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Objective:. No ideal training system exists for pancreaticoduodenectomy (PD). We developed an educational system that uses an objective structured assessment of technical skills. Methods:. This retrospective observational study was conducted using the data of consecutive trainees and patients who underwent PD from 2007 to 2013 in Kansai Medical University Hospital. The total score on the task checklist (21 parameters) for measuring technical performance during PD by self assessment and instructor assessment was compared between junior (JN) and hepatobiliary pancreatic (HBP) trainees at a university hospital. Surgical outcomes of 303 PDs (2007–2013) were also compared among JN trainees, HBP trainees, and instructors, and the present position of the trainees was investigated. This study was approved by the institutional review board of Kansai Medical University on May 26, 2020. Results:. The self-assessment score on the task checklist was significantly higher for the HBP trainees than for the JN trainees on all parts of PD (P

Objective: The present study aimed to identify the clinical significance of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in patients with occupational cholangiocarcinoma. Methods: This study included 10 men with occupational cholangiocarcinoma who were former or current workers at a printing company in Osaka, Japan. Of the 10 patients, 2 had 2 main tumors and 1 had 3 main tumors. Twelve FDG-PET imaging findings in the 10 patients could be analyzed. We evaluated the relationships between FDG-PET imaging parameters and clinicopathological findings of occupational cholangiocarcinoma. Results: Abnormal FDG uptake was observed in 8 of the 14 main tumors, with maximum standardized uptake values ranging from 2.9 to 11.0, and the sensitivity was 57.1%. Four patients had lymph node metastases, and abnormal marrow uptake was detected in all these patients. Although precancerous lesions, such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB) without any invasion, were not detected, abnormal FDG uptake was demonstrated in 2 of 4 patients with IPNB having an associated invasive carcinoma.Conclusions: Although FDG-PET may be useful for assessing tumor progression factors, such as lymph node metastasis, it cannot accurately detect precancerous lesions, such as BilIN and IPNB without invasive carcinoma.

To determine the recommended dose (RD) of gemcitabine (GEM) plus S-1 (GS) in curatively resected biliary tract cancer (BTC) patients without major hepatectomy. A standard 3 + 3 dose-escalation design was used with planned dose levels (mg/m2) of GEM (administered intravenously on days 1 and 8) and S-1 (administered orally twice daily on days 1–14, with a 1-week rest, every 3 weeks for up to 24 weeks) of 1000/80 (Level 2), 1000/65 (Level 1), 800/65 (Level − 1), and 800/50 (Level − 2). Thirty-one patients (17 men and 14 women; median age, 70 years) were enrolled. Level 1 was chosen as the starting dose. Three of seven patients developed dose-limiting toxicities at Level 1 and the dose was de-escalated to Level − 1. Five of 12 patients developed Grade 4 neutropenia at Level − 1 and the dose was de-escalated to Level − 2. One patient developed Grade 4 neutropenia at Level − 2. Another patient was unable to receive the day 8 dose due to Grade 3 neutropenia at Level − 2. Level − 1 was confirmed as the maximum tolerated dose and Level − 2 the RD for this regimen. The 1- and 2-year recurrence-free survival rates were 77.0 and 54.0%, respectively. The recurrence-free survival rate of patients in the GS completion group was significantly higher than that of the GS discontinuation group. Level − 2 was confirmed as the RD (GEM 800 mg/m2 and S-1 50 mg/m2) for GS adjuvant chemotherapy in curatively resected BTC patients without major hepatectomy.

Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy.Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800-1,000 mg/m(2) gemcitabine on days 1, 8, and 15 and then every 3-4 weeks or 40-80 mg/m(2)/day S-1 on days 1-28 and every 3-6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm.Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10% of DLT, the recommended dose was 1,000 mg/m(2) gemcitabine biweekly and 80 mg/m(2)/day S-1 on days 1-28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted.We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10%.

Background The purpose of the present study was to analyze the survival benefit and safety of adjuvant surgery in patients with initially unresectable pancreatic cancer following chemo(radio)therapy. Methods The 130 patients with unresectable pancreatic cancer treated during 2006 to 2013 were divided into a study group (15 patients) with planned adjuvant surgery, and a control group (115 patients with locally advanced disease) without adjuvant surgery. Results The study group of 15 patients had shrunken tumor, decreased tumor marker, and maintained performance status after 9 months (range 5–18 months) of chemo(radio)therapy. Thirteen patients had curative resection and two patients were not resected. The remaining controls of 115 patients did not undergo surgical resection due to poor response to chemo(radio)therapy or performance status. The median survival time in the study group was better than in the control group (36 vs. 9 months, P < 0.001). The mortality and morbidity rates in the study group were 0% and 46% respectively, in spite of concomitant organ resections in 77%. Conclusion Patients who had adjuvant surgery had significant improvement of survival without increase in morbidity and mortality, relative to patients with locally advanced disease. Thus, adjuvant surgery may provide the promising results in this group who responded favorably to initial chemo(radio)therapy in unresectable pancreatic cancer.

347 Background: GC has become a standard chemotherapy for patients with locally advanced or metastatic BTC. The benefit of adjuvant therapy for BTC is unclear, however, it is used worldwide due to BTC’s dismal prognosis. We conducted a phase I study for adjuvant chemotherapy with GC in patients with BTC in order to determine the maximum-tolerated dose (MTD) and recommended dose (RD). Methods: Patients with BTC were eligible if they met the following criteria: Stage IB or higher; undergoing resection without major hepatectomy; over 20 years of age; ECOG PS 0-1; adequate organ functions. The starting dose (Level 1) of GC was the same as the standard dose of advanced disease and dose was planned to adjust, using a 3+3 design with cohorts of 3-6 patients and further cohort expansion took place. The Dose Limiting Toxicities (DLTs) were determined during the first six weeks and RD was determined through the entire treatment. Results: One DLT out of 6 patients, with grade 4 neutropenia, was observed at Level 1 and an expanded cohort was further examined. A total of eighteen patients were enrolled and one DLT was observed as described above. During the first six weeks, the most common grade 3 or 4 related adverse events were neutropenia (n=10: 56%) and leukopenia (n=6: 33%). Through the entire treatment, non-hematologic toxicities were manageable. Seven (39%) patients completed the protocol treatment, seven (39%) dropped off due to the need of second time dose reduction, two didn’t meet starting criteria of creatinin with grade 1 increase in CTCAE, one had rapid tumor progression died within 30 days after the last administration of GC and one withdrew after reporting dead case. Conclusions: A standard dose of GC might be feasible for adjuvant chemotherapy for BTC undergoing curative resection without major hepatectomy. We selected standard dose of GC as RD for a subsequent phase II study. Clinical trial information: NCT01297998.

Background and Aim Few studies have reported the efficacy and safety of palliative chemotherapy in elderly patients with advanced biliary tract cancer. We aimed to investigate the clinical outcomes of palliative chemotherapy for advanced biliary tract cancer in elderly patients. Methods We retrospectively evaluated 403 consecutive patients who received palliative chemotherapy between April 2006 and March 2009 for pathologically confirmed unresectable or recurrent biliary tract cancer. Clinical outcomes of the elderly group (≥ 75 years old; n = 94) were compared with those of the non-elderly group (

Background An outbreak of cholangiocarcinoma occurred among workers in the offset color proof-printing department at a printing company in Japan. The aim of this study was to clarify the characteristics of the patients with cholangiocarcinoma. Methods This was a retrospective study conducted in 13 Japanese hospitals between 1996 to 2013. The clinicopathological findings of cholangiocarcinoma developed in 17 of 111 former or current workers in the department were investigated. Most workers were relatively young. Results The cholangiocarcinoma was diagnosed at 25–45 years old. They were exposed to chemicals, including dichloromethane and 1,2-dichloropropane. The serum γ-glutamyl transpeptidase activity was elevated in all patients. Dilated intrahepatic bile ducts without tumor-induced obstruction were observed in five patients. The cholangiocarcinomas arose from the large bile ducts. The precancerous or early cancerous lesions, such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile ducts, as well as non-specific bile duct injuries, such as fibrosis, were observed in various sites of the bile ducts in all eight patients for whom operative specimens were available. Conclusions The present results showed that cholangiocarcinomas occurred at a high incidence in relatively young workers of a printing company, who were exposed to chemicals including chlorinated organic solvents.

The objective of this study was to examine whether the development of cholangitis after preoperative biliary drainage (PBD) can increase the incidence of postoperative pancreatic fistula (POPF). The study population included 185 consecutive patients who underwent pancreaticoduodenectomy from April 2006 to March 2011. All patients were divided into two groups, which consisted of a “no PBD” group (73 patients) and a PBD group (112 patients). Moreover, the PBD group was divided into a “cholangitis” group (21 patients) and a “no cholangitis” group (91 patients). Clinical background, clinical outcome, and postoperative complications were compared between groups. All patients received prophylactic antibiotics using cefmetazole until 1 or 2 days postoperatively. There was no difference between noncholangitis and non-PBD groups except the frequency of overall POPF. Clinically relevant POPF and drain infection occurred in the cholangitis group significantly more than in the noncholangitis group ( P < 0.05). Univariate and multivariate analyses showed that development of preoperative cholangitis after preoperative biliary drainage and small pancreatic duct (less than 3 mm diameter) were independent risk factors for clinically relevant POPF. The frequency of clinically relevant POPF was 8 per cent (eight of 99) in patients without two risk factors, 19 per cent (15 of 80) in patients with one risk factor, and 50 per cent (three of six) in patients with both risk factors. The development of preoperative cholangitis after PBD was closely associated with the development of clinically relevant POPF under the limited use of prophylactic antibiotics.

Background The most common postoperative complication after distal pancreatectomy (DP) is still postoperative pancreatic fistula (POPF), which is closely associated with other major complications and remains an unsolved problem. Methods This retrospective study included 47 consecutive patients who underwent a distal pancreatectomy with (DP-PG group, n = 21) or without (DP group, n = 26) duct-to-mucosa pancreaticogastrostomy from June 2010 to May 2012. Clinical data including POPF-related complications (POPF, fluid collection, intra-abdominal abscess, bleeding and delayed gastric emptying) as a primary endpoint were compared between the two groups. Results The frequencies of POPF-related complications as well as overall POPF and complications in the DP-PG group were lower than in the DP group (P = 0.037, P < 0.001, respectively). The 30 days morbidity after hospital discharge in the DP-PG group was less than in the DP group (P = 0.014). In both groups median hospital stay was similar. Although additional time needed for pancreaticogastrostomy was 35 (20–55) min, there was no difference in operative times. Patients in the DP group had a higher medical cost for hospitalization than the DP-PG group (P = 0.048). Conclusion Pancreaticogastrostomy as an additional procedure following distal pancreatectomy was associated with a reduced rate of POPF-related complications that resulted in relatively lower medical cost for hospitalization.

Background The aim of this study was to retrospectively compare morbidity and mortality before and after introduction of a new departmental policy for patients who undergo distal pancreatectomy. Methods We have introduced the use of an ultrasonically-activated device in distal pancreatectomy, an “early removal of drains” policy and perioperative management using a clinical pathway since May 2006. Group A consisted of 52 consecutive patients from 2000 to February 2006. Group B consisted of 57 consecutive patients from May 2006 to 2010. Results Although there was no difference in the fluid collection rate within 30 postoperative days (Group A, 44% vs. Group B, 35%), the rates of intra-abdominal abscess (A, 19% vs. B, 4%) and grade 3/4 of the Clavien classification (A, 23% vs. B, 9%) in Group B were significantly lower than in Group A (P

Background Postoperative nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD) has recently become recognized. However, the pathoetiology of postoperative NAFLD is largely unknown. Furthermore, the optimal treatment has not been established. The aim of this prospective study was to clarify whether pancrelipase, which contains digestive pancreatic enzymes, could reverse NAFLD. Methods A collaborative clinical trial has been conducted (UMIN000006841). A total of 30 patients who developed NAFLD after PD were prospectively treated with pancrelipase. NAFLD was defined and evaluated by the liver-to-spleen attenuation ratio on computed tomography (CT). Clinical symptoms and laboratory findings were also assessed. Results The mean liver-to-spleen CT ratio before surgery in 30 patients was 1.233. It declined to 0.453 at diagnosis of NAFLD. It was significantly improved by the treatment and the CT ratios at 1, 3 and 6 months after treatment were 0.762, 0.958 and 0.904, respectively (vs. pretreatment, P

Background Prognostic factors for patients with advanced biliary tract cancer (BTC) who received palliative chemotherapy have not been fully established. Especially, the status of unresectable/recurrent disease has not been well studied because of a small number of patients with recurrent BTC in previous studies. Methods This multicenter retrospective study was conducted in 18 institutions in Japan. We retrospectively reviewed data regarding 403 patients with pathologically proven BTC who received palliative chemotherapy between April 2006 and March 2009. One hundred and ninety-two patients with recurrent BTC were included. Univariate and multivariate analyses were performed to identify prognostic factors. Results The median overall survival was significantly longer in the recurrent BTC patients than in the unresectable BTC patients (398 days vs. 323 days, P = 0.004). After adjustment using multivariate analysis, the status of recurrent/unresectable disease remained an independent prognostic factor (hazard ratio 1.33, 95% confidence interval 1.04–1.70, P = 0.022) in addition to performance status, extent of disease, carbohydrate antigen 19-9 levels, and carcinoembryonic antigen levels. Conclusions The status of unresectable/recurrent disease was shown as an independent prognostic factor in the BTC patients. This result may help to predict life expectancy of BTC patients and design future clinical trials evaluating palliative chemotherapy in BTC.

To investigate the behavior of activated pancreatic stellate cells (PSCs), which express alpha-smooth muscle actin (α-SMA), and pancreatic cancer cells in vivo, we examined the expression of α-SMA-positive myofibroblast-like cells in pancreatic cancer tissue after treatment with gemcitabine (GEM) using a Lewis orthotopic rat pancreatic cancer model.The effect of GEM on DSL-6A/C1 cell proliferation was determined by cell counting method. The orthotopic pancreatic cancer animals were prepared with DSL-6A/C cells, and treated with GEM (100 mg/kg/weekly, for 3 weeks). At the end of treatment, α-SMA expression, fibrosis, transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) were evaluated by histopathological and Western blot analyses.DSL-6A/C1 cell proliferation was significantly reduced by co-culturing with GEM in vitro. Survival time of pancreatic cancer animals (59.6 ± 13.4 days) was significantly improved by treatment with GEM (89.6 ± 21.8 days; p = 0.0005). Alpha-SMA expression in pancreatic cancer tissue was significantly reduced after treatment with GEM (p = 0.03), however, there was no significant difference in Sirius-red expression. Expression of VEGF was significantly reduced by GEM treatment, but the expression of TGF-β1 was not inhibited.GEM may suppress not only the tumor cell proliferation but also suppress PSCs activation through VEGF reduction.

Cystic duct leakage with metal clips persists after laparoscopic cholecystectomy (LC). The aim of the study is to evaluate the preventive effect of locking clips on leaks from the cystic duct stump after LC as an alternative to metal clips. Locking clips were routinely used to close the cystic duct in LC. A total of 1101 patients who underwent LC were retrospectively assessed from a database of the surgical department at our university hospital. A main outcome measurement is bile leakage after LC. From January 2006 to April 2011, 1053 LCs were performed. Of these, the cystic duct was closed with locking clips in 1017 cases, and no bile leaks from the cystic duct were observed in any of these 1017 cases. Locking clips should be routinely used to close the cystic duct in preference to metallic clips to reduce postoperative bile leaks after LC.

Background The aim of current study is to verify usefulness of staging laparoscopy (stag-lap) for patient’s selection and to find prognostic factors in patients with radiographically defined locally advanced (RD-LA) pancreatic ductal adenocarcinoma (PDAC). Methods The LA disease was defined as an unresectable disease without distant organ metastasis based on resectability status of NCCN guideline in this study. Stag-lap was performed in 67 patients with RD-LA (2007–2012) which were divided into 4 groups according to metastatic site: group CY (peritoneal fluid or washing cytology positive and without any distant organ metastasis); group P (peritoneal dissemination); group L (liver metastasis); group LA (peritoneal fluid or washing cytology negative and without any distant organ metastasis). Clinical backgrounds, survival curves, and prognostic factors were investigated. Results There were 16 patients in CY group (24 %), 13 patients in P group (19 %), 10 patients in L group (15 %), and 28 patients in LA group (42 %). Median survival time was 13 months in CY group and 11 months in LA group, which was significantly better than 7 months in P group, respectively (p

Objective Pancreatic cancer is a malignant neoplasm with poor prognosis that might be associated with defective immune function. We aimed to determine the influence on survival of circulating myeloid dendritic cells (c-m-DCs), circulating lymphoid DCs (c-l-DCs), and DCs within the tumor tissue in patients with pancreatic cancer. Patients and Methods Between December 2001 and June 2006, of a total of 110 patients with ductal adenocarcinoma of the pancreas, 42 underwent pancreatectomy, and 68 had unresectable disease. Numbers of c-m-DCs and c-l-DCs were assessed by flow cytometry, and DCs in the tumor tissue by immunohistochemical staining with anti-fascin mAb. Results The percentage of the c-m-DCs subset in pancreatic cancer patients was significantly lower than in healthy volunteers, and the similar finding was observed between patients who underwent surgical resection and non-resection. Patients with a high percentage of c-m-DCs or with many DCs accumulated in the cancer tissue survived longer than patients with a low percentage or low number in peripheral blood or the tumor, respectively. Moreover, there was a positive correlation between c-m-DCs within peripheral blood mononuclear cells and the number of DCs per field in the cancer tissue. Conclusions Preoperative c-m-DCs levels in the PBMC of patients with pancreatic cancer and DCs counts in the cancer tissue can be a prognostic factor after surgical resection. Modulating the distribution of DCs may be an effective therapy in pancreatic cancer patients with a dismal prognosis.

A 74-year-old man was diagnosed with small cell carcinoma arising from the extrahepatic bile duct according to a histological examination of the biopsy specimen obtained during endoscopic retrograde cholangiopancreatography. Additionally, bulky hilar lymphadenopathy was observed, and the patient was treated with the combination of radiation and chemotherapy (cisplatin and irinotecan). Post-therapy, he underwent pancreaticoduodenectomy. The histological examination of the resected specimen revealed no residual cancer cells in the bile duct wall and a small amount of cancer cells in only a single lymph node. Due to this multidisciplinary therapy, the patient showed no signs of recurrence 12 months postoperatively.

The aim of this study was to compare short-term surgical results in pancreatic cancer patients who underwent surgical resection after neo-adjuvant chemoradiation therapy (NACRT) using S-1. The study population comprised 77 patients with pancreatic cancer between 2006 and 2010. Out of 34 patients who underwent staging laparoscopy between 2008 and 2010, 31 patients without occult distant organ metastasis underwent chemoradiation and of whom 30 underwent pancreatectomy (NACRT group). Of the other 43 patients, 36 underwent surgical resection in 2006–2008, followed by adjuvant therapy (adjuvant group). The primary endpoint was frequency of pathological curative resection (R0). The new regimen of NACRT was feasible and safe. Twenty-eight of 30 (93%) patients in the NACRT group had R0 resection, which was significantly higher than in the adjuvant group (21 of 36 patients, 58%, p = 0.005). The number and extent of metastatic lymph nodes in the NACRT group (1 (0–25), N0/1; 18 of 38) was significantly lower than in the adjuvant group (2 (0–19), N0/1; 23 of 30), p = 0.0363). The frequency of intractable ascites in the NACRT group (eight of 30) was significantly higher than in the adjuvant group (two of 36, p = 0.035). Neo-adjuvant chemoradiation therapy using S-1 followed by pancreatectomy can improve the rate of pathologically curative resection and reduces the number and extent of lymph node metastasis.

The aims of this study were to verify whether the selective use of staging laparoscopy can prevent unnecessary laparotomy and to find a surrogate marker for surgical unresectability in patients with potentially or borderline resectable pancreatic cancer.Group A consisted of consecutive 33 patients evaluated between 2005 and 2006 and who directly underwent open laparotomy for planned surgical resection. Group B consisted of consecutive 61 patients evaluated between 2007 and 2009 and of whom 16 patients (26%) had a staging laparoscopy due to the presence of high-risk markers of unresectability defined as carbohydrate antigen 19-9 level 150 U/mL or greater and tumor size 30 mm or greater.The frequency of unnecessary laparotomies for occult distant organ metastasis was significantly different between groups A and B (18% and 3%, respectively; P = 0.021). Of 16 patients who underwent staging laparoscopy in group B, 5 patients (31%) had occult metastases. The multivariate analysis showed that the presence of high-risk markers and extrapancreatic plexus invasion on multidetector-row computed tomography were significant independent risk factors for unresectability.The presence of high-risk markers was associated with surgical unresectability in patients with potentially or borderline resectable pancreatic cancer. The selective use of staging laparoscopy decreased the frequency of unnecessary laparotomy by detecting minute metastases.

Primary splenic mucinous cystadenocarcinoma (MCCa) is extremely rare, and only six cases appear to have been reported previously. We present herein a case of primary splenic MCCa resulting in pseudomyxoma peritonei (PMP). A 66-year-old Japanese woman presented to a hospital with a chief complaint of upper abdominal pain and a 7-year history of splenic cyst. Cyst rupture was noted on computed tomography, and splenectomy was performed. The abdominal cavity was filled with a large amount of gelatinous ascites, with the appearance of PMP. On the cut surface, multiple cysts containing mucinous material were found within and outside the spleen. Microscopically, splenic parenchyma was occupied by large mucinous pools focally lined with mucinous epithelial cells and mesothelial cell-like cells, which were considered benign. Outside the spleen, a low-grade MCCa component was found. No ectopic pancreatic or intestinal tissue was identified. Although most PMP cases are known to be caused by low-grade mucinous appendiceal tumor, the present case represents the first report of a splenic MCCa resulting in PMP.

2002年9月より悪性腫瘍に対する（全胃温存）膵頭十二指腸切除術（以下，PD）に際して一定の条件化で自己血輸血を導入したのでその影響について検討した．2000年1月∼2007年4月までのPD連続135例の内，自己血導入前の38例を導入前群，その後の97例を導入後群とした．2群間で背景因子，輸血率，合併症率を比較検討し，さらに導入後群内で同種輸血を要する危険因子の同定を行った．2群間の比較にて，出血量のみ導入後群で有意に減少していた．術中同種輸血率は61%から35%へと有意に減少した（pl）と術中出血量過多（>1270ml）と同定された．

Carbon monoxide (CO), a product of heme degradation by heme oxygenases (HO), has been shown to provide cytoprotection in various tissue injury models. This study examined the efficacy and molecular mechanisms of exogenously delivered inhaled CO in protecting liver grafts from cold ischemia/reperfusion (I/R) injury associated with liver transplantation. Orthotopic syngenic liver transplantation (OLT) was performed in Lewis rats with 18-h cold preservation in University of Wisconsin solution. Recipients were exposed to air or different concentrations of CO (20–250 ppm) for 1 h before and 24 h after OLT and killed 1–48 h posttransplant. CO inhalation significantly decreased serum alanine transaminase (ALT) levels and suppressed hepatic necrosis and neutrophil accumulation at 24–48 h after OLT in a dose-dependent manner. Reduced hepatic injury with inhaled CO is associated with marked downregulation of early mRNA expression for TNF-α and IL-6. Expression in liver grafts of mRNA and protein of the stress-responding enzyme inducible nitric oxide synthase was significantly reduced by CO, while HO-1 was only marginally suppressed. Cold hepatic I/R injury was associated with prompt MAPK phosphorylation in liver grafts at 1 h after OLT, and CO significantly inhibited phosphorylation of ERK1/2 MAPK and its upstream MEK1/2 and downstream transcriptional factor c-Myc. CO also significantly inhibited I/R injury-induced STAT1 and STAT3 activation. In contrast, CO did not inhibit p38 or JNK MAPK pathways during hepatic I/R injury. Results demonstrate that exogenous CO suppresses early proinflammatory and stress-response gene expression and efficiently ameliorates hepatic I/R injury. The possible mechanism may include the downregulation of MEK/ERK1/2 signaling pathway with CO.

To retrospectively evaluate the efficacy and tolerability of 5-fluorouracil and low-dose cisplatin (FP)-based preoperative concurrent chemoradiotherapy (PCRT) and gemcitabine (GEM)-based PCRT in patients with potentially resectable pancreatic cancer.Between December 2000 and December 2004, 32 patients with potentially resectable pancreatic cancer were treated with PCRT. All patients received external beam radiotherapy (total dose of 40 Gy) for 4 weeks. Concurrently, chemotherapy was performed intravenously with continuous 5-fluorouracil 200 mg/m2/d and intermittent cisplatin bolus 3 to 6 mg/m2/d for 4 weeks (Arm FP-PCRT, n = 14) or weekly GEM 400 mg/m2 for 3 weeks (Arm GEM-PCRT, n = 18). The patients were restaged 3 to 4 weeks after the end of PCRT and explored for resection in cases without distant metastases.The 3-year survival rates and median survival were 29.4% and 20.5 months for the resected patients (n = 24) and 0% and 5.5 months for unresected patients (n = 8), respectively (P0.0001). The 1-, 2-, 3-year survival rates and median survival were 87.5%, 62.5%, 33.3%, and 26 months for the resected patients treated with FP-PCRT and 75%, 40%, 26.7%, and 19.9 months for the resected patients treated with GEM-PCRT (respectively; P = not significant). Most of the toxicities of both regimens were slight and were in grade1 to 2. Grade 1 to 3 leukopenia (43% vs 100%) and thrombocytopenia (0% vs 39%) were significantly different between the FP-PCRT and GEM-PCRT patients.The PCRT regimens in this article enabled selection of 24 of 32 patients for surgery and resulted in encouraging survival results and acceptable toxicities.

Following transplantation of green fluorescent protein (GFP)-labeled bone marrow (BM) into irradiated, wild-type Sprague-Dawley rats, propagated GFP+ cells migrate to adipose tissue compartments. To determine the relationship between GFP+ BM-derived cells and tissue-resident GFP− cells on the stem cell population of adipose tissue, we conducted detailed immunohistochemical analysis of chimeric whole fat compartments and subsequently isolated and characterized adipose-derived stem cells (ASCs) from GFP+ BM chimeras. In immunohistochemistry, a large fraction of GFP+ cells in adipose tissue were strongly positive for CD45 and smooth muscle actin and were evenly scattered around the adipocytes and blood vessels, whereas all CD45+ cells within the blood vessels were GFP+. A small fraction of GFP+ cells with the mesenchymal marker CD90 also existed in the perivascular area. Flow cytometric and immunocytochemical analyses showed that cultured ASCs were CD45−/CD90+/CD29+. There was a significant difference in both the cell number and phenotype of the GFP+ ASCs in two different adipose compartments, the omental (abdominal) and the inguinal (subcutaneous) fat pads; a significantly higher number of GFP−/CD90+ cells were isolated from the subcutaneous depot as compared with the abdominal depot. The in vitro adipogenic differentiation of the ASCs was achieved; however, all cells that had differentiated were GFP−. Based on phenotypical analysis, GFP+ cells in adipose tissue in this rat model appear to be of both hematopoietic and mesenchymal origin; however, infrequent isolation of GFP+ ASCs and their lack of adipogenic differentiation suggest that the contribution of BM to ASC generation might be minor. Disclosure of potential conflicts of interest is found at the end of this article.

Organ allografts have been shown to provide a syngeneic microenvironment for organ-based donor hematopoietic stem cells to maintain long-lasting chimerism after transplantation. We hypothesized that organ allografts would also support engraftment and hematopoiesis of adjunctively infused donor marrow stem cells, syngeneic to organ grafts, in nonmyeloablated recipients. In BN-to-LEW and GFP-to-ACI rat combinations, donor bone marrow (BM) infusion together with small intestine transplantation (SITx) under short-course tacrolimus immunosuppression resulted in persistent macrochimerism (more than 5%) for 150 days. In contrast, after BM infusion or SITx alone, chimerism was temporary and disappeared by day 100. Y-chromosome polymerase chain reaction (PCR) in sex-mismatched male BM plus female intestine or female BM plus male intestine transplantation into female recipients suggested that persistent macrochimerism was derived from infused BM. BM infusion together with lymphoid-depleted intestine grafts also supported macrochimerism development; however, third-party intestine grafts did not. After GFP-positive BM plus wild-type (WT) SITx into ACI, large numbers of GFP-positive leukocytes were found in WT intestine grafts. Isolated cells from WT intestine grafts developed GFP-positive CFU-Cs and propagated multilineage GFP-positive leukocytes when adoptively transferred into lethally irradiated WT recipients. These findings suggest that intestine allograft supports simultaneously infused donor (syngeneic to organ grafts) marrow stem cell engraftment, differentiation, and persistence of chimerism.

Unequivocal eradication of donor leukocyte microchimerism from recipients of long-surviving organ transplants has never been reported. Here we describe a drastic attempt to accomplish this objective.In control experiments, a rank order of microchimerism and of associated donor specific nonreactivity was produced in Brown-Norway (BN) rats by transplantation of Lewis (LEW) liver, bone marrow cell (BMC) and heart allografts under a brief course of tacrolimus. The degree of microchimerism at 60 and 110 days was estimated with semiquanitative immunocytochemical and PCR techniques. Tolerance at 110 days was assessed in the different control groups by challenge transplantation of naïve LEW hearts. In parallel experimental groups, an attempt was made to eliminate microchimerism from the BN recipients. The animals were submitted at 60 days to 9.5-Gy total body irradiation (TBI), reconstituted immediately with naïve BN BMC, and tested for donor specific nonreactivity by LEW heart transplantation at 110 days.After the TBI-reconstitution at 60 days, microchimerism was undetectable in BMC recipients at 110 days, significantly reduced in heart recipients, and least affected in liver recipients. Except in liver recipients, abrogation of LEW-specific nonreactivity was demonstrated by rejection of the priming grafts, or by rejection of the challenge heart grafts, and by in vitro immune assay.It is difficult to eliminate microchimerism in organ recipients once the donor cells have settled into tissue niches.

Background: Dendritic cells (DCs) are important for an immune surveillance. Myeloid DCs (DC1) are important for an effective antitumor immune system. The function and count of circulating DC1 (cDC1) in hosts with a malignant tumor would be defective. This study focused on analyzing the immunological features of cDC1 in patients with pancreatic cancer during the perioperative period. Materials and methods: Thirty-two pancreatic cancer patients who underwent pancreatectomy and 18 age-matched healthy individuals as controls were enrolled in this study. The perioperative cDC count, the stimulatory capacity of cDC1 against allogeneic T cells and TGF-β1 level in the serum were measured. The cDC count was measured at 12 months after the operation. Results: The preoperative cDC1/cDC2 ratio, cDC1 count, and stimulatory capacity of cDC1 were impaired in patients in comparison to controls (P

Background Carbon monoxide (CO), a product of heme degradation by heme oxygenase, induces cytoprotection against ischemia/reperfusion (I/R) injury in a variety of organs such as the heart, lung, kidney, and small intestine. We examined whether CO would protect liver grafts against cold I/R injury associated with transplantation. Methods Orthotopic liver transplantation (OLT) was performed in syngeneic Lewis rats with 18 hours preservation in cold University of Wisconsin solution. Recipients were exposed to air or CO (100 ppm) for 1 hour before and 24 hours after OLT. Recipients were sacrificed 0.5 to 48 hours post-transplant. Results CO inhalation significantly decreased serum aspartate aminotransferase and alanine aminotransferase levels and suppressed hepatic necrosis formation and neutrophil accumulation at 6 to 48 hours after OLT, compared with air control. The expressions of tumor necrosis factor α, intercellular adhesion molecule 1, and inducible nitric oxide synthase messenger RNA in the liver graft were significantly inhibited in the CO-treated group at 1 hour after reperfusion. Hepatic nuclear factor-κB activation did not differ between the groups. Conclusions The results demonstrate that exogenous CO treatment suppresses early proinflammatory gene expression and neutrophil infiltration, and efficiently ameliorates hepatic I/R injury. The possible mechanism by which CO protects the liver against cold I/R does not seem to be associated with downregulation of the nuclear factor-κB–signaling pathway.

Introduction: Between April 1992 and December 2000, 167 patients with pancreatic carcinoma were evaluated and treated in our department. One hundred eight patients (64.7%) with pancreatic carcinoma underwent pancreatectomy. Of these patients, 94 had histologically proven ductal adenocarcinoma. The overall postoperative mortality rate was 3.2% (3 patients), and the morbidity rate was 35.1% (33 patients). The estimated 1- 2-, 3-. and 5-year survival rates were 43.6%. 28.7%, 21.8%, and 12.9% respectively. There were only six long-term survivors who survived >5 years after surgery. Methodology and Aims: Institutional experience with 94 consecutive patients with ductal adenocarcinoma who underwent pancreatectomy was reviewed to clarify the influence of 29 prognostic factors (5 host, 17 tumor, and 7 treatment factors). Special reference was made to determine whether these significant factors have an effect on long-term survival. Univariate and multivariate models were used to analyze the effect of prognostic factors on survival. Results: Univariate analysis indicated that blood loss, operative time, postoperative complications, histopathologic lymphatic and venous permeation, lymph node metastasis, conclusive stage, conclusive curability, resection margins, serosal invasion, size of tumor, retroperitoneal invasion, major arterial invasion, and mode of histologic infiltration were associated with significantly longer survival (p < 0.05). By Cox proportional hazards survival analysis, the most powerful predictors of outcome were venous permeation, lymph node metastasis, tumor diameter, and conclusive curability. The longest-term survivor had the most advanced stage (stage lV b ) of disease and curability C. No long-term survivors had all of the good prognostic factors (according to multi variate analysis). Conclusions: The prognosis after surgical resection of pancreatic carcinoma mostly depends on tumor factors. In this study, it was difficult to identify the determinants of long-term survival in patients with resectable tumors.

The aim of this study was to investigate the synergistic inhibitory effects of gemcitabine and losartan, angiotensin II type 1 (AT1) receptor blockers, on an orthotopic rat pancreatic cancer model.The rat orthotopic pancreatic cancer model was prepared using DSL-6A/C cells, a rat ductal pancreatic adenocarcinoma cell line. The rats were treated with gemcitabine alone (100 mg/kg per week), losartan alone (100 mg/kg per day), or gemcitabine plus losartan.Survival was significantly improved by treatment with gemcitabine (89.6 ± 21.8 days) or losartan (76.9 ± 18.7 days) alone compared with that in the control group (59.6 ± 13.4 days; P0.05). Treatment with gemcitabine plus losartan further prolonged the survival time to 102.6 ± 16.5 days compared with that in the control group (P0.0001). Gemcitabine or losartan significantly and dose-dependently reduced the proliferation of DSL-6A/C cells in vitro. Both drugs inhibited pancreatic vascular endothelial growth factor expression compared with that in the control group (P0.05).The results of this study indicate that combined treatment with gemcitabine and losartan significantly improved the survival of rats with orthotopic pancreatic cancer by inhibiting vascular endothelial growth factor synthesis and suppressing cancer cell proliferation via AT1 receptor blockade. Thus, an AT1 receptor blocker in combination with gemcitabine might improve the clinical outcomes of patients with advanced pancreatic cancer.

Pancreaticoduodenectomy (PD) is still associated with high morbidity. To reduce the frequency of postoperative complications, we have made revisions in perioperative managements of pancreaticoduodenectomy.Subjects were 128 consecutive patients who underwent PD between January 2000 and August 2006. In June 2004, the following new departmental guidelines were introduced: (1) modified Kakita method of pancreaticojejunostomy, (2) omental wrapping, (3) early removal of closed-suction drain, and (4) restrictive use of pancreatic and biliary duct stenting. Operative mortality and morbidity between 77 patients managed conventionally (group A) and 51 patients since 2004 (group B) were compared. Risk factors for postoperative complications were determined.Postoperative morbidity in group B (39%) was significantly lower than in group A (64%; P = 0.019). Occurrence of grade B/C pancreatic fistula (PF) in group B (6%) was significantly lower than in group A (19%; P = 0.0376). Delayed gastric emptying was significantly reduced in group B relative to group A (23% vs 6%; P = 0.0133). Logistic regression analyses showed that the modified Kakita method was a negative independent factor for overall complications, PF, and delayed gastric emptying.The incidence of overall postoperative complications, grade B/C PF, and delayed gastric emptying after PD has been reduced because of the introduction of a new guideline.

Few studies have reported the efficacy and safety of palliative chemotherapy in elderly patients with advanced biliary tract cancer. We aimed to investigate the clinical outcomes of palliative chemotherapy for advanced biliary tract cancer in elderly patients.We retrospectively evaluated 403 consecutive patients who received palliative chemotherapy between April 2006 and March 2009 for pathologically confirmed unresectable or recurrent biliary tract cancer. Clinical outcomes of the elderly group (≥ 75 years old; n = 94) were compared with those of the non-elderly group ( 75 years old; n = 309).Except for the extent of disease, patient baseline characteristics were well balanced between both groups. The median overall survival was 10.4 months in the elderly group and 11.5 months in the non-elderly group (hazard ratio, 1.14; 95% confidence interval, 0.89-1.45; P = 0.31). Although the frequency of adverse events between both groups was similar, interstitial pneumonitis was significantly more frequent in the elderly group than in the non-elderly group (4.3% vs 0%, P 0.01).In advanced biliary tract cancer, overall survival of elderly patients receiving palliative chemotherapy is comparable with that of non-elderly patients. To our knowledge, this is one of the largest studies that have reported the clinical outcomes of elderly patients following palliative chemotherapy.

The aim of the study was to evaluate the potential advantages of the ultrasonic scalpel compared with the conventional technique in gastric cancer surgery.Patients with resectable adenocarcinoma of the stomach were randomly assigned to ultrasonic scalpel or conventional technique. We used the HARMONIC FOCUS (Ethicon Endo-Surgery, Inc.) as ultrasonic scalpel.Between February 2010 and December 2010, 60 patients with resectable gastric cancer were enrolled into the study. Operative time was significantly shorter with the ultrasonic arm than with the conventional arm (median 238.5 vs. 300.5 min; P = 0.0004). Blood loss was also significantly lower in the ultrasonic arm than in the conventional arm (median 351.0 vs. 569.5 ml; P = 0.016). Clavien-Dindo grades of postoperative complications were similar in the two groups. From a questionnaire survey of operators, the ultrasonic scalpel significantly reduced the stress of lymph node dissection (3.67 vs. 2.87; P = 0.0006). However, in assisting surgeons, the contributions to surgery, study, and technical improvement of the ultrasonic group were lower than in the conventional group.This study shows that the ultrasonic scalpel is a reliable and safe tool for open gastric cancer surgery.

Regulatory T cells (Treg) can inhibit immune responses mediated by T cells. The aim of this study was to evaluate the prevalence of Treg in peripheral blood mononuclear cells from patients with pancreatic cancers in relation to their clinical outcomes.Among a total of 100 patients with ductal adenocarcinoma of the pancreas, 40 underwent pancreatectomy and 60 had unresectable disease. Their peripheral blood mononuclear cells were evaluated to determine the proportion of CD4CD25 (FoxP3) T cells, as a percentage of the total CD4 cells, by flow cytometric analysis.The percentage of Treg in the patients with pancreatic cancer was significantly lower than that in the healthy volunteers (P = 0.048), and the patients who underwent surgical resection had lower Treg levels than those with unresectable disease (P = 0.040). Patients in the resected group with a higher percentage of Treg survived longer (P = 0.021). Treg in patients who remained disease free at postoperative 12 months significantly decreased compared to that of the postoperative period (P = 0.009).A relative increase in Treg may be related to immunosuppression and tumor progression in patients with pancreatic cancer. The immunological monitoring of Treg may be useful to predict the prognosis for patients with pancreatic cancer.

Pancreatic cancer is a malignant neoplasm with a poor prognosis that might be associated with defective immune function. In this study, we aimed to clarify the role of circulating myeloid dendritic cells (cmDCs) and lymphoid (cl) DCs in patients with unresectable pancreatic cancer.This study covered the period from January 2001 to December 2009, and involved 104 patients with unresectable pancreatic cancer. We measured the number of cmDCs and clDCs using flow cytometry before and after chemotherapy, chemoradiotherapy and immuno-chemotherapy.The percentage of the cmDC subset in the unresectable pancreatic cancer patients was significantly lower than in healthy volunteers (p=0.006). There was no difference in the cmDC subset between patients with distant organ metastasis and locally advanced pancreatic cancer. The patients with a high percentage (≥0.23%) of cmDC subset survived longer than patients with a low percentage (0.23%) (p=0.0030). Multivariate analysis showed that cmDC was the only independent prognostic factor (p=0.0059). The percentage of cmDC subset was significantly increased after immuno-chemotherapy (p=0.0055).A high level of cmDCs is associated with better survival rate and is an independently favorable prognostic factor in patients with unresectable pancreatic cancer. It is likely that immunochemotherapy increases the number of cmDCs.

Ischemia/reperfusion (I/R) injury in liver grafts, which is initiated by cold preservation and is augmented by reperfusion, is a major problem that complicates graft quality, posttransplant patient care, and outcomes of liver transplantation (LT). Kupffer cells (KCs) play important roles in I/R injury; however, little is known about their changes during cold preservation. We examined whether a pretreatment with carbon monoxide (CO), a cytoprotective product of heme degradation, could influence KC activity during cold storage and protect liver grafts against LT-induced I/R injury. In vitro, primary rat KCs were stimulated for 24 hours under hypothermic conditions (4°C, 20% O(2)), with lipopolysaccharide, or under hypoxic conditions (37°C, 5% O(2)) with or without a CO pretreatment. When rat KCs were exposed to hypothermic conditions, they produced reactive oxygen species (ROS), but they did not produce tumor necrosis factor α (TNF-α) or nitric oxide. The preincubation of KCs with CO up-regulated heat shock protein 70 (HSP70) and inhibited ROS generation. When liver grafts from donor rats exposed to CO (250 ppm) for 24 hours were transplanted after 18 hours of cold preservation in University of Wisconsin solution, HSP70 expression increased in these grafts versus control grafts, and serum aspartate aminotransferase and alanine aminotransferase levels as well as necrotic areas and inflammatory infiltrates were significantly reduced after LT. CO-pretreated liver grafts showed less up-regulation of TNF-α and inducible nitric oxide synthase messenger RNA (mRNA) and reduced expression of proapoptotic B cell lymphoma 2-associated X protein mRNA, cleaved caspase-3, and poly(adenosine diphosphate ribose) polymerase. In conclusion, the pretreatment of donors with CO ameliorates LT-associated I/R injury with increased hepatic HSP70 expression, particularly in the KC population.

To examine whether the use of the new ultrasonically curved shear (UCS) can reduce the number of surgical stitches, extent of blood loss, and operation time in (pylorus-preserving) pancreaticoduodenectomy (PD) for periampullary cancer. The study population comprised 26 consecutive patients who underwent PD for periampullary cancer. Intraoperative data, including number of stitches used, was prospectively collected. Results from 13 patients who underwent conventional PD (Group A) were compared with those from 13 patients who underwent PD using UCS (Group B). There were no significant differences in baseline characteristics between the two patient groups. The extent of blood loss in Group B was significantly less than in Group A (p

We explored the outcome of the multi-disciplinary management for obtaining long-term survivors in patients with pancreatic cancer that extended beyond the pancreas. This single-institution experience indicates that surgical resection following the neoadjuvant chemoradiation (NACRT) therapy is able to increase the resectability rate with clear margins and to decrease the rate of metastatic lymph nodes, resulting in improved prognosis of curative cases with pancreatic cancer that extended beyond the pancreas.

We evaluated the safety of, and clinical and immune responses to personalized peptide vaccination with gemcitabine (GEM) as the first line therapy in patients with non-resectable pancreatic cancer. Pre-vaccination peripheral blood mononuclear cells (PBMCs) and plasma were prepared to examine cellular and humoral responses to 14 and 16 peptides in human leukocyte antigen (HLA)-A24+ or -A2+ patients, respectively. Only the reactive peptides (maximum of 4) were administered weekly at 3 mg/peptide. GEM was administered at 1000 mg/m(2) per week for 3 weeks, followed by 1 week of rest. Twenty-one patients with untreated and non-resectable pancreatic cancer were enrolled. The combination therapy was generally well tolerated. Boosting of cellular and humoral responses to the vaccinated peptides was observed in the post-vaccination (eighth) PBMCs and plasma from 14 of 18 and 13 of 18 patients tested, respectively. The best clinical responses were 7 cases of partial response, 9 cases of stable disease, and 5 cases of progressive disease. Median survival time of all 21 patients was 9.0 months (95% CI, 6-15.5 months) with a one year survival rate of 38%. Immune boosting in both cellular and humoral responses was well correlated with overall survival with a hazard ratio of 0.2 (95% CI, 0.06-0.73; log-rank p=0.0239). These results suggest a potential clinical benefit of this combination therapy for non-resectable pancreatic cancer patients as the first line therapy. Further exploration of this approach is warranted.

OBJECTIVES After standardization of the perioperative management of pancreaticoduodenectomy, we retrospectively compared results in nonstented pancreaticojejunostomy with external-stented pancreaticojejunostomy. METHODS The study population included 129 consecutive patients who underwent pancreaticoduodenectomy between 2004 and 2008. The postoperative mortality and morbidity were compared between 51 patients with restrictive use of external stenting (group A) and 78 patients without external stenting (group B). The patient with a pancreatic duct of less than 3 mm in diameter was 31% in group A and 46% in group B. RESULTS There were no differences in postoperative morbidity and mortality between the 2 groups. Although the frequency of overall postoperative pancreatic fistula development was significantly higher in group B than in group A (44% vs 27%, P = 0.0004), there was no difference in grade B/C postoperative pancreatic fistula rate (group A: 5.9% vs group B: 14.1%). The length of in-hospital stay in group B was significantly shorter than group A (13 vs 24 days, P < 0.0001). There were no differences in postoperative morbidity and mortality between subgroups that were consisted of patients with small pancreatic duct diameter. CONCLUSION This retrospective single-center study showed that nonstented duct-to-mucosa anastomosis was a safe procedure and was associated with a shortened in-hospital stay.

Background/Aims. Our policy for the surgical treatment of hepatocellular carcinoma (HCC) has been to minimize the extent of liver resection using a microwave tissue coagulator (MTC) and to not perform Pringle's maneuver for the prevention of ischemic injury to the liver routinely. We verify the safety of liver resection using MTC in HCC patients with poor liver functional reserve, and clarify the long-term outcome of HCC patients who underwent curative resection using MTC. Methodology. One hundred sixty-eight patients who underwent curative resection using MTC between 1992 and 2001 were divided into two groups according each patient's score in the Indocyanin Green Retension 15 Test (ICG-R15 test). The high (ICG-R15 values>20) and low ICG-R15 groups (ICG-R15 values

The interaction of donor passenger leukocytes and host leukocytes in recipient secondary lymphoid tissues during the early posttransplantation period is crucial in directing host immune reactions toward allograft rejection or acceptance. Responsible T cell clones could be activated through the direct and indirect pathways of allorecognition. We examined the role of the indirect pathway in liver transplantation (LT) tolerance by depleting host antigen-presenting cells (APC) with phagocytic activity [e.g., cluster domain (CD)68+/CD163+ macrophages, CD11c+ dendritic cells (DC)] using liposome-encapsulating clodronate (LP-CL). After Lewis rat cell or liver graft transplantation, Brown Norway (BN) rat recipients pretreated with LP-CL showed a significantly reduced type 1 helper T cell cytokine up-regulation than control-LP-treated recipients. In the LT model, LP-CL treatment and host APC depletion abrogated hepatic tolerance; Lewis liver grafts in LP-CL-treated-BN recipients developed mild allograft rejection, failed to maintain donor major histocompatibility complex (MHC) class II+ leukocytes, and developed chronic rejection in challenged donor heart allografts, while control-LP-treated BN recipients maintained tolerance status and donor MHC class II+ hepatic leukocytes. Furthermore, in the BN to Lewis LT model, LP-CL recipient treatment abrogated spontaneous hepatic allograft acceptance, and graft survival rate was reduced to 43% from 100% in the control-LP group. In conclusion, the study suggests that host cells with phagocytic activity could play significant roles in developing LT tolerance.

Carbon monoxide (CO), a byproduct of heme catalysis, was shown to have potent cytoprotective and anti-inflammatory effects. In vivo recipient CO inhalation at low concentrations prevented ischemia/reperfusion (I/R) injury associated with small intestinal transplantation (SITx). This study examined whether ex vivo delivery of CO in University of Wisconsin (UW) solution could ameliorate intestinal I/R injury. Orthotopic syngenic SITx was performed in Lewis rats after 6 h cold preservation in control UW or UW that was bubbled with CO gas (0.1-5%) (CO-UW). Recipient survival with intestinal grafts preserved in 5%, but not 0.1%, CO-UW improved to 86.7% (13/15) from 53% (9/17) with control UW. At 3 h after SITx, grafts stored in 5% CO-UW showed improved intestinal barrier function, less mucosal denudation and reduced inflammatory mediator upregulation compared to those in control UW. Preservation in CO-UW associated with reduced vascular resistance (end preservation), increased graft cyclic guanosine monophosphate levels (1 h), and improved graft blood flow (1 h). Protective effects of CO-UW were reversed by ODQ, an inhibitor of soluble guanylyl cyclase. In vitro culture experiment also showed better preservation of vascular endothelial cells with CO-UW. The study suggests that ex vivo CO delivery into UW solution would be a simple and innovative therapeutic strategy to prevent transplant-induced I/R injury.

The pancreaticoduodenectomy with extended resection has been frequently performed in patients with pancreatic cancer in Japan. One result of this additional surgical stress may be that postoperative complications in patients with pancreatic cancer are more frequent than in patients with periampullary cancer.The 198 patients with pancreatic and periampullary cancer underwent pancreaticoduodenectomy. The operative mortality and morbidity between patients with pancreatic and periampullary cancer were compared, and the risk factors of postoperative complications and in-hospital death were determined.Patients with pancreatic and periampullary cancer made up 52% and 48% of total patients. The duration of surgery and volume of intraoperative blood loss were significantly higher in patients with pancreatic cancer than in patients with periampullary cancer. Additional organ resections were frequently performed in patients with pancreatic cancer. However, significantly lower morbidity rates were observed in patients with pancreatic cancer. Among all complications evaluated, pancreatic fistula and abdominal abscess were found less frequently in patients with pancreatic cancer. Logistic regression analyses showed a positive correlation between periampullary cancer and an increased risk of complications, pancreatic fistula, and abdominal abscess. The in-hospital mortality rate has significantly reduced since 2000. When pancreatic fistula was clinically diagnosed, we immediately started a closed lavage using continuous administration of natural saline at 1000 to 4000 mL/d, after exchange of a nasogastric tube drain.Pancreaticoduodenectomy for patients with pancreatic cancer can be a safe procedure in spite of surgical stress. Further surgical strategies will be needed to reduce postoperative complications, especially in patients with periampullary cancer.

The exact role of inducible NOS (iNOS) in liver ischemia/reperfusion (I/R) injury is controversial. This study was designed to investigate whether donor liver pretreatment with adenovirus encoding iNOS (AdiNOS) ameliorates I/R injury associated with liver transplantation. Orthotopic syngeneic LEW rat liver transplantation (OLT) was performed after 18 or 24 hours' preservation in cold UW. AdiNOS or control gene vector (AdLacZ) was delivered to the liver by donor intravenous pretreatment 4 days before graft harvesting. Uninfected grafts also served as control. Recipients were sacrificed 1 to 48 hours posttransplantation. An abundant hepatic iNOS protein expression and marked serum NO elevation was observed in the AdiNOS-treated group, without affecting endothelial nitric oxide synthase (eNOS) expression, before harvesting and after OLT. AdiNOS pretreatment markedly improved liver function assessed by serum aspartate aminotransferase/alanine aminotransferase levels and reduced liver necrosis formation. AdiNOS treatment also was associated with reduced ICAM-1 mRNA expression and neutrophil accumulation in the liver graft after OLT compared with untransfected or AdLacZ-treated group. Furthermore, AdiNOS delivery significantly improved transplant survival, compared with AdLacZ or saline controls. AdiNOS pretreatment did not attenuate I/R-induced apoptotic cell death in the liver graft. Administration of a selective inhibitor for iNOS abrogated the protection afforded by AdiNOS pretreatment. In conclusion, donor pretreatment with AdiNOS led to improved liver graft injury and posttransplantation survival. Downregulation of ICAM-1 mRNA and neutrophil infiltration may be associated with the mechanisms by which AdiNOS pretreatment confer the protection against transplant-associated hepatic I/R injury.