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.

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.

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.

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.

A spontaneous nitric oxide donor ameliorates small bowel ischemia-reperfusion injury in dogs.

Nitric oxide (NO) appears to play an important role in tissue injury during reperfusion. FK409 is the first spontaneous NO donor that increases plasma guanosine 3',5'-cyclic monophosphate. We investigated the effects of the NO donor FK409 (FK) on ischemia-reperfusion injury in a canine warm ischemia model. Fourteen adult mongrel dogs were divided into two groups: the control group and the FK group, which received FK. The superior mesenteric artery and vein were both clamped for 2 h and then reperfused for 12 h. Arterial and intramucosal pH were well maintained in the FK group in comparison with the control group. Histologically, ischemia-reperfusion injury was significantly more severe in the control group than in the FK group. The serum NO levels were significantly higher in the FK group than in the control group during FK administration. FK409 has protective effects on ischemia-reperfusion injury of the small intestine due to NO release.

The effect of a selective cyclooxygenase-2 inhibitor in extended liver resection with ischemia in dogs.

BACKGROUND: Pringle's procedure is commonly used during liver surgery, and it sometimes causes liver failure. Metabolites of arachidonic acid, which are converted by cyclooxygenase (Cox), are involved in ischemia-reperfusion injury. This study evaluated the effects of FK 3311, which selectively inhibits Cox-2, on ischemia-reperfusion injury during liver resection in dogs. MATERIALS AND METHODS: The animals were divided into four groups and subjected to 60 min of warm ischemia by partial inflow occlusion. The FK-treated groups (FK0.2: 0.2 mg/kg, FK1: 1 mg/kg, FK3: 3mg/kg) received FK3311, and the control group received vehicle. Following reperfusion, the nonischemic lobes were resected and remnant liver function was evaluated. RESULTS: Tissue blood flow and serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase were significantly better in the FK1 and FK3 groups, especially FK1, than in the control group. Thromboxane B(2) was significantly lower in the FK1 and FK3 groups than in the control group. The level of 6-keto-prostaglandin F(1alpha) was significantly lower in the FK3 group and relatively unchanged in the FK1 group. Histological damage was milder in the FK1 group. There were significantly fewer polymorphonuclear neutrophils in the FK1 group than in the control group. CONCLUSIONS: FK3311 ameliorates the ischemia-reperfusion injury caused by Pringle's procedure during extensive liver resection. This agent may be clinically useful in extended liver surgery involving vascular isolation.

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.

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.

Effects of FK3311 on pulmonary ischemia-reperfusion injury in a canine model.

BACKGROUND: This study investigated the effects of a selective COX-2 inhibitor, FK3311, on warm ischemia-reperfusion (I/R) injury in the canine lung. MATERIALS AND METHODS: Sixteen adult mongrel dogs were used in this study. In the FK group (n = 8), FK (1 mg/kg) was administered intravenously 15 min before ischemia and 15 min before reperfusion. In the control group (n = 8), a vehicle was injected in the same manner. Warm ischemia was induced for 3 h by clamping the left pulmonary artery, veins, and bronchus. Five-minute clamping tests of the right pulmonary artery were performed before ischemia and 30 min after reperfusion. During the test, left pulmonary vascular resistance (L-PVR), cardiac output (CO), and arterial oxygen pressure (PaO(2)) were measured. The lung specimens were simultaneously harvested for wet-to-dry weight ratio (WDR) measurements, histopathological studies, and polymorphonuclear neutrophil (PMN) counts. Serum thromboxane (Tx) B(2) and 6-keto-prostaglandin (PG) F(1alpha) (stable metabolites of TxA(2) and PGI(2), respectively) were also measured 30 min after reperfusion. RESULTS: L-PVR, CO, PaO(2), and WDR were significantly (P < 0.05) better in the FK group than in the control group. Histological tissue edema was mild, and PMN infiltration was significantly (P < 0.05) reduced in the FK group compared to the control group. The serum TxB(2) levels were significantly (P < 0.05) lower in the FK group than in the control group, while 6-keto-PGF(1alpha) levels were not significantly (P < 0.05) reduced. Two-day survival rate was significantly (P < 0.05) better in the FK group than in the control group. CONCLUSIONS: FK has protective effects on pulmonary I/R injury stemming from marked inhibition of TxA(2).

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.