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.

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.

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.

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.

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.

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 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.

[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.

Inhibition of nuclear factor-kappaB augments antitumor activity of adenovirus-mediated melanoma differentiation-associated gene-7 against lung cancer cells via mitogen-activated protein kinase kinase kinase 1 activation.

Nuclear factor-kappaB (NF-kappaB) activation promotes cell survival and growth. Reports show that chemotherapeutic agents and cytokines that are used for cancer therapy activate NF-kappaB expression in tumor cells and its suppression enhanced the antitumor activity. We hypothesized that adenovirus-mediated overexpression of melanoma differentiation-associated gene-7/interleukin-24 (Ad-mda7/IL-24) induces NF-kappaB expression and that inhibition of this expression results in enhanced tumor cell killing. Treatment of human lung tumor (H1299 and A549) cells with Ad-mda7 resulted in NF-kappaB activation in a dose- and time-dependent manner before activation of cell death pathways. To establish that inhibition of Ad-mda7-mediated NF-kappaB activation results in enhanced tumor cell killing, H1299 cells that overexpress the dominant-negative I kappa B alpha (dnI kappa B alpha) were treated with Ad-mda7 in vitro. An enhanced growth arrest and apoptosis was observed in Ad-mda7-treated H1299-dnI kappa B alpha compared with H1299-Neo cells. This Ad-mda7-mediated enhanced killing of H1299-dnI kappa B alpha cells involved cleavage of mitogen-activated protein kinase kinase kinase 1 (MEKK1) and caspase-3 in a feedback loop mechanism. The inhibition of MEKK1 or caspase-3 cleavage in H1299-dnI kappa B alpha cells resulted in reduced Ad-mda7-mediated cell killing. In vivo, the treatment of H1299-dnI kappa B alpha s.c. tumors with Ad-mda7 resulted in increased drug sensitivity and delayed the tumor growth rate compared with Ad-mda7-treated H1299-Neo tumors. Molecular analysis of Ad-mda7-treated H1299-dnI kappa B alpha tumors showed increased MEKK1 cleavage and activation of caspase-3 compared with Ad-mda7-treated H1299-Neo tumors. Our findings thus showed that the NF-kappaB activation induced by Ad-mda7 treatment of lung cancer cells is an intrinsic survival mechanism and that the inhibition of this NF-kappaB expression results in enhanced tumor cell killing.

Experimental model of two-colonoscope surgery for superficially spreading colonic tumors larger than 3 cm in the right colon.

In the present study, we experimentally examined the feasibility of two-colonoscope surgery using two types of forceps to achieve safe, reliable, and complete endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD) of large superficial tumors in the right colon. It was confirmed at all experimental sessions that the two pairs of forceps intersected with each other over a wide angle of at least 90 degrees in the cecum, and that the tips of the forceps could be moved by at least 180 degrees in the longitudinal and horizontal directions. In another experiment, a piece of tissue measuring 3x3 cm or larger could be safely resected from a chicken thigh as the pseudo-tumor. Based on these results, two-colonoscope surgery is considered clinically promising as a next-generation EMR/ESD technique for safe, reliable, and complete resection of superficial tumors of the right colon measuring 3 cm or more in diameter.

Pelvic recurrence after Miles' operation for anastomotic recurrence in a patient with stage I rectal cancer invading the proper muscle layer: Case report.

We performed D2 low anterior resection in a patient with stage I rectal cancer [pathological diagnosis: proper muscle (pm) invasion, n0, lymphatic invasion (ly), (-); venous invasion (v), (-); anal margin, (-)]. The tumor recurred at the anastomotic site approximately one year later and was treated with Miles' operation [pm, n0, ly (+); v (-); deep border of the primary tumor (-)]. The tumor marker CEA increased to 50.4 ng/ml at four months after surgery and pelvic local recurrence was detected. Since then, the patient has been receiving chemoradiotherapy on an out-patient basis. Cytokeratin immunostaining of all the lymph nodes collected during the two operations showed clusters of occult neoplastic cells (ONCs) in the perinodal fat around the nodes harvested at the first operation. These findings suggest that the risk of local recurrence of rectal cancer is increased even in stage I disease if ONCs are found in the perinodal fat. Further studies are required to examine the relationship between local recurrence and extranodal ONCs in patients with primary rectal cancer.

End-to-end anastomosis after medial pancreatectomy for tumor.

Reconstruction by pancreaticoenterostomy has generally been employed after medial pancreatectomy for tumor. As a less invasive procedure, here we report three patients who successfully underwent pancreatic end-to-end anastomosis after medial pancreatectomy. The subjects consisted of 2 patients with serous cystadenomas and 1 patient with an intraductal papillary mucinous tumor. These tumors were detected in the pancreatic neck or body, and the maximal tumor diameters ranged from 10 to 33mm. The pancreatic duct diameters were 2 mm in 2 patients and 4 mm in 1 patient. The procedure was carried out by ductal anastomosis and parenchymal anastomosis with interrupted sutures. A pancreatic tube was inserted for decompression at the anastomotic site in all patients. The mean operative time was 3 hours and 31 minutes, and the intraoperative blood loss was 428 mL. Although pancreatic fistula was observed in 2 patients with the normal pancreas, conservative therapy relieved this complication. Neither tumor relapse nor stenosis of the pancreatic duct at the anastomotic site was detected in any patient, with a follow-up of 4 to 27 months. Our experience confirmed that in selected cases, this reconstructive procedure was feasible and safe for physiological reconstruction without involvement of the digestive tract.

MDA-7/IL-24-based cancer gene therapy: translation from the laboratory to the clinic.

Despite recent advances in treatment strategies, the overall 5-year survival rate for patients with common epithelial cancers is poor largely because of the difficulty in treating metastatic cancers. Therefore, therapeutic agents are urgently needed that can effectively inhibit both primary epithelial tumors and their metastases. One such agent that has shown promise in preclinical studies is the tumor suppressor/cytokine, melanoma differentiation associated gene-7 also known as interleukin-24 (mda-7/IL-24). Preclinical studies from our and other laboratories have shown that overexpression of MDA-7/IL-24 causes a strong tumor- suppressive effect in many human cancer cells but spares normal cells. This gene therapy also enhances the tumor-suppressive activity of radiotherapy and chemotherapy. Secreted MDA-7 protein that is glycosylated also has been shown to have potent antiangiogenic activity both in vitro and in vivo. Studies examining the immune properties of mda-7 have shown that MDA-7/IL-24 unlike the related IL-10, functions as a Th1 cytokine. Recently, an MDA-7 protein-mediated "bystander effect" on tumor cells has been documented. Building on these findings we successfully completed a Phase I clinical trial of adenovirus-based mda-7 cancer therapy that confirmed the safety of this gene therapy. Phase II trials evaluating the efficacy of mda-7-based gene therapy are warranted. The outcome of such ongoing mda-7-based gene therapy trials will allow us to better understand this therapy's clinical utility.

Poor outcome of patients with pulmonary adenocarcinoma showing decreased E-cadherin combined with increased S100A4 expression.

A loss or reduced expression of E-cadherin, the main cell-to-cell adhesion molecule, correlates with distant metastasis in various cancers. Recent studies have reported a close correlation between the expression of E-cadherin and that of S100A4, calcium-binding protein. In this study, we investigated the expression of E-cadherin and S100A4 status in relation to the clinicopathological parameters of pulmonary adenocarcinoma. We finely and quantitatively examined the expression of E-cadherin and S100A4 using real-time polymerase chain reaction (PCR) in a total of 92 pulmonary adenocarcinomas obtained by surgical resection. All of the pulmonary adenocarcinomas showed significant expression of E-cadherin and S100A4. Real-time PCR showed lower E-cadherin expression in 21 adenocarcinomas, while 71 adenocarcinomas expressed a higher expression of E-cadherin. Of 21 adenocarcinomas with lower-expressing E-cadherin, 12 showed a higher expression of S100A4. These 12 cases significantly showed a poorer prognosis than others (p=0.047, Kaplan-Meier, log-rank test) and significantly showed more frequent venous involvement than others (p=0.042, chi2 test). These results suggested that reduced E-cadherin expression combined with higher S100A4 expression is related to a poor prognosis through hematogenous metastasis in pulmonary adenocarcinoma.

The preserved expression of neuropilin (NRP) 1 contributes to a better prognosis in colon cancer.

Vascular endothelial growth factor A (VEGF-A) plays an essential role in tumor progression through stromal neovascularization in malignant solid tumors. Neuropilin (NRP) is considered to be the specific receptor for limited types of VEGF-A isoform, VEGF165. The clinicopathological implications of NRP are not well understood in colon cancer, while almost all colon cancers overexpressed VEGF-A. We examined the expression levels of NRP1 and NRP2 genes in 54 colon cancer cases and paired extraneoplastic tissue with quantitative real-time polymerase chain reaction. The gene expression levels of NRP1 in the tumor (0.431+/-0.583) were significantly decreased compared to those in the extraneoplastic tissue (0.754+/-0.799) (paired t-test, p=0.0208). On the other hand, the gene expression levels of NRP2 in the tumor (0.763+/-0.791) were not decreased compared to those in the extraneoplastic tissue (0.508+/-0.386) (paired t-test, p=0.0511). Twenty cases, with preserved expression of the NRP1 gene in the tumor, showed a better prognosis as compared to the 34 cases with decreased NRP1 expression (p=0.0258, log-rank test). No significant relationship was noted between NRP2 gene expression and prognosis. The results suggested that preserved NRP1 expression provides colon cancer patients with a better prognosis.

Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer.

The calcium-binding protein, S100A4, with an inverse association of E-cadherin, is known to correlate with prognosis in various cancers. In this study, we investigated the expression of the S100A4 and E-cadherin status in relation to the clinicopathological parameters of pancreatic cancer. The expression status of these two proteins was examined in 72 specimens of primary pancreatic carcinoma with immunohistochemistry. Fifty-six of 72 (78%) surgical specimens of primary pancreatic cancer were positive for S100A4 according to immunohistochemistry. Thirty-one (43%) specimens of pancreatic cancer showed positive expression of E-cadherin. The inverse association of S100A4 and E-cadherin expression was significant in the cancers (p < 0.0001). The S100A4 expression correlated significantly with the pathological T stage and poorer prognosis (p = 0.024). The 41 E-cadherin-negative cases showed poorer prognoses and a higher incidence of liver metastasis (p = 0.0344, p = 0.027). The 10 cases with S100A4-negative/E-cadherin-positive cancers showed a significantly better prognosis than the others (p < 0.05). The histological grade (p = 0.004), nodal status (p < 0.0001) and S100A4-positive status (p = 0.048) were highly significant independent prognostic predictors (p < 0.05). These results suggest that S100A4 overexpression combined with reduced E-cadherin expression play important roles in tumor progression and metastasis in pancreatic cancer. The combined examination of these two molecules is useful in evaluating the outcome of pancreatic cancer patient.