The size of juxtaluminal hypoechoic area in ultrasound images of asymptomatic carotid plaques predicts the occurrence of stroke

Objective: To test the hypothesis that the size of a juxtaluminal black (hypoechoic) area (JBA) in ultrasound images of asymptomatic carotid artery plaques predicts future ipsilateral ischemic stroke. Methods: A JBA was defined as an area of pixels with a grayscale value <25 adjacent to the lumen without a visible echogenic cap after image normalization. The size of a JBA was measured in the carotid plaque images of 1121 patients with asymptomatic carotid stenosis 50% to 99% in relation to the bulb (Asymptomatic Carotid Stenosis and Risk of Stroke study); the patients were followed for up to 8 years. Results: The JBA had a linear association with future stroke rate. The area under the receiver-operating characteristic curve was 0.816. Using Kaplan-Meier curves, the mean annual stroke rate was 0.4% in 706 patients with a JBA <4 mm 2, 1.4% in 171 patients with a JBA 4 to 8 mm2, 3.2% in 46 patients with a JBA 8 to 10 mm2, and 5% in 198 patients with a JBA >10 mm2 (P <.001). In a Cox model with ipsilateral ischemic events (amaurosis fugax, transient ischemic attack [TIA], or stroke) as the dependent variable, the JBA (<4 mm2, 4-8 mm2, >8 mm2) was still significant after adjusting for other plaque features known to be associated with increased risk, including stenosis, grayscale median, presence of discrete white areas without acoustic shadowing indicating neovascularization, plaque area, and history of contralateral TIA or stroke. Plaque area and grayscale median were not significant. Using the significant variables (stenosis, discrete white areas without acoustic shadowing, JBA, and history of contralateral TIA or stroke), this model predicted the annual risk of stroke for each patient (range, 0.1%-10.0%). The average annual stroke risk was <1% in 734 patients, 1% to 1.9% in 94 patients, 2% to 3.9% in 134 patients, 4% to 5.9% in 125 patients, and 6% to 10% in 34 patients. Conclusions: The size of a JBA is linearly related to the risk of stroke and can be used in risk stratification models. These findings need to be confirmed in future prospective studies or in the medical arm of randomized controlled studies in the presence of optimal medical therapy. In the meantime, the JBA may be used to select asymptomatic patients at high stroke risk for carotid endarterectomy and spare patients at low risk from an unnecessary operation

The comparative responsiveness of Hospital Universitario Princesa Index and other composite indices for assessing rheumatoid arthritis activity

Objective To evaluate the responsiveness in terms of correlation of the Hospital Universitario La Princesa Index (HUPI) comparatively to the traditional composite indices used to assess disease activity in rheumatoid arthritis (RA), and to compare the performance of HUPI-based response criteria with that of the EULAR response criteria. Methods Secondary data analysis from the following studies: ACT-RAY (clinical trial), PROAR (early RA cohort) and EMECAR (pre-biologic era long term RA cohort). Responsiveness was evaluated by: 1) comparing change from baseline (Delta) of HUPI with Delta in other scores by calculating correlation coefficients; 2) calculating standardised effect sizes. The accuracy of response by HUPI and by EULAR criteria was analyzed using linear regressions in which the dependent variable was change in global assessment by physician (Delta GDA-Phy). Results Delta HUPI correlation with change in all other indices ranged from 0.387 to 0.791); HUPI's standardized effect size was larger than those from the other indices in each database used. In ACT-RAY, depending on visit, between 65 and 80% of patients were equally classified by HUPI and EULAR response criteria. However, HUPI criteria were slightly more stringent, with higher percentage of patients classified as non-responder, especially at early visits. HUPI response criteria showed a slightly higher accuracy than EULAR response criteria when using Delta GDA-Phy as gold standard. Conclusion HUPI shows good responsiveness in terms of correlation in each studied scenario (clinical trial, early RA cohort, and established RA cohort). Response criteria by HUPI seem more stringent than EULAR''s

Upregulated miR-16 expression is an independent indicator of relapse and poor overall survival of colorectal adenocarcinoma patients

Colorectal adenocarcinoma is one of the most common malignant tumors of the gastrointestinal tract and the second leading cause of cancer-related deaths among adults in Western countries. miR-16 is heavily involved in cancer progression. In this study, we examined the potential diagnostic and prognostic utility of miR-16 expression in colorectal adenocarcinoma. Total RNA was extracted from 182 colorectal adenocarcinoma specimens and 86 non-cancerous colorectal mucosae. After polyadenylation of 2 μg total RNA by poly(A) polymerase and subsequent reverse transcription with an oligo-dT adapter primer, miR-16 expression was determined using an in-house developed reverse transcription quantitative real-time PCR method, based on SYBR Green chemistry. SNORD43 (RNU43) and SNORD48 (RNU48) were used as reference genes. Next, we performed extensive biostatistical analysis. miR-16 was shown to be significantly upregulated in colorectal adenocarcinoma specimens compared to non-cancerous colorectal mucosae, suggesting its potential exploitation for diagnostic purposes. Moreover, high miR-16 expression predicts poor disease-free survival (DFS) and overall survival (OS) of colorectal adenocarcinoma patients. Multivariate Cox regression analysis confirmed that miR-16 overexpression is a significant unfavorable prognosticator in colorectal adenocarcinoma, independent of other established prognostic factors, radiotherapy, and chemotherapy. Interestingly, miR-16 overexpression retains its unfavorable prognostic value in patients with advanced yet locally restricted colorectal adenocarcinoma that has not grown through the wall of the colon or rectum (T3) and in those without distant metastasis (M0). Overexpression of the cancer-associated miR-16 predicts poor DFS and OS of colorectal adenocarcinoma patients, independently of clinicopathological factors that are currently used for prognostic purposes. © 2017 Walter de Gruyter GmbH, Berlin/Boston

MicroRNA-155-5p Overexpression in Peripheral Blood Mononuclear Cells of Chronic Lymphocytic Leukemia Patients Is a Novel, Independent Molecular Biomarker of Poor Prognosis

MicroRNA-155-5p (miR-155-5p) is a proinflammatory, oncogenic miRNA, involved in various physiological processes, including hematopoiesis, immunity, inflammation, and cell lineage differentiation. It regulates important transcription factors, such as E2F2, hypoxia-inducible factor 1 (HIF1), and FOXO3. Recently, the dysregulation of miR-155-5p expression has been linked to chronic lymphocytic leukemia (CLL) pathogenesis. In this research study, we investigated the potential diagnostic and prognostic value of miR-155-5p in CLL. To achieve our goal, we isolated total RNA from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients and 36 nonleukemic blood donors and performed polyadenylation of total RNA and reverse transcription. Next, we quantified miR-155-5p levels using an in-house-developed real-time quantitative PCR method, before proceeding to extensive biostatistical analysis. Thus, it appears that miR-155-5p is significantly overexpressed in PBMCs of CLL patients and can distinguish them from nonleukemic population. Kaplan-Meier OS analysis and bootstrap univariate Cox regression showed that high miR-155-5p expression predicts inferior OS for CLL patients (p<0.001). Interestingly, miR-155-5p overexpression retains its unfavorable prognostic role in CLL patients stratified according to established prognostic factors [CD38 expression and mutational status of the immunoglobulin heavy chain variable region (IGHV)]. Thus, miR-155-5p appears as a promising, independent molecular biomarker of unfavorable prognosis in CLL. © 2017 Sotirios G. Papageorgiou et al

MicroRNA-92a-3p overexpression in peripheral blood mononuclear cells is an independent predictor of prolonged overall survival of patients with chronic lymphocytic leukemia

MicroRNA-92a-3p (miR-92a-3p) derives from the oncogenic miR-17/92 cluster and its highly homologous miR-106a/363 cluster. miR-92a-3p regulates the expression of key transcription factors such as HIF1 and inhibits SOCS1 to enhance the anti-apoptotic STAT3/IL6 signaling pathway. In this study, we assessed the putative usefulness of miR-92a-3p as a prognostic and/or diagnostic biomarker in chronic lymphocytic leukemia (CLL). For this purpose, total RNA was extracted from mononuclear cells isolated from the peripheral blood of 88 CLL patients and 36 non-leukemic blood donors, was polyadenylated and reversely transcribed. miR-92a-3p expression was quantified using an accurate qPCR method. miR-92a-3p levels were significantly lower in peripheral blood mononuclear cells of CLL patients. Overall survival (OS) analysis revealed that high miR-92a-3p expression predicts significantly prolonged OS of CLL patients. Interestingly, miR-92a-3p overexpression remains a significant prognosticator in subgroups of CLL patients with distinct prognosis. In conclusion, miR-92a-3p overexpression is a potential surrogate biomarker of favorable outcome of CLL patients. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group

mRNA overexpression of the hypoxia inducible factor 1 alpha subunit gene (HIF1A): An independent predictor of poor overall survival in chronic lymphocytic leukemia

The hypoxia inducible factor 1 (HIF1) is a heterodimeric transcription factor that ultimately regulates cellular responses to changes in oxygen tension. In this study, we examined the potential diagnostic and prognostic potential of the mRNA expression of HIF1 regulatory α-subunit (HIF1A) in chronic lymphocytic leukemia (CLL). For this purpose, total RNA was isolated from peripheral blood mononuclear cells collected from 88 CLL patients and 33 non-leukemic blood donors, and poly(A)-RNA was reversely transcribed. HIF1A mRNA levels were quantified using real-time PCR. Kaplan-Meier survival analysis showed that high HIF1A mRNA expression predicts inferior overall survival for CLL patients (p = 0.001). Bootstrap univariate Cox regression analysis confirmed that HIF1A mRNA overexpression is a significant unfavorable prognosticator in CLL (hazard ratio = 3.75, bias-corrected and accelerated 95% confidence interval = 1.43–24.36, bootstrap p < 0.001), independent of other established prognostic factors, including CD38 expression, the mutational status of the immunoglobulin heavy chain variable region (IGHV), and the clinical stage (Binet or Rai stage) or risk group (p < 0.001 in all cases). Interestingly, HIF1A mRNA positivity retains its unfavorable prognostic value in distinct subgroups of patients, stratified according to established prognostic factors. Thus, HIF1A mRNA overexpression can be regarded as a promising, independent molecular biomarker of unfavorable prognosis in CLL. © 2016 Elsevier Lt

The outcome of patients with high-risk MDS achieving stable disease after treatment with 5-azacytidine: A retrospective analysis of the Hellenic (Greek) MDS Study Group

The demethylating factor 5-azacytidine (5-AZA) improves survival in intermediate-2 and high-risk myelodysplastic syndrome (MDS) patients [according to the International Prognostic Score System (IPSS)] responding to treatment. However, the outcome of patients achieving stable disease (SD) is unclear. This retrospective study of the Hellenic MDS Study Group included 353 intermediate-2 or high IPSS risk patients treated with 5-AZA. Forty-four out of 86 (51.6%) patients achieving SD and continuing treatment with 5-AZA showed a lower risk of transformation of MDS to acute myeloid leukemia (AML) and increased overall survival (OS), compared to SD patients who discontinued the treatment (estimated median AML-free survival = 38 months, 95% CI = 10.7-65.3 vs 15 months, 95% CI = 10.4-19.6, P <.001; estimated median OS = 20 months, 95% CI = 5.5-34.5 vs 11 months, 95% CI = 5.8-16.2, P <.001). Moreover, SD patients continuing treatment with 5-AZA had no differences in AML-free survival compared to patients showing response to 5-AZA (estimated median AML-free survival = 38 months, 95% CI = 10.7-65.3 vs 31 months, 95% CI = 23.6-38.4, P =.45; estimated median OS 20 months, 95% CI = 5.5-34.5 vs 25 months, 95% CI = 21.3-28.7, P =.50). In conclusion, MDS patients achieving SD in the first 6 months of treatment with 5-AZA as best response should continue receiving 5-AZA as they may benefit from prolonged treatment. © 2018 John Wiley & Sons, Ltd