Case report of pharmacokinetic analysis of continuous intravenous infusion of fentanyl in a patient with severe burn: burn shock stage complicates pain management.

BACKGROUND: Fentanyl is widely used as an analgesic and sedative for patients with severe burn injuries in intensive care units. However, pharmacokinetic (PK) data for fentanyl, particularly for continuous intravenous infusion during the acute phase of burn injuries, are limited. Here, we report the clinical course and changes in blood fentanyl concentrations during the acute phase in a patient with severe burns treated with continuous intravenous infusion of fentanyl. CASE PRESENTATION: A woman in her 40s, with burns caused by a gas cylinder explosion, was transported to our hospital. The patient had burn wounds on face, neck, shoulders, and all four extremities, with a total burn area of 39.0%. For pain relief, the patient received a continuous infusion of 0.01 mg/mL fentanyl (20-30 µg/h) with a target blood concentration of 1.0-1.5 ng/mL, but continued to suffer from pain due to burning during the acute phase. We measured the blood fentanyl concentrations and found that all concentrations obtained during the acute phase were subtherapeutic. Notably, during the burn shock stage, blood concentrations of fentanyl were 0.50 ng/mL on day 1 and 0.66 ng/mL on day 2, indicating that the blood concentration did not rise sufficiently for the dosage. From days 0 to 2, the patient was administered a massive fluid load for burn shock. After the burn shock stage resolved, fentanyl concentrations gradually approached the target range, and the pain rating scale improved, even though the fentanyl administration rate remained unchanged (30 µg/h). CONCLUSIONS: Major changes in the fluid volumes of body compartments that occur with large burns might increase the volume of fentanyl distribution, thereby lowering its concentration when a standard dose is administered. Our findings indicate that the PK of fentanyl in patients with severe burns can be substantially affected, especially during the shock phase, implying the importance of titrating analgesics for clinical efficacy in the acute phase.

Daily dose of metformin caused acute kidney injury with lactic acidosis: a case report.

BACKGROUND: Metformin-induced lactic acidosis with acute kidney injury is rare but well known. Here we report a case of a Japanese patient taking metformin who experienced severe acute renal failure accompanied with significantly elevated metformin plasma concentrations and signs of lactic acidosis. CASE PRESENTATION: A 60-year-old Japanese man with type II diabetes, who was taking metformin (500 mg three times a day) along with several other medications, visited the emergency department with dizziness, malaise, and oliguria. The initial laboratory test results showed elevated levels of serum creatinine and blood urea nitrogen, although his renal function was normal approximately 2 weeks earlier. His lactate level was raised (4.27 mmol/L), and he was diagnosed with lactic acidosis. Considering the low creatinine clearance and elevated urinary albumin/serum creatinine ratio, urinary N-acetyl-ß-D-glucosaminidase level, and ß2-microglobulin level, the patient was further diagnosed with AKI (in other words, acute tubular necrosis). A renal biopsy performed on day 3 after admission revealed renal tubular epithelium necrosis, supporting this diagnosis. The patient underwent intermittent hemodialysis until he was discharged on day 13. The metformin concentrations on days 3, 5, and 7 were 8.95, 2.58, and 0.16 µg/mL, respectively, which is significantly higher than the maximal steady-state concentration of metformin at the recommended dosage (approximately 1 µg/mL). The calculated pharmacokinetic parameters of metformin suggested poor renal excretion and a low distribution volume at higher metformin levels. Other possible acute kidney injury-causing factors included dehydration, alcohol consumption, and the use of an angiotensin receptor blocker or SGLT2 inhibitor. CONCLUSIONS: This is the first reported case of acute kidney injury possibly caused by high levels of metformin with lactic acidosis in a patient treated with the recommended metformin dose. Thus, the development of metformin-induced acute kidney injury should be considered for patients with several acute kidney injury risk factors who are taking metformin.

Establishment to measure oxycodone in plasma with liquid chromatography-tandem mass spectrometry.

Oxycodone (OXY) is classified as a "strong opioid" in the World Health Organization system of cancer pain treatment. However, OXY also causes severe adverse reactions, such as respiratory depression. Thus, in order to adjust the dosage of OXY for well-managed pain relief with less toxicity, we tried establishing and validating a system for measuring plasma concentrations of OXY using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Human pooled plasma samples containing OXY diluted with 0.1% formic acid solution and internal standard (papaverine) were used for solid-phase extraction. The eluents were injected into LC-MS/MS with Unison UK-Silica column (100 × 2 mm, 3 µm, Imtakt). Mobile phase was a mixture of 1 mM ammonium formate solution and acetonitrile containing 0.1% formic acid (50:50). OXY in plasma could be measurable with good linearity in a concentration range of 2-100 ng/ml by using 100 µl of plasma within 4 min. Relative standard deviations of all validation results were within ±15%. These results suggest that our established method using LC-MS/MS to measure OXY in plasma would be useful to adjust the dosage of OXY in order to obtain its efficacy and to avoid its adverse reactions.

Simplified daptomycin dosing regimen for adult patients with methicillin-resistant Staphylococcus aureus infections based on population pharmacokinetic analysis.

Daptomycin is used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. Current guidelines recommend higher daptomycin doses (8-10 mg/kg) for severe infections; however, pharmacokinetic (PK) and pharmacodynamic-based dosing strategies are still limited. Therefore, we designed a new optimal daptomycin dosing regimen for patients with MRSA infections using a population PK modeling approach. A total of 110 plasma concentrations from 47 adult patients who received daptomycin in general wards were enrolled for population PK modeling. The target area under the concentration-time curve/minimum inhibitory concentration (MIC) ratio, target peak/MIC ratio, and threshold of the trough concentration for safety were set to >666, >60, and 24.3 mg/L, respectively. Renal function was indicated as a significant covariate for daptomycin clearance. The simulated probability of target attainment was more than 90% at MIC values of 0.25 and 0.5 mg/L in all patients at the standard dose (6 mg/kg). In contrast, comprehensive simulation assessments recommended 10 mg/kg every 24 h in patients with creatinine clearance >60 mL/min for MIC values of 1.0 mg/L. We propose a new simplified daptomycin dosing regimen stratified by renal function and MIC values based on PK model-based simulation analyses. The proposed regimen is expected to maximize clinical efficacy and minimize adverse events.

Combined Use of Calcium-channel Blockers With Ombitasvir/Paritaprevir/Ritonavir Exacerbates Peripheral Edema in Elderly Japanese Patients.

BACKGROUND/AIM: The antiviral agent ritonavir is a substrate for cytochrome P450 3A4 (CYP3A4); therefore, concomitant use of CYP3A4-metabolising drugs might cause adverse reactions to this drug. We investigated the plasma level of calcium channel blockers (CCBs) as CYP3A4 substrates and peripheral edema as a potential adverse drug reaction possibly caused by the anti-hepatitis C virus (HCV) regimen of ombitasvir/paritaprevir/ritonavir (OPR) and CCBs. PATIENTS AND METHODS: We enrolled Japanese patients prescribed OPR for HCV infection. Peripheral edema was graded according to the Common Terminology Criteria for Adverse Events ver. 4. Plasma samples were collected on days 0, 7, 14, 28, and 42 after antiviral treatment, at the trough level. RESULTS: Out of 52 patients, 64% experienced grade 1 or grade 2 peripheral edema, but not grade 3. Concomitant use of CCBs significantly increased the emergence of grade 2 edema (62%), compared with patients treated solely with OPR (48%). The use of OPR significantly increased the plasma concentration of amlodipine. CONCLUSION: Peripheral edema in patients treated with OPR and CCBs, although tolerable, should be closely monitored.

Giant left-sided inguinoscrotal hernia containing the cecum and appendix (giant left-sided Amyand's hernia).

KEY CLINICAL MESSAGE: The present case involved a 62-year-old male with a large left-sided inguinoscrotal hernia. A CT scan and a clinical examination led to a diagnosis of a giant left-sided Amyand's hernia. The hernia was repaired using the ULTRAPRO Hernia System (UHS), and the patient exhibited an uneventful postoperative course.

Delirium and coma evaluated in mechanically ventilated patients in the intensive care unit in Japan: a multi-institutional prospective observational study.

PURPOSE: The object of this study is to evaluate the prevalence and effects of delirium on 28-day mortality in critically ill patients on mechanical ventilation in Japan. MATERIALS AND METHODS: Prospective cohort study was conducted in medical and surgical intensive care units (ICUs) of 24 medical centers. Patients were followed up daily for delirium during ICU stay after enrollment. Coma was defined with the Richmond Agitation Sedation Scale score of -4 or -5. Delirium was diagnosed using the Confusion Assessment Method for the ICU. The Cox proportional hazards regression model was used to assess the effects of delirium and coma on 28-day mortality, time to extubation, and time to ICU discharge; delirium and coma were included as time-varying covariates after controlling for age, Acute Physiology and Chronic Health Evaluation II score, ventilator-associated pneumonia, and the reason for intubation with infection. RESULTS: Of 180 patients, 115 patients (64%) developed delirium. Moreover, 15 patients (8%) died within 28 days after ICU admission, including 7 patients who experienced coma and 8 patients who experienced both coma and delirium. There were no deaths among patients who did not experience coma. Delirium was associated with a shorter time to extubation (hazard ratio [HR], 2.52; 95% confidence interval [CI], 1.65-3.85; P<.001) and a shorter ICU length of stay in comatose patients (HR, 1.59; 95% CI, 1.04-2.44; P=.034), whereas delirium appeared with prolonged time to ICU discharge among patients without coma, although statistical significance was not detected due to limited analytical power (HR, 0.62; 95% CI, 0.34-1.12; P=.114). Delirium during ICU stay was not associated with higher mortality. CONCLUSIONS: Further study is needed to investigate the discrepancy between these and previous data.

Heparin-binding EGF-like growth factor is required for synaptic plasticity and memory formation.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of epidermal growth factor (EGF) family, is a potent mitogenic peptide for various types of cells. HB-EGF is widely expressed in central nervous system, including hippocampus and cerebral cortex, and is considered to play pivotal roles in the developing and adult nervous system. In this study, we assessed the role of HB-EGF in learning and memory by testing HB-EGF conditional knock-out mice (KO) in two different learning tasks, and evaluated the long-term potentiation (LTP) in hippocampus slices from these mice. The HB-EGF KO mice were impaired in spatial memory in the Morris water maze and in fear learning in a passive avoidance test. HB-EGF KO mice also showed an impaired LTP, and reduction in activity of Ca²âº/calmodulin-dependent protein kinase II (CaMKII) and phosphorylated GluR1. We also found that the levels of neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or glial cell line-derived neurotrophic factor (GDNF), were altered in several brain regions in the HB-EGF KO mice. These results confirm the importance of the HB-EGF in synaptic plasticity and memory formation.

Post-treatment of a BiP inducer prevents cell death after middle cerebral artery occlusion in mice.

We previously reported the effect of a selective inducer of BiP (a BiP inducer X; BIX) after permanent middle cerebral artery occlusion (MCAO) in mice. However, in acute stroke, almost all drugs have been used clinically after the onset of events. We evaluated the effect of post-treatment of BIX after permanent MCAO in mice, and examined its neuroprotective properties in in vivo mechanism. BIX (intracerebroventricular injection at 20µg) administered either at 5min or 3h after occlusion reduced both infarct volume and brain swelling, but at 6h after occlusion there was no reduction. BIX protected against the decrease in a dose-dependent manner. Furthermore, BIX reduced the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells induced by the ischemia in ischemic penumbra. These findings indicate that post-treatment with BIX after ischemia has neuroprotective effects against acute ischemic neuronal damage in mice even when given up to 3h after MCAO. BIX may therefore be a potential drug for stroke.

Generation and characterization of conditional heparin-binding EGF-like growth factor knockout mice.

Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder.

Wall-invasion pattern correlates with survival of patients with gallbladder adenocarcinoma.

Gallbladder carcinomas (GBC) frequently show vascular invasion and metastasis when the carcinoma cells invade the perimuscular connective tissue (pT2 according to the TNM classification) through the muscular layer. In this study, two intramural invasion patterns were defined as (i) infiltrative growth (IG) type, infiltrative growth in the muscle layer without destruction and (ii) destructive growth (DG) type, massive growth with destruction of the muscle layer. Sixty-six surgically resected gallbladder adenocarcinomas invading the perimuscular connective tissue (pT2) and beyond the gallbladder wall, including the visceral serosa, (pT3/pT4) were examined. The overall survival rate of the patients with the DG type was significantly lower than that of the patients with the IG type (p = 0.018). Lymphatic invasion (37.5% of IG and 62.5% of DG, p = 0.014), venous invasion (41.9%, 58.1%, p = 0.089), nodal status (30.4%, 69.6%, p = 0.015) and scirrhous growth (INFgamma) (31.0%, 69.0%, p = 0.0035) were more frequently detected in DG cases than in IG cases. In addition, median survival and survival rates were statistically analyzed. The patients with a high grade of lymphatic and venous invasion had lower survival rates (p < 0.0001 and p < 0.05, respectively). The patients with the DG type and scirrhous growth (INFgamma) also had lower survival rates (p < 0.05 and p < 0.0001, respectively) than did patients with the IG type and expansive/intermediate growth (INFalpha,beta). On multivariate analysis, neural invasion (odds ratio, 0.157; 95% confidence interval, 0.039-0.629) was an independent predictor of mortality. In conclusion, the DG invasion pattern is an indicator of high malignant potential and indirectly worsens the prognosis of patients with gallbladder adenocarcinoma.

Stromal laminin-5gamma2 chain expression is associated with the wall-invasion pattern of gallbladder adenocarcinoma.

Our previous study demonstrated that the pT2 and pT3-4 gallbladder carcinomas can be classified into two groups, i.e. infiltrative growth type (IG type) and destructive growth type (DG type) and that the DG type is associated with poor differentiation, aggressive infiltration, and decreased postoperative survival. The present study focused on the clinicopathologic significance of laminin-5gamma2 chain expression as an indicator of local aggressiveness and Ki-67 labeling index (Ki-67 LI) as an indicator of the cell proliferation activity of gallbladder carcinoma. Ki-67 LI was higher in the DG type (26.3%) than in the IG type (21.4%), and the rate of high-grade cell proliferation cases (Ki-67 LI > or = 30%) was high in the DG type (P = 0.012). Gallbladder carcinoma cases with high Ki-67 LI were significantly associated with poorly differentiation (P = 0.089) and distant lymph node metastasis (P = 0.079). Laminin-5gamma2 expression patterns of gallbladder carcinoma were divided into two distinct types, extracellular staining and cytoplasmic staining. The extracellular staining was subclassified into two groups, basement membrane staining and stromal staining. In the basement membrane staining, laminin-5gamma2 was present in the basement membranes surrounding neoplastic glandular structures. The basement membrane staining of laminin-5gamma2 was more frequent in the IG type (40%) than in the DG type (12.9%) (P = 0.025). The stromal staining was more frequent in the DG type. Furthermore, the stroma-positive group was more closely associated with decreased overall survival than the stroma-negative group (P = 0.028). The cytoplasmic staining was not significantly correlated with invasion pattern in gallbladder carcinoma (P = 0.545). Univariate analysis demonstrated that laminin-5gamma2 stromal staining is a predictor of lymphatic invasion, venous invasion, neural invasion, the mode of subserosal infiltration, and lymph nodal status. Multivariate analysis revealed the mode of subserosal infiltration is the strongest predictor of stromal invasion (P = 0.068). In conclusion, high-grade cell proliferation and stromal laminin-5gamma2 staining were significantly correlated with a wall-invasion pattern of aggressive gallbladder carcinoma indicating destructive growth (DG type).

Comparison between intravenous and oral postoperative adjuvant immunochemotherapy in patients with stage II colorectal cancer.

The present study was designed to retrospectively examine the efficacy of postoperative adjuvant chemotherapy in 107 patients with stage II primary colorectal cancer who underwent curative resection. The chemotherapy regimen was intravenous 5FU/LV in 30 patients (FL-IV group) and oral UFT/PSK in 77 patients (oral group). There were no significant differences between the FL-IV and the oral group with respect to the 3-year relapse-free survival rate, 5-year relapse-free survival rate, and 5-year overall survival rate, which were 82.4 vs. 83.0% (p=0.8546), 78.8 vs. 80.0% (p=0.756), and 81.6 vs. 92.8% (p=0.1609), respectively. Grade 3 adverse events that occurred in the FL-IV group were leukopenia in one patient (3.3%), nausea/vomiting in two (6.6%), anorexia in two (6.6%), diarrhea in one (3.3%), and fatigue in one (3.3%). No grade 3 or 4 adverse events were observed in the oral group. These results suggest that the oral regimen achieved equivalent efficacy to the FL-IV regimen in patients with stage II colorectal cancer, while improving their postoperative quality of life.

Laparoscopic-assisted resection of gastrointestinal stromal tumor in small intestine.

Gastrointestinal stromal tumors (GISTs) in the small intestine are relatively rare. We present a case of GIST arising from the small intestine, which could be resected under laparoscopic assistance. A 60-year-old male visited another hospital due to massive anal bleeding. Blood examination showed severe anemia. Although anemia improved after conservative treatment, the bleeding site was not identified and he was referred to our hospital for close examination. Abdominal CT showed a well-defined mass with homogeneous internal density in the left upper abdomen. On abdominal angiography, selective enhancement of the second jejunal artery revealed a tumor stain. Due to suspected GIST in the small intestine, laparoscopic-assisted resection of the jejunum was performed. Histopathological examination demonstrated low-grade malignant GIST. The laparoscopic procedure is considered to be useful as minimally invasive surgery for diagnosis and treatment of selected cases with GISTs in the small intestine.

[A case of ruptured common hepatic arterial pseudoaneurysm and penetration into duodenum related with hepatic artery infusion chemotherapy].

In a 64-year-old male patient, liver metastasis recurred after surgery for transverse colon cancer. He received 6 courses of continuous intra-arterial infusion therapy with a catheter for hepatic intra-arterial infusion, which was retained by the GDA-coil technique. In April 2005, the patient suddenly developed hematemesis, and he was hospitalized for emergency treatment. Upper gastrointestinal endoscopy on the day after hospitalization revealed no distinct source of bleeding. Since he had massive hematemesis again on hospital day 4, endoscopic examination was repeated, which revealed that the metallic coil for embolization retained in the gastroduodenal artery protruded from the superior wall of the duodenal bulb with bleeding. Emergency angiography revealed that the bleeding arose from rupture of a common hepatic artery aneurysm. Hemostasis was induced by embolization of the region ranging from the right and left hepatic arteries to the entire common hepatic artery aneurysm with the metallic coil. The present case revealed serious complications of the hepatic intra-arterial chemotherapy and intra-arterial retention of the catheter.

Two-port hand-assisted laparoscopic surgery for the 2-stage treatment of a complete bowel obstruction by left colon cancer: a case report.

A 69-year-old woman presented to her local clinic with vomiting and abdominal distension. Since a bowel obstruction by left colon cancer was suspected due to a marked dilation of the transverse colon, she was referred to our hospital. On admission, an enema disclosed a complete obstruction at the splenic flexure of the colon. An emergency operation was performed, and a temporary loop colostomy was fashioned on the left side of the transverse colon within the range of resection for 2-stage radical surgery. On hospital day 16, a left hemicolectomy D2 was performed by 2-port hand-assisted laparoscopic surgery (2P-HALS) using the stoma as the hand access site, and the tumor was resected along with the removal of the stoma. After surgery, a slight wound infection occurred at the hand access site, but this healed with conservative management. On day 36, she was discharged from hospital. The histological diagnosis was Type 2 circumferential well-differentiated adenocarcinoma with local peritoneal dissemination. Our experience suggests that 2-stage surgery combined with 2P-HALS is applicable even to a large obstructing left colon cancer. This method is less invasive, safe and achieves excellent results, including a good cosmetic outcome.

FDG-PET and diffusion-weighted MR imaging appearance in retroperitoneal Castleman's disease: a case report.

Castleman's disease is a rare lymphoid neoplasm that is characterized by the proliferation of lymphoid tissue. A case of young woman having the plasma cell type of retroperitoneal Castleman's disease is reported, and radiological findings of the condition are discussed with a review of the radiological literature.

[A case of advanced gastric cancer effectively treated with combination of weekly paclitaxel and hepatic arterial infusion of 5-FU/LV].

The patient was a 66-year-old woman who underwent upper gastrointestinal endoscopy as part of a detailed examination because of loss of appetite and anemia, and type 2 gastric cancer was detected on the greater curvature in the pyloric area. Abdominal ultrasonography and CT revealed lymph node enlargement around the pyloric area and multiple liver metastases in both lobes of the liver. Curative resection was judged to be impossible, and oral S-1 therapy was started. However, no efficacy was observed even after the completion of three courses, and especially because of the rapid increase in the size of the liver metastases, treatment was switched to combination therapy consisting of a continuous hepatic artery infusion of 5-FU+Leucovorin (day 1-7) and weekly PTX for 3 consecutive weeks (day 8, 15, 22) followed by a 1-week rest. The tumor marker levels decreased rapidly, and at the end of 4 courses marked regression of the primary tumor and lymph node metastases as well as of the metastatic foci in the liver was observed. Adverse events have been mild, and at present, 6 months after the switch in treatment, good QOL has been maintained, and treatment is continuing. This method appears to be an effective treatment strategy for unresectable advanced gastric cancer complicated by liver metastasis.

Inflammatory pseudotumor of the liver: case report and review of literature.

Inflammatory pseudotumor (IPT) is a benign tumorous lesion of unknown cause, which is composed of fibrous tissue with infiltration of plasma cells and lymphocytes. A 57-year-old male with gastritis was indicated to have hepatic dysfunction during observation of the course of gastritis at a nearby hospital. He was referred to our facility to undergo detailed examinations. When he visited our hospital for the initial examination, he had no subjective symptoms. His past medical history was unremarkable. There were no distinct abnormalities on the medical examination. Blood tests revealed a white blood cell count of 10400 / L, CRP of 0.29 mg/dl, AST of 31 IU/L, ALT of 46 IU/L, ALP of 583 IU/L and -GTP of 408 IU/L, showing a mild inflammatory reaction and elevated hepatobiliary enzymes. Abdominal ultrasonographic examination revealed a tumor mass approximately 4 cm in diameter in a lateral hepatic segment. The margin and center of the mass were hypoechoic and iso- to hyperechoic, respectively, and the inside of the mass was non-homogeneous. Needle biopsy revealed only inflammatory findings with no indications of malignancy. Since computed tomography (CT) of the abdomen, done 4 months after detection of the tumor mass, revealed the mass to have increased to approximately 6 cm in diameter, excision biopsy was considered. The CT taken 2 months later revealed the mass to have regressed to approximately 2 cm in diameter, but excision of the lateral hepatic segment was undertaken at the patient's request. As a result, the diagnosis of IPT of the liver was confirmed. Imaging findings of hepatic IPT are variable and specific findings are lacking. Since the rate of correct diagnosis with needle biopsy is also low, IPT of the liver is often very difficult to differentiate from malignant tumors. On the other hand, since it may show spontaneous regression, indications for surgery must be assessed very carefully.

Thrombospondin-2 inhibits tumor cell invasion through the modulation of MMP-9 and uPA in pancreatic cancer cells.

The extracellular matrix protein thrombospondin (TSP) plays an important role in a variety of biological processes, including cell-cell and cell-matrix interactions. The biological role of TSP-2 in invasion and metastasis is poorly understood, while it is known that TSP-1 regulates a proteolytic cascade that allows tumor cells to invade and metastasize. In this study, we examined the role of TSP-2 in tumor cell invasion and its association with proteolytic proteins, matrix metalloproteinase (MMP) and the plasminogen/plasmin system, including urokinase-type plasminogen activator (uPA), in the human pancreatic cancer cell line PANC-1. PANC-1 cells expressed a low level of TSP-2, but significant levels of TSP-1. We isolated three clones of PANC-1 transformants stably overexpressing human TSP-2 (PANC-T). PANC-T highly expressed the TSP-2 gene and protein, while TSP-1 expression was not altered. In vitro invasion assays demonstrated that the invasiveness of PANC-T clones was significantly suppressed (p<0.05; Welch test). Zymography revealed that restoration of TSP-2 synthesis in the PANC-T clones significantly inhibited MMP-9 activity (p<0.05; Welch test). uPA activity in the PANC-T clones was significantly suppressed (p<0.05; Welch test). We concluded that restoration of TSP-2 can inhibit cell invasion through the down-regulation of MMP-9 and uPA activity in pancreatic cancer cell lines. Thus, TSP-2 may be a potent inhibitor of metastasis in pancreatic cancer.