 patients from 109 clinical sites were used for these analyses. We determined the rates of control at baseline for systolic blood pressure (SBP), defined as <140 mmHg (or ≥140 with >15mmHg orthostatic drop), and low density lipoprotein (LDL), defined as <70 mg/dl. We then tested differences in these baseline control rates by site-related characteristics, including site type, StrokeNet site vs. not, specialty of site Principal Investigator (PI), type of hospital, central vs local IRB, type of research team and whether site is enrolling in one or both trials. P-value <0.05 was considered significant. Results: At baseline, the mean SBP was 140.4±20.5 mmHg, but only 62% of participants were in target. The mean LDL at baseline was 83.7±36.9, mg/dl, with 42% in target. None of the site characteristics were associated with a higher level of control for SBP at baseline. The only characteristic associated with having a higher level of LDL control was sites enrolling in only the CAS trial (57%) compared to those enrolling in the CEA only (24%) or in both trials (42%) (p=0.02). Conclusions: Opportunities to improve on risk factors are common among CREST-2 participants, but site characteristics did not predict the likelihood of being at goal for SBP while sites enrolling in only the CAS trial had a higher level of LDL control.

AbstractWe aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical‐grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis‐associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47–2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30–2.75, p = 0.004), while absence was associated with shorter OS in low‐grade serous carcinomas (HR: 2.95, 95% CI 1.61–5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype‐specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.

Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by levels of histologic grade and proliferation. We pooled risk factor and pathology data on 5,905 HR+ breast cancer cases and 26,281 controls from 11 epidemiological studies. Proliferation was determined by centralized automated measures of KI67 in tissue microarrays. Odds ratios (OR), 95% confidence intervals (CI) and p‐values for case–case and case–control comparisons for risk factors in relation to levels of grade and quartiles (Q1–Q4) of KI67 were estimated using polytomous logistic regression models. Case–case comparisons showed associations between nulliparity and high KI67 [OR (95% CI) for Q4 vs. Q1 = 1.54 (1.22, 1.95)]; obesity and high grade [grade 3 vs. 1 = 1.68 (1.31, 2.16)] and current use of combined hormone therapy (HT) and low grade [grade 3 vs. 1 = 0.27 (0.16, 0.44)] tumors. In case–control comparisons, nulliparity was associated with elevated risk of tumors with high but not low levels of proliferation [1.43 (1.14, 1.81) for KI67 Q4 vs. 0.83 (0.60, 1.14) for KI67 Q1]; obesity among women ≥50 years with high but not low grade tumors [1.55 (1.17, 2.06) for grade 3 vs. 0.88 (0.66, 1.16) for grade 1] and HT with low but not high grade tumors [3.07 (2.22, 4.23) for grade 1 vs. 0.85 (0.55, 1.30) for grade 3]. Menarcheal age and family history were similarly associated with HR+ tumors of different grade or KI67 levels. These findings provide insights into the etiologic heterogeneity of HR+ tumors.