Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in a subset of patients with non-small cell lung cancer (NSCLC). We have now examined PD-L1 expression ...and its regulation in NSCLC positive for the EML4-ALK fusion gene.
The expression of PD-L1 at the protein and mRNA levels in NSCLC cell lines was examined by flow cytometry and by reverse transcription and real-time PCR analysis, respectively. The expression of PD-L1 in 134 surgically resected NSCLC specimens was evaluated by immunohistochemical analysis.
The PD-L1 expression level was higher in NSCLC cell lines positive for EML4-ALK than in those negative for the fusion gene. Forced expression of EML4-ALK in Ba/F3 cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in EML4-ALK-positive NSCLC cells was attenuated by treatment with the specific ALK inhibitor alectinib or by RNAi with ALK siRNAs. Furthermore, expression of PD-L1 was downregulated by inhibitors of the MEK-ERK and PI3K-AKT signaling pathways in NSCLC cells positive for either EML4-ALK or activating mutations of the EGFR. Finally, the expression level of PD-L1 was positively associated with the presence of EML4-ALK in NSCLC specimens.
Our findings that both EML4-ALK and mutant EGFR upregulate PD-L1 by activating PI3K-AKT and MEK-ERK signaling pathways in NSCLC reveal a direct link between oncogenic drivers and PD-L1 expression.
Background
Few studies have evaluated both liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD) using both FibroScan
®
M and XL probes. This study was performed to ...investigate the accuracy of both FibroScan
®
probes to diagnose liver fibrosis and steatosis in patients with NAFLD.
Methods
We prospectively enrolled 137 consecutive patients with clinically suspected NAFLD in our joint-research facilities. Liver biopsies, liver stiffness measurements (LSMs), and controlled attenuation parameter (CAP) measurements were performed, and 122 patients with NAFLD diagnosed pathologically by central pathologists were included in the final analysis.
Results
Reliable LSM results were obtained in 85.2% (M) and 89.3% (XL) of patients, and CAP was reliable in 90.2% (M) and 90.2% (XL). The median LSM was significantly lower with the XL than M probe, and CAP was significantly higher with the XL than M probe. The optimal cut-off values for diagnosing the fibrosis stage were lower for LSM with the XL than M probe (stage ≥ 2, 6.7 vs. 7.0; stage ≥ 3, 8.2 vs. 10.8; stage 4, 14.3 vs. 16.8, respectively), whereas those of CAP were higher for the XL than M probe (score of ≥ 2, 273 vs. 267; score of 3, 302 vs. 286, respectively). There were no significant differences in accuracy of the LSM and CAP between the probes.
Conclusions
Liver fibrosis and steatosis could be equally evaluated with FibroScan
®
M and XL probes in patients with NAFLD. There was no significant difference in diagnostic accuracy between the two probes using probe-specific cut-off values.
Background
Accurately evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) is important for identifying those who may develop complications. The aims of this study ...were (1) to measure serum
Wisteria floribunda
agglutinin-positive Mac-2 binding protein (WFA
+
-M2BP) using the glycan sugar chain-based immunoassay and (2) to compare the results with clinical assessments of fibrosis.
Methods
Serum WFA
+
-M2BP values were retrospectively evaluated in 289 patients with NAFLD who had undergone liver biopsy. Histological findings were evaluated by three blinded, experienced liver-specific pathologists.
Results
For stages 0 (
n
= 35), 1 (
n
= 113), 2 (
n
= 49), 3 (
n
= 41), and 4 (
n
= 51) of liver fibrosis, the serum WFA
+
-M2BP cutoff indexes were 0.57, 0.70, 1.02, 1.57, and 2.96, respectively. Multivariate regression analysis showed that serum WFA
+
-M2BP values were associated with the stage of fibrosis (≥stage 2). The areas under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of serum WFA
+
-M2BP were 0.876, 85.9, and 74.6 %, respectively, for severe fibrosis (≥stage 3) and were 0.879, 74.6, and 87.0 %, respectively, for cirrhosis. When compared with six non-invasive conventional markers, serum WFA
+
-M2BP had the greatest AUROC for diagnosing severe fibrosis and cirrhosis.
Conclusions
Serum WFA
+
-M2BP values are useful for assessing the stage of liver fibrosis in patients with NAFLD.
Aim
Hepatic fibrosis is associated with various factors, including metabolic dysfunction‐associated fatty liver disease (MAFLD), insulin resistance, and alcohol intake in patients with morbid ...obesity. We investigated factors directly associated with hepatic fibrosis in patients with morbid obesity using a graphical model.
Methods
We enrolled 134 consecutive patients with morbid obesity who underwent liver biopsy during sleeve gastrectomy (median age 43.5 years; MAFLD 78.4%; homeostasis model assessment of insulin resistance HOMA‐IR 5.97; >20 g/day alcohol intake 14.2%). Patients were classified into none/mild (F0/1; n = 77) or significant/advanced fibrosis (F2/3; n = 57) groups, based on histology. Factors associated with F2/3 were analyzed using logistic regression analysis and a graphical model.
Results
F2/3 was observed in 42.5% of the enrolled patients. The prevalence of MAFLD and HOMA‐IR values were significantly higher in the F2/3 group than in the F0/1 group; however, no significant difference in alcohol intake was observed between the two groups. On logistic regression analysis, MAFLD, but not HOMA‐IR or alcohol intake, was the only independent factor associated with F2/3 (odds ratio 7.555; 95% confidence interval 2.235–25.544; p = 0.0011). The graphical model revealed that F2/3 directly interacted with MAFLD, diabetes mellitus, HOMA‐IR, and low‐density lipoprotein cholesterol. Among these factors, MAFLD showed the strongest interaction with F2/3.
Conclusions
We determined that MAFLD was more directly associated with significant/advanced fibrosis than insulin resistance or hyperlipidemia, and alcohol intake was not directly associated with hepatic fibrosis. Metabolic dysfunction‐associated fatty liver disease could be the most important factor for hepatic fibrosis in patients with morbid obesity.
EGF receptor (EGFR) kinase inhibitors, including gefitinib and erlotinib, exert potent therapeutic efficacy in non-small cell lung cancers harboring EGFR-activating mutations. However, most patients ...ultimately develop resistance to these drugs. Here, we report a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors and the reversal of which could improve clinical outcomes. In erlotinib-resistant lung cancer cells harboring activating EGFR mutations that we established, there was increased expression of Src, integrin β1, α2, and α5 along with enhanced cell adhesion activity. Interestingly, RNAi-mediated silencing of integrin β1 restored erlotinib sensitivity and reduced activation of Src and Akt after erlotinib treatment. Furthermore, Src silencing inhibited Akt phosphorylation and cell growth, with this inhibitory effect further augmented by erlotinib treatment. Increased expression of integrin β1, α5, and/or α2 was also observed in refractory tumor samples from patients with lung cancer treated with erlotinib and/or gefitinib. Together, our findings identify the integrin β1/Src/Akt signaling pathway as a key mediator of acquired resistance to EGFR-targeted anticancer drugs.
Hepatic vena cava syndrome, also known as membranous obstruction of inferior vena cava (IVC), was considered a rare congenital disease and classified under Budd–Chiari syndrome. It is now recognized ...as a bacterial infection‐induced disease related to poor hygiene. Localized thrombophlebitis of the IVC at the site close to hepatic vein outlets is the initial lesion which converts on resolution into stenosis or complete obstruction, the circulatory equilibrium being maintained by development of cavo‐caval collateral anastomosis. These changes persist for the rest of the patient's life. The patient remains asymptomatic for a variable period until acute exacerbations occur, precipitated by bacterial infection, resulting in deposition of thrombi at the site of the lesion and endophlebitis in intrahepatic veins. Large thrombus close to hepatic vein outlets results in ascites from hepatic venous outflow obstruction, which is followed by development of venocentric cirrhosis. Endophlebitis of intrahepatic veins results in ischemic liver damage and development of segmental stenosis or membrane. Acute exacerbations are recognized clinically as intermittent jaundice and/or elevation of aminotransferase or ascites associated with neutrophil leukocytosis and elevation of C‐reactive protein; sonologically, they are recognized as the presence of thrombi of different ages in IVC and thrombosis of intrahepatic veins. Development of liver cirrhosis and hepatocellular carcinoma is related to severity or frequency of acute exacerbations and not to duration or type of caval obstruction. Hepatic vena cava syndrome is a common co‐morbid condition with other liver diseases in developing countries and it should be considered in differential diagnosis in patient with intermittent elevation serum bilirubin and or aminotransferase or development of ascites and cirrhosis.
Background and Aims
Chronic liver congestion reflecting right‐sided heart failure (RHF), Budd‐Chiari syndrome, or Fontan‐associated liver disease (FALD) is involved in liver fibrosis and HCC. ...However, molecular mechanisms of fibrosis and HCC in chronic liver congestion remain poorly understood.
Approach and Results
Here, we first demonstrated that chronic liver congestion promoted HCC and metastatic liver tumor growth using murine model of chronic liver congestion by partial inferior vena cava ligation (pIVCL). As the initial step triggering HCC promotion and fibrosis, gut‐derived lipopolysaccharide (LPS) appeared to induce LSECs capillarization in mice and in vitro. LSEC capillarization was also confirmed in patients with FALD. Mitogenic factor, sphingosine‐1‐phosphate (S1P), was increased in congestive liver and expression of sphingosine kinase 1, a major synthetase of S1P, was increased in capillarized LSECs after pIVCL. Inhibition of S1P receptor (S1PR) 1 (Ex26) and S1PR2 (JTE013) mitigated HCC development and liver fibrosis, respectively. Antimicrobial treatment lowered portal blood LPS concentration, LSEC capillarization, and liver S1P concentration accompanied by reduction of HCC development and fibrosis in the congestive liver.
Conclusions
In conclusion, chronic liver congestion promotes HCC development and liver fibrosis by S1P production from LPS‐induced capillarized LSECs. Careful treatment of both RHF and liver cancer might be necessary for patients with RHF with primary or metastatic liver cancer.
Aim
Recently, FibroScan‐AST (FAST) score was reported to be effective for identifying non‐alcoholic steatohepatitis (NASH) with significant activity and fibrosis in non‐alcoholic fatty liver disease ...(NAFLD). The aim of this study was to confirm the diagnostic accuracy of FAST score of Japanese patients and compare the cut‐off values and diagnostic accuracy between the FibroScan M and XL probes.
Methods
Eighty‐two and 84 patients were included the verification and validation sets, respectively. All patients were diagnosed with NAFLD by biopsy by two central expert pathologists. Liver stiffness measurements and controlled attenuation parameter were carried out, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis.
Results
No significant difference existed in FAST score between the M and XL probes (0.489 vs. 0.483, P = 0.187). No significant difference existed in the area under the ROC between the two probes (M, 0.7598; XL, 0.7614; P = 0.958). According to the Youden index, the cut‐off value using the M probe was 0.57 with 68.2% sensitivity and 78.3% specificity. For the XL probe, the cut‐off value was 0.56 with 68.2% sensitivity and 73.3% specificity. To obtain sensitivity and specificity values higher than 90%, cut‐off values of 0.35 and 0.66 were chosen for the M probe and 0.32 and 0.63 were chosen for the XL probe.
Conclusions
There was no significant difference in diagnostic accuracy of FAST score between the FibroScan M and XL probes. The FAST score can be used to identify NASH with significant risk in Japanese patients regardless of probe selection.
Background
Thrombocytopenia is a marked feature of chronic liver disease and cirrhosis. We tried to clarify whether an accumulation of platelets in the liver contributes to thrombocytopenia and liver ...fibrosis in chronic liver disease.
Methods
Thirty-eight patients who underwent hepatectomy for hepatocellular carcinoma (HCC) with hepatitis C virus infection were included. The locations of platelets and Kupffer cells and the expression of platelet-derived growth factor (PDGF) receptor-β and smooth muscle actin (SMA) were identified by immunohistochemistry. Perisinusoidal mesenchymal cells that express PDGF receptor-β and SMA were interpreted as transformed hepatic stellate cells (HSCs).
Results
Patients with cirrhosis had a more extensive platelet area in the liver compared to controls (5601 ± 5611 vs. 564 ± 361 μm
2
,
p
= 0.02), although the blood platelet count significantly decreased along with the progression of liver fibrosis. In cirrhotic liver, most platelets were present in the sinusoidal space of the periportal area with inflammation, where HSCs expressing PDGF receptor-β were frequently observed. In addition, the platelet and Kupffer cell areas were significantly smaller in cancerous tissue than those in noncancerous tissues (platelet area: 492 ± 823 vs. 3643 ± 4055 μm
2
,
p
= 0.001; Kupffer cell area: 450 ± 841 vs. 3012 ± 3051 μm
2
,
p
= 0.001).
Conclusions
The accumulation of platelets in the liver with chronic hepatitis may be involved in thrombocytopenia and liver fibrosis through the activation of HSCs. In addition, our findings also indicate that both platelets and Kupffer cells decrease in HCC tissues.
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