Wnt/ß-catenin signaling activation promotes lipogenesis in the steatotic liver via physical mTOR interaction.

Background and aims: Wnt/ß-catenin signaling plays an important role in regulating hepatic metabolism. This study is to explore the molecular mechanisms underlying the potential crosstalk between Wnt/ß-catenin and mTOR signaling in hepatic steatosis. Methods: Transgenic mice (overexpress Wnt1 in hepatocytes, Wnt+) mice and wild-type littermates were given high fat diet (HFD) for 12 weeks to induce hepatic steatosis. Mouse hepatocytes cells (AML12) and those transfected to cause constitutive ß-catenin stabilization (S33Y) were treated with oleic acid for lipid accumulation. Results: Wnt+ mice developed more hepatic steatosis in response to HFD. Immunoblot shows a significant increase in the expression of fatty acid synthesis-related genes (SREBP-1 and its downstream targets ACC, AceCS1, and FASN) and a decrease in fatty acid oxidation gene (MCAD) in Wnt+ mice livers under HFD. Wnt+ mice also revealed increased Akt signaling and its downstream target gene mTOR in response to HFD. In vitro, increased lipid accumulation was detected in S33Y cells in response to oleic acid compared to AML12 cells reinforcing the in vivo findings. mTOR inhibition by rapamycin led to a down-regulation of fatty acid synthesis in S33Y cells. In addition, ß-catenin has a physical interaction with mTOR as verified by co-immunoprecipitation in hepatocytes. Conclusions: Taken together, our results demonstrate that ß-catenin stabilization through Wnt signaling serves a central role in lipid metabolism in the steatotic liver through up-regulation of fatty acid synthesis via Akt/mTOR signaling. These findings suggest hepatic Wnt signaling may represent a therapeutic strategy in hepatic steatosis.

Surgical Outcomes of Laparoscopic versus Open Hepatectomy for Left Hepatocellular Carcinoma: Propensity Score Analyses Using Retrospective Japanese and Korean Individual Patient Data.

Introduction: This study aimed to compare the prognostic impact of laparoscopic left hepatectomy (LLH) with that of open left hepatectomy (OLH) on patient survival after resection of left hepatocellular carcinoma (HCC). Methods: Among the 953 patients who received initial treatment for primary HCC that was resectable by either LLH or OLH from 2013 to 2017 in Japan and Korea, 146 patients underwent LLH and 807 underwent OLH. The inverse probability of treatment weighting approach based on propensity scoring was used to address the potential selection bias inherent in the recurrence and survival outcomes between the LLH and OLH groups. Results: The occurrence rate of postoperative complications and hepatic decompensation was significantly lower in the LLH group than in the OLH group. Recurrence-free survival (RFS) was better in the LLH group than in the OLH group (hazard ratio, 1.33; 95% confidence interval, 1.03-1.71; p = 0.029), whereas overall survival (OS) was not significantly different. Subgroup analyses of RFS and OS revealed an almost consistent trend in favor of LLH over OLH. In patients with tumor sizes of ≥4.0 cm or those with single tumors, both RFS and OS were significantly better in the LLH group than in the OLH group. Conclusions: LLH decreases the risk of tumor recurrence and improves OS in patients with primary HCC located in the left liver.

Primary Hepatic Neuroendocrine Tumor Arising at a Young Age: Rare Case Report and Literature Review.

Neuroendocrine tumors (NETs) are low-grade malignancies arising from neuroendocrine cells. Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare and difficult to differentiate from other liver tumors, such as hepatocellular carcinoma (HCC) or cholangiocarcinoma. A 22-year-old male presented with intermittent abdominal pain. A preoperative imaging study revealed a 5.1cm-sized heterogeneously enhancing mass in S6 of the liver, suggesting HCC. Laparoscopic right hepatectomy was performed, and a well-demarcated brown solid mass was found. The pathology report revealed a neuroendocrine tumor of the liver. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography was performed postoperatively to exclude extrahepatic lesions, and no lesions were found. This is a rare case of PHNET that developed at a young age and was misdiagnosed as HCC preoperatively. This suggests that PHNET should be considered one of the differential diagnoses when a non-specific enhanced hepatic tumor is found, even when the patient is young.

Comparison of laparoscopic versus open distal pancreatectomy for benign, pre-malignant, and low grade malignant pancreatic tumors.

BACKGROUNDS/AIMS: The purpose of this study is to demonstrate that laparoscopic distal pancreatectomy in benign disease is is safer and more favorable to patients than open distal pancreatectomy. METHODS: We retrospectively reviewed data of 150 patients who underwent laparoscopic (n=69) or open (=81) distal pancreatectomy at a double institutes from 2008 to 2018. We reviewed each patient's history for age, sex, pathologic diagnosis. Specific outcomes that were included hospital stay, operative time (in minutes), operative blood loss (in milliliters), 30-daymajormorbidity and mortality (Clavian-Dindo classification), pancreatic leak rate (grade of leak A, B, or C), pancreatic hemorrhage. RESULTS: From 2008 to 2018, there were 150 patients underwent distal pancreatectomy with or without splenectomy for benign pancreatic disease. 81 patients underwent open and 69 patients underwent laparoscopic distal pancreatectomy (LDP) Intra-operative estimated blood loss was significantly lower in the LDP group than in the OPD group (200 vs. 400 ml p<0.01). There was no difference in blood transfusion between the two groups. There was a significant difference in the resection method between the two groups (p<0.01) and there was a significant difference in the use of mesh for prevention of postoperative pancreatic fistula (POPF) (53 vs. 34 p<0.01). There was no significant difference in incidence of POPF (15.9% in LDP vs 7.4% in ODP, p=0.235) between the two groups, morbidity rate between the two groups (18 vs. 30 p=0.152), post - pancreatectomy hemorrhage, wound infection, hospital stay and readmission. CONCLUSIONS: LDP showed there was no difference in the occurrence of POPF, complication and hospital stay. In contrast, intra-operative blood loss was significantly lower in the LDP group than in the ODP group, and LDP was also significantly better in the view point of the feeding advance. In other words, LDP is safer and more favorable to patients than ODP.

Mature Cystic Teratoma of the Pancreas: A Rare Cystic Neoplasm.

Mature cystic teratoma of the pancreas is an extremely rare benign neoplasm. Only 51 cases have been reported in the literature. Its cystic nature often appears to have malignant potential in preoperative image studies. Moreover, no characteristic features could be shown on image studies, such as abdominal CT scan or pancreas MRI. The accurate diagnosis is generally obtained after surgical resection. We present a rare case of a 53-year-old male with mature cystic teratoma of the pancreas, which was confirmed on pathology after laparoscopic distal pancreatectomy.

Augmented Wnt signaling as a therapeutic tool to prevent ischemia/reperfusion injury in liver: Preclinical studies in a mouse model.

The Wnt signaling pathway has established biological roles in liver development, regeneration, and carcinogenesis. Given the common need for cellular energy utilization in each of these processes, we hypothesized that Wnt signaling would directly regulate hepatocyte mitochondrial function. Mice were engineered to overexpress Wnt1 in hepatocytes under the control of a tetracycline analogue. Wnt1 and wild-type mice underwent ischemia/reperfusion injury (IRI) to induce oxidative mitochondrial injury. Alpha mouse liver 12 (AML12) hepatocytes were exposed to Wnt agonists for in vitro hypoxia/reoxygenation (H-R) experiments. We observed stabilized mitochondrial membrane potential and reduced levels of hepatocyte apoptosis involving the mitochondrial pathway in Wnt1 mice compared to controls following IRI. Wnt1 mice also demonstrated increased mitochondrial DNA copy number, as well as an increased tricarboxylic acid cycle activity and adenosine triphosphate levels indicating that mitochondrial function is preserved by Wnt1 overexpression following IRI. AML12 cells treated by Wnt3a or the glycogen synthase kinase 3ß inhibitor LiCl exposed to H-R demonstrated decreased reactive oxygen species and reduced apoptosis compared to controls. Increased nucleus-localized PGC-1α and phosphorylated SIRT1 was observed in both Wnt1+ mice as well as AML12 cells treated with Wnt3a or LiCl. Activated Wnt signaling protects hepatocytes against oxidative injury and apoptosis through mitochondrial stabilization and preserved oxidative phosphorylation function. Mechanistically, these effects are accompanied by an increase in phosphorylated SIRT1 and nucleus-localized PGC-1α. These findings expand the understanding of Wnt signaling biology in hepatocytes and suggest the potential for the therapeutic application of Wnt pathway manipulation in a variety of clinical applications including organ transplantation.

Impact of lymph node ratio as a valuable prognostic factor in gallbladder carcinoma, focusing on stage IIIB gallbladder carcinoma.

PURPOSE: It is increasingly being recognized that the lymph node ratio (LNR) is an important prognostic factor for gallbladder carcinoma patients. The present study evaluated predictors of tumor recurrence and survival in a large, mono-institutional cohort of patients who underwent surgical resection for gallbladder carcinoma, focusing specifically on the prognostic value of lymph node (LN) status and of LNR in stage IIIB patients. METHODS: Between 2004 and 2011, 123 patients who underwent R0 radical resection for gallbladder carcinoma at the Chonnam National University Hwasun Hospital were reviewed retrospectively. Patients were staged according to the American Joint Committee on Cancer 7th edition, and prognostic factors affecting disease free survival, such as age, sex, comorbidity, body mass index, presence of preoperative symptoms, perioperative blood transfusion, postoperative complications, LN dissection, tumor size, differentiation, lymph-vascular invasion, perineural invasion, T stage, presence of LN involvement, N stage, numbers of positive LNs, LNR and implementation of adjuvant chemotherapy, were statistically analyzed. RESULTS: LN status was an important prognostic factor in patients undergoing curative resection for gallbladder carcinoma. The total number of LNs examined was implicated with prognosis, especially in N0 patients. LNR was a powerful predictor of disease free survival even after controlling for competing risk factors, in curative resected gallbladder cancer patients, and especially in stage IIIB patients. CONCLUSION: LNR is confirmed as an independent prognostic factor in curative resected gallbladder cancer patients, especially in stage IIIB gallbladder carcinoma.

Sclerosing angiomatoid nodular transformation of the spleen related to IgG4-associated disease: report of a case.

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a rare benign vascular mass, with fewer than 100 cases documented. It is generally recognized as a vascular lesion that develops in the red pulp of the spleen; however, its pathogenesis is not clearly defined. We report a case of SANT of the spleen, which presents evidence to support the hypothesis that this disease entity is associated with IgG4-associated disease. Microscopically, the tumor was composed of multiple vascular structures separated by fibrous connective tissue and immunohistochemical examination revealed positive staining for CD31, CD34, factor VIII, and IgG4. Further research based on large number of cases is warranted to clarify the pathogenesis of this tumor.

Pancreatic hamartoma diagnosed after surgical resection.

A pancreatic hamartoma is a rare benign lesion that may be mistaken for malignancy. A pancreatic hamartoma can present with vague, non-specific symptoms, which can be difficult to diagnose despite modern diagnostic tools. We report here a pancreatic hamartoma diagnosed after surgical resection. A 52-year-old female presented with postprandial abdominal discomfort. Abdominal computed tomography and pancreatic magnetic resonance imaging revealed a 2.2 × 2.5-cm cystic mass in the pancreatic head. The patient underwent a pylorus-preserving pancreaticoduodenectomy. The histopathological and immunohistochemical studies helped make the diagnosis of pancreatic hamartoma. Here, we report a case of pancreatic hamartoma and review the relevant medical literature.

Current status of laparoscopic liver resection in Korea.

Since laparoscopic liver resection was first introduced in 2001, Korean surgeons have chosen a laparoscopic procedure as one of the treatment options for benign or malignant liver disease. We distributed and analyzed a nationwide questionnaire to members of the Korean Laparoscopic Liver Surgery Study Group (KLLSG) in order to evaluate the current status of laparoscopic liver resection in Korea. Questionnaires were sent to 24 centers of KLLSG. The questionnaire consisted of operative procedure, histological diagnosis of liver lesions, indications for resection, causes of conversion to open surgery, and postoperative outcomes. A laparoscopic liver resection was performed in 416 patients from 2001 to 2008. Of 416 patients, 59.6% had malignant tumors, and 40.4% had benign diseases. A total laparoscopic approach was performed in 88.7%. Anatomical laparoscopic liver resection was more commonly performed than non-anatomical resection (59.9% vs 40.1%). The anatomical laparoscopic liver resection procedures consisted of a left lateral sectionectomy (29.3%), left hemihepatectomy (19.2%), right hemihepatectomy (6%), right posterior sectionectomy (4.3%), central bisectionectomy (0.5%), and caudate lobectomy (0.5%). Laparoscopy-related serious complications occurred in 12 (2.8%) patients. The present study findings provide data in terms of indication, type and method of liver resection, and current status of laparoscopic liver resection in Korea.

Carcinosarcoma of the gallbladder: report of two cases.

Adenocarcinoma is the predominant histological type of carcinoma of the gallbladder, accounting for more than 80% of all gallbladder carcinomas. In contrast, carcinosarcoma of the gallbladder is an extremely atypical subset of gallbladder malignancies. It is characterized by the presence of both epithelial and mesenchymal components. Currently, fewer than 100 cases have been reported in the English literature. Therefore, knowledge and experience regarding this disease are limited. Recently, we experienced two cases of gallbladder carcinosarcoma, which were diagnosed as gallbladder carcinoma based on the preoperative clinical and radiological examinations. Cholecystectomies were performed in both cases, and the malignant tumor cells included carcinomatous and sarcomatous components histologically. The final pathological diagnoses were carcinosarcoma of the gallbladder. We herein report these two cases of gallbladder carcinosarcoma and review the previous pertinent literature.

Primary extragastrointestinal stromal tumor arising in the pancreas: report of a case.

Primary extragastrointestinal stromal tumors (EGISTs) arising in the pancreas are extremely rare, with only ten cases documented to our knowledge. We report a further case of EGIST of the pancreas. The patient was a 55-year-old man who presented with postprandial abdominal discomfort. Abdominal computed tomography and magnetic resonance imaging showed a lobulated heterogenous enhancing mass, 11 cm in diameter, in the abdominal cavity. No regional lymphadenopathy, ascites, or metastasis was seen radiologically. There was no obvious lesion in the stomach or small intestine. The initial diagnosis was a solid pseudopapillary tumor or serous cystic neoplasm. The patient underwent distal pancreatectomy with splenectomy. Microscopically, the tumor consisted of spindle cells arranged in short fascicles. Mitotic figures were seen in 7/50 high-power fields. Immunohistochemical examination revealed strongly positive staining for CD117. Based on these findings, the final pathologic diagnosis was a primary EGIST of the pancreas. This case consolidates the possibility that this rare tumor can involve the pancreas as a primary site and should be included in the differential diagnosis of cystic lesions in this site.

Peripheral eosinophilia - is it a predictable factor associated with eosinophilic cholecystitis?

BACKGROUNDS/AIMS: The purpose of this study was to evaluate the role of peripheral eosinophilia as a predictable factor associated with Eosinophilic cholecystitis (EC) compared with other forms of cholecystitis in patients who underwent a cholecystectomy. METHODS: Between January 2001 and May 2011, the histopathologic features of 3,539 cholecystectomy specimens were reviewed retrospectively. EC was diagnosed in 30 specimens (0.84%). Data from 30 consecutive patients with EC (eosinophilic cholecystitis group [E-group]) were compared with a retrospective control group of 60 patients (other cholecystitis group [O-group]) during the same period. The two groups were matched for age, gender, and the presence of cholelithiasis. RESULTS: The median absolute eosinophil count 1 day post-operatively was 144 cells/mm(3) (range: 9-801 cells/mm(3)) in the E-group and 93 cells/mm(3) (range: 0-490 cells/mm(3)) in the O-group (p=0.036). Pre-operative peripheral eosinophilia was more common in the E-group than the O-group (20% vs. 3.3%, p=0.015). Multivariate analysis revealed that pre-operative peripheral eosinophilia was an independent significant predictable factor associated with EC (odds ratio=7.250, 1.365 <95% confidence interval<38.494, p=0.020). CONCLUSIONS: In the present study, pre-operative peripheral eosinophilia was shown to be an independent predictable factor associated with EC. Further researches seem to be necessary to confirm this finding.

KITENIN is associated with activation of AP-1 target genes via MAPK cascades signaling in human hepatocellular carcinoma progression.

KITENIN promotes cancer cell migration and invasion in vitro and cancer metastasis in mouse cancer models, including colon and head and neck cancers. The purposes of this study were to observe the effect of KITENIN on tumor cell behaviors of human hepatocellular carcinoma (HCC) cells and to evaluate its expression in human HCC tissues. To functionally characterize KITENIN in human HCC, we depleted its expression in human HCC cell lines, HepG2 and Huh7, by using small interfering RNA (siRNA). Invasion and proliferation assays were performed. The activator protein-1 (AP-1) transcriptional activity and expression of AP-1 target genes were evaluated by AP-1 luciferase reporter assay and RT-PCR. The contribution of mitogen-activated protein kinase (MAPK) cascade signaling involved in AP-1 activation was assessed by Western blotting. We evaluated the expression of KITENIN and AP-1 target genes at mRNA levels by RT-PCR in human HCC tissues and paired normal hepatic mucosa of the same patients taken by surgery. Knockdown of KITENIN in HepG2 and Huh7 cells resulted in a significant reduction of tumor cell invasion. The tumor cell proliferation was significantly decreased in the KITENIN knocked down Huh7 cells compared to the negative control. The mRNA expressions of MMP-3 and COX-2 were decreased in KITENIN knocked down Huh7 cells. The mRNA expression of MMP-1 was decreased in KITENIN knocked down HepG2 cells. The AP-1 transcriptional activity in Huh7 cells was significantly decreased by knockdown of KITENIN. The JNK and ERK1/2 phosphorylations were decreased in KITENIN knocked down HepG2 and the p38 phosphorylation was decreased in KITENIN knocked down Huh7 cells. The mRNA expressions of KITENIN, MMP-1, and MMP-3 were significantly upregulated in human HCC tissues compared to paired normal mucosa. These results indicate that KITENIN is associated with activation of AP-1 target genes via MAPK cascades signaling in human HCC progression.

Antitumor effect of all-trans retinoic acid-encapsulated nanoparticles of methoxy poly(ethylene glycol)-conjugated chitosan against CT-26 colon carcinoma in vitro.

All-trans retinoic acid (ATRA)-incorporated nanoparticles of methoxy poly(ethylene glycol) (MPEG)-grafted chitosan were prepared through ion-complex formation between ATRA and chitosan. This nanoparticle has around 100 nm of diameter and favorable reconstitution properties. ATRA-incorporated nanoparticles has almost similar cytotoxicity against CT-26 tumor cells when compared to free ATRA. But nanoparticles was more effective to inhibit invasion of tumor cells than free ATRA at invasion test using matrigel. These results can be explained by apoptosis analysis using flow cytometer. When free ATRA or ATRA-incorporated nanoparticles were treated, tumor cells were slight progressed apoptosis. Furthermore, apoptosis was also progressed by treated with MPEG-grafted chitosan.

Pancreatic metastasis of leiomyosarcoma in the right thigh: a case report.

Pancreatic tumors are primary in most of the cases. Pancreatic metastases associated with other primary malignancies, especially pancreatic metastasis of leiomyosarcoma, are uncommon. A 66-year-old woman underwent surgical resection of malignant mesenchymoma (70% osteosarcoma and 30% leiomyosarcoma) in the right thigh. In the postoperative period, a pancreatic mass was identified radiologically by abdominal computed tomography. Pylorus-preserving pancreaticoduodenectomy was performed. The surgical specimen revealed leiomyosarcoma metastasized to the pancreas. A metastatic nodule on the remnant pancreatic tail was discovered 9 mo after the first pancreatic resection, and distal pancreatectomy was performed. Cases of pancreatic metastasis from leiomyosarcoma are extremely rare, especially when the tumor was resectable. We report here a unique case of pancreatic metastasis from a leiomyosarcoma in the right thigh that had been treated surgically.

Expression of cyclooxygenase-2, p53 and Ki-67 in gastric cancer.

It has been reported that p53 mutation may contribute to upregulate cyclooxygenase (COX)-2 expression that is observed in malignant tissues. These molecules are involved in carcinogenesis by affecting tumor cell proliferation. The aim of this study was to examine the relationship between COX-2 or p53 expression and clinico-pathological characteristics including tumor cell proliferation in gastric cancer. COX-2 and p53 expressions were investigated with immunostaining, in tissue specimens obtained from 119 patients who underwent surgery for gastric cancer. The Ki-67 labeling index (LI) was counted by Ki-67 immunostaining. COX-2 and p53 expressions correlated significantly with depth of tumor invasion. However, there was no association between COX-2 or p53 expression and survival. p53 expression did not correlate with COX-2 expression. There was no significant difference in various clinicopathological variables between Ki-67 LI subgroups. The mean Ki-67 LI value of COX-2 positive tumors was significantly higher than that of negative tumors. The mean Ki-67 LI value of p53 positive tumors was not significantly higher than that of negative tumors. The mean Ki-67 LI value of both COX-2 and p53 positive tumors was significantly higher than that of both negative tumors. These results imply that COX-2 expression is associated with tumor cell proliferation of gastric cancer.

Expression of survivin in gastric cancer and its relationship with tumor angiogenesis.

BACKGROUND/AIMS: Survivin, a member of inhibitors of apoptosis, has been found in various human cancers. Its expression is associated with tumor progression and adverse outcome. Angiogenesis is an essential process for the primary tumor to grow and invade the adjacent normal structures. Angiogenic factors such as vascular endothelial growth factor induce survivin expression in endothelial cells. The current study was designed to investigate the possible role of survivin and vascular endothelial growth factor status for angiogenesis in human gastric cancer. METHODS: In this study, we conducted an immunohistochemical investigation of survivin and vascular endothelial growth factor expression in 106 tissue samples obtained from gastric cancer patients undergoing surgical treatment. To assess tumor angiogenesis, microvessel density was counted by staining endothelial cells immunohistochemically using anti-CD34 monoclonal antibody. RESULTS: The positive expression of survivin and vascular endothelial growth factor in gastric cancer tissues was demonstrated in 50.0 and 69.8% of cases, respectively. The expression of survivin did not associate with vascular endothelial growth factor expression. Expression of survivin was significantly associated with tumor size, depth of invasion, lymph node metastasis, tumor stage and poor survival (P=0.011, 0.004, 0.020, 0.002, 0.046, respectively). High microvessel density was significantly associated with lymph node metastasis and poor survival (P=0.006 and 0.017, respectively). The mean microvessel density value of survivin positive tumors was 87.4+/-34.4 and significantly higher than that of survivin negative tumors (P=0.016). The mean microvessel density value of vascular endothelial growth factor positive tumors was 98.7+/-37.0 and significantly higher than that of vascular endothelial growth factor negative tumors (P=0.001). A combined analysis of survivin and vascular endothelial growth factor status showed that the mean microvessel density value of both positive tumors was 103.7+/-33.1 and significantly higher than that of both negative tumors (P<0.001). CONCLUSION: These results suggest that survivin may play an important role in carcinogenesis by stimulating tumor angiogenesis in human gastric cancer.

Zollinger-Ellison syndrome associated with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder with characteristic features of skin and central nervous system involvement. Gastrointestinal involvement is rare, but the risk of malignancy development is considerable. Zollinger-Ellison syndrome is caused by gastrin-secreting tumors called gastrinomas. Correct diagnosis is often difficult, and curative treatment can only be achieved surgically. CASE PRESENTATION: A 41-year-old female affected by neurofibromatosis type 1 presented with a history of recurrent epigastric soreness, diarrhea, and relapsing chronic duodenal ulcer. Her serum fasting gastrin level was over 1000 pg/mL. An abdominal CT scan revealed a 3 x 2-cm, well-enhanced mass adjacent to the duodenal loop. She was not associated with multiple endocrine neoplasia type 1. Operative resection was performed and gastrinoma was diagnosed by immunohistochemical staining. The serum gastrin level decreased to 99.1 pg/mL after surgery, and symptoms and endoscopic findings completely resolved without recurrences. CONCLUSION: Gastrinoma is difficult to detect even in the general population, and hence symptoms such as recurrent idiopathic peptic ulcer and diarrhea in neurofibromatosis type 1 patients should be accounted for as possibly contributing to Zollinger-Ellison syndrome.