Tomonori Iida

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.

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.

Combination treatment using adenovirus vector-mediated tumor necrosis factor-alpha gene transfer and a NF-κB inhibitor for pancreatic cancer in mice

Gene therapy using an adenoviral vector expressing tumor necrosis factor-alpha (TNF-α) is a new therapeutic approach for pancreatic cancer. However, the efficacy of TNF-α is limited, because it activates nuclear factor-κB (NF-κB). We investigated the combined use of AxCAhTNF-α, adenoviral vector-expressing human TNF-α, and nafamostat mesilate, a serine-protease inhibitor, a NF-κB inhibitor, using pancreatic cancer in mice. In vitro, nafamostat mesilate inhibited TNF-α-induced NF-κB activation and enhanced TNF-α-induced apoptosis in human cancer cell line (MIAPaCa-2). In vivo, we assessed combination treatment of AxCAhTNF-α and nafamostat mesilate using xenograft models in nude mice by subcutaneous injection of MIAPaCa-2. When the implanted tumor size reached 8.0mm, TNF-α group (n=12), was injected AxCAhTNF-α intra-tumorally once a week, while combination group (n=12), was injected AxCAhTNF-α intra-tumorally once a week and nafamostat mesilate intraperitoneally thrice a week. In combination group, tumor growth was significantly slower, and the number of apoptosis cells was significantly greater than those in AxCAhTNF-α group (p<0.05). In conclusion, adenovirus vector-mediated TNF-α gene therapy combined with nafamostat mesilate was effective for pancreatic cancer in mice.

Adenovirus-mediated CD40L gene therapy induced both humoral and cellular immunity against rat model of hepatocellular carcinoma

Adenoviral‐vector expressing CD40L (AxCAmCD40L)‐mediated gene therapy was studied for treatment of hepatocellular carcinoma (HCC) using CD40 ligand (CD40L) complementary DNA in rats. The particular focus was whether humoral immunity took part in antitumor effect. When tumor cells transduced by AxCAmCD40L were implanted into the subcutaneous tissues of syngeneic rats, the tumor growth was suppressed. Intratumoral injection of AxCAmCD40L to pre‐existing tumor in rats also led to significant reduction of tumor size. When tumor cells were re‐implanted to prevention model rats and treatment model rats, no tumor growth was observed. Many studies to date have reported that cellular immunity induces antitumor immunity. However, the present study demonstrated that not only cellular immunity but also humoral immunity plays an essential role in a HCC model. These observations suggested that CD40L‐mediated immune gene therapy for HCC was very effective treatment by activation of both cellular and humoral immune system. (Cancer Sci 2008; 99: 2097–2103)

Combination paclitaxel and inhibitor of nuclear factor κB activation improves therapeutic outcome for model mice with peritoneal dissemination of pancreatic cancer.

Objectives: Paclitaxel (PTX) is a useful treatment for peritoneal dissemination of malignant tumors. However, chemoresistance due to PTX-induced nuclear factor &kgr;B (NF-&kgr;B) activation is an important cause of suboptimal therapeutic effect. We previously reported nafamostat mesilate (FUT175) inhibits NF-&kgr;B activation and promotes apoptosis in pancreatic cancer. We hypothesized that addition of FUT175 to PTX may enhance the antitumor effect in peritoneal dissemination of pancreatic cancer. Methods: In vitro, we assessed NF-&kgr;B activity and apoptosis by the combination of FUT175 and PTX using human pancreatic cancer cell line (AsPc-1). In vivo, we established peritoneal dissemination in nude mice by intraperitoneal injection of AsPc-1 cells. The animals were treated with intraperitoneal injection thrice a week of FUT175, once a week of PTX, or a combination of thrice a week of FUT175 and once a week of PTX (combination group). Results: In the combination groups, PTX-induced NF-&kgr;B activation was inhibited, and apoptosis was enhanced in comparison with other groups both in vitro and in vivo. In the combination group, tumor growth, serum tumor marker, and survival rate were significantly better than those in other groups (P < 0.05). Conclusions: Combination chemotherapy using PTX with FUT175 exerts an antitumor effect for peritoneal dissemination of pancreatic cancer.

Proton-pump inhibitor as palliative care for chemotherapy-induced gastroesophageal reflux disease in pancreatic cancer patients.

Relief of adverse events induced by chemotherapy is an important issue for patients, especially those with a poor prognosis, such as with pancreatic cancer. There are no reports of the relationship between gastroesophageal reflux disease (GERD) and chemotherapy, so we investigated the incidence of chemotherapy-induced GERD in patients undergoing treatment with gemcitabine or S-1 for pancreatic cancer and the effect of sodium rabeprazole (RPZ), a proton-pump inhibitor. GERD was diagnosed in 40% of the patients according to the Frequency Scale for Symptoms of GERD score, and RBZ therapy significantly improved their symptoms.

Immunogene therapy against colon cancer metastasis using an adenovirus vector expressing CD40 ligand

BACKGROUND Colon cancer is one of the most common cancers worldwide, and liver metastasis is a poor prognostic factor for all types of digestive cancers, including colon cancer. We studied CD40 ligand (CD40L)-mediated immunogene therapy for metastatic liver cancer in rats. METHODS We studied whether in vitro infection of a rat colon cancer cell line (RCN9) with an adenoviral-vector that expresses the CD40L (AxCAmCD40L) induced CD40L expression. In vivo to confirm the antitumor effect induced by AxCAmCD40L, the tumor cells that had been transduced by AxCAmCD40L were implanted into the subcutaneous tissues of syngenic rats (prevention model) or AxCAmCD40L was injected into the tumor tissues of the rats (treatment model). Furthermore, immune cells including NK cells, cytotoxic T cells, and tumor-specific antibodies induced by AxCAmCD40L were examined. RESULTS Immunogene therapy using AxCAmCD40L suppressed the tumor growth strongly or reduced tumor size in the prevention model and treatment model. NK cells, cytotoxic T cells, and tumor-specific antibodies contributed to this antitumor effect in both groups. CONCLUSION These observations suggest that CD40L-mediated immunogene therapy for metastatic colon cancer in the liver and lungs is effective and is mediated by the activation of both the cellular and humoral immune systems.

Successful liver transplantation from a living donor with asymptomatic pulmonary cryptococcosis

Cryptococcosis is the third most common invasive fungal disease in patients receiving solid organ allograft transplants; it has an overall incidence of 2.8% and a mortality rate of 33% to 42%. Invasive cryptococcosis (especially meningitis) in organ transplant recipients is associated with significant mortality. Liver transplant recipients have an increased risk of infectious complications because of multiple factors, such as decreased host resistance due to chronic endstage organ failure and immunosuppressive treatment after invasive surgery. Therefore, the transplantation of organs from donors with cryptococcosis could result in life-threatening infectious complications. Fungemia and invasive fungal infections of tissue are difficult to treat; therefore, persons with such conditions should be excluded from organ donation. On the other hand, the use of suboptimal organs harboring possible pathogens such as fungi might need to be considered in countries with an extreme shortage of cadaveric donors. To the best of our knowledge, donor-to-host transmission of Cryptococcus neoformans in liver transplant recipients has seldom been reported. A 45-year-old woman with end-stage primary biliary cirrhosis was admitted to our hospital for evaluation as a candidate for living donor liver transplantation (LDLT) in May 2008. On admission, neither hepatic encephalopathy nor ascites was observed. The laboratory data for the patient were as follows: white blood cell count, 6600 cells/lL; red blood cell count, 2.95 10 cells/lL; hemoglobin level, 9.8 g/dL; hematocrit, 28.2%; platelet count, 126 10/lL; prothrombin time international normalized ratio, 1.2 (prothrombin time, 71% or 15.4 seconds); albumin level, 2.8 g/dL; total bilirubin level, 12.0 mg/dL; NH3 level, 54 lg/dL; blood urea nitrogen level, 7 mg/dL; and creatinine level, 0.4 mg/dL. The Model for End-Stage Liver Disease score was calculated to be 18, the Child-Pugh score was 10, and the updated Mayo risk score was 9.8. During the pretransplant workup of the husband, computed tomography (CT) incidentally revealed multiple nodules in the lower lobe of the left lung (Fig. 1). Cryptococcal antigens were detected in the serum but not in the cerebrospinal fluid. A section of the lung that was stained with periodic acid–Schiff and Grocott stains revealed clusters of encapsulated yeast-like organisms (Cryptococcus). Therefore, asymptomatic pulmonary cryptococcosis was diagnosed. The recipient was also screened for a cryptococcal infection with serum cryptococcal antigen determinations, serial chest X-rays, and chest CT, and she was proved to be negative. Because no other suitable donor was available, we decided to treat the husband for cryptococcosis before donation to prevent the transmission of pathogens. Based on the 2007 Japanese guidelines for the management of deep-seated mycoses and on the US practice guidelines for the management of cryptococcal disease, the treatments for the donor and the recipient were as follows:

Metastatic gingival tumor from rectal cancer diagnosed with CDX2

Metastatic tumors of the oral region are very rare, accounting for approximately 1% of intraoral malignant tumors. Caudal-related homeobox transcription factor (CDX2) regulates the development and differentiation of intestinal epithelial cells. We report herein a case of metastatic gingival tumor from rectal cancer after low anterior resection in which immunohistochemical analysis of CDX2 was useful for diagnosis of the origin. To the best of our knowledge, our case is the first report that immunohistochemical staining with CDX2 can contribute to diagnose metastatic gingival tumor from rectal cancer.

Central Bisegmentectomy for Malignant Liver Tumors: Experience in 8 Patients

Central bisegmentectomy (CBS) of the liver is an en bloc hepatic resection of Couiaud segments 4, 5, and 8. The indications for CBS include benign and malignant tumors occupying both the left medial and right anterior segments. However, CBS has rarely been reported. Here, we investigate CBS in patients with suboptimal liver function for whom an extended lobectomy is not an optimal solution. Each case was 1 of 8 patients who underwent CBS for hepatocellular carcinoma (HCC) or colorectal cancer liver metastasis (CRLM) at the Department of Surgery, Jikei University Hospital. Indications for CBS consisted of CRLM in 3 patients and HCC in 5 patients. The median duration of operation was 552 minutes, and median blood loss was 2263 g. No postoperative nor in-hospital mortalities occurred. In this study, 1-, 2-, and 3-year disease-free survival rates were 62.5%, 12.5%, and 12.5%, respectively, and 1-, 2-, and 3-year overall survival rates were 100%, 100%, and 85.7%, respectively. CBS is advocated for central liver tumors in patients with suboptimal liver function for whom extended lobectomy could result in less than optimal remnant liver volume and function.