Integrated quantitative susceptibility and R2 * mapping for evaluation of liver fibrosis: An ex vivo feasibility study.

To develop a method for noninvasive evaluation of liver fibrosis, we investigated the differential sensitivities of quantitative susceptibility mapping (QSM) and R2 * mapping using corrections for the effects of liver iron. Liver fibrosis is characterized by excessive accumulation of collagen and other extracellular matrix proteins. While collagen increases R2 * relaxation, measures of R2 * for fibrosis are confounded by liver iron, which may be present in the liver over a wide range of concentrations. The diamagnetic collagen contribution to susceptibility values measured by QSM is much less than the contribution of highly paramagnetic iron. In 19 ex vivo liver explants with and without fibrosis, QSM (χ), R2 * and proton density fat fraction (PDFF) maps were constructed from multiecho gradient-recalled echo (mGRE) sequence acquisition at 3 T. Median parameter values were recorded and differences between the MRI parameters in nonfibrotic vs. advanced fibrotic/cirrhotic samples were evaluated using Mann-Whitney U tests and receiver operating characteristic analyses. Logistic regression with stepwise feature selection was employed to evaluate the utility of combined MRI measurements for detection of fibrosis. Median R2 * increased in fibrotic vs. nonfibrotic liver samples (P = .041), while differences in χ and PDFF were nonsignificant (P = .545 and P = .395, respectively). Logistic regression identified the combination of χ and R2 * significant for fibrosis detection (logit [prediction] = -8.45 + 0.23 R2 * - 28.8 χ). For this classifier, a highly significant difference between nonfibrotic vs. advanced fibrotic/cirrhotic samples was observed (P = .002). The model exhibited an AUC of 0.909 (P = .003) for detection of advanced fibrosis/cirrhosis, which was substantially higher compared with AUCs of the individual parameters (AUC 0.591-0.784). An integrated QSM and R2 * analysis of mGRE 3 T imaging data is promising for noninvasive diagnostic assessment of liver fibrosis.

HHLA2 is a novel immune checkpoint protein in pancreatic ductal adenocarcinoma and predicts post-surgical survival.

HHLA2 is a newly identified member of the B7 immune checkpoint family, but its function and crosstalk with immune cells is not fully understood. To gain insights into the HHLA2 expression profile and to determine the clinical significance and function of HHLA2 in pancreatic cancer, we performed immunohistochemistry (IHC) analyses on tissue microarrays (TMAs) of pancreatic ductal adenocarcinoma (PDAC, n = 92) with matched peritumoral tissues as well as in cohorts of precancerous lesions: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). We found that HHLA2 was rarely detected in normal acinar, islet, and ductal cells but widely expressed from early pancreatic precancerous lesions to invasive PDAC. The overall HHLA2 positivity was 95% (19/20) in low grade PanIN and 70.73% (29/41) in IPMN. HHLA2 expression was detected in 77.17% (71/92) of the PDAC cases and was significantly associated with better prognosis in this cohort. Our findings suggest that HHLA2 may behave as a costimulatory ligand in pancreatic cancer, which differs from other B7 family members that are largely characterized as checkpoint inhibitors. Further investigation of the HHLA2 signaling pathway and its receptors is warranted by our data and may lead to novel therapeutic interventions.

Current concepts in the immunohistochemical evaluation of liver tumors.

Immunohistochemistry often plays an important role in the evaluation of liver tumors. Recent advances have established a classification system for hepatocellular adenomas (HCAs) based on morphology, molecular alterations, and immunohistochemistry. Specifically, loss of liver fatty acid binding protein is seen in HNF1α-inactivated HCA, staining with serum amyloid A is seen in inflammatory HCA, and diffuse staining with glutamine synthetase (GS) is seen in ß-catenin activated HCA. A panel of immunohistochemical stains including glypican-3 (GPC-3), heat shock protein 70, and GS are useful in distinguishing HCC from non-malignant dysplastic nodules. Immunohistochemistry is also useful to determine whether a liver tumor is of primary hepatocellular or metastatic origin. Recently described markers useful for this purpose include arginase-1, GPC-3, and bile salt export pump. These newer markers may offer superior utility when compared to traditional markers of hepatocellular differentiation such as alpha-fetoprotein, hepatocyte paraffin-1, polyclonal carcinoembryonic antigen, and CD10. This paper will review recent advances in the immunohistochemical evaluation of liver tumors.