Publications by authors named "Rongping Guo"

23 Publications

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Comparison Between Portal Vein Perfusion Chemotherapy and Neoadjuvant Hepatic Arterial Infusion Chemotherapy for Resectable Intermediate to Advanced Stage Hepatocellular Carcinoma.

Ann Surg Oncol 2021 Oct 12. Epub 2021 Oct 12.

Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.

Background: Patients with intermediate to advanced stage hepatocellular carcinoma (HCC; Barcelona Clinic Liver Cancer [BCLC] stage B/C) have few choices of curable treatments and thus suffer from dismal outcomes. Although surgical resection could prolong survival in certain selected patients with BCLC stage B/C HCC, the frequent postoperative recurrence and poor survival of these patients need to be improved by combining other therapies perioperatively.

Objective: This study was conducted to investigate the survival associations of adjuvant portal vein perfusion chemotherapy (PVC) and neoadjuvant hepatic arterial infusion chemotherapy (HAIC) in patients with resectable BCLC stage B/C HCC.

Methods: A retrospective study was conducted in consecutive patients who underwent R0 resection for intermediate to advanced stage HCC, combined with either PVC or HAIC perioperatively between January 2017 and December 2018. Patients treated with PVC or HAIC were analyzed according to intention-to-treat (ITT) and per protocol (PP) principles, respectively. The chemotherapy regimen of adjuvant PVC and neoadjuvant HAIC included 5-fluorouracil/leucovorin/oxaliplatin. Survival analysis and Cox regression for overall survival (OS) and event-free survival (EFS) were used to compare the outcomes.

Results: Among all 64 patients enrolled in this study, 28 received perioperative PVC and 36 received HAIC for ITT analysis. Age (median 44.00 vs. 46.50 years; p = 0.364), sex (male: 25/28 vs. 35/36; p = 0.435), and tumor size (median 9.55 vs. 8.10 cm; p = 0.178) were comparable between the two groups. In the ITT analysis, the median OS was significantly longer in patients in the HAIC group compared with the PVC group (median OS not reached vs. 19.47 months; p = 0.004); in the PP analysis, patients who received neoadjuvant HAIC followed by hepatectomy presented with much better EFS than patients in the PVC group (modified EFS 16.90 vs. 3.17 months; p = 0.022); and in the multivariate analysis, neoadjuvant HAIC presented as a significant predictor for enhanced EFS (hazard ratio [HR] 0.296; p = 0.007) and OS (HR 0.095; p = 0.007) for BCLC stage B/C HCC patients who received hepatectomy.

Conclusions: Compared with adjuvant PVC, neoadjuvant HAIC treatment was associated with better survival and fewer recurrences in HCC patients who received R0 resection at the intermediate to advanced stage. These results need to be further validated prospectively.
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http://dx.doi.org/10.1245/s10434-021-10903-4DOI Listing
October 2021

Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis.

Genes (Basel) 2021 Aug 25;12(9). Epub 2021 Aug 25.

Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.

Background: In recent years, metabolic reprogramming has been identified as a hallmark of cancer. Accumulating evidence suggests that glutamine metabolism plays a crucial role in oncogenesis and the tumor microenvironment. In this study, we aimed to perform a systematic and comprehensive analysis of six key metabolic node genes involved in the dynamic regulation of glutamine metabolism (referred to as GLNM regulators) across 33 types of cancer.

Methods: We analyzed the gene expression, epigenetic regulation, and genomic alterations of six key GLNM regulators, including , , , , , and , in pan-cancer using several open-source platforms and databases. Additionally, we investigated the impacts of these gene expression changes on clinical outcomes, drug sensitivity, and the tumor microenvironment. We also attempted to investigate the upstream microRNA-mRNA molecular networks and the downstream signaling pathways involved in order to uncover the potential molecular mechanisms behind metabolic reprogramming.

Results: We found that the expression levels of GLNM regulators varied across cancer types and were related to several genomic and immunological characteristics. While the immune scores were generally lower in the tumors with higher gene expression, the types of immune cell infiltration showed significantly different correlations among cancer types, dividing them into two clusters. Furthermore, we showed that elevated GLNM regulators expression was associated with poor overall survival in the majority of cancer types. Lastly, the expression of GLNM regulators was significantly associated with PD-L1 expression and drug sensitivity.

Conclusions: The elevated expression of GLNM regulators was associated with poorer cancer prognoses and a cold tumor microenvironment, providing novel insights into cancer treatment and possibly offering alternative options for the treatment of clinically refractory cancers.
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http://dx.doi.org/10.3390/genes12091305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466418PMC
August 2021

High SGO2 Expression Predicts Poor Overall Survival: A Potential Therapeutic Target for Hepatocellular Carcinoma.

Genes (Basel) 2021 06 7;12(6). Epub 2021 Jun 7.

Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.

Shugoshin2 (SGO2) may participate in the occurrence and development of tumors by regulating abnormal cell cycle division, but its prognostic value in hepatocellular carcinoma (HCC) remains unclear. In this study, we accessed The Cancer Genome Atlas (TCGA) database to get the clinical data and gene expression profile of HCC. The expression of SGO2 in HCC tissues and nontumor tissues and the relationship between SGO2 expression, survival, and clinicopathological parameters were analyzed. The SGO2 expression level was significantly higher in HCC tissues than in nontumor tissues ( < 0.001). An analysis from the Oncomine and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) databases also demonstrated that SGO2 was upregulated in HCC (all < 0.001). A logistic regression analysis revealed that the high expression of SGO2 was significantly correlated with gender, tumor grade, pathological stage, T classification, and Eastern Cancer Oncology Group (ECOG) score (all < 0.05). The overall survival (OS) of HCC patients with higher SGO2 expression was significantly poor ( < 0.001). A multivariate analysis showed that age and high expression of SGO2 were independent predictors of poor overall survival (all < 0.05). Twelve signaling pathways were significantly enriched in samples with the high-SGO2 expression phenotype. Ten proteins and 34 genes were significantly correlated with SGO2. In conclusion, the expression of SGO2 is closely related to the survival of HCC. It may be used as a potential therapeutic target and prognostic marker of HCC.
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http://dx.doi.org/10.3390/genes12060876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226836PMC
June 2021

Surgical strategies for hepatocellular carcinoma located in the left lateral lobe: A propensity score-matched and prognostic nomogram study.

Cancer Med 2021 05 1;10(10):3274-3287. Epub 2021 May 1.

Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.

Purpose: For hepatocellular carcinoma (HCC) located in the left lateral lobe, the optimal surgical procedure is still controversial. This study aimed to optimize surgical strategies and to construct a nomogram to predict the postoperative survival of patients with HCC.

Methods: Between 1 January 2005 and 30 September 2018, a total of 493 patients were enrolled. Propensity score matching (PSM) was performed between the left lateral lobectomy (LLL) and left hepatectomy (LH) groups (1:1). The study endpoints were overall survival (OS), recurrence-free survival (RFS), and safety. A nomogram was generated using a multivariate Cox proportional hazards model. The discriminative ability and calibration of the nomogram were evaluated using C-statistics and calibration plots.

Results: After matching, 87 pairs were included. The LH group had better 1-, 3-, and 5-year OS rates than the LLL group (88%, 73%, and 69% vs. 73%, 57%, and 49%, respectively; p = 0.017). The 1-, 3-, and 5-year RFS rates of the LH group were similar to those of the LLL group (64%, 49%, and 46% vs. 63%, 51%, and 42%, respectively; p = 0.652). There were no significant differences in postoperative complications. Eight factors were integrated into the nomogram and it had good discriminative ability and calibration.

Conclusion: Our data revealed that compared to LLL, LH may result in better OS and have similar postoperative complications for HCC. The nomogram may serve as a practical tool for the individual prognostic evaluation of patients with HCC.
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http://dx.doi.org/10.1002/cam4.3894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124126PMC
May 2021

Immune-related adverse events predict responses to PD-1 blockade immunotherapy in hepatocellular carcinoma.

Int J Cancer 2021 Apr 22. Epub 2021 Apr 22.

Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.

Immune checkpoint blockade has demonstrated remarkable efficacy in hepatocellular carcinoma (HCC) but is also commonly accompanied by immune-related adverse events (irAEs). However, the association between irAEs and antitumor efficacy in HCC patients remains unknown. All patients with HCC treated with anti-PD-1 antibodies from July 2018 to November 2019 were analyzed and divided into different groups according to their irAEs' status. In total, 101 HCC patients, including 21 (20.8%) patients who presented with irAEs (irAEs ), were enrolled. Among the adverse events, rash (n = 9, 8.9%) was the most frequent irAE, followed by mucositis (n = 3, 3.0%) and thyroiditis (n = 3, 3.0%). Patients in the irAEs group showed a higher tumor response rate than those in the irAEs group (overall response rate: 28.6% vs 6.3%, P = .011; disease control rate: 85.7% vs 60.0%, P = .028). The median progression-free survival (PFS) times were 14.8 months in the irAEs group and 4.1 months in the irAEs group (P < .001). Further analysis based on the presence or absence of rash showed that the PFS of the patients in the irAEs /rash group was better than that of those in the irAEs /rash or irAEs group (all P < .05). Multivariate analysis showed that irAEs were an independent prognostic factor for PFS (hazard ratio [HR]: 0.22, P = .002). Thus, the occurrence of irAEs, especially rash, was associated with markedly improved PFS. Awareness of irAEs may help classify the subtype of HCC patients with an unprecedented survival benefit from anti-PD-1 antibodies.
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http://dx.doi.org/10.1002/ijc.33609DOI Listing
April 2021

A new horizon in risk stratification of hepatocellular carcinoma by integrating vessels that encapsulate tumor clusters and microvascular invasion.

Hepatol Int 2021 Jun 9;15(3):651-662. Epub 2021 Apr 9.

Department of Hepatobiliary Oncology of Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China.

Background: Vessels that encapsulate tumor clusters (VETC) is a novel described vascular pattern different from microvascular invasion (MVI) for patients with hepatocellular carcinoma (HCC). The prognostic value of integrating VETC and MVI (VETC-MVI model) in HCC patients after resection remains unclear.

Methods: From January 2013 to December 2016, 498 HCC patients who underwent curative resection were enrolled from five academic centers and stratified into different groups according to their VETC and MVI statuses. Overall survival (OS), disease-free survival (DFS), and early and late recurrence rates were evaluated.

Results: The patients were divided into four subgroups: VETC/MVI (n = 277, 55.6%), VETC/MVI (n = 110, 22.1%), VETC/MVI (n = 53, 10.6%), and VETC/MVI (n = 58, 11.6%). The patients in the VETC/MVI and VETC/MVI groups had similar long-term outcomes (OS: p = 0.402; DFS: p = 0.990), VETC/MVI patients showed the best prognosis, and VETC/MVI patients had the worst prognosis. Further analysis revealed that the VETC-MVI model showed a similar stratification ability for early recurrence but not for late recurrence. The area under the curve values for early recurrence was 0.70, 0.63 and 0.64 for the VETC-MVI model, VETC, and MVI, respectively (VETC-MVI model vs VETC: p < 0.001; VETC-MVI model vs MVI: p = 0.004; VETC vs MVI: p = 0.539). Multivariate Cox regression analysis showed that the VETC-MVI model successfully predicted OS, DFS and early recurrence.

Conclusions: VETC status provides additional discriminative information for patients with either MVI or MVI. A combination of VETC and MVI may help classify subtypes and predict the prognosis of HCC patients.
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http://dx.doi.org/10.1007/s12072-021-10183-wDOI Listing
June 2021

Lack of Response to Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma: Abandon or Repeat?

Radiology 2021 03 19;298(3):680-692. Epub 2021 Jan 19.

From the Division of Interventional Ultrasound (S.C., M.K.), Cancer Center (S.C., M.K.), Department of Radiation Oncology (Z.P.), Clinical Trial Unit (Z.P., B.L., J.M.), Institute of Precision Medicine (Z.P., M.K.), Department of Interventional Oncology (Jiaping Li), Department of Radiology (S.F.), and Department of Liver Surgery (M.K.), The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Road 2, Guangzhou, China 510080; Department of Hepatobiliary Surgery, Cancer Centre, Sun Yat-sen University, Guangzhou, China (Y.Z., M.C., R.G.); and Department of Liver Surgery, Dongguan People's Hospital, Dongguan, China (Jiali Li).

Background Transarterial chemoembolization (TACE) is the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). It is unknown whether conventional TACE (cTACE) should be continued or abandoned after initial nonresponse for intermediate-stage HCC. The optimal number of sessions before abandoning cTACE remains debated. Purpose To define the number of sessions that patients who do not respond to treatment (hereafter, nonresponders, with stable disease [SD] or progressive disease [PD]) should undergo before abandoning cTACE. Materials and Methods Patients with intermediate-stage HCC and Child-Pugh A liver function who underwent consecutive cTACE sessions between January 2005 and December 2012 were retrospectively included from three centers. Radiologic response rate to each session and its correlation with overall survival were evaluated. Response was assessed by modified Response Evaluation Criteria in Solid Tumors. A nomogram constructed by using tumor size, tumor capsule, and α-fetoprotein to predict patients who responded to treatment (hereafter, responders) was validated with sensitivity and specificity. Results This study evaluated 4154 patients (mean age, 58 years ± 6 [standard deviation]; 3777 men; primary cohort, 3442 patients [mean age, 58 years ± 6; 3129 men]; validation cohort, 712 patients [mean age, 58 years ± 7; 648 men]). Response rate to first cTACE was 35.6% (1227 of 3442, primary cohort) and 36.7% (261 of 712, validation cohort). For patients with SD who were nonresponders to first cTACE, the response rates after second cTACE were 46.1% (719 of 1560) and 48.4% (147 of 304); for patients with SD who were nonresponders to the second cTACE session, the response rates after the third cTACE session were 58.3% (591 of 1014) and 48.5% (98 of 202). For patients with SD who were nonresponders to third, fourth, and fifth cTACE sessions, response rates after fourth, fifth, and sixth cTACE sessions were less than 10%. All response rates in patients with PD who were nonresponders to the next cTACE were less than 5%. Responders to first, second, and third cTACE had higher 5-year overall survival than nonresponders (all < .001) but responders to the fourth cTACE did not ( = .21). The sensitivity and specificity of a nomogram predicted responders to third cTACE: 75.0% and 79.4% (internal validation) and 78.6% and 87.0% (external validation), respectively. Conclusion Three sessions were recommended before abandoning conventional transarterial embolization (cTACE) for intermediate-stage hepatocellular carcinoma. The nomogram developed in this study identified responders to third cTACE. © RSNA, 2021 See also the editorial by Georgiades in this issue.
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http://dx.doi.org/10.1148/radiol.2021202289DOI Listing
March 2021

Postoperative Adjuvant Transarterial Infusion Chemotherapy with FOLFOX Could Improve Outcomes of Hepatocellular Carcinoma Patients with Microvascular Invasion: A Preliminary Report of a Phase III, Randomized Controlled Clinical Trial.

Ann Surg Oncol 2020 Dec 16;27(13):5183-5190. Epub 2020 May 16.

Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China.

Background: Microvascular invasion (MVI) is a risk factor for tumor recurrence after hepatectomy in hepatocellular carcinoma (HCC) patients.

Objective: This study aimed to investigate the efficacy and safety of postoperative adjuvant transarterial infusion chemotherapy (TAI) with the FOLFOX regimen for HCC patients with MVI.

Methods: In this prospective, phase III, randomized, open-label, controlled clinical trial, HCC patients with histologically confirmed MVI were randomly assigned (1:1) after hepatectomy to receive either one to two cycles of adjuvant TAI (AT group) or follow-up without any adjuvant treatment (FU group). The primary endpoint was disease-free survival (DFS), while secondary endpoints were overall survival (OS) and safety.

Results: Between June 2016 and April 2019, 127 patients were randomly assigned to the AT group (n = 63) or FU group (n = 64). Clinicopathological characteristics of the two groups were well-balanced. The 6-, 12-, and 18-month OS rates for the AT group were 100.0%, 97.7%, and 97.7%, respectively, and 94.5%, 89.6%, and 78.5% for the FU group, respectively. The 6-, 12-, and 18-month DFS rates for the AT and FU groups were 84.7%, 61.8%, and 58.7%, and 62.9%, 48.1%, and 38.6%, respectively. OS and DFS were significantly better in the AT group than in the FU group (p = 0.037 and 0.023, respectively). No patients in the AT group experienced grade 3 or more severe adverse events.

Conclusions: Adjuvant TAI after hepatectomy may bring survival benefits to HCC patients with MVI.

Trial Registration: Trial number: NCT03192618.
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http://dx.doi.org/10.1245/s10434-020-08601-8DOI Listing
December 2020

Chinese Expert Consensus on Multidisciplinary Diagnosis and Treatment of Hepatocellular Carcinoma with Portal Vein Tumor Thrombus (2018 Edition).

Liver Cancer 2020 Jan 6;9(1):28-40. Epub 2019 Nov 6.

aDepartment of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.

Portal vein tumor thrombus (PVTT) is very common, and it plays a major role in the prognosis and clinical staging of hepatocellular carcinoma (HCC). We have published the first version of the Consensus in 2016. Over the past several years, many new evidences for the treatment of PVTT become available especially for the advent of new targeted drugs which have further improved the prognosis of PVTT. So, the Chinese Association of Liver Cancer revised the 2016 version of consensus to adapt to the development of PVTT treatment. Future treatment strategies for HCC with PVTT in China would depend on new evidences from more future clinical trials.
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http://dx.doi.org/10.1159/000503685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024893PMC
January 2020

Effect of Remote Ischemic Preconditioning in Patients Undergoing Hepatectomy With Portal Triad Clamping: A Randomized Controlled Trial.

Anesth Analg 2019 12;129(6):1742-1748

From the Department of Anesthesia, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: Remote ischemic preconditioning (RIPC) is reported to reduce liver injury in patients undergoing hepatectomy for colorectal liver metastasis, but its role is unclear in hepatocellular carcinoma patients with portal triad clamping during hepatectomy.

Methods: In this prospective, randomized trial, 140 patients with hepatocellular carcinoma undergoing liver resection requiring portal triad clamping were randomized to a RIPC group or a control group. Patients in the RIPC group received RIPC (3 cycles of 5-minute ischemia and 5-minute reperfusion in right upper limb with cuff pressure at 30 kPa [225 mm Hg]) approximately 10 minutes after induction of anesthesia. In the control group, patients received sham RIPC (the cuff was not inflated). The primary outcome was the postoperative peak level of total bilirubin (TBIL) and was analyzed with the independent t test. Secondary outcomes were liver function test at postoperative days 1, 3, and 5; postoperative morbidity and mortality during the first month; and the length of postoperative hospital stay.

Results: Data from 136 patients (69 in the RIPC group and 67 in the control group) were analyzed. The RIPC group had on average a 5.9 μmol lower peak level of TBIL than the control group; the mean difference is -5.9, and the 95% confidence interval (CI) reverses to -17.9 to 6.1. There were no significant differences between the 2 groups in liver function test at postoperative days 1, 3, and 5; postoperative morbidity and mortality during the first month; and the length of postoperative hospital stay.

Conclusions: We found no evidence that RIPC can reduce postoperative liver injury after hepatectomy.
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http://dx.doi.org/10.1213/ANE.0000000000004434DOI Listing
December 2019

Transarterial Chemoembolization Combined with Radiofrequency Ablation in the Treatment of Stage B1 Intermediate Hepatocellular Carcinoma.

J Oncol 2019 16;2019:6298502. Epub 2019 Sep 16.

Clinical Trials Unit, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, China.

Background: Due to the heterogeneity of patients with Barcelona clinic liver cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC), Bolondi criteria were proposed and patients were divided into four substages. The purpose of this study was to compare the survival of substage B1 patients who were initially treated with a combination of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) (TACE-RFA) or TACE alone.

Methods: 404 patients with stage B1 HCC were retrospectively analyzed from January 2005 to December 2012. 209 patients received TACE-RFA, and 195 received TACE alone as initial treatment. The overall survival (OS) and progression-free survival (PFS) rates were estimated by the Kaplan-Meier method and compared by the log-rank test.

Results: 1-, 3-, and 5-year OS rates were 83.7%, 45.8%, and 24.8% in the TACE-RFA group and 80.7%, 26.4%, and 16.7% in the TACE group, respectively (=0.003). The corresponding PFS rates were 71.8%, 26.6%, and 13.0% and 59.1%, 11.0%, and 2.2% in the TACE-RFA group and TACE group, respectively ( < 0.001). Multivariate regression analysis indicated that tumor size (OS: hazard ratio (HR) = 0.683, =0.001; PFS: HR = 0.761, =0.013), along with treatment allocation (OS: HR = 0.701, =0.003; PFS: HR = 0.620, < 0.001), was the independent prognostic factor for both OS and PFS.

Conclusions: Combination TACE and RFA treatment yielded better survival than TACE alone for patients with stage B1 HCC according to the Bolondi criteria.
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http://dx.doi.org/10.1155/2019/6298502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766138PMC
September 2019

Risk factors of extra-hepatic progression after transarterial chemoembolization for hepatocellular carcinoma patients: a retrospective study in 654 cases.

J Cancer 2019 27;10(20):5007-5014. Epub 2019 Aug 27.

Department of Hepatobiliary Oncology of the Sun Yat-sen University Cancer Center; Guangzhou 510060, P.R. China.

: To investigate the risk factors of extra-hepatic progression after TACE in HCC. : The study population included 654 HCC patients who underwent TACE between October 2005 and September 2012. We collected and analyzed their clinical characteristics and survival information. TACE was performed as previously described with minor modifications. When necessary, superselective chemoembolization was performed through the segmental or subsegmental arteries, based on the tumor location and extent and hepatic function reserve. If stasis could not be achieved in a tumor-feeding artery, iodized oil was used solely in some patients. Embolization was then performed with injection of absorbable gelfoam particles (1-2 mm in diameter) through the angiographic catheter. : The tumor response to initial TACE was evaluated in 645 patients. The CR rate, response rate (RR), and disease control rate (DCR) were 9.92%, 25.89%, and 70.39%, respectively. The median overall survival (OS) period was 14.5 months. The 6-month, 1-, 2-, 3-, and 5-year OS rates were 75.5%, 55.0%, 33.9%, 22.8%, and 14.9%, respectively. The median progression-free survival (PFS) period was 4.3 months. The 6-month, 1-, 2-, 3-, and 5-year PFS rates were 40.7%, 27.1%, 16.7%, 13.9%, and 9.3%, respectively. One hundred and fifty patients developed extrahepatic progression during follow-up. We demonstrated that in the absence of radical treatment after initial TACE (p<0.001), the presence of extrahepatic metastasis before initial TACE (p<0.001), AST >45 U/L (p=0.024), ALB <35 g/L (p=0.012), and tumor response were evaluated as PD and SD after initial TACE (p<0.001) and were found to be independent predictors of a poorer prognosis of extrahepatic PFS. : We identified risk factors for extrahepatic progression after TACE in HCC patients. Early combination treatment was strongly recommended in patients that met these risk factors.
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http://dx.doi.org/10.7150/jca.35355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775514PMC
August 2019

Predictive factors for the benefit of triple-drug transarterial chemoembolization for patients with unresectable hepatocellular carcinoma.

Cancer Med 2019 08 17;8(9):4200-4213. Epub 2019 Jun 17.

Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Background: Compared with single-drug TACE, our previous phase III study demonstrated that triple-drug transarterial chemoembolization (TACE) prolonged overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). The aim of this study was to find which patients can benefit from the triple drugs TACE compared with single-drug TACE.

Methods: Patients in the triple-drug TACE arm received sponge embolization and emulsions composed of 50 mg epirubicin, 50 mg lobaplatin, 6 mg mitomycin C, and lipiodol, while patients in the single-drug TACE arm received sponge embolization and emulsions composed of 50 mg epirubicin and lipiodol. From July 2007 to November 2009, 244 patients (224 men and 20 women; age ranged from 21 to 75 years) from our phase III study formed the initial cohort. From January 2010 to June 2015, external validation cohort was composed of 449 patients (411 men and 38 women; age ranged from 18 to 75 years) from another institution. The validation cohort after propensity score matching (PSM) (n = 374) was analyzed. Cox proportional hazard model was used to evaluate the interaction term between treatments for each subgroup. This retrospective study was approved by the institutional review board at each center.

Results: No difference was observed in the baseline characteristic of three cohorts. This exploratory analysis showed that triple-drug TACE brought a survival benefit in the initial cohort, validation cohort (before PSM), and validation cohort (after PSM) compared with single-drug TACE. The outcomes of three cohorts all showed that a significantly greater OS triple-drug chemotherapy benefit versus single-drug chemotherapy was seen in patients with large tumors (larger than 10 cm) while no survival difference was seen in patients with small tumors (10 cm or smaller).

Conclusions: Triple-drug TACE seems to benefit patients with HCC larger than 10 cm in particular compared with single-drug TACE.
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http://dx.doi.org/10.1002/cam4.2355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675716PMC
August 2019

Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin vs Sorafenib Alone for Hepatocellular Carcinoma With Portal Vein Invasion: A Randomized Clinical Trial.

JAMA Oncol 2019 07;5(7):953-960

Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Importance: Sorafenib is the first-line treatment for hepatocellular carcinoma with portal vein invasion; however, it has shown unsatisfactory survival benefit. Sorafenib plus hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown promising results for these patients in a previous phase 2 study.

Objective: To investigate the efficacy and safety of sorafenib plus HAIC compared with sorafenib for hepatocellular carcinoma with portal vein invasion.

Design, Setting, And Participants: This randomized, open-label clinical trial enrolled 818 screened patients. Of the 818 participants, 247 with hepatocellular carcinoma and portal vein invasion were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib plus HAIC or sorafenib. This trial was conducted at 5 hospitals in China and enrolled patients from April 1, 2016, to October 10, 2017, with a follow-up period of 10 months.

Interventions: Randomization to receive 400 mg sorafenib twice daily (sorafenib group) or 400 mg sorafenib twice daily plus HAIC (SoraHAIC group) (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks).

Main Outcomes And Measures: The primary endpoint was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment.

Results: For 247 patients (median age, 49 years; range, 18-75 years; 223 men and 24 women), median overall survival was 13.37 months (95% CI, 10.27-16.46) in the SoraHAIC group vs 7.13 months (95% CI, 6.28-7.98) in the sorafenib group (hazard ratio [HR], 0.35; 95% CI, 0.26-0.48; P < .001). The SoraHAIC group showed a higher response rate than the sorafenib group (51 [40.8%] vs 3 [2.46%]; P < .001), and a longer median progression-free survival (7.03 [95% CI, 6.05-8.02] vs 2.6 [95% CI, 2.15-3.05] months; P < .001). Grade 3/4 adverse events that were more frequent in the SoraHAIC group than in the sorafenib group included neutropenia (12 [9.68%] vs 3 [2.48%]), thrombocytopenia (16 [12.9%] vs 6 [4.96%]), and vomiting (8 [6.45%] vs 1 [0.83%]).

Conclusions And Relevance: Sorafenib plus HAIC of FOLFOX improved overall survival and had acceptable toxic effects compared with sorafenib in patients with hepatocellular carcinoma and portal vein invasion.

Trial Registration: ClinicalTrials.gov identifier: NCT02774187.
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http://dx.doi.org/10.1001/jamaoncol.2019.0250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512278PMC
July 2019

Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin in Hepatocellular Cancer with Extrahepatic Spread.

J Vasc Interv Radiol 2019 03;30(3):349-357.e2

Department of Minimally Invasive Interventional Radiology, Center of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, China. Electronic address:

Purpose: To compare treatment with hepatic arterial infusion of chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) with both extrahepatic spread (EHS) and intrahepatic tumor and patients with intrahepatic tumor only.

Materials And Methods: This single-center retrospective study comprised 116 patients with advanced HCC with both intrahepatic tumor and EHS (EHS group; n = 50) or with intrahepatic tumor only (non-EHS group; n = 66) treated with HAIC including oxaliplatin, fluorouracil, and leucovorin between June 2014 and July 2016. Overall survival (OS) and radiologic responses to treatment were determined and compared between the 2 groups.

Results: Both the objective response rate and the clinical benefit rate were higher in the non-EHS group than in the EHS group (37.9% vs 16% objective response rate, P = .010; 81.8% vs 62% clinical benefit rate, P = .017). Median OS was not statistically different between the 2 groups (14.8 months vs 9.8 months, P = .068). Subgroup analysis of OS found that patients with lung metastases survived for a shorter time (OS 7 months) than patients with other metastatic sites (P = .003) and patients free of metastases (P = .001).

Conclusions: HAIC is a potential treatment option for advanced HCC with limited extrahepatic metastases in a population with hepatitis B virus infection.
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http://dx.doi.org/10.1016/j.jvir.2018.09.004DOI Listing
March 2019

Association of Sustained Response Duration With Survival After Conventional Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma.

JAMA Netw Open 2018 10 5;1(6):e183213. Epub 2018 Oct 5.

Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Importance: Defining early reliable surrogate end points for survival in patients with hepatocellular carcinoma (HCC) after conventional transarterial chemoembolization (cTACE) is of great value.

Objective: To evaluate the association between sustained response duration (SRD) and overall survival (OS) after cTACE for intermediate HCC.

Design, Setting, And Participants: This multicenter cohort study enrolled 2403 consecutive patients in China with naive intermediate HCC between June 1, 2000, and December 31, 2008, as the primary cohort, and 331 consecutive patients with intermediate naive HCC between January 1, 2011, to June 30, 2012, as the validation cohort. All patients received cTACE as an initial treatment. Initial response and best response were defined as the radiological response after first cTACE or best radiological response after 2 or more sessions of cTACE, respectively. Responders were those who experienced complete response or partial response. Sustained response duration was defined as the time between the date when complete response, partial response, or stable disease was achieved and the date progressive disease occurred after cTACE. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors. Information about patients in the study was collected from January 1, 2018, to March 31, 2018, and analysis of these data was performed in April 2018.

Main Outcomes And Measures: Overall survival.

Results: A total of 2734 total patients (2499 of 2734 [91.4%] male; median [range] age, 56.5 [18-75] years) were included in the analysis. In the primary cohort, SRD of 6 months or more was found to have the strongest association with 5-year OS after cTACE among different durations of sustained response. Patients with SRD of 6 months or more (387 of 430 male; median [range] age, 57 [18-75] years) had the longest median (range) OS (67.7 [64.8-72.1] months), followed by initial responders (760 of 874 male; median [range] age, 56 [18-75] years; median [range] OS, 55.8 [55.0-57.7] months) and best responders (939 of 1032 male; median [range] age, 57 [18-75] years; median [range] OS, 53.2 [52.2-54.6] months). Response duration of 6 months or more was found to be an independent prognostic factor for OS (hazard ratio, 0.145; 95% CI, 0.124-0.170; P < .001). The significance of SRD as a factor associated with OS was confirmed in the validation cohort.

Conclusions And Relevance: Sustained response duration of 6 months or more was associated with OS and may serve as an early surrogate end point after cTACE for intermediate HCC.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.3213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324454PMC
October 2018

Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma.

J Hepatol 2018 07 20;69(1):60-69. Epub 2018 Feb 20.

Minimally Invasive Interventional Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Background & Aims: To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib.

Methods: This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16-82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models.

Results: The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months [RECIST]/7.4 vs. 3.6 months [mRECIST], respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio [HR] 0.389 [RECIST]/0.402 [mRECIST]; p <0.001 for each) and OS (HR 0.129; p <0.001).

Conclusion: HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding.

Lay Summary: We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.jhep.2018.02.008DOI Listing
July 2018

Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma.

Nat Mater 2017 11 9;16(11):1155-1161. Epub 2017 Oct 9.

Moores Cancer Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA.

An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive 'liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.
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http://dx.doi.org/10.1038/nmat4997DOI Listing
November 2017

Surgical Strategy for Hepatocellular Carcinoma Patients with Portal/Hepatic Vein Tumor Thrombosis.

PLoS One 2015 15;10(6):e0130021. Epub 2015 Jun 15.

Department of Hepatobiliary Surgery, Cancer Center of Sun Yat-Sen University, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center of Sun Yat-Sen University, Guangzhou, China.

Background: Portal/hepatic vein tumor thrombosis (PVTT/HVTT) in hepatocellular carcinoma (HCC) is a sign of advanced stage disease and is associated with poor prognosis. This study investigated the surgical outcomes of patients with HCC and PVTT/HVTT to determine the most appropriate surgical treatment strategy for these patients.

Materials And Methods: The study population included 77 HCC patients from January 2004 to June 2009 who underwent hepatectomy in our department and were diagnosed with PVTT/HVTT based on pathological examination. The patients were divided into two groups: in group 1, PVTT/HVTT was located in the hepatic resection area and removed with the tumor en bloc (38 cases); in group 2, PVTT/HVTT was beyond the resection line and removed by suction or thrombectomy (39 cases). Concerning the factor of surgical margins, the patients were further divided into four subgroups: group 1A: patients in group 1 with surgical margins ≤1 cm (28 cases); group 1B: patients in group 1 with surgical margins >1 cm (9 cases); group 2A: patients in group 2 with surgical margins ≤1 cm (28 cases); and group 2B: patients in group 2 with surgical margins >1 cm (9 cases).

Results: Most of the characteristics of groups 1 and 2 were similar. Patients in group 2 had significantly higher median blood loss (p=0.002) and higher blood transfusion rate (p=0.002) during the operation, which were not considered prognostic factors (p=0.323 and 0.571, respectively). The median overall survival (OS) duration in group 1 was significantly longer than that in group 2 (14.3 vs. 10.4 months, p=0.047). The median OS durations in groups 1A, 1B, 2A, and 2B were 14.3, 42.7, 7.5, and 18.0 months, respectively, which were significantly different(p=0.018).

Conclusions: When PVTT/HVTT is located in the hepatic resection area and removed with the tumor en bloc, the median OS duration is longer. Based on this finding, widening the surgical margins when technically possible may increase OS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130021PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468137PMC
April 2016

Effects of antiviral therapy on hepatitis B virus reactivation and liver function after resection or chemoembolization for hepatocellular carcinoma.

Liver Int 2013 Apr 13;33(4):595-604. Epub 2013 Feb 13.

Department of Hepatobilliary Oncology, Sun Yat-sen University Cancer Center & State Key Laboratory of Oncology in Southern China, Guangzhou, China.

Background: How hepatitis B virus (HBV) infection react to hepatocellular carcinoma (HCC) treatment remains unclear, and the roles of anti-HBV therapy were seldom reported in HCC.

Aims: To evaluate changes of HBV replication and liver function after hepatectomy or transarterial chemoembolization (TACE) for HCC, also the short-term effects of anti-viral therapy were analyzed.

Methods: Totally, 590 HBsAg (+) HCC patients were recruited into two groups: only surgical resection, and only TACE, and subgrouped according to anti-HBV therapy or none. Clinical data were analyzed for statistical significance and risk factors for adverse events.

Results: In the no antiviral therapy groups, rates of HBV reactivation were 15.7% and 17.5% in patients who underwent hepatectomy and TACE, respectively, while the rates of deterioration of liver function were 4.1% and 8.1%, respectively. In contrast, in the antivirus group, the rates of reactivation were 0% and 1.5% after hepatectomy and TACE respectively, while the liver function deterioration rates were 2.4% and 1.5%, respectively. For patients who underwent hepatectomy, no antiviral therapy, and long hepatic inflow occlusion times increased the risk of HBV reactivation. For TACE, no antivirus and HBeAg negativity were the risk factors for reactivation. HBV reactivation was significantly correlated to liver function exacerbation after hepatectomy, while HBV reactivation, baseline ALT (alanine aminotransferase), and α-fetoprotein levels were significantly correlated to liver function exacerbation after TACE.

Conclusions: HBV reactivation can occur after hepatectomy or TACE. Anti-HBV therapy can reduce the risk of reactivation, thus reducing the risk of liver failure especially in patients undergoing TACE.
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http://dx.doi.org/10.1111/liv.12112DOI Listing
April 2013

Changes in hepatitis B virus DNA levels and liver function after transcatheter arterial chemoembolization of hepatocellular carcinoma.

Hepatol Res 2011 Jun 29;41(6):553-63. Epub 2011 Mar 29.

Department of Hepatobilliary Oncology, Sun Yat-sen University Cancer Center and State Key Laboratory of Southern China, Guangzhou, China Department of Surgical Oncology of University of Michigan University of Michigan, Ann Arbor, Michigan, USA.

Aim:   Reports concerning changes in hepatitis B virus (HBV) status and liver function in hepatocellular carcinoma (HCC) during or after transcatheter arterial chemoembolization (TACE) have been rare and the results inconsistent. The objective of this retrospective study was to evaluate these parameters in a large cohort of HBV-related HCC patients.

Methods:   One hundred and seventy-two hepatitis B surface antigen positive HCC patients with Child-Pugh grade A or B liver disease who underwent 228 sessions of TACE were enrolled, and related clinical and laboratory data were analyzed.

Results:   In total, HBV reactivated in 33 (14.5%), remained stable in 152 (66.7%) and decreased in 43 (18.8%) sessions. Univariate analysis revealed that sex and HBV DNA levels correlated with changes in HBV DNA status after TACE, while hepatitis B e-antigen (HBeAg), prothrombin time and chemotherapeutic agents were marginally significant factors. Multivariate analysis demonstrated that the major factors that influenced the HBV DNA status were baseline HBV DNA levels(P = 0.0002) and HBeAg (P = 0.0387). A comparison of the post-TACE (30-90 days) liver function to the baseline revealed no significant differences. The reactivation group has the highest rate of exacerbation (12.1%) compared with the stable group (5.9%) and downregulation group (4.7%).

Conclusion:   HBV DNA changes after TACE included reactivated, decreased and stable HBV DNA levels. Although HBV reactivation did not necessarily result in exacerbation of liver damage and most HCC patients with Child-Pugh grade A and B tolerated TACE well, careful post-procedure monitoring and managing is needed.
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http://dx.doi.org/10.1111/j.1872-034X.2011.00796.xDOI Listing
June 2011

[Micrometastasis distribution in liver tissue surrounding hepatocellular carcinoma].

Zhonghua Zhong Liu Za Zhi 2002 May;24(3):257-60

Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University of Medical Sciences, Guangzhou 510060, China.

Objective: To study the micrometastasis distribution in liver tissue surrounding hepatocellular carcinoma (HCC), and provide reference for appropriate surgical safety margin.

Methods: Thirty-six patients with HCC but without clinical metastasis underwent hepatectomy. Their specimens showing ample surgical margin were made into giant sections. Tumor micrometastasis in liver tissue around the primary tumor were examined microscopically. In each specimen, the surrounding tissue was divided into proximal(p) and distal(d) areas. In either area, three lines of demarcation 0.5 cm, 1.0 cm, and 2.0 cm away from the margin of the primary tumor were designated as L(0.5), L(1.0) and L(2.0). Therefore, the surrounding tissue was divided into six zones - Z(p0.5), Z(p1.0), Z(p2.0) and Z(d0.5), Z(d1.0), Z(d2.0). The maximum micrometastasis spread distance (MMSD) and density (D(p0.5), D(p1.0), D(p2.0) and D(d0.5), D(d1.0), D(d2.0)) in each zone were analyzed after search for micrometastasis in the giant sections.

Results: 72.5% (111/153) micrometastases were found in form of microscopic tumor emboli. Their spread distance could be up to 6.1 cm. In 66.7% (24/36) specimens, micrometastases were found in the surrounding tissue. In 91.7% (22/24) of them, the distal MMSD was less than 3 cm. The proximal MMSD was less than 1.5 cm in 92.3% (12/13). The comparison of micrometastasis density in the different zones were D(d0.5) > D(d1.0) > D(d 2.0); D(p0.5) > D(p1.0) > D(p2.0); D(d1.0) > D(p1.0); D(d2.0) > D(p2.0) with significant differences.

Conclusion: (1) Micrometastases of HCC exist mainly in form of microscopic tumor emboli, (2) The longer the distance from the primary focus, the lower the micrometastasis incidence, (3) In zones more than 0.5 cm away from the primary focus, tumor micrometastasis incidence is significantly lower in the proximal zones than that in the distal zones and (4) For HCC patients without clinical metastasis, a surgical margin of 3 cm wide in the distal area and 1.5 cm wide in the proximal area may reduce the rate of postoperative recurrence.
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May 2002
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