mTOR inhibitor reduces nontumour-related death in liver transplantation for hepatocellular carcinoma.

Sirolimus is a regularly applied immunosuppressant for patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). Sirolimus not only significantly inhibits HCC recurrence but also protects renal function. However, the improvement effect of sirolimus on nontumour-related death in patients is still unknown. The aim of our study was to investigate the therapeutic effect of sirolimus on nontumour-related deaths. In this study, we retrospectively enrolled 403 LT patients with HCC from January 1, 2015, to December 31, 2018. The median follow-up time was 47.1 months. The patients were divided into the sirolimus group (N = 184) and the sirolimus-free group (N = 219). There were no significant differences between the sirolimus group and the sirolimus-free group in survival (P = 0.054). In transplant patients who exceeded the Milan or Hangzhou criteria, the sirolimus group achieved higher survival than the sirolimus-free group (P = 0.005; P = 0.02). Moreover, multivariate analysis showed that sirolimus strongly reduced the hazard ratio (HR) for nontumour-related death in LT patients who exceeded the Milan (HR: 0.42; 95% CI: 0.18-1; P = 0.05) or Hangzhou criteria (HR: 0.26; 95% CI: 0.08-0.89; P = 0.032). HCC recurrence increased the risk of nontumour-related death. In conclusion, sirolimus-based immunosuppression can significantly reduce nontumour-related death in LT patients who exceed the criteria for transplantation. In addition, this finding will further promote the application of sirolimus after liver transplantation for hepatocellular carcinoma.

Advance of Metformin in Liver Disease.

Metformin is a first-line drug for the treatment of type 2 diabetes with a good safety profile and relatively low cost. In recent years, many other effects of metformin have been discovered. In this review, we provide the research advances in metformin in liver disease. High-dose metformin can activate AMPK by inhibiting mitochondrial complex 1. In addition, low-dose metformin could activate lysosomal AMPK through PEN2. Activated AMPK can reduce fatty acid synthesis, inhibit tumor proliferation and metastasis, and reshape the tumor microenvironment. In addition, metformin can reduce ROS production by inhibiting mitochondrial complex 1, which can reduce liver damage. Therefore, metformin has been found to alleviate nonalcoholic fatty liver disease and cirrhosis, relieve liver damage, and reduce the incidence of hepatocellular carcinoma and cholangiocarcinoma. This information suggests that metformin may represent a new possibility for the prevention and treatment of liver diseases.

Insights into the history and tendency of liver transplantation for liver cancer: a bibliometric-based visual analysis.

Research on liver transplantation (LT) for liver cancer has gained increasing attention. This paper has comprehensively described the current status, hotspots and trends in this field. A total of 2991 relevant articles from 1 January 1963 to 28 February 2023 were obtained from the Web of Science Core Collection. VOSviewer and CiteSpace software were utilized as bibliometric tools to analyze and visualize knowledge mapping. Between 1963 and 2023, the number of papers in the area of LT for liver cancer increased continuously. A total of 70 countries/regions, 2303 institutions and 14 840 researchers have published research articles, with the United States and China being the two most productive countries. Our bibliometric-based visual analysis revealed the expansion of LT indications for liver cancer and the prevention/treatment of cancer recurrence as ongoing research hotspots over the past decades. Meanwhile, emerging studies also focus on downstaging/bridging treatments before LT and the long-term survival of LT recipient, in particular the precise application of immunosuppressants.

Ubiquitin-specific protease 22 promotes tumorigenesis and progression by an FKBP12/mTORC1/autophagy positive feedback loop in hepatocellular carcinoma.

Ubiquitin-specific protease 22 (USP22) has been identified as a potential marker for cancer stem cells in hepatocellular carcinoma (HCC). It can promote HCC stemness, which is considered a driver of tumorigenesis. Here, we sought to determine the role of USP22 in tumorigenesis, elucidate its underlying mechanism, and explore its therapeutic significance in HCC. As a result, we found that tissue-specific Usp22 overexpression accelerated tumorigenesis, whereas Usp22 ablation decelerated it in a c-Myc/NRasGV12-induced HCC mouse model and that the mammalian target of rapamycin complex 1 (mTORC1) pathway was activated downstream. USP22 overexpression resulted in increased tumorigenic properties that were reversed by rapamycin in vitro and in vivo. In addition, USP22 activated mTORC1 by deubiquitinating FK506-binding protein 12 (FKBP12) and activated mTORC1, in turn, further stabilizing USP22 by inhibiting autophagic degradation. Clinically, HCC patients with high USP22 expression tend to benefit from mTOR inhibitors after liver transplantation (LT). Our results revealed that USP22 promoted tumorigenesis and progression via an FKBP12/mTORC1/autophagy positive feedback loop in HCC. Clinically, USP22 may be an effective biomarker for selecting eligible recipients with HCC for anti-mTOR-based therapy after LT.

TP53/mTORC1-mediated bidirectional regulation of PD-L1 modulates immune evasion in hepatocellular carcinoma.

BACKGROUND: Immunotherapy has facilitated great breakthroughs in the treatment of hepatocellular carcinoma (HCC). However, the efficacy and response rate of immunotherapy are limited and vary among different patients with HCC. TP53 mutation substantially affects the expression of immune checkpoint molecules in multiple cancers. However, the regulatory relationship between programmed death ligand 1 (PD-L1) and TP53 is poorly studied in HCC. We aimed to elucidate the regulatory mechanism of PD-L1 in HCC with different TP53 statuses and to assess its role in modulating immune evasion in HCC. METHODS: HCC mouse models and cell lines with different TP53 statuses were constructed. PD-L1 levels were detected by PCR, western blotting and flow cytometry. RNA-seqencing, immunoprecipitation, chromatin immunoprecipitation and transmission electron microscopy were used to elucidate the regulatory mechanism in HCC with different TP53 status. HCC mouse models and patient with HCC samples were analyzed to demonstrate the preclinical and clinical significance of the findings. RESULTS: We report that loss of p53 promoted PD-L1 expression and reduced CD8+ T-cell infiltration in patient with HCC samples and mouse models. Mammalian target of rapamycin (mTOR) pathway was activated in p53-loss-of-function HCC or after knocking down TP53. The transcription factor E2F1 was found to bind to the p53 protein in TP53 wild-type HCC cells, and inhibiting mammalian target of rapamycin complex 1 (mTORC1) disrupted this binding and enhanced E2F1 translocation to the nucleus, where it bound to the PD-L1 promoter and transcriptionally upregulated PD-L1. In p53-loss-of-function HCC cells, autophagosomes were activated after mTORC1 suppression, promoting the degradation of PD-L1 protein. The combination of mTOR inhibitor and anti-PD-L1 antibody enhanced CD8+ T-cell infiltration and tumor suppression in TP53 wild-type HCC mouse models, but no benefit was observed in p53-loss-of-function HCC mouse models. In patients with TP53 wild-type HCC, PD-L1 levels were significantly higher in the high E2F1 group than in the low E2F1 group, and the low E2F1 level group had significantly superior survival. CONCLUSION: We revealed the bidirectional regulatory mechanism of PD-L1 mediated by TP53/mTORC1 in HCC. The combination of mTOR inhibitor and anti-PD-L1 antibody could be a novel precise immunotherapy scheme for TP53 wild-type HCC.

The predictive value of the modified AFP model for liver transplantation outcomes in multinodular hepatocellular carcinoma patients.

BACKGROUND: There is a lack of studies focusing on the benefit of liver transplantation (LT) in hepatocellular carcinoma (HCC) patients with > 3 tumors. This study aims to establish a model to effectively predict overall survival in Chinese HCC patients with multiple tumors (> 3 tumors) who undergo LT. METHODS: This retrospective study included 434 HCC liver transplant recipients from the China Liver Transplant Registry. All HCC patients had more than 3 tumor nodules. Three selection criteria systems (i.e., AFP, Metroticket 2.0, and Up-to-7) were compared regarding the prediction of HCC recurrence. The modified AFP model was established by univariate and multivariate competing risk analyses. RESULTS: The AFP score 2 and the AFP score ≥ 3 groups had 5-year recurrence rates of 19.6% and 40.5% in our cohort. The prediction of HCC recurrence based on the AFP model was associated with a c-statistic of 0.606, which was superior to the Up-to-7 and Metroticket 2.0 models. AFP level > 1000 ng/mL, largest tumor size ≥ 8 cm, vascular invasion, and MELD score ≥ 15 were associated with overall survival. The 5-year survival rate in the modified AFP score 0 group was 71.7%. CONCLUSIONS: The AFP model is superior in predicting tumor recurrence in HCC patients with > 3 tumors prior to LT. With the modified AFP model, patients likely to derive sufficient benefit from LT can be identified.

PDZ-binding kinase aggravates pancreatic neuroendocrine neoplasm progression by activating the AKT/mTOR pathway.

The therapeutic effects of existing drug regimens against pancreatic neuroendocrine neoplasms (pNENs) remain limited, and identifying ideal therapeutic targets is warranted. PDZ binding kinase (PBK) may play an oncogenic role in most solid tumors. However, its function in pNEN remains unclear. In this study, pNEN samples and International Cancer Genome Consortium data were used to determine the clinical significance of PBK. Cell counting and CCK8 assays were used to assess cell proliferation. Flow cytometry was used to assess drug-induced apoptosis and cell cycle arrest. An in vivo PBK-targeting experiment was performed in mice bearing pNENs. Western blotting, quantitative PCR, and immunohistochemistry were performed to assess the molecular mechanisms. PBK was significantly upregulated in pNEN tissues compared with paracancerous tissues. Additionally, PBK was a poor prognostic factor for pNEN patients. PBK was found to promote the proliferation of pNEN cells by activating the AKT/mTOR pathway. Furthermore, PBK inhibition combined with everolimus treatment had enhanced antitumour effects on pNEN via inhibiting AKT/mTOR pathway and inducing G0/G1 phase cell cycle arrest. This study highlights that PBK plays an oncogenic role in and is a promising therapeutic target for pNEN.

Prognostic implication of early posttransplant hypercholesterolemia in liver transplantation for patients with hepatocellular carcinoma.

BACKGROUND: Hyperlipidemia is a common complication after liver transplantation (LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia. METHODS: From January 2015 to December 2017, a total of 806 HCC patients from China Liver Transplant Registry database were retrospectively enrolled. The prognostic relevance of early posttransplant hypertriglyceridemia or hypercholesterolemia was examined using survival analysis, and subgroup analysis was implemented based on LT criteria. RESULTS: Early posttransplant hypercholesterolemia (EPHC) was independently inversely associated with the risk of recurrence [hazard ratio (HR) = 0.630; P = 0.022], but was not significantly correlated with the mortality. However, early posttransplant hypertriglyceridemia was not related to prognosis. Intriguingly, with further classification, we found that borderline EPHC (B-EPHC), instead of significant EPHC, was a predictor of lower risk for both recurrence (HR = 0.504; P = 0.006) and mortality (HR = 0.511; P = 0.023). Compared with non-EPHC patients, B-EPHC patients achieved significantly superior 1-year and 3-year tumor-free survival (89.6% and 83.7% vs. 83.8% and 72.7% respectively; P = 0.023), and 1-year and 3-year overall survival (95.8% and 84.8% vs. 94.6% and 77.6% respectively; P = 0.039). In the subgroup analysis, B-EPHC remained an independent predictor of better prognosis in patients beyond Milan criteria and those within Hangzhou criteria; whereas there was no significant relationship between B-EPHC and prognosis in patients within Milan criteria and those beyond Hangzhou criteria. More interestingly, patients beyond Milan criteria but within Hangzhou criteria were identified as the crucial subpopulation who benefited from B-EPHC (recurrence HR = 0.306, P = 0.011; mortality HR = 0.325, P = 0.031). CONCLUSIONS: B-EPHC could assist transplant teams in dynamically evaluating prognosis after LT for HCC as a postoperative non-oncological biomarker, especially in patients beyond Milan criteria but within Hangzhou criteria.

A mixed blessing for liver transplantation patients - Rapamycin.

BACKGROUND: Liver transplantation (LT) is an effective treatment option for end-stage liver disease. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, are widely used post LT. DATA SOURCES: In this review, we focused on the anti-cancer activities and metabolic side effects of rapamycin after LT. The literature available on PubMed for the period of January 1999-September 2022 was reviewed. The key words were rapamycin, sirolimus, liver transplantation, hepatocellular carcinoma, diabetes, and lipid metabolism disorder. RESULTS: Rapamycin has shown excellent effects and is safer than other immunosuppressive regimens. It has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma (HCC) recurrence post LT. Rapamycin is closely related to two long-term complications after LT, diabetes and lipid metabolism disorders. CONCLUSIONS: Rapamycin prevents HCC recurrence post LT in some patients, but it also induces metabolic disorders. Reasonable use of rapamycin benefits the liver recipients.

Novel γδ T cell-based prognostic signature to estimate risk and aid therapy in hepatocellular carcinoma.

BACKGROUND: Numerous studies have revealed that gamma delta (γδ) T cell infiltration plays a crucial regulatory role in hepatocellular carcinoma (HCC) development. Nonetheless, a comprehensive analysis of γδ T cell infiltration in prognosis evaluation and therapeutic prediction remains unclear. METHODS: Multi-omic data on HCC patients were obtained from public databases. The CIBERSORT algorithm was applied to decipher the tumor immune microenvironment (TIME) of HCC. Weighted gene co-expression network analysis (WGCNA) was performed to determine significant modules with γδ T cell-specific genes. Kaplan-Meier survival curves and receiver operating characteristic analyses were used to validate prognostic capability. Additionally, the potential role of RFESD inhibition by si-RFESD in vitro was investigated using EdU and CCK-8 assays. RESULTS: A total of 16,421 genes from 746 HCC samples (616 cancer and 130 normal) were identified based on three distinct cohorts. Using WGCNA, candidate modules (brown) with 1755 significant corresponding genes were extracted as γδ T cell-specific genes. Next, a novel risk signature consisting of 11 hub genes was constructed using multiple bioinformatic analyses, which presented great prognosis prediction reliability. The risk score exhibited a significant correlation with ICI and chemotherapeutic targets. HCC samples with different risks experienced diverse signalling pathway activities. The possible interaction of risk score with tumor mutation burden (TMB) was further analyzed. Subsequently, the potential functions of the RFESD gene were explored in HCC, and knockdown of RFESD inhibited cell proliferation in HCC cells. Finally, a robust prognostic risk-clinical nomogram was developed and validated to quantify clinical outcomes. CONCLUSIONS: Collectively, comprehensive analyses focusing on γδ T cell patterns will provide insights into prognosis prediction, the mechanisms of immune infiltration, and advanced therapy strategies in HCC.

E2F7 promotes mammalian target of rapamycin inhibitor resistance in hepatocellular carcinoma after liver transplantation.

The mammalian target of rapamycin (mTOR) pathway is frequently deregulated and has critical roles in cancer progression. mTOR inhibitor has been widely used in several kinds of cancers and is strongly recommended in patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). However, the poor response to mTOR inhibitors due to resistance remains a challenge. Hypoxia-associated resistance limits the therapeutic efficacy of targeted drugs. The present study established models of HCC clinical samples and cell lines resistance to mTOR inhibitor sirolimus and screened out E2F7 as a candidate gene induced by hypoxia and promoting sirolimus resistance. E2F7 suppressed mTOR complex 1 via directly binding to the promoter of the TSC1 gene and stabilizes hypoxia-inducible factor-1α activating its downstream genes, which are responsible for E2F7-dependent mTOR inhibitor resistance. Clinically, low E2F7 expression could be an effective biomarker for recommending patients with HCC for anti-mTOR-based therapies after LT. Targeting E2F7 synergistically inhibited HCC growth with sirolimus in vivo. E2F7 is a promising target to reverse mTOR inhibition resistance. Collectively, our study points to a role for E2F7 in promoting mTOR inhibitor resistance in HCC and emphasizes its potential clinical significance in patients with HCC after LT.

Role of surgical treatments in high-grade or advanced gastroenteropancreatic neuroendocrine neoplasms.

Over the last 40 years, the incidence and prevalence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have continued to increase. Compared to other epithelial neoplasms in the same organ, GEP-NENs exhibit indolent biological behavior, resulting in more chances to undergo surgery. However, the role of surgery in high-grade or advanced GEP-NENs is still controversial. Surgery is associated with survival improvement of well-differentiated high-grade GEP-NENs, whereas poorly differentiated GEP-NENs that may benefit from resection require careful selection based on Ki67 and other tissue biomarkers. Additionally, surgery also plays an important role in locally advanced and metastatic disease. For locally advanced GEP-NENs, isolated major vascular involvement is no longer an absolute contraindication. In the setting of metastatic GEP-NENs, radical intended surgery is recommended for patients with low-grade and resectable metastases. For unresectable metastatic disease, a variety of surgical approaches, including cytoreduction of liver metastasis, liver transplantation, and surgery after neoadjuvant treatment, show survival benefits. Primary tumor resection in GEP-NENs with unresectable metastatic disease is associated with symptom control, prolonged survival, and improved sensitivity toward systemic therapies. Although there is no established neoadjuvant or adjuvant strategy, increasing attention has been given to this emerging research area. Some studies have reported that neoadjuvant therapy effectively reduces tumor burden, improves the effectiveness of subsequent surgery, and decreases surgical complications.

Liver transplantation in patients with liver failure: Twenty years of experience from China.

Liver transplantation (LT) is the only effective method of treating end-stage liver disease, such as various types of liver failure. China has the largest number of patients with hepatitis B virus-related disease, which is also the main cause of liver failure. From the first LT performed in 1977, and especially over the past two decades, LT has experienced rapid development as a result of continuous research and innovation in China. China performs the second-highest number of LTs every year worldwide, and the quality of LT continues to improve. Starting January 1, 2015, all donor's livers have been from deceased donors and familial donors. Thus, China entered into a new era of LT. However, LT is still a challenging procedure in China. In this review, we introduced the brief history of LT in China, the epidemiology, aetiology and clinical outcomes of LT for liver failure in China and summarized the experience of LT from Chinese LT surgeons and scholars. The future perspectives of LT were also discussed, and it is expected that China's LT research could be further integrated elsewhere in the world.

[Corrigendum] Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel­7402/5­fluorouracil cells.

Subsequently to the publication of the above paper, the authors have reviewed its content and the primary data, and have realized that the western blots selected to show the ß­actin experiments featured in Fig. 4A and Fig. 3C were the same blot, albeit with a different exposure time. The control blots correctly presented for Fig. 3C were inadvertently copied into Fig. 4A owing to an error made during the figure compilation process. The revised version of Fig. 4, containing the correct ß­actin blots for Fig. 4A, is shown below. Note that this error did not significantly affect the results or the conclusions reported in this paper, and all the authors agree to this Corrigendum. The authors thank the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 10: 2891­2897, 2014; DOI: 10.3892/mmr.2014.2614].

Polyploidy Spectrum Correlates with Immunophenotype and Shapes Hepatocellular Carcinoma Recurrence Following Liver Transplantation.

PURPOSE: Patients receiving liver transplantation (LT) for hepatocellular carcinoma (HCC) are at high risk of tumor recurrence. Polyploidy is a fascinating characteristic of the liver and correlates with HCC development and progression. This study aims to investigate the association between hepatocyte polyploidy spectrum and HCC recurrence after LT. PATIENTS AND METHODS: Thirty-two paired HCC, peritumoral, cirrhotic, and normal liver specimens were employed to examine the hepatocyte polyploidization pattern during liver tumorigenesis. Clinicopathological implications of polyploidy spectrum for LT recipients with HCC were investigated in 205 patients from two transplant centers. Immunofluorescence staining was performed on paraffin-embedded tissue sections to determine the ploidy profiles in situ. Expression levels of CD4, CD8, forkhead box protein 3 (Foxp3) and programmed death-ligand 1 (PD-L1) were measured using immunohistochemistry. An array-based multiplex ELISA system was used for the quantitative measurement of 40 unique inflammatory cytokines. RESULTS: The fraction of mononuclear polyploidy increased, whereas that of binuclear polyploidy reduced during hepatocarcinogenesis. Recipients with highly mononuclear polyploid HCC (HMP-HCC) had inferior recurrence-free survival and HCC-specific survival than poorly mononuclear polyploid HCC recipients. These two groups differed in abundance of infiltrative CD8+ cytotoxic T cells and FoxP3+ Treg cells, and PD-L1 expression, as well as circulating granulocyte-macrophage colony-stimulating factor, interferon-γ and interleukin-10 levels. HMP-HCC constituted an independent recurrence predictor and could improve the discriminative efficacy of clinical prediction models (Milan criteria, AFP model, and Metroticket 2.0 criteria). A scoring system incorporating the ploidy signature was developed and validated, allowing for an improved risk prediction relative to the RETREAT score and post-MORAL score. CONCLUSION: Polyploid spectra are associated with tumor immunophenotype and provide supplementary prognostic information in LT for HCC.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

Long-term outcomes of deceased donor liver transplantation in hepatocellular carcinoma patients with portal vein tumor thrombus: A multicenter study.

BACKGROUND: The incidence of portal vein tumor thrombus (PVTT) has been reported to be as high as approximately 10%-40% in patients with hepatocellular carcinoma (HCC). The long-term prognosis of deceased donor liver transplantation (DDLT) in HCC patients with PVTT remains unknown. METHODS: Data of 961 HCC patients who underwent DDLT between 2015 and 2018 in six centers were analyzed. Based on the Milan criteria (MC) and Cheng's classification of PVTT, the patients were divided into 4 groups: within MC, beyond MC without PVTT, type 1 PVTT, and type 2 PVTT groups. RESULTS: 489 (50.9%) were within the MC, 296 (30.8%) beyond the MC but without PVTT, 83 (8.6%) type 1 PVTT, and 93 (9.7%) type 2 PVTT. Kaplan-Meier analysis showed that type 1 or 2 PVTT patients with alpha-fetoprotein (AFP) ≤ 100 ng/mL had overall survival (OS) similar to that of patients within the MC (P = 0.957), and superior OS (P = 0.003 and 0.009) and recurrence-free survival (RFS) (P = 0.038 and <0.001) than those of patients beyond the MC and PVTT patients with AFP > 100 ng/mL. Multivariable Cox-regression analysis identified type 1 and 2 PVTT to be independent risk factor for RFS [hazard ratio (HR) 1.523 95% confidence interval (CI) 1.162-1.997, P = 0.002], but not for OS (HR 1.283, 95%CI 0.922-1.786, P = 0.139). CONCLUSION: HCC patients with type 1 or 2 PVTT may be acceptable candidates for DDLT. To achieve better outcomes, preoperative AFP levels should be seriously considered when selecting patients with PVTT for DDLT.