Prognostic significance of L-type amino-acid transporter 1 expression in surgically resected pancreatic cancer.

BACKGROUND: The expression of L-type amino-acid transporter 1 (LAT1) is tumour-specific and has been shown to have essential roles in cell growth and survival. However, little is known regarding the clinical significance of LAT1 expression in pancreatic cancer. This study was conducted to determine the prognostic significance of LAT1 expression. METHODS: A total of 97 consecutive patients with surgically resected pathological stage I-IV pancreatic ductal adenocarcinoma were retrospectively reviewed. Tumour sections were stained by immunohistochemistry for LAT1, CD98, Ki-67 and vascular endothelial growth factor (VEGF), and microvessel density was determined by CD34 and p53. RESULTS: L-type amino-acid transporter 1 and CD98 were highly expressed in 52.6% (51/97) and 56.7% (55/97) of cases, respectively (P=0.568). The expression of LAT1 within pancreatic cancer cells was significantly associated with disease stage, tumour size, Ki-67, VEGF, CD34, p53 and CD98. L-type amino-acid transporter 1 expression was confirmed to be a significant prognostic factor for predicting poor outcome by multivariate analysis. CONCLUSION: L-type amino-acid transporter 1 expression is a promising pathological marker for the prediction of outcome in patients with pancreatic cancer.

FR167653 ameliorates pulmonary damage in ischemia-reperfusion injury in a canine lung transplantation model.

BACKGROUND: Interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-alpha) are recognized as important factors in ischemia-reperfusion (I/R) injury. FR167653 has been characterized as a potent suppressant of IL-1 and TNF-alpha production. We previously reported that FR167653 suppressed the expression of IL-1 beta mRNA after reperfusion and ameliorated pulmonary I/R injury following 3-hour left lung warm ischemia in dogs. The aim of this study was to investigate the effects of FR167653 on I/R injury in a canine left, single, lung transplantation model. METHODS: We used 10 pairs of weight-matched dogs. We assigned 5 pairs to the FR group, in which each animal received FR167653 (1 mg/kg/hr) IV from 30 minutes before ischemia until 2 hours after reperfusion; we treated the transplanted lungs with FR167653 after the onset of reperfusion. The others were assigned to the control group. After 8-hour preservation with 4 degrees C Euro-Collins solution, orthotopic left, single, lung transplantation was performed. During a 5-minute clamping test at the right pulmonary artery of each recipient, the left (transplanted) pulmonary arterial pressure (L-PAP), left (transplanted) pulmonary vascular resistance (L-PVR), arterial oxygen pressure (PaO(2)), and alveolar-arterial oxygen pressure difference (A-aDO(2)) were measured. We harvested transplanted lung specimens for histologic study, and we counted polymorphonuclear neutrophils (PMNs), which were identified by staining with naphthol AS-D cholroacetate esterase. Pulmonary perfusion and ventilation scintigraphy (Tc-99m-MAA and Xe-133) were performed. We observed the animals for 3 days after transplantation. RESULTS: The PAP, L-PVR, PaO(2), and A-aDO(2) revealed significantly (p < 0.05) better function in the FR group than in the control group. Histologically, lung edema was milder, and PMN infiltration was significantly (p < 0.05) lower in the FR group than in the control group. Xe-133 and Tc-99m-MAA were widely distributed throughout the graft lung in the FR group. Three-day survival rates in FR and control groups were 60% and 20%, respectively. CONCLUSIONS: FR167653 appears to generate a protective effect on I/R injury in lung transplantation in dogs.

The effect of FK409-a nitric oxide donor-on canine lung transplantation.

BACKGROUND: Nitric oxide (NO) is known to have beneficial effects in ischemia-reperfusion (I/R) injury through maintaining endothelial integrity, inhibiting leukocyte adhesion and platelet aggregation, and inducing vasodilation. The effect of FK409 (FK), a spontaneous NO donor, was investigated in a canine lung transplantation model. METHODS: Ten pairs of weight-matched dogs were used. Five pairs were assigned to the FK group, to which FK (5 microg/kg/min) was administered intravenously from 30 minutes prior to ischemia until the induction of ischemia in the donor, and from 15 minutes prior to reperfusion until 45 minutes after reperfusion in the recipient. The others were assigned to the control group. After 8-hour preservation in 4 degrees C Euro-Collins solution, orthotopic single-lung transplantation was performed. During a 5-minute clamping test of the right pulmonary artery, left pulmonary arterial pressure (L-PAP), left pulmonary vascular resistance (L-PVR), arterial oxygen pressure (PaO(2)), and alveolar-arterial oxygen pressure difference (A-aDO(2)) were measured. The lung specimens were harvested for histologic study, and polymorphonuclear neutrophils (PMNs) were counted. Pulmonary perfusion and ventilation scintigraphy (Tc-99m-MAA and Xe-133) were performed. RESULTS: PAP, L-PVR, PaO(2), and A-aDO(2) revealed significantly (p < 0.05) better function in the FK group than in the control group. Histologically, edema was more mild, and PMN infiltration was significantly (p < 0.05) lower in the FK group than in the control group. Xe-133 and Tc-99m-MAA were widely distributed throughout the graft lung in the FK group. The 2-day survival rate was 100% in the FK group, which was significantly (p < 0.05) better than the rate (40%) in the control group. CONCLUSIONS: FK appears to generate a protective effect on I/R injury in lung transplantation.

Effects of endothelin receptor antagonist TAK-044 on small bowel autograft from a controlled non-heart-beating donor model.

BACKGROUND: This study investigated the possibility of pharmacologic protection using an endothelin (ET) receptor antagonist, TAK-044 (TAK), for small bowel autograft in a canine controlled non-heart-beating donor (NHBD) model. METHODS: Sixteen adult mongrel dogs were allocated into 2 groups. TAK (3 mg/kg) (n = 8) was administered intravenously 30 minutes before ischemia and 30 minutes before graft reperfusion. Vehicle was administered in the control (n = 8). The superior mesenteric artery and vein were clamped for 90 minutes to induce warm ischemia as a controlled NHBD model. The entire small bowel then was harvested and stored in 4 degrees C University of Wisconsin solution for 4 hours. The autograft was transplanted orthotopically. Mucosal tissue blood flow, intramucosal pH (pHi), and serum ET-1 levels were measured. Specimens were evaluated histopathologically and ET-1 immunohistochemically. RESULTS: TAK provided significantly higher tissue blood flow and pHi at 3 and 6 hours after graft reperfusion and significantly higher serum ET-1 levels at 1 hour after graft reperfusion as compared with the control group. TAK had histopathologic tissue damage graded as superficial, did not reach to grade 5 on Park's grading as in controls, and provided less intense immunoreactivity for ET-1 immunohistochemical staining. CONCLUSIONS: TAK may have clinical application in small bowel transplantation from controlled NHBD or conditions related to ischemia-reperfusion (I/R) injury.

Effect of a cyclooxygenase-2 inhibitor, FK3311, in a canine lung transplantation model.

BACKGROUND: In the process of ischemia-reperfusion, inflammatory cytokines and arachidonic acid metabolites are released and followed by tissue damage. FK3311 (FK) is a selective cyclooxygenase-2 inhibitor that inhibits conversion of arachidonic acid into thromboxane A2 or prostaglandin I2. We investigated the effects of FK in canine lung transplantation. METHODS: FK3311 was administered in the FK group, and vehicle was injected in the control group. The left lung was orthotopically transplanted after 12-hour preservation in Euro-Collins solution. After reperfusion, the right pulmonary artery and bronchus were ligated, and the animals were observed. Pulmonary gas exchange and hemodynamics were measured, histopathologic damages were investigated, and technetium-99m-labeled albumin scintigraphy was performed. The serum prostanoid levels were also measured. RESULTS: In the FK group, pulmonary gas exchange and hemodynamics were significantly (p < 0.05) better, histologic damage and neutrophil infiltration was reduced, and technetium-99m-albumin accumulation was considerably suppressed. Also, thromboxane B2 was significantly (p < 0.05) lower, but 6-keto-prostaglandin F1alpha was not significantly reduced. CONCLUSIONS: FK3311 generates protective effects on lung transplantation by a marked inhibition of thromboxane A2.

Optimal end point of FR167653 administration and expression of interleukin-8 messenger RNA on extended liver resection with ischemia in dogs.

BACKGROUND: FR167653 is a potent suppressant of interleukin-1 and tumor necrosis factor production. We previously reported that FR167653 inhibited the expression of interleukin-1 messenger RNA (mRNA) after ischemia-reperfusion and provided a protective effect against ischemia-reperfusion injury after extended liver resection. In this study we investigated the optimal end point of FR167653 administration and the inhibition of interleukin-8 (IL-8) mRNA expression caused by the administration of FR167653 during extended liver resection with ischemia in a dog model. STUDY DESIGN: The right portal pedicle was clamped for 60 minutes but the left portal vein was left patent to avoid portal congestion. After reperfusion 75% of the liver was resected. EXPERIMENT I: Adult mongrel dogs were divided into three groups: the control group (n = 9); the FR-2 group (n = 6), which received FR167653 through the portal vein starting 30 minutes before the onset of ischemia until 2 hours after reperfusion; and the FR-6 group (n = 6), which received FR167653 starting 30 minutes before ischemia until 6 hours after reperfusion. Hepatic venous blood was collected to measure liver enzymes. Liver specimens were harvested for histologic study 6 hours after reperfusion and polymorphonuclear neutrophils were counted. EXPERIMENT II: The expression of IL-8 was measured by reverse-transcriptase polymerase chain reaction. RESULTS: Aspartate aminotransferase and alanine aminotransferase levels after reperfusion and hyaluronic acid levels 6 hours after reperfusion were significantly (p < 0.05) lower in the FR-2 and FR-6 groups than in the control group. There were no significant differences between the FR-2 and FR-6 groups after reperfusion. Histologically liver tissue damage was mild in the FR-2 and FR-6 groups, and polymorphonuclear neutrophil infiltration was significantly lower in the FR-2 and FR-6 groups than in the control group. The 3-day survival rate was statistically (p < 0.05) better in the FR-2 and FR-6 groups than in the control group. IL-8 mRNA expression was inhibited in the FR-treated group. CONCLUSIONS: FR167653 should be administered until shortly after reperfusion and need not be administered for many hours after reperfusion. FR167653 inhibits IL-8 mRNA production and inhibits polymorphonuclear neutrophil infiltration.

The effect of cyclooxygenase-2 inhibitor FK3311 on ischemia-reperfusion injury in a canine total hepatic vascular exclusion model.

BACKGROUND: Liver grafts from non-heart-beating donors inevitably suffer from warm ischemic injury. In these grafts, large quantities of inflammatory cytokines and arachidonic acid metabolites are induced, further aggravating injury. Cyclooxygenase (COX) is an intracellular enzyme that converts arachidonic acid into prostaglandin (PG)G2 and PGH2. COX has two isoforms: constitutive COX-1 and inducible COX-2. The aim of this study was to evaluate the effects of COX-2 inhibition by FK3311 (FK) on warm ischemic injury in a canine total hepatic vascular exclusion (THVE) model. STUDY DESIGN: Sixteen mongrel adult dogs were studied. The portal triad of the hilum and the inferior vena cava above and below the liver was clamped for 1 hour. Splanchnic decompression was achieved by active splenofemorojugular bypass. The animals were divided into two groups. FK (1 mg/kg) was administered in the FK group (n = 8), and saline was administered in the control group (n = 8). Hepatic venous blood was collected to measure serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase (LDH), and hyaluronic acid levels. Serum thromboxane (Tx)B2 and 6-keto-PGF1alpha levels were also measured. Hepatic tissue blood flow was estimated simultaneously. Liver specimens were harvested for histologic study and polymorphonuclear neutrophils were counted. RESULTS: Alanine aminotransferase, aspartate aminotransferase, and hyaluronic acid 2 and 6 hours after reperfusion and LDH 30 minutes and 2 and 6 hours after reperfusion were significantly (p < 0.05) lower in the FK group than in the control group. Hepatic tissue blood flow remained significantly (p < 0.05) higher in the FK group than in the control group 1, 2, and 6 hours after reperfusion. Histologic tissue damage was mild and polymorphonuclear neutrophil infiltration was significantly lower (p < 0.05) in the FK group than in the control group 1 and 6 hours after reperfusion. Thirty minutes after reperfusion, TxB2 was significantly reduced (p < 0.05) in the FK group, and 6-keto-PGF1alpha was not significantly lower. CONCLUSIONS: FK protected against hepatic warm ischemia-reperfusion injury by marked inhibition of TxA2.

Novel nitric oxide donor (FK409) ameliorates liver damage during extended liver resection with warm ischemia in dogs.

BACKGROUND: Nitric oxide attenuates ischemia-reperfusion injury by maintaining organ circulation through its actions as a vasoregulator, an inhibitor of platelet aggregation, and an attenuator of leukocyte adhesion. Otherwise, the harmful effects of enhanced nitric oxide production induced by inducible nitric oxide synthase mediate ischemia-reperfusion injury. FK409 has been characterized as a spontaneous nitric oxide donor. The aim of this study was to evaluate the effects of FK409 on extended liver resection with ischemia using a canine model. STUDY DESIGN: Adult mongrel dogs were subjected to 60 minutes of warm ischemia by partial inflow occlusion. After reperfusion the nonischemic lobes were resected and the remnant liver function was evaluated. The dogs were divided into two groups: the control group (n = 7) and the FK409 group (n = 6), which was given FK409 through the portal vein. RESULTS: The hepatic tissue blood flow, serum liver enzymes levels, and serum endothelin-1 level after reperfusion were significantly better in the FK409 group than in the control group. Electron microscopy demonstrated that endothelial cells and Ito cells were well-preserved in the FK409 group. The 3-day survival rate was statistically better in the FK409 group (67%) than in the control group (14%). CONCLUSIONS: FK409 appears to have protective effects during extended liver resection with ischemia.

FR128998 ameliorates liver injury in extended liver resection with ischemia in dogs.

BACKGROUND/AIMS: Platelet-activating factor is one of the most potent phospholipid mediators associated with inflammatory conditions such as ischemia and reperfusion injury. FR128998 (FR) is a novel platelet-activating factor receptor antagonist. In this study, we evaluated the effect of FR during an extended liver resection with ischemia in a canine model. METHODOLOGY: Animals were divided into two groups: the control group (n = 8), and the FR-treated group (n = 7) in which FR was administered via the portal vein. While the right portal pedicle was clamped for 60 min, the left portal branch remained patent to avoid splanchnic congestion. Following reperfusion, 75% of the liver (including the right central, quadrate, left central, left lateral, and papillary lobes) was resected. Hepatic venous blood was collected to measure GPT, GOT, and LDH levels. Hepatic tissue blood flow was measured by a laser Doppler flow meter. The liver specimen was harvested for histological study. RESULTS: GPT, GOT, and LDH levels after reperfusion were significantly (P < 0.05) lower in the FR-treated group than in the control group. Hepatic tissue blood flow was maintained significantly (P < 0.05) higher in the FR-treated group than in the control group. Histologically, accumulation of polymorphonuclear neutrophils significantly (P < 0.05) decreased in the FR-treated group compared with the control group. The 2-day survival rate was statistically (P < 0.05) better in the FR-treated group than in the control group. CONCLUSIONS: FR128998 provides a protective effect for liver parenchyma and sinusoidal endothelial cells during extended liver resection with ischemia.

Omentoplasty for cervical esophagogastrostomy following radical esophagectomy with three-field dissection.

BACKGROUND/AIMS: Anastomotic leakage is the main cause of postoperative mortality and incidence of which, following three-field lymph node dissection, is around 30%. The study was undertaken to investigate the role of omentoplasty to reinforce cervical esophagogastrostomy with the expectation of lowering the rate of anastomotic leakage after radical esophagectomy with three-field lymph node dissection. METHODOLOGY: Between July 1995 and Dec 1997, a total of 32 patients underwent total thoracic esophagectomy with three-field lymph node dissection and cervical esophagogastrostomy. Eleven patients were stage IIA, 3 stage IIB, 5 stage III and 13 stage IV. After radical esophagectomy and lymph node dissection, several omental branches of the gastroepiploic vessels remained to supply a gastric tube. An end-to-side cervical esophagogastrostomy was performed on the posterior wall of the gastric tube using a circular stapler. The omentoplasty--wrapping the esophagogastrostomy--was performed. A retrosternal route for reconstruction was used in 23 patients and a posterior mediastinal route in 9 patients. RESULTS: Esophageal anastomotic leakage occurred in only 1 patient, 3.1% overall. There was neither pyothorax nor mediastinitis. There was no lethal anastomotic leakage. Later, 2 patients (6.2%) developed an anastomotic stricture that required balloon dilatation. CONCLUSIONS: Omentoplasty to reinforce cervical esophagogastrostomy decreases anastomotic failure following radical esophagectomy with three-field lymph node dissection.

Perioperative real-time monitoring of indocyanine green clearance by pulse spectrophotometry predicts remnant liver functional reserve in resection of hepatocellular carcinoma.

BACKGROUND: There is no standard method for predicting remnant liver functional reserve after hepatectomy or for monitoring it in real time. METHODS: Indocyanine green (ICG) clearance (K) was measured non-invasively and instantaneously using pulse spectrophotometry before surgery, during inflow occlusion and after hepatectomy in 75 patients who underwent anatomical liver resection for hepatocellular carcinoma (HCC). RESULTS: Eight patients (11 per cent) suffered liver failure and one (1 per cent) died in hospital. An estimated remnant K value of 0.090 per min was the cut-off value for liver failure. In a logistic regression model, the estimated remnant K (0.090 per min; P = 0.022) and age (65 years; P = 0.025) were significant predictors of postoperative liver failure. There was a correlation between the estimated and measured post-hepatectomy K, and between the inflow occlusion K and measured post-hepatectomy K (P < 0.001). The cut-off value of less than 0.090 per min for the estimated remnant K resulted in 88 per cent sensitivity and 82 per cent specificity for predicting liver failure. CONCLUSION: Perioperative real-time monitoring of ICG-K is useful for evaluating the remnant liver functional reserve before, during and after liver resection for HCC. The estimated remnant K is a significant predictor of liver failure.