HHLA2 promotes hepatoma cell proliferation, migration, and invasion via SPP1/PI3K/AKT signaling pathway.

Hepatocellular carcinoma (HCC) stands as one of the most malignant tumors characterized by poor prognosis and high mortality rates. Emerging evidence underscores the crucial role of the B7 protein family in various cancers, including HCC. However, the involvement of the human endogenous retrovirus H long-terminal repeat-associated protein 2 (HHLA2, or B7-H5) in HCC remains unclear. Immunohistochemistry was employed to assess the differential expression of HHLA2 between HCC and normal liver tissues. A battery of assays, including CCK8, EdU, tablet clone-forming, Transwell, and wound healing assays, were conducted to elucidate the function and potential mechanisms of HHLA2 in the malignant biological behaviors of HCC. Additionally, a xenograft mouse model was established to evaluate the tumorigenicity of hepatoma cell lines exhibiting different HHLA2 expression levels in vivo. Western blot analysis was used to analyze HHLA2, secretory phosphoprotein 1 (SPP1), and PI3K/AKT/mTOR levels. HHLA2 exhibited elevated expression in HCC tissues, correlating with poor tumor differentiation and shortened overall survival in HCC patients. In vitro experiments demonstrated that HHLA2 overexpression (OE) promoted the proliferation, migration, and invasion of hepatoma cells, while in vivo experiments revealed that HHLA2 OE enhanced HCC tumor growth. Conversely, inhibition of HHLA2 expression yielded the opposite effect. Downregulation of SPP1 inhibited the proliferation, migration, and invasion induced by HHLA2 OE, and this effect was linked to the PI3K/AKT/mTOR signaling pathway. Our findings indicate that HHLA2 promotes the proliferation, migration, and invasion of hepatoma cells via the SPP1/PI3K/AKT signaling pathway, establishing it as a potential therapeutic target for HCC.

Predictive nomograms based on gamma-glutamyl transpeptidase to prealbumin ratio for prognosis of hepatocellular carcinoma patients without microvascular invasion.

BACKGROUND: Hepatocellular carcinoma (HCC) presents a significant threat to individuals and healthcare systems due to its high recurrence rate. Accurate prognostic models are essential for improving patient outcomes. Gamma-glutamyl transpeptidase (GGT) and prealbumin (PA) are biomarkers closely related to HCC. This study aimed to investigate the predictive value of the GGT to PA ratio (GPR) and to construct prognostic nomograms for HCC patients without microvascular invasion. METHODS: We retrospectively analyzed data from 355 HCC patients who underwent radical hepatectomy at Shengjing Hospital of China Medical University between December 2012 and January 2021. Patients were randomly assigned to a training cohort (n = 267) and a validation cohort (n = 88). The linearity of GPR was assessed using restricted cubic spline (RCS) analysis, and the optimal cut-off value was determined by X-tile. Kaplan-Meier survival curves and log-rank tests were used to investigate the associations between GPR and both progression-free survival (PFS) and overall survival (OS). Cox multivariate regression analysis identified independent risk factors, enabling the construction of nomograms. Time-dependent receiver operating characteristic (ROC) and calibration curves were used to evaluate the accuracy of the nomograms. Decision curve analysis (DCA) assessed the predictive value of the models. RESULTS: Patients were categorized into GPR-low and GPR-high groups based on a GPR value of 333.33. Significant differences in PFS and OS were observed between the two groups (both P < 0.001). Cox multivariate analysis identified GPR as an independent risk factor for both PFS (OR = 1.80, 95% CI: 1.24-2.60, P = 0.002) and OS (OR = 1.87, 95% CI: 1.07-3.26, P = 0.029). The nomograms demonstrated good predictive performance, with C-index values of 0.69 for PFS and 0.76 for OS. Time-dependent ROC curves and calibration curves revealed the accuracy of the models in both the training and validation cohorts, with DCA results indicating notable clinical value. CONCLUSIONS: GPR emerged as an independent risk factor for both OS and PFS in HCC patients without microvascular invasion. The nomograms based on GPR demonstrated relatively robust predictive efficiency for prognosis.

Ultrasound-guided percutaneous microwave ablation for hepatocellular carcinoma adjacent to large vessels: a propensity score matching analysis.

PURPOSE: This study aimed to compare the efficacy and safety of ultrasound-guided percutaneous microwave ablation (MWA) for hepatocellular carcinoma (HCC) adjacent to large vessels with those far from large vessels. METHODS: The clinical data of patients who underwent ultrasound-guided percutaneous MWA for HCC were retrospectively analyzed between January 2011 and December 2018 in Shengjing Hospital. Patients with HCC adjacent to large vessels were included in the Vessel group, the remaining patients were included in the Control group. Propensity score matching analysis was used to reduce confounding bias. The rates of complete ablation, local recurrence, recurrence-free survival (RFS), overall survival (OS) and complications were compared between the two groups. RESULTS: A total of 134 patients with 157 nodules (size range, 0.6-3.8 cm) were enrolled in this study, 23 in the Vessel group and 111 in the Control group. A total of 21 patients in the Vessel group (91.3%) and 105 patients in the Control group (94.6%) achieved complete ablation (p = .902). Following 1:2 propensity score matching, 22 patients were included in the Vessel group and 40 patients were enrolled in the Control group. Local recurrence was observed in 2 (9.1%) patients in the Vessel group and 5 (12.5%) in the Control group (p = .86). No significant difference in local recurrence rate, RFS and OS were observed between the two groups. CONCLUSIONS: Ultrasound-guided percutaneous MWA appears to be a safe procedure and can achieve comparable oncological efficacy for HCC abutting large vessels.

Beneficial impact of microwave ablation-assisted laparoscopic hepatectomy in cirrhotic hepatocellular carcinoma patients: a propensity score matching analysis.

PURPOSE: In this study, we evaluated the efficacy of microwave ablation-assisted laparoscopic hepatectomy (MLH) for the management of hepatocellular carcinoma (HCC) in cirrhotic patients. METHODS: Data from HCC patients with liver cirrhosis who underwent laparoscopic hepatectomy (LH) or MLH in Shengjing Hospital (Shenyang, China) were retrospectively analyzed from January 2013 to June 2017. The demographic characteristics, clinical features, intraoperative parameters and surgical outcomes were analyzed and compared. Propensity scores matching (PSM) analysis was used to minimize bias. RESULTS: A total of 54 patients were enrolled in the MLH group and 39 patients in the LH group. Following 1:1 matching by PSM analysis, 26 patients were selected from each group. Compared to the LH group, patients in the MLH group had significantly decreased intraoperative bleeding (48.0 vs. 203.9 ml, p < .0001) and reduced demand for hepatic inflow occlusion (0 vs. 6, p = .009). No significant difference was observed in average operation time (155.7 vs. 148.5 min) and postoperative hospitalization time (8.3 vs. 9.3 d) between the MLH and LH groups. Similarly, the 1-year and 3-year recurrence-free survival (RFS) rates as well as the 1-year and 3-year overall survival (OS) rates of the MLH and LH groups were not significantly different (83.1 vs. 82.4% and 64.6 vs. 36.6% as well as 100 vs. 95.8% and 93.8 vs. 59.1%, respectively: p > .05). CONCLUSIONS: MLH significantly decreased intraoperative bleeding and reduced the need for hepatic occlusion without compromising the surgical outcome. Therefore, microwave ablation could be a valuable tool for LH in HCC patients with cirrhosis.

Biomarkers predicting the efficacy of immune checkpoint inhibitors in hepatocellular carcinoma.

In recent years, immune checkpoint inhibitors (ICIs) have emerged as a transformative approach in treating advanced hepatocellular carcinoma (HCC). Despite their success, challenges persist, including concerns about their effectiveness, treatment costs, frequent occurrence of treatment-related adverse events, and tumor hyperprogression. Therefore, it is imperative to identify indicators capable of predicting the efficacy of ICIs treatment, enabling optimal patient selection to maximize clinical benefits while minimizing unnecessary toxic side effects and economic losses. This review paper categorizes prognostic biomarkers of ICIs treatment into the following categories: biochemical and cytological indicators, tumor-related markers, imaging and personal features, etiology, gut microbiome, and immune-related adverse events (irAEs). By organizing these indicators systematically, we aim to guide biomarker exploration and inform clinical treatment decisions.

Pan-cancer analyses and molecular subtypes based on the cancer-associated fibroblast landscape and tumor microenvironment infiltration characterization reveal clinical outcome and immunotherapy response in epithelial ovarian cancer.

Background: Cancer-associated fibroblasts (CAFs) are essential components of the tumor microenvironment (TME). These cells play a supportive role throughout cancer progression. Their ability to modulate the immune system has also been noted. However, there has been limited investigation of CAFs in the TME of epithelial ovarian cancer (EOC). Methods: We comprehensively evaluated the CAF landscape and its association with gene alterations, clinical features, prognostic value, and immune cell infiltration at the pan-cancer level using multi-omic data from The Cancer Genome Atlas (TCGA). The CAF contents were characterized by CAF scores based on the expression levels of seven CAF markers using the R package "GSVA." Next, we identified the molecular subtypes defined by CAF markers and constructed a CAF riskscore system using principal component analysis in the EOC cohort. The correlation between CAF riskscore and TME cell infiltration was investigated. The ability of the CAF riskscore to predict prognosis and immunotherapy response was also examined. Results: CAF components were involved in multiple immune-related processes, including transforming growth factor (TGF)-ß signaling, IL2-STAT signaling, inflammatory responses, and Interleukin (IL) 2-signal transducer and activator of transcription (STAT) signaling. Considering the positive correlation between CAF scores and macrophages, neutrophils, and mast cells, CAFs may exert immunosuppressive effects in both pan-cancer and ovarian cancer cohorts, which may explain accelerated tumor progression and poor outcomes. Notably, two distinct CAF molecular subtypes were defined in the EOC cohort. Low CAF riskscores were characterized by favorable overall survival (OS) and higher efficacy of immunotherapy. Furthermore, 24 key genes were identified in CAF subtypes. These genes were significantly upregulated in EOC and showed a strong correlation with CAF markers. Conclusions: Identifying CAF subtypes provides insights into EOC heterogeneity. The CAF riskscore system can predict prognosis and select patients who may benefit from immunotherapy. The mechanism of interactions between key genes, CAF markers, and associated cancer-promoting effects needs to be further elucidated.

Prognostic value of combined inflammatory and nutritional biomarkers in HCC within the Milan criteria after hepatectomy.

Aims: This study aimed to evaluate the predictive value of the combined prognostic nutritional index (PNI) and GGT/ALT for the postoperative prognosis of patients with hepatocellular carcinoma (HCC) within Milan criteria undergoing radical hepatectomy. Methods: This single-center retrospective study included 283 patients with HCC within the Milan criteria who underwent hepatectomy. The receiver operating characteristic (ROC) curve was used to calculate the optimal PNI and GGT/ALT cut-off values. Pre-treatment PNI, GGT/ALT, and PNI-GGT/ALT grades were calculated. Overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method, and multivariate analysis was used to identify prognostic factors. Results: Multivariate Cox regression analysis identified that the PNI, GGT/ALT, tumor number were significant prognostic markers for OS, and that the GGT/ALT, tumor number were significant prognostic markers for OS. The survival curves showed that low PNI, high GGT/ALT ratio, and high PNI-GGT/ALT grade were associated with poorer OS and DFS. With an area under the curve (AUC) of 0.690, PNI-GGT/ALT outperformed each individual score. Conclusion: PNI-GGT/ALT, a new prognostic scoring model, qualifies as a novel prognostic predictor for patients with HCC within the Milan criteria after curative resection.

NK cell immunometabolism as target for liver cancer therapy.

Natural killer (NK) cells are being used effectively as a potential candidate in tumor immunotherapy. However, the migration and transport of NK cells to solid tumors is inadequate. NK cell dysfunction, tumor invasiveness, and metastasis are associated with altered metabolism of NK cells in the liver cancer microenvironment. However, in liver cancers, metabolic impairment of NK cells is still not understood fully. Evidence from various sources has shown that the interaction of NK cell's immune checkpoints with its metabolic checkpoints is responsible for the regulation of the development and function of these cells. How immune checkpoints contribute to metabolic programming is still not fully understood, and how this can be beneficial needs a better understanding, but they are emerging to be incredibly compelling to rebuilding the function of NK cells in the tumor. It is expected to represent a potential aim that focuses on improving the efficacy of therapies based on NK cells for treating liver cancer. Here, the recent advancements made to understand the NK cell's metabolic reprogramming in liver cancer have been summarized, along with the possible interplay between the immune and the metabolic checkpoints in NK cell function. Finally, an overview of some potential metabolic-related targets that can be used for liver cancer therapy treatment has been presented.

Therapeutic efficacy of microwave coagulation versus liver resection for hepatocellular carcinoma within the Milan criteria: A propensity score matching analysis.

INTRODUCTION: This study aimed to compare the therapeutic efficacy of resection (RES) and microwave ablation (MWA) for hepatocellular carcinoma (HCC) within the Milan criteria. MATERIALS AND METHODS: Between 2011 and 2019, 426 HCC patients within the Milan criteria were treated at our institution (RES: n = 291; MWA: n = 135). We compared overall survival (OS), disease-free survival (DFS), complications, and hospital stay in these patients using propensity score matching (PSM) and determined the prognostic factors using multivariate Cox analysis. RESULTS: Following 1:1 matching using PSM, 121 patients were matched in each group. The 1-, 3-, and 5-year OS rates were 98.3%, 84.7%, and 69.6% for the MWA group and 96.5%, 81.8%, and 78.1% for the RES group (p = 0.667). The corresponding DFS rates for the MWA and RES groups were 81.8%, 54.4%, and 42.3% and 85.4%, 67.8%, and 57.9%, respectively (p = 0.174). The MWA group had less blood loss and shorter hospital stays (both p < 0.001) than the RES group. CONCLUSION: MWA resulted in survival outcomes that were similar to those of RES for HCC within the Milan criteria. However, it had more favorable hospital stay and blood loss outcomes than RES.

The CD112R/CD112 axis: a breakthrough in cancer immunotherapy.

The recent discovery of immune checkpoint inhibitors is a significant milestone in cancer immunotherapy research. However, some patients with primary or adaptive drug resistance might not benefit from the overall therapeutic potential of immunotherapy in oncology. Thus, it is becoming increasingly critical for oncologists to explore the availability of new immune checkpoint inhibitors. An emerging co-inhibitory receptor, CD112R (also called PVRIG), is most commonly expressed on natural killer (NK) and T cells. It binds to its ligand (CD112 or PVRL2/nectin-2) and inhibits the strength with which T cells and NK cells respond to cancer. Therefore, CD112R is being presented as a new immune checkpoint inhibitor with high potential in cancer immunotherapy. CD112 is easily detectable on antigen-presenting or tumor cells, and its high level of expression has been linked with tumor progression and poor outcomes in most cancer patients. This review explores the molecular and functional relationship between CD112R, TIGIT, CD96, and CD226 in T cell responses. In addition, this review comprehensively discusses the recent developments of CD112R/CD112 immune checkpoints in cancer immunotherapy and prognosis.

Surgical and local treatment of hepatic metastasis in pancreatic ductal adenocarcinoma: recent advances and future prospects.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with increasing incidence and mortality. More than half of PDAC patients develop metastases, with the liver being the most common site. Patients with pancreatic ductal adenocarcinoma with liver metastases (PCLM) have a very limited scope for surgery due to aggressive tumor behavior and poor prognosis. However, with the improvements in preoperative systemic therapy and perioperative outcomes, an increasing number of patients are being considered for surgical management. However, the best choice of surgical treatment and criteria for selecting suitable PCLM patients who may benefit from surgical treatment remains controversial. Palliative local treatments, such as ablation, locoregional chemotherapy, and brachytherapy, which are less invasive and have fewer contraindications and complications, are the preferred alternatives to surgery. The present study reviews the advances in the management of PCLM, with focus on resection and local therapies.

Mitochondrial metabolic reprogramming: An important player in liver cancer progression.

Mitochondria are known as essential biosynthetic, bioenergetic and signaling organelles, and play a critical role in cell differentiation, proliferation, and death. Nowadays, cancer is emergingly considered as a mitochondrial metabolic disease. Mitochondria also play an essential role in liver carcinogenesis. Liver cells are highly regenerative and require high energy. For that reason, a large number of mitochondria are present and functional in liver cells. Abnormalities in mitochondrial metabolism in human liver are known to be one of the carcinogenic factors. Interestingly, immune checkpoints regulate mitochondrial metabolic energetics of the tumor, the tumor microenvironment, as well as the tumor-specific immune response. This regulation forms a positive loop between the metabolic reprogramming of both cancer cells and immune cells. In this review, we discuss the evidence and mechanisms that mitochondria interplay with immune checkpoints to influence different steps of oncogenesis, as well as the potential of mitochondria as therapeutic targets for liver cancer therapy.

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy.

Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK's potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

Immune checkpoint therapy in liver cancer.

Immune checkpoints include stimulatory and inhibitory checkpoint molecules. In recent years, inhibitory checkpoints, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand 1 (PD-L1), have been identified to suppress anti-tumor immune responses in solid tumors. Novel drugs targeting immune checkpoints have succeeded in cancer treatment. Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan. Preclinical and clinical studies show immune checkpoint therapy provides survival benefit for greater numbers of patients with liver cancer, including hepatocellular carcinoma and cholangiocarcinoma, two main primary liver cancers. The combination of anti-PD-1/PD-L1 with anti-CTLA-4 antibodies is being evaluated in phase 1, 2 or 3 trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. In addition, studies on activating co-stimulatory receptors to enhance anti-tumor immune responses have increased our understanding regarding this immunotherapy in liver cancer. Epigenetic modulations of checkpoints for improving the tumor microenvironment also expand our knowledge of potential therapeutic targets in improving the tumor microenvironment and restoring immune recognition and immunogenicity. In this review, we summarize current knowledge and recent developments in immune checkpoint-based therapies for the treatment of hepatocellular carcinoma and cholangiocarcinoma and attempt to clarify the mechanisms underlying its effects.

Current status of surgical treatment of colorectal liver metastases.

Liver metastasis (LM) is one of the major causes of death in patients with colorectal cancer (CRC). Approximately 60% of CRC patients develop LM during the course of their illness. About 85% of these patients have unresectable disease at the time of presentation. Surgical resection is currently the only curative treatment for patients with colorectal LM (CRLM). In recent years, with the help of modern multimodality therapy including systemic chemotherapy, radiation therapy, and surgery, the outcomes of CRLM treatment have significantly improved. This article summarizes the current status of surgical treatment of CRLM including evaluation of resectability, treatment for resectable LM, conversion therapy and liver transplantation for unresectable cases, liver resection for recurrent CRLM and elderly patients, and surgery for concomitant hepatic and extra-hepatic metastatic disease (EHMD). We believe that with the help of modern multimodality therapy, an aggressive oncosurgical approach should be implemented as it has the possibility of achieving a cure, even when EHMD is present in patients with CRLM.