In vitro study of relationship between signal intensity and gadolinium‐DTPA concentration at high magnetic field strength

Although gadolinium‐diethylene triamine pentaacetic acid (Gd‐DTPA) has been used as a contrast material in MRI, it is known that the contrast enhancement effect is not uniform for high concentrations of Gd‐DTPA. In order to evaluate the proper pulse sequences for dynamic MRI in aqueous solutions of Gd‐DTPA, blood samples and melanoma cells, the signal intensity for several concentrations of Gd‐DTPA were measured under inversion recovery (T₁‐weighted) at high magnetic field strength (7.0 Tesla). For aqueous solutions of Gd‐DTPA, signal intensity correlated linearly with the concentration of Gd‐DTPA between 0 mmol/L and 4 mmol/L. Using blood and melanoma cells, signal intensity correlated non‐linearly with the concentration of Gd‐DTPA between 0 mmol/L and 1.5 mmol/L. For concentrations of more than 4 mmol/L in aqueous solutions of Gd‐DTPA, 1 mmol/L in blood and 1.5 mmol/L in melanoma, signal intensity decreased with increased Gd‐DTPA concentration.     

Fatty liver creates a pro‐metastatic microenvironment for hepatocellular carcinoma through activation of hepatic stellate cells

Fatty liver (FL) is associated with development of hepatocellular carcinoma (HCC). However, whether FL itself promotes the progression of HCC is unclear. We recently found that hepatic stellate cells (HSCs) were prominently activated in the steatotic liver. Here, we investigated whether steatotic livers promote HCC progression and whether HSCs of steatotic liver are associated with HCC progression. We implanted rat HCC cells into diet‐induced steatotic livers in rats via portal vein injection. Thereafter, HSCs and HCC cells were co‐implanted subcutaneously into nude rats. Migration and proliferation of HCC cells were measured, and activation of ERK and Akt in these cells was determined by western blotting. Chemokines secreted from HSCs and HCC cells were also evaluated by ELISA. Steatotic livers significantly promoted HCC metastasis compared with non‐steatotic livers. Additionally, co‐implantation of HCC cells with HSCs from steatotic livers produced significantly larger tumors in recipient rats as compared to those induced by HCC cells co‐implanted with HSCs from normal livers (NLs). HSCs isolated from steatotic livers, compared with HSCs isolated from NLs, secreted greater amounts of interleukin‐1α, vascular endothelial growth factor, and transforming growth factor‐β. These cytokines may enhance the proliferation and migration of HCC cells by increasing the phosphorylation of ERK and Akt in HCC cells. Moreover, we noted that the Rho‐kinase inhibitor deactivated activated HSCs and attenuated HCC progression. In conclusion, the rat steatotic liver microenvironment favors HCC metastasis, and this effect appears to be promoted by activated HSCs in the steatotic liver.     

Stenosis of the hepatic vein anastomosis after liver transplantation: Treatment with a heparin‐coated metal stent

Delayed‐onset fibrotic stenosis of the hepatic‐vein anastomosis following liver transplantation resulted in ascites and abnormal liver‐function tests. The stenosis was treated with balloon dilatation resulting in a clinical improvement; however, this had to be repeated four times in the 9 months after transplantation due to recurrent stenosis. The stenosis was eventually successfully treated with percutaneous insertion of a metal stent. Aspirin 50 mg daily was prescribed for 1 month. The patient was not anticoagulated. The patient remains clinically well at follow up after 18 months.     

Improving the detection of patients with inherited predispositions to hematologic malignancies using next‐generation sequencing‐based leukemia prognostication panels

Recognizing and referring patients with possible inherited cancer predisposition syndromes for appropriate genetic evaluation and testing provides insights into optimal patient treatment approaches and also can provide education and testing opportunities for family members. Next‐generation sequencing (NGS)‐based, targeted genotyping for somatic mutations is increasingly used in the diagnosis, prognostication, and treatment selection for patients with hematologic malignancies. However, certain mutations that may be somatically acquired can also be present as germline mutations in some individuals and families. Whether the results of NGS‐based leukemia panels can be used to inform decisions and subsequent evaluation of patients with possible inherited cancer predispositions has not been described previously. Because a normal control often is not available when using NGS panels in patients with hematologic malignancies, NGS panel results offer both an opportunity and a challenge to determine the origin and pathogenicity of identified mutations. In the absence of a matched germline control, variant allele frequency (VAF) estimation and data from publically available data sets provide important clues to the possible germline origin of a variant. Careful annotation and review of NGS panels in patients with hematologic malignancies can provide a useful screening tool to systematically improve upon the detection of potentially pathogenic germline variants. Cancer 2018;124:2704‐2713 . © 2018 American Cancer Society     

New onset non‐alcoholic fatty liver disease after resection of pancreatic neuroendocrine tumors

Background and Objectives

Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatis (NASH) may occur after pancreatic resection due to exocrine pancreatic insufficiency (EPI). Patients with long‐term survival, such as after pancreatic neuroendocrine tumor (pNET) resection, are at risk of NAFLD/NASH. We aimed to determine the incidence and risk factors for new onset NAFLD/NASH and EPI after pNET resection.

Methods

Retrospective monocenter cohort study. Patients who underwent pNET resection (1992‐2016) were assessed for new onset NAFLD/NASH and EPI. Postoperative NAFLD/NASH was determined by a blinded abdominal radiologist, who compared pre‐ and postoperative imaging.

Results

Out of 235 patients with pNET, a total of 112 patients underwent resection and were included with a median follow‐up of 54 months. New onset NAFLD/NASH occurred in 20% and EPI in 49% of patients. Multivariate analysis showed that the only risk factor for new onset NAFLD/NASH was recurrent disease (OR 4.4, 95% CI 1.1‐16.8, P = 0.031), but not EPI (OR 0.94, 95% CI 0.3‐2.8, P = 0.911). The only risk factor for EPI was pancreatoduodenectomy (OR 4.3, 95% CI 1.4‐13.7, P = 0.012).

Conclusions

New onset NAFLD/NASH is occasionally found after pNET resection, especially in patients with recurrent disease, but is not related to EPI.     

Down‐modulation of keratin 8 phosphorylation levels by PRL‐3 contributes to colorectal carcinoma progression

Phosphatase of regenerating liver‐3 (PRL‐3) is a member of the PRL protein tyrosine phosphatase family and has been proposed to promote the invasiveness and metastastic capability of colorectal cancers (CRCs); however, the underlying mechanisms and target molecules of PRL‐3 protein remain unknown. On the basis of the biological significance of PRL‐3 phosphatase activity confirmed by the catalytically inactive PRL‐3 mutant (C104S) and a PRL‐3 inhibitor in CRC‐derived SW480 cells, we performed protein expression profiling to search for PRL‐3‐mediated effector proteins. By a comparative study of phosphorylated proteins that differentially expressed in wild type and C104S mutant PRL‐3‐transfected SW480 cells; the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL‐3‐interacting protein. Indeed, treatment with the PRL‐3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431. Moreover, we detected the physiological interaction between PRL‐3 and KRT8 and their colocalization at cellular lamellipodias and ruffles in vivo. In CRC tissue samples, tumor cells with high PRL‐3 expression showed reduction or loss of phosphorylated KRT8 expression, particularly at the invasive front and in the liver metastases. In conclusion, our results indicate that PRL‐3 may play an important role for the promotion of CRC cell migration and metastatic potential through direct KRT8 dephosphorylation. © 2008 Wiley‐Liss, Inc.     

Hepatocarcinogenesis in mice with a conditional knockout of the hepatocyte growth factor receptor c‐Met

The receptor for the hepatocyte growth factor/scatter factor (HGF/SF), c‐Met, plays a role in tumour promotion, progression and metastasis. In this study, we analysed chemically induced hepatocarcinogenesis in mice lacking a functional HGF receptor in their liver. Control and c‐Met deficient mice were injected with a single dose of N‐nitrosodiethylamine (DEN, 90 μg/g b.wt.) at 6 weeks of age and mice were subsequently kept on a phenobarbital (PB) containing diet (0.05%) for 35 weeks or on control diet. At the end of the experiment, the carcinogenic response in liver of the animals was monitored. Conditional c‐met knockout (KO) mice showed a higher prevalence of macroscopically visible liver tumours and of glutamine synthetase positive and glucose‐6‐phosphatase deficient lesions in liver. Tumour promotion by PB led to significant increases in the number of preneoplastic and neoplastic lesions in liver of both wild‐type and c‐met knockout mice, with only minor differences in response. Our results indicate that a defect in c‐Met‐mediated signaling increases chemically induced tumour initiation in liver but does not significantly affect PB‐mediated tumour promotion. © 2008 Wiley‐Liss, Inc.