A phase 2 multicenter study of stereotactic body radiotherapy for hepatocellular carcinoma: Safety and efficacy.

BACKGROUND: Although several prospective studies have reported the efficacy of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC), treatment-related toxicity varies and has not been determined. Therefore, the authors evaluated the safety and efficacy of SBRT for patients with HCC in a hepatitis B virus-endemic area. METHODS: This multicenter phase 2 trial enrolled patients with unresectable HCC. Patients received SBRT with 45 to 60 Gy in 3 fractions. To evaluate gastroduodenal toxicity, esophagogastroduodenoscopy (EGD) was performed before and 2 months after SBRT. The primary endpoint was treatment-related severe toxicity at 1 year after SBRT. The secondary endpoints were the 2-year local control, progression-free survival, and overall survival rates. RESULTS: In total, 74 patients were enrolled between January 2012 and April 2015, and 65 eligible patients were analyzed. One patient experienced radiation-induced liver disease with acute grade ≥3 toxicity 1 month after SBRT. In addition, 1 patient had a grade 3 esophageal ulcer with stenosis 5 months after SBRT. The actuarial rate of treatment-related severe toxicity at 1 year was 3%. The pre-SBRT and post-SBRT EGD findings were not significantly different among the 57 evaluable patients who underwent EGD. The 2-year and 3-year local control rates were 97% and 95%, respectively. The progression-free and overall survival rates were 48% and 84% at 2 years, respectively, and 36% and 76% at 3 years, respectively. CONCLUSIONS: With a median follow-up of 41 months, this prospective multicenter study demonstrated that SBRT for patients with HCC is well tolerated and is an effective treatment modality.

Depletion of proteasome subunit PSMD1 induces cancer cell death via protein ubiquitination and DNA damage, irrespective of p53 status.

Hepatocellular carcinoma (HCC) is characterized by high incidence and fatality rates worldwide. In our exploration of prognostic factors in HCC, the 26s proteasome subunit, non-ATPase 1 (PSMD1) protein emerged as a significant contributor, demonstrating its potential as a therapeutic target in this aggressive cancer. PSMD1 is a subunit of the 19S regulatory particle in the 26S proteasome complex; the 19S particle controls the deubiquitination of ubiquitinated proteins, which are then degraded by the proteolytic activity of the complex. Proteasome-targeting in cancer therapy has received significant attention because of its practical application as an established anticancer agent. We investigated whether PSMD1 plays a critical role in cancer owing to its prognostic significance. PSMD1 depletion induced cell cycle arrest in G2/M phase, DNA damage and apoptosis of cancer cells, irrespective of the p53 status. PSMD1 depletion-mediated cell death was accompanied by an increase in overall protein ubiquitination. These phenotypes occurred exclusively in cancer cells, with no effects observed in normal cells. These findings indicate that PSMD1 depletion-mediated ubiquitination of cellular proteins induces cell cycle arrest and eventual death in cancer cells, emphasizing PSMD1 as a potential therapeutic target in HCC.

A Cell-Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer-Specific Synthetic Lethality.

Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof-of-principle evidence is presented that a cell-penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene-addicted cancer cells through transcription activity-independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2-p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome-wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C-resistant cancers. This study enhances the understanding of ACP52C-induced cancer-specific apoptosis induction and supports the use of ACP52C in anticancer drug development.

NPFFR2 Contributes to the Malignancy of Hepatocellular Carcinoma Development by Activating RhoA/YAP Signaling.

G protein-coupled receptors (GPCRs) are a diverse family of cell surface receptors implicated in various physiological functions, making them common targets for approved drugs. Many GPCRs are abnormally activated in cancers and have emerged as therapeutic targets for cancer. Neuropeptide FF receptor 2 (NPFFR2) is a GPCR that helps regulate pain and modulates the opioid system; however, its function remains unknown in cancers. Here, we found that NPFFR2 is significantly up-regulated in liver cancer and its expression is related to poor prognosis. Silencing of NPFFR2 reduced the malignancy of liver cancer cells by decreasing cell survival, invasion, and migration, while its overexpression increased invasion, migration, and anchorage-independent cell growth. Moreover, we found that the malignant function of NPFFR2 depends on RhoA and YAP signaling. Inhibition of Rho kinase activity completely restored the phenotypes induced by NPFFR2, and RhoA/F-Actin/YAP signaling was controlled by NPFFR2. These findings demonstrate that NPFFR2 may be a potential target for the treatment of hepatocellular carcinoma.

Prognosis after intrahepatic recurrence in the patients who underwent curative resection for hepatocellular carcinoma.

BACKGROUNDS/AIMS: Intrahepatic recurrence is frequent result after hepatectomy for hepatocellular carcinoma (HCC). We analyzed the clinical results of patients who had the intrahepatic recurrences of HCC after curative surgical resections. METHODS: From January 2009 to December 2016, 320 patients underwent curative surgical resection for HCC in department of Surgery, Korea Cancer Center Hospital. After surgical resection, 155 patients had suffered HCC recurrence during follow-up period. Among them, 122 patients had only intrahepatic recurrence initially, who were included in this retrospective study. We analyzed about the period of the recurrence after surgery, treatment methods for the recurred tumors, and poor prognostic factors for survival after intrahepatic recurrences. RESULTS: Among the 122 patients, 83 patients had recurrence within 24 months after surgery. Thirty-eight patients underwent curative treatment for the recurred tumors (re-resection in 18, radiofrequency ablation in 20 patients). Non-curative treatments were performed in 77 patients (TACE in 68 patients, radiotherapy in 9 patients) and conservative management in 7 patients. Five-year survival rate of patients who underwent curative treatment is 86.4% (p≤0.001). Five-year survival rate of non-curative treatment is 55.7% (p≤0.001), conservative management is 0% (p=0.021). Among the clinical factors, non-curative treatment for recurred tumor, AFP level at the time of recurrence, size of recurred tumor were independent poor prognostic factors for survival after intrahepatic recurrences (p<0.001). CONCLUSIONS: For the patients who had intrahepatic recurrent HCC after surgery, aggressive local treatment can improve the prognosis in selective cases. Further study is necessary to validate this retrospective investigation.

Comparison of the clinical results of surgical resection for extrahepatic cholangiocarcinomas: Hilar cholangiocarcinoma and mid-to-distal cholangiocarcinoma.

BACKGROUNDS/AIMS: Hilar cholangiocarcinomas (HLC) are known to have worse prognoses than mid-to-distal cholangiocarcinomas (CBDC). We analyzed the clinical results of surgical resections for extrahepatic cholangiocarcinomas to validate the differences in the prognoses of HLC and CBDC. METHODS: Two hundred and eighty-one patients underwent curative surgical resections for extrahepatic cholangiocarcinomas at the Department of Surgery in the Korea Cancer Center Hospital. Among them, we analyzed the T2 and T3 patients and compared the clinical results between those with HLC (n=74) and those with CBDC (n=65). RESULTS: The rate of R1 resections was significantly higher in the HLC patients compared to the CBDC patients (31.1% vs 12.3%, p=0.006). The overall survival rate of the T2/T3 patients was lower in the HLC group than in the CBDC group (24.5% vs 51.7, p=0.039). The recurrence-free survival rate was 23.3% in the HCL patients and 50.9% in the CBDC patients (p=0.06). In the subgroup analysis, the survival rates were not different in patients who had lymph node metastases or in patients who underwent R1 resections between the HLC and CBDC patients. Poor independent prognostic factors for the overall and recurrence-free survival rates in the T2/T3 extrahepatic cholangiocarcinoma patients were the presence of lymph node metastases and the hilar locations of tumor. CONCLUSIONS: HLC patients had poorer prognoses than CBDC patients. However, in patients with lymph node metastases, the prognosis was poor and was not different between the HLC and CBDC patients. Other adjuvant treatment methods are needed for extrahepatic cholangiocarcinoma patients with lymph node metastases to improve their prognoses.

Effect of preoperative biliary drainage on surgical results after pancreaticoduodenectomy in patients with distal common bile duct cancer: focused on the rate of decrease in serum bilirubin.

AIM: To examine if the rate of decrease in serum bilirubin after preoperative biliary drainagecan be used as a predicting factor for surgical complications and postoperative recovery after pancreaticoduodenectomy in patients with distal common bile duct cancer. METHODS: A retrospective study was performed in 49 consecutive patients who underwent pancreaticoduodenectomy for distal common bile duct cancer. Potential risk factors were compared between the complicated and uncomplicated groups. Also, the rates of decrease in serum bilirubin were compared pre- and postoperatively. RESULTS: Preoperative biliary drainage (PBD) was performed in 40 patients (81.6%). Postoperative morbidity and mortality rates were 46.9% (23/49) and 6.1% (3/49), respectively. The presence or absence of PBD was not different between the complicated and uncomplicated groups. In patients with PBD, neither the absolute level nor the rate of decrease in serum bilirubin was significantly different. Patients with rapid decrease preoperatively showed faster decrease during the first postoperative week (5.5 +/- 4.4 micromol/L vs -1.7 +/- 9.9 micromol/L, P = 0.004). CONCLUSION: PBD does not affect the surgical outcome of pancreaticoduodenectomy in patients with distal common bile duct cancer. There is a certain group of patients with a compromised hepatic excretory function, which is represented by the slow rate of decrease in serum bilirubin after PBD.

TMEM165, a Golgi transmembrane protein, is a novel marker for hepatocellular carcinoma and its depletion impairs invasion activity.

Transmembrane protein 165 (TMEM165), a Golgi protein, functions in ion homeostasis and vesicular trafficking in the Golgi apparatus. While mutations in TMEM165 are known to cause human 'congenital disorders of glycosylation', a recessive autosomal metabolic disease, the potential association of this protein with human cancer development has not been explored to date. In the present study, we revealed that TMEM165 is overexpressed in HCC and its depletion weakens the invasive activity of cancer cells through suppression of matrix metalloproteinase­2 (MMP­2) expression. Levels of TMEM165 mRNA and protein were clearly increased in HCC patient tissues and cell cultures. Quantitative real­time RT­PCR analysis of fresh HCC tissues (n=88) revealed association of TMEM165 overexpression with more frequent macroscopic vascular invasion, microscopic serosal invasion and higher α­fetoprotein levels. Notably, depletion of TMEM165 led to a marked decrease in the invasive activity of two different HCC cell types, Huh7 and SNU475, accompanied by downregulation of MMP­2. Our collective findings clearly indicated that TMEM165 contributed to the progression of HCC by promoting invasive activity, supporting its utility as a novel biomarker and therapeutic target for cancer.

Protein arginine methyltransferase 5 is implicated in the aggressiveness of human hepatocellular carcinoma and controls the invasive activity of cancer cells.

Protein arginine methyltransferase 5 (PRMT5) is a protein that catalyzes transfer of methyl groups to the arginine residues of proteins and is involved in diverse cellular and biological responses. While the participation of PRMT5 in cancer progression has been increasingly documented, its association with the invasive phenotype currently remains poorly understood. In the present study, we revealed that PRMT5 is overexpressed in human hepatocellular carcinoma (HCC) and in colon cancer and its depletion leads to the suppression of cell invasive activity via the reduction of the expression of MMP-2. Real-time quantitative RT-PCR analysis of 120 HCC patient tissues revealed the overexpression of PRMT5 in HCC and the association of PRMT5 with aggressive clinicopathological parameters, such as poorer differentiation (P=0.004), more frequent hepatic vein invasion (P=0.019), larger tumor size (P=0.011) and higher α-fetoprotein levels (P=0.020). Similarly to the data obtained with HCC, overexpression of PRMT5 was also displayed in colon cancer tissues, compared to matched non-tumor regions. Consistent with the significant association of the overexpression of PRMT5 with hepatic vein invasion in patient specimens, PRMT5 depletion via siRNA transfection led to a marked reduction in the invasion rate in both HCC and colon cancer cells. Reduced invasion associated with PRMT5 depletion was accompanied by a decrease in the expression of MMP-2. Collectively, our results indicated that PRMT5 overexpression in HCC and colon cancer cells contributed to their acquisition of aggressive characteristics, such as invasiveness, thus presenting a promising therapeutic target for the treatment of these diseases.

A revised scoring system utilizing serum alphafetoprotein levels to expand candidates for living donor transplantation in hepatocellular carcinoma.

BACKGROUND: The development of living donor liver transplantation has stimulated discussion about the expansion of tumor burden limits for patients with hepatocellular carcinoma (HCC). Although serum alphafetoprotein (AFP) level is an important predictor of tumor recurrence, it is not included in the existing selection criteria for HCC in transplantation. METHODS: We performed a retrospective study of 63 consecutive adults with HCC diagnosed preoperatively who received living donor liver transplantation from February 1999 to September 2005 and survived over 1 month. The authors devised new scoring criteria that included tumor size, tumor number, and pretransplant AFP level as prognostic factors. The score of each parameter was classified from 1 to 4 points (tumor size, < or =3, 3.1 to 5, 5.1 to 6.5, >6.5 cm; tumor number, 1, 2 or 3, 4 or 5, or > or =6 nodules; and AFP, < or =20, 20.1 to 200, 200.1 to 1000, >1000 ng/mL, respectively). We defined that 3 to 6 points and 7 to 12 points were "transplantable" and "nontransplantable," respectively. The usefulness of the devised criteria was then investigated as a method of selecting candidates with HCC for transplantation. RESULTS: The candidates' overall 3-year survival rate and recurrence-free survival rate were 67% and 70% after transplantation, respectively. Based on pretransplant imaging, 37 (59%), 41 (65%), and 44 (70%) of the 63 patients met the Milan criteria, University of Californica, San Francisco (UCSF) criteria, and the new scoring criteria. Their 3-year survival rates were 80%, 78%, and 79%, respectively. Moreover, based on posttransplant data, the scoring criteria correlated with the risk of death and HCC recurrence (Milan criteria, P = .005 and .001; UCSF criteria, P = .013 and .001 for death and recurrence; scoring criteria, P < .001 for both). CONCLUSIONS: The newly devised scoring criteria could expand usefully current selection criteria for transplantation without detrimentally affecting outcome in the living donor transplantation setting for HCC.

Liver transplantation for hepatocellular carcinoma in patients who do not meet the Milan criteria.

BACKGROUND: To expand the Milan criteria, prognostic factors other than size and number of tumor may be necessary. We analyzed outcome and prognostic factors in patients with hepatocellular carcinoma (HCC) exceeding Milan criteria to select favorable group of patients. METHODS: Between November 1997 and December 2005, 104 cases of liver transplantation for patients with HCC were performed at our center. Twenty-four patients did not meet the Milan criteria preoperatively. Among these 24 patients, 19 had no major vascular invasion at the time of surgery. We analyzed the survival and prognostic factors of these 19 patients. The mean follow-up period was 33 months (range 6-89). RESULTS: Three-year survival rate in 19 patients was 67.4%. Three-year survival rates were significantly higher when preoperative alpha-fetoprotein was less than 400 ng/ml (86.2 vs. 0%, p<0.001) when Edmonson-Steiner's histological grade 1 or 2 (100 vs. 40%, p = 0.036) and when microvascular invasion was absent (78.6 vs. 30%, p = 0.039). CONCLUSION: If vascular invasion is absent in preoperative radiological studies, and the preoperative alpha-fetoprotein is less than 400 ng/ml, our findings suggest a good prognosis after liver transplantation for HCC patients who do not meet the Milan criteria.

Anatomic versus non-anatomic resection for small single hepatocellular carcinomas.

BACKGROUND/AIMS: Anatomical hepatectomy for small hepatocellular carcinomas (HCCs) is widely preferred but evidence concerning its benefits is inadequate. The aim of this study was to determine whether patient outcome is influenced by the method used to treat small single HCCs. METHODOLOGY: An analysis was performed on 168 patients who underwent curative hepatectomy for a single HCC smaller than 5cm between Jan 1998 and Dec 2001 at Seoul National University Hospital. Ninety-nine of these patients underwent anatomic resection and 69 patients non-anatomic resection. Overall survival rates, disease-free survival rates, and prognostic factors for survival and recurrence were analyzed. RESULTS: The cumulative 1-, 3- and 5-year overall survival rates were 86.9%, 73.6% and 65.5% in the anatomic resection group, and 88.4%, 63.8% and 49.7%% in the non-anatomic resection group, respectively (P = 0.032). And, the cumulative 1-, 3- and 5-year disease-free survival rates were 77.8%, 58.6% and 54.4% in the anatomic resection group and 62.3%, 42.0% and 28.6% in the non-anatomic resection group, respectively (P = 0.003). Anatomic resection was confirmed to be an independent favorable factor of disease-free survival by multivariate analysis. CONCLUSIONS: Anatomic resection for single small HCCs is superior to non-anatomic resection.

Preoperative lamivudine therapy in HBV DNA positive recipients: is it always necessary?

BACKGROUND/AIMS: Long-term preoperative lamivudine therapy has been recommended for patients with positive HBV DNA to suppress HBV replication before liver transplantation. However, it is unclear whether preoperative lamivudine therapy is mandatory in HBV DNA positive patients to reliably prevent HBV recurrence or whether transplantation should be delayed to allow time for sufficient preoperative lamivudine therapy. METHODOLOGY: From January 2000 to January 2004, thirty-eight patients serum positive for HBV DNA who survived more than 3 months after transplantation and received postoperative combination prophylaxis with hepatitis B immune globulin and lamivudine were enrolled. RESULTS: Total 2-year recurrence rate was 8.7%. When these 38 patients were divided into two groups according to preoperative lamivudine therapy duration: group 1 (n = 11) 4 weeks or more and group 2 (n = 27) less than 4 weeks, recurrences were detected in 3 (27.2%) and 4 (14.8%) patients in groups 1 and 2, respectively, i.e. a similar recurrence rate in both groups (p = 0.390). Moreover, in a subgroup of 20 patients who received preoperative lamivudine therapy for less than one week, only one (5%) experienced HBV recurrence. CONCLUSIONS: Our findings indicate that postoperative combination prophylaxis is effective and that preoperative lamivudine therapy is unlikely to be obligatory despite a positive preoperative serum HBV DNA status.

Acute graft versus host disease following living donor liver transplantation: first Korean report.

Graft-versus-host disease (GVHD) after liver transplantation is an uncommon fatal complication and no effective preventive or therapeutic measure is available. We report the first case of fatal GVHD after liver transplantation in Korea. A 51-year-old male underwent living donor liver transplantation for hepatitis B virus (HBV)-related liver cirrhosis and hepatocellular carcinoma. The donor was his 21-year-old son. The patient was discharged uneventfully. However, 56 days after transplantation, he was readmitted due to watery diarrhea, which was subsequently accom-panied by a skin rash and leukopenia. Diagnosis was made by skin biopsy and by donor DNA chimerism testing in recipient tissue. A one-way donor-recipient HLA match was identified by HLA typing for both donor and recipient. The patient was treated by increasing immunosuppression, but died of septic shock. A pretransplant HLA typing of both donor and recipient should be taken, and in cases of one-way donor-recipient HLA matching, liver transplantation should be avoided.

Promoter methylation of cysteine dioxygenase type 1: gene silencing and tumorigenesis in hepatocellular carcinoma.

BACKGROUNDS/AIMS: Cysteine dioxygenase type 1 (CDO1) acts as a tumor suppressor and is silenced by promoter methylation in various malignancies. The relationship between the CDO1 methylation status and hepatocellular carcinoma (HCC) tumorigenesis was evaluated. METHODS: Using a HCC cell line (SNU423), an in vitro demethylation study was performed to confirm whether promoter methylation causes CDO1 down-regulation. The SNU423 cells transfected with the CDO1 cell function was compared to that of naïve cells. An in vivo study using immunohistochemical staining of HCC specimens that were collected from patients who underwent curative liver resection was also performed. RESULTS: CDO1 was activated after demethylation treatment in the HCC specimens. Moreover, tumor cell proliferation, colony-forming, migration, and invasion activities significantly decreased after CDO1 transfection (p<0.05). The percentage of tumors that were larger than 5 cm was higher in patients who had a lower expression of CDO1 (p=0.030). Vascular invasion and histological grade were independent prognostic factors for poor overall and recurrence-free survival. The degree of CDO1 expression was not an independent prognostic factor in this study's population. CONCLUSIONS: These results suggested that methylation down-regulated CDO1 expression in the HCC cells. CDO1 methylation may be a potentially valuable diagnostic biomarker for HCC.

The mitochondrial hinge protein, UQCRH, is a novel prognostic factor for hepatocellular carcinoma.

Alterations in mitochondrial respiration contribute to the development and progression of cancer via abnormal biogenesis, including generation of reactive oxygen species. Ubiquinol-cytochrome c reductase hinge protein (UQCRH) consists of the cytochrome bc1 complex serving respiration in mitochondria. In the present study, we analyzed UQCRH abnormalities in hepatocellular carcinoma (HCC) and its association with clinical outcomes of patients. UQCRH expression in HCC was determined via semiquantitative and quantitative real-time reverse transcriptase polymerase chain reaction of 96 surgically resected HCC tissues positive for hepatitis B virus surface antigen. UQCRH was frequently overexpressed in HCC tissues (46.8%, based on 2.1-fold cutoff). UQCRH overexpression was observed in HCCs with larger tumor size, poorer differentiation, or vascular invasion. Kaplan-Meier analysis revealed significantly shorter overall (P = 0.005) and recurrence-free survival (P = 0.027) in patients with tumors overexpressing UQCRH. The prognostic impact of UQCRH was significant in subgroups of patients divided according to the α-fetoprotein (AFP) level. The patient subgroup with higher AFP levels (≥20 ng/mL) exhibited significant differences in 5-year overall (18.5% vs. 67.9%) and recurrence-free survival rates (11.1% vs. 46.4%) between groups with and without UQCRH overexpression. In contrast, no marked survival differences were observed between subgroups with lower AFP levels (<20 ng/mL). Multivariate analysis defined UQCRH as an independent poor prognostic factor. Conclusively, our results indicate that UQCRH overexpression is correlated with poor outcomes of HCC patients. Furthermore, in patients grouped as high risk based on elevated AFP, lack of UQCRH overexpression could be a useful indicator for clinical treatment.

Surgical clips found at the hepatic duct after laparoscopic cholecystectomy: a possible case of clip migration.

Surgical clip migration and subsequent stone formation in the common bile duct is a rare but well-established complication after laparoscopic cholecystectomy. There are some suggestions about the mechanisms of the migration process, but the details are still unclear. We report here a case in which common bile duct stones were formed around surgical clips, and other clips were found to have penetrated into the common hepatic duct, which we believe were in the process of migration after laparoscopic cholecystectomy. The patient required a laparotomy to retrieve the bile duct stones due to the distal stricture, and another laparotomy was necessary to remove the penetrating clips, which were deeply embedded in the bile duct wall. Although a variety of endoscopic and percutaneous interventional procedures are available in this era of modern medical technology, it is sometimes impractical to apply these procedures in such cases as ours, and exploratory laparotomy is sometimes required to correctly treat the patient. This case shows that the metallic surgical clips can penetrate into the intact bile duct wall through serial maceration, and we believe that careful application of clips may be the only way to prevent their migration after laparoscopic cholecystectomy.

Hepatectomy, combined with intraoperative radiofrequency ablation in patients with multiple hepatocellular carcinomas.

BACKGROUNDS/AIMS: We compared the efficacy and safety of a hepatectomy, combined with intraoperative radiofrequency ablation to those of wider extent hepatectomy, alone, in patients with multiple hepatocellular carcinomas (HCCs). METHODS: Between January 2004 and December 2013, 78 patients with multiple HCCs underwent surgery. 25 patients were treated by hepatectomy, combined with intraoperative radiofrequency ablation (RFA) (group A), and 53 underwent hepatectomy only (group B). We retrospectively analyzed medical records to compare the clinical features of these two groups. RESULTS: Patients in group A had more limited resections (less than 2 segments) than those in group B (p<0.001). Patients in group A also tended to have fewer red blood cell transfusions than those in group B (p=0.060). Liver function- and surgery-related complications occurred only in group B. There were no in-hospital mortalities in both groups. The overall survival and disease-free survival outcomes were not significantly different between groups A and B (p=0.177 and p=0.305, respectively). CONCLUSIONS: Hepatectomy combined with intraoperative RFA could be a safe and effective treatment option for patients with multiple HCCs, comparable to extended hepatectomy alone.

CD44 expression in patients with combined hepatocellular cholangiocarcinoma.

PURPOSE: Combined hepatocellular cholangiocarcinoma (ChC) is a rare type of primary liver cancer, which is thought to have a poorer prognosis than hepatocellular carcinoma (HCC). Cancer stem cells are associated with tumorigenesis, tumor progression, recurrence, metastasis, and poor prognosis in several malignancies including HCC. The aim of this study was to investigate the expression pattern of cancer stem cell markers in ChC and HCC, and to evaluate whether this pattern correlated to patient prognosis. METHODS: Thirteen patients who underwent curative hepatic resection for ChC and 13 patients who underwent curative hepatic resection for HCC (matched control cases) were included. Immunohistochemical staining for cancer stem cell markers (cytokeratin [CK]7, CK19, C-kit, cluster of differentiation [CD] 44, CD133, and epithelial cell adhesion molecule) was performed and clinical outcomes were analyzed retrospectively. RESULTS: There was no significant difference in cancer stem cell marker expression between ChC and HCC. In ChC, the group that expressed CD44 showed earlier recurrence than the group that did not express CD44 (P = 0.040). CONCLUSION: The expression of cancer stem cell markers in ChC did not show a different pattern compared to that found in HCC. The expression of cancer stem cell marker CD44 was associated with poor prognosis in patients with ChC.