Huaier granule improves liver inflammation and fibrosis and prevents recurrence in hepatitis B virus related hepatocellular carcinoma
Highlight box
Key findings
• Huaier granule can improve liver inflammation, fibrosis, and liver function and prolong the time to recurrence in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).
What is known and what is new?
• There is basic research suggesting that Huaier granule can inhibit liver cirrhosis and HCC, but this conclusion has not been clinically verified.
• The results showed that liver inflammation improved significantly in the Group A [19 (37.3%) cases improved, 31 (60.8%) cases remained unchanged, and one (2.0%) case deteriorated] was significantly more than that in the Group B [7 (12.5%) cases improved, 32 (57.1%) cases remained unchanged, and 17 (30.4%) cases deteriorated] (P<0.001). The liver fibrosis in the Group A [17 (33.3%) cases improved, 32 (62.7%) cases remained unchanged, and 2 (3.9%) cases deteriorated] was significantly improved in the Group B [5 (8.9%) cases improved, 45 (80.4%) cases remained unchanged, and 6 (10.7%) cases deteriorated] (P=0.005). The recurrence interval (27.0±21.2 months) in the Group A was significantly longer than that in the Group B (19.0±14.2 months) (P=0.026).
What is the implication, and what should change now?
• Given the high rate of postoperative recurrence and poor prognosis of HBV-related HCC, our findings may have useful clinical significance in the prevention of tumor recurrence in these patients.
Introduction
Hepatocellular carcinoma (HCC) ranks fifth in terms of global incidence and it is the third leading cause of death worldwide (1). In China, 90% of HCC patients are hepatitis B virus (HBV) infection, and with approximately 450,000 new cases of HCC annually, accounting for more than 50% of the new cases of HCC worldwide (2). HCC has become the second leading cause of death among cancer patients in China, with approximately 130,000 deaths each year (2). HBV and liver fibrosis are closely related to the development of HCC and postoperative recurrence, especially late recurrence (3,4).
Hepatic resection, ablation, chemotherapy, and liver transplantation are the main curative treatment options for patients with HCC (5-8). However, the high incidence of postoperative recurrence limits the efficacy of hepatic resection. Clinical practice shows that traditional Chinese medicine (TCM) plays an active role in improving clinical symptoms, enhancing the body’s immunity, delaying tumor growth, alleviating adverse effects, and improving patients’ life quality in HCC patients (9,10). At present, TCM has become an integral part of comprehensive treatment, more and more medical professionals have gradually agreed with its unique advantages, and tend to implement combination therapies in the treatment of HCC (11,12). To date, guidelines for diagnosis and treatment of oncology with TCM are developed as per international standards and are consistent with modern clinical practice (13,14).
Huaier is a kind of higher fungal fruiting body parasitic on old Sophora japonica. Huaier granule contains over 10 minerals and a diversity of organic ingredients. It has been widely used in traditional Chinese Medicine for nearly 1,600 years (15). In recent years, Huaier granule approved by the Chinese State Food and Drug Administration (SFDA) can be used alone or in combination with other drugs for the treatment of leukemia, osteosarcoma, malignant lymphoma cancer, breast cancer, lung cancer, rectal cancer, HCC, stomach cancer, colon cancer, and pancreatic cancer (16). Huaier granule can promote tumor cell apoptosis and enhance the immunity of the body (17). A recent multicenter, randomized, phase 3 clinical trial showed that Huaier granule significantly improved the tumor-free survival time and reduced the incidence of extrahepatic metastases after hepatectomy of HCC (18).
In liver cirrhosis, reversal of cirrhosis is difficult. Recently, an animal experiment found that Huaier granule had a strong inhibitory effect on cirrhosis and development of HCC, and the efficacy was closely correlated with the course of treatment (16). Therefore, Huaier granule may reduce post-operative relapse by inhibiting liver inflammation and fibrosis. However, this conclusion has not been clinically verified.
Therefore, we analyzed the distant cancerous tissues of HBV-related HCC patients who were/were not taking Huaier granule. To clarify the effect of Huaier granule on liver inflammation, liver fibrosis, and recurrence after hepatectomy in these patients. We present this article in accordance with the MDAR reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1347/rc).
Methods
Patient eligibility
Clinicopathological data of HCC patients who received 2 surgery procedures at Mengchao Hepatobiliary Hospital of Fujian Medical University in China from January 2014 to December 2020 were initially collected. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics committee of Mengchao Hepatobiliary Hospital of Fujian Medical University (No. 2022_020_01). Informed consent requirement was waived due to the fact that this study did not involve personal privacy nor commercial interests and patient data were confidential.
Eligibility criteria included (I) pathologically confirmed HCC; (II) with combined hepatitis B; (III) received standardized anti-HBV treatment; (IV) with residual distant cancerous tissue in both surgeries.
Exclusion criteria included (I) patients with incomplete clinical data; (II) with postoperative transcatheter arterial chemoembolization (TACE); (III) patients who received other anti-tumor treatments.
Study design
Patients according to taking or not taking Huaier granule after the first hepatectomy were divided into two groups: patients in the Huaier granule treatment group started oral administration of Huaier granule after a week of hepatectomy and kept the administration for over 6 months (20 g/time, 3 times a day, Group A); patients in the control group did not take Huaier granule (Group B).
Measurements
Baseline clinical variables for the included subjects included gender, age, liver function, alpha-fetoprotein (AFP), hepatitis B virus deoxyribonucleic acid (HBV-DNA) load, tumor size, tumor number, Barcelona Clinic Liver Cancer (BCLC) stage, recurrence interval, liver inflammation grade, liver fibrosis grade. All pathological specimens were independently reassessed by two pathologists. Modified Scheuer scoring system was used for liver inflammation and fibrosis. According to the changes in inflammation and fibrosis grading of distant cancerous tissues at the time of the first and second surgery, three conditions were defined: improved, unchanged, and deteriorated.
Statistical analysis
Continuous variables were expressed as mean ± standard deviation (SD) and compared by t-tests, and categorical variables were expressed as n (%). Differences in categorical variables were compared with the Chi-squared test or Fisher’s exact test. All statistical tests were two-tailed, and P<0.05 was considered statistically significant. All statistical analyses were performed using R version 3.5.2 (http://www.r-project.org/).
Results
Demographics
Between January 2014 and December 2020, 158 patients with HCC treated with two surgeries from Mengchao Hepatobiliary Hospital of Fujian Medical University were included.15 cases were excluded from postoperative TACE, 16 cases were excluded from receiving other antitumor therapy, and 20 cases were excluded from incomplete clinical data. A total of 107 cases were eligible for enrollment in this study (Figure 1). Among them, 51 cases who took Huaier granule for more than six months after surgery were set up as treatment group (Group A, 51 cases); 56 cases who did not take Huaier granule were set up as control group (Group B, 56 cases).
Baseline characteristics of study patients at first surgery
Table 1 shows the baseline characteristics of patients who received their first surgery. The mean age of these patients was 58.1±11.6 years; 92 cases (86%) were males; the albumin was 39.7±5.49 g/L, total bilirubin 17.8±8.83 µmol/L, alanine aminotransferase (ALT) 50.1±68.1 U/L and aspartate aminotransferase (AST) 45.2±44.8 U/L; the AFP level was ≥400 ng/mL in 38 patients (35.5%), HBV-DNA ≥10,000 IU/L in 42 patients (39.3%); mean tumor size was 4.53±3.34 cm; there were 92 (86%) cases in with single-tumor, 88 (82.2%) in BCLC stage 0/A, 11 (10.3%) in BCLC stage B and 8 (7.5%) in BCLC stage C. No significant differences were found between the two groups in age, gender, liver function, AFP, HBV-DNA, tumor size and number, BCLC stage at first surgery.
Table 1
| Variables | Overall (n=107) | Group A (n=51) | Group B (n=56) | P value |
|---|---|---|---|---|
| Age, years | 58.1 (11.6) | 58.0 (11.9) | 58.2 (11.3) | 0.950 |
| Gender | 0.996 | |||
| Female | 15 (14.0) | 7 (13.7) | 8 (14.3) | |
| Male | 92 (86.0) | 44 (86.3) | 48 (85.7) | |
| ALB, g/L | 39.7 (5.49) | 40.3 (5.29) | 39.2 (5.67) | 0.302 |
| TBIL, μmol/L | 17.8 (8.83) | 18.2 (8.04) | 17.5 (9.55) | 0.686 |
| ALT, U/L | 50.1 (68.1) | 56.3 (87.4) | 44.4 (44.0) | 0.381 |
| AST, U/L | 45.2 (44.8) | 48.2 (58.5) | 42.6 (27.1) | 0.537 |
| AFP | 0.334 | |||
| <400 ng/mL | 69 (64.5) | 30 (58.8) | 39 (69.6) | |
| ≥400 ng/mL | 38 (35.5) | 21 (41.2) | 17 (30.4) | |
| HBV-DNA | 0.557 | |||
| <10,000 IU/L | 65 (60.7) | 29 (56.9) | 36 (64.3) | |
| ≥10,000 IU/L | 42 (39.3) | 22 (43.1) | 20 (35.7) | |
| Tumor size, cm | 4.53 (3.34) | 4.73 (3.10) | 4.34 (3.57) | 0.543 |
| Tumor number | 0.451 | |||
| Solitary | 92 (86.0) | 45 (88.2) | 47 (83.9) | |
| Multiple | 15 (14.0) | 6 (11.8) | 9 (16.1) | |
| BCLC stage | 0.729 | |||
| 0/A | 88 (82.2) | 43 (84.3) | 45 (80.4) | |
| B | 11 (10.3) | 4 (7.8) | 7 (12.5) | |
| C | 8 (7.5) | 4 (7.8) | 4 (7.1) |
Categorical variables are presented as number (percentage). Mean (standard deviation) presented for distributed continuous variables. Group A: with Huaier granual; Group B: without Huaier ganual. ALB, albumin; TBIL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AFP, alpha-fetoprotein; HBV-DNA, hepatitis B virus deoxyribonucleic acid; BCLC, Barcelona Clinic Liver Cancer.
Baseline characteristics of study patients at the second surgery
Table 2 shows the liver function of patients who received second surgery. The albumin was 39.1±7.07 g/L, total bilirubin 18.4±12.5 µmol/L, ALT 33.7±42.7 U/L and AST 33.6±35.8 U/L; the AFP level was ≥400 ng/mL in 20 patients (18.7%), HBV-DNA ≥10,000 IU/L in one patient (0.9%). The albumin levels at the second operation of HCC patients in the Group A were significantly higher than those in the Group B (P=0.038).
Table 2
| Variables | Overall (n=107) | Group A (n=51) | Group B (n=56) | P value |
|---|---|---|---|---|
| ALB, g/L | 39.1 (7.07) | 40.6 (6.00) | 37.8 (7.73) | 0.038 |
| TBIL, μmol/L | 18.4 (12.5) | 16.6 (5.74) | 20.0 (16.4) | 0.153 |
| ALT, U/L | 33.7 (42.7) | 27.6 (14.1) | 39.2 (57.2) | 0.149 |
| AST, U/L | 33.6 (35.8) | 29.3 (11.5) | 37.6 (48.1) | 0.217 |
| AFP | 0.987 | |||
| <400 ng/mL | 87 (81.3) | 42 (82.4) | 45 (80.4) | |
| ≥400 ng/mL | 20 (18.7) | 9 (17.6) | 11 (19.6) | |
| HBV-DNA | 0.963 | |||
| <10,000 IU/L | 106 (99.1) | 50 (98.0) | 56 (100.0) | |
| ≥10,000 IU/L | 1 (0.9) | 1 (2.0) | 0 (0) |
Categorical variables are presented as no. (%). Mean (standard deviation) presented for distributed continuous variables. Group A: with Huaier granual; Group B: without Huaier ganual. ALB, albumin; TBIL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AFP, alpha-fetoprotein; HBV-DNA, hepatitis B virus deoxyribonucleic acid.
The effect of Huaier granule on hepatitis, liver fibrosis, and recurrence time
Figure 2 shows the hematoxylin-eosin (HE) stained pictures of the hepatic inflammation grading of distant cancer tissues from 3 patients. Figure 2A,2B showed the liver inflammation grades in the distant cancer tissue of the first and the second operations of case 1, showing improvement in liver inflammation in this patient (G2 becomes G1). Figure 2C,2D showed the liver inflammation grades in the distant cancer tissue of the first and the second operations of case 2, showing no change in liver inflammation of this patient. Figure 2E,2F showed the liver inflammation grades in the distant cancer tissue of the first and the second operations of case 3, showing worse liver inflammation in this patient (G1 becomes G2). The results showed that the liver inflammation improved significantly in the Group A [19 (37.3%) cases improved, 31 (60.8%) cases remained unchanged, and 1 (2.0%) case deteriorated] was significantly more than that in the Group B [7 (12.5%) cases improved, 32 (57.1%) cases remained unchanged, and 17 (30.3%) cases deteriorated] (P<0.001) (Table 3).
Table 3
| Variables | Overall (n=107) | Group A (n=51) | Group B (n=56) | P value |
|---|---|---|---|---|
| Liver inflammation | <0.001 | |||
| Improved | 26 (24.3) | 19 (37.3) | 7 (12.5) | |
| Unchanged | 63 (58.9) | 31 (60.8) | 32 (57.1) | |
| Deteriorated | 18 (16.8) | 1 (2.0) | 17 (30.4) | |
| Liver cirrhosis | 0.005 | |||
| Improved | 22 (20.6) | 17 (33.3) | 5 (8.9) | |
| Unchanged | 77 (72.0) | 32 (62.7) | 45 (80.4) | |
| Deteriorated | 8 (7.5) | 2 (3.9) | 6 (10.7) | |
| Recurrence interval, months | 22.9 (18.2) | 27.0 (21.2) | 19.0 (14.2) | 0.026 |
Categorical variables are presented as number (percentage). Mean (standard deviation) presented for distributed continuous variables. Group A: with Huaier granual; Group B: without Huaier ganual.
Figure 3 shows the Masson-stained pictures of the hepatic inflammation grading of distant cancer tissues from 3 patients. Figure 3A,3B showed the liver fibrosis grades in the distant cancer tissue of the first and the second operations of case 1, showing improvement in liver fibrosis in this patient (S4 becomes S3). Figure 3C,3D showed the liver fibrosis grades in the distant cancer tissue of the first and the second operations of case 2, showing no change in liver fibrosis of this patient. Figure 3E,3F showed the liver fibrosis grades in the distant cancer tissue of the first and the second operations of case 3, showing worse liver fibrosis in this patient (S2 becomes S3). The liver fibrosis in the Group A [17 (33.4%) cases improved, 32 (62.7%) cases remained unchanged, and 2 (3.9%) cases deteriorated] was significantly improved than that in the Group B [5 (8.9%) cases improved, 45 (80.4%) cases remained unchanged, and 6 (10.7%) cases deteriorated] (P=0.005) (Table 3).
In addition, the recurrence interval (27.0±21.2 months) in the Group A was significantly longer than that in the Group B (19.0±14.2 months) (P=0.026). The above results indicated that Huaier granule can improve liver inflammation and liver fibrosis and prolong the recurrence time of HCC after surgery in HBV-related HCC.
Discussion
In China, 90% of HCC patients are HBV-related HCC. The incidence of HCC is particularly high in the Chinese population due to the high prevalence of HBV infection in China (19). HBV and liver cirrhosis are closely related to the development of HCC and its recurrence after surgery (20,21).
The incidence rate of HCC in patients with cirrhosis is as high as 50–85%. Liver cirrhosis is an important contributing factor for the development of HCC (22). Huaier granule has the effect of strengthening and consolidating body resistance, promoting blood circulation, and removing blood stasis consolidating body resistance (23). A study has shown that it can promote tumor cell apoptosis, regulate body immunity, reverse drug resistance, and inhibit angiogenesis, etc. (24). It is used in the treatment of HCC, stomach cancer, breast cancer, and other cancers (16).
Basic experimental study has also shown that Huaier granule have the effect of improving liver cirrhosis (16). Chen et al. found Huaier presented a strong inhibitory effect on cirrhosis and HCC and its efficacy was closely related to the duration of treatments (16). However, this result has not been clinically validated. The effect of Huaier granule on liver inflammation and cirrhosis has not been reported. This study is the first to clinically demonstrate that Huaier granule can improve liver inflammation and liver function and reverse liver fibrosis/cirrhosis in HBV-related HCC.
A randomized, controlled, and multicenter clinical study by Chen et al. confirmed Huaier granule had an anti-recurrence effect after radical resection of HCC (18). Currently, it is commonly believed that postoperative recurrence of HCC is divided into early recurrence (less than 2 years) and late recurrence (more than 2 years) (3,4,25). Early recurrence is associated with residual tumor (seed theory) and late recurrence is mainly related to the patient’s underlying liver pathology (soil theory) (26,27). The results of this study showed that taking Huaier granule can significantly prolong the postoperative recurrence time of patients with HBV-related HCC, with an average recurrence time of 27 months. This suggests that Huaier granule have an anti-HCC recurrence effect, and the effect is mainly reflected in the anti-late recurrence.
Our study has several limitations. Firstly, a retrospective study is inherently biased. Therefore, in future experiments, expanding the sample size and future prospective randomized studies are required to confirm the findings. Secondly, inhibition of the transformation of liver fibrosis/cirrhosis to HCC may be one of the mechanisms. However, the molecular mechanisms need to be further investigated.
Conclusions
Huaier granule can improve liver inflammation, fibrosis, and liver function and prolong the time to recurrence in HBV-related HCC. Given the high rate of postoperative recurrence and poor prognosis of HBV-related HCC, our findings may have useful clinical significance in the prevention of tumor recurrence in these patients.
Acknowledgments
Funding: This study was supported by
Footnote
Reporting Checklist: The authors have completed the MDAR reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1347/rc
Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1347/dss
Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1347/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1347/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics committee of Mengchao Hepatobiliary Hospital of Fujian Medical University (No. 2022_020_01). Informed consent requirement was waived due to the fact that this study did not involve personal privacy nor commercial interests and patient data were confidential.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
- Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018;391:1301-14. [Crossref] [PubMed]
- Poon RT, Fan ST, Ng IO, et al. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer 2000;89:500-7. [Crossref] [PubMed]
- Portolani N, Coniglio A, Ghidoni S, et al. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg 2006;243:229-35. [Crossref] [PubMed]
- European Association for the Study of the Liver. Electronic address: easloffice@easloffice; . EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018;69:182-236. [Crossref]
- Xie DY, Ren ZG, Zhou J, et al. 2019 Chinese clinical guidelines for the management of hepatocellular carcinoma: updates and insights. Hepatobiliary Surg Nutr 2020;9:452-63. [Crossref] [PubMed]
- Sun HC, Zhou J, Wang Z, et al. Chinese expert consensus on conversion therapy for hepatocellular carcinoma (2021 edition). Hepatobiliary Surg Nutr 2022;11:227-52. [Crossref] [PubMed]
- Yang X, Xu H, Zuo B, et al. Downstaging and resection of hepatocellular carcinoma in patients with extrahepatic metastases after stereotactic therapy. Hepatobiliary Surg Nutr 2021;10:434-42. [Crossref] [PubMed]
- Liu X, Li M, Wang X, et al. Effects of adjuvant traditional Chinese medicine therapy on long-term survival in patients with hepatocellular carcinoma. Phytomedicine 2019;62:152930. [Crossref] [PubMed]
- Zhu XD, Li KS, Sun HC. Adjuvant therapies after curative treatments for hepatocellular carcinoma: Current status and prospects. Genes Dis 2020;7:359-69. [Crossref] [PubMed]
- Sparkman J, Hernaez R, El-Serag HB. Traditional Chinese Medicine to the rescue of allopathic medicine in the co-adjuvant treatment of hepatocellular carcinoma. Transl Gastroenterol Hepatol 2018;3:97. [Crossref] [PubMed]
- Zhu LY, Hou JC, Yang L, et al. Application value of mixed reality in hepatectomy for hepatocellular carcinoma. World J Gastrointest Surg 2022;14:36-45. [Crossref] [PubMed]
- Li Y, Li Y, Zhang J, et al. Current Perspective of Traditional Chinese Medicines and Active Ingredients in the Therapy of Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022;9:41-56. [Crossref] [PubMed]
- Jia W, Liang S, Cheng B, et al. The Role of Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and the Value of Traditional Chinese Medicine Treatment. Front Oncol 2021;11:763519. [Crossref] [PubMed]
- Su D, Jiang B, Yang Y, et al. Effect of Huaier on Melanoma Invasion, Metastasis, and Angiogenesis. Biomed Res Int 2020;2020:8163839. [Crossref] [PubMed]
- Chen J, Chen S, Zhou Y, et al. Efficacy and Safety of Huaier Granule as an Adjuvant Therapy for Cancer: An Overview of Systematic Reviews and Meta-Analyses. Integr Cancer Ther 2022;21:15347354221083910. [Crossref] [PubMed]
- Wang Z, Yu XL, Zhang J, et al. Huaier granule prevents the recurrence of early-stage hepatocellular carcinoma after thermal ablation: A cohort study. J Ethnopharmacol 2021;281:114539. [Crossref] [PubMed]
- Chen Q, Shu C, Laurence AD, et al. Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial. Gut 2018;67:2006-16. [Crossref] [PubMed]
- Zhou J, Sun HC, Wang Z, et al. Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition). Liver Cancer 2018;7:235-60. [Crossref] [PubMed]
- Sasaki K, Shindoh J, Nishioka Y, et al. Impact of Viral Etiology on Postoperative De Novo Recurrence After Hepatectomy for Hepatocellular Carcinoma in Cirrhotic Patients. J Gastrointest Surg 2017;21:487-95. [Crossref] [PubMed]
- Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38:200-7. [Crossref] [PubMed]
- Global Burden of Disease Liver Cancer Collaboration. The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015. JAMA Oncol 2017;3:1683-91. [Crossref] [PubMed]
- Xu X, Wei Q, Wang K, et al. Anticancer effects of Huaier are associated with down-regulation of P53. Asian Pac J Cancer Prev 2011;12:2251-4. [PubMed]
- Tao Y, Shan L, Xu X, et al. Huaier Augmented the Chemotherapeutic Sensitivity of Oxaliplatin via Downregulation of YAP in Hepatocellular Carcinoma. J Cancer 2018;9:3962-70. [Crossref] [PubMed]
- Xu XF, Xing H, Han J, et al. Risk Factors, Patterns, and Outcomes of Late Recurrence After Liver Resection for Hepatocellular Carcinoma: A Multicenter Study From China. JAMA Surg 2019;154:209-17. [Crossref] [PubMed]
- Yang SL, Luo YY, Chen M, et al. A systematic review and meta-analysis comparing the prognosis of multicentric occurrence and vs. intrahepatic metastasis in patients with recurrent hepatocellular carcinoma after hepatectomy. HPB (Oxford) 2017;19:835-42. [Crossref] [PubMed]
- Du ZG, Wei YG, Chen KF, et al. Risk factors associated with early and late recurrence after curative resection of hepatocellular carcinoma: a single institution's experience with 398 consecutive patients. Hepatobiliary Pancreat Dis Int 2014;13:153-61. [Crossref] [PubMed]
