Citations

Long intergenic non-coding RNA (lincRNA) is a family of gene transcripts, the functions of which are largely unknown. Although cigarette smoking is the main cause for lung cancer, lung cancer in non-smokers is a separate entity and its underlying cause is little known. Growing evidence suggests lincRNAs play a significant role in cancer development and progression; however, such data is lacking for lung cancer in non-smokers, or those who have never smoked. This study conducted comprehensive profiling of lincRNAs from RNA sequencing (RNA-seq) data of non-smoker patients with lung adenocarcinoma. Both known and novel lincRNAs distinctly segregated tumors from normal tissues. Approximately one third of lincRNAs were differentially expressed between tumors and normal samples and most of them were coordinated with their putative protein gene targets. More importantly, lincRNAs defined two clusters of tumors that were associated with tumor aggressiveness and patient survival. We identified a subset of lincRNAs that were differentially expressed and also associated with patient survival. Very high concordance (R2 = 0.9) was observed for the differentially expressed lincRNAs in the Cancer Genome Atlas (TCGA) validation set of 85 transcriptomes and the lincRNAs associated with survival from the discovery set were similarly predictive in the validation set. These lincRNAs warrant further investigation as potential diagnostic and prognostic markers.

SummaryDue to the introduction of newer, more efficacious treatment options, there is a pressing need for policy makers and public health officials to develop or adapt national hepatitis C virus (HCV) control strategies to the changing epidemiological landscape. To do so, detailed, country‐specific data are needed to characterize the burden of chronic HCV infection. In this study of 17 countries, a literature review of published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates was conducted, and inputs were validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Hong Kong to 2.4% in Taiwan, while the largest viraemic populations were in Nigeria (2 597 000 cases) and Taiwan (569 000 cases). Diagnosis, treatment and liver transplant rates varied widely across the countries included in this analysis, as did the availability of reliable data. Addressing data gaps will be critical for the development of future strategies to manage and minimize the disease burden of hepatitis C.

SummaryFactors influencing the morbidity and mortality associated with viremic hepatitis C virus (HCV) infection change over time and place, making it difficult to compare reported estimates. Models were developed for 17 countries (Bahrain, Bulgaria, Cameroon, Colombia, Croatia, Dominican Republic, Ethiopia, Ghana, Hong Kong, Jordan, Kazakhstan, Malaysia, Morocco, Nigeria, Qatar and Taiwan) to quantify and characterize the viremic population as well as forecast the changes in the infected population and the corresponding disease burden from 2015 to 2030. Model inputs were agreed upon through expert consensus, and a standardized methodology was followed to allow for comparison across countries. The viremic prevalence is expected to remain constant or decline in all but four countries (Ethiopia, Ghana, Jordan and Oman); however, HCV‐related morbidity and mortality will increase in all countries except Qatar and Taiwan. In Qatar, the high‐treatment rate will contribute to a reduction in total cases and HCV‐related morbidity by 2030. In the remaining countries, however, the current treatment paradigm will be insufficient to achieve large reductions in HCV‐related morbidity and mortality.

SummaryThe hepatitis C virus (HCV) epidemic was forecasted through 2030 for 17 countries in Africa, Asia, Europe, Latin America and the Middle East, and interventions for achieving the Global Health Sector Strategy on viral hepatitis targets—“WHO Targets” (65% reduction in HCV‐related deaths, 90% reduction in new infections and 90% of infections diagnosed by 2030) were considered. Scaling up treatment and diagnosis rates over time would be required to achieve these targets in all but one country, even with the introduction of high SVR therapies. The scenarios developed to achieve the WHO Targets in all countries studied assumed the implementation of national policies to prevent new infections and to diagnose current infections through screening.

AbstractBackground & AimsAlthough hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain major risk factors for hepatocellular carcinoma (HCC), non‐viral causes of HCC, particularly non‐alcoholic fatty liver disease (NAFLD), are becoming increasingly prevalent. The aim of this study was to compare the clinical characteristics and survival of cryptogenic and viral HCC.MethodsWe conducted a retrospective cohort study involving 3878 consecutive HCC patients seen at two tertiary centres in the United States and one in Taiwan from 2004 to 2014. We compared the clinical characteristics, treatment and survival of patients by underlying aetiology: cryptogenic (n = 696), HBV (n = 1304) or HCV (n = 1878).ResultsCirrhosis was present in 66.8% of the cryptogenic HCC patients, compared with 74.7% of HBV‐related HCC (HBV‐HCC) (P = .001) and 85.9% of HCV‐HCC (P < .001). Compared to viral HCC, cryptogenic HCC patients presented with larger tumours and at later stages of disease. Five‐year overall survival was 16.3% among cryptogenic HCC patients compared with 31.9% among HBV‐HCC patients and 27.7% among HCV‐HCC patients (P < .001 for both by the log‐rank test). HCC aetiology was not an independent predictor of survival, though ethnicity, cirrhosis status, meeting Milan criteria and treatment allocation were.ConclusionsCompared with viral HCC patients, those with cryptogenic HCC had lower prevalence of cirrhosis, were diagnosed with larger tumours at more advanced stages of disease, and had poorer overall survival. Additional efforts are needed to identify patients at risk of cryptogenic HCC and to identify cryptogenic HCC at earlier stages of disease.

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF V600 mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%–16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%–25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.

Platelets interact with tumor cells and promote metastasis. The importance of platelets in posttransplant hepatocellular carcinoma (HCC) recurrence is unclear. Thus, we aimed to evaluate the association between preoperative platelet count (PLT) and HCC recurrence after living donor liver transplantation. Of 359 recipients of livers from living donors for HCC, 209 of 240 patients who had preoperative PLT ≤75 × 109/L were matched with 97 of 119 patients who had preoperative PLT >75 × 109/L using propensity score matching, with an unfixed matching ratio based on factors such as tumor biology. The cutoff value of 75 × 109/L was set based on optimum stratification analysis. Survival analysis was performed with death as a competing risk event. The primary outcome was overall HCC recurrence. The median follow‐up time was 59 months. Before matching, recurrence probability at 1, 2, and 5 years after transplantation was 4.7%, 9.2%, and 11.3% for the low platelet group and 14.5%, 23.0%, and 30.5% for the high platelet group. Recurrence risk was significantly greater in the high platelet group in both univariate (hazard ratio [HR] = 3.09; 95% confidence interval [CI], 1.86‐5.14; P < 0.001) and multivariate analyses (HR = 2.10; 95% CI, 1.23‐3.60; P = 0.007). In the matched analysis, recurrence risk was also greater in the high platelet group in both univariate (HR = 2.33; 95% CI, 1.36‐4.01; P = 0.002) and multivariate analyses (HR = 1.90; 95% CI, 1.02‐3.54; P = 0.04). Preoperative PLT had no interaction with the Milan criteria, alpha‐fetoprotein level, Edmonson grade, microvascular invasion, or intrahepatic metastasis. Incorporation of preoperative PLT into the Milan criteria significantly improved predictive power. Inflammation‐based scores including neutrophil‐to‐lymphocyte ratio, platelet‐to‐lymphocyte ratio, and the inflammation‐based index did not show superiority to preoperative PLT in predicting HCC recurrence. In conclusion, preoperative PLT appears to be an important host factor affecting HCC recurrence after living donor liver transplantation. Liver Transplantation 24 44–55 2018 AASLD.

Abstract Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the N-acetyltransferase NAT10, which we found to be overexpressed in human steatosis–associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance. Cancer Res; 77(23); 6576–88. ©2017 AACR.

Objective The primary aim was to compare independent and joint performance of retrieving smoking status through different sources, including narrative text processed by natural language processing (NLP), patient-provided information (PPI), and diagnosis codes (ie, International Classification of Diseases, Ninth Revision [ICD-9]). We also compared the performance of retrieving smoking strength information (ie, heavy/light smoker) from narrative text and PPL Materials and Methods Our study leveraged an existing lung cancer cohort for smoking status, amount, and strength information, which was manually chart-reviewed. On the NLP side, smoking-related electronic medical record (EMR) data were retrieved first. A pattern-based smoking information extraction module was then implemented to extract smoking-related information. After that, heuristic rules were used to obtain smoking status-related information. Smoking information was also obtained from structured data sources based on diagnosis codes and PPI. Sensitivity, specificity, and accuracy were measured using patients with coverage (ie, the proportion of patients whose smoking status/strength can be effectively determined). Results NLP alone has the best overall performance for smoking status extraction (patient coverage: 0.88; sensitivity: 0.97; specificity: 0.70; accuracy: 0.88); combining PPI with NLP further improved patient coverage to 0.96. ICD-9 does not provide additional improvement to NLP and its combination with PPI. For smoking strength, combining NLP with PPI has slight improvement over NLP alone. Conclusion These findings suggest that narrative text could serve as a more reliable and comprehensive source for obtaining smoking-related information than structured data sources. PPI, the readily available structured data, could be used as a complementary source for more comprehensive patient coverage.