Salvage Surgery for Initially Unresectable HCC With PVTT Converted by Locoregional Treatment Plus Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody.

BACKGROUND: This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies. METHODS: The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT. RESULTS: Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS. CONCLUSIONS: For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.

Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial.

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .

Postoperative adjuvant aspirin for patients with hepatitis B virus-related hepatocellular carcinoma and portal vein tumor thrombus: An open-label, randomized controlled trial.

Purpose: To compare the survival outcomes of postoperative adjuvant aspirin with surgery alone in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). Methods: From June 2013 to July 2015, an open-label, randomized controlled study was conducted in patients with resectable HBV-related HCC and PVTT. Patients were randomly assigned to undergo surgical resection and postoperative adjuvant aspirin (n = 40) or hepatectomy alone (n = 40). The primary end point was overall survival (OS). The secondary end points were time to recurrence of primary tumor (t-TTR) and time to recurrence of PVTT (p-TTR). The expression levels of COX1 and COX2 in surgical specimens of the aspirin group were correlated with patients' survival. Results: The median OS were 16.2 and 13.4 months for the adjuvant aspirin and surgery alone groups, respectively. The median t-TTR were 5.3 and 3.2 months for the adjuvant aspirin and surgery alone groups, respectively. There was no significant difference in the OS and t-TTR between the two groups of patients (P = 0.078 and 0.336, respectively). The median p-TTR were 12.0 months and 5.4 months for the adjuvant aspirin group and the surgery alone group, respectively. Patients in the adjuvant aspirin group had markedly longer p-TTR (P = 0.001). Increased expressions of COX1 or COX2 in tumor tissues denoted better prognosis for patients receiving adjuvant aspirin. Conclusion: For patients with resectable HBV-related HCC and PVTT, postoperative adjuvant aspirin significantly prolonged time to recurrence of PVTT than surgery alone. Expression of COX1 or COX2 may predict survival in these patients.

A new staging system for hepatocellular carcinoma associated with portal vein tumor thrombus.

BACKGROUND: A new staging system for patients with hepatocellular carcinoma (HCC) associated with portal vein tumor thrombus (PVTT) was developed by incorporating the good points of the BCLC classification of HCC, and by improving on the currently existing classifications of HCC associated with PVTT. METHODS: Univariate and multivariate analysis with Wald χ2 test were used to determinate the clinical prognostic factors for overall survival (OS) in patients with HCC and PVTT in the training cohort. Then the conditional inference trees analysis was applied to establish a new staging system. RESULTS: A training cohort of 2,179 patients from the Eastern Hepatobiliary Surgery Hospital and a validation cohort of 1,550 patients from four major liver centers in China were enrolled into establishing and validating a new staging system. The system was established by incorporating liver function, general health status, tumor resectability, extrahepatic metastasis and extent of PVTT. This staging system had a good discriminatory ability to separate patients into different stages and substages. The median OS for the two cohorts were 57.1 (37.2-76.9), 12.1 (11.0-13.2), 5.7 (5.1-6.2), 4.0 (3.3-4.6) and 2.5 (1.7-3.3) months for the stages 0 to IV, respectively (P<0.001) in the training cohort. The corresponding figures for the validation cohort were 6.4 (4.9-7.9), 2.8 (1.3-4.4), 10.8 (9.3-12.4), and 1.5 (1.3-1.7) months for the stages II to IV, respectively (P<0.001). The mean survival for stage 0 to 1 were 37.6 (35.9-39.2) and 30.4 (27.4-33.4), respectively (P<0.001). CONCLUSIONS: A new staging system was established which provided a good discriminatory ability to separate patients into different stages and substages after treatment. It can be used to supplement the other HCC staging systems.

Scinderin suppresses cell proliferation and predicts the poor prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains an intractable disease despite numerous advancements made in the available treatments over recent decades. Therefore, investigation of the underlying pathogenesis of HCC is urgently required. Our previous microarray result showed that SCIN was generally downregulated in 23 paired tumor/normal tissues. Reverse transcription-quantitative PCR, western blotting and immunohistochemistry were performed in the present study in order to detect the expression of scinderin (SCIN). Lentivirus-mediated gene delivery was used in order to produce SCIN-manipulated cell lines. MTT and crystal violet assays were performed in order to investigate cell growth, and fluorescence-activated cell sorting analysis was used in order to determine cell cycle distribution. SCIN was downregulated in HCC samples, and low SCIN expression predicted the poor prognosis of patients with HCC. Notably, SCIN may have the potential to serve as an independent risk factor for overall survival (3-year overall survival rate of 28.6 and 10.3% in high SCIN expression and low SCIN expression groups, respectively) and disease-free survival (3-year recurrence rate of 71.4 and 84.6% in high SCIN expression and low SCIN expression groups, respectively) in HCC. SCIN inhibited HCC cell proliferation both in vitro and in subcutaneous tumor formation assay. Furthermore, SCIN decreased the levels of phosphorylated STAT3, thereby downregulating cyclin A1 levels in HCC cells. The results of the present study demonstrate the tumor suppressive role of SCIN in HCC, providing a candidate strategy to treat this disease.

The impact of portal vein tumor thrombus on long-term survival after liver resection for primary hepatic malignancy.

BACKGROUND: The aim of this study was to evaluate the effect of portal vein tumor thrombus (PVTT) on the prognosis of patients undergoing liver resection (LR) for primary liver malignancies (PLC). METHODS: The recurrence-free survival (RFS) and overall survival (OS) for patients undergoing LR with and without PVTT for three primary liver malignancies, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and hepato-cholangio carcinoma (CHC) were compared using the Kaplan-Meier method and Cox regression analysis. RESULTS: In total, 3775 patients with PLC who underwent LR were included in this study. The incidence of PVTT in patients undergoing LR with HCC, IHC and CHC were 46%, 20%, and 17%, respectively. The median RFS and OS were significantly better for patients with HCC as compared to ICC or CHC (16 vs 11 vs 13 months; 21 vs 16 vs 18 months, respectively; P < 0.001). However, the presence of PVTT resulted in similarly poor RFS and OS in these 3 subgroups of patients (9 vs 8 vs 8 months, P = 0.062; 14 vs 13 vs 12 months, respectively, P = 0.052). CONCLUSION: Although the prognosis of patients with PLC varied by histological subtype, once PVTT occurred, survival outcomes after LR were similarly poor across all three subgroups.

Outcomes of intrahepatic cholangiocarcinoma with portal vein tumor thrombus following hepatic resection.

BACKGROUND AND AIM: Portal vein tumor thrombus (PVTT) is not commonly used in the treatment of intrahepatic cholangiocarcinoma (ICC), and its impact on the prognosis of ICC is unclear. We aimed to assess the outcomes of ICC with or without PVTT after hepatic resection. METHODS: From January 2000 to December 2005, the data from all consecutive patients with ICC who underwent hepatic resection at our hospital were retrospectively analyzed. According to the Cheng's PVTT Classification (types I-IV), we compared the survival outcomes of ICC patients (with or without PVTT) and prognosis of patients with ICC with different types of PVTT. RESULTS: Three hundred and three patients with ICC were enrolled in this study (59 with PVTT). The incidence of PVTT was 19.4% (59/303). The median survival times were 12.68 and 28.91 months for ICC patients with and without PVTT, respectively (P < 0.001). The multivariate analysis demonstrated that PVTT (hazard ratio [HR] 1.783; confidence interval 95% [1.279; 2.487]) was an independent risk factor for overall survival. Patients with type I PVTT exhibited significantly better survival than those with types II and III PVTT. CONCLUSION: The ICC patients with PVTT exhibit a poorer prognosis compared with ICC patients without PVTT after hepatic resection.

Risk factors of surgical site infection after hepatic resection.

A study of 7,388 consecutive patients after hepatic resection between 2011 and 2012 identified hepatolithiasis, cirrhosis, and intraoperative blood transfusion as the only independent risk factors of both incisional and organ/space surgical site infection (SSI). Patients with these conditions should be cared for with caution to lower SSI rates.

Hepatitis B virus-related combined hepatocellular-cholangiocarcinoma: clinicopathological and prognostic analysis of 390 cases.

BACKGROUND: The reported treatment outcomes of combined hepatocellular-cholangiocarcinoma (HCC-CC) are inconsistent and the clinicopathological factors influencing treatment outcome remain to be defined. PATIENTS AND METHODS: Patients with hepatitis B virus (HBV)-related HCC-CC undergoing surgical treatment at our institution between January 1997 and September 2010 were retrospectively analyzed. Univariate and multivariate analyses were carried out to identify independent clinicopathological factors affecting surgical outcome. RESULTS: A total of 390 patients with HBV-related HCC-CC were included in this study; there were 328 men and 62 women, with a median age of 49 years (range 21-77 years). Among these patients, 74.4% had underlying liver cirrhosis. The median tumor size was 6.5 cm (range 1.3-33 cm) with 68.7% microvascular invasion and 12.3% lymphatic metastasis. The median survival after surgical resection was 1.68 years and the cumulative survival at 1, 2, 5, and 10 years was 62.1, 46.4, 32, and 25.5%, respectively. The disease-free survival at 1, 2, 5, and 10 years was 36.1, 22.3, 15, and 11.3%, respectively. Independent predictors for decreased survival were male sex, tumor number (≥2), major thrombus, microvascular thrombus, γ-glutamyl transpeptidase (GGT) over 60 U/l, and carbohydrate antigen 19-9 level. Independent negative factors affecting disease-free survival included tumor size (>5 cm), major thrombus, and GGT over 60 U/l. CONCLUSION: Long-term surgical survival of HBV-related HCC-CC seemed to be influenced by sex, tumor-related factors (tumor number, major thrombus, and microvascular thrombus), serum GGT, and carbohydrate antigen 19-9 level. Tumor size, major thrombus, and serum GGT level tended to be associated with disease-free survival.

Tumor size does not independently affect long-term survival after curative resection of solitary hepatocellular carcinoma without macroscopic vascular invasion.

OBJECTIVE: The aim of this study was to investigate the prognostic value of tumor size alone on long-term survival and recurrence after curative resection for solitary hepatocellular carcinoma (HCC) without macroscopic vascular invasion. METHODS: A single-center cohort of 615 patients with solitary HCC (a single tumor, without macroscopic vascular invasion or distant metastasis) undergoing curative hepatic resection from 2002 to 2010 was retrospectively studied. Using 2.0, 3.0, 4.0, 5.0, 8.0, and 10.0 cm as cut-off values of tumor size, the overall survival (OS) and recurrence-free survival (RFS) rates were compared between the groups of patients with tumor size up to a certain cut-off value and the groups of patients with tumor size above that cut-off value. Thus, multiple comparisons were done. The prognostic factors of OS and RFS were evaluated using univariate and multivariate analyses. RESULTS: The median tumor size of all HCCs was 4.0 cm (range 0.9-22.0 cm). The in-hospital mortality rate was 1.0 %, and the overall morbidity rate was 22.3 %. The 1-, 3-, and 5-year OS rates were 96.0, 79.8, and 69.9 %, and the corresponding RFS rates were 83.6, 72.7, and 57.2 %, respectively. On univariate analyses, the 1-, 3-, and 5-year OS and RFS rates were significantly different between the individual two groups of patients as divided by the aforementioned different cut-off values of tumor sizes (all p < 0.05). However, when tumor size was put as a continuous variable into multivariate analysis, it was no longer an independent prognostic factor of OS or RFS after curative resection. CONCLUSIONS: Tumor size did not independently affect long-term survival and recurrence after curative resection of solitary HCC without macroscopic vascular invasion. Therefore, there is no size limit that precludes hepatic resection for solitary HCC, provided the tumor is resectable.

Vitamin analogues in chemoprevention of hepatocellular carcinoma after resection or ablation--a systematic review and meta-analysis.

OBJECTIVE: While hepatic resection or local ablative therapy may provide a potentially curative treatment for hepatocellular carcinoma (HCC), more than half of these patients develop recurrent HCC within 5 years after treatment. Thus identification of any therapy which can decrease or delay the incidence of recurrence will improve the results of treatment. However, no chemopreventive agent has been approved for HCC. METHODS: A MEDLINE database, Embase, Cancerlit (National Cancer Institute), and CBM (Chinese Biomedical Database) search from 1990 to 2009 was performed to identify relevant articles using the keywords "hepatocellular carcinoma," "vitamin analogue," and "chemoprevention." Additional papers were identified by a manual search of the references from the key articles. The fixed effect model was used for a meta-analysis. RESULTS: Oral administration of acyclic retinoids (vitamin A analogue), and menatetrenone (vitamin K2 analogue) have been tested as chemopreventive agents after hepatic resection or local ablative therapy for HCC. There were one and four randomised, controlled trials (RCTs) which evaluated the efficacy of polyprenoic acid and menatetrenone, respectively. All studies were conducted in Japan. One RCT showed the preventive effect of polyprenoic acid in lowering the incidence of HCC recurrence after hepatic resection or percutaneous ethanol injection, and this effect lasted up to 199 weeks after randomization (or 151 weeks after completion of retinoid administration). Four RCTs evaluated the preventive efficacy of menatetrenone on HCC recurrence after hepatic resection or local ablative therapy. The results of three studies, as well as the meta-analysis of all four studies, showed significantly better tumour recurrence-free survival. The beneficial effect on the overall survival was less definite. CONCLUSION: There is evidence to suggest that chemopreventive therapy after partial hepatectomy or local ablative therapy is beneficial in prolonging disease-free survival, but the evidence is less for an effect on the overall survival. To confirm the beneficial role of vitamin A or K analogues in the chemoprevention of HCC further and larger randomised trials are now required.