Kunihiko Izuishi

Cutting Edge: High-Mobility Group Box 1 Preconditioning Protects against Liver Ischemia-Reperfusion Injury

High mobility group box 1 (HMGB1) is a NF released extracellularly as a late mediator of lethality in sepsis and as an early mediator of inflammation following injury. Here we demonstrate that in contrast to the proinflammatory role of HMGB1, preconditioning with HMGB1 results in protection following hepatic ischemia/reperfusion (I/R). Pretreatment of mice with HMGB1 significantly decreased liver damage after I/R. The protection observed in mice pretreated with HMGB1 was associated with a higher expression of IL-1R-associated kinase-M, a negative regulator of TLR4 signaling, compared with controls. We thus explored the possibility that HMGB1 preconditioning was mediated through TLR4 activation. HMGB1 preconditioning failed to provide protection in TLR4 mutant (C3H/HeJ) mice, but successfully reduced damage in TLR4 wild-type (C3H/HeOuj) mice. Our studies demonstrate that in contrast to the role of HMGB1 as an early mediator of inflammation and organ damage in hepatic I/R, HMGB1 preconditioning can be protective.

Is preoperative portal vein embolization effective in improving prognosis after major hepatic resection in patients with advanced-stage hepatocellular carcinoma?

The impact of the use of preoperative portal vein embolization (PVE) on long‐term survival after surgery was evaluated by retrospective analysis of prognostic factors in patients with advanced‐stage hepatocellular carcinoma (HCC) who had undergone hepatic resection with or without PVE.

Detection of gastric cancer using 18F-FLT PET: comparison with 18F-FDG PET.

PurposeWe prospectively investigated the feasibility of 3′-deoxy-3′-18F-fluorothymidine (FLT) positron emission tomography (PET) for the detection of gastric cancer, in comparison with 2-deoxy-2-18F-fluoro-d-glucose (FDG) PET, and determined the degree of correlation between the two radiotracers and proliferative activity as indicated by Ki-67 index.MethodsA total of 21 patients with newly diagnosed advanced gastric cancer were examined with FLT PET and FDG PET. Tumour lesions were identified as areas of focally increased uptake, exceeding that of surrounding normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUV) was calculated.ResultsFor detection of advanced gastric cancer, the sensitivities of FLT PET and FDG PET were 95.2% and 95.0%, respectively. The mean (±SD) SUV for FLT (7.0 ± 3.3) was significantly lower than that for FDG (9.4 ± 6.3 p < 0.05). The mean FLT SUV and FDG SUV in nonintestinal tumours were higher than in intestinal tumours, although the difference was not statistically significant. The mean (±SD) FLT SUV in poorly differentiated tumours (8.5 ± 3.5) was significantly higher than that in well and moderately differentiated tumours (5.3 ± 2.1; p < 0.04). The mean FDG SUV in poorly differentiated tumours was higher than in well and moderately differentiated tumours, although the difference was not statistically significant. There was no significant correlation between Ki-67 index and either FLT SUV or FDG SUV.ConclusionFLT PET showed as high a sensitivity as FDG PET for the detection of gastric cancer, although uptake of FLT in gastric cancer was significantly lower than that of FDG.

Ischemic preconditioning of the murine liver protects through the akt kinase pathway

Hepatic ischemia‐reperfusion (I/R) injury occurs in the settings of transplantation, trauma, and elective liver resection. Ischemic preconditioning has been used as a strategy to reduce inflammation and organ damage from I/R of the liver. However, the mechanisms involved in this process are poorly understood. We examined the role of the phosphatidylinositol 3 (PI3) kinase/Akt‐signaling pathway during hepatic ischemic preconditioning (IPC). Prior to a prolonged warm ischemic insult, BALB/c mice were subjected to a 20‐minute IPC period consisting of 10 minutes of ischemia and 10 minutes of reperfusion. Mice undergoing IPC demonstrated a significantly greater level and earlier activation of Akt in the liver compared with control animals. IPC also resulted in markedly less hepatocellular injury and improved survival compared with control animals. Akt activation associated with hepatic IPC suppressed the activity of several modulators of apoptosis, including Bad, glycogen synthase kinase β, and caspase‐3. In addition, IPC also inhibited the activities of c‐Jun N‐terminal kinase and nuclear factor κB after I/R. Pretreatment of mice with PI3 kinase inhibitors completely abolished Akt phosphorylation and the protective effects seen with IPC. In conclusion, these results indicate that the PI3 kinase/Akt pathway plays an essential role in the protective effects of IPC in hepatic I/R injury. Modulation of this pathway may be a potential strategy in clinical settings of ischemic liver injury to decrease organ damage. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2006;44:573–580.)

Impact of 18-fluorodeoxyglucose positron emission tomography on the management of pancreatic cancer.

BackgroundWe compared the usefulness of positron emission tomography with the glucose analogue 2-deoxy-2-[18F]-fluoro-d-glucose (FDG-PET) and multidetector-row computed tomography (MD-CT) in diagnosing pancreatic cancer and in determining the patients’ suitability for surgery.MethodsWe reviewed the clinical FDG-PET data of 103 consecutive pancreatic cancer patients between July 2004 and March 2009.ResultsThe detection rates of pancreatic cancer by MD-CT (89%) and FDG-PET (91%) were similar. From the MD-CT findings, 38 patients were judged as operable, and 65, inoperable. Among the inoperable patients, noncurative factors (metastasis to the liver, peritoneum, remote lymph nodes, bones, and other organs and major arterial invasion) were detected by MD-CT and/or FDG-PET. Detection rates of liver metastasis and arterial invasion by FDG-PET were significantly inferior to those of MD-CT (neither was detected by FDG-PET alone). Remote lymph nodes and bone metastasis were detected in 20 lesions by FDG-PET alone; however, MD-CT indicated other noncurative factors in these patients. All 65 patients could be diagnosed as inoperable without FDG-PET.ConclusionsFDG-PET is not a suitable imaging modality for either diagnosis or preoperative treatment in pancreatic cancer patients. Since it is expensive, FDG-PET as a routine diagnostic tool in pancreatic cancer patients must be used with caution.

Modulating effect of the PI3-kinase inhibitor LY294002 on cisplatin in human pancreatic cancer cells

BackgroundChemoresistance is a serious problem in pancreatic cancer, but the mechanism of resistance and strategies against the resistance have not been elucidated. We examined the potential of the phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor LY294002 to enhance the anti-tumor effect of cisplatin and investigated the mechanism of chemoresistance in pancreatic cancer cells using a combination therapy of cisplatin and LY294002, both in vitro and in vivo.MethodsCisplatin and LY294002, individually or in combination, were given to AsPC-1 and PANC-1 cell lines. Tumor growth, DNA fragments, and Akt phosphorylation were examined in vitro. To examine the therapeutic effect of cisplatin and LY294002, individually or combination an AsPC-1 tumor xenograft model was prepared for in vivo study.ResultsCisplatin induced growth inhibition and Akt phosphorylation in pancreatic cancer cells. LY294002 also inhibited cell proliferation but without showing Akt phosphorylation. However, the combination therapy markedly increased cleavage of caspase-3 and cytoplasmic histone-associated DNA fragments compared to the results with cisplatin alone. In the in vivo study, blocking the PI3K/Akt cascade with LY294002 increased the efficacy of cisplatin-induced inhibition of tumor growth in nude mice, suppressing half the tumor growth with cisplatin alone. There were no detectable side effects in mice treated with combination therapy.ConclusionOur studies suggest that the PI3K/Akt pathway plays an important role in cisplatin resistance of pancreatic cancer cells. The augmentation of cisplatin with PI3K/Akt inhibitor may resolve the chemoresistance problem of cisplatin, and this might be a plausible strategy for achieving tolerance for chemotherapeutic agents in pancreatic cancer therapy.

Establishment of pure NOTES procedure using a conventional flexible endoscope: review of six cases of gastric gastrointestinal stromal tumors

An increasing number of reports have recently been published on hybrid natural orifice transluminal endoscopic surgery (NOTES). These reports do not address how to complete an operation with a flexible endoscope alone (pure NOTES), but rather how to combine use of an endoscope and a laparoscope. Surgical procedures using flexible and rigid endoscopes have been developed using different processes and concepts. Recognizing this conceptual difference, we conducted a study to address how to establish a pure NOTES procedure. Six patients with gastric gastrointestinal stromal tumors (GISTs) underwent hybrid NOTES. Each case was retrospectively reviewed to determine the appropriateness of the treatment and the usefulness of the endoscopic submucosal dissection (ESD) method, double-scope method, spaced perforation method, duodenal balloon occlusion method, and loop clip technique. The development of operative procedures that take advantage of the characteristics of flexible endoscopes, even with conventional flexible endoscopic devices and conventional endoscopes alone, may contribute to the realization of pure NOTES.

A simple and safe pancreas transection using a stapling device for a distal pancreatectomy

Pancreatic fistula is the most common major complication to occur after distal pancreatectomy, ranging in frequency from 5% to 40%. The appropriate technique for treating the pancreatic stump still remains controversial. Thirty-six patients underwent distal pancreatectomy in Kagawa University Hospital between January 2000 and February 2007. Their hospital records were reviewed to evaluate the usefulness of a stapling closure using several types of staplers in comparison to a suture closure. They were subdivided according to the method used to close the pancreas stump: the suture group comprised 11 patients, the staple group comprised 24 patients, including 7 patients for whom was used the new endopath stapler Echelon 60 (Ethicon Endo-surgery; Johnson & Johnson, Cincinnati, OH, USA). Overall pancreatic fistula rate was 17% (6/36) in this series. In the staple group, 3 of the 24 patients (12%) developed a pancreatic fistula, whereas in the suture group, 3 of 11 patients (27%) developed a pancreatic fistula. Of the 7 patients for whom the Echelon 60 was used, none developed a pancreatic fistula. The length of postoperative hospital stay was also significantly shorter for the patients with the Echelon 60 than in the patients either with sutures or another stapling device. These findings support the advantages of using a stapler closure in distal pancreatectomy. This method, using a new stapler device, is considered to be a simple and safe alternative to the standard suture closure technique.

Neutrophil Elastase Inhibitor (Sivelestat) Preserves Antitumor Immunity and Reduces the Inflammatory Mediators Associated with Major Surgery

PurposeTo examine the effects of the administration of perioperative sivelestat, a selective neutrophil elastase inhibitor, on tumor immunity and inflammatory mediators in patients who undergo major surgery.MethodsThirteen patients admitted to the hospital for elective surgery were equally randomized into one of two groups: the Sivelestat group (n = 6) and the control group (n = 7). Thereafter, the immunosuppressive acidic protein (IAP), serum interleukin-6 (IL-6), and type 1/type 2 T-helper cell balance were all assessed at several time points before and after surgical intervention.ResultsThe serum IL-6 values at 1 and 12 h after surgery and on postoperative days 1 and 3 were all significantly lower in the sivelestat group than in the control group. The IAP values at postoperative days 7 and 28 in the sivelestat group were also significantly lower than those in the control group. There was a significant correlation between the IL-6 level at 1 h after surgery and the IAP level at postoperative days 7 and 28.ConclusionsIn this preliminary study, the perioperative administration of sivelestat was thus suggested to reduce surgical stress by decreasing the cytokine release and preserving the antitumor immunity.

Reduced expression of cell cycle regulator p18INK4C in human hepatocellular carcinoma

Cyclins, cyclin‐dependent kinases (Cdks), and Cdk inhibitors (CdkIs) are frequently altered in human cancer. p18INK4C, a member of the INK4 family of CdkIs, is a potential tumor‐suppressor gene product. However, the expression of p18INK4C in hepatocellular carcinoma (HCC) remains unknown. The aim of this study was to examine the expression of p18INK4C in various liver diseases including HCC and to assess its clinical significance in HCC. To that end, we examined the expression of p18INK4C by immunohistochemistry in various liver diseases, including 51 HCCs, and also studied the relationship between p18INK4C expression, the phosphorylation of retinoblastoma protein (pRb), and the activity level of Cdk4 and Cdk6. Immunohistochemical analysis revealed the frequent loss of p18INK4C expression in HCC, especially in poorly differentiated HCC. The loss of p18INK4C expression was shown to be associated with a poor prognosis compared with that associated with p18INK4C‐ positivity. Further, the kinase activity of Cdk4 was found to be higher in p18INK4C‐negative HCCs than in p18INK4C‐ positive HCCs. However, the level of Cdk6 activity was similar in the 2 groups of HCCs. In p18INK4C‐ positive HCCs, p18INK4C dominantly interacted with Cdk4 rather than with Cdk6. pRb phosphorylated at serine(Ser) 780 was detected more frequently in p18INK4C ‐ negative than in p18INK4C ‐ positive HCCs. In conclusion, the loss of p18INK4C expression may play a role in the differentiation and development of HCC through the up‐regulation of Cdk4 activity. (HEPATOLOGY 2004;40:677–686.)