Comparison of pure laparoscopic donor right posterior sectionectomy versus right hemihepatectomy for living donor liver transplantation.

The right posterior section (RPS) graft for living donor liver transplantation is an alternative graft in a live liver donor with insufficient remnant left lobe volume and portal vein anomaly. Although there have been some reports regarding pure laparoscopic donor right posterior sectionectomy (PLDRPS), no study has compared PLDRPS versus pure laparoscopic donor right hemihepatectomy (PLDRH). The aim of our study was to compare the surgical outcomes of PLDRPS versus PLDRH at centers achieving a complete transition from open to laparoscopic approach in liver donor surgery. From March 2019 to March 2022, a total of 351 living donor liver transplantations, including 16 and 335 donors who underwent PLDRPS and PLDRH, respectively, were included in the study. In the donor cohort, there were no significant differences in major complication (≥grade III) rate and comprehensive complication index between the PLDRPS versus PLDRH group (6.3% vs. 4.8%; p = 0.556 and 2.7 ± 8.6 vs.1.7 ± 6.4; p = 0.553). In the recipient cohort, there was a significant difference in major complication (≥grade III) rate (62.5% vs. 35.2%; p = 0.034) but no significant difference in comprehensive complication index (18.3 ± 14.9 vs. 15.2 ± 24.9; p = 0.623) between the PLDRPS and PLDRH groups. PLDRPS in live liver donors with portal vein anomaly and insufficient left lobe was technically feasible and safe with experienced surgeons. The PLDRPS group might be comparable with the PLDRH group based on the surgical outcomes of donors and recipients. However, in terms of recipient outcomes, more careful selection of donors of the RPS graft and further research in a large number of cases are necessary to evaluate the usefulness of PLDRPS.

Proposal of nomograms to predict clinical outcomes in patients with ampulla of Vater cancer based on the Korea-Japan collaborative study.

BACKGROUND: In this study, we aimed to develop and validate a nomogram to predict overall survival (OS) and recurrence-free survival (RFS) in patients who underwent curative resection of ampulla of Vater (AOV) cancer. This is the first study for nomograms in AOV cancer patients using retrospective data based on an international multicenter study. METHODS: A total of 2007 patients with AOV adenocarcinoma who received operative therapy between 2002 January and 2015 December in Korea and Japan were retrospectively assessed to develop a prediction model. Nomograms for 5-year OS and 3-year RFS were constructed by dividing the patients who received and who did not receive adjuvant therapy after surgery, respectively. Significant risk factors were identified by univariate and multivariate Cox analyses. Performance assessment of the four prediction models was conducted by the Harrell's concordance index (C-index) and calibration curves using bootstrapping. RESULTS: A total of 2007 and 1873 patients were collected for nomogram construction to predict 5-year OS and 3-year RFS. We developed four types of nomograms, including models for 5-year OS and 3-year RFS in patients who did not receive postoperative adjuvant therapy, and 5-year OS and 3-year RFS in patients who received postoperative adjuvant therapy. The C-indices of these nomograms were 0.795 (95% confidence interval [CI]: 0.766-0.823), 0.712 (95% CI: 0.674-0.750), 0.804 (95% CI: 0.7778-0.829), and 0.703 (95% CI: 0.669-0.737), respectively. CONCLUSIONS: This predictive model could help clinicians to choose optimal treatment and precisely predict prognosis in AOV cancer patients.

Factors influencing patterns of recurrence following pancreaticoduodenectomy for patients with distal bile duct cancer and ampulla of Vater cancer.

Backgrounds/Aims: Pancreaticoduodenectomy (PD) is a standard surgical procedure for patients with periampullary cancer. During the follow-up period after PD, recurrence can be observed in various places with different prognosis. The aim of this study was to clarify the pattern of recurrence and factors affecting the survival of patients with periampullary cancer. Methods: Overall, 88 patients who received PD for distal common bile duct cancer or ampulla of Vater cancer were finally included and their clinical characteristics were analyzed. Patients were divided into three groups: recurrence-free (RF) group, an isolated locoregional recurrence (LR) group, and a distant metastasis (DM) group. Prognostic factors affecting recurrence in each group were analyzed and a survival analysis was performed. Results: Perineural invasion (PNI), T stage, and lymphovascular invasion (LVI) were significant risk factors for LR and PNI, lymph node metastasis, LVI, and T stage were associated with DM group compared to RF group in univariate analysis, respectively. N stage and PNI were significant risk factors (p = 0.046, p = 0.041) in overall survival of the LR and the DM groups. There was no significant difference in 5-year overall survival between the LR and DM groups. Conclusions: T stage was a significant risk factor of LR, while PNI was a significant risk factor of DM. There was no significant difference in overall survival depending on the site of recurrence.

Clinical impact of anatomical resection on long-term outcomes after hepatectomy for primary solitary hepatocellular carcinoma with or without preoperative positron emission tomography positivity.

BACKGROUND: There is little evidence indicating that anatomical resection (AR) is associated with improved survival in patients with solitary hepatocellular carcinoma (HCC) who were preoperatively evaluated by positron emission tomography (PET). The aim of our study was to compare the oncologic outcomes of AR in PET-positive versus PET-negative patients with HCC. METHODS: From January 2007 to September 2015, 259 patients with preoperative PET underwent hepatectomy as the primary treatment for solitary HCC. Patients were divided into four groups according to PET uptake and hepatectomy type [AR or non-anatomical resection (NAR)]: Group 1 (PET-negative and AR, n=62); Group 2 (PET-negative and NAR, n= 46); Group 3 (PET-positive and AR, n=100); Group 4 (PET-positive and NAR, n=51). RESULTS: PET positivity was associated with higher protein induced by vitamin K antagonist-II (P=0.025), lager tumor size (P=0.05), microvascular invasion (MVI) (P=0.012), and portal vein invasion (P=0.031). In Kaplan-Meier analysis for RFS, Group 1 showed remarkable difference from Group 3 and Group 4 (P=0.045, P=0.023, respectively). In the PET-positive subgroup with HCC under 3 cm, AR was associated with better RFS than NAR (P=0.016). CONCLUSIONS: A combination of AR and PET negativity showed good prognosis in long-term outcomes. Finally, AR can decrease the risk of tumor recurrence in patients with a solitary PET-positive HCC less than 3 cm.

A Comparison of Short-Term Outcomes between Laparoscopic and Open Liver Resection in Elderly Patients.

Purpose: The aim of this study was to compare the short-term outcomes between laparoscopic liver resection (LLR) and open liver resection (OLR) in elderly patients with hepatic tumors. Methods: From January 2013 to December 2019, a retrospective study was conducted for a total of 143 patients with over 70 years of age, who underwent liver resection for hepatic tumors. Forty-five patients who received biliary reconstruction at the same time were excluded. According to surgical approaches, 98 patients were classified into LLR and OLR groups. All postoperative complications were classified according to the Clavien-Dindo grading system and the Comprehensive Complication Index (CCI). Results: Incidence of the postoperative complications was not statistically different between LLR and OLR groups. The CCI was significantly lower in the LLR group, with a median of 8.556, and a median of 19.698 in the OLR group (p=0.042). The length of hospital stay in the LLR group was significantly shorter than in the OLR group (p=0.008). Conclusion: LLR is safe and feasible as a treatment for hepatic tumor in elderly patients with potentially less postoperative complications compared to OLR.

Role and limitation of neoadjuvant hepatic arterial infusion chemotherapy in advanced hepatocelluar carcinoma patients with Child-Pugh class A.

BACKGROUND: Patients with advanced hepatocellular carcinoma (HCC) have a poor oncologic outcome. In this study, we evaluated the role and limitation of neoadjuvant hepatic arterial infusion chemotherapy (HAIC) in advanced HCC patients with Child-Pugh class A and the efficacy of liver resection subsequent to downstaging after neoadjuvant HAIC. METHODS: In the present retrospective study, 103 patients with advanced HCC, who underwent neoadjuvant HAIC from April 2003 to March 2015 were analyzed. Response to HAIC was evaluated by dividing time period into after 3 cycles and after 6 cycles, each defined as early and late period. Liver resection after neoadjuvant HAIC was offered in patients who were considered as possible candidates for curative resection with tumor-free margin as well as sufficient future liver remnant volume. RESULTS: The median survival time (MST) in all patients was 14 ± 1.7 months. Response rate and disease control rate were 36.3% (37) and 81.4% (83) in early period, respectively, and 26.4% (14) and 47.2% (25), in late period, respectively (P = 0.028). Twelve patients (11.7%) underwent liver resection after neoadjuvant HAIC and the MST was 37 ± 6.6 months. One-, 3-, and 5-year recurrence-free survival after liver resection were 58.3%, 36.5%, and 24.3% respectively. Liver resection was identified as the only independent prognostic factor that associated with overall survival in multivariate analysis (P = 0.002) CONCLUSION: HAIC could be further alternative for the treatment of advanced HCC in patients with good liver function. If liver resection is possible after neoadjuvant HAIC, liver resection would provide better outcomes than HAIC alone.

EGFR expression in pancreatic intraepithelial neoplasia and ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignant tumor with poor prognosis. Epidermal growth factor receptor (EGFR) is an important cell adhesion and signaling pathway mediator. The aim of this study was to evaluate the expression of EGFR in both pancreatic intraepithelial neoplasia (PanIN) and PDA and their relationship to clinicopathologic characteristics. Formalin-fixed, paraffin-embedded tissues including 81 cases with pancreatic ductal adenocarcinoma, 27 with normal pancreas, 16 with PanIN-1A, 18 with PanIN-1B, 11 with PanIN-2, and 24 with PanIN-3 were used for construction of tissue microarrays. Imunohistochemistry for EGFR was performed. Normal pancreatic ducts, PanIN-1A, and PanIN-1B did not show EGFR overexpression. EGFR overexpression was observed in 18.2% (2/9) of PanIN-2, 41.7% (10/14) of PanIN-3, and 64.2% (52/81) of PDA, respectively. Significantly higher EGFR overexpression was observed in PDAs than in PanIN lesions (P<0.05). No statistically significant correlation was observed between EGFR overexpression and patient age, sex, tumor location, size, histological grade, vascular invasion, lymph node metastasis and stage at presentation, respectively. In conclusion, EGFR expression increased from PanIN to PDA. EGFR may be involved in early stage in development of PDA.

Rationale and surgical technique of laparoscopic left lateral sectionectomy using endoscopic staples.

PURPOSE: Laparoscopic left lateral sectionectomy (LLLS) has been widely accepted due to benefits of minimally invasive surgery. Some surgeons prefer to isolate glissonian pedicles to segments II and III and to control individual pedicles with surgical clips, whereas opt like to control glissonian pedicles simultaneously using endoscopic stapling devices. The aim of this study was to find the rationale of LLLS using endoscopic staples. METHODS: We retrospectively analyzed and compared the clinical outcomes (operation time, drainage length, transfusion, hospital stay, and complication rate) of 35 patients that underwent LLLS between April 2004 and February 2012. Patients were dichotomized by surgical technique based on whether glissonian pedicles were isolated and controlled (the individual group, n = 21) or controlled using endoscopic staples at once (the batch group, n = 14). RESULTS: Mean operation time was 265.3 ± 21.3 minutes (mean ± standard deviation) in the individual group and 170 ± 22.9 minutes in the batch group. Operation time in the batch group was significantly shorter than the individual group (P = 0.007). Mean drainage length was 4.8 ± 1.6 and 2.6 ± 1.5 days in the individual and the batch group. There was significantly shorter in the batch group, also (P = 0.006). No transfusion was required in the batch group, but 4 patients in the individual group needed transfusion. Mean hospital stay was 10.7 ± 1.1 and 9.4 ± 0.8 days in the individual and the batch groups (P = 0.460). There were no significant complications or mortality in both groups. CONCLUSION: LLLS using endoscopic staples (batch group) was found to be an easier and safer technique without morbidity or mortality.

The risk factors of early recurrence after hepatectomy in hepatocellular carcinoma.

PURPOSE: Early recurrence after hepatectomy is a well-known poor prognostic factor in patients with hepatocellular carcinoma. This study was undertaken to identify the risk factors of early recurrence in patients with hepatocellular carcinoma after hepatectomy. METHODS: One hundred and sixty-seven patients that underwent hepatectomy for hepatocellular carcinoma from January 2005 to December 2010 were enrolled. The numbers of patients with or without early recurrence group were 40 and 127, respectively. Clinico-pathologic factors were retrospectively analyzed. RESULTS: Potential risk factors were classified as host, tumor, or surgical factors. Of the host factors examined, lobular hepatitis activity was found to be a significant risk factor of early recurrence, and of the tumor factors, infiltrative type of gross appearance, level of preoperative AFP and worst Edmondson-Steiner grade were significant. CONCLUSION: The present study shows that an infiltrative gross appearance, a high preoperative AFP level, high lobular hepatitis activity, and a poor Edmondson-Steiner grade are independent risk factors of early recurrence. Accordingly, patients with these risk factors should be followed closely after hepatectomy.

[Clinical review and case report of ceftriaxone-associated gallbladder pseudolithiasis in adult].

Although ceftriaxone can be used safely in most instances, it can sometimes induce biliary sludge or stone formation. Most of the patients remain asymptomatic and children are more susceptible to develop this condition, but adults can be affected as well. Because sludge or stones disappear after discontinuing ceftriaxone, this condition is referred to as ceftriaxone-associated pseudolithiasis. A 54-year-old woman was admitted to a local clinic for management of ileus. During admission, she had received ceftriaxone and metronidazole, and had been on nil per os for the past 6 days. She was then referred to our hospital for cholecystectomy due to persistent right upper quadrant pain. Although imaging studies showed gallbladder sludge, pseudolithiasis was suspected because of ceftriaxone administration history and prolonged fasting. After careful watch-and-wait, the condition resolved spontaneously after ceftriaxone discontinuation. Our clear understanding on ceftriaxone-associated gallbladder pseudolithiasis allowed us to avoid an unnecessary cholecystectomy. Herein, we report the case of a 54-year-old woman with ceftriaxone-associated gallbladder pseudolithiasis that was successfully managed by ceftriaxone discontinuation alone.

The comparison of oncologic and clinical outcomes of laparoscopic liver resection for hepatocellular carcinoma.

PURPOSE: We evaluate the operative outcome and oncologic outcome of laparoscopic liver resection for hepatocellular carcinoma (HCC), and compare with open liver resection. METHODS: From January 2004 to December 2012, clinical data of 70 patients who underwent laparoscopic liver resection for HCC (laparoscopic liver resection group, lapa-group) were collected and analyzed retrospectively. Control group (open liver resection group, open-group) were retrospectively matched, and compared with lapa-group. RESULTS: Laparoscopic major liver resections were performed in 4 patients. Laparoscopic anatomical resections and nonanatomical resections were performed in 39 patients, and 31 patients, respectively. Mean operative time was shorter in lapa-group (215.5 ± 121.84 minutes vs. 282.30 ± 80.34 minutes, P = 0.001), mean intraoperative transfusion rate and total amount were small in lapa-group (24.28%, 148.57 ± 3,354.98 mL vs. 40.78%, 311.71 ± 477.01 mL). Open conversion occurred in 6 patients (8.57%) because of bleeding, inadequate resection, invisible mass on intraoperative ultrasonography, and tumor rupture. In lapa-group and open-group, 3-year disease-free survival rates were 58.3% ± 0.08%, and 62.6% ± 0.06%, respectively (P = 0.773). In lapa-group and open-group 3-year overall survival rates were 65.3% ± 0.8%, and 65.7% ± 0.6%, respectively (P = 0.610). CONCLUSION: Laparoscopic liver resection for HCC is feasible and safe in a large number of patients, with reasonable operative and oncologic results.

Systemic metastasis of hepatocellular carcinoma responsive to multidisciplinary treatment including debulking surgery.

The lung, followed by regional lymph node and bone, is the most common site for extrahepatic metastasis of hepatocellular carcinoma (HCC). Metastatic skin lesion of HCC is rare, and it is a sign of poor prognosis, indicating the strong possibility of metastases in other regions of the body. We report the case of a 52-year-old male with multiple metastases, including skin metastasis of HCC, which were treated with multidisciplinary therapy.

Outflow failure caused by mesothelial cell lining sheet wrapping in a patient with peritoneal dialysis.

A 60-year-old male was admitted to our hospital due to nausea and poor oral intake. He had received distal pancreatectomy due to a traffic accident 15 years ago, and therefore, had a midline abdominal scar. Peritoneal dialysis (PD) was selected for renal replacement therapy. PD catheter was inserted by a surgical method with left paramedian incision under local anesthesia. Initially, dialysate flow was good, but outflow failure developed on postoperative day nine. Even after the use of laxatives and a fibrinolytic agent to correct the catheter obstruction, the problem was not resolved. Therefore, we performed an open laparotomy. When PD catheter was examined during laparotomy, a single thick band (0.6 cm × 36 cm), without blood vessels was wrapped around it. One of the ends of this band originated from the jejunum and the other was attached on the most proximal side hole of the catheter. A band was removed surgically, and then the PD catheter was repositioned in the abdominal cavity. On post-revision Day 7, PD started again and dialysate flow was good. The pathologic finding was consistent with mesothelial cell lining sheet. Considering its location and the history of a major abdominal operation, the adhesive band or sheet may be the cause in this case.

Surgical outcomes of hepatocellular carcinoma with bile duct tumor thrombus: a Korean multicenter study.

BACKGROUND: The long-term outcomes after resection for hepatocellular carcinoma (HCC) with macroscopic bile duct tumor thrombus (BDTT) are unclear. This multicenter study was conducted to determine the prognosis of HCC patients with macroscopic BDTT who underwent resection with curative intent. METHODS: Of 4,308 patients with HCC from four Korean institutions, this single-arm retrospective study included 73 patients (1.7 %) who underwent resection for HCC with BDTT. RESULTS: Jaundice was also present in 34 patients (46.6 %). According to Ueda classification, BDTT was type 2 in 34 cases (46.6 %) and type 3 in 39 cases (53.4 %). Biliary decompression was performed in 33 patients (45.2 %), decreasing the median lowest bilirubin level to 1.4 mg/dL before surgery. Systematic hepatectomy was performed in 69 patients (94.5 %), and concurrent bile duct resection was performed in 31 patients (42.5 %). Surgical curability types were R0 (n = 57; 78.1 %), R1 (n = 11; 15.1 %), and R2 (n = 5; 6.8 %). Patient survival rates were 76.5 % at 1 year, 41.4 % at 3 years, 32.0 % at 5 years, and 17.0 % at 10 years. Recurrence rates were 42.9 % at 1 year, 70.6 % at 3 years, 77.3 % at 5 years, and 81.1 % at 10 years. Results of univariate survival analysis showed that maximal tumor size, bile duct resection, and surgical curability were significant risk factors for survival, and surgical curability was a significant risk factor for recurrence. Multivariate analysis did not reveal any independent risk factors. CONCLUSIONS: Hepatocellular carcinoma patients with BDTT achieved relatively favorable long-term results after resection; therefore extensive surgery should be recommended when complete resection is anticipated.

Current status of laparoscopic liver resection in Korea.

Since laparoscopic liver resection was first introduced in 2001, Korean surgeons have chosen a laparoscopic procedure as one of the treatment options for benign or malignant liver disease. We distributed and analyzed a nationwide questionnaire to members of the Korean Laparoscopic Liver Surgery Study Group (KLLSG) in order to evaluate the current status of laparoscopic liver resection in Korea. Questionnaires were sent to 24 centers of KLLSG. The questionnaire consisted of operative procedure, histological diagnosis of liver lesions, indications for resection, causes of conversion to open surgery, and postoperative outcomes. A laparoscopic liver resection was performed in 416 patients from 2001 to 2008. Of 416 patients, 59.6% had malignant tumors, and 40.4% had benign diseases. A total laparoscopic approach was performed in 88.7%. Anatomical laparoscopic liver resection was more commonly performed than non-anatomical resection (59.9% vs 40.1%). The anatomical laparoscopic liver resection procedures consisted of a left lateral sectionectomy (29.3%), left hemihepatectomy (19.2%), right hemihepatectomy (6%), right posterior sectionectomy (4.3%), central bisectionectomy (0.5%), and caudate lobectomy (0.5%). Laparoscopy-related serious complications occurred in 12 (2.8%) patients. The present study findings provide data in terms of indication, type and method of liver resection, and current status of laparoscopic liver resection in Korea.

Single center experience of laparoscopic hepatectomy: the comparison of perioperative outcomes between early and late period.

BACKGROUNDS/AIMS: The aim of this study is to clarify the safety and feasibility of laparoscopic hepatectomy, through comparing the early and late periods of perioperative outcomes. METHODS: We retrospectively analyzed 138 patients who underwent laparoscopic hepatectomy from January 2003 to June 2011, at Yeungnam University Hospital. We divided the total patients to early period (from January 2003 to February 2007, n=49) and late period (from March 2007 to June 2011, n=89) groups and compared the perioperative outcomes including the mean operation time, intra-operative blood loss, postoperative hospital stay, intensive care unit (ICU) stay, and duration of liver function test (LFT) normalization. RESULTS: The mean operation time was 308 minutes (range: 140-510) in the early group and 193 minutes (range: 40-350) in the late period group (p<0.001). The mean intraoperative blood loss was 171 ml (range: 50-1,200) in the early and 44 ml (range: 0-400) in the late group (p=0.005). The postoperative hospital stay was 9.7 days (range: 4-31) in the early and 6.8 days (range: 2-9) in the late period (p<0.001). The ICU stay hour was 21.6 hours (range: 0-120) in the early and 2.8 hour (range: 0-24) in the late period (p<0.001). The duration of LFT normalization was 5.7 days (range: 0-39) in the early and 2.1 days (range: 0-20) in the late period (p=0.003). The perioperative outcomes in the late period were better than the early period, which showed a statistically significant difference. CONCLUSIONS: Laparoscopic hepatectomy is feasible and can be safely performed in selected patients but requires a long experience in open liver resection and mastery of laparoscopic surgical skills.

Determination of malignant and invasive predictors in branch duct type intraductal papillary mucinous neoplasms of the pancreas: a suggested scoring formula.

Prediction of malignancy or invasiveness of branch duct type intraductal papillary mucinous neoplasm (Br-IPMN) is difficult, and proper treatment strategy has not been well established. The authors investigated the characteristics of Br-IPMN and explored its malignancy or invasiveness predicting factors to suggest a scoring formula for predicting pathologic results. From 1994 to 2008, 237 patients who were diagnosed as Br-IPMN at 11 tertiary referral centers in Korea were retrospectively reviewed. The patients' mean age was 63.1 ± 9.2 yr. One hundred ninty-eight (83.5%) patients had nonmalignant IPMN (81 adenoma, 117 borderline atypia), and 39 (16.5%) had malignant IPMN (13 carcinoma in situ, 26 invasive carcinoma). Cyst size and mural nodule were malignancy determining factors by multivariate analysis. Elevated CEA, cyst size and mural nodule were factors determining invasiveness by multivariate analysis. Using the regression coefficient for significant predictors on multivariate analysis, we constructed a malignancy-predicting scoring formula: 22.4 (mural nodule [0 or 1]) + 0.5 (cyst size [mm]). In invasive IPMN, the formula was expressed as invasiveness-predicting score = 36.6 (mural nodule [0 or 1]) + 32.2 (elevated serum CEA [0 or 1]) + 0.6 (cyst size [mm]). Here we present a scoring formula for prediction of malignancy or invasiveness of Br-IPMN which can be used to determine a proper treatment strategy.

Bioelectrical impedance may predict cell viability during ischemia and reperfusion in rat liver.

Ischemia and reperfusion (I/R) injury is a major cause of hepatic failure after liver surgery, but no method could monitor or predict it real-time during surgery. We measured bioelectrical impedance (BEI) and cell viability to assess the usefulness of BEI during I/R in rat liver. A 70% partial liver ischemia model was used. BEI was measured at various frequencies. Adenosine triphosphate (ATP) content, and palmitic acid oxidation rate were measured, and histological changes were observed in order to quantify liver cell viability. BEI changed significantly during ischemia at low frequency. In the ischemia group, BEI increased gradually during 60 min of ischemia and had a tendency to plateau thereafter. The ATP content decreased below 20% of the baseline level. In the I/R group, BEI recovered to near baseline level. After 24 hr of reperfusion, the ATP contents decreased to below 50% in 30, 60 and 120 min of ischemia and the palmitic acid metabolic rates decreased to 91%, 78%, and 74%, respectively, compared with normal liver. BEI may be a good tool for monitoring I/R during liver surgery. The liver is relatively tolerant to ischemia, however after reperfusion, liver cells may be damaged depending upon the duration of ischemia.

Cellular mechanisms of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MAPK signaling in hepatocellular carcinoma.

AIMS AND BACKGROUND: The hepatocyte growth factor, its receptor c-Met, and urokinase-type plasminogen mediate various cellular responses on activation, including proliferation, survival, invasion, and metastasis. The regulatory mechanisms for the proliferation and the particular invasive phenotypes of hepatocellular carcinoma are not yet fully understood. In order to clarify the intracellular downstream signal for hepatocyte growth factor/c-Met signaling in tumor progression and metastasis in hepatoma, we determined the effects of a specific MEK1 inhibitor (PD 098059) and a p38 kinase inhibitor (SB 203580) on hepatocyte growth factor-mediated cell proliferation and urokinase-type plasminogen expression in hepatoma cell lines (HepG2 and Hep3B). RESULTS: Hepatocyte growth factor treatment induced the phosphorylation of ERK and p38 kinase in a dose-dependent manner, resulting in an early peak of phosphorylation at 3 to 10 min, which then rapidly decreased to a near basal level. Pretreatment with PD 098059 reduced hepatocyte growth factor-mediated cell proliferation and urokinase-type plasminogen secretion. In contrast, SB 203580 pretreatment enhanced cell proliferation and urokinase-type plasminogen secretion due to induction of ERK phosphorylation. Treatment with PD 098059 and SB 203580 resulted in a decrease in phospho-ERK activity. Stable expression of dominant negative-MEK1 in HepG2 cells showed a decrease in hepatocyte growth factor-mediated urokinase-type plasminogen secretion. CONCLUSIONS: Such results suggest that interaction of an MEK/ERK and a p38 kinase might be critical in intrahepatic invasion and metastasis of human hepatoma cells.