Natural killer cells modified with a Gpc3 aptamer enhance adoptive immunotherapy for hepatocellular carcinoma.

INTRODUCTION: Natural killer cells can attack cancer cells without prior sensitization, but their clinical benefit is limited owing to their poor selectivity that is caused by the lack of specific receptors to target tumor cells. In this study, we aimed to endow NK cells with the ability to specifically target glypican-3+ tumor cells without producing cell damage or genetic alterations, and further evaluated their therapeutic efficiency. METHODS: NK cells were modified with a Gpc3 DNA aptamer on the cell surface via metabolic glycoengineering to endow NK cells with specific targeting ability. Then, the G-NK cells were evaluated for their specific targeting properties, cytotoxicity and secretion of cytokines in vitro. Finally, we investigated the therapeutic efficiency of G-NK cells against glypican-3+ tumor cells in vivo. RESULTS: Compared with NK cells modified with a random aptamer mutation and unmodified NK cells, G-NK cells induced significant apoptosis/necrosis of GPC3+ tumor cells and secreted cytokines to preserve the intense cytotoxic activities. Moreover, G-NK cells significantly suppressed tumor growth in HepG2 tumor-bearing mice due to the enhanced enrichment of G-NK cells at the tumor site. CONCLUSIONS: The proposed strategy endows NK cells with a tumor-specific targeting ability to enhance adoptive therapeutic efficiency in GPC3+ hepatocellular carcinoma.

Resection Margin Width Does Not Influence the Prognosis of Solitary Hepatocellular Carcinoma After Anatomic Resection: A Real-World Study from China.

Purpose: The influence of resection margin (RM) width on the prognosis of solitary hepatocellular carcinoma (HCC) following anatomical resection (AR) has yet to be determined. Therefore, we conducted a real-world study to identify the optimal RM width and assess its impact on the outcomes of solitary HCC patients undergoing AR. Methods: The data pertaining to patients diagnosed with solitary HCC who underwent AR between December 2012 and December 2015 were retrospectively collected. The optimal cutoff value for the width of the RM was determined using X-tile software. The Kaplan-Meier method was utilized to compare the overall survival (OS) and disease-free survival (DFS) between the narrow and wide RM groups. Additionally, propensity score matching (PSM) was performed to minimize potential bias in the data. Results: Of the 1033 patients who met the inclusion criteria, 293 (28.4%) were categorized into the narrow RM group (≤4 mm) and 740 (71.6%) into the wide RM group (> 4mm). Before and after PSM, there were no significant differences in OS and DFS between the two groups (before PSM: OS, HR=0.78, P=0.071; DFS, HR=0.95, P=0.620; after PSM: OS, HR=0.77, P=0.150; DFS, HR=0.90, P=0.470). Multivariate analysis demonstrated that RM width was not an independent risk factor for DFS and OS both before and after PSM (all P>0.05). However, subgroup analyses revealed that patients with ALBI grade 1, absence of cirrhosis, and AJCC stage II significantly benefited from wide RM in OS (all P< 0.05). Similarly, patients without HBV infection and absence of cirrhosis also exhibited significant benefits from wide RM in DFS (both P< 0.05). Conclusion: In patients with solitary HCC undergoing AR, the width of the RM does not appear to have a significant impact on their prognosis. However, in certain selected patients, a wider RM may confer benefits.

A novel preoperative inflammation score system established for postoperative prognosis predicting of intrahepatic cholangiocarcinoma.

BACKGROUND: Inflammation is implicated in tumorigenesis and has been reported as an important prognostic factor in cancers. In this study, we aimed to develop and validate a novel inflammation score (IFS) system based on 12 inflammatory markers and explore its impact on intrahepatic cholangiocarcinoma (ICC) survival after hepatectomy. METHODS: Clinical data of 446 ICC patients undergoing surgical treatment were collected from the Primary Liver Cancer Big Data, and then served as a training cohort to establish the IFS. Furthermore, an internal validation cohort including 175 patients was used as internal validation cohort of the IFS. A survival tree analysis was used to divide ICC patients into three groups (low-, median-, and high- IFS-score groups) according to different IFS values. Kaplan-Meier (KM) curves were used to compare the overall survival (OS) and recurrence-free survival (RFS) rates among three different groups. Cox regression analyses were applied to explore the independent risk factors influencing OS and RFS. RESULTS: In the training cohort, 149 patients were in the low-IFS-score group, 187 in the median-IFS-score group, and 110 in the high-IFS-score group. KM curves showed that the high-IFS-score group had worse OS and RFS rates than those of the low- and median-IFS-score groups (P < 0.001) in both the training and validation cohorts. Moreover, multivariable Cox analyses identified high IFS as an independent risk factor for OS and RFS in the training cohort. The area under the curve values for OS prediction of IFS were 0.703 and 0.664 in the training and validation cohorts, respectively, which were higher than those of the American Joint Committee on Cancer (AJCC) 7th edition TNM stage, AJCC 8th edition TNM stage, and the Child-Pugh score. CONCLUSION: Our results revealed the IFS was an independent risk factor for OS and RFS in patients with ICC after hepatectomy and could serve as an effective prognostic prediction system in daily clinical practice.

Postoperative Adjuvant Transarterial Chemoembolization Plus Tyrosine Kinase Inhibitor for Hepatocellular Carcinoma: a Multicentre Retrospective Study.

Purpose: This study aimed to assess the efficacy and safety of adjuvant transarterial chemoembolization (TACE) plus tyrosine kinase inhibitor (TKI) treatment in patients with hepatocellular carcinoma (HCC) with a high risk of early recurrence after curative resection. Patients and Methods: Patients from multiple centres were divided into postoperative adjuvant TACE with (n=57) or without (n=142) TKI administration groups. The disease-free survival (DFS) curve was depicted by the Kaplan-Meier method, and the difference between the two groups was tested using the log rank test. Univariate and multivariate Cox analyses were performed to identify independent risk factors for DFS. Additionally, three propensity score analyses were performed to minimise the potential confounding factors to facilitate a more reliable conclusion. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events, version 4.0. Results: The 1-and 2-year DFS rates of the TACE plus TKI treatment group were 45.5% and 34.9%, respectively, which were significantly better than those of the TACE alone group (26.8% and 18.3%, respectively). Multivariate analysis identified adjuvant TACE plus TKI treatment as an independent prognostic factor for DFS (hazard ratio: 0.611, 95% confidence interval: 0.408-0.915, P=0.017). Further analysis based on the various propensity score methods yielded similar results. Subgroup analysis showed that patients with tumour diameter ≥5 cm, tumour number <3, absence of hepatic vein tumour thrombus and bile duct tumour thrombus, ruptured tumours, and stage IIIB could benefit more from TACE plus TKI treatment (all P<0.05). Some patients (33.33%) experienced grade ≥3 AEs in the TACE plus TKI group. Conclusion: TACE plus TKI treatment can reduce the incidence of early recurrence with tolerable adverse events in HCC patients at high risk of recurrence after hepatectomy and may be an appropriate option in postoperative anti-recurrence treatment.

Redirecting natural killer cells to potentiate adoptive immunotherapy in solid tumors through stabilized Y-type bispecific aptamer.

Modulating interactions between immune effector cells and tumor cells in vivo using a bispecific aptamer (Ap) is a promising strategy for cancer immunotherapy. However, it remains a technical challenge owing to the complex and dynamic internal environment accompanied by severe degradation. Herein, by using a Y-shaped DNA scaffold, a bispecific and stabilized Y-type Ap is designed to redirect natural killer (NK) cells to enhance adoptive immunotherapy of hepatocellular carcinoma (HCC) solid tumors. Y-type Ap is constituted by the HCC-specific Ap TLS11a linked with the CD16-specific Ap through a Y-shaped DNA scaffold. Owing to the rigid structure, Y-type Ap shows high stability in 10% serum for over 72 h and resistance to denaturation by 8 M urea. Additionally, the Y-type Ap exhibits more potent avidity to bind with NK cells and tumor cells both in vitro and in vivo, resulting in higher cytokine secretion and excellent antitumor efficiency. Collectively, this study offers a translational platform for constructing stable bispecific Ap, offering considerable potential to enhance adoptive immunotherapy of solid tumors.

[Hand-assisted laparoscopic hepatectomy for large liver cancer in 56 cases].

OBJECTIVE: To investigate the practical value of hand-assisted laparoscopic hepatectomy for large liver cancer in peripheral segments. METHODS: From March 2004 to December 2007, 56 patients with large liver cancer underwent hand-assisted laparoscopic hepatectomy including 53 cases of hepatocellular carcinoma, 2 cases of cholangiocellular carcinoma, 1 case of hepatic metastatic squamous carcinoma. RESULTS: The operation procedures were completed safely in all patients including 27 left lateral segment hepatectomy, 6 left hemi-hepatectomy and 23 atypical right hepatectomy. Thirty-one cases with hepatic hilum blocking in the procedure and the mean time was 16.7 minutes. Mean surgical time was 105.3 minutes. Mean blood loss was 97 ml. Mean gross tumor size was 8.6 cm. Mean excisional hepatic tissue volume was 10.5 cm. No serious postoperative complications occurred. Mean eating time was 2.1 days. The mean postoperative hospital stay was 7.3 days. CONCLUSION: Hand-assisted laparoscopic hepatectomy for large liver carcinoma is feasible and safe for selected patients.