Daiki Soma

Sphingosine-1-Phosphate Transporters as Targets for Cancer Therapy

Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, the recruitment of immune cells, angiogenesis, and lymphangiogenesis, all of which are involved in cancer progression. S1P is generated inside cancer cells by sphingosine kinases then exported outside of the cell into the tumor microenvironment where it binds to any of five G protein coupled receptors and proceeds to regulate a variety of functions. We have recently reported on the mechanisms underlying the “inside-out” signaling of S1P, its export through the plasma membrane, and its interaction with cell surface receptors. Membrane lipids, including S1P, do not spontaneously exchange through lipid bilayers since the polar head groups do not readily go through the hydrophobic interior of the plasma membrane. Instead, specific transporter proteins exist on the membrane to exchange these lipids. This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporters in cancer and in the tumor microenvironment. Based on our research and the emerging understanding of the role of S1P signaling in cancer and in the tumor microenvironment, S1P transporters and S1P signaling hold promise as new therapeutic targets for cancer drug development.

DNA damage response and sphingolipid signaling in liver diseases

Patients with unresectable hepatocellular carcinoma (HCC) cannot generally be cured by systemic chemotherapy or radiotherapy due to their poor response to conventional therapeutic agents. The development of novel and efficient targeted therapies to increase their treatment options depends on the elucidation of the molecular mechanisms that underlie the pathogenesis of HCC. The DNA damage response (DDR) is a network of cell-signaling events that are triggered by DNA damage. Its dysregulation is thought to be one of the key mechanisms underlying the generation of HCC. Sphingosine-1-phosphate (S1P), a lipid mediator, has emerged as an important signaling molecule that has been found to be involved in many cellular functions. In the liver, the alteration of S1P signaling potentially affects the DDR pathways. In this review, we explore the role of the DDR in hepatocarcinogenesis of various etiologies, including hepatitis B and C infection and non-alcoholic steatohepatitis. Furthermore, we discuss the metabolism and functions of S1P that may affect the hepatic DDR. The elucidation of the pathogenic role of S1P may create new avenues of research into therapeutic strategies for patients with HCC.

The long term follow-up of laparoscope-assisted living donor hepatectomy

BACKGROUND We have introduced and performed laparoscope-assisted surgery in living donor hepatectomy. The objective of this study was to investigate the long-term results of laparoscope-assisted living donor hepatectomy. METHODS From 2006 to 2016, laparoscope-assisted living donor hepatectomy was performed in 11 patients (laparoscopic group), and conventional open living donor hepatectomy was performed in 40 patients (conventional group). Intraoperative and postoperative complications were evaluated according to the Clavien-Dindo classification and analyzed in the laparoscopic group for comparison with the conventional group. RESULTS The median postoperative follow-up period was 88 months (range, 58-120 months) in the laparoscopic group. One donor in the conventional group died from a motor vehicle crash 16 months after surgery. All others were alive and returned to their preoperative activity level. Regarding intraoperative and early (≤90 days after surgery) postoperative complications, 1 patient (1/11, 9%) showed biliary fistula (Grade IIIa) in the laparoscopic group. In the conventional group, 6 patients (6/40, 15%) showed surgical complications of Grade I in 2 patients and Grade II in 4 patients. Regarding late (>90 days after surgery) postoperative complications, biliary stricture was observed in 1 patient of the laparoscopic group; this patient developed hepatolithiasis 6 years after surgery, and endoscopic lithotomy and extracorporeal shockwave lithotripsy were performed, resulting in successful treatment. Late complications were not observed in the conventional group. CONCLUSION One donor in the laparoscopic group showed Grade IIIa late complications. The introduction of laparoscopic surgery to living donor hepatectomy should be performed carefully.

Development of the Total Pancreatectomy and Autologous Islet Transplantation Models as the Step for Allogenic Islet Transplantation Experiments in the Swine

Background Islet transplantation has been established as a treatment for type 1 diabetes mellitus (DM). However, there are some problems to overcome, such as the necessity of transplantation from multiple donors repeatedly and the difficulty of achievement of the long term insulin independence. Creating an experimental model with large animal is extremely important as a preclinical study aiming to overcome those problems. We successfully established the total pancreatectomy combined with autologous islet transplantation model in the swine. Materials and Methods Thirteen swine weighing 10-20 kg underwent total pancreatectomy under general anesthesia. [Experiment 1] Eight swine underwent only total pancreatectomy (TP group), and the results of body weight, fasting blood glucose (FBS) and intravenous glucose tolerance test (IVGTT) before and after total pancreatectomy were compared and analyzed. [Experiment 2] Five swine underwent total pancreatectomy, then 50% of the excised pancreas were isolated by Ricordi method. Isolated pancreatic islets were autologously transplanted from portal vein into the liver (Islet Tx group) and their postoperative data was compared with that of TP group. Results [Experiment 1] Loss of body weight was significantly severer (+0.8 kg vs -1.9 kg, p=0.032) in 7 days after total pancreatectomy than in 7 days before total pancreatectomy. The value of FBS (49.4 mg/dl vs 327.0 mg/dl, p=0.001)) and IVGTT 120 min (84.0 mg/dl vs 364.7 mg/dl, p=0.044) were increased significantly after total pancreatectomy. Insulin secretion after glucose injection was not detected in this series. [Experiment 2] Compared with TP group, the loss of body weight was mild (-1.9 kg vs -0.1 kg, p=0.22), and the survival rate was significantly increased (38% vs 100%, p=0.035) in Islet Tx group. The value of postoperative FBS (327.0 mg/dl vs 97.4 mg/dl, p=0.001) and IVGTT 120 min (364.7 mg/dl vs 153.5 mg/dl, p=0.016) were significantly lower in the Islet Tx group. In the Islet Tx group, insulin secretion after glucose injection was detected. This is because transplanted islets were survive and functioning. Pathological specimens on the 7th day after islet transplantation showed the engraftment of transplanted pancreatic islets into the intrahepatic portal vein. Conclusions We successfully established the insulin dependent DM model by using total pancreatectomy in the swine. We also successfully established the total pancreatectomy and islet autotransplantation model in the swine. Improvement in the outcomes of islet transplantation would be expected by developing this model to allogeneic islet transplantation experiments.

Surgical management of carcinoma in situ at ductal resection margins in patients with extrahepatic cholangiocarcinoma

Recent advances in dimensional imaging, surgical technique, and perioperative patient care have resulted in increased rates of complete resection with histopathologically negative margins and improved surgical outcomes in patients with extrahepatic cholangiocarcinoma. However, achieving cancer‐free resection margins at ductal stumps in surgery for this disease remains challenging because of longitudinal extension, which is one of the hallmarks of extrahepatic cholangiocarcinoma. When the ductal resection margins are shown to be positive on examination of frozen sections, discrimination between carcinoma in situ and invasive carcinoma is clinically important because residual carcinoma in situ may lead to late local recurrence whereas residual invasive carcinoma is associated with early local recurrence. Residual invasive carcinoma at the ductal margins should be avoided whenever technically feasible. Residual “carcinoma in situ” at the ductal margins appears to be allowed in resection for the advanced disease because it has less effect on survival than other adverse prognostic factors (pN1 and/ or pM1). However, in surgery for early‐stage (pTis‐2N0M0) extrahepatic cholangiocarcinoma, residual carcinoma in situ at the ductal margins may have an adverse effect on long‐term survival, so should be avoided whenever possible. In this review, we focus on the histopathological term “carcinoma in situ,” the biological behavior of residual carcinoma in situ at ductal resection margins, intraoperative histological examination of the ductal resection margins, outcome of additional resection for positive ductal margins, and adjuvant therapy for patients with positive margins.

Successful Endoscopic Management of Acute Necrotic Pancreatitis and Walled Off Necrosis After Auxiliary Partial Orthotopic Living-Donor Liver Transplantation: A Case Report

Endoscopic management of acute necrotic pancreatitis and walled off necrosis is less invasive than surgical treatment and has become the 1st choice for treating pancreatic necrosis and abscess. We treated a case of acute necrotic pancreatitis and walled off necrosis after auxiliary partial orthotopic living-donor liver transplantation (APOLT). A 24-year-old woman was admitted to our university hospital for removal of the internal biliary stent, which had already been placed endoscopically for the treatment of biliary stricture after APOLT. She had been treated for acute liver failure by APOLT 10 years before. After we removed the internal stent with the use of an endoscopic retrograde approach, she presented with severe abdominal pain and a high fever. Her diagnosis was severe acute pancreatitis after endoscopic retrograde cholangiography (ERC). Her symptoms worsened, and she had multiple organ failure. She was transferred to the intensive care unit (ICU). Immunosuppression was discontinued because infection treatment was necessary and the native liver had already recovered sufficiently. After she had been treated for 19 days in the ICU, she recovered from her multiple organ failure. However, abdominal computerized tomography demonstrated the formation of pancreatic walled off necrosis and an abscess on the 20th day after ERC. We performed endoscopic ultrasonography-guided abscess drainage and repeated endoscopic necrosectomy. The walled off necrosis diminished gradually in size, and the symptoms disappeared. The patient was discharged on the 87th day after ERC. This is the 1st report of a case of acute necrotic pancreatitis and walled off necrosis that was successfully treated by endoscopic management after APOLT.

Study of Immune Tolerance Cases in Adult Living Donor Liver Transplantation

BACKGROUND Complete immune tolerance is the chief goal in organ transplantation. This study aimed to evaluate patients who successfully withdrew from immunosuppressive (IS) agents after living donor liver transplantation (LDLT). MATERIALS AND METHODS A retrospective review of all adult LDLT from July 1999 to March 2012 was conducted. In patients who acquired immune tolerance after LDLT, their background and the course of surgical procedures were evaluated. RESULTS Of a total of 101 adult LDLT patients, 8 patients were completely free of IS agents. Six of these patients (75%) were female, and the median age at the time of transplantation was 56 years (range, 31-66 years). The primary disease causing liver failure was type C liver cirrhosis (50%), fulminant hepatitis (25%), type B liver cirrhosis (12%), and alcoholic liver cirrhosis (12%). The median Child-Pugh score and MELD score were 13 points (range, 8-15 points) and 19 points (range, 10-18 points), respectively. The living related donor was the recipients child (75%), sibling (12%), or parent (12%). ABO compatibility was identical in 62%, compatible in 25%, and incompatible in 12%. CONCLUSIONS In this study, we evaluated the adult patients who successfully withdrew from IS agents after LDLT. In most cases, it took more than 5 years to reduce IS agents. Because monitoring of the serum transaminase level is not adequate to detect chronic liver fibrosis in immune tolerance cases, further study is required to find appropriate protocols for reducing IS agent use after LDLT.