Background Alcohol consumption promotes hepatocellular carcinoma (HCC). The responsible mechanisms are not well understood. Hepatocarcinogenesis increases with age and is enhanced by factors that impose a demand for liver regeneration. Because alcohol is hepatotoxic, habitual alcohol ingestion evokes a recurrent demand for hepatic regeneration. The alcohol-preferring (P) rat model mimics the level of alcohol consumption by humans who habitually abuse alcohol. Previously, we showed that habitual heavy alcohol ingestion amplified age-related hepatocarcinogenesis in P-rats, with over 80% of alcohol-consuming P rats developing HCCs after 18 months of alcohol exposure, compared to only 5% of water-drinking controls. Methods Herein, we used quantitative real time PCR and quantitative immunocytochemistry to compare liver tissues from alcohol-consuming P rats and water-fed P rat controls after 6, 12, or 18 months of drinking. We aimed to identify potential mechanisms that might underlie the differences in liver cancer formation, and hypothesized that chronic alcohol ingestion would activate Hedgehog (HH), a regenerative signaling pathway that is over-activated in HCC. Results Chronic alcohol ingestion amplified age-related degenerative changes in hepatocytes, but did not cause appreciable liver inflammation or fibrosis even after 18 months of heavy drinking. HH signaling was also enhanced by alcohol exposure, as evidenced by increased levels of mRNAs encoding HH ligands, HH-regulated transcription factors, and HH-target genes. Immunocytochemistry confirmed increased alcohol-related accumulation of HH ligand-producing cells and HH-responsive target cells. HH-related regenerative responses were also induced in alcohol-exposed rats. Three of these processes (i.e., deregulated progenitor expansion, the reverse-Warburg effect, and epithelial-to-mesenchymal transitions) are known to promote cancer growth in other tissues. Conclusions Alcohol-related changes in Hedgehog signaling and resultant deregulation of liver cell replacement might promote hepatocarcinogenesis.

ObjectivesTo test the external validity of a previously developed risk table, designed to predict the probability of a positive bone scan among men with non-metastatic (M0) castrationresistant prostate cancer (CRPC), in a separate cohort. Patients and MethodsWe retrospectively analysed 429 bone scans of 281 patients with CRPC, with no known previous metastases, treated at three Veterans Affairs Medical Centers. We assessed the predictors of a positive scan using generalized estimating equations. Area under the curve (AUC), calibration plots and decision-curve analysis were used to assess the performance of our previous model to predict a positive scan in the current data. ResultsA total of 113 scans (26%) were positive. On multivariable analysis, the only significant predictors of a positive scan were log-transformed prostate-specific antigen (PSA): hazard ratio (HR) 2.13; 95% confidence interval (CI) 1.71-2.66 (P < 0.001) and log-transformed PSA doubling time (PSADT): HR 0.53; 95% CI 0.41-0.68 (P < 0.001). Among men with a PSA level <5 ng/mL, the rate of positive scans was 5%. The previously developed risk table had an AUC of 0.735 to predict positive bone scan with excellent calibration, and provided additional net benefit in the decision-curve analysis. ConclusionWe have validated our previously developed table to predict the risk of a positive bone scan among men with M0/Mx CRPC. Use of this risk table may allow better tailoring of patients' scanning to identify metastases early, while minimizing over-imaging. Regardless of PSADT, positive bone scans were rare in men with a PSA <5 ng/mL.

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Background: There are limited contemporary, national data describing diagnostic cardiac catheterization with subsequent percutaneous coronary intervention (ad hoc percutaneous coronary intervention [PCI]) performed by an invasive-diagnostic and interventional (Dx/IC) operator team versus solo interventional operator (solo-IC). Using the CathPCI Registry, this study aimed at analyzing trends and outcomes in ad hoc PCI among Dx/IC versus solo-IC operators. Methods: Quarterly rates (January 2012 to March 2018) of ad hoc PCI cases by Dx/IC and solo-IC operators were obtained. Odds of inhospital major adverse cardiovascular events, net adverse cardiovascular events (ie, composite major adverse cardiovascular event+bleeding), and rarely appropriate PCI were estimated using multivariable regression. Results: From 1077 sites, 1 262 948 patients were included. The number of invasive-diagnostic operators and cases performed by Dx/IC teams decreased from nearly 9% to 5% during the study period. Patients treated by Dx/IC teams were more often White and had fewer comorbidities compared with patients treated by solo-IC operators. Considerable variation existed across sites, and over two-fifths of sites had 0% ad hoc PCI performed by Dx/IC. In adjusted analyses, ad hoc performed by Dx/IC had similar risks of major adverse cardiovascular event (OR, 1.04 [95% CI, 0.97–1.11]) and net adverse cardiovascular events (OR, 0.98 [95% CI, 0.94–1.03]) compared with solo-IC. Rarely appropriate PCI, although low overall (2.1% versus 1.9%) occurred more often by Dx/IC compared with solo-IC (OR, 1.20 [95% CI, 1.13–1.26]). Conclusions: Contemporary, nationwide data from the CathPCI Registry demonstrates the number of Dx/IC operator teams and cases has decreased but that case volume is stable among operators. Outcomes were independent of operator type, which supports current practice patterns. The finding of a higher risk of rarely appropriate PCI in Dx/IC teams should be further studied.