Standardized laparoscopy-assisted distal gastrectomy with a novel surgical technique for lifting the liver.

BACKGROUND/AIMS: It is very important to achieve a sufficient field and space in laparoscopic assisted distal gastrectomy (LADG) for a less-experienced surgeon. In this study, the usefulness of a novel surgical technique to lift the liver was evaluated in LADG. METHODOLOGY: Fifty-four patients who underwent standardized LADG for gastric cancer using the novel technique of lifting the liver were retrospectively evaluated based on video records. Patient characteristics, the time required to lift the liver and for gastrectomy, total operation time, blood loss and complications were analyzed. RESULTS: The mean time necessary to lift the liver using this novel technique was 240.1±86.1 seconds and that for gastrectomy was 167.6±50.4 minutes. Blood loss was 72.5±59.6mL. The morbidity rate was 4/54 (7.4%). CONCLUSIONS: Standardized LADG using this novel technique is feasible and possible in a period of time.

[A case of curatively resected biliary tract cancer with peritoneal dissemination through effective response to chemotherapy of S-1].

The patient is a 55-year-old woman who has biliary tract cancer with peritoneal dissemination (T3N1P2M0, Stage IV b). Since a curative operation was deemed impossible, we conducted chemotherapy using S-1. S-1 (120 mg/day) was administered for 2 weeks and then chemotherapy was discontinued for 1 week, which was regarded as one course. After 2 courses of the chemotherapy, CT scan showed that the metastatic lymph node and tumor of peritoneal dissemination were reduced in size, and that there was no ascites. Left lobectomy of the liver, cholecystectomy, and partial resection of omentum were carried out. The pathological diagnosis was also curative (pT1, pN0, pP0, Stage I). We think this case shows the possibility of S-1 for patients with unresectable biliary tract cancer.

[A successfully resected case of rectal cancer with liver metastases treated with mFOLFOX6 and bevacizumab].

A sixties-man had complained of melena. Colonoscopy revealed type 2 tumor at rectum. Computed tomography (CT)demonstrated lymph node metastasis in front of sacrum and two low density areas which were suspected metastases in the liver. The patient was diagnosed stageIV rectal cancer and resected primary focus and lymph node metastasis.[ Ra-RS, ant, type 2, moderately differentiated adenocarcinoma, ly1, v3, pSE, pN2, sH1(Grade C), sP0, pM1(No. 270)]without liver resection. It was due to high level of CEA and remote lymph node metastasis. The patient was treated with mFOLFOX6 and bevacizumab after the operation. The level of CEA decreased to normal level and CT revealed a partial response after 4 cycles of systemic chemotherapy. Liver resection was performed safely. Histological response was Grade 2 at liver metastases.

Delta-catenin/NPRAP (neural plakophilin-related armadillo repeat protein) interacts with and activates sphingosine kinase 1.

Sphingosine kinase (SPHK) is a key enzyme catalysing the formation of sphingosine 1-phosphate (SPP), a lipid messenger that is implicated in the regulation of a wide variety of important cellular events acting through intracellular, as well as extracellular, mechanisms. However, the molecular mechanism of intracellular actions of SPP remains unclear. Here, we have identified delta-catenin/NPRAP (neural plakophilin-related armadillo repeat protein) as a potential binding partner for SPHK1 by yeast two-hybrid screening. From co-immunoprecipitation analyses, the C-terminal portion of delta-catenin/NPRAP containing the seventh to tenth armadillo repeats was found to be required for interaction with SPHK1. Endogenous delta-catenin/NPRAP was co-localized with endogenous SPHK1 and transfected delta-catenin/NPRAP was co-localized with transfected SPHK1 in dissociated rat hippocampal neurons. MDCK (Madin-Darby canine kidney) cells stably expressing delta-catenin/NPRAP contained elevated levels of intracellular SPP. In a purified system delta-catenin/NPRAP stimulated SPHK1 in a dose-dependent manner. Furthermore, delta-catenin/NPRAP-induced increased cell motility in MDCK cells was completely inhibited by dimethylsphingosine, a specific inhibitor of SPHK1. These results strongly suggest that at least some of delta-catenin/NPRAP functions, including increased cell motility, are mediated by an SPHK-SPP signalling pathway.

Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis.

Sphingosine kinase-1 (SPHK1) is a key enzyme catalyzing the formation of an important bioactive lipid messenger, sphingosine 1-phosphate, and is implicated in the regulation of cell proliferation and antiapoptotic processes. Biological features of another isozyme SPHK2, however, remain unclear. The present studies were undertaken to characterize SPHK2 by comparison with SPHK1. When SPHK2 was transiently expressed in various cell lines, it was localized in the nuclei as well as in the cytosol, whereas SPHK1 was distributed in the cytosol but not in the nucleus. We have mapped a functional nuclear localization signal (NLS) to the N-terminal region of SPHK2. We have observed that the expression of SPHK2 in various cell types causes inhibition of DNA synthesis, resulting in the cell cycle arrest at G1/S phase. We have also demonstrated that an NLS mutant of SPHK2, SPHK2R93E/R94E, failed to enter the nucleus and to inhibit DNA synthesis. Moreover, a fusion protein, NLS-SPHK1, where SPHK1 was fused to the NLS sequence of SPHK2 acquired the ability to enter nuclei and inhibited DNA synthesis. These results indicate that SPHK2 localizes in the nuclei and causes inhibition of DNA synthesis, and this may affect subsequent cellular events.

Identification and characterization of RPK118, a novel sphingosine kinase-1-binding protein.

Sphingosine kinase (SPHK) is a key enzyme catalyzing the formation of sphingosine 1 phosphate (SPP), a lipid messenger that is implicated in the regulation of a wide variety of important cellular events through intracellular as well as extracellular mechanisms. However, the molecular mechanism of the intracellular actions of SPP remains unclear. Here we have cloned a novel sphingosine kinase-1 (SPHK1)-binding protein, RPK118, by yeast two-hybrid screening. RPK118 contains several functional domains whose sequences are homologous to other known proteins including the phox homology domain and pseudokinase 1 and 2 domains and is shown to be a member of an evolutionarily highly conserved gene family. The pseudokinase 2 domain of RPK118 is responsible for SPHK1 binding as judged by yeast two-hybrid screening and immunoprecipitation studies. RPK118 is also shown to co-localize with SPHK1 on early endosomes in COS7 cells expressing both recombinant proteins. Furthermore, RPK118 specifically binds to phosphatidylinositol 3-phosphate. These results strongly suggest that RPK118 is a novel SPHK1-binding protein that may be involved in transmitting SPP-mediated signaling into the cell.