Kung-Kai Kuo

Potential prognostic value of leptin receptor in hepatocellular carcinoma

Background: Obesity is associated with several human malignancies, including hepatocellular carcinoma (HCC). This association may result from the deregulated expression of adipokines. Aims: To explore the potential role and the prognostic value of leptin receptor (Ob-R) in HCC. Methods: 66 patients with pathologically confirmed HCC were included in this study. Immunohistochemistry was used to evaluate the expression of Ob-R, microvessel density (MVD) and Ki-67 index in these patients. Eventually, the profiles of Ob-R expression, obtained by a semiquantitative scoring system, were further correlated with Ki-67 expression, intratumour MVD, clinicopathological characteristics and overall survival. Results: High Ob-R expression was seen in 53% of patients with HCC and was significantly correlated with intratumour MVD (high v low; 59.4 ?3.2) v 44.7 ?3.7); p = 0.004), but not with Ki-67 expression. In addition, Ob-R expression was inversely correlated with vascular invasion (p = 0.037), but not with other known clinicopathological characteristics. The Kaplan–Meier survival curve showed that high Ob-R expression was associated with a better overall survival (p = 0.027). Meanwhile, multivariate analysis showed that Ob-R expression was a significant determinant for HCC (odds ratio 0.02, 95% confidence interval 0.01 to 0.85; p = 0.041). Conclusion: Ob-R expression may have a potential role in the carcinogenesis of HCC. The positive association of Ob-R expression in the cancerous lesions of HCC with the survival outcome can be explained by its inverse correlation with vascular invasion, and may have prognostic value in HCC.

Positive Feedback Loop of OCT4 and c‐JUN Expedites Cancer Stemness in Liver Cancer

The network of stemness genes and oncogenes in human patient‐specific reprogrammed cancer stem cells (CSCs) remains elusive, especially in liver cancer. HepG2‐derived induced pluripotent stem cell‐like cells (HepG2‐iPS‐like cells) were generated by introducing Yamanaka factors and the knockdown vector shTP53. They exhibited features of stemness and a higher tumorigenesis after xenograft transplantation compared with HepG2 cells. The cancerous mass of severe combined immunodeficiency (SCID) mice derived from one colony was dissected and cultured to establish reprogrammed HepG2‐derived CSC‐like cells (designated rG2‐DC‐1C). A single colony exhibited 42% occurrence of tumors with higher proliferation capacities. rG2‐DC‐1C showed continuous expression of the OCT4 stemness gene and of representative tumor markers, potentiated chemoresistance characteristics, and invasion activities. The sphere‐colony formation ability and the invasion activity of rG2‐DC‐1C were also higher than those of HepG2 cells. Moreover, the expression of the OCT4 gene and the c‐JUN oncogene, but not of c‐MYC, was significantly elevated in rG2‐DC‐1C, whereas no c‐JUN expression was observed in HepG2 cells. The positive‐feedback regulation via OCT4‐mediated transactivation of the c‐JUN promoter and the c‐JUN‐mediated transactivation of the OCT4 promoter were crucial for promoting cancer development and maintaining cancer stemness in rG2‐DC‐1C. Increased expression of OCT4 and c‐JUN was detected in the early stage of human liver cancer. Therefore, the positive feedback regulation of OCT4 and c‐JUN, resulting in the continuous expression of oncogenes such as c‐JUN, seems to play a critical role in the determination of the cell fate decision from iPS cells to CSCs in liver cancer. Stem Cells 2016;34:2613–2624

The impact of body mass index on laparoscopic cholecystectomy in Taiwan: an oriental experience

BACKGROUND/PURPOSE The outcome analysis of obese patients undergoing laparoscopic cholecystectomy (LC) in Asia-Pacific countries is rarely reported. This study examined associations between body mass index (BMI) and clinical outcomes of elective LC in Taiwan. METHODS A total of 627 patients with gallbladder disease due to gallstones undergoing LC were divided into three groups based on BMI: <25.0 kg/m2 (normal, NO; n = 310), 25.0-29.9 kg/m2 (overweight, OW; n = 252), and >30 kg/m2 (obese, OB; n = 65). RESULTS Both overweight and obesity were not associated with conversion and complication rates. The conversion rates of the three groups were 5.5 (NO), 6.0 (OW), and 4.6% (OB), and the complication rates were 3.2 (NO), 2.4% (OW), and 4.6% (OB), respectively. However, overweight and obesity were related to a trend toward longer operating time (NO 67.4 +/- 31.8; OW 77.8 +/- 35.6; OB 79.0 +/- 37.9 min) (P trend <0.001). One death (BMI 40.6 kg/m2) was due to septic complications. In the multivariable logistic analysis, only acute cholecystitis, but not BMI, was a predictor for conversion and complications. CONCLUSIONS Based on these results, it appears that BMI was not associated with clinical outcomes and that LC is a safe procedure in obese patients with uncomplicated gallstone disease in Taiwan.

Natural course of splenic artery aneurysm with associated spontaneous splenorenal shunt in non-cirrhotic liver: An 18-year observational follow-up and review of literature

Through a review of the literature, a splenic artery aneurysm (SAA) with associated spontaneous splenorenal shunt (SSRS) was only reported in patients with liver cirrhosis and portal hypertension. However, a natural course of a SAA with associated SSRS was found in a non‐cirrhotic male patient during an 8‐year observational follow‐up, and thus reported. Initially, splenomegaly and thrombocytopenia were noted; SSRS was observed later with a tortuous dilated splenic artery, and a SAA was then progressively formed and found. The patient received splenectomy with aneurysm resection and SSRS was preserved. Post‐operative follow‐up revealed that the size of the SSRS was reduced. Through the course, no abnormalities of liver enzymes, portal hypertension, or esophageal‐gastric varicose were found in the patient. No positive association was demonstrated between the formation of SSRS and the severity of liver cirrhosis in patients, implying some other factors, e.g., vascular endothelial growth factor (VEGF) mentioned in the literature, might be involved.

Control of Oxidative Stress and Generation of Induced Pluripotent Stem Cell-like Cells by Jun Dimerization Protein 2

We report here that the Jun dimerization protein 2 (JDP2) plays a critical role as a cofactor for the transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and MafK in the regulation of the antioxidants and production of reactive oxygen species (ROS). JDP2 associates with Nrf2 and MafK (Nrf2-MafK) to increase the transcription of antioxidant response element-dependent genes. Oxidative-stress-inducing reagent led to an increase in the intracellular accumulation of ROS and cell proliferation in Jdp2 knock-out mouse embryonic fibroblasts. In Jdp2-Cre mice mated with reporter mice, the expression of JDP2 was restricted to granule cells in the brain cerebellum. The induced pluripotent stem cells (iPSC)-like cells were generated from DAOY medulloblastoma cell by introduction of JDP2, and the defined factor OCT4. iPSC-like cells expressed stem cell-like characteristics including alkaline phosphatase activity and some stem cell markers. However, such iPSC-like cells also proliferated rapidly, became neoplastic, and potentiated cell malignancy at a later stage in SCID mice. This study suggests that medulloblastoma cells can be reprogrammed successfully by JDP2 and OCT4 to become iPSC-like cells. These cells will be helpful for studying the generation of cancer stem cells and ROS homeostasis.

Spontaneous multiple cholecystoenteric fistulas--a case report.

Spontaneous multiple cholecystoenteric fistulas are relatively rare complications of chronic cholecystitis. One cholecystoduodenal and two cholecystocolonic fistulas were observed in a 65-year-old woman whose symptoms included fever, chills, jaundice, diarrhea, and prolonged right upper quadrant pain. Pneumobilia, which is a pathognomonic sign of bilioenteric fistula, was also detected by her plain abdomen X-ray on admission. Both types of fistulas were correctly diagnosed preoperatively by barium enema, upper GI series and endoscopic retrograde cholangiopancreaticography. The patient was referred for surgery and fistulas were identified during laparotomy. Cholecystectomy, division of these fistulas, and primary repair of these bowel defects were successfully performed. The postoperative course was unremarkable. We report this unusual case and briefly review the hypothesized pathogenesis, typical symptomatology, radiographic diagnosis, complications and therapeutic modalities of this condition.

The value of primary vascular stents in management of early portal vein stenosis after liver transplantation

If portal vein stenosis (PVS) occurs within 1 month after liver transplantation (LT), especially within 1 week, it can be catastrophic and result in rapid loss of the grafts and mortality. Although surgical treatments have been considered standard treatment for PVS, patients are usually unable to receive operations or re‐transplantations, because of their critical conditions and a shortage of grafts. Recently, primary percutaneous transhepatic portal vein stents (PTPS) were suggested as alternative and less‐invasive treatments of PVS. However, because lethal complications may follow these primary stent placements for patients in early stages after LT, primary PTPS placements for patients suffering PVS 1 month after LT has been suggested. From November 2009 to July 2015, 38 consecutive adult patients underwent LT at our institution. Among them, six recipients suffered PVS within 1 month after LT. Technical success was achieved in all six patients. Clinical success was obtained in two of the four patients suffering PVS within 1 week after LT, and in the other two patients suffering PVS > 1 week after LT. All surviving patients and their grafts were in good condition, and their stents remained patent. Our experience showed that primary PTPS placements can be used to effectively treat patients with PVS encountered within 1 month, and even within 1 week, after LT with acceptable short‐term results. However, possible fatal complications should be kept in mind. Long‐term results of these procedures need further follow‐up.

Solid and Cystic Tumor of the Pancreas - Three Cases Report

Solid and cystic tumor of the pancreas is a rare, low-grade malignant tumor that predominantly occurs in young women. Clinically, the patients are often asymptomatic and are usually found incidentally due to other diseases. The pre-operative diagnosis is difficult due to the similarity to other cystic pancreatic lesions (such as serous adenoma, mucinous cystadenoma and endocrinologically inactive islet cell tumor), or inflammatory changes (such as pancreatic pseudocyst). This tumor has a slow growth, usually does not have metastases and has a favorable prognosis. Complete removal is the treatment of choice for the tumors arising anywhere in the pancreas. We collected specimens of pancreatic tumors that were kept at Kaohsiung Medical University Hospital (KMUH) in the past 11 years. Three cases varying in clinical course were found. The first is a case of a middle aged woman with a slow growing tumor who had a misdiagnosis of pseudocyst eight years ago. The second is a case of a young woman that showed no symptoms, while the third case was also a young woman diagnosed with a huge tumor with portal vein and inferior vessel encasement. We review some articles to revise the study of this disease in order to make the correct diagnosis before proceeding with the operation, and to provide proper treatment.

Reprogramming Antagonizes the Oncogenicity of HOXA13‐Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells

Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)‐homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS‐like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed‐lineage leukemia 1 lysine N‐methyltransferase, WD repeat‐containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis‐element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13‐mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13–HOTTIP and HOXA13–HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer‐binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. Stem Cells 2017;35:2115–2128

Bile Duct Cancer 25 Years After Choledochoduodenostomy: A Case Report

We describe a 65-year-old man who had undergone choledochoduodenostomy (CDS) for choledocholithiasis 25 years prior to admission to our hospital for cholangitis. Abdominal sonography and computerized tomography (CT) scan revealed a tumor mass at the hilar region with bilateral intrahepatic duct dilatation. Upper gastrointestinal endoscopic examination indicated the site of the CDS. Biopsy was taken from the mucosa of the bile duct, and pathology revealed well-differentiated adenocarcinoma. CT scan and angiography further confirmed unresectable hilar bile duct cancer. Conservative treatment with intra-arterial chemotherapy was arranged. After briefly reviewing the hypothesized pathogenesis and radiographic diagnosis of this rare case, we recommend that chronic cholangitis consequent to CDS should be closely followed for late development of biliary tract malignancy.