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Purpose: Constitutive NF-κB activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required for oncogenic KRAS-induced PDAC development in mouse models. We sought to determine whether targeting IL-1α pathway would inhibit NF-κB activity and thus suppress PDAC cell growth.Experimental Design: We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-κB activation. Assays for cell proliferation, migration, and invasion were performed with rhIL-1R antagonist using the human PDAC cell lines AsPc1, Colo357, MiaPaCa-2, and HPNE/K-rasG12V/p16sh. In vivo NF-κB activation–dependent tumorigenesis was assayed using an orthotopic nude mouse model (n = 20, 5 per group) treated with a combination of gemcitabine and rhIL-1RA.Results: rhIL-1R antagonist treatment led to a significant decrease in NF-κB activity. PDAC cells treated with rhIL-1R antagonist plus gemcitabine reduced proliferation, migration, and invasion as compared with single gemcitabine treatment. In nude mice, rhIL-1R antagonist plus gemcitabine significantly reduced the tumor burden (gemcitabine plus rhIL-1RA vs. control, P = 0.014).Conclusions: We found that anakinra, an FDA-approved drug that inhibits IL-1 receptor (IL-1R), when given with or without gemcitabine, can reduce tumor growth by inhibiting IL1α-induced NF-κB activity; this result suggests that it is a useful therapeutic approach for PDAC. Clin Cancer Res; 22(6); 1432–44. ©2015 AACR.

We found that rhIL-1RA inhibits IL-1 receptor activation and NF-κB activity. Furthermore, in PDAC cells treated with or without gemcitabine, rhIL-1RA significantly decreases proliferation, migration, invasion, and tumor burden in orthotopic nude mouse model (gemcitabine plus rhIL-1RA vs. control, P=0.014). Thus, these results suggest that IL-1RA can reduce tumor growth by inhibiting IL-1a -induced NF-kB activity; the result also suggests that IL-R is a potential surrogate therapeutic target for mutant Kras and activated NF-kB in treatment of PDAC.

Figure S5. A, Q-PCR assay of genetically engineered mice showed that the IL-1α -/- gene was knocked out.

Background Although indications of laparoscopic hepatectomy have been expanded, the laparoscopic approach after right hepatic lobectomy has a very high burden. The purpose of this study was to evaluate patients undergoing laparoscopic repeat hepatectomy for recurrent hepatic tumors after open right lobectomy. Patients and methods Five cases of laparoscopic repeat hepatectomy for recurrent hepatic tumors after open right lobectomy were included in the study. Results All the tumors in segment 3 were intraoperatively detected and curatively resected by partial hepatectomy. The tumors in segment 2 could not be detected intraoperatively due to hypertrophic liver deformity and adhesion. They were curatively resected by anatomical subsegmental approach. Conclusion For recurrent tumors located in segment 2 after right lobectomy, anatomical subsegmental approach should be preferred, not only from an oncological standpoint, but also for securing curative laparoscopic resection and overcoming anatomical difficulties.

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Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of solid organ transplantation. We herein report a case of PTLD after living-donor liver re-transplantation (reLDLT) for recurrent primary sclerosing cholangitis (PSC), for which complete response was achieved by surgical resection and rituximab. A 47-year-old man, who had undergone living-donor liver transplantation (LDLT) twice at age of 43 and 45 years for end-stage liver disease firstly for PSC and secondary for recurrent PSC, suffered liver dysfunction due to an acute cellular rejection (ACR) 17 months after reLDLT. At reLDLT, a right liver lobe was donated from his spouse. Although steroid was effective for ACR, PTLD developed in the ileocecal area. The patient received rituximab for treatment of PTLD, and ileocecal resection for hemorrhage from ileocecal PTLD. The patient achieved complete response by rituximab and surgical resection for PTLD, but PSC recurred and hemophagocytic syndrome (HPS) developed with hyperbilirubinemia and elevated serum ferritin. The patient received steroid treatment for HPS, but thrombocytopenia and coagulopathy developed presumably due to thrombotic microangiopathy. Therefore, tacrolimus was switched to mycophenolate mofetil. Despite intensive treatment including plasmapheresis and platelet infusion, fungal infection of both lungs developed, and the patient died 22 months after reLDLT. Autopsy revealed complete response of PTLD, recurrence of PSC and persistance of HPS.

A 70-year-old man with epigastralgia who initially visited a local hospital was referred to us for further examination. Gastrointestinal endoscopy exhibited a type 3 tumor of the stomach from the body to the antrum(adenocarcinoma, por1). Contrast-enhanced CT revealed thickness in the wall of the gastric body with bulky lymph nodes and ascites. Staging laparoscopy showed that the patient was diagnosed with sStage Ⅳ gastric cancer with positive peritoneal cytology. Therefore, SOX therapy was administered. Subsequently, total gastrectomy with D2 lymph node dissection was performed, since the primary tumor and lymph nodes were significantly reduced. Histopathologically, the residual lesion was only observed in the mucosal layer without lymph node metastases. We herein report a case of Stage Ⅳ gastric cancer, which was successfully treated by conversion surgery after SOX therapy.

Surgical site infections (SSIs) are a well-known potential complication of surgery. They are assocaited with preoperative malnutrition and lead to increased medical costs and longer hospital stays. Therefore, surgeons should appropriately identify patients who are at a high risk. The geriatric nutritional risk index (GNRI) is a tool, increasingly utilized to assess the degree of malnutrition, particularly in elderly patients. Therefore, the present study attempted to validate whether GNRI could predict the risk of SSI in patients following pancreaticoduodenectomy (PD). A cohort study was retrospectively conducted on 106 patients in the Department of Digestive Surgery, Kawaguchi Municipal Medical Center, Japan from January 2007 to December 2017. All patients were subjected to nutritional screening using GNRI and followed up for the occurrence of postoperative complications, including SSI post PD. Additionally, risk factors for developing SSI, and the patient's height, body mass index and preoperative laboratory values were documented. Patients were divided into SSI (n=15) and non-SSI (n=91) groups with a determined incidence of 14.2% (15/106) for SSI. The results revealed that the SSI group had GNRI values that were significantly reduced compared with the non-SSI group (P

NF-κB essential modulator (NEMO) binds and regulates IκB kinase (IKK) and is required for NF-κB activation. The NEMO-binding domain peptide (NBDP) of IKK was found to inhibit NF-κB activation and promote apoptosis in cancer cells. Studies have shown that constitutive NF-κB activation, one of the signature molecular alterations in pancreatic ductal adenocarcinoma (PDAC), is a potential therapeutic target. However, preclinical and therapeutic evidence that supports direct targeting of IKK activation in therapy is lacking. The aim of this study was to determine whether the combination of NBDP and gemcitabine would sensitize pancreatic cancer to the gemcitabine. We confirmed that NBDP inhibited NF-κB activation and found that NBDP indeed promoted chemo-sensitivity to gemcitabine in PDAC. NBDP increased PARP and caspase 3 cleavage in the apoptosis pathway, increased apoptosis of PDAC cells, and suppressed PDAC cell growth in vitro. In addition, NBDP combined with gemcitabine significantly decreased levels of NF-κB activity and inhibited the growth of PDAC in vivo in an orthotopic xenograft mouse model. Mechanistic investigations showed that NBDP effectively competed with NEMO/IKKγ for binding to IKKs and thus inhibited IKK and NF-κB activation, down-regulated expression levels of Erk, and decreased PDAC cell growth. Taken together, our current data demonstrate that NBDP sensitizes human pancreatic cancer to gemcitabine by inhibiting the NF-κB pathway. NBDP is a potential adjuvant chemotherapeutic agent for treating pancreatic cancer.

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.

A 78-year-old male was admitted to our hospital for treatment of multiple hepatic tumors, which were suspected as hepatic epithelioid hemangioendothelioma (HEHE) by percutaneous tumor needle biopsy. With a diagnosis of HEHE, the patient underwent hepatic resection. In pathological findings, the tumor was composed of numerous endothelial cells without epithelioid cells, and was diagnosed as hepatic angiosarcoma (HAS). The patient received percutaneous radiofrequency ablation for recurrent HAS at 5 and 25 months postoperatively, and remains well with recurrence as of 28 months after the primary hepatic resection. In spite of improvement in radiological imaging, preoperative differential diagnosis between HAS and other malignant vascular tumors of the liver is still difficult. We herein report a case of HAS mimicking HEHE, treated successfully.

Systemic inflammation, as evidenced by the Glasgow prognostic score (GPS), predicts cancer-specific survival in various cancer types. The aim of this study was to evaluate the significance of the GPS in the therapeutic outcome of the patient following surgical resection for hepatocellular carcinoma. In total, 144 patients underwent surgical resection for hepatocellular carcinoma. For the assessment of systemic inflammatory response using the GPS, patients were classified into three groups: Patients with normal serum albumin (1.0 mg/dl) were classified as GPS 1 (n=58), and those with low serum albumin (1.0 mg/dl) were classified as GPS 2 (n=10). Retrospectively, the relationship between patient characteristics including GPS, disease-free as well as overall survival were investigated. In disease-free survival, GPS 2 (P=0.019), with a tumor number ≥3 (P=0.004), and positive portal or venous invasion (P=0.034) were independent predictors of cancer recurrence in multivariate analysis. In overall survival, GPS 1 (P=0.042), GPS 2 (P

Constitutive NF-κB activation is considered to play a key role in the aggressive behavior of pancreatic cancer. Although NF-κB in tumors may contribute to aggressive characteristic features via transcription of angiogenesis and invasion-related factors, there is no definitive evidence showing a correlation between quantitated NF-κB activity and prognosis. In this study, we quantitated NF-κB activity of various human pancreatic cancer cell lines and evaluated whether NF-κB activity was related to tumor progression and prognosis for pancreatic cancer in mice. We quantitated NF-κB activity in six pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-2, MIAPaCa-2, Panc-1 and PL45) and evaluated downstream target genes of NF-κB such as VEGF, IL-8 and MMP-9 in vitro. Next, we evaluated tumor progression and prognosis using subcutaneous tumor model in vivo between cell lines with the highest and lowest NF-κB activity. BxPC-3 had the highest and AsPC-1 had the lowest NF-κB activity in the 6 cell lines. Expression of VEGF, IL-8 and MMP-9 in BxPC-3 was significantly higher than those in AsPC-1 cells in vitro (p

Systemic inflammation as evidenced by the Glasgow prognostic score (GPS) predicts cancer-specific survival in various types of cancer. The aim of this study was to evaluate the significance of GPS in patients with both synchronous and metachronous unresectable colorectal cancer liver metastases (CRLM). The subjects were 40 patients who were diagnosed as having unresectable CRLM between March 2000 and August 2010 at Jikei University Hospital. For the assessment of systemic inflammatory response using the GPS, the patients were classified into three groups: patients with normal albumin (≥3.5 g/dl) and normal CRP (≤1.0 mg/dl) as GPS 0 (n=27), those with low albumin (1.0 mg/dl) as GPS 1 (n=6), and both low albumin (1.0 mg/dl) as GPS 2 (n=7). We retrospectively investigated the relationship between patient characteristics including GPS and survival using univariate and multivariate analyses. Results of the univariate analysis revealed that absence of primary tumor resection (p=0.0161), absence of systemic chemotherapy (p=0.0119), serum carcinoembroynic antigen (CEA) of ≥100 ng/ml (p=0.0148), serum carbohydrate antigen (CA)19-9 of ≥100 U/ml (p

Constitutive activation of nuclear factor kappa-B (NF-κB) contributes to the aggressive behavior of pancreatic cancer. Over-expression of downstream target genes of NF-κB such as intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) leads to the promotion of cell adhesion, angiogenesis, invasion and metastasis. We previously reported that nafamostat mesilate, a synthetic serine protease inhibitor, blocks NF-κB activation in pancreatic cancer. We hypothesized that nafamostat mesilate may inhibit cell adhesion, angiogenesis, invasion and metastases in peritoneal dissemination of pancreatic cancer.In vitro, we assessed inhibition of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9 activity by nafamostat mesilate using human pancreatic cancer cell lines (AsPC-1, BxPC-3 and PANC-1). Changes in adhesion and invasion abilities of cancer cells were then evaluated by nafamostat mesilate treatment. In vivo, the efficacy of nafamostat mesilate treatment was assessed using peritoneal dissemination of pancreatic cancer in mice.In vitro, nafamostat mesilate inhibited activities of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9. Moreover, nafamostat mesilate not only inhibited cell adhesion and invasion but also increased the sensitivity of anoikis. In vivo, tumor growth using AsPC-1 cells of the treatment group was significantly slower, and survival rate was significantly better, than those in control group (p0.05).Nafamostat mesilate reduced peritoneal metastasis and prolonged survival of pancreatic cancer-bearing mice.

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.

In spite of improvements in surgical management, hepatocellular carcinoma (HCC) still recurs after operation in 60–70% of patients. Therefore, we investigated the relation between perioperative change in white blood cell count (WBC) and tumor recurrence as well as survival in patients with HCC after hepatic resection. Subjects were 53 patients who underwent elective hepatic resection for HCC. We retrospectively examined the relation between perioperative change in WBC and recurrence of HCC as well as overall survival. Advanced tumor stage and increasing of WBC on postoperative day (POD) 1 were positively associated with worse disease-free survival rate on both univariate and multivariate analysis (P

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. 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. 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). LS using a Ligasure in combination with the splenic hilum hanging maneuver may reduce intraoperative blood loss.

Preoperative systemic inflammatory response is associated with a poor long-term prognosis following resection surgery for malignant tumors. Several markers of systemic inflammation have been reported to be associated with the outcome; however, they have not currently been fully investigated. Therefore, the association between preoperative peripheral blood neutrophil count and oncological outcome following hepatic resection for colorectal liver metastasis (CRLM) was retrospectively investigated. The present study comprised 89 patients who had undergone hepatic resection for CRLM between January 2000 and March 2010. The association between preoperative peripheral blood neutrophil count and disease-free survival, in addition to overall survival, was investigated. In multivariate analysis, the presence of neoadjuvant chemotherapy (P=0.015), bilobar distribution (P=0.015) and neutrophil count ≥3,500/µl (P=0.025) were independent and significant predictors of poor disease-free survival, while significant predictors of poor overall survival consisted of >4 lymph node metastases (P=0.001), neo-adjuvant chemotherapy (P=0.003), bilobar distribution (P=0.039) and neutrophil count ≥3,500/µl (P=0.040). Additionally, tumor diameter (P=0.021) and monocyte count (P

In living-donor liver transplantation, graft selection is especially important for the safety of the live donor and an acceptable outcome for the recipient. The essential medical requirements for living liver donation at Jikei University Hospital are as follows: an adult aged 65 years or younger, in good general condition, with partial liver volume of more than 35% of the standard liver volume (SLV) for the recipient, and without severe liver steatosis. Based on our criteria, we performed 13 living-donor liver transplantations between 2007 and 2013, including 1 retransplantation. Three cases were outside our standard donor criteria, including age (18 and 66 years) and 33% graft volume (GV) to SLV ratio for the recipient on preoperative volumetry using computed tomography. In 2 cases, the actual GV to SLV ratio at transplantation was less than 35%. Median postoperative hospital stay was 11 days for the donors, and 29 days for the recipients. All donors returned to their preoperative status, and all recipients were discharged in good condition. Our medical requirements for living liver donation seem to be acceptable because of the good outcome.

Purpose: Constitutive NF-κB activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required for oncogenic KRAS-induced PDAC development in mouse models. We sought to determine whether targeting IL-1α pathway would inhibit NF-κB activity and thus suppress PDAC cell growth. Experimental Design: We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-κB activation. Assays for cell proliferation, migration, and invasion were performed with rhIL-1R antagonist using the human PDAC cell lines AsPc1, Colo357, MiaPaCa-2, and HPNE/K-rasG12V/p16sh. In vivo NF-κB activation–dependent tumorigenesis was assayed using an orthotopic nude mouse model (n = 20, 5 per group) treated with a combination of gemcitabine and rhIL-1RA. Results: rhIL-1R antagonist treatment led to a significant decrease in NF-κB activity. PDAC cells treated with rhIL-1R antagonist plus gemcitabine reduced proliferation, migration, and invasion as compared with single gemcitabine treatment. In nude mice, rhIL-1R antagonist plus gemcitabine significantly reduced the tumor burden (gemcitabine plus rhIL-1RA vs. control, P = 0.014). Conclusions: We found that anakinra, an FDA-approved drug that inhibits IL-1 receptor (IL-1R), when given with or without gemcitabine, can reduce tumor growth by inhibiting IL1α-induced NF-κB activity; this result suggests that it is a useful therapeutic approach for PDAC. Clin Cancer Res; 22(6); 1432–44. ©2015 AACR.

The aim of this retrospective study was to examine whether various laboratory parameters could predict viability of strangulation in patients with bowel obstruction. Forty patients diagnosed with bowel strangulation were included. We performed operations for all patients within 72 hours of the start of symptoms. Blood samples were obtained from all patients immediately before operation. Arterial blood was examined for pH and lactate levels using a blood gas analyzer. We also evaluated white blood cell count and serum levels of creatine phosphokinase, lactic dehydrogenase, amylase, and C-reactive protein. At surgery, 18 patients had viable strangulation and did not undergo resection, whereas 22 had nonviable strangulation and underwent resection of the necrotic bowel. None of the patients died. Bowel strangulation was caused most commonly by adhesions. In terms of diagnostic efficiency, lactate level was the only laboratory parameter significantly associated with viability ( P < 0.01, Mann-Whitney test). Other laboratory data did not show statistically significant associations. These results suggest that arterial blood lactate level (2.0 mmol/L or greater) is a useful predictor of nonviable bowel strangulation.

Systemic inflammation as evidenced by the Glasgow prognostic score (GPS) predicts cancer-specific survival in various types of cancer. The aim of this study was to evaluate the significance of GPS in therapeutic outcome after surgical resection of gallbladder cancer.The subjects were 51 patients who underwent surgical resection for gallbladder cancer. For the assessment of systemic inflammatory response using the GPS, patients were classified into three groups: patients with normal albumin (≥3.5 g/dl) and normal C-reactive protein (CRP) (≤1.0 mg/dl) as GPS 0 (n = 38), those with low albumin (3.5 g/dl) or elevated CRP (1.0 mg/dl) as GPS 1 (n = 8), and those with low albumin (3.5 g/dl) and elevated CRP (1.0 mg/dl) as GPS 2 (n = 5). We retrospectively investigated the relation between patient characteristics including GPS, and disease-free as well as overall survival.In disease-free survival, advanced tumor stage based on pathology (p = 0.006), positive lymph node metastasis (p = 0.001), and GPS 1 or 2 (p = 0.006) were independent predictors of cancer recurrence in multivariate analysis. In overall survival, positive lymph node metastasis (p = 0.002) and GPS 1 or 2 (p = 0.032) were independent predictors of poor patient outcome in multivariate analyses.The GPS in patients with gallbladder cancer is an independent prognostic predictor after surgical resection.

A 63-year-old woman was admitted to our Hospital for treatment of pancreatic head ductal carcinoma, and underwent pancreaticoduodedectomy (PD) in October 2007. At one month after surgery, she received systemic adjuvant chemotherapy using S-1 for three months. Because the serum carbohydrate antigen 19-9 (CA19-9) value was elevated at 23 months after surgery, the patient underwent systemic chemotherapy using gemcitabine. The serum CA19-9 decreased, but abdominal Computed Tomography (CT) revealed a hepatic metastasis in the ventrolateral segment of left hepatic lobe at 28 months after surgery. The chemotherapy was changed to oral S-1. At 35 months after surgery, abdominal CT revealed reduction of liver metastasis and that the serum CA19-9 was normalized, but chemotherapy had to be withdrawn because of severe myelosuppression. Because of her good general condition, the patient underwent partial hepatectomy for the liver metastasis. Histopathological examination demonstrated a complete response. Thirty six months after hepatectomy and 6 years after PD, the patient remains well without recurrence. We herein report a case of successful treatment for metachronous liver metastasis from pancreatic ductal carcinoma after PD by chemotherapy and hepatectomy and review the current literature.

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.

A 44-year-old man was admitted to our hospital with abdominal pain. Enhanced abdominal computed tomography demonstrated intraperitoneal free air and fluid collection. Peritonitis due to intestinal perforation was suspected and an emergency laparotomy was performed. Exploration of the abdominal cavity confirmed perforation of the ileum at a site 20cm from the terminal ileum. Therefore, we performed partial ileal resection that included the perforation and placed an ileostomy. Histopathological examination of the ileum revealed infiltration of eosinophilic leukocytes between the submucosal and subserosal layers, compatible with the diagnosis of eosinophilic gastroenteritis.

Excessive blood loss and blood transfusion may influence postoperative complications and prognosis of patients after pancreatic resection. We evaluated the influence of blood products use on postoperative recurrence and outcome of patients with pancreatic ductal adenocarcinoma.The study included 82 patients who underwent elective pancreatic resections for pancreatic ductal adenocarcinoma without distant metastasis or other malignancies between January 2001 and December 2010. We retrospectively investigated the influence of the use of perioperative blood products including red cell concentrate, fresh-frozen plasma (FFP), and albumin preparation, and clinical variables regarding disease-free and overall survival.In disease-free survival, serum carcinoembryonic antigen more than 10 ng/ml (p=0.015), serum carbohydrate antigen 19-9 (CA19-9) more than 200 U/ml (p=0.0032), R1 resection (p=0.005), and FFP transfusion were independent risk factors for cancer recurrence in the Cox proportional regression model, pancreaticoduodenectomy (p=0.057) and advanced tumor stage (p=0.083) tended to associate with poor disease-free survival, but were not statistically significant. In overall survival, male gender (p=0.012), advanced tumor stage (p=0.005), serum CA19-9 more than 200 U/ml (p0.001), and FFP transfusion (p=0.003) were positively associated with poor overall survival in the Cox proportional regression model.FFP transfusion is associated with poor therapeutic outcome after elective pancreatic resection for pancreatic ductal adenocarcinoma.

No evidence currently exists to demonstrate the prognostic value of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in patients with unresectable colorectal cancer liver metastases (CRLM). Therefore, we retrospectively investigated the correlation between serum CEA and CA19-9 levels and overall survival in patients with unresectable CRLM. The study involved 40 patients who were diagnosed with unresectable CRLM between March 2000 and August 2010 at Jikei University Hospital, Japan. We retrospectively investigated the correlation between patient characteristics, including serum CEA and CA19-9 levels, and overall survival using univariate and multivariate analyses. In the univariate analysis, the absence of primary tumor resection (p=0.0161), the absence of systemic chemotherapy (p=0.0119), serum CEA ≥100 ng/ml (p=0.0148) and CA19-9 ≥100 U/ml (p

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

Systemic inflammation before surgery, as evidenced by the Glasgow prognostic score (GPS), predicts postoperative complications and cancer-specific survival in various types of cancer. The aim of this study was to evaluate the significance GPS in hepatic resection for hepatocellular carcinoma (HCC).Sixty-six patients who underwent elective hepatic resections for HCC were include in the study. Patients were classified into three groups: GPS 0 [C-reactive protein (CRP)≤1.0 mg/dl and serum albumin ≥3.5 g/dl, n = 54], GPS 1 [CRP1.0 mg/dl or serum albumin3.5 g/dl, n = 11], and GPS 2 [CRP1.0 mg/dl and serum albumin3.5 g/dl, n = 1]. We retrospectively examined the association between GPS (0 or 1) and perioperative clinical variables and outcome.In univariate analysis, GPS 0 patients had significantly better preoperative the retention rate of indocyanine green at 15 minutes (ICGR15) (p=0.0418), Child-Pugh classification (p = 0.0075) and model for end-stage liver disease score (p = 0.0007) than did GPS 1 patients. In multivariate analysis, blood loss and GPS 1 were independent risk factors for pulmonary complications (p = 0.0118 for blood loss, p = 0.0143 for GPS 1), red blood cell concentration transfusion (p = 0.0036 for blood loss, p = 0.0117 for GPS 1) and flesh frozen plasma transfusion (p = 0.0020 for blood loss, p = 0.0044 for GPS 1). Albumin product transfusion, duration of operation (p = 0.0478), blood loss (p = 0.0420) and GPS 1 (p = 0.0111) were independent risk factors. Disease-free and overall survival of GPS 0 and GPS 1 patients were comparable.GPS reflects preoperative patient status, and is associated with blood transfusion and pulmonary complications in elective hepatic resection for HCC.

Constitutive NF-kappaB activation plays a key role in the aggressive behavior of pancreatic cancer. We have reported that nafamostat mesilate, a serine-protease inhibitor, inhibited NF-kappaB activation and induced apoptosis in human pancreatic cancer cells. The aim of this study is to evaluate the therapeutic efficacy of nafamostat mesilate against pancreatic cancer. In vitro, nafamostat mesilate inhibited NF-kappaB activation of human pancreatic cancer cell line (Panc-1) by suppressing IkappaBalpha phosphorylation and induced caspase-8 mediated apoptosis. In vivo, Panc-1 was implanted into the back of nude mice. Five weeks after implantation, nafamostat mesilate was injected intraperitoneally as the treatment group (n=11) three times a week for six weeks, while the control group (n=13) received vehicle only. At the end of six-week treatment, the tumors grew up to 12.89+/-4.27 mm (mean +/- SD) in the treatment group, and 17.93+/-4.45 mm in the control group, respectively. The tumor volume and weight of the treatment group were reduced by 43 and 61% as compared with the control group. The tumor growth was significantly inhibited in the treatment group (p

Tetracyclines such as doxycycline are reported to possess cytotoxic activity against mammalian tumor cells, but the mechanism of their effects on cell proliferation remains unclear.The antitumor effect of doxycycline was investigated in human pancreatic cancer cell line, PANC-1. We also investigated the effect of doxycycline on expression of a potent proangiogenic factor, interleukin (IL)-8.In excess of 20 microg/ml, cytotoxic effects of doxycycline were accompanied by G(1)-S cell cycle arrest and DNA fragmentation in PANC-1 cells. Doxycycline consistently activated transcription of p53, p21 and Fas/FasL-cascade-related genes, while reducing the expression of Bcl-xL and Mcl-1. Doxycycline (5 microg/ml) below the cytotoxic level suppressed endogenous and paclitaxel-induced IL-8 expression. In the mouse xenograft model, doxycycline treatment was shown to suppress tumor growth by 80%.These data suggest that doxycycline exerts its antitumor effect by activating proapoptotic genes, inhibiting IL-8 expression, and suppressing antiapoptotic genes.

We present a case of nontraumatic intramural hematoma of the duodenum. A 77-year-old woman complained of nausea, vomiting, and abdominal pain during hospitalization. There was no traumatic episode. Laboratory data showed anemia (hemoglobin, 7.7 g/dl). The diagnosis was confirmed by computed tomography (CT), which showed a mixed hyperdense and hypodense mass obstructing the third portion of the duodenum. The cause was considered to be bleeding tendency caused by an antiplatelet drug. The patient was treated conservatively and the size of the hematoma was followed on CT. She was able to resume oral feeding 2 weeks after admission.

In 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. The 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. In 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. Transfusion of blood products is associated with increased recurrence rate and worse survival after elective hepatic resection for patients with hepatocellular carcinoma.

The fibrin glue system (FGS) consists of liquid forms of fibrinogen and thrombin and is used widely in surgery for hemostasis. In this study, as a novel and unique approach, the possibility and efficacy of locoregional gene transfer using the FGS containing an adenoviral vector was determined.The optimum concentration of the adenoviral vector mixed with the FGS (AxCALacZ/FGS) for gene transduction was evaluated in vitro by X-gal (beta-galactosidase) staining and NIH (National Institute of Health) imaging in RCN-9, a rat colon carcinoma cell line. To determine the survival period of the adenoviral vector in the fibrin glue, RCN-9 cells were exposed to AxCALacZ/FGS after it had been incubated for various periods and the transduction efficiencies were evaluated by beta-galactosidase (beta-gal) assay. AxCALacZ/FGS was also applied in vivo to the resected site of rat liver. AxCALacZ diluted in PBS (AxCALacZ/PBS) was used as the control. The transduction efficiencies in the liver were compared by X-gal staining and beta-gal assay.Almost 100% transgene expression was demonstrated by the X-gal staining and NIH imaging at a concentration level greater than 1 multiplicity of infection. LacZ expression (as beta-galactosidase) revealed gene-transduced RCN-9 cells when the AxCALacZ/FGS was held for a period of less than 96 hours. The treatment with the AxCALacZ/FGS in vivo resulted in greater transgene expression than the treatment with AxCALacZ/PBS.The adenoviral vector survives and remains stable in the FGS for sufficient time for transduction to occur and AxCALacZ/FGS can efficiently transduce the target gene both in vitro and vivo.

We have explored a gene-therapeutic approach to stimulate antitumor immunity by adenoviral-mediated transfer of CD40 ligand (CD40L) to treat metastatic liver cancer in a rat model.Rat metastatic liver cancer cells were implanted into the back of rats bilaterally. When the larger tumor reached 8.0 mm in diameter, adenovirus vector-expressing mouse CD40L was injected intratumorally as treatment group (n=5), while LacZ was injected in the control group (n=5).In the control group, the tumor gradually grew to be 20.7+/-1.6 (mean+/-SD) mm in intratumorally injected tumors and 21.8+/-3.7 mm in opposite tumors seven weeks after injection, respectively. In contrast, in the treatment group, the tumor was reduced to 3.6+/-8.2 mm and 3.7+/-8.2 mm. The tumor growth and survival rate were significantly different (p0.001).Adenovirus vector-mediated CD40L gene therapy is an effective therapeutic method for metastatic liver cancer.

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.

When gene therapy is performed for malignant tumors, gene transfer efficiency and selectivity are extremely important. The usefulness of gene therapy by intraarterial injection of an adenovirus vector with iodized oil esters (IOEs) for hepatocellular carcinoma (HCC) was studied.HCC was induced in rats with diethyl nitrosamine and phenobarbital, after which either adenovirus vector expressing the herpes simplex virus thymidine kinase (AxCAHSVtk) and IOEs or AxCAHSVtk alone was injected through the hepatic artery. On postoperative days 2, 4 and 6, gancyclovir was injected into the peritoneum; blood sampling was performed on day 7.Aspartate aminotransferase and alanine aminotransferase levels in the AxCAHSVtk with IOEs group were lower than in the AxCAHSVtk alone group (p = 0.0274, p = 0.0323). However, the survival rate was not significantly different between groups (p = 0.7122).Intra-arterial injection of an adenovirus vector with IOEs can result in cancer-selective but not effective gene therapy for HCC.