Repeat hepatectomy versus thermal ablation therapy for recurrent hepatocellular carcinoma: a systematic review and meta-analysis.

Background: This meta-analysis was conducted to assess the survival benefits of repeat hepatectomy (RH) and thermal ablation therapy (TAT) in managing recurrent hepatocellular carcinoma (HCC). Methods: A comprehensive search was conducted in the PubMed, SinoMed, Embase, Cochrane Library, Medline, and Web of Science databases using relevant keywords to identify all studies published on this specific topic. Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were estimated using a fixed-effects model. Results: This meta-analysis included a total of 21 studies, comprising 2580 patients with recurrent HCC, among whom 1189 underwent RH and 1394 underwent TAT. Meta-analysis results demonstrated that the RH group exhibited superior overall survival (OS) (HR=0.85, 95%CI 0.76∼0.95, P=0.004) and recurrence-free survival (RFS) (HR=0.79, 95%CI 0.7∼0.9, P<0.01) compared to the TAT group. Regarding postoperative complications, the TAT group experienced fewer complications than the RH group (OR=3.23, 95%CI 1.48∼7.07, P=0.003), while no significant difference in perioperative mortality was observed between the two groups (OR=2.11, 95%CI 0.54∼8.19, P=0.28). Conclusion: The present study demonstrates that, in comparison to TAT, RH may confer superior survival benefits for patients with recurrent HCC.

Optimal treatment strategy for recurrent hepatocellular carcinoma based on recurrence time and tumor size: A propensity score matching study.

BACKGROUND: Recurrent hepatocellular carcinoma (RHCC) is commonly treated with transcatheter arterial chemoembolization (TACE) combined with microwave ablation (MWA) or repeated hepatectomy(RH), but the optimal treatment strategy is still controversial. This study aimed to compare the efficacy and safety of TACE-MWA and RH in RHCC patients after initial radical hepatectomy. METHODS: A total of 210 RHCC patients were included between June 2014 and January 2021, with 126 patients in the TACE-MWA group and 84 patients in the RH group. The primary endpoints were median repeat recurrence-free survival (rRFS) and overall survival (OS), and the secondary endpoint was complications. Propensity-score matching (PSM) was conducted to minimize bias. Subgroup analysis based on recurrence patterns (recurrence time and tumor size) was performed, and prognostic factors were studied. RESULTS: Before PSM, the RH group had better median OS (37.0 vs 26.0 months, P<0.001) and rRFS (15.0 vs 14.0 months, P = 0.003). After PSM, the RH group also had a better median OS (33.5 vs 29.0 months, P = 0.038), but there was no significant difference in median rRFS between the two groups (14.0 vs 13.0 months, P = 0.099). Subgroup analysis showed that when RHCC diameter>5 cm, RH had a better median OS (33.5 vs 25.0 months, P = 0.013) and rRFS (14.0 vs 10.9 months, P = 0.030). When the RHCC diameter was≤5 cm, there was no significant difference in the median OS (37.0 vs 31.0 months, P = 0.338) and rRFS (15.0 vs 17.0 months, P = 0.758) between the two groups. When RHCC relapses in the early stage (≤2 years), there is no significant difference in the median OS (26.0 vs 26.0 months, P = 0.310) and rRFS (12.0 vs 10.5 months, P = 0.089) between the two groups. When RHCC relapses in the late stage (>2 years), the RH group has better median OS (41.0 vs 33.0 months, P<0.001) and rRFS (30.0 vs 20.0 months, P = 0.010). CONCLUSION: Individualized therapy is necessary for RHCC. TACE -MWA may be a good choice for RHCC with early recurrence or tumor diameter ≤5 cm. However, RH should be the first choice for RHCC with late recurrence or tumor diameter>5 cm.

Experimental study on preparation and anti-tumor efficiency of nanoparticles targeting M2 macrophages.

This study aimed to develop an effective therapy against M2 macrophages and to investigate the effects of imidazole and mannose modified carboxymethyl chitosan-nanoparticles (MIC-NPs) on tumor growth and antitumor immune responses. MIC-NPs were constructed and analyzed through 1H NMR, nano-laser particle size analyzer, and transmission electron microscopy. The nanoparticles were mainly distributed in 75-85 nm, and zeta potential was 1.5 mV. Cytotoxicity studies in vitro and in vivo indicated that MIC-NPs were safe. The targeting effect of MIC-NPs on M2 macrophages was observed through fluorescence microscope and microplate system. The results demonstrated the uptake of a large amount of FITC-loaded MIC-NPs by M2. Cell growth inhibition experiments showed that MIC-NPs significantly inhibited M2 through cell apoptosis. The evaluation of anti-tumor activity in vivo showed that MIC-NPs could accumulate in the tumor site to exert an anti-tumor effect. Flow cytometry showed that the proportion of M2 macrophages at the tumor site in the experimental group was significantly lower than that in the control group, while the Treg cells and cytotoxic T cells (CTL) were found to be increased. PCR detection showed that the cDNA of FIZZ, MR, TGF-ß, and arginase, closely related to M2 macrophages, in the experimental group, was significantly lower than that in the control group, but there was no significant difference in the cDNA of Treg cell characteristic Foxp3 between the two groups. These results suggest that MIC-NPs are expected to provide a new and effective treatment for tumor.

HIF1α regulates glioma chemosensitivity through the transformation between differentiation and dedifferentiation in various oxygen levels.

Chemotherapy plays a significant role in glioma treatment; however, it has limited effectiveness in extending the life expectancies of glioma patients. Traditional studies have attributed this lack of efficacy to glioma stem cells (GSCs) and their high resistance to chemotherapy, and hypoxia worsens this issue. In contrast, hyperoxia effectively alleviates hypoxia in glioma and sensitizes glioma cells to chemotherapy. In a summary of traditional studies, the majority of researchers overlooked the influence of hypoxia on differentiated cells because they only focused on the maintenance of GSCs stemness, which thus resulted in chemoresistance. Because of this background, we hypothesized that GSCs may be induced through dedifferentiation under hypoxic conditions, and hypoxia maintains GSCs stemness, which thus leads to resistance to chemotherapy. In contrast, hyperoxia inhibits the dedifferentiation process and promotes GSCs differentiation, which increases the sensitization of glioma cells to chemotherapy. Hypoxia-inducible factor-1α (HIF1α) contributes substantially to the stemness maintenance of GSCs and resistance of glioma to chemotherapy; thus, we investigated whether HIF1α regulates the resistance or sensitization of glioma cells to chemotherapy in different oxygen levels. It highlights a novel viewpoint on glioma chemosensitivity from the transformation between dedifferentiation and differentiation in different oxygen levels.

HIF1α regulates single differentiated glioma cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential under hypoxia.

The standard treatment for Glioblastoma multiforme (GBM) is surgical resection and subsequent radiotherapy and chemotherapy. Surgical resection of GBM is typically restricted because of its invasive growth, which results in residual tumor cells including glioma stem cells (GSCs) and differentiated cells. Recurrence has been previously thought to occur as a result of these GSCs, and hypoxic microenvironment maintains the GSCs stemness also plays an important role. Summarizing traditional studies and we find many researchers ignored the influence of hypoxia on differentiated cells. We hypothesized that the residual differentiated cells may be dedifferentiated to GSC-like cells under hypoxia and play a crucial role in the rapid, high-frequency recurrence of GBM. Therefore, isolated CD133-CD15-NESTIN- cells were prepared as single-cell culture and treated with hypoxia. More than 95% of the surviving single differentiated CD133-CD15-NESTIN- cell dedifferentiated into tumorigenic CD133+CD15+NESTIN+ GSCs, and this process was regulated by hypoxia inducible factor-1α. Moreover, the serum also played an important role in this dedifferentiation. These findings challenge the traditional glioma cell heterogeneity model, cell division model and glioma malignancy development model. Our study also highlights the mechanism of GBM recurrence and the importance of anti-hypoxia therapy. In addition to GSCs, residual differentiated tumor cells also substantially contribute to treatment resistance and the rapid, high recurrence of GBM.

Cancer stem-like cells can be induced through dedifferentiation under hypoxic conditions in glioma, hepatoma and lung cancer.

Traditional studies have shown that transcription factors, including SOX-2, OCT-4, KLF-4, Nanog and Lin-28A, contribute to the dedifferentiation and reprogramming process in normal tissues. Hypoxia is a physiological phenomenon that exists in tumors and promotes the expression of SOX-2, OCT-4, KLF-4, Nanog and Lin-28A. Therefore, an interesting question is whether hypoxia as a stimulating factor promotes the process of dedifferentiation and induces the formation of cancer stem-like cells. Studies have shown that OCT-4 and Nanog overexpression induced the formation of cancer stem cell-like cells through dedifferentiation and enhanced malignancy in lung adenocarcinoma, and reprogramming SOX-2 in pancreatic cancer cells also promoted the dedifferentiation process. Therefore, we investigated this phenomenon in glioma, lung cancer and hepatoma cells and found that the transcription factors mentioned above were highly expressed under hypoxic conditions and induced the formation of spheres, which exhibited asymmetric division and cell cycle arrest. The dedifferentiation process induced by hypoxia highlights a new pattern of cancer development and recurrence, demonstrating that all kinds of cancer cells and the hypoxic microenvironment should be taken into consideration when developing tumor therapies.