Pulmonary Metastasis Of Hepatocellular Carcinoma Research Articles

Dual indocyanine green fluorescence imaging for segmentectomy in pulmonary metastasis of hepatocellular carcinoma: a case report

Dual indocyanine green fluorescence imaging for segmentectomy in pulmonary metastasis of hepatocellular carcinoma: a case report

Pulmonary interleukin 1 beta/serum amyloid A3 axis promotes lung metastasis of hepatocellular carcinoma by facilitating the pre-metastatic niche formation

BackgroundIncreasing evidence suggests a vital role of the pre-metastatic niche in the formation of distant metastasis of many cancers. However, how the pre-metastatic niche is formed and promotes pulmonary metastasis of hepatocellular carcinoma (HCC) remains unknown.MethodsOrthotopic liver tumor models and RNA-Seq were used to identify dysregulated genes in the pre-metastatic lung. Il1b knockout (Il1b−/−) mice and lentivirus-mediated gene knockdown/overexpression were utilized to demonstrate the role of interleukin 1 beta (IL-1β)/serum amyloid A3 (SAA3) in the pre-metastatic niche formation and pulmonary metastasis. The potential molecular mechanisms were investigated by RNA-Seq, real-time quantitative PCR (qPCR), western blotting, immunohistochemistry (IHC), flow cytometry, luciferase reporter assay, double immunofluorescent staining and H&E staining.ResultsAccumulation of myeloid cells and upregulation of IL-1β were observed in the pre-metastatic lung of orthotopic liver tumor models. Myeloid cells accumulation and pulmonary metastasis were suppressed in Il1b−/− mice and Il1r1-silencing mice. Mechanistically, SAA3 and matrix metallopeptidase 9 (MMP9) were identified as potential downstream targets of IL-1β. Overexpression of SAA3 in the lungs of Il1b−/− mice restored myeloid cells accumulation and pulmonary metastasis of the orthotopic HCC xenografts. Moreover, alveolar macrophages-derived IL-1β dramatically enhanced SAA3 expression in alveolar epithelial cells in an NF-κB dependent manner and increased MMP9 levels in an autocrine manner. Furthermore, SAA3 recruited myeloid cells to the lung without affecting the expression of MMP9 in myeloid cells.ConclusionsOur study suggests a key role of pulmonary IL-1β and SAA3 in creating a permissive lung pre-metastatic niche by enhancing MMP9 expression and recruiting myeloid cells, respectively, thus promoting pulmonary metastasis of HCC.

N-acetyl-galactosamine modified metal-organic frameworks to inhibit the growth and pulmonary metastasis of liver cancer stem cells through targeted chemotherapy and starvation therapy

Hepatocellular carcinoma (HCC) is a common high-mortality malignancy which still needs efficient treatments. HCC patients undergoing extrahepatic metastases are mostly with unsatisfactory prognosis. Therefore, specific attention has been paid to extrahepatic HCC metastasis. We integrated Sorafenib (Sor) and glucose oxidase (GOx) into a N-acetyl-galactosamine (GalNAc) modified zeolitic imidazolate framework (ZIF-8), designated as SG@GR-ZIF-8, for targeted bimodal therapies of chemotherapy and starvation therapy against HCC. The hepatic delivery of SG@GR-ZIF was mediated by the specific recognition of GalNAc residues with asialoglycoprotein (ASGPR) on the liver cell surface. Sor is a clinically approved anti-proliferation and anti-angiogenesis drug for advanced HCC treatment. GOx can efficiently induce cell death and disturb malignant progression by suppressing glucose supply of cancer cells, which is highly associated with metabolic rewiring in metastasis. The nano-formulation exhibit significant anti-metastatic HCC activity against C5WN1 cells, a liver cancer stem cell-like cell line with tumorigenicity and pulmonary metastasis activity. In a subcutaneous C5WN1-tumor carrying mouse model, SG@GR-ZIF exhibits potent synergistic anti-tumor activity with a tumor inhibition rate of 89% and a prolonged survival status. The growth and pulmonary metastasis of HCC in an orthotopic mouse model of HCC was remarkably suppressed in SG@GR-ZIF treated group. The therapeutic strategy targeting energy supply combined with first-line treatment holds great promise for the future treatment of metastatic HCC. Statement of significanceSG@GR-ZIF, a N-acetyl-galactosamine modified metal-organic framework carrying Sorafenib and glucose oxidase, was fabricated for treating metastatic hepatocellular carcinoma (HCC). Sorafenib is an anti-proliferation and anti-angiogenesis drug for advanced HCC treatment. Glucose oxidase blocks energy demand in HCC metastasis by depleting glucose. C5WN1 was used for therapeutic evaluations as a liver cancer stem cell-like cell line with tumorigenicity and pulmonary metastasis activity. In subcutaneous C5WN1-tumor bearing mice, SG@GR-ZIF exhibited a tumor inhibition rate of 89% and prolonged survival period. In orthotopic C5WN1-tumor carrying mice, the growth and pulmonary metastasis of hepatocarcinoma was remarkably suppressed by SG@GR-ZIF. Together, this study suggests the great potential of synergistic chemo/starvation therapy mediated by SG@GR-ZIF for treating metastatic HCC.

Stereotactic ablative radiotherapy for pulmonary oligometastases from primary hepatocellular carcinoma: a multicenter and retrospective analysis (KROG 17-08).

Hypofractionated radiotherapy has recently been applied to treat pulmonary metastases of hepatocellular carcinoma. However, there is no definite evidence on its safety and efficacy. We evaluate the clinical outcomes of hypofractionated radiotherapy for oligo pulmonary metastases of hepatocellular carcinoma in the multicenter and retrospective study. From March 2011 to February 2018, 58 patients with fewer than five pulmonary metastases of hepatocellular carcinoma who underwent hypofractionated radiotherapy in nine tertiary university hospitals were analyzed retrospectively. The primary endpoint was the local control rate. The secondary endpoints were overall survival, progression-free survival, prognostic factors affecting the treatment outcomes and treatment-related side effects. The local tumor response rate including complete and partial response was 77.6% at 3months after hypofractionated radiotherapy. The median survival and progression-free survival times were 20.9 and 5.3months, respectively. The 1-year overall survival and progression-free survival rates were 65.5 and 22.4%, respectively. The good treatment response after hypofractionated radiotherapy (P=0.001), the absence of intrahepatic tumor (P=0.004) and Child-Pugh class A (P=0.010) were revealed as significant prognostic factors for overall survival in the multivariate analysis. A progression-free interval of <6months (P=0.009) was a negative prognostic factor for overall survival in the multivariate analysis. Of 58 patients, five (8.6%) had grade 2 or higher radiation pneumonitis after hypofractionated radiotherapy. The favorable local control rate and acceptable toxicity indicate the clinical usefulness of hypofractionated radiotherapy for hepatocellular carcinoma patients who have less than five pulmonary metastases.

Surgical Outcome of Pulmonary Metastasectomy for Hepatocellular Carcinoma Recurrence in Liver Transplant Patients

BackgroundRecurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) results in poor survival outcome. This study assessed the clinical outcomes of pulmonary metastasectomy in LT recipients with pulmonary metastasis of HCC in a high-volume transplant center and analyzed factors prognostic of survival following metastasectomy.Material/MethodsThis study analyzed outcomes in 52 patients who underwent pulmonary resection due to pulmonary metastasis as the first recurrence of HCC after LT from January 2004 to December 2017 in a single center.ResultsThe 52 enrolled patients included 46 men and 6 women, aged 56.0±6.6 years. Their 1-, 3-, and 5-year survival rates after pulmonary resection were 75.0%, 43.5%, and 33.9%, respectively. The 1-, 3-, and 5-year survival rates were 85.3%, 47.1%, and 34.2%, respectively, in patients with further metastases and 55.6%, 38.1%, and 38.1%, respectively, in patients without further metastases (P=0.45). The size and number of pulmonary metastatic nodules were unrelated to survival rates (all P>0.10). A shorter recurrence-free period after LT (hazard ratio [HR]=0.553, P=0.006), elevated alpha-fetoprotein concentration at metastasectomy (HR=2.142, P=0.03), and adjuvant chemotherapy after metastasectomy (HR=3.79, P=0.003) were independent risk factors for survival after metastasectomy.ConclusionsPulmonary metastasectomy for HCC recurrence in LT recipients showed favorable survival outcomes. Independent risk factors for survival after metastasectomy included recurrence-free survival after LT, alpha-fetoprotein level at metastasectomy, and adjuvant chemotherapy after metastasectomy.

Surgical outcomes of pulmonary metastasectomy in hepatocellular carcinoma patients according to approach method: thoracoscopic versus open approach

BackgroundThe role of surgical intervention as a treatment for pulmonary metastasis (PM) from hepatocellular carcinoma (HCC) has not been established. In this study, we investigated the clinical outcomes of pulmonary metastasectomy. Using propensity score matching (PSM) analysis, we compared the results according to the surgical approach: video-assisted thoracic surgery (VATS) versus the open method.MethodsA total of 134 patients (115 men) underwent pulmonary metastasectomy for isolated PM of HCC between January 1998 and December 2010 at Seoul Asan Medical Center. Of these, 84 underwent VATS (VATS group) and 50 underwent thoracotomy or sternotomy (open group). PSM analysis between the groups was used to match them based on the baseline characteristics of the patients.ResultsDuring the median follow-up period of 33.4 months (range, 1.8–112.0), 113 patients (84.3%) experienced recurrence, and 100 patients (74.6%) died of disease progression. There were no overall survival rate, disease-free survival rate, and pulmonary-specific disease-free survival rate differences between the VATS and the open groups (p = 0.521, 0.702, and 0.668, respectively). Multivariate analysis revealed local recurrence of HCC, history of liver cirrhosis, and preoperative alpha-fetoprotein level as independent prognostic factors for overall survival (hazard ratio, 1.729/2.495/2.632, 95% confidence interval 1.142–2.619/1.571–3.963/1.554–4.456; p = 0.010/< 0.001/< 0.001, respectively).ConclusionsMetastasectomy can be considered a potential alternative for selected patients. VATS metastasectomy had outcomes comparable to those of open metastasectomy.

Clinical Factors Predictive of a Better Prognosis of Pulmonary Metastasectomy for Hepatocellular Carcinoma

The lung is the most common site of extrahepatic metastasis of hepatocellular carcinoma (HCC). The aim of this study was to identify prognostic factors for pulmonary metastasectomy of HCC. One hundred three patients who underwent pulmonary metastasectomy for HCC between January 2005 and December 2016 were retrospectively evaluated. Patient demographic data and characteristics of the primary tumors and pulmonary metastasis were investigated to identify factors significantly correlated with prognosis. Of 103 patients, 75 (72.8%) had 1 site pulmonary metastasis, 22 (21.4%) had 2, and 6 (5.8%) had 3 or more. Liver recurrence at the time of pulmonary metastasectomy was noted in 34 patients. The estimated 5-year overall survival rate was 38.5% after pulmonary metastasectomy. Univariate prognostic analysis showed that liver recurrence at the time of pulmonary metastasectomy, extent of resection, laterality of pulmonary metastasis, tumor location, number of metastatic sites, and metastatic tumor size were significantly associated with favorable overall survival after pulmonary metastasectomy. Multivariate analysis revealed that liver recurrence at the time of pulmonary metastasectomy and the number of metastatic sites wereindependent prognostic factors. Subgroup analysis with a combination of these 2 independent prognostic factors revealed 5-year overall survival rates for patients with 0, 1, and 2 risk factors of 58.5%, 23.8%, and 0.0%, respectively. Pulmonary metastasectomy is a safe and effective treatment for well-selected patients with pulmonary metastasis of HCC. Liver recurrence at the time of pulmonary metastasectomy and the number of metastatic sites were identified as independent prognostic factors. The number of risk factors significantly influenced patient survival.

Combination Therapy of Angiotherapy, Radiation Therapy, and Radiofrequency Ablation for Pulmonary Metastasis of Hepatocellular Carcinoma Accompanied by Nontuberculous Mycobacteria

With the advances in hepatocellular carcinoma (HCC) treatment, the lung metastasis of HCC is becoming increasingly important. In treating the lung metastasis of HCC, a multidisciplinary approach can lead to better results than systemic chemotherapy alone. Here, we report on a patient who presented with pulmonary masses, while the HCC was being controlled in the abdominal cavity. The presence of nontuberculous mycobacteria was identified during the diagnosis of the pulmonary masses. The pulmonary metastases of HCC were treated with a combination of angiotherapy, radiation therapy, and radiofrequency ablation. The patient showed a satisfactory progress with this multidisciplinary localized treatment. We report the clinical progress and review the recent literature regarding the treatment of pulmonary metastasis without intrahepatic HCC herein. (J Liver Cancer 2019;19:79-84)

Indocyanine green fluorescence imaging for resection of pulmonary metastasis of hepatocellular carcinoma.

Indocyanine green (ICG) accumulates in hepatocellular carcinoma (HCC), and tumor fluorescence can be observed under irradiation with near infrared light (NIR). This study investigated the clinical utility of ICG fluorescence imaging during resection of pulmonary metastases of HCC. From April 2010 to June 2018, six patients with suspected pulmonary metastasis of HCC were enrolled prospectively. Prior to surgery, all patients underwent the ICG hepatic function test following intravenous administration of ICG (0.5 mg/kg body weight). During surgery, metastatic HCC was identified by observation of ICG fluorescence, allowing assessment of the surgical margin. Tumor fluorescence was also evaluated on cut sections. A total of 11 metastatic HCCs were resected in six patients at nine operations. Eight lesions were removed by wedge resection and 3 lesions were managed by lobectomy. During surgery, tumor fluorescence could be confirmed through the visceral pleura in 6 out of 7 lesions treated by wedge resection, while NIR irradiation was difficult for 1 lesion. For these 6 lesions, the median distance from the tumor to the visceral pleura and the median surgical margin were 0 mm (range, 0-2 mm) and 14 mm (range, 11-17 mm), respectively. When cut sections were examined, all tumors emitted fluorescence. All lesions were histologically confirmed to be metastatic HCC. In patients with pulmonary metastasis of HCC, ICG fluorescence imaging is useful for identifying the tumor and securing its margin when the lesion is peripheral and wedge resection is planned.

Exosome-mediated secretion of LOXL4 promotes hepatocellular carcinoma cell invasion and metastasis

BackgroundLysyl oxidase-like 4 (LOXL4) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). However, the role of LOXL4 in HCC progression remains largely unclear. In this study, we investigated the clinical significance and biological involvement of LOXL4 in the progression of HCC.MethodsLOXL4 expression was measured in HCC tissues and cell lines. Overexpression, shRNA-mediated knockdown, recombinant human LOXL4 (rhLOXL4), and deletion mutants were applied to study the function of LOXL4 in HCC. Exosomes derived from HCC cell lines were assessed for the ability to promote cancer progression in standard assays. The effects of LOXL4 on the FAK/Src pathway were examined by western blotting.ResultsLOXL4 was commonly upregulated in HCC tissues and predicted a poor prognosis. Elevated LOXL4 was associated with tumor differentiation, vascular invasion, and tumor-node-metastasis (TNM) stage. Overexpression of LOXL4 promoted, whereas knockdown of LOXL4 inhibited cell migration and invasion of HCC in vitro, and overexpressed LOXL4 promoted intrahepatic and pulmonary metastases of HCC in vivo. Most interestingly, we found that HCC-derived exosomes transferred LOXL4 between HCC cells, and intracellular but not extracellular LOXL4 promoted cell migration by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. In addition, HCC-derived exosomes transferred LOXL4 to human umbilical vein endothelial cells (HUVECs) though a paracrine mechanism to promote angiogenesis.ConclusionsTaken together, our data demonstrate a novel function of LOXL4 in tumor metastasis mediated by exosomes through regulation of the FAK/Src pathway and angiogenesis in HCC.

Natural killer cells inhibit pulmonary metastasis of hepatocellular carcinoma in nude mice.

Natural killer (NK) cells have been demonstrated to inhibit tumor growth. However, the role of NK cells in the inhibition of hepatocellular carcinoma metastasis is not well understood. The present study aimed to investigate the roles that NK cells may serve in inhibiting hepatocellular carcinoma metastasis. The role of isolated NK cells in the inhibition, proliferation, migration and invasion of the hepatoma cell line, MHCC97-H, was examined in vitro. Additionally, the survival rate of NK cells labeled with carboxyfluorescein diacetate-succinimidyl ester was assessed in vivo. An orthotopic implantation model was used to evaluate the role of NK cells in suppressing MHCC97-H cells in vivo. The effect of interleukin (IL)-2 stimulation on the tumor-inhibitory role of the NK cells was measured indirectly by analyzing the expression of various NK cell receptors and activated NK cell markers. It was observed that the NK cells inhibited the proliferation, migration and invasion of the MHCC97-H cells in vitro. Furthermore, the NK cells demonstrated long-term survival in the livers of the nude mice, and inhibited lung metastasis of hepatocellular carcinoma in vivo. However, liver tumor growth was not inhibited by the NK cells. IL-2 was identified to enhance the tumor-inhibitory effect of NK cells. The present study concludes that IL-2 may enhance the antitumor activity of the NK cells, and thereby inhibit the metastases of hepatocellular carcinoma in mice.

고주파 열치료술로 성공적으로 치료된 간세포암종의 폐전이 1예

고주파 열치료술로 성공적으로 치료된 간세포암종의 폐전이 1예

CT-guided radioactive 125I seed implantation treatment of multiple pulmonary metastases of hepatocellular carcinoma

To investigate the clinical value of computed tomography (CT)-guided radioactive (125)I seed implantation for the treatment of multiple pulmonary metastases of hepatocellular carcinoma (HCC). From March 2007 to August 2010, 27 HCC patients with pulmonary metastases who had received computed tomography (CT)-guided radioactive (125)I seed implantation were enrolled in the study. All patients had ≥ 2 metastatic lesions (mean diameter 2 ± 0.6 cm). Under CT-guidance, (125)I seeds were implanted into the pulmonary metastases using the plane implantation technique. Among 27 cases, complete response, partial response, stable disease, and progressive disease were observed in four, 15, six, and two cases, respectively, during 6-48 months (mean 20.1 ± 2.2 months) of follow-up CT. The response rate was 92.6%. The mean follow-up time after (125)I implantation was 20.1 months (range 6-48 months). The survival rates at 1 and 2 years were 67% and 30.8%, respectively, with a median survival of 13.5 months. Side effects during the procedure included minor pulmonary effusions and pneumothorax. Pulmonary haemorrhage was observed in 18 cases and haemoptysis occurred in five patients. Radial shadows were observed in three cases on follow-up CT images, and seed migration in two cases on follow-up spiral CT images. CT-guided radioactive (125)I seed implantation may be a safe and effective treatment option for HCC patients with multiple pulmonary metastases.

A nomogram predicting pulmonary metastasis of hepatocellular carcinoma following partial hepatectomy

Background:Pulmonary metastasis (PM) following curative hepatectomy for hepatocellular carcinoma (HCC) is indicative of a poor prognosis. This study aimed to develop a nomogram to identify patients at high risks of PM.Methods:A primary cohort of patients who underwent curative hepatectomy for HCC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2010 was prospectively studied. A nomogram predicting PM was constructed based on independent risk factors of PM. The predictive performance was evaluated by the concordance index (c-index), calibration curve and decision curve analysis (DCA). During the study period, a validation cohort was included at the First Affiliated Hospital of Fujian Medical University.Results:Postoperative PMs were detected in 106 out of 620 and 45 out of 218 patients, respectively, in two cohorts. Factors included in the nomogram were microvascular invasion, serum alpha-fetoprotein, tumour size, tumour number, encapsulation and intratumoral CD34 staining. The nomogram had a c-index of 0.75 and 0.82 for the two cohorts for predicting PM, respectively. The calibration curves fitted well. In the two cohorts, the DCA demonstrated positive net benefits by the nomogram, within the threshold probabilities of PM >10%.Conclusion:The nomogram was accurate in predicting PM following curative hepatectomy for HCC.

Correlated factors of pulmonary metastasis of hepatocellular carcinoma

Objective To investigate the correlated factors of pulmonary metastasis of hepatocellular carcinoma (HCC),so as to provide theoretical evidences for the prevention and treatment.Methods The clinical data of 862 patients with HCC who were admitted to the First Affiliated Hospital of Fujian Medical University from January 2008 to March 2012 were retrospectively analyzed.There were 107 patients with pulmonary metastasis.Factors including serum alpha fetoprotein (AFP) level,serum gamma-glutamyl transpeptidase (GGT) level,hepatitis B virus (HBV) infection,presence and treatment of intrahepatic tumor were analyzed to screen out relevant factors of pulmonary infection of HCC.Univariate and multivariate COX regression model analysis were performed for data analysis.Results The results of univariate analysis showed that high level of AFP (≥400 μg/L),ultra-high level of GGT (≥ 150 U/L),presence of HBV infection,the number of intrahepatic tumors ≥2,no radical resection (or radiofrequency ablation) for intrahepatic tumors,combining with tumor thrombi in the vessels,lymph node metastasis were risk factors of pulmonary metastasis of HCC (RR =1.986,3.653,0.365,3.675,0.252,0.379,0.352,P ＜ 0.05).The results of multivariate analysis showed that high level of AFP (≥400 μg/L),HBV infection,the number of intrahepatic tumors ≥2,no radical resection (or radiofrequency ablation) for intrahepatic tumors,combining with tumor thrombi in the vessels were risk factors of pulmonary metastasis of HCC (RR =2.391,3.462,3.425,3.396,2.418,0.638,P ＜ 0.05).Conclusions AFP ≥400 μg/L,HBV infection,the number of intrahepatic tumors ≥ 2,no radical resection (or radiofrequency ablation),tumor thrombi in the vessels and lymph node metastasis are risk factors of pulmonary metastasis of HCC.Anti-hepatitis virus treatment and early treatment are helpful for the prevention and treatment. Key words: Liver neoplasms ;  Pulmonary metastasis ;  Risk factors

肝細胞癌術後7年後に心筋・肺転移で再発した1例

肝細胞癌術後7年後に心筋・肺転移で再発した1例

TGF beta1 and related-Smads contribute to pulmonary metastasis of hepatocellular carcinoma in mice model

BackgroundRecent studies indicate that Transforming Growth Factor beta (TGF β) correlated with pulmonary metastasis of cancers. However, the correlation between TGF β and pulmonary metastasis of hepatocellular carcinoma (HCC) is till unknown.MethodsWe detected the in vitro and in vivo expression levels of TGF β1/Smads by Real-time PCR and Western blot in MHCC97-H and MHCC97–L cell lines, which are HCC cell lines and have higher and lower pulmonary metastatic potential respectively.ResultsTGF β1 mRNA level in MHCC97-L tumors were higher than that in MHCC97-H tumors, (2.81±1.61 vs. 1.24±0.96, P=0.002), TGF β1 protein level in MHCC97-L tumors were also higher than that in MHCC97-H tumors (1.37±0.95 vs. 0.32±0.22, P<0.001). In addition, the TGF β1 mRNA level positively correlated with pulmonary metastasis, and the relations between TGF β1 and Smads were also found (R2=0.12 and 0.40, respectively).ConclusionsOur results suggest that TGF β/ Smads promote pulmonary metastasis of HCC.

Novel roles of Vmp1: Inhibition metastasis and proliferation of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most deadly human cancers because of its high incidence of metastasis. Despite extensive efforts, therapies against metastasis of HCC remain underdeveloped. Vacuole membrane protein 1 (Vmp1) was recently identified to be involved in cancer-relevant processes; however, its expression, clinical significance and biological function in HCC progression are still unknown. Therefore, we evaluated the expression of Vmp1 in human HCC specimens. To functionally characterize Vmp1 in HCC, we upregulated its expression in HCCLM3 cells using a plasmid transfection approach, following which both in vitro and in vivo models were used to elucidate its role. A significant downregulation of Vmp1 was found in human HCC tissues and closely correlated with multiple tumor nodes, absence of capsular formation, vein invasion and poor prognosis of HCC. Such expression was verified with HCC cell lines including HepG2, MHCC97-L and HCCLM3, and the Vmp1 expression levels negatively correlated with metastatic potential. Interestingly, upregulation of Vmp1 significantly affects proliferation, migration, invasion and adhesion of HCCLM3 cells. Using a mouse model, we demonstrated that upregulation of Vmp1 was associated with suppression of growth and pulmonary metastases of HCC. Therefore, our data suggest Vmp1 is a novel prognostic marker and potential therapeutic target for metastasis of HCC.

Risk factors and prediction equation linked to early pulmonary metastasis of hepatocellular carcinoma after curative hepatic resection

Objective To investigate the risk factors and the prediction equation linked to early pulmonary metastasis of hepatocellular carcinoma after curative hepatic resection.Methods A series of 400 hepatocelluar carcinoma patients who received radical operation were investigated retrospectively. Single factor analysis and multivariate logistic regression analysis were performed to analyze the relevant clinical and pathological indicators,including sex,ages,tumor diameter,the level of alpha fetal protein (AFP),hepatitis B virus (HBV) infection,number of tumors,hepatic cirrhosis,tumor envelop,tumor thrombus,and pathological classification,etc.Results The ratio of pulmonary metastasis one year postoperation was 8.0％ (32/400).The indicators,including the tumor diameter,the level of AFP,and tumor thrombus were different significantly between pulmonary metastasis group and non-pulmonary metastasis group.The multivariate logistic regression analysis indicated that the independent prognostic factors of pulmonary metastasis of hepatocelluar carcinoma one year after curative hepatic resection were the tumor diameter and tumor thrombus.The prediction equation indicated that the predicted ratio of pulmonary metastasis was from 1.14％ to 27.23％.Conclusion The independent prognostic factors of pulmonary metastasis of hepatocelluar carcinoma one year after curative hepatic resection were the tumor diameter and tumor thrombus. Key words: Carcinoma, hepatocelluar; Pulmonary metastasis; Prediction

Abstract 1556: A novel tripeptide, tyroserleutide, inhibits irradiation-induced invasiveness and metastasis of hepatocellular carcinoma

Abstract Background: In preliminary studies, we have shown increased intrahepatic and pulmonary metastases of hepatocellular carcinoma (HCC) long-time after radiotherapy using a metastatic human HCC orthotopic nude mice model. Tyroserleutide (YSL), which was authorized by Food and Drug Administration of USA as an orphan drug in September 2004, is a novel small molecule antitumor tripeptide. Previous studies have demonstrated YSL inhibited tumor growth of HCC in animal model. However, its effects on HCC metastasis are still unknown. We investigated YSL effects on the irradiation-induced invasiveness and metastatic potential of HCC and its related mechanism. Methods: The invasiveness of MHCC97L cells in vitro was detected using transwell invasion assay. A metastatic human HCC orthotopic nude mice model of MHCC97L was applied. YSL was administered directly to the model and further to the model postradiotherapy. Effects on tumor growth and pulmonary metastasis were evaluated. Pimonidazole and hypoxia-inducible factor 1α (HIF-1α) were used as hypoxia markers. Hypoxia, matrix metalloproteinase-2 (MMP-2), transmembrane protease serine 4 (TMPRSS4), and epithelial mesenchymal transition (EMT) related proteins (E-cadherin, SIP1, Vimentin, and N-cadherin) were determined by immunohistochemistry, quantitative real-time PCR, and Western blot. Results: YSL inhibited MHCC97L cells proliferation and invasion in vitro with or without irradiation. YSL did not significantly prohibit tumor growth but decreased pulmonary metastasis and prolonged life-span, which correlated with down-regulation of MMP-2. Radiotherapy inhibited tumor growth in early stage and promoted tumor hypoxia. Considering the limited life-span of mice, as well as discharging the effects of tumor load on mice, we adopted “tumor re-inoculation”. Although the replanted tumor volume in radiotherapy group had no significance in statistics as compared to its control, the incidence of lung metastasis increased postradiotherapy (6/6 versus 3/6, P = 0.046). YSL inhibited the growth of replanted tumor with radiotherapy. Furthermore, YSL almost completely inhibited lung metastasis induced by irradiation. YSL at 160 or 320 μg/kg/day significantly reduced lung metastases (1/6 versus 6/6, P = 0.002 for both groups, compared with the radiotherapy group). YSL down-regulated HIF-1α and TMPRSS4, and eventually inhibited EMT (up-regulation of E-cadherin and down-regulation of SIP1, Vimentin and N-cadherin) were associated with its anti-metastasis capability. Conclusions: YSL inhibits the enhanced invasiveness and metastatic potential of HCC induced by irradiation through down-regulation of HIF-1α and TMPRSS4 and inhibition of EMT. YSL may act as a new anti-metastasis agent for the clinical use of combination with radiotherapy. [Supported by China Postdoctoral Science Foundation-funded project (No. 20080440077)] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1556.