Takeyuki Misawa

Negative impact of blood transfusion on recurrence and prognosis of hepatocellular carcinoma after hepatic resection.

BackgroundIn perioperative management of hepatic resection for hepatocellular carcinoma, excessive blood loss and blood transfusion greatly influence postoperative complications and prognosis of the patients. We evaluated the influence of blood products use on postoperative recurrence and prognosis of patients with hepatocellular carcinoma.MethodsThe subjects were 66 patients who underwent elective hepatic resection for hepatocellular carcinoma without concomitant microwave or radiofrequency ablation therapy nor other malignancies between January 2001 and June 2006. We retrospectively investigated the influence of the use of blood products including red cell concentration and fresh frozen plasma on recurrence of hepatocellular carcinoma and overall survival.ResultsIn multivariate analysis, the dose of blood products transfusion was a significant predictor of disease-free and overall survival. Both disease-free and overall survival rates of those who were given blood products were significantly worse than those who did not receive. On the other hand, in univariate analysis of disease-free and overall survival after hepatic resection and clinical variables, the amount of blood loss was not a significant predictor of recurrence or death.ConclusionTransfusion of blood products is associated with increased recurrence rate and worse survival after elective hepatic resection for patients with hepatocellular carcinoma.

Adeno-Associated Viral Vector-Mediated Expression of Endostatin Inhibits Tumor Growth and Metastasis in an Orthotropic Pancreatic Cancer Model in Hamsters

We examined the feasibility of using adeno-associated virus (AAV)-mediated systemic delivery of endostatin in gene therapy to treat metastasis of pancreatic cancer. We established an animal model of orthotopic metastatic pancreatic cancer in which the pancreatic cancer cell line PGHAM-1 was inoculated into the pancreas of Syrian golden hamsters. Transplanted cells proliferated rapidly and metastasized to the liver. An AAV vector expressing endostatin (5 × 1010 particles) was injected intramuscularly into the left quadriceps or intravenously into the portal vein. These routes of vector administration were evaluated by comparing various parameters of tumor development. Intramuscular injection of the vector modestly increased the serum endostatin level. The numbers of metastases and the incidence of hemorrhagic ascites were decreased in the treated animals. In contrast, the serum concentration of endostatin was significantly increased after intraportal injection of the vector. The antitumor effects on all parameters (including the size and microvessel density of primary pancreatic tumors, the sizes and number of liver metastases, and the incidence of hemorrhagic ascites) were significant. These results suggest that systemic delivery of endostatin represents a potentially effective treatment for pancreatic cancer and liver metastases. The route of vector administration influences the efficacy of AAV-mediated endostatin expression. Intraportal injection of the AAV vector appears to be more effective as an antiangiogenic gene therapy for pancreatic cancer.

Single‐incision laparoscopic distal pancreatectomy with or without splenic preservation: How we do it

Recent interest in improving cosmetic outcomes has led to single‐incision laparoscopic surgery (SILS) being performed in a variety of organs. However, this innovative technique has rarely been introduced in pancreatic surgery, as it is considered to be a challenging procedure. We report herein our technique of single‐incision laparoscopic distal pancreatectomy with or without splenic preservation.

Phase II study of gemcitabine in combination with regional arterial infusion of nafamostat mesilate for advanced pancreatic cancer.

Purpose:To evaluate the efficacy of regional arterial infusion of the synthetic serine protease inhibitor nafamostat mesilate combined with gemcitabine for the treatment of patients with unresectable locally advanced or metastatic pancreatic cancer. Materials and Methods:A single-arm, single center, institutional review board-approved phase II trial was conducted. Thirty-five of 38 consecutive patients were included in the study. Patients received nafamostat mesilate (4.8 mg/kg continuous regional arterial infusion) with gemcitabine (1000 mg/m2 intravenously) on days 1, 8, and 15. This treatment was repeated at 28-day intervals. The primary endpoints were to evaluate overall survival and 1-year survival rate. The secondary endpoints were to assess therapeutic response and clinical benefit response. Overall survival times were estimated by the Kaplan-Meier survival analysis. Results:The median survival time was 10.0 months, and the 1-year survival rate was 40.0%. The response rate and disease control rate were 17.1% and 88.6%, respectively. A fraction of 25% of the patients who required opioids for cancer-related pain could reduce their opioid intake, and 37.1% of the patients showed healthy weight gain. Among the patients with metastatic pancreatic cancer, the median survival time was 9.0 months, and the 1-year survival rate was 32.0%. The proposed regimen offers an economic advantage compared with recent therapy regimens that have shown significant improvements in median survival over standard chemotherapy with gemcitabine. Conclusions:An alternative regimen for unresectable pancreatic cancer, especially for metastatic pancreatic cancer, is proposed based on acceptable survival time, clinical benefit, and cost advantage.

Combination chemotherapy of serine protease inhibitor nafamostat mesilate with oxaliplatin targeting NF-κB activation for pancreatic cancer

In this study, we assessed if nafamostat mesilate may enhance anti-tumor effects of oxaliplatin on Panc-1 cells and pancreatic cancer mouse model. In combination treatment with nafamostat mesilate and oxaliplatin, NF-κB activation was inhibited by suppressing IκBα phosphorylation, and caspase-8-mediated apoptosis was more prominent than that treated with oxaliplatin alone, both in vitro and in vivo. Nafamostat mesilate reduced proliferation rate of Panc-1 cells as compared with oxaliplatin alone in vitro and enhanced oxaliplatin-induced tumor growth inhibition in vivo. Combination chemotherapy using nafamostat mesilate and oxaliplatin induces synergistic cytotoxicity in pancreatic cancer and could be a novel strategy for treatment.

Perioperative change in peripheral blood monocyte count may predict prognosis in patients with colorectal liver metastasis after hepatic resection

Prognostic value of perioperative change in peripheral blood leukocyte subset count of cancer patients have not been fully investigated. Therefore, we retrospectively investigated the relation between perioperative change in peripheral blood monocyte count and disease‐free as well as overall survival after hepatic resection for colorectal liver metastasis (CRLM).

Minimizing intraoperative bleeding using a vessel‐sealing system and splenic hilum hanging maneuver in laparoscopic splenectomy

BACKGROUND/PURPOSE The most common cause of conversion to laparotomy (open splenectomy) during laparoscopic splenectomy (LS) is bleeding from the splenic hilar vessels. Recently, the efficacy of Ligasure (a vessel-sealing system) as a safety device for sealing vessels and reducing intraoperative blood loss has been reported with various laparoscopic procedures. The objective of this report was to describe our techniques for minimizing bleeding during LS, characterized by the application of Ligasure (which reduces the number of clips and staples, and reduces unnecessary bleeding) and a splenic hilum hanging maneuver with a Diamond-Flex flexible retractor to obtain optimal exposure of the splenic hilum. METHODS We have performed 87 LSs since February 1993, and have employed the Ligasure instead of metal clips and staplers since September 2003. We have also introduced the splenic hilum hanging maneuver paired with Ligasure use. We have performed this new LS in 30 consecutive adult patients presenting with idiopathic thrombocytopenic purpura (n = 14), benign splenic tumor (n = 5), lymphoma (n = 4), hereditary spherocytosis (n = 2), liver cirrhosis (n = 2), and other pathologies (n = 3). The splenic ligaments and vessels, including the splenic artery and vein, were divided using a 5-mm Ligasure instead of a clip or stapler. The splenic hilum was encircled and elevated, using a Diamond-Flex, to ensure better exposure in all patients. RESULTS LS was successfully completed in 29 patients (97%), with only one conversion to open splenectomy. Mean blood loss for all patients with completed LS was only 21.6 ml (range 0-250 ml). Moreover, blood loss was not determinable (considered as 0 ml in this study) in 15 patients (52%). Mean spleen weight and operating time were 319.4 g (range 80-1605 g) and 143.4 min (range 90-180 min), respectively. No postoperative mortalities were encountered. Two patients experienced complications, including grade B pancreatic fistula and atelectasis, for an overall morbidity rate of 6.7%. Mean postoperative stay was 6.5 days (range 3-14 days). CONCLUSIONS LS using a Ligasure in combination with the splenic hilum hanging maneuver may reduce intraoperative blood loss.

Tetrahydrouridine inhibits cell proliferation through cell cycle regulation regardless of cytidine deaminase expression levels.

Tetrahydrouridine (THU) is a well characterized and potent inhibitor of cytidine deaminase (CDA). Highly expressed CDA catalyzes and inactivates cytidine analogues, ultimately contributing to increased gemcitabine resistance. Therefore, a combination therapy of THU and gemcitabine is considered to be a potential and promising treatment for tumors with highly expressed CDA. In this study, we found that THU has an alternative mechanism for inhibiting cell growth which is independent of CDA expression. Three different carcinoma cell lines (MIAPaCa-2, H441, and H1299) exhibited decreased cell proliferation after sole administration of THU, while being unaffected by knocking down CDA. To investigate the mechanism of THU-induced cell growth inhibition, cell cycle analysis using flow cytometry was performed. This analysis revealed that THU caused an increased rate of G1-phase occurrence while S-phase occurrence was diminished. Similarly, Ki-67 staining further supported that THU reduces cell proliferation. We also found that THU regulates cell cycle progression at the G1/S checkpoint by suppressing E2F1. As a result, a combination regimen of THU and gemcitabine might be a more effective therapy than previously believed for pancreatic carcinoma since THU works as a CDA inhibitor, as well as an inhibitor of cell growth in some types of pancreatic carcinoma cells.

Acute tumor lysis syndrome after transarterial chemoembolization for hepatocellular carcinoma

A 77‐year‐old‐man was admitted to hospital for treatment of a huge hepatocellular carcinoma by transarterial chemoembolization. After treatment, the patient developed acute tumor lysis syndrome with hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis and acute renal failure, which was successfully treated. In the treatments of solid organ tumors, acute tumor lysis syndrome is an extremely rare complication. To the best of the authors’ knowledge, this patient is the third case of such a complication after transarterial chemoembolization for a hepatocellular carcinoma in the English literature. (Cancer Sci 2008; 99: 2104–2105)

Hemangiopericytoma of the Greater Omentum

A 41-year-old Chinese woman was admitted to our hospital with epigastric pain. Computed tomography detected a heterogeneous enhancement tumor fed by the left gastroepiploic artery in the left lower quadrant and cholelithiasis. Excision of the tumor in the greater omentum and cholecystectomy were performed laparoscopically. Histological findings confirmed a diagnosis of hemangiopericytoma with low-grade malignancy. To our knowledge, hemangiopericytoma of the greater omentum is very rare, and only 12 cases were reported in English literature. We report a case of hemangiopericytoma arising in the greater omentum and review the literature.