Su Cheol Park

Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization

The objective of this study was to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) as a local salvage treatment after incomplete transarterial chemoembolization (TACE) for inoperable hepatocellular carcinoma (HCC).

Preliminary result of stereotactic body radiotherapy as a local salvage treatment for inoperable hepatocellular carcinoma.

To evaluate the toxicity and efficacy of stereotactic body radiotherapy (SBRT) for the treatment of localized hepatocellular carcinoma (HCC) in the absence of another standard treatment option.

High-dose stereotactic body radiotherapy correlates increased local control and overall survival in patients with inoperable hepatocellular carcinoma

BackgroundRecent studies using stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) have reported high tumor response and local control. However, the optimal SBRT dose remains unknown, and it is still not clear whether a dose response relationship for local control (LC) and overall survival (OS) exist or not. We performed this study to determine whether a dose response relationship for LC and OS is observed in SBRT for inoperable HCC.MethodsBetween 2003 and 2011, 108 patients with HCC were treated with SBRT. All patients were unsuitable for surgery or local ablation and had incomplete response to transarterial chemoembolization. Eighty-two patients with a longest tumor diameter (LD) less than or equal to 7.0 cm who were treated with 3-fraction SBRT and were analyzed. This cohort comprised 74 Child-Turcotte-Pugh (CTP) class A patients and 8 CTP class B7 patients. The median LD was 3.0 cm (range, 1.0–7.0 cm), and the median dose was 51 Gy (range, 33–60 Gy).ResultsLC and OS rates at 2 years after SBRT were 87% and 63%, respectively, with a median follow-up duration of 30 months for all patients. The 2-year LC/OS rates for patients treated with doses of > 54, 45–54, and < 45 Gy were 100/71, 78/64, and 64%/30%, respectively (p = .009/p < .001). Multivariate analysis revealed that the SBRT dose (p = .005) and Barcelona Clinic Liver Cancer stage (p = .015) were significant prognostic factors for OS. Correlation analysis revealed a positive linear relationship between the SBRT dose and LC (p = .006, R = .899)/OS (p = .002, R = .940) at 2 years. Based on the tumor-control probability model, a dose of 54.8 Gy provides 2-year LC with a 90% probability. Five patients experienced grade 3 or higher gastrointestinal toxicity, and 6 had deteriorating of CTP score by greater than or equal to 2 within 3 months of SBRT.ConclusionsThis study demonstrated a dose response relationship for LC and OS with SBRT for HCC. Higher LC rates resulting from an increased dose may translate into survival benefits for patients with HCC.

High prevalence of hepatitis B virus infection in patients with B-cell non-Hodgkin's lymphoma in Korea.

This study assessed the association of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection with non‐Hodgkins lymphoma in a highly HBV‐endemic area. The prevalence of either HBV or HCV infection in 235 patients with non‐Hodgkins lymphoma was compared with that of an age‐ and sex‐matched hospital control group of 235 patients. The prevalence of HBV infection was higher in B‐cell non‐Hodgkins lymphoma (15.5%) than control (8.1%), but the prevalence of HCV infection in the non‐Hodgkins lymphoma patients (2.1%) and control group (3%) was similar. HBV prevalence increased significantly with age in the B‐cell non‐Hodgkins lymphoma patients. The presence of HBV proteins and DNA in lymphoma tissues and peripheral blood mononuclear cells (PBMCs) from HBV‐infected non‐Hodgkins lymphoma patients was also investigated using immunohistochemistry and PCR. HBV DNA was frequently detected in PBMCs from HBV‐infected non‐Hodgkins lymphoma patients, but HBV antigens were not. Therefore, HBV infection, but not HCV infection, was associated with B‐cell non‐Hodgkins lymphoma in Korea, suggesting a possible role for HBV in the development of non‐Hodgkins lymphoma. J. Med. Virol. 80:960–966, 2008.

Combined inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors

PurposeH1650 non-small cell lung cancer (NSCLC) cells display primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) although they have a deletion mutation on exon 19 of the EGFR gene. We investigated the effect of inhibition of both insulin-like growth factor receptor (IGFR) and EGFR signaling considering that IGFR signaling pathway has been implicated in the development and progression with therapeutic resistance of various cancers including lung cancer.MethodsThree human NSCLC cell lines with an EGFR mutation of PC-9, HCC827 and H1650 were used for experiment. Cell viability and proliferative activity were assessed by MTT and three-dimensional culture assay. Combination index was obtained by CalcuSyn software. The change of EGFR- and IGFR-related signals was evaluated by western blots.ResultsH1650 cells were 1,000 times more resistant to gefitinib and erlotinib than HCC827 and PC-9 cells possessing the same EGFR mutation. Phosphatase and tensin homolog loss and sustained phosphorylation of Akt in spite of treatment with gefitinib were evident only in H1650 cells. Interestingly, IGFR phosphorylation was decreased by gefitinib in HCC827 and PC-9 cells while being maintained in H1650 cells. Combined treatment with the IGFR inhibitors α-IR3 and AG1024 enhanced gefitinib-induced growth inhibition and apoptosis, and down-regulated phosphorylation of Akt, EGFR and IGFR.ConclusionCombined inhibition of IGFR signaling enhances the growth inhibitory and apoptosis-inducing effects of gefitinib, suggesting that this approach could be useful to overcome the primary resistance to EGFR-TKIs in lung cancer.

Feasibility and Efficacy of Stereotactic Ablative Radiotherapy for Barcelona Clinic Liver Cancer-C Stage Hepatocellular Carcinoma

The purpose of this study was to assess the feasibility and efficacy of stereotactic ablative radiotherapy (SABR) for liver tumor in patients with Barcelona Clinic Liver Cancer (BCLC)-C stage hepatocellular carcinoma (HCC). We retrospectively reviewed the medical records of 35 patients between 2003 and 2011. Vascular invasion was diagnosed in 32 patients, extrahepatic metastases in 11 and both in 8. Thirty-two patients were categorized under Child-Pugh (CP) class A and 3 patients with CP class B. The median SABR dose was 45 Gy (range, 30-60 Gy) in 3-5 fractions. The median survival time was 14 months. The 1- and 3-yr overall survival (OS) rate was 52% and 21%, respectively. On univariate analysis, CP class A and biologically equivalent dose ≥ 80 Gy10 were significant determinants of better OS. Severe toxicity above grade 3, requiring prompt therapeutic intervention, was observed in 5 patients. In conclusion, SABR for BCLC-C stage HCC showed 1-yr OS rate of 52% but treatment related toxicity was moderate. We suggest that patients with CP class A are the best candidate and at least SABR dose of 80 Gy10 is required for BCLC-C stage.

Hedgehog Signaling Between Cancer Cells and Hepatic Stellate Cells in Promoting Cholangiocarcinoma

BackgroundAberrant Hedgehog (HH) signaling activation is important in cancer growth and mediates the interaction between cancer cells and the surrounding stromal cells. This study investigated the role of HH signaling on the growth of cholangiocarcinoma (CC), focusing on the interaction of CC cells with stromal cells.MethodsTo evaluate the interaction between human CC cells (SNU-1196, SNU-246, SNU-308, SNU-1079, and HuCCT-1) and stromal cells (hepatic stellate cell line, Lx-2), co-culture proliferation, migration, and invasion assays were performed. In vivo nude mice experiments were conducted using two groups—HuCCT-1 single implant xenograft (SX) and co-implant xenograft (CX) with HuCCT-1 and Lx-2.ResultsWhen HuCCT-1 cells were co-cultured with Lx-2 cells, the expression of HH signaling-related proteins increased in both HuCCT-1 and Lx-2 cells. Co-culture with Lx-2 cells stimulated the proliferation, migration, and invasion of CC cells, and these effects were mediated by HH signaling. Co-culture of HuCCT-1 and Lx-2 cells increased the secretion of several cytokines. In an ectopic xenograft model, Lx-2 co-implantation increased CC tumor growth and stimulated angiogenesis. Cyclopamine attenuated tumor growth in the CX group, but not in the HuCCT-1 mono-implant (SX) group. Cyclopamine treatment decreased CC cell proliferation, suppressed microvessel density, and increased tumor necrosis in the CX group, but not in the SX group.ConclusionHepatic stellate cells stimulate the proliferation, migration, and invasion of CC cells, promote angiogenesis through HH signaling activation, and render CC more susceptible to necrosis by HH inhibitor.

Pilot study of stereotactic body radiotherapy for huge hepatocellular carcinoma unsuitable for other therapies

Aims To determine the feasibility and efficacy of stereotactic body radiotherapy (SBRT) for huge hepatocellular carcinoma unsuitable for other therapies. Methods Six patients with very large hepatocellular carcinomas (>10 cm) unsuitable for surgical resection or that failed to respond to transcatheter arterial chemoembolization (TACE) were treated by SBRT. Doses ranged from 32 Gy to 40 Gy in four fractions. Survival, response, and toxicities were evaluated. Results After a median follow-up of 25.9 months (range 8.1-56 months), three patients had died and three were alive. Overall, treatment was well tolerated and no dose-limiting toxicity or radiation-induced liver disease was observed. The median survival was 10 months (range 3–56 months) and the median progression-free duration was 6 months (range, 2–21 months). Partial response was achieved by four patients, stable disease by one, and one patient had disease progression. One patient with a partial response who underwent lobectomy after SBRT was alive 56 months post-SBRT. Conclusion This study suggests that SBRT can be delivered safely at 32–40 Gy in four fractions to huge hepatocellular carcinoma. Furthermore, combinations of SBRT with other modalities such as surgery or TACE might prolong survival.

Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells

Background/Aims Silibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells. Methods Several different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis. Results Gefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin. Conclusions Combined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future.

Low Hepatic Toxicity in Primary and Metastatic Liver Cancers after Stereotactic Ablative Radiotherapy Using 3 Fractions.

This study evaluated the incidence of hepatic toxicity after stereotactic ablative radiotherapy (SABR) using 3 fractions to the liver, and identified the predictors for hepatic toxicity. We retrospectively reviewed 78 patients with primary and metastatic liver cancers, who underwent SABR using 3 fractions between 2003 and 2011. To examine the incidence of hepatic toxicity, we defined newly developed hepatic toxicity≥grade 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 within 3 months after the end of SABR as a significant adverse event. To identify the predictors for hepatic toxicity, we analyzed several clinical and dosimetric parameters (rV5Gy-rV35Gy: normal liver volume receiving <X Gy, reverse VXGy). Hepatic toxicity≥grade 2 occurred in 10 patients (13%): grade 2 in 9 patients and grade 3 in 1 patient. On univariate analysis, baseline Child-Pugh (CP) score (5 vs. 6-8), normal liver volume, and planning target volume were the significant clinical predictors. All dosimetric parameters were significant: rV20Gy was the most significant predictor. On multivariate analysis, baseline CP score (hazard ratio, 0.026; P=0.001) was the only significant predictor. In conclusion, SABR using 3 fractions in primary and metastatic liver cancers produces low hepatic toxicity, especially in patients with a baseline CP score of 5. However, further studies are needed to minimize hepatic toxicity in patients with baseline CP scores≥6. Graphical Abstract