Jae-Won Joh

Liver transplantation for adult patients with hepatocellular carcinoma in Korea: Comparison between cadaveric donor and living donor liver transplantations

Current selection criteria of liver transplantation (LT) for patients with hepatocellular carcinoma (HCC) were derived from the outcomes of cadaveric donor LT (CDLT). We tried to assess the applicability of such criteria to living donor LT (LDLT) through a comparative study between CDLT and LDLT. We analyzed the outcomes of 312 HCC patients who underwent LT at 4 Korean institutions during 1992 to 2002. There were no gross differences of tumor characteristics between CDLT group (n = 75) and LDLT group (n = 237). Overall 3‐year survival rate (3‐YSR) was 61.1% after CDLT and 73.2% after LDLT including 38 cases of perioperative mortality. Comparison of HCC recurrence curves did not reveal any statistical difference between these 2 groups. Patient survival period till 50% mortality after HCC recurrence was 11 months after CDLT and 7 months after LDLT. Significant risk factors for HCC recurrence were alpha‐fetoprotein level, tumor size, microvascular invasion, gross major vessel invasion, bilateral tumor distribution, and histologic differentiation in the LDLT group on univariate analysis, and tumor size, gross major vessel invasion, and histologic differentiation on multivariate analysis. Milan criteria were met in 70.4%: Their 3‐YSR was 89.9% after CDLT and 91.4% after LDLT with exclusion of perioperative mortality. University of California San Francisco criteria were met in 77.7%: Their 3‐YSR was 88.1% after CDLT and 90.6% after LDLT. In conclusion, we think that currently available selection criteria for HCC patients can be applicable to LDLT without change of prognostic power. (Liver Transpl 2005;11:1265–1272.)

Biology of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a common cancer in the world due to high prevalence of hepatitis B or C virus infection. Research in recent years has uncovered important molecular pathways involved in development and progression of HCC. Several genetic aberrations and molecular mechanisms responsible for initiation of hepatocarcinogenesis have been identified. Novel biomarkers for HCC are being developed for better detection and prognostication. Alpha-fetoprotein, the conventional marker of HCC, has limited sensitivity and specificity. Serum levels of isoforms of AFP based on differential lectin binding of the glycan moiety appear to be more sensitive and specific than total AFP level in early detection of HCC. The clinical usefulness of other HCC biomarkers such as des-γ-carboxy prothrombin and glypican-3 are under investigation. HCC is an aggressive tumor with early vascular invasion and metastasis. Studies over the past two decades have elucidated the clinical predictors of outcome, leading to several staging systems for HCC based on clinical parameters. However, the predictive accuracy of clinical staging systems is limited. Recent studies suggested that biological factors may provide additional prognostic information. In particular, gene expression profiling appears to be a promising approach. Study of tumor angiogenesis in HCC reveals that the expression of angiogenic factors such as vascular endothelial growth factor and angiopoietins may also predict prognosis. The elucidation of tumor biology of HCC is of particular importance in the current era of rapid development of anti-cancer molecular targeting agents, which provide hope for an effective systemic therapy for HCC.

Clinical Outcomes of Hepatic Resection and Radiofrequency Ablation in Patients With Solitary Colorectal Liver Metastasis

Background The role of the radiofrequency ablation (RFA) in treatment of solitary liver metastasis has not been established yet. Both hepatic resection (HR) and RFA have been used increasingly in the treatment of colorectal liver metastases. Study A systemic review was performed to determine the impact of treatment modality of solitary liver metastasis on recurrence patterns, disease-free survival, and overall survival (OS) rates. Results Solitary liver metastases were treated by HR in 116 patients (75.8%) and 37 patients (24.2%) were treated with RFA. Prognostic factors, recurrence rate, recurrence patterns, and survival rates were analyzed. The cumulative 3-year and 5-year local recurrence free survival rates were markedly higher in the HR group (88.0% and 84.6%) as compared with those in the RFA group [53.3% and 42.6%, respectively (P≤0.001)]. The 5-year OS rate was lower in the RFA group as compared with the HR group without statistical significance (5-year OS, 65.7% in the HR, 48.5% in the RFA group, P=0.227). Conclusions Despite of higher local recurrence rate, RFA may be considered as a therapeutic option for patients who are considered unsuitable for conventional surgical treatment. Randomized prospective controlled trials comparing the therapeutic outcome of RFA and HR are definitely warranted.

Isolation and Characterization of Mouse Mesenchymal Stem Cells

OBJECTIVE Mesenchymal stem cells (MSCs) have been studied in regenerative medicine because of their unique immunologic characteristics. However, before clinical application in humans, animal models are needed to confirm their safety and efficacy. To date, appropriate methods and sources to obtain mouse MSCs have not been identified. Therefore, we investigated MSCs isolated from 3 strains of mice and 3 sources for the development of MSCs in a mouse model. MATERIALS AND METHODS Male BALB/c, C3H and C57BL/6 mice were used to isolate MSCs from various tissues including bone marrow (BM), compact bone, and adipose tissue. The MSCs were maintained in StemXVivo medium. Immunophenotypes of the MSCs were analyzed by FACS and their growth potential estimated by the number of colony-forming unit fibroblasts. RESULTS All MSCs that were isolated from BM, compact bone, and adipose tissue showed plastic-adherent, fibroblastic-like morphologic characteristics regardless of the mouse strain or cell source. However, culture of BM MSCs was less successful than the other tissue types. The FACS phenotype analysis revealed that the MSCs were positive for CD29, CD44, CD105, and Sca-1, but negative for CD34, TER-119, CD45, and CD11b. According to the results of the characterization, the adipose tissue MSCs showed higher growth potential than did other MSCs. CONCLUSION The results of this study showed that culture of adipose tissue and compact bone-MSCs was easier than BM MSCs. Based on the results of immunophenotype and growth potential, C57BL/6 AT-MSCs might be a suitable source to establish a mouse model of MSCs.

Predicting survival after surgical resection for pancreatic ductal adenocarcinoma.

Objectives: We reviewed the pancreatectomies that were done for pancreatic ductal adenocarcinoma to evaluate patient survival and prognostic predictors. Methods: A review was performed on 94 patients who underwent surgical resection for pancreatic ductal adenocarcinomas from 1995 to 2002. The perioperative factors were compared between the proximal and distal lesions by the χ2 test and t test. Possible predictors for survival were examined for by univariate and multivariate analysis. Results: The 5-year survival was 16%. The proximal lesions had a smaller tumor size (3.0 ± 0.11 vs. 3.9 ± 0.33 cm, respectively; P = 0.03), a higher incidence of nodal involvement (60.6% vs. 34.8%, respectively; P = 0.031), and poorer histologic differentiation (25.4% vs. 13.0%, respectively; P = 0.01) compared with the distal lesions, and both types of lesions had similar rates of intraoperative transfusion, complete resection, and survival. The factors shown to have favorable independent prognostic significance were negative resection margins (hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.12-0.42; P < 0.001), a tumor diameter less than 3 cm (HR = 0.46; 95% CI = 0.27-0.78; P = 0.004), well/moderate tumor differentiation (HR = 0.37; 95% CI = 0.19-0.72; P = 0.004), and adjuvant therapy (HR = 0.61; 95% CI = 0.37-0.99; P = 0.49). Conclusions: For the long-term survival of patients with pancreatic ductal adenocarcinoma, complete excision is the most important therapeutic option, and adjuvant therapy is a significant contributing factor.

Hepatocyte transplantation for glycogen storage disease type Ib.

Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. The two major subtypes are GSD-Ia, caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib, caused by a deficiency of glucose-6-phosphate transporter (G6PT). We report that a substantial improvement was achieved following several infusions of hepatocytes in a patient with GSD-Ib. Hepatocytes were isolated from the unused cadaveric whole livers of two donors. At the first transplantation, approximately 2 × 109 cells (2% of the estimated recipients total hepatocytes) were infused. Seven days later 1 × 109 (1% of liver mass) cryopreserved hepatocytes from the same donor were infused, and an additional 3 × 109 (3% of liver mass) cells from the second donor were infused 1 month after the second transplantation. After the hepatocyte transplantation, the patient showed no hypoglycemic symptoms despite the discontinuation of cornstarch meals. Liver biopsies on posttransplantation days 20 and 250 showed a normal level of glucose-6-phosphatase activity in presolubilization assay that was very low before transplantation. This was the first and successful clinical hepatocyte transplantation in Korea. In this study, hepatocyte transplantation allowed a normal diet in a patient with GSD-Ib, with substantial improvement in their quality of life. Hepatocyte transplantation might be an alternative to liver transplantation and dietary therapy in GSD-Ib.

Comparison of combined hepatocellular and cholangiocarcinoma with hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

PurposeCombined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare primary hepatic neoplasm (PHN) with features of both hepatocellular and biliary differentiation. We compared the outcome of hepatic resection in patients with HCC-CC, those with hepatocelluar carcinoma (HCC), and those with cholangiocarcinoma (ICC).MethodsBetween November 1994 and December 2003, 952 patients underwent hepatic resection for a PHN.ResultsThe incidence of HCC-CC was 3.5%. Hepatitis B surface antigen was positive in 51.2% of these patients and the HCV antibody was positive in 12.2%. Positive hepatitis serology was more common in the HCC group (66.7%). The prevalence of underlying liver cirrhosis was significantly lower in the ICC group (7.8%) than in the HCC (49%) and HCC-CC (41.5%) groups (P < 0.0001). The median overall survival periods after hepatic resection of HCC-CC, HCC, and ICC were 47.3, 71.7, and 21.5 months, respectively (P < 0.0001). The median disease-free survival (DFS) periods after hepatic resection for HCC-CC, HCC, and ICC were 23.4, 68.2, and 15.5 months, respectively (P < 0.0001).ConclusionPatients with transitional type HCC-CC had significantly poorer survival rates than those with HCC, after hepatic resection. Therefore, a more aggressive treatment modality should be explored to improve the survival rate of these patients.

High hilar dissection: New technique to reduce biliary complication in living donor liver transplantation

Biliary complications after living donor liver transplantation (LDLT) continue to be problematic. For reducing the biliary complications, the authors applied an intrahepatic Glissonian approach to the recipient hepatectomy. We called this Glissonian dissection technique at the high hilar level high hilar dissection (HHD). In this study, we introduced this HHD technique and evaluated its outcome in 31 recipients of a living donor liver transplant (LDLT). With total occlusion of hepatoduodenal ligament Glissonia pedicles were divided at the intrahepatic level at the third level of pedicles or beyond. After portal vein and hepatic artery were isolated from the hepatoduodenal ligament, unused bile ducts and bleeding were controlled with continuous suture of the hilar plate. Single duct anastomosis was performed in about 21 and dual duct anastomosis in 10 recipients. Bile leakage of the biliary anastomosis did not occur. There were 6 biliary complications in five patients; 2 bile leaks from the cut liver surface and 4 biliary strictures of which one of unknown etiology. In none of the patients with biliary complications, conversion to a hepaticojejunostomy was necessary. This new HHD technique during recipient hepatectomy may contribute to reduce the biliary complications in duct‐to‐duct anastomosis by allowing a tension free anastomosis and preserving adequate blood supply to the bile duct. Moreover, it facilitates multiple ductal anastomoses without difficult surgical manipulation. (Liver Transpl 2004;10:1158–1162.)

Characterization, in vitro cytotoxicity assessment, and in vivo visualization of multimodal, RITC-labeled, silica-coated magnetic nanoparticles for labeling human cord blood-derived mesenchymal stem cells.

UNLABELLED Live imaging is a powerful technique that can be used to characterize the fate and location of stem cells in animal models. Here we investigated the characteristics and in vitro cytotoxicity of human mesenchymal stem cells (MSCs) labeled with silica-coated magnetic nanoparticles incorporating rhodamine B isothiocyanate, MNPs@SiO2(RITC). We also conducted various in vivo-uptake tests with nanoparticle-labeled human MSCs. MNPs@SiO2(RITC) showed photostability against ultraviolet light exposure and were nontoxic to human MSCs, based on the MTT, apoptosis, and cell cycle arrest assays. In addition, MNPs@SiO2(RITC) did not affect the surface phenotype or morphology of human MSCs. We also demonstrated that MNPs@SiO2(RITC) have stable retention properties in MSCs in vitro. Furthermore, using optical and magnetic resonance imaging, we successfully detected a visible signal from labeled human MSCs that were transplanted into NOD.CB17-Prkdc(SCID) (NOD-SCID) mice. These results demonstrate that MNPs@SiO2(RITC) are biocompatible and useful tools for human MSC labeling and bioimaging. FROM THE CLINICAL EDITOR The characteristics and in vitro cytotoxicity of human mesenchymal stem cells (MSCs) labeled with silica-coated magnetic nanoparticles incorporating rhodamine B isothiocyanate, RITC were investigated in this study. RITC showed photostability against ultraviolet light exposure and was nontoxic to human MSCs. Using both optical and magnetic resonance imaging, successful detection of signal from labeled human MSCs transplanted into mice is demonstrated.

Patterns of failure in gastric carcinoma after D2 gastrectomy and chemoradiotherapy: a radiation oncologist's view

The risk of locoregional recurrence in resected gastric adenocarcinoma is high, but the benefit of adjuvant treatment remains controversial. In particular, after extended lymph node dissection, the role of radiotherapy is questionable. Since 1995, we started a clinical protocol of adjuvant chemoradiotherapy after D2 gastrectomy and analysed the patterns of failure for 291 patients. Adjuvant chemotherapy consisted of five cycles of fluorouracil and leucovorin, and concurrent radiotherapy was given with 4500 cGy from the second cycle of chemotherapy. With a median follow-up of 48 months, 114 patients (39%) showed any type of failure, and the local and regional failures were seen in 7% (20 out of 291) and 12% (35 out of 291), respectively. When the recurrent site was analysed with respect to the radiation field, in-field recurrence was 16% and represented 35% of all recurrences. Our results suggest that adjuvant chemoradiotherapy has a potential effect on reducing locoregional recurrence. Moreover, low locoregional recurrence rates could give a clue as to which subset of patients could be helped by radiotherapy after D2 gastrectomy. However, in order to draw a conclusion on the role of adjuvant radiotherapy, a randomised study is needed.