COCH predicts survival and adjuvant TACE response in patients with HCC
- Authors:
- Published online on: February 10, 2021 https://doi.org/10.3892/ol.2021.12536
- Article Number: 275
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Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer worldwide and the cause of 8.2% of cancer-related fatalities in 2008 (1). Hepatectomy remains the first option for patients with HCC, while non-surgical approaches, such as chemotherapy, radiation, radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and percutaneous ethanol injection, have been used to inhibit tumor progression and recurrence (2). Due to inadequate resection, unprecedented tumor formation or intrahepatic metastases that were not detected during resection, the majority of patients experience recurrence within 5 years of surgery (3).
TACE is globally performed as an effective treatment for HCC, as it inhibits residual tumor growth, suppresses metastasis, prevents relapse and prolongs patient survival time (4). The patients with large HCC tumor size, Child Pugh A/B or intrahepatic metastases are considered as candidates for receiving TACE 1–2 months after resection (5,6). However, not all patients are suitable candidates for TACE, as it can also result in a deterioration of liver function and prognosis after surgery (7). Individual analysis of the molecular mechanism, prediction of the effects of different treatments and selection of the most appropriate treatment based on the histological characteristics is the main focus of personalized and precision medicine (8).
Cochlin (COCH) is a secreted protein identified in glaucomatous but not normal trabecular meshwork, that has been shown to be responsive to altered fluid shear dynamics (9). COCH is mainly detected in the normal inner ear and its mutation has been found to be associated with hearing loss, glaucoma and DFNA9 (an autosomal dominant cause of non-syndromic adult-onset sensorineural hearing loss with associated variable vestibular dysfunction), while it is expressed at lower levels in the eye, spleen, cerebellum, lung, brain and thymus (10–12). Through RNA-seq analysis of 20 HCC tissues and adjacent non-neoplastic tissues, we observed that COCH was highly expressed in HCC samples (preliminary research, data not shown). However, to the best of our knowledge, whether COCH is associated with the tumorigenesis and progression of HCC has not been reported to date. Therefore, the aim of the present study was to investigate the prognostic value of COCH and its association with the effects of TACE in patients with HCC.
Materials and methods
Patients and tissue samples
A total of 135 patients with HCC were recruited from the Shanghai Eastern Hepatobiliary Surgery Hospital (Shanghai, China) between January 2005 and December 2007. All the patients underwent hepatectomy with or without postoperative TACE. The tumor tissues were embedded in paraffin and underwent tissue microarray (TMA) analysis. The patients were selected according to the following inclusion criteria: World Health Organization performance status 0–1, Child-Pugh class A, absence of ascites, no chemotherapy or radiotherapy prior to curative resection, and confirmation of HCC diagnosis by pathological examination (13,14). The following histological features were examined: Thin beam, thick beam or pseudoglandular duct, the degree of differentiation, the degree of necrosis and infiltration, cell type and microvascular invasion. Hepatectomy was performed as previously described, Tumor-Node-Metstasis (TNM) stage was then determined (5,15). Tumor tissue, adjacent non-neoplastic tissues and non-neoplastic distant tissues were collected after hepatectomy. The tissues outside the capsule (distance ≤1 cm) were defined as adjacent non-neoplastic tissues, while the tissues outside the capsule (distance >1 cm) were defined as non-neoplastic distant tissues. The protocol of the present study was approved by the Ethics Committee of Shanghai Eastern Hepatobiliary Surgery Hospital. Patients provided written informed consent for the publication of any associated data and accompanying images.
Adjuvant TACE
Patients received hepatic arterial angiography and adjuvant TACE within 1–2 months of hepatectomy. Patients without a tumor in the residual liver received preventive TACE (10 mg hydroxycamptothecin, 20 mg pirarubicin and 1 ml lipiodol). Patients with tumor in the residual liver received therapeutic TACE (10 mg hydroxycamptothecin, 20 mg pirarubicin, 100 mg oxaliplatin and 5 ml Lipiodol). Positron emission tomography-computed tomography (PET-CT) or magnetic resonance imaging evaluation was performed 1 month after the treatment, in order to decide whether subsequent TACE treatment should be performed.
Follow-up
The follow-up visits took place once every 3–6 months in the first 5 years after surgery. A complete physical examination was performed at each follow-up visit. Serum α-fetoprotein measurements, liver function tests and an abdominal ultrasound were performed. Furthermore, PET-CT or magnetic resonance imaging was performed upon suspicion of recurrence or metastasis. Patients with recurrence received repeat hepatectomy, chemotherapy, radiotherapy or local ablative therapy, depending on the size, location and number of recurrent tumors, as well as the liver function. Overall survival (OS) time was defined as the time from hepatectomy to the date of death or the date of the last follow-up. Disease-free survival (DFS) time was defined as the time from hepatectomy to recurrence or the date of the last follow-up.
TMA and immunohistochemical analysis
The clinical tissue samples were fixed with 10% formaldehyde at room temperature for 24 h and embedded in paraffin. The section thickness was 3–5 µm. Hematoxylin and eosin staining (room temperature for 50 sec for both) was performed on the tumor tissues, adjacent non-neoplastic tissues and non-neoplastic distant tissues to determine optimal contents. Tissue samples (1 mm in diameter) were punched from paraffin-embedded tissues and then arranged in a TMA module with 0.2-mm intervals (Shanghai Biochip Company, Ltd.). An immunohistochemical assay was performed as previously reported (16). The antibody against COCH was purchased from Abcam (cat. no. ab171410; 1:100 dilution). Secondary antibody was purchased from Agilent Technologies, Inc. (anti-Rabbit-HRP; cat. no. K400311-2; 1:100 dilution). Stained sections were evaluated by three different researchers who were blinded to the clinical characteristics. The immunohistochemical staining intensity was scored as follows based on the coloration intensity and the percentage of stained cells: The staining intensity was score as: 0, negative; 1, weak; 2, moderate; or 3, strong. The percent positivity was scored as 0–100%. The percentage and staining intensity scores were multiplied to yield immunoreactive score: Scores of 0 or 1 were defined as low expression of COCH, while scores of 2 and 3 were defined as high expression of COCH (17). Cases in which there were disagreements on the immunohistochemistry staining intensity score were discussed with other researchers until a consensus was reached.
RNA collection, cDNA synthesis and reverse transcription-quantitative (RT-q)PCR analysis
Total RNA was extracted from cell lines, fresh-frozen tumor specimens and healthy control tissues using TRIzol® (Invitrogen; Thermo Fisher Scientific, Inc.). cDNA synthesis was performed using random hexamers (Roche Diagnostics) and SuperScriptII reverse transcription (Invitrogen; Thermo Fisher Scientific, Inc.). RT-qPCR was performed using an ABI 7900 Fast Real-Time PCR system (Applied Biosystems; Thermo Fisher Scientific, Inc.) and SYBR Green PCR kit (Takara Bio, Inc.). The temperature protocol of RT-PCR was: 95°C for 1 min, 35 cycles (95°C for 30 secs, 60°C for 30 secs and 72°C for 30 secs). 18S was qualified as reference gene (18). The primer sequences were as follows: COCH, forward: 5′-AGAAAACACCCGAGAAGAAAACT-3′ and reverse: 5′-CCAATTCCCAACATTAGAGCCA-3′ and 18S, forward: 5′-CGGCTACGACATCCAAGGAA-3′ and reverse: 5′-GCTGGAATTAGCGCGGCT-3′. The quantity of mRNA was determined using the 2−ΔΔCq method (19).
Statistical analysis
All the statistical analyses were conducted using SPSS version 20.0 (IBM Corp.). The differences between tumor tissues, adjacent non-neoplastic tissues and non-neoplastic distant tissues were determined by Kruskal-Wallis test, followed by Dunn's test. The associations between COCH expression and clinical data were determined using the χ2 test (once expected values were ≤5, Fisher's exact test was chosen). The differences in OS and DFS times between groups were determined by Kaplan-Meier analysis with log-rank tests. A univariate analysis was performed to determine the variants with statistical significance. The Cox regression model was used to analyze the effect of independent factors on OS and DFS time, based on the variants selected by univariate analysis. P<0.05 was considered to indicate a statistically significant difference.
Results
Patient histological characteristics
The characteristics of the patients (n=135) are summarized in Table I. All the patients were diagnosed through radiological and pathological examination, and had undergone hepatectomy, with or without TACE. Reverse transcription-PCR analysis of 27 patients revealed that the mRNA level of COCH was higher in the tumor tissues compared with that in the adjacent and distant non-neoplastic tissues (Fig. 1A). The patients were divided into two groups according to the expression of COCH, which was determined by the immunostaining intensity of TMA slides (Fig. 1B). The immunostaining results were analyzed and evaluated by three individual researchers independently.
High COCH expression predicts a poor prognosis of HCC
In all patients, COCH expression levels were found to be significantly associated with portal vein tumor thrombosis (PVTT; P=0.039) and BCLC stage (P=0.049) (Table II). Kaplan-Meier analysis revealed that patients with high COCH expression exhibited a markedly shorter OS time compared with patients with low COCH expression (high-COCH patients: Median OS time, 12.208 months; 95% confidence interval (CI), 9.000–15.415; and low-COCH patients: Median OS time, 24.259 months; 95% CI, 18.218–30.389; P<0.001; Fig. 1C). Furthermore, patients with high COCH expression exhibited earlier recurrence of HCC (high-COCH patients: Median DFS time, 9.371 months; 95% CI, 5.085–13.657; and low-COCH patients: Median DFS time, 18.388 months; 95% CI, 11.981–24.769; P=0.010; Fig. 1D).
COCH expression level may predict the effect of adjuvant TACE
The aim of adjuvant TACE is mainly to prevent HCC recurrence. As shown in Fig. 2A and B, adjuvant TACE prolonged the OS (adjuvant TACE group: Median OS time, 25.647 months; 95% CI, 19.250–32.044; and control group: Median OS time, 12.396 months; 95% CI, 9.045–15.693; P<0.001; Fig. 2A) and 5-year DFS (adjuvant TACE group: Median DFS time, 19.836 months; 95% CI, 13.250–26.422; and control group: Median DFS time, 10.103 months; 95% CI, 5.211–14.994; P<0.001; Fig. 2B) times of the patients.
The results shown in Fig. 1 indicated that COCH predicted a poor patient prognosis and early cancer recurrence. The present study also investigated the association between COCH expression and the effectiveness of TACE. TACE treatment did not decrease the recurrence rate of patients with high COCH expression compared with that of patients who did not receive TACE (control group vs. TACE group: Median DFS time, 8.254 months vs. 12.402 months; 95% CI, 2.725–13.782 vs. 4.915–19.890; P=0.087; Fig. 3B). However, patients with low COCH expression exhibited a significantly lower recurrence rate after TACE (low COCH group vs. high COCH group: Median DFS time, 27.348 months vs. 12.386 months; 95% CI, 17.310–37.385 vs. 3.895–20.878; P=0.002; Fig. 3D). As recurrence significantly affects the prognosis of patients with HCC, the OS time of patients in different COCH expression groups, with and without TACE, was analyzed. TACE treatment was found to not be suitable for patients with high COCH expression, as it did not reduce recurrence or prolong OS time (control group vs. TACE group: Median OS time, 11.000 months vs. 14.214 months; 95% CI, 7.574–14.426 vs. 7.923–20.505; P=0.485; Fig. 3A). However, TACE improved the OS time of the HCC patients with low COCH expression (control group vs. TACE group: Median OS time, 39.565 months vs. 14.200 months; 95% CI, 30.422–48.708 vs. 7.947–20.453; P<0.001; Fig. 3C).
Univariate and multivariate analysis of prognostic factors
Cox regression analysis was employed to analyze the association between COCH level and the effects of TACE. As shown in Table III, univariate Cox regression analysis indicated that adjuvant TACE, the size and number of tumors, completeness of the tumor capsule and HBV infection (shown as HBsAg in the table) were associated with recurrence in patients with low COCH expression. Multivariate Cox regression analysis based on the factors identified as statistically significant on the univariate Cox regression analysis revealed that TACE was an independent biomarker for 5-year DFS in HCC patients with low COCH expression (hazard ratio, 0.4727; 95% CI, 0.3503–2.139; P=0.0324). In addition, tumor number (P=0.0033) and tumor size (P=0.0393) were independent predictors of 5-year DFS. However, the univariate analysis revealed that no variable was significantly associated with tumor recurrence in patients with high COCH expression.
 | Table III.Univariate and multivariate Cox regression analyses of 5-year disease-free survival in patients with different COCH expression levels. |
Discussion
Partial hepatectomy is the recommended first-line treatment for primary HCC. However, the local recurrence rate in the first 5 years following resection is as high as 70% (20). Satellite lesions, cirrhosis and tumor size are considered to be closely associated with postoperative recurrence (21). Several treatment options may be used to prevent the recurrence of HCC, including repeat hepatectomy, RFA and TACE (3). RFA and TACE may be considered more suitable for patients with Child-Pugh grade A or B, and for those with a greater size or number of tumors (22). However, based on the heterogeneity of HCC, not all patients will benefit from TACE. Patients with large tumors or venous invasion are at higher risk of recurrence and are advised to receive TACE in clinical practice (23). Molecular analysis of in situ and recurrent tumors may improve our understanding of the mechanisms underlying recurrence and help identify prognostic biomarkers (24,25). Several systematic analyses based on >10,000 patients with HCC demonstrated that patients receiving TACE experienced a survival benefit compared with the control group (26,27). However, other studies have reported different results regarding recurrence and survival after receiving TACE. A Cochrane analysis of 6 trials observed no superior effectiveness of TACE compared with the control group (28,29). This controversy focuses not only on patient recruitment for TACE, but also on the need for more large-scale trials (30,31). Therefore, patient selection is crucial when considering TACE.
The present study demonstrated that COCH was a suitable predictor of survival and recurrence in patients with HCC. The expression of COCH was closely associated with PVTT, HBV infection and BCLC stage. However, when the efficacy of adjuvant TACE was analyzed, only patients with low COCH expression appeared to benefit from the treatment. To the best of our knowledge, the present study is the first to report that COCH is associated with recurrence and may be useful in evaluating prognosis. It may also serve as a factor determining whether TACE should be administered to prevent recurrence and prolong OS time. Measuring COCH expression may also help evaluate the effect of TACE following hepatectomy and to determine whether to select TACE as a first-line adjuvant therapy. However, the univariate analysis in patients with high COCH expression revealed that the recurrence rate was not associated with any variables, including BCLC and TNM stage, which was reported to be associated with recurrence (3,32). This discrepancy may be due to the limited number of included patients. A larger study is required to confirm the results of the present study.
The mechanisms underlying the beneficial effect of TACE treatment on patients with low COCH expression remain elusive. The results of immunohistochemical analysis revealed that COCH was expressed in both the nucleus and the cytoplasm. It has not yet been reported whether COCH is more highly expressed in HCC and whether its expression is associated with the survival and recurrence of HCC, but the expression of COCH in normal liver tissue is low (33). TACE inhibits recurrence mainly by suppressing the early metastasis of tumor cells (34). However, it is difficult to detect the small intrahepatic metastases that contribute to early tumor recurrence, before or after hepatectomy. Theoretically, therapies focusing on undetected intrahepatic metastases are crucial for preventing the recurrence of HCC. However, some studies highlight the need for the careful selection of patients for TACE, as the treatment may damage liver cells and compromise liver function, which is important to help optimize the benefit of the overall HCC treatment course (7,35). The side effects of TACE may affect patient survival, which may explain why patients with high COCH expression do not benefit from TACE treatment.
In the present study, COCH was identified as a potential biomarker of HCC prognosis. Patients with high COCH expression exhibited poor OS times, early recurrence and no obvious response to adjuvant postoperative TACE. By contrast, patients with low COCH expression exhibited better OS and DFS times, as well as a better response to TACE. However, the predictive value of COCH for the clinical selection of TACE usage requires further verification by large-scale clinical trials, and the underlying mechanism must also be further investigated.
Acknowledgements
The authors would like to thank Dr Liwei Dong, Miss Xiao-Fan Feng and Mr. Meng-Qi Zhuang for their technical assistance (all National Center for Liver Cancer, Shanghai, China).
Funding
This study was supported by grants from the National Natural Science Foundation of China (nos. 81702339, 81802499 and 81802311), Jiangsu Province's Science and Technology Support Program (Social Development) Project (no. BE2017658) and the Applied Foundational Research of Medical and Health Care of Suzhou City (nos. SYSD2018206, SYS2019079 and SYS2018104).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
CW performed the experiments and performed the statistical analysis. ZWD and CGZ collected the pathological data of the patients and prepared the tissue microarray. SW analyzed revised the clinical data and the manuscript. ZHL and ZMZ performed the molecular experiments. JP and JW designed and conceived the experiment and confirmed the authenticity of the raw data. CY conceived the study and wrote the manuscript. All authors have read and approved the manuscript.
Ethics approval and consent to participate
HCC samples were obtained from the Shanghai Eastern Hepatobiliary Surgery Hospital, and studies on human tissues were approved by the Ethics Board of the Shanghai Eastern Hepatobiliary Surgery Hospital. Written consent was obtained from all patients.
Patient consent for publication
Patients provided written informed consent for the publication of any associated data and accompanying images.
Competing interests
The authors declare that they have no competing interests.
References
|
Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Bruix J and Sherman M; American Association for the Study of Liver Diseases, : Management of hepatocellular carcinoma: An update. Hepatology. 53:1020–1022. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Tabrizian P, Jibara G, Shrager B, Schwartz M and Roayaie S: Recurrence of hepatocellular cancer after resection: Patterns, treatments, and prognosis. Ann Surg. 261:947–955. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Forner A, Reig M and Bruix J: Hepatocellular carcinoma. Lancet. 391:1301–1314. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, Tateishi R, Han KH, Chawla YK, Shiina S, et al: Asia-pacific clinical practice guidelines on the management of hepatocellular carcinoma: A 2017 update. Hepatol Int. 11:317–370. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Chan SL, Mo FK, Johnson PJ, Liem GS, Chan TC, Poon MC, Ma BB, Leung TW, Lai PB, Chan AT, et al: Prospective validation of the Chinese University prognostic index and comparison with other staging systems for hepatocellular carcinoma in an Asian population. J Gastroenterol Hepatol. 26:340–347. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Yang B, Zheng B, Yang M, Zeng Z, Yang F, Pu J, Li C and Liao Z: Liver resection versus transarterial chemoembolization for the initial treatment of Barcelona clinic liver cancer stage B hepatocellular carcinoma. Hepatol Int. 12:417–428. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Marquardt JU, Galle PR and Teufel A: Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): An emerging field for advanced technologies. J Hepatol. 56:267–275. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Chance MR, Chang J, Liu S, Gokulrangan G, Chen DH, Lindsay A, Geng R, Zheng QY and Alagramam K: Proteomics, bioinformatics and targeted gene expression analysis reveals up-regulation of cochlin and identifies other potential biomarkers in the mouse model for deafness in Usher syndrome type 1F. Hum Mol Genet. 19:1515–1527. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Ikezono T, Matsumura T, Matsuda H, Shikaze S, Saitoh S, Shindo S, Hasegawa S, Oh SH, Hagiwara Y, Ogawa Y, et al: The diagnostic performance of a novel ELISA for human CTP (Cochlin-tomoprotein) to detect perilymph leakage. PLoS One. 13:e01914982018. View Article : Google Scholar : PubMed/NCBI | |
|
Jung J, Kim HS, Lee MG, Yang EJ and Choi JY: Novel COCH p.V123E mutation, causative of DFNA9 sensorineural hearing loss and vestibular disorder, shows impaired cochlin post-translational cleavage and secretion. Hum Mutat. 36:1168–1175. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Nyström A, Bornert O, Kühl T, Gretzmeier C, Thriene K, Dengjel J, Pfister-Wartha A, Kiritsi D and Bruckner-Tuderman L: Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa. Proc Natl Acad Sci USA. 115:E705–E714. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET and Carbone PP: Toxicity and response criteria of the Eastern cooperative oncology group. Am J Clin Oncol. 5:649–655. 1982. View Article : Google Scholar : PubMed/NCBI | |
|
Suman A, Barnes DS, Zein NN, Levinthal GN, Connor JT and Carey WD: Predicting outcome after cardiac surgery in patients with cirrhosis: A comparison of Child-Pugh and MELD scores. Clin Gastroenterol Hepatol. 2:719–723. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Wang K, Liu J, Yan ZL, Li J, Shi LH, Cong WM, Xia Y, Zou QF, Xi T, Shen F, et al: Overexpression of aspartyl-(asparaginyl)- beta-hydroxylase in hepatocellular carcinoma is associated with worse surgical outcome. Hepatology. 52:164–173. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Dong LW, Hou YJ, Tan YX, Tang L, Pan YF, Wang M and Wang HY: Prognostic significance of Beclin 1 in intrahepatic cholangiocellular carcinoma. Autophagy. 7:1222–1229. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Wang Q, Tan YX, Ren YB, Dong LW, Xie ZF, Tang L, Cao D, Zhang WP, Hu HP and Wang HY: Zinc finger protein ZBTB20 expression is increased in hepatocellular carcinoma and associated with poor prognosis. BMC Cancer. 11:2712011. View Article : Google Scholar : PubMed/NCBI | |
|
Bas A, Forsberg G, Hammarström S and Hammarström ML: Utility of the housekeeping genes 18S rRNA, beta-actin and glyceraldehyde-3-phosphate-dehydrogenase for normalization in real-time quantitative reverse transcriptase-polymerase chain reaction analysis of gene expression in human T lymphocytes. Scand J Immunol. 59:566–573. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, Roberts LR and Heimbach JK: Diagnosis, staging, and management of hepatocellular carcinoma: 2018 Practice guidance by the american association for the study of liver diseases. Hepatology. 68:723–750. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Kim JM, Lee SH, Shin WY, Lee KY, Kim JM and Ahn SI: Intrahepatic recurrence of single nodular hepatocellular carcinoma after surgical resection: An analysis by segmental distribution. ANZ J Surg. 88:E840–E844. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Wang K, Liu G, Li J, Yan Z, Xia Y, Wan X, Ji Y, Lau WY, Wu M and Shen F: Early intrahepatic recurrence of hepatocellular carcinoma after hepatectomy treated with re-hepatectomy, ablation or chemoembolization: A prospective cohort study. Eur J Surg Oncol. 41:236–242. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Huang L, Li J, Yan J, Cao J, Liu C, Zhang X, Wu M and Yan Y: Early recurrence after curative resection in oligonodular hepatocellular carcinoma. Hepatogastroenterology. 60:28–31. 2013.PubMed/NCBI | |
|
Feng AL, Zhu JK, Yang Y, Wang YD, Liu FY, Zhu M and Liu CZ: Repeated postoperative adjuvant TACE after curative hepatectomy improves outcomes of patients with HCC. Minim Invasive Ther Allied Technol. 1–6. Dec 27–2019.(Epub ahead of print). doi: 10.1080/13645706.2019.1707689. View Article : Google Scholar : PubMed/NCBI | |
|
Chen J, Huang J, Chen M, Yang K, Chen J, Wang J, Xu L, Zhou Z and Zhang Y: Transcatheter arterial chemoembolization (TACE) versus hepatectomy in hepatocellular carcinoma with macrovascular invasion: A meta-analysis of 1683 patients. J Cancer. 8:2984–2991. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Llovet JM and Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology. 37:429–442. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Lencioni R, de Baere T, Soulen MC, Rilling WS and Geschwind JF: Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data. Hepatology. 64:106–116. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Oliveri RS, Wetterslev J and Gluud C: Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev. CD0047872011.PubMed/NCBI | |
|
Forner A, Llovet JM and Bruix J: Chemoembolization for intermediate HCC: Is there proof of survival benefit? J Hepatol. 56:984–986. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Farinati F, Giacomin A, Vanin V, Giannini E and Trevisani F: TACE treatment in hepatocellular carcinoma: What should we do now? J Hepatol. 57:221–222. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Li KW, Li X, Wen TF and Lu WS: The effect of postoperative TACE on prognosis of HCC: An update. Hepatogastroenterology. 60:248–251. 2013.PubMed/NCBI | |
|
Zhang Y, Chen SW, Liu LL, Yang X, Cai SH and Yun JP: A model combining TNM stage and tumor size shows utility in predicting recurrence among patients with hepatocellular carcinoma after resection. Cancer Manag Res. 10:3707–3715. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Li L, Ikezono T, Watanabe A, Shindo S, Pawankar R and Yagi T: Expression of full-length Cochlin p63s is inner ear specific. Auris Nasus Larynx. 32:219–223. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Galle PR, Tovoli F, Foerster F, Wörns MA, Cucchetti A and Bolondi L: The treatment of intermediate stage tumours beyond TACE: From surgery to systemic therapy. J Hepatol. 67:173–183. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Miksad RA, Ogasawara S, Xia F, Fellous M and Piscaglia F: Liver function changes after transarterial chemoembolization in US hepatocellular carcinoma patients: The LiverT study. BMC Cancer. 19:7952019. View Article : Google Scholar : PubMed/NCBI |
