Real-life assessment of standardized contrast-enhanced ultrasound (CEUS) and CEUS algorithms (CEUS LI-RADS®/ESCULAP) in hepatic nodules in cirrhotic patients—a prospective multicenter study

Objectives Hepatocellular carcinoma (HCC) can be diagnosed non-invasively with contrast-enhanced ultrasound (CEUS) in cirrhosis if the characteristic pattern of arterial phase hyperenhancement followed by hypoenhancement is present. Recent studies suggest that diagnosis based on this “hyper-hypo” pattern needs further refinement. This study compares the diagnostic accuracies of standardized CEUS for HCC according to the current guideline definition and following the newly developed CEUS algorithms (CEUS LI-RADS®, ESCULAP) in a prospective multicenter real-life setting. Methods Cirrhotic patients with liver lesions on B-mode ultrasound were recruited prospectively from 04/2018 to 04/2019, and clinical and imaging data were collected. The CEUS standard included an additional examination point after 4–6 min in case of no washout after 3 min. The diagnostic accuracies of CEUS following the guidelines (“hyper-hypo” pattern), based on the examiner’s subjective interpretation (“CEUS subjective”), and based on the CEUS algorithms ESCULAP and CEUS LI-RADS® were compared. Results In total, 470 cirrhotic patients were recruited in 43 centers. The final diagnosis was HCC in 378 cases (80.4%) according to the reference standard (histology 77.4%, MRI 16.4%, CT 6.2%). The “hyper-hypo” pattern yielded 74.3% sensitivity and 63% specificity. “CEUS subjective” showed a higher diagnostic accuracy (sensitivity, 91.5%; specificity, 67.4%; positive predictive value, 92%; negative predictive value, 66%). Sensitivity was higher for ESCULAP (95%) and “CEUS subjective” (91.5%) versus CEUS LI-RADS® (65.2%; p < 0.001). Specificity was highest for CEUS LI-RADS® (78.6%; p < 0.001). Conclusions CEUS has an excellent diagnostic accuracy for the non-invasive diagnosis of HCC in cirrhosis. CEUS algorithms may be a helpful refinement of the “hyper-hypo” pattern defined by current HCC guidelines. Key Points • Contrast-enhanced ultrasound (CEUS) has a high diagnostic accuracy for the non-invasive diagnosis of hepatocellular carcinoma (HCC) in cirrhosis. • The CEUS algorithm ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) showed the highest sensitivity, whereas the CEUS LI-RADS® (Contrast-Enhanced UltraSound Liver Imaging Reporting and Data System) algorithm yielded the highest specificity. • A standardized CEUS examination procedure with an additional examination point in the late phase, after 4–6 min in lesions with no washout after 3 min, is vital

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Real-life assessment of standardized contrast-enhanced ultrasound (CEUS) and CEUS algorithms (CEUS LI-RADS®/ESCULAP) in hepatic nodules in cirrhotic patients—a prospective multicenter study

Objectives Hepatocellular carcinoma (HCC) can be diagnosed non-invasively with contrast-enhanced ultrasound (CEUS) in cirrhosis if the characteristic pattern of arterial phase hyperenhancement followed by hypoenhancement is present. Recent studies suggest that diagnosis based on this "hyper-hypo" pattern needs further refinement. This study compares the diagnostic accuracies of standardized CEUS for HCC according to the current guideline definition and following the newly developed CEUS algorithms (CEUS LI-RADS (R), ESCULAP) in a prospective multicenter real-life setting. Methods Cirrhotic patients with liver lesions on B-mode ultrasound were recruited prospectively from 04/2018 to 04/2019, and clinical and imaging data were collected. The CEUS standard included an additional examination point after 4-6 min in case of no washout after 3 min. The diagnostic accuracies of CEUS following the guidelines ("hyper-hypo" pattern), based on the examiner's subjective interpretation ("CEUS subjective"), and based on the CEUS algorithms ESCULAP and CEUS LI-RADS (R) were compared. Results In total, 470 cirrhotic patients were recruited in 43 centers. The final diagnosis was HCC in 378 cases (80.4%) according to the reference standard (histology 77.4%, MRI 16.4%, CT 6.2%). The "hyper-hypo" pattern yielded 74.3% sensitivity and 63% specificity. "CEUS subjective" showed a higher diagnostic accuracy (sensitivity, 91.5%; specificity, 67.4%; positive predictive value, 92%; negative predictive value, 66%). Sensitivity was higher for ESCULAP (95%) and "CEUS subjective" (91.5%) versus CEUS LI-RADS (R) (65.2%; p < 0.001). Specificity was highest for CEUS LI-RADS (R) (78.6%; p < 0.001). Conclusions CEUS has an excellent diagnostic accuracy for the non-invasive diagnosis of HCC in cirrhosis. CEUS algorithms may be a helpful refinement of the "hyper-hypo" pattern defined by current HCC guidelines

Inhibition of ataxia telangiectasia- and Rad3-related function abrogates the in vitro and in vivo tumorigenicity of human colon cancer cells through depletion of the CD133^+&nbsp;tumor-initiating cell fraction.

The identification of novel approaches to specifically target the DNA-damage checkpoint response in chemotherapy-resistant cancer stem cells (CSC) of solid tumors has recently attracted great interest. We show here in colon cancer cell lines and primary colon cancer cells that inhibition of checkpoint-modulating phosphoinositide 3-kinase-related (PIK) kinases preferentially depletes the chemoresistant and exclusively tumorigenic CD133(+) cell fraction. We observed a time- and dose-dependent disproportionally pronounced loss of CD133(+) cells and the consecutive lack of in vitro and in vivo tumorigenicity of the remaining cells. Depletion of CD133(+) cells was initiated through apoptosis of cycling CD133(+) cells and further substantiated through subsequent recruitment of quiescent CD133(+) cells into the cell cycle followed by their elimination. Models using specific PIK kinase inhibitors, somatic cell gene targeting, and RNA interference demonstrated that the observed detrimental effects of caffeine on CSC were attributable specifically to the inhibition of the PIK kinase ataxia telangiectasia- and Rad3-related (ATR). Mechanistically, phosphorylation of CHK1 checkpoint homolog (S. pombe; CHK1) was significantly enhanced in CD133(+) as compared with CD133(-) cells on treatment with DNA interstrand-crosslinking (ICL) agents, indicating a preferential activation of the ATR/CHK1-dependent DNA-damage response in tumorigenic CD133(+) cells. Consistently, the chemoresistance of CD133(+) cells toward DNA ICL agents was overcome through inhibition of ATR/CHK1-signaling. In conclusion, our study illustrates a novel target to eliminate the tumorigenic CD133(+) cell population in colon cancer and provides another rationale for the development of specific ATR-inhibitors