Hironobu Amano

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.

Rho‐kinase inhibitor targeting the liver prevents ischemia/reperfusion injury in the steatotic liver without major systemic adversity in rats

Rho‐kinase (ROCK) inhibitors improve liver blood flow after ischemia/reperfusion (IR) injury, especially in the setting of steatosis, by decreasing the resistance of intrahepatic microcirculation through hepatic stellate cell (HSC) relaxation. However, the systemic administration of ROCK inhibitors causes severe hypotension; therefore, liver‐specific ROCK inhibition is required. Here, we tested vitamin A (VA)–coupled liposomes carrying the ROCK inhibitor Y‐27632 for targeted HSCs in steatotic rats. Rat livers with steatosis induced by a choline‐deficient diet were subjected to IR injury. The delivery site and effect of the ROCK inhibitor were investigated. After liposomal Y‐27632 injection, the survival rate after IR, the liver blood flow, the portal perfused pressure, and the hemodynamics were investigated. Immunohistochemical studies showed VA–coupled liposome accumulation in livers. Liposomal Y‐27632 was 100‐fold more effective in inhibiting HSC activation than free Y‐27632. Liposomal Y‐27632 improved the survival rate after IR injury, the liver blood flow, and the portal perfusion pressure without severe hypotension. In contrast, untargeted Y‐27632 elicited severe systemic hypotension. We conclude that VA–coupled liposomes carrying the ROCK inhibitor yield enhanced drug accumulation in the liver and thus mitigate IR injury in the steatotic liver and reduce major systemic adversity. Liver Transpl 21:123‐131, 2015.

Obstructive jaundice caused by a giant liver hemangioma with Kasabach-Merritt syndrome: a case report

Hemangioma is the most common benign tumor of the liver. Liver hemangioma (LH) usually remains asymptomatic, but the most common symptoms associated with LH are abdominal pain and discomfort. LH is an uncommon cause of bile duct dilatation and obstructive jaundice. An 83-year-old Japanese woman who received hemodialysis at another hospital was referred to our hospital because of abnormal liver function and obstructive jaundice. Abdominal computed tomography and magnetic resonance imaging revealed a 13-cm tumor in liver segments IV–V and intrahepatic bile duct dilatation. Endoscopic retrograde cholangiopancreatography revealed extrinsic compression of the bile duct at the hepatic hilar region. Laboratory tests showed that the patient had low platelet counts and low fibrinogen levels. Because the patient had hyperbilirubinemia and Kasabach-Merritt syndrome, we performed a segmentectomy of liver segments IV and V. Histological examination showed hemangioma of the liver. The patient’s thrombocytopenia and coagulopathy improved immediately after surgery. In conclusion, LH is a very rare cause of obstructive jaundice. LH has the potential to compress the bile duct and cause obstructive jaundice.

Methotrexate-associated primary hepatic malignant lymphoma following hepatectomy: A case report

Highlights • Primary hepatic lymphoma is difficult to diagnose preoperatively.• MTX use encouraged MTX-related ML.• In MTX-related MLs, withdrawing MTX had a therapeutic effect.

Early diagnosis of pancreatic cancer: Current trends and concerns

Early detection of pancreatic cancer (PC) is essential for a better prognosis. Some recent studies have demonstrated that a slight dilatation of the main pancreatic duct (MPD) and small cystic lesions were detected initially in most cases diagnosed at an early stage. Detecting these abnormal findings in cases with high risk factors through an effective screening system including image diagnosis, some biological markers, or familial cancer registrations should contribute to early diagnosis of PC. It has been reported that endoscopic ultrasonography (EUS) is essential for detecting tumors <10 mm with a favorable prognosis. Additionally, EUS‐guided fine‐needle aspiration biopsy is useful for confirming final histological diagnosis. For the diagnosis of stage 0 PC, local irregular stenosis of MPD should be an important initial abnormal sign detected by EUS or magnetic resonance cholangiopancreatography. Cytodiagnosis multiple times using pancreatic juice obtained by endoscopic nasopancreatic drainage should be essential for the final diagnosis. Recently, activities of regional networks between specialist doctors in medical centers and general practitioners for early diagnosis of PC have been reported in Japan. In the future, these activities may play an important role in the early diagnosis of PC.

Mixed adenoneuroendocrine carcinoma derived from the cystic duct: A case report

Highlights • We report here an extremely rare case of mixed adenoneuroendocrine carcinomas (MANECs) derived from cystic duct. Histologically, the tumor had components of both well-differentiated tubular adenocarcinoma and neuroendocrine carcinoma with massive venous invasion.• R0 resection was established, but the risk of recurrence in liver was estimated to be significantly high, due to the detected venous invasion of the neuroendocrine carcinoma in the resection margin of the hepatic duct. Eight months after surgery, multiple liver metastases were discovered, and treatment with adjuvant chemotherapy was initiated.• Though standards of diagnosis and treatment for MANECs of the bile duct have not been established, multidisciplinary therapy is necessary to improve outcomes.

A rare case of spontaneous rupture of an aneurysm of the right gastric artery

Highlights • We report here a rare case of intra-abdominal bleeding from a ruptured aneurysm of the right gastric artery.• Transcatheter arterial embolization (TAE) could not be adopted due to thrombotic occlusion of arteries, so we performed an urgent laparotomy.• We should not hesitate to convert endovascular approach into a laparotomy in an emergency situation.

A case of cholangiolocellular carcinoma featuring intratumoral hepatic artery penetration: A case report

Highlights • Cholangiolocellular carcinoma (CoCC) is a rare type of liver cancer.• We report a 79-year-old woman with CoCC detected following elevated C19-9 levels.• Uniquely, the hepatic artery was observed penetrating the >60 mm tumor on imaging.• Recurrence with multiple liver metastases occurred 6 months after surgery.• Tumor size and/or this unique growth pattern may be risk factors for recurrence.

Complete torsion of gallbladder following laparoscopic cholecystectomy: A case study

Highlights • Accurate preoperative diagnosis of gallbladder torsion is challenging because of the absence of clinical characteristics associated with it.• Careful attention to symptoms during clinical presentation, including acute severe pain in the right quadrant and gallbladder deviation observed during radiological investigation, is required for accurate diagnosis of the condition.• Upon confirmation of diagnosis, laparoscopic cholecystectomy would be the gold-standard treatment option rather than open cholecystectomy.