Purpose: We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods: This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight <50 kg) every 2 weeks plus oral apatinib 250 mg daily. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC) per RECIST v1.1. Results: Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred. Conclusions: Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients. See related commentary by Pinato et al., p. 908

Studies have shown that metallothionein 1 M (MT1M) is a tumor suppressor gene which is frequently down-regulated in human hepatocellular carcinoma (HCC). The methylation of MT1M promoter region is one of the important transcriptional regulation mechanisms that contribute to the loss of its expression. In our study, we found that there are still half of the 55 HCC tumor tissues in our cohort do not share the promoter methylation of MT1M. So, we speculated there maybe another mechanism participating in the downregulation of MT1M in HCC. Then, we provided evidences that miR-545-3p, which served as a tumor promoter, post-transcriptionally regulate MT1M in HCC through binding to its untranslated region (3'UTR). Taking together, we investigated the role of miR-545-3p in the process of HCC through regulating MT1M.

BackgroundOur preliminary study suggested that the expression of Fascin was increased in cholangiocarcinoma, which indicating poor prognosis The present study aimed to explore the roles and mechanisms of Fascin during the progression of cholangiocarcinoma.Material/MethodsWe evaluated the knockdown effect of endogenous Fascin expression by Short hairpin RNA (shRNA) in QBC939 cells. Cell proliferation was confirmed by MTS assay. Migration and invasion assay was used to examine the cell invasive ability. Tumorigenesis abilities in vivo were analyzed with a xenograft tumor model. Western blot analysis was used to test epithelial-mesenchymal transition (EMT) biomarkers and critical proteins in the Wnt/β-catenin signaling pathway.ResultsshRNA-mediated gene knockdown of Fascin significantly inhibited cell proliferation, invasion, and EMT, and shRNA-Fascin markedly inhibited the xenograft tumor volume. Silencing of Fascin up-regulated phosphorylation of β-catenin and decreased its nuclear localization. Additionally, knockdown of Fascin led to the upregulation of β-catenin and E-cadherin expression in plasma membrane fraction of QBC939 cells.ConclusionsOur data indicate a key role of Fascin in cell proliferation, migration, and invasion in cholangiocarcinoma. Fascin promotes EMT of cholangiocarcinoma cells, in part through regulating Wnt/β-catenin signaling.

The aim of this study was to investigate the role of ADAM15 in MHC class I polypeptide-related sequence B (MICB) protein ectodomain shedding and observe whether or not gemcitabine affects MICB shedding from PANC-1 cells. In this study, immunohistochemistry of MICB and ADAM15 were performed on tumor samples obtained from 93 patients with pancreatic ductal adenocarcinoma (PDAC). The expression of MICB and ADAM15 in the PDAC tissues was significantly higher compared with that in the normal tissues of the pancreas. Statistical analysis showed a significant correlation between the expression of MICB and certain classic clinicopathological characteristics (i.e., histological grade and TNM stage). ADAM15 expression was found to correlate with lymph node metastasis and TNM stage. The Spearman's rank test suggested that the expression of MICB was inversely correlated with that of ADAM15 in PDAC tissues. Knockdown of ADAM15 in PANC-1 cells clearly upregulated MICB expression on the cellular surface and downregulated soluble MICB (sMICB) levels in the culture supernatants. A non-toxic dose of 0.5 µmol/l gemcitabine suppresses ADAM15 expression leading, at the same time, to an increase in MICB expression and a decrease in sMICB production in PANC-1 cells. The mRNA levels of MICB did not change following PANC-1 exposure to gemcitabine. Further study suggests that the suppressive effect of gemcitabine on MICB shedding in PANC-1 cells is mediated by ADAM15 downregulation. In conclusion, the results of the present study support the hypothesis that ADAM15 is involved in MICB shedding of PANC-1 cells and that gemcitabine inhibits MICB ectodomain shedding through the suppression of ADAM15.

BackgroundThe preoperative nutritional status and the immunological status have been reported to be independent prognostic factors of patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to investigate whether prognostic nutritional index (PNI) + albumin–bilirubin (ALBI) could be a better predictor than PNI and ALBI alone in patients with ICC after radical resection.MethodsThe prognostic prediction evaluation of the PNI, ALBI, and the PNI+ALBI grade was performed in 373 patients with ICC who underwent radical resection between 2010 and 2018 at six Chinese tertiary hospitals, and external validation was conducted in 162 patients at four other Chinese tertiary hospitals. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan–Meier method. Multivariate analysis was conducted to identify independent prognostic factors. A time-dependent receiver operating characteristic (ROC) curve and a nomogram prediction model were further constructed to assess the predictive ability of PNI, ALBI, and the PNI+ALBI grade. The C-index and a calibration plot were used to assess the performance of the nomogram models.ResultsUnivariate analysis showed that PNI, ALBI, and the PNI+ALBI grade were prognostic factors for the OS and RFS of patients with ICC after radical resection in the training and testing sets (p < 0.001). Multivariate analysis showed that the PNI+ALBI grade was an independent risk factor for OS and RFS in the training and testing sets (p < 0.001). Analysis of the relationship between the PNI+ALBI grade and clinicopathological characteristics showed that the PNI+ALBI grade correlated with obstructive jaundice, alpha-fetoprotein (AFP), cancer antigen 19-9 (CA19-9), cancer antigen 125 (CA125), PNI, ALBI, Child–Pugh grade, type of resection, tumor size, major vascular invasion, microvascular invasion, T stage, and N stage (p < 0.05). The time-dependent ROC curves showed that the PNI+ALBI grade had better prognostic predictive ability than the PNI, ALBI, and the Child–Pugh grade in the training and testing sets.ConclusionPreoperative PNI+ALBI grade is an effective and practical predictor for the OS and RFS of patients with ICC after radical resection.