Optimal patient selection for radiotherapy in pancreatic ductal adenocarcinoma (PDAC) is unestablished. Molecular profiling may select patients at high risk for locoregional recurrence (LRR) who would benefit from radiation.We included resectable pancreatic cancer (R-PDAC) patients, divided into training and validation cohorts, treated among three institutions with surgery and adjuvant chemotherapy, and borderline resectable or locally advanced pancreatic cancer (BR/LA-PDAC) patients treated with chemotherapy with or without radiation at the primary study institution. We isolated RNA from R-PDAC surgical specimens. Using NanoString, we identified miRNAs differentially expressed between normal and malignant pancreatic tissue. ElasticNet regression identified two miRNAs most predictive of LRR in the training cohort, miR-181b/d and miR-575, which were used to generate a risk score (RS). We evaluated the association of the median-dichotomized RS with recurrence and overall survival (OS).We identified 183 R-PDAC and 77 BR/LA-PDAC patients with median follow up of 37 months treated between 2001 and 2014. On multivariable analysis of the R-PDAC training cohort (n = 90), RS was associated with worse LRR (HR = 1.34; 95%CI 1.27-11.38; p = 0.017) and OS (HR = 2.89; 95%CI 1.10-4.76; p = 0.027). In the R-PDAC validation cohort, RS was associated with worse LRR (HR = 2.39; 95%CI 1.03-5.54; p = 0.042), but not OS (p = 0.087). For BR/LA-PDAC, RS was associated with worse LRR (HR = 2.71; 95%CI 1.14-6.48; p = 0.025), DR (HR = 1.93; 95%CI 1.10-3.38; p = 0.022), and OS (HR = 1.97; 95%CI 1.17-3.34; p = 0.011). Additionally, after stratifying by RS and receipt of radiation in BR/LA-PDAC patients, high RS patients who did not receive radiation had worse LRR (p = 0.018), DR (p = 0.006), and OS (p < 0.001) compared to patients with either low RS or patients who received radiation, irrespective of RS.RS predicted worse LRR and OS in R-PDAC and worse LRR, DR, and OS in BR/LA-PDAC. This may select patients who would benefit from radiation and should be validated prospectively.
Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high-fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte-derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4-/- ), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro.Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).
The Liver Imaging Reporting and Data System (LI-RADS) was created to standardize the diagnostic criteria for hepatocellular carcinoma (HCC) and has undergone multiple revisions including a recent update in 2018 (v2018). The primary aim of this study was to determine the diagnostic performance and interrater reliability (IRR) of LI-RADS v2018 for distinguishing HCC from non-HCC primary hepatic malignancy in patients 'at-risk' for HCC. A secondary aim was to assess the impact of changes introduced in the v2018 diagnostic algorithm.This retrospective study combined a 10-year experience of pathologically proven primary liver malignancies from two large liver transplant centers. Two blinded readers independently evaluated each lesion and assigned a LI-RADS diagnostic category, additionally scoring all relevant imaging features. Changes in category based on the reader-provided features and the new v2018 criteria were assessed by a study coordinator.The final study cohort comprised 105 HCCs and 73 non-HCC primarily liver malignancies. LI-RADS had a high specificity for distinguishing HCC from non-HCC (89% and 90% for reader 1 and reader 2, respectively), and IRR was moderate to substantial for final LI-RADS category and most features. Revision of the LI-RADS v2018 diagnostic algorithm resulted in very few changes [5 (2.8%) and 3 (1.7%) for reader 1 and reader 2, respectively] in overall lesion classification.LI-RADS diagnostic categories and features had moderate to substantial IRR and high specificity for distinguishing HCC from non-HCC primary liver malignancy. Revision of LI-RADS v2018 diagnostic algorithm resulted in reclassification of very few lesions.
Abstract Objective Cancer caregivers are at increased risk for cardiovascular disease (CVD) and mortality. The aims of this study were to examine psychosocial and behavioral predictors of metabolic syndrome, an intermediate endpoint of CVD. Methods Cancer caregivers were administered a battery of questionnaires assessing sociodemographic characteristics, depressive symptoms, perceived stress, caregiver quality of life, sleep, physical activity, alcohol and tobacco use, social support, relationship quality, and loneliness. Metabolic syndrome was defined using the American Heart Association guidelines and the National Cholesterol Education Program's Adult Treatment Panel (ATP) III, which includes the presence of at least three of the following abnormalities: blood pressure, glucose, abdominal girth, high‐density lipoprotein (HDL), and triglycerides. Results Of the 104 caregivers, 77% were female, 94% were Caucasian, and the mean age was 59.5 (SD = 12.8). Of the 104 caregivers, 35.6% reported depressive symptoms in the clinical range of the Center for Epidemiologic Studies‐Depression (CES‐D) and 69.2% reported Perceived Stress Scale scores at least one standard deviation above the general population norms. A total of 16.3% of caregivers currently used tobacco, 28.8% consumed alcohol, and 26.7% were overweight (BMI = 25‐29.9) and 48.5% were obese (BMI ≥ 30). Forty‐nine percent of the caregivers met the criteria for metabolic syndrome. After age, gender, and race were adjusted, the following remained as significant predictors of metabolic syndrome: low levels of caregiver quality of life (Odds Ratio (OR) = 1.067; 95% CI, 1.019‐1.117; P = .006), high levels of hostility (OR = 1.142; 95% CI, 1.030‐1.267; P = .012), and current alcohol use (OR = 4.193; 95% CI, 1.174‐14.978; P = .027). Conclusion Development of interventions to reduce the risk of metabolic syndrome in cancer caregivers is recommended.
