Real-world study of hepatic artery infusion chemotherapy combined with anti-PD-1 immunotherapy for hepatocellular carcinoma patients with portal vein tumor thrombus.

Background: Patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) present a poor prognosis. Current systemic therapies offer limited benefits. Hepatic artery infusion chemotherapy (HAIC) is a local regional treatment for advanced HCC, particularly in selected patients such as patients with PVTT or high intrahepatic tumor burden. Objectives: The purpose of this study is to retrospectively evaluate the efficacy and safety of HAIC combined with anti-PD-1 immunotherapy for HCC patients with PVTT, and explore factors related to survival prognosis, providing clues for treatment decisions for HCC patients. Design: This is a single-center retrospective study conducted over 2 years on consecutive PVTT patients receiving HAIC combined anti-PD-1 antibodies. Methods: The primary endpoint was overall survival (OS). Univariate and multivariate analyses were performed to identify prognostic factors affecting OS. Treatment-associated adverse events were evaluated as well. Results: A total of 119 patients were analyzed. The median OS and PFS were 14.9 months and 6.9 months. A total of 31.1% of grade 3-4 adverse events were reported, with elevated transaminase and total bilirubin being the most common. The independent variables correlated with survival include treatment-related alpha-fetoprotein (AFP) response, the presence of extrahepatic organ metastasis, absolute value of platelet (PLT), neutrophil-to-lymphocyte ratio, and combined usage of tyrosine kinase inhibitors (TKIs). Conclusion: In HCC patients with PVTT, combination therapy with HAIC and anti-PD-1 antibodies might be a promising therapy. The efficacy and safety of this combination protocol on patients with HCC complicated by PVTT warrants further investigation prospectively, especially in combination with TKIs.

Maternal prednisone exposure during pregnancy elevates susceptibility to osteoporosis in female offspring: The role of mitophagy/FNDC5 alteration in skeletal muscle.

Maternal exposure to glucocorticoids has been associated with adverse outcomes in offspring. However, the consequences and mechanisms of gestational exposure to prednisone on susceptibility to osteoporosis in the offspring remain unclear. Here, we found that gestational prednisone exposure enhanced susceptibility to osteoporosis in adult mouse offspring. In a further exploration of myogenic mechanisms, results showed that gestational prednisone exposure down-regulated FNDC5/irisin protein expression and activation of OPTN-dependent mitophagy in skeletal muscle of adult offspring. Additional experiments elucidated that activated mitophagy significantly inhibited the expression of FNDC5/irisin in skeletal muscle cells. Likewise, we observed delayed fetal bone development, downregulated FNDC5/irisin expression, and activated mitophagy in fetal skeletal muscle upon gestational prednisone exposure. In addition, an elevated total m6A level was observed in fetal skeletal muscle after gestational prednisone exposure. Finally, gestational supplementation with S-adenosylhomocysteine (SAH), an inhibitor of m6A activity, attenuated mitophagy and restored FNDC5/irisin expression in fetal skeletal muscle, which in turn reversed fetal bone development. Overall, these data indicate that gestational prednisone exposure increases m6A modification, activates mitophagy, and decreases FNDC5/irisin expression in skeletal muscle, thus elevating osteoporosis susceptibility in adult offspring. Our results provide a new perspective on the earlier prevention and treatment of fetal-derived osteoporosis.

Development and Preliminary Validation of a Novel Convolutional Neural Network Model for Predicting Treatment Response in Patients with Unresectable Hepatocellular Carcinoma Receiving Hepatic Arterial Infusion Chemotherapy.

The goal of this study was to evaluate the performance of a convolutional neural network (CNN) with preoperative MRI and clinical factors in predicting the treatment response of unresectable hepatocellular carcinoma (HCC) patients receiving hepatic arterial infusion chemotherapy (HAIC). A total of 191 patients with unresectable HCC who underwent HAIC in our hospital between May 2019 and March 2022 were retrospectively recruited. We selected InceptionV4 from three representative CNN models, AlexNet, ResNet, and InceptionV4, according to the cross-entropy loss (CEL). We subsequently developed InceptionV4 to fuse the information from qualified pretreatment MRI data and patient clinical factors. Radiomic information was evaluated based on several constant sequences, including enhanced T1-weighted sequences (with arterial, portal, and delayed phases), T2 FSE sequences, and dual-echo sequences. The performance of InceptionV4 was cross-validated in the training cohort (n = 127) and internally validated in an independent cohort (n = 64), with comparisons against single important clinical factors and radiologists in terms of receiver operating characteristic (ROC) curves. Class activation mapping was used to visualize the InceptionV4 model. The InceptionV4 model achieved an AUC of 0.871 (95% confidence interval [CI] 0.761-0.981) in the cross-validation cohort and an AUC of 0.826 (95% CI 0.682-0.970) in the internal validation cohort; these two models performed better than did the other methods (AUC ranges 0.783-0.873 and 0.708-0.806 for cross- and internal validations, respectively; P < 0.01). The present InceptionV4 model, which integrates radiomic information and clinical factors, helps predict the treatment response of unresectable HCC patients receiving HAIC treatment.

Preliminary investigation on the effect of extracorporeal shock wave combined with traction on joint contracture based on PTEN-PI3K/AKT pathway.

To investigate the intervention effect of extracorporeal shock wave combined with manual traction on fixation-induced knee contracture and its influence on PTEN-PI3K/AKT signaling pathway. Thirty-six SD male rats were randomly divided into six groups. The left knee joints were not fixed in the control group (C group). Rats in other groups underwent brace fixation in the extended position of the left knee. After 4 weeks of bracing, it is randomly divided into five groups: Model group (M group), natural recovery group (NR group), extracorporeal shock wave treatment group (ET group), manual traction group (MT group), and extracorporeal shock wave combined with manual traction group (CT group). Joint range of motion (ROM) of left knee was carried out to assess joint function. Hematoxylin and eosin (HE) staining and Masson staining were respectively used to assess the cell number and collagen deposition expression. Immunohistochemical staining and Western blot were used to assess protein levels of phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (AKT). The combined therapy was more effective than extracorporeal shock wave therapy or manual traction alone against the joint ROM, cell number and the collagen deposition, low-expression of PTEN, and overexpression of PI3K/AKT in the anterior joint capsule of rats with knee extension contracture. Extracorporeal shock wave combined with manual traction can promote the histopathological changes of anterior joint capsule fibrosis, upregulate the protein expression of PTEN and downregulate the protein expression of PI3K/AKT in the fibrotic joint capsule in a rat joint contracture model.

The effect of extracorporeal shock wave on joint capsule fibrosis based on A2AR-Nrf2/HO-1 pathway in a rat extending knee immobilization model.

Joint capsule fibrosis, a common complication of joint immobilization, is mainly characterized by abnormal collagen deposition. The present study aimed to investigate the effect of extracorporeal shock wave therapy (ESWT) on reduced collagen deposition in the joint capsule during immobilization-induced joint capsule fibrosis. Additionally, the potential involvement of the adenosine A2A receptor (A2AR)-Neurotrophic factor e2-related factor 2 (Nrf2)/Haem oxygenase-1 (HO-1) pathway was explored. Thirty 3-month-old male Sprague-Dawley rats were randomly assigned to five groups: control (C), immobilization model (IM), natural recovery (NR), ESWT intervention (EI), and ESWT combined with A2AR antagonist SCH 58261 intervention (CI). After the left knee joints of rats in the IM, NR, EI and CI groups were immobilized using a full-extension fixation brace for 4 weeks, the EI and CI groups received ESWT twice a week for 4 weeks. The CI group was also treated with ESWT following intraperitoneal injection of SCH 58261 (0.01 mg/kg) for 4 weeks. The range of motion of the left knee joint was measured, and the protein levels of collagens I and III, A2AR, phosphorylated-protein kinase A/protein kinase A (p-PKA/PKA), p-Nrf2/Nrf2, and HO-1 were analysed by Western blotting. The IM and NR groups showed significantly greater arthrogenic contracture than the C group (P < 0.05). Compared to the NR group, the EI and CI groups exhibited significant improvement in arthrogenic contracture (P < 0.05). Conversely, the EI group showed lower contracture than the CI group (P < 0.05). Similar results were observed for collagen deposition and the protein levels of collagens I and III. The intervention groups (EI and CI groups) showed higher levels of p-Nrf2/Nrf2 and HO-1 than the NR group (P < 0.05). Moreover, the EI group exhibited higher levels of p-PKA/PKA, p-Nrf2/Nrf2, and HO-1 than the CI group (P < 0.05). However, no significant difference was found in the A2AR levels among the five groups (P > 0.05). ESWT may activate A2AR, leading to the phosphorylation of PKA. Subsequently, Nrf2 may be activated, resulting in the upregulation of HO-1, which then reduces collagen deposition and alleviates immobilization-induced joint capsule fibrosis.

LINC02362/hsa-miR-18a-5p/FDX1 axis suppresses proliferation and drives cuproptosis and oxaliplatin sensitivity of hepatocellular carcinoma.

Cuproptosis is a novel cell death mechanism caused by copper overload, with FDX1 serving as the key regulator. LncRNAs are known to play a significant role in the aberrant regulation of gene expression in hepatocellular carcinoma (HCC). In this study, we investigated the biological role of the LINC02362/hsa-miR-18a-5p/FDX1 axis in HCC. We first explored the expression pattern, prognostic value, biological functions, drug sensitivity, and immune effect of FDX1. Using bioinformatics techniques, we then predicted several potential target lncRNAs and miRNAs. We identified a lncRNA-miRNA-FDX1 axis based on the ceRNA mechanism. In vitro experiments were conducted to validate the relationship between the lncRNA-miRNA-FDX1 axis and its biological effects in HCC. Finally, we investigated the relationship between the LINC02362/hsa-miR-18a-5p/FDX1 axis and oxaliplatin-induced cuproptosis in HCC. Our findings indicated that FDX1 expression was downregulated in HCC tissues; however, elevated FDX1 expression correlates with improved prognosis and heightened sensitivity to oxaliplatin. We confirmed that LINC02362 binds to and directly regulates the expression of miR-18a-5p, with FDX1 a target of miR-18a-5p. Experimental results suggested that upregulating LINC02362/hsa-miR-18a-5p/FDX1 axis suppressed the proliferation of HCC cells. Furthermore, LINC02362 knockdown led to a reduction in copper concentration and resistance to elesclomol-Cu. We also discovered that augmenting the LINC02362/hsa-miR-18a-5p/FDX1 axis could bolster the sensitivity of HCC to oxaliplatin through cuproptosis. This work presents the LINC02362/hsa-miR-18a-5p/FDX1 axis as a novel pathway that triggers cuproptosis and enhances the sensitivity of HCC to oxaliplatin, presenting a promising therapeutic avenue to combat oxaliplatin resistance in HCC.

NLRP3/IL-1ß induced myeloid-derived suppressor cells recruitment and PD-L1 upregulation promotes oxaliplatin resistance of hepatocellular carcinoma.

Oxaliplatin is commonly used as the first-line chemotherapeutic agent for advanced hepatocellular carcinoma (HCC). Unfortunately, the acquired resistance, limits the effectiveness of oxaliplatin and the underlying mechanisms remain unknown. Therefore, we explored the role of NOD-like receptor protein 3 (NLRP3)/IL-1ß in mediating oxaliplatin resistance in HCC. We observed that NLRP3/IL-1ß expression was much higher in oxaliplatin-resistant HCC cells. To further understand its impact on drug resistance, we knocked down NLRP3 and observed that it sensitized HCC cells to the growth-inhibitory effects of oxaliplatin and induced cell apoptosis. NLRP3/IL-1ß overexpressing tumor cells also attracted polymorphonuclear myeloid-derived suppressor cells. Using mouse models, we demonstrated that NLRP3/IL-1ß inhibition by short hairpin RNA or MCC950 effectively overcame oxaliplatin resistance. Furthermore, NLRP3/IL-1ß inhibition resulted in reduced expression of PD-L1. We also found that PD-L1 antibody combined with NLRP3/IL-1ß blockade displayed significant antitumor effect in HCC. Overall, our study provides compelling evidence supporting the essential role of NLRP3/IL-1ß in conferring resistance to oxaliplatin and reshaping the immunosuppressive microenvironment in HCC. Targeting NLRP3/IL-1ß presents a potential therapeutic target for overcoming oxaliplatin resistance and reshaping microenvironment of HCC.

Gas7 attenuates hepatocellular carcinoma progression and chemoresistance through the PI3K/Akt signaling pathway.

Growth arrest-specific gene 7 (Gas7) was involved in various cellular functions, although its specific roles and molecular mechanisms in hepatocellular carcinoma (HCC) remained unclear. So the current study was to investigate the role of Gas7 in HCC. Our findings revealed that Gas7 was downregulated in various HCC cell lines and low Gas7 expression was associated with decreased overall survival in patients with HCC. Additionally, our functional assays showed that Gas7 inhibited cell proliferation and migration, induced cell cycle arrest, apoptosis, and autophagy, and enhanced oxaliplatin sensitivity by inhibiting the PI3K/Akt signaling pathway. We also observed that transcription factorSp1 was responsible for inhibiting Gas7. These findings provide insights into the role and elucidated a potential mechanism of Gas7 in HCC progression and metastasis. It was also observed that the Sp1/Gas7/PI3K/Akt axis was critical for malignant phenotype and oxaliplatin sensitivity in HCC. Therefore, Gas7 can be considered as a prognostic predictor and therapeutic target for HCC.

The worsening of skeletal muscle atrophy induced by immobilization at the early stage of remobilization correlates with BNIP3-dependent mitophagy.

BACKGROUND: Recent studies have shown that immobilization enhances reactive oxygen species (ROS) production and mitophagy activity in atrophic skeletal muscle. However, there are relatively few studies examining the biological changes and underlying mechanisms of skeletal muscle during remobilization. In this study, we aimed to investigate the effects of remobilization on skeletal muscle and explore the role of BNIP3-dependent mitophagy in this process. METHODS: Thirty rats were randomly divided into six groups based on immobilization and remobilization time: control (C), immobilization for two weeks (I-2w), and remobilization for one day (R-1d), three days (R-3d), seven days (R-7d), and two weeks (R-2w). At the end of the experimental period, the rectus femoris muscles were removed and weighed, and the measurements were expressed as the ratio of muscle wet weight to body weight (MWW/BW). Sirius Red staining was performed to calculate the values of cross-sectional area (CSA) of rectus femoris. Oxidative fluorescent dihydroethidium was used to evaluate the production of ROS, and the levels of superoxide dismutase (SOD) were also detected. The morphological changes of mitochondria and the formation of mitophagosomes in rectus femoris were examined and evaluated by transmission electron microscope. Immunofluorescence was employed to detect the co-localization of BNIP3 and LC3B, while Western blot analysis was performed to quantify the levels of proteins associated with mitophagy and mitochondrial biogenesis. The total ATP content of the rectus femoris was determined to assess mitochondrial function. RESULTS: Within the first three days of remobilization, the rats demonstrated decreased MWW/BW, CSA, and ATP concentration, along with increased ROS production and HIF-1α protein levels in the rectus femoris. Results also indicated that remobilization triggered BNIP3-dependent mitophagy, supported by the accumulation of mitophagosomes, the degradation of mitochondrial proteins (including HSP60 and COX IV), the elevation of BNIP3-dependent mitophagy protein markers (including BNIP3, LC3B-II/LC3B-I, and Beclin-1), and the accumulation of puncta representing co-localization of BNIP3 with LC3B. Additionally, PGC-1α, which is involved in the regulation of mitochondrial biogenesis, was upregulated within the first seven days of remobilization to counteract this adverse effect. CONCLUSION: Our findings suggested that BNIP3-denpendent mitophagy was sustained activated at the early stages of remobilization, and it might contribute to the worsening of skeletal muscle atrophy.

Oxaliplatin-Resistant Hepatocellular Carcinoma Drives Immune Evasion Through PD-L1 Up-Regulation and PMN-Singular Recruitment.

BACKGROUND & AIMS: Previously, we showed the inhibitor of differentiation or DNA binding 1 (ID1)/Myc signaling is highly expressed in oxaliplatin-resistant hepatocellular carcinoma (HCC). This study sought to investigate the role of ID1/Myc signaling on immune evasion in oxaliplatin-resistant HCC. METHODS: The oxaliplatin (OXA)-resistant HCC cell lines (Hepa 1-6-OXA, 97H-OXA, and 3B-OXA) were established and their oxaliplatin tolerance was confirmed in vitro and in vivo. The relationship between ID1/Myc and programmed death-ligand 1 (PD-L1) up-regulation and polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) accumulation was explored. The underlying mechanism in which ID1/Myc signaling regulated PD-L1 expression and PMN-MDSC accumulation was investigated in vitro and vivo. RESULTS: Increased ID1/Myc expression was identified in oxaliplatin-resistant HCC and correlated with PD-L1 up-regulation and PMN-MDSC accumulation. The knockdown of Myc sensitized oxaliplatin-resistant HCC cells to oxaliplatin and resulted in a decrease of PMN-MDSCs and an increase of interferon-γ+ CD8+ T cells in a tumor microenvironment. Polymerase chain reaction array, enzyme-linked immunosorbent assay, and MDSC Transwell migration assay indicated that oxaliplatin-resistant HCC cells recruited PMN-MDSCs through chemokine (C-C motif) ligand 5 (CCL5). The dual luciferase reporter assay and chromatin immunoprecipitation assay indicated that Myc could directly increase the transcriptions of PD-L1 and CCL5. Furthermore, anti-PD-L1 antibody combined with CCL5 blockade showed significant antitumor effects in oxaliplatin-resistant HCC. CONCLUSIONS: ID1/Myc signaling drives immune evasion in oxaliplatin-resistant HCC via PD-L1 up-regulation and PMN-MDSC recruitment. Blocking the ID1/Myc-induced immune tolerance represents a promising treatment target to conquer chemoresistance in HCC.

PVR-A Prognostic Biomarker Correlated with Immune Cell Infiltration in Hepatocellular Carcinoma.

The poliovirus receptor (PVR) is a member of the immunoglobulin superfamily (Ig SF) and is essential for the promotion of cancer cell proliferation and invasion. However, the correlation between PVR expression and prognosis as well as immune infiltration in hepatocellular carcinoma (HCC) remains unclear. The expression level of PVR was quantified using the Tumor and Tumor Immunity Evaluation Resource (TIMER) and Sangerbox. The Gene Expression Omnibus (GEO) database was used to validate the PVR expression. The receiver operating characteristic (ROC) curve was used to evaluate the feasibility of using PVR as a differentiating factor according to the area under curve (AUC) score. A PVR binding protein network was built using the STRING tool. An enrichment analysis using the R package clusterProfiler was used to explore the potential function of PVR. Immune infiltration analysis was calculated with ESTIMATE algorithms. We also assessed the correlation between PVR expression and immune infiltration by the single-sample Gene Set Enrichment Analysis (ssGSEA) method from the R package GSVA and TIMER database. The results showed that PVR was commonly overexpressed in multiple types of tumors including HCC. The data of GSE64041 confirmed the same result. The ROC curve suggested that PVR could be a potential diagnostic biomarker. Additionally, high mRNA expression of PVR in HCC was significantly correlated with poor overall survival (OS) and relapse free survival (RFS). Results also indicated correlations between PVR mRNA expression with the level of infiltration immune cells including B cells, CD8+ T cells, cytotoxic cells, DCs, CD56dim NK cells, pDCs, and Th2 cells. Furthermore, the PVR level was significantly correlated with immune markers for immunosuppressive cells in HCC. In conclusion, PVR might be an important regulator of tumor immune cell infiltration and a valuable prognostic biomarker in HCC. However, additional work is needed to fully elucidate the underlying mechanisms.

Tumor-triggered targeting ammonium bicarbonate liposomes for tumor multimodal therapy.

Tumor-triggered targeting ammonium bicarbonate (TTABC) liposomes were proposed to improve the uptake of ammonium bicarbonate (ABC) liposomes in tumor cells and retain their long circulation in vivo in our previous study. However, it must be solved how to precisely release the loaded drugs of the TTABC liposomes into tumor cells. In addition, synergistic multimodal therapy could result in better tumor treatment outcomes than monomodal chemotherapy. In the research, we prepared indocyanine green (ICG) and doxorubicin (DOX) encapsulated TTABC liposomes (ICG&DOX@TTABC) to achieve near-infrared (NIR) light-controlled chemo/photothermal/photodynamic multimodal therapy guided by fluorescence and photothermal imaging. In vitro and vivo studies show that ICG&DOX@TTABC can specifically accumulate in tumor tissues, effectively transform NIR light into local thermo-therapy, and have excellent anti-tumor ability without obvious side effects. ICG&DOX@TTABC could be promising for fluorescence and photothermal imaging-guided chemo/photothermal/photodynamic tumor treatment.

Predicting Disease-Specific Survival for Patients With Primary Cholangiocarcinoma Undergoing Curative Resection by Using a Decision Tree Model.

Background: The aim of this study was to derive and validate a decision tree model to predict disease-specific survival after curative resection for primary cholangiocarcinoma (CCA). Method: Twenty-one clinical characteristics were collected from 482 patients after curative resection for primary CCA. A total of 289 patients were randomly allocated into a training cohort and 193 were randomly allocated into a validation cohort. We built three decision tree models based on 5, 12, and 21 variables, respectively. Area under curve (AUC), sensitivity, and specificity were used for comparison of the 0.5-, 1-, and 3-year decision tree models and regression models. AUC and decision curve analysis (DCA) were used to determine the predictive performances of the 0.5-, 1-, and 3-year decision tree models and AJCC TNM stage models. Results: According to the fitting degree and the computational cost, the decision tree model derived from 12 variables displayed superior predictive efficacy to the other two models, with an accuracy of 0.938 in the training cohort and 0.751 in the validation cohort. Maximum tumor size, resection margin, lymph node status, histological differentiation, TB level, ALBI, AKP, AAPR, ALT, γ-GT, CA19-9, and Child-Pugh grade were involved in the model. The performances of 0.5-, 1-, and 3-year decision tree models were better than those of conventional models and AJCC TNM stage models. Conclusion: We developed a decision tree model to predict outcomes for CCA undergoing curative resection. The present decision tree model outperformed other clinical models, facilitating individual decision-making of adjuvant therapy after curative resection.

Coiled-Coil Domain-Containing Protein 45 Is a Potential Prognostic Biomarker and Is Associated with Immune Cell Enrichment of Hepatocellular Carcinoma.

Objective: The role of coiled-coil domain-containing protein 45 (CCDC45) in the development of hepatocellular carcinoma (HCC) has not been reported. The present study is aimed at investigating the expression and prognosis of CCDC45 in HCC and its relevance to immune infiltration. Methods: We conducted CCDC45 expression analysis using The Cancer Genome Atlas (TCGA) tumor database, the Human Protein Atlas (HPA) database, and the Tumor Immunological Evaluation Resource (TIMER). We used the University of Alabama at Birmingham Cancer data analysis Portal (UALCAN) database to show the correlation of CCDC45 with clinical features. We examined the prognostic impact of CCDC45 expression levels on HCC patients with the Kaplan-Meier mapper database. Genes coexpressed with CCDC45 and its regulators were also identified using LinkedOmics. The enriched Gene Ontology (GO) categories and associated signaling pathways were estimated using GO, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Assay (GSEA) pathway data. Correlations between CCDC45 and cancer immune infiltration was analyzed through the TIMER and an integrated repository portal for Tumor-Immune System Interactions (TISIDB) databases. Results: The expression of CCDC45 was elevated in HCC tissues compared to adjacent liver tissues, and overexpression of CCDC45 was significantly correlated with tumor stage. Furthermore, HCC patients with CCDC45 overexpression had a shorter overall survival (OS). Functional network analysis indicated that CCDC45 was involved in homologous recombination, spliceosome, and DNA replication. Interestingly, CCDC45 expression was positively correlated with the level of immune cell infiltration. Conclusions: CCDC45 is associated with prognosis and immune infiltration of HCC and may be a potential therapeutic target for HCC.

The Prognostic Value of the Albumin to Gamma-Glutamyltransferase Ratio in Patients with Hepatocellular Carcinoma Undergoing Radiofrequency Ablation.

Albumin to gamma-glutamyltransferase ratio (AGR) is a newly developed biomarker for the prediction of patients' prognosis in solid tumors. The purpose of the study was to establish a novel AGR-based nomogram to predict tumor prognosis in patients with early-stage HCC undergoing radiofrequency ablation (RFA). 394 hepatocellular carcinoma (HCC) patients who had received RFA as initial treatment were classified into the training cohort and validation cohort. Independent prognostic factors were identified by univariate and multivariate analyses. The value of AGR was evaluated by the concordance index (C-index), receiver operating characteristic (ROC) curves, and likelihood ratio tests (LAT). Logistic regression and nomogram were performed to establish the pretreatment scoring model based on the clinical variables. As a result, AGR = 0.63 was identified as the best cutoff value to predict overall survival (OS) in the training cohort. According to the results of multivariate analysis, AGR was an independent indicator for OS and recurrence-free survival (RFS). In both training cohort and validation cohort, the high-AGR group showed better RFS and OS than the low-AGR group. What is more, the C-index, area under the ROC curves, and LAT χ 2 values suggested that AGR outperformed the Child-Pugh (CP) grade and albumin-bilirubin (ALBI) grade in terms of predicting OS. The AGR, AKP, and tumor size were used to establish the OS nomogram. Besides, the results of Hosmer-Lemeshow test and calibration curve analysis displayed that both nomograms in the training and validation cohorts performed well in terms of calibration. Therefore, the AGR-based nomogram can predict the postoperative prognosis of early HCC patients undergoing RFA.

Development and validation of an individualized prediction calculator of postoperative mortality within 6 months after surgical resection for hepatocellular carcinoma: an international multicenter study.

BACKGROUND: Evidence-based decision-making is critical to optimize the benefits and mitigate futility associated with surgery for patients with malignancies. Untreated hepatocellular carcinoma (HCC) has a median survival of only 6 months. The objective was to develop and validate an individualized patient-specific tool to predict preoperatively the benefit of surgery to provide a survival benefit of at least 6 months following resection. METHODS: Using an international multicenter database, patients who underwent curative-intent liver resection for HCC from 2008 to 2017 were identified. Using random assignment, two-thirds of patients were assigned to a training cohort with the remaining one-third assigned to the validation cohort. Independent predictors of postoperative death within 6 months after surgery for HCC were identified and used to construct a nomogram model with a corresponding online calculator. The predictive accuracy of the calculator was assessed using C-index and calibration curves. RESULTS: Independent factors associated with death within 6 months of surgery included age, Child-Pugh grading, portal hypertension, alpha-fetoprotein level, tumor rupture, tumor size, tumor number and gross vascular invasion. A nomogram that incorporated these factors demonstrated excellent calibration and good performance in both the training and validation cohorts (C-indexes: 0.802 and 0.798). The nomogram also performed better than four other commonly-used HCC staging systems (C-indexes: 0.800 vs. 0.542-0.748). CONCLUSIONS: An easy-to-use online prediction calculator was able to identify patients at highest risk of death within 6 months of surgery for HCC. The proposed online calculator may help guide surgical decision-making to avoid futile surgery for patients with HCC.

Hyaluronic acid and albumin based nanoparticles for drug delivery.

Albumin, a multifunctional protein, is widely used to prepare nanocarriers. Hyaluronic acid (HA) is a natural glycosaminoglycan that can specifically bind receptors, such as cluster of differentiation-44. Therefore, HA is commonly used as ligands for the surface modification of versatile nanocarriers. The combined utilization of albumin and HA as nanocarriers shows outstanding superiorities including efficient targeting, reducible particle size, pH and/or hyaluronidase sensitive drug release, combining capacity for various drugs, biocompatibility, non-immunogenicity, biodegradability and high stability. However, to the best of our knowledge, HA and albumin based nanoparticles have not been reviewed for drug delivery so far. This review involves the introduction of the essential information of HA and albumin as well as a brief presentation of the preparation methods of HA and albumin based nanocarriers. Moreover, the application of HA and albumin based nanoparticles as drug delivery carriers in tumors, joints, vitreum and skin tissue is systematically discussed with the potential and prospect in combined therapy and theranostics. In addition, the unique advantages of the HA and albumin based nanoparticles and their contributions to the improvement of drug delivery systems are further expounded in detail.

First-Line Systemic Treatment Strategies for Unresectable Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials.

OBJECTIVE: Several new first-line treatments were recently approved for unresectable hepatocellular carcinoma (HCC). In this meta-analysis, we compare the efficacy and safety of first-line systemic treatments to provide information for clinical decision making in unresectable HCC. METHODS: Pubmed, Science Direct, Web of Science, Scopus, Ovid MEDLINE, Embase, Google Scholar, the Cochrane Library, EMbase, CNKI, CBM, VIP, and the Wanfang databases, as well as the Cochrane Central Register of Controlled Trails were searched for randomized clinical trials evaluating the efficacy of first-line chemotherapy, molecular targeted therapy, or immunotherapy for unresectable HCC. Hazard ratios with 95% confidence intervals (CIs) were calculated to explore the effects of various treatment options on overall survival (OS) and progression-free survival (PFS), whereas odd ratios with 95% CIs were used for adverse events (AEs) and serious adverse events (SAEs). A network meta-analysis was performed to synthesize data and for direct and indirect comparisons between treatments. The cumulative ranking curve (SUCRA) and P score were used to rank treatments. The risk of bias across studies was assessed graphically and numerically using the funnel plot and Egger's regression test. RESULTS: Fifteen studies including 9005 patients were analyzed. Sintilimab plus bevacizumab, atezolizumab plus bevacizumab, and donafenib had better OS outcomes than sorafenib. Sintilimab plus bevacizumab, atezolizumab plus bevacizumab, lenvatinib, and linifanib had better PFS outcomes than sorafenib. The results of network meta-analysis showed that sintilimab plus bevacizumab was associated with the best OS and PFS. Egger's tests indicated that none of the included studies had obvious publication deviation. CONCLUSION: Sintilimab plus bevacizumab showed the best OS and PFS outcomes with no additional AEs or SAEs. Thus, sintilimab plus bevacizumab may be a better first line choice for the treatment of patients with unresectable HCC. SYSTEMATIC REVIEW REGISTRATION: PROSPEROI [https://www.crd.york.ac.uk/PROSPERO/index.php], identifier CRD42021269734.

Repeat hepatectomy for patients with early and late recurrence of hepatocellular carcinoma: A multicenter propensity score matching analysis.

BACKGROUND: Repeat hepatectomy is a feasible treatment modality for intrahepatic recurrence after hepatectomy of hepatocellular carcinoma, yet the survival benefit remains ill-defined. The objective of the current study was to define long-term, oncologic outcomes after repeat hepatectomy among patients with early and late recurrence. METHODS: Patients undergoing curative-intent repeat hepatectomy for recurrent hepatocellular carcinoma were identified using a multi-intuitional database. Early and late recurrence was defined by setting 1 year after initial hepatectomy as the cutoff value. Patient clinical characteristics, overall survival, and disease-free survival were compared among patients with early and late recurrence before and after propensity score matching. RESULTS: Among all the patients, 81 had early recurrence and 129 had late recurrence from which 74 matched pairs were included in the propensity score matching analytic cohort. Before propensity score matching, 5-year overall survival and disease-free survival after resection of an early recurrence were 41.7% and 17.9%, respectively, which were worse compared with patients who had resection of a late recurrence (57.0% and 39.4%, both P < .01). After propensity score matching, 5-year overall survival and disease-free survival among patients with early recurrence were worse compared with patients with late recurrence (41.0% and 19.2% vs 64.3% and 43.2%, both P < .01). After adjustment for other confounding factors on multivariable Cox-regression analysis, early recurrence remained independently associated with decreased overall survival and disease-free survival (hazard ratio 2.22, 95% confidence interval 1.35-3.34, P = .001; hazard ratio 1.86, 95% confidence 1.26-2.74, P = .002). CONCLUSION: Repeat hepatectomy for early recurrence was associated with worse overall survival and disease-free survival compared with late recurrence. These data may help inform patients and selection of patients being considered for repeat hepatectomy of recurrent hepatocellular carcinoma.

A novel online calculator based on noninvasive markers (ALBI and APRI) for predicting post-hepatectomy liver failure in patients with hepatocellular carcinoma.

BACKGROUND AND AIM: Post-hepatectomy liver failure (PHLF) remains the primary cause of in-hospital mortality after hepatectomy. Identifying predictors of PHLF is important to improve surgical safety. We sought to identify the predictive accuracy of two noninvasive markers, albumin-bilirubin (ALBI) and aspartate aminotransferase to platelet count ratio index (APRI), to predict PHLF among patients with hepatocellular carcinoma (HCC), and to build up an online prediction calculator. METHODS: Patients who underwent resection for HCC between 2013 and 2016 at 6 Chinese hospitals were retrospectively analyzed. The independent predictors of PHLF were identified using univariate and multivariate analyses; derivative data were used to construct preoperative and postoperative nomogram models. Receiver operating characteristic (ROC) curves for the two predictive models, and ALBI, APRI, Child-Pugh, model for end-stage liver disease (MELD) scores were compared relative to predictive accuracy for PHLF. RESULTS: Among the 767 patients in the analytic cohort, 102 (13.3%) experienced PHLF. Multivariable logistic regression analysis identified high ALBI grade (>-2.6) and high APRI grade (>1.5) as independent risk factors associated with PHLF in both the preoperative and postoperative models. Two nomogram predictive models and corresponding web-based calculators were subsequently constructed. The areas under the ROC curves for the postoperative and preoperative models, APRI, ALBI, MELD and Child-Pugh scores in predicting PHLF were 0.844, 0.789, 0.626, 0.609, 0.569, and 0.560, respectively. CONCLUSIONS: ALBI and APRI demonstrated more accurate ability to predict PHLF than Child-Pugh and MELD. Two online calculators that combined ALBI and APRI were proposed as useful preoperative and postoperative tools for individually predicting the occurrence of PHLF among patients with HCC.