IMPORTANCEWhether intravenous thrombolysis is needed in combination with mechanical thrombectomy in patients with acute large vessel occlusion stroke is unclear.OBJECTIVE To examine whether mechanical thrombectomy alone is noninferior to combined intravenous thrombolysis plus mechanical thrombectomy for favorable poststroke outcome. Investigator-initiated, multicenter, randomized, open-label, noninferiority clinical trial in 204 patients with acute ischemic stroke due to large vessel occlusion enrolled at 23 hospital networks in DESIGN, SETTING, AND PARTICIPANTS

Assessing liver fibrosis is important for predicting the efficacy of antiviral therapy and patient prognosis. Liver biopsy is the gold standard for diagnosing liver fibrosis, despite its invasiveness and problematic diagnostic accuracy. Although noninvasive techniques to assess liver fibrosis are becoming important, reliable serum surrogate markers are not available. A glycoproteomics study aimed at identifying such markers discovered Mac 2-Binding Protein Gylcan Isomer (M2BPGi), which is a reliable marker for assessing liver fibrosis in patients with viral hepatitis and other fibrotic liver diseases such as primary biliary cholangitis, biliary atresia, autoimmune hepatitis, and nonalcoholic fatty liver disease. M2BPGi predicts the development of hepatocellular carcinoma (HCC) in patients infected with hepatitis B and C as well as the prognosis of liver cirrhosis in those with HCC after therapy. The unique features of M2BPGi are as follows: (1) cut-off values differ for the same stages of fibrosis according to the cause of fibrosis; and (2) M2BPGi levels rapidly decrease after patients achieve a sustained antiviral response to hepatitis C virus. These observations cannot be explained if M2BPGi levels reflect the amount of fibrotic tissue. Hepatic stellate cells (HSCs) secrete M2BPGi, which may serve as a messenger between HSCs and Kupffer cells via Mac-2 (galectin 3) that is expressed in Kupffer cells during fibrosis progression. Here we show that M2BPGi is a surrogate marker for assessing HSC activation. These findings may reveal the roles of HSCs in extrahepatic fibrotic disease progression.

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Perimesencephalic nonaneurysmal subarachnoid haemorrhage (PN-SAH) is characterised by accumulation of blood around the midbrain, normal angiographic findings and an excellent prognosis. The etiology of PN-SAH has not yet been determined. Therefore we decided to compare the venograms of patients with PN-SAH with those of patients with aneurysmal SAH (A-SAH) in order to examine the relationship between PN-SAH and venous structures. We retrospectively studied 6 patients with PN-SAH and 102 cases of angiographically evaluated A-SAH during the past 12 years by reviewing their venograms for possible abnormalities in venous structures, particularly in the basal vein of Rosenthal (BVR). More abnormalities in venous structures were found in the patients with PN-SAH than in those with A-SAH. Most of the BVR in the patients with PN-SAH appeared to drain into various dural sinuses instead of the galenic system. The relationship between PN-SAH and abnormalities in venous structures was determined.

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Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling (Mac-2結合蛋白糖鎖修飾異性体はmTORシグナル伝達経路を活性化することにより肝細胞癌の悪性度を増悪させる) Background: Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, mostly occurs in people with liver cirrhosis. For HCC patients with severe liver fibrosis, treatment option is limited. Therefore, deeper understanding of HCC in fibrotic liver is important for clinical management of HCC. Wisteria floribunda agglutinin (WFA) + Mac-2 binding protein ( M2BPGi) is a novel serum marker for liver fibrosis. Clinical studies reported that an elevated serum level of M2BPGi can predict development

Background Intrahepatic cholangiocarcinoma (ICC) is a malignancy that is challenging to treat. Fibroblasts in ICC tissues have been identified as cancer-associated fibroblasts (CAFs) that promote the malignant behaviour of ICC cells. An antifibrotic drug nintedanib has been reported to suppress activated hepatic stellate cells in liver fibrosis. Methods We investigated whether nintedanib could suppress the cancer-promoting effect of CAFs derived from ICC tissues in vitro and in vivo. Results CAFs promoted the proliferation and invasion of ICC cells. Nintedanib suppressed activated CAFs expressing α-smooth muscle actin (α-SMA) and inhibited the ICC-promoting effects of CAFs. Nintedanib greatly reduced the levels of cancer-promoting cytokines, such as interleukin (IL)-6 (IL-6) and IL-8, secreted by CAFs. An in vivo study demonstrated that nintedanib reduced xenografted ICC growth and activated CAFs expressing α-SMA, and that combination therapy with nintedanib and gemcitabine against CAFs and ICC cells showed the strongest inhibition of tumour growth compared with the control and single-treatment groups. Conclusions Nintedanib inhibited the cancer-promoting effect of CAFs via the suppression of CAF activation and secretion of cancer-promoting cytokines. Our findings suggest that therapeutic strategies combining conventional cytotoxic agents with nintedanib targeting CAFs are promising for overcoming refractory ICC with activated CAFs.

The natural killer group 2 member D (NKG2D) receptor and its ligands are important mediators of immune responses to tumors. NKG2D ligands are overexpressed in several malignant tumor types; however, the prognostic value of these ligands is unclear. Here, we aimed to elucidate the role of NKG2D ligands in extrahepatic cholangiocarcinoma (EHCC). We therefore investigated the expression of the NKG2D receptor and its ligands MHC class I chain-related proteins A and B (MICA ⁄ B), unique long 16 binding protein (ULBP) 1, and ULBP2 ⁄ 5 ⁄ 6 in resected specimens from 82 patients with EHCC. All NKG2D ligands were highly expressed in EHCC. High expression of MICA ⁄ B or ULBP2 ⁄ 5 ⁄ 6 correlated with overall and disease-free survival. In contrast, high expression of ULBP1 was significantly associated with improved overall survival, but not disease-free survival. Concurrent high expression of multiple NKG2D ligands revealed significantly better overall and disease-free survival than that observed with the overexpression of any one NKG2D ligand. Co-expression of multiple NKG2D ligands was an independent prognostic indicator of improved survival. Furthermore, co-overexpression of multiple NKG2D ligands was significantly correlated with high expression of the NKG2D receptor. Inhibiting interactions between multiple NKG2D ligands and the NKG2D receptor might be a promising approach for controlling cancer progression and improving patient prognosis in EHCC.C holangiocarcinoma is a malignant cancer that originates from epithelial cells in bile ducts.(1,2) It is classified as intrahepatic or extrahepatic, and EHCC is subcategorized into perihilar and distal forms. (3,4) Although EHCC is relatively uncommon in North America and Europe, its incidence and mortality rates continue to rise worldwide. (5,6) This is especially true in Japan, where the annual mortality due to EHCC was approximately 12 000 in 2013.(7) There is no curative treatment for cholangiocarcinoma except surgical resection and, despite recent advances in surgical techniques, recurrence occurs in most patients even after resection. Regrettably, post-resection 5-year survival rates are only 20-30%.(8) Therefore, the identification of new therapeutic targets and biomarkers is critical for improving outcomes in patients with cholangiocarcinoma.We previously reported that epithelial-mesenchymal transition-related factors, such as epithelial ⁄ neural-cadherin and forkhead box protein C2, were correlated with the prognosis and progression of EHCC.(9,10) Due to recent advancements in cancer immunotherapeutics, the editors of Science named cancer immunotherapy as the Breakthrough of the Year in 2013.(11) In particular, the immune checkpoint blockade approach involving the use of the anti-cytotoxic T-lymphocyte antigen 4 antibody and the anti-PD-1 antibody were significant recent developments. The US FDA has approved ipilimumab, pembrolizumab, and nivolumab for the treatment of metastatic melanoma, and the Pharmaceuticals and Medical Devices Agency in Japan has approved nivol...