Cold to Hot: Tumor Immunotherapy by Promoting Vascular Normalization Based on PDGFB Nanocomposites.

Immunotherapy is a promising cancer therapeutic strategy. However, the "cold" tumor immune microenvironment (TIME), characterized by insufficient immune cell infiltration and immunosuppressive status, limits the efficacy of immunotherapy. Tumor vascular abnormalities due to defective pericyte coverage are gradually recognized as a profound determinant in "cold" TIME establishment by hindering immune cell trafficking. Recently, several vascular normalization strategies by improving pericyte coverage have been reported, whereas have unsatisfactory efficacy and high rates of resistance. Herein, a combinatorial strategy to induce tumor vasculature-targeted pericyte recruitment and zinc ion-mediated immune activation with a platelet-derived growth factor B (PDGFB)-loaded, cyclo (Arg-Gly-Asp-D-Phe-Lys)-modified zeolitic imidazolate framework 8 (PDGFB@ZIF8-RGD) nanoplatform is proposed. PDGFB@ZIF8-RGD effectively induced tumor vascular normalization, which facilitated trafficking and infiltration of immune effector cells, including natural killer (NK) cells, M1-like macrophages and CD8+ T cells, into tumor microenvironment. Simultaneously, vascular normalization promoted the accumulation of zinc ions inside tumors to trigger effector cell immune activation and effector molecule production. The synergy between these two effects endowed PDGFB@ZIF8-RGD with superior capabilities in reprogramming the "cold" TIME to a "hot" TIME, thereby initiating robust antitumor immunity and suppressing tumor growth. This combinatorial strategy for improving immune effector cell infiltration and activation is a promising paradigm for solid tumor immunotherapy.

Epigenetic silencing of miR-144/451a cluster contributes to HCC progression via paracrine HGF/MIF-mediated TAM remodeling.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is among the malignancies with the highest mortality. The key regulators and their interactive network in HCC pathogenesis remain unclear. Along with genetic mutations, aberrant epigenetic paradigms, including deregulated microRNAs (miRNAs), exert profound impacts on hepatocyte transformation and tumor microenvironment remodeling; however, the underlying mechanisms are largely uncharacterized. METHODS: We performed RNA sequencing on HCC specimens and bioinformatic analyses to identify tumor-associated miRNAs. The miRNA functional targets and their effects on tumor-infiltrating immune cells were investigated. The upstream events, particularly the epigenetic mechanisms responsible for miRNA deregulation in HCC, were explored. RESULTS: The miR-144/miR-451a cluster was downregulated in HCC and predicted a better HCC patient prognosis. These miRNAs promoted macrophage M1 polarization and antitumor activity by targeting hepatocyte growth factor (HGF) and macrophage migration inhibitory factor (MIF). The miR-144/miR-451a cluster and EZH2, the catalytic subunit of polycomb repressive complex (PRC2), formed a feedback circuit in which miR-144 targeted EZH2 and PRC2 epigenetically repressed the miRNA genes via histone H3K27 methylation of the promoter. The miRNA cluster was coordinately silenced by distal enhancer hypermethylation, disrupting chromatin loop formation and enhancer-promoter interactions. Clinical examinations indicated that methylation of this chromatin region is a potential HCC biomarker. CONCLUSIONS: Our study revealed novel mechanisms underlying miR-144/miR-451a cluster deregulation and the crosstalk between malignant cells and tumor-associated macrophages (TAMs) in HCC, providing new insights into HCC pathogenesis and diagnostic strategies.

CRP­1 promotes the malignant behavior of hepatocellular carcinoma cells via activating epithelial­mesenchymal transition and Wnt/ß­catenin signaling.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. It has been reported that cysteine rich protein 1 (CRP-1) is dysregulated in several types of human cancer; however, its role in HCC is poorly understood. Therefore, the current study aimed to investigate the role of CRP-1 in HCC. Western blotting and reverse transcription-quantitative PCR results showed that CRP-1 was upregulated in HCC cell lines. Furthermore, for in vitro experiments, CRP-1 was knocked down and overexpressed in the HCC cell lines Hep 3B2.1-7 and BEL-7405, respectively. c-Myc and proliferating cell nuclear antigen upregulation, and cleaved caspase 3 and poly(ADP-ribose) polymerase downregulation suggested that CRP-1 silencing could inhibit the proliferation and colony-forming ability of HCC cells, and induce apoptosis. In addition, CRP-1 overexpression promoted the malignant behavior of HCC cells and induced epithelial-mesenchymal transition (EMT), as verified by E-cadherin downregulation, and N-cadherin and vimentin upregulation. Additionally, CRP-1 overexpression promoted the nuclear translocation of ß-catenin, and activated the expression of cyclin D1 and matrix metalloproteinase-7. Furthermore, inhibition of Wnt/ß-catenin signaling, following cell treatment with XAV-939, an inhibitor of the Wnt/ß-catenin signaling pathway, abrogated the effects of CRP-1 on enhancing the proliferation and migration of HCC cells. These findings indicated that the regulatory effect of CRP-1 on HCC cells could be mediated by the Wnt/ß-catenin signaling pathway. Overall, CRP-1 could promote the proliferation and migration of HCC cell lines, partially via promoting EMT and activating the Wnt/ß-catenin signaling pathway.

Bioinspired porous three-coordinated single-atom Fe nanozyme with oxidase-like activity for tumor visual identification via glutathione.

Inspired by structures of natural metalloenzymes, a biomimetic synthetic strategy is developed for scalable synthesis of porous Fe-N3 single atom nanozymes (pFeSAN) using hemoglobin as Fe-source and template. pFeSAN delivers 3.3- and 8791-fold higher oxidase-like activity than Fe-N4 and Fe3O4 nanozymes. The high catalytic performance is attributed to (1) the suppressed aggregation of atomically dispersed Fe; (2) facilitated mass transfer and maximized exposure of active sites for the created mesopores by thermal removal of hemoglobin (2 ~ 3 nm); and (3) unique electronic configuration of Fe-N3 for the oxygen-to-water oxidation pathway (analogy with natural cytochrome c oxidase). The pFeSAN is successfully demonstrated for the rapid colorimetric detection of glutathione with a low limit of detection (2.4 nM) and wide range (50 nM-1 mM), and further developed as a real-time, facile, rapid (~6 min) and precise visualization analysis methodology of tumors via glutathione level, showing its potentials for diagnostic and clinic applications.

Insights into the Effect of Catalytic Intratumoral Lactate Depletion on Metabolic Reprogramming and Immune Activation for Antitumoral Activity.

Lactate, a characteristic metabolite of the tumor microenvironment (TME), drives immunosuppression and promotes tumor progression. Material-engineered strategies for intratumoral lactate modulations demonstrate their promise for tumor immunotherapy. However, understanding of the inherent interconnections of material-enabled lactate regulation, metabolism, and immunity in the TME is scarce. To address this issue, urchin-like catalysts of the encapsulated Gd-doped CeO2 , syrosingopine, and lactate oxidase are used in ZIF-8 (USL, where U, S, and L represent the urchin-like Gd-doped CeO2 @ZIF-8, syrosingopine, and lactate oxidase, respectively) and orthotopic tumor models. The instructive relationships of intratumoral lactate depletion, metabolic reprogramming, and immune activation for catalytic immunotherapy of tumors is illustrated. The catalysts efficiently oxidize intratumoral lactate and significantly promote tumor cell apoptosis by in situ-generated ·OH, thereby reducing glucose supply and inducing mitochondrial damage via lactate depletion, thus reprogramming glycometabolism. Subsequently, such catalytic metabolic reprogramming evokes both local and systemic antitumor immunity by activating M1-polarizaed macrophages and CD8+ T cells, leading to potent antitumor immunity. This study provides valuable mechanistic insights into material-interfered tumor therapy through intratumoral lactate depletion and consequential connection with metabolic reprogramming and immunity remodeling, which is thought to enhance the efficacy of immunotherapy.

Potential candidates for liver resection in liver-confined advanced HCC: a Chinese multicenter observational study.

Background: Advanced hepatocellular carcinoma (HCC) is characterized as symptomatic tumors [performance status (PS) score of 1-2], vascular invasion and extrahepatic spread, but patients with PS1 alone may be eliminated from this stage. Although liver resection is used for liver-confined HCC, its role in patients with PS1 alone remains controversial. Therefore, we aimed to explore its application in such patients and identify potential candidates. Methods: Eligible liver-confined HCC patients undergoing liver resection were retrospectively screened in 15 Chinese tertiary hospitals, with limited tumor burden, liver function and PS scores. Cox-regression survival analysis was used to investigate the prognostic factors and develop a risk-scoring system, according to which patients were substratified using fitting curves and the predictive values of PS were explored in each stratification. Results: From January 2010 to October 2021, 1535 consecutive patients were selected. In the whole cohort, PS, AFP, tumor size and albumin were correlated with survival (adjusted P<0.05), based on which risk scores of every patient were calculated and ranged from 0 to 18. Fitting curve analysis demonstrated that the prognostic abilities of PS varied with risk scores and that the patients should be divided into three risk stratifications. Importantly, in the low-risk stratification, PS lost its prognostic value, and patients with PS1 alone achieved a satisfactory 5-year survival rate of 78.0%, which was comparable with that PS0 patients (84.6%). Conclusion: Selected patients with PS1 alone and an ideal baseline condition may benefit from liver resection and may migrate forward to BCLC stage A.

Computational Characterizing Necroptosis Reveals Implications for Immune Infiltration and Immunotherapy of Hepatocellular Carcinoma.

Necroptosis is a programmed form of necrotic cell death in regulating cancer ontogenesis, progression, and tumor microenvironment (TME) and could drive tumor-infiltrating cells to release pro-inflammatory cytokines, incurring strong immune responses. Nowadays, there are few identified biomarkers applied in clinical immunotherapy, and it is increasingly recognized that high levels of tumor necroptosis could enhance the response to immunotherapy. However, comprehensive characterization of necroptosis associated with TME and immunotherapy in Hepatocellular carcinoma (HCC) remains unexplored. Here, we computationally characterized necroptosis landscape in HCC samples from TCGA and ICGA cohorts and stratified them into two necroptosis clusters (A or B) with significantly different characteristics in clinical prognosis, immune cell function, and TME-landscapes. Additionally, to further evaluate the necroptosis levels of each sample, we established a novel necroptosis-related gene score (NRGscore). We further investigated the TME, tumor mutational burden (TMB), clinical response to immunotherapy, and chemotherapeutic drug sensitivity of HCC subgroups stratified by the necroptosis landscapes. The NRGscore is robust and highly predictive of HCC clinical outcomes. Further analysis indicated that the high NRGscore group resembles the immune-inflamed phenotype while the low score group is analogous to the immune-exclusion or metabolism phenotype. Additionally, the high NRGscore group is more sensitive to immune checkpoint blockade-based immunotherapy, which was further validated using an external HCC cohort, metastatic melanoma cohort, and advanced urothelial cancer cohort. Besides, the NRGscore was demonstrated as a potential biomarker for chemotherapy, wherein the high NRGscore patients with more tumor stem cell composition could be more sensitive to Cisplatin, Doxorubicin, Paclitaxel-based chemotherapy, and Sorafenib therapy. Collectively, a comprehensive characterization of the necroptosis in HCC suggested its implications for predicting immune infiltration and response to immunotherapy of HCC, providing promising strategies for treatment.

Phytic acid-modified CeO2 as Ca2+ inhibitor for a security reversal of tumor drug resistance.

Ca2+ plays critical roles in the development of diseases, whereas existing various Ca regulation methods have been greatly restricted in their clinical applications due to their high toxicity and inefficiency. To solve this issue, with the help of Ca overexpressed tumor drug resistance model, the phytic acid (PA)-modified CeO2 nano-inhibitors have been rationally designed as an unprecedentedly safe and efficient Ca2+ inhibitor to successfully reverse tumor drug resistance through Ca2+ negative regulation strategy. Using doxorubicin (Dox) as a model chemotherapeutic drug, the Ca2+ nano-inhibitors efficiently deprived intracellular excessive free Ca2+, suppressed P-glycoprotein (P-gp) expression and significantly enhanced intracellular drug accumulation in Dox-resistant tumor cells. This Ca2+ negative regulation strategy improved the intratumoral Dox concentration by a factor of 12.4 and nearly eradicated tumors without obvious adverse effects. Besides, nanocerias as pH-regulated nanozyme greatly alleviated the adverse effects of chemotherapeutic drug on normal cells/organs and substantially improved survivals of mice. We anticipate that this safe and effective Ca2+ negative regulation strategy has potentials to conquer the pitfalls of traditional Ca inhibitors, improve therapeutic efficacy of common chemotherapeutic drugs and serves as a facile and effective treatment platform of other Ca2+ associated diseases. Electronic Supplementary Material: Supplementary material (further details of the XRD pattern of CeO2, TEM images, XPS spectra, cellular uptake study, cytotoxicity data, apoptosis study, biodistribution, and biosecurity of nanocerias in vivo, etc.) is available in the online version of this article at 10.1007/s12274-022-4069-0.

Identify optimal HAP series scores for unresectable HCC patients undergoing TACE plus sorafenib: A Chinese multicenter observational study.

Background: Hepatoma arterial-embolization prognostic (HAP) series scores have been proposed for prognostic prediction in patients with unresectable hepatocellular carcinoma (uHCC) undergoing transarterial chemoembolization (TACE). However, their prognostic value in TACE plus sorafenib (TACE-S) remains unknown. Here, we aim to evaluate their prognostic performance in such conditions and identify the best model for this combination therapy. Methods: Between January 2012 and December 2018, consecutive patients with uHCC receiving TACE-S were recruited from 15 tertiary hospitals in China. Cox regression analyses were used to investigate the prognostic values of baseline factors and every scoring system. Their prognostic performance and discriminatory performance were evaluated and confirmed in subgroup analyses. Results: A total of 404 patients were enrolled. In the whole cohort, the median follow-up period was 44.2 (interquartile range (IQR), 33.2-60.7) months, the median overall survival (OS) time was 13.2 months, and 336 (83.2%) patients died at the end of the follow-up period. According to multivariate analyses, HAP series scores were independent prognostic indicators of OS. In addition, the C-index, Akaike information criterion (AIC) values, and time-dependent area under the receiver operating characteristic (ROC) curve (AUC) indicated that modified HAP (mHAP)-III had the best predictive performance. Furthermore, the results remained consistent in most subsets of patients. Conclusion: HAP series scores exhibited good predictive ability in uHCC patients accepting TACE-S, and the mHAP-III score was found to be superior to the other HAP series scores in predicting OS. Future prospective high-quality studies should be conducted to confirm our results and help with treatment decision-making.

Clinical course and outcomes of COVID-19 patients with a history of cerebrovascular disease: a retrospective study in Wuhan.

BACKGROUND: Data on patients with coronavirus disease 2019 (COVID-19) who have pre-existing cerebrovascular disease (CVD) are scarce. This study set out to describe the clinical course and outcomes of these patients. METHODS: This single-center retrospective study was performed at Huoshenshan Hospital in Wuhan, China. Patients with confirmed COVID-19 who had pre-existing CVD (N=69) were identified. COVID-19 patients without CVD were randomly selected and matched by age and sex to the patients with CVD. Clinical data were analyzed and compared between the 2 groups. The composite endpoint included intensive care unit admission, use of mechanical ventilation, and death. Multivariable Cox regression analyses with control for medical comorbidities were used to examine the relationship between pre-existing CVD and clinical outcome of COVID-19. RESULTS: Compared with patients without CVD, patients with pre-existing CVD were more likely to present with unapparent symptoms at first; however, at admission, these patients tended to be in a severer condition than those without CVD, with more underlying hypertension and diabetes. The levels of interleukin-6, creative kinase MB, aspartate transaminase, and creatinine, as well as prothrombin time, were also markedly higher in patients with CVD. Patients with pre-existing CVD were more likely to develop multi-organ dysfunction, deteriorate to critical condition, and yield poorer clinical outcomes than patients without CVD. Concerning therapeutics, greater proportions of patients with pre-existing CVD required mechanical ventilation, higher-order anti-bacterials, and drugs targeting underlying diseases and complications. In the multivariable analysis, pre-existing CVD was significantly associated with a poor clinical outcome. CONCLUSIONS: Patients with a history of CVD are more vulnerable to an over-activated inflammatory response and subsequent multi-organ dysfunction, resulting in a poor clinical outcome. Close monitoring is advisable for these patients.

Implications of Laboratory Tests in Disease Grading and Death Risk Stratification of COVID-19: A Retrospective Study in Wuhan, China.

Background: Although laboratory tests have become an indispensable part in clinical practice, its application in severity classification and death risk stratification of COVID-19 remains unvalidated. This study aims to explore the significance of laboratory tests in the management of COVID-19. Methods: In 3,342 hospitalized patients with COVID-19, those of mild or moderate subtype were categorized into the non-severe group, while those of severe or critical subtype were categorized into the severe group. Initial laboratory data were analyzed and compared according to disease severity and outcome. Diagnostic models for the severe group were generated on risk factors identified by logistic regression and receiver operating characteristic (ROC) analyses. Cox regression and ROC analyses on risk factors were utilized to construct prognostic models. Results: In identification of patients in the severe group, while age, neutrophil-to-lymphocyte ratio, and α-hydroxybutyrate dehydrogenase were identified as independent predictors, the value of combination of them appears modest [area under the curve (AUC) = 0.694]. Further ROC analyses indicated that among patients in the severe group, laboratory indices had a favorable value in identifying patients of critical subtype rather than severe subtype. For death outcome, IL-6, co-existing cerebrovascular disease, prothrombin time activity, and urea nitrogen were independent risk factors. An IL-6 single-parameter model was finalized for distinguishing between fatal and recovered individuals (AUC = 0.953). Finally, a modified death risk stratification strategy based on clinical severity and IL-6 levels enables more identification of non-survivors in patients with non-critical disease. Conclusions: Laboratory screening provides a useful tool for COVID-19 management in identifying patients with critical condition and stratifying risk levels of death.

Comparison between Child-Pugh score and Albumin-Bilirubin grade in the prognosis of patients with HCC after liver resection using time-dependent ROC.

BACKGROUNDS: The Child-Pugh score is a scoring system used to measure liver function and predict postoperative outcomes in patients with hepatocellular carcinoma (HCC). Recently, the Albumin-Bilirubin (ALBI) grade has been proposed for the evaluation of hepatic reserve function in HCC. This study aimed to assess and compare the capability of ALBI grade and Child-Pugh score in predicting overall survival (OS). METHODS: A total of 196 consecutive HCC patients who treated with hepatectomy were enrolled in this retrospective study. The prognostic values of ALBI grade and Child-Pugh score in predicting postoperative OS were respectively estimated using the Kaplan-Meier method and time-dependent receiver operating curves (ROC). Univariate and multivariate Cox regression analyses were performed to investigate the prognostic factors for OS. RESULTS: Stratified by the Albumin-Bilirubin (ALBI) system, there were 81 (41.3%) patients with grade 1 and 115 (58.7%) patients with grade 2. The cumulative 1-, 3-, 5-year OS rates in patients with ALBI-1 were 82.7%, 51.5% and 35.5%, respectively. For patients with ALBI-2, the cumulative 1-, 3-, 5-year OS rates were 57.6%, 19.4% and 0%, respectively. Based on the Child-Pugh classification, 136 (69.4%) patients had a score of 5, and 60 (30.6%) patients had a score of 6. Patients with Child-Pugh-A5 showed a better OS than those with Child-Pugh-A6, with respective OS at 1, 3 and 5 years (72.7%, 29.2%, 20.3% vs. 53.9%, 21.1%, 0%, Log-rank P<0.001). Besides, the ALBI grade revealed two prognostic groups within Child-Pugh-A5 (P<0.001), while the Child-Pugh score did not distinguish ALBI-2 in different prognostic groups (P=0.705). The multivariate analysis indicated that both ALBI grade and Child-Pugh score could significantly stratify the patients with different OS [hazard ratio (HR), 3.088 and 1.783; 95% confidence interval (CI), 1.985 to 4.805 and 1.272 to 2.731; P<0.001 and P=0.032 for ALBI grade and Child-Pugh score, respectively]. Additionally, time-dependent ROC analysis in the entire cohort proved that the ALBI grade had a better discriminatory ability than the Child-Pugh score in predicting survival, especially for long-term outcomes. According to the subgroup analyses, the ALBI grade had a better discriminatory ability and survival prediction accuracy in overall subsets than the Child-Pugh score for the prediction of OS. CONCLUSIONS: ALBI grade supplied better prognostic performance and distribution of liver function than Child-Pugh score in stratifying prognosis for HCC patients treated by hepatectomy. These results declared that ALBI grade could be an alternative liver function grading system for stratification in patients with HCC.

The neutrophil-to-lymphocyte ratio is a predictive factor for the survival of patients with hepatocellular carcinoma undergoing transarterial chemoembolization.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) is considered as a prognostic predictor of hepatocellular carcinoma (HCC). However, its prognostic ability is still controversial. This study aimed to evaluate the prognostic value of NLR changes in HCC patients undergoing transarterial chemoembolization (TACE). METHODS: The patients who were newly diagnosed with HCC and treated with TACE in our center from July 2010 to December 2014 were enrolled in the study. The factors, including NLR, were recorded at baseline and three days and one month after TACE. RESULTS: A total of 380 consecutive patients were studied retrospectively. The median NLR values at baseline, 3 days and 1 month after TACE (2.4, 6.3 and 2.4 respectively), were used as the cut-off value for patient stratification. Compared with the patients in low NLR group, those with high NLR had a larger tumor size. For baseline measurement, the low NLR group showed improved overall survival (OS) compared with the high group (median OS, 27.1 vs. 15.6 months, P=0.004). There was no survival difference between the low and high NLR groups when measured at 3 days and at 1 month after TACE (P>0.05). Multivariate analysis showed that baseline NLR >2.4 was an independent prognostic predictor of poor OS. There was significant survival difference between the normal NLR group and the high or increased NLR group, with a median OS of 29.1 and 19.1 months, respectively (P=0.023). CONCLUSIONS: The dynamic changes of baseline NLR are significantly associated with OS in HCC patients treated with TACE, and as a result patient selection and prognostic prediction may be refined.

Prognostic value of the albumin-bilirubin grade in patients with hepatocellular carcinoma and other liver diseases.

One of the most commonly used systems for grading liver function in hepatocellular carcinoma (HCC) patients is the Child-Pugh (CP) score. However, the CP scoring system is not without its shortcomings: for example, the cut-off values for the parameters are calculated arbitrarily and the assessment of ascites and hepatic encephalopathy is subjective. More recently, an alternative to traditional CP grade has emerged in the form of albumin-bilirubin (ALBI) grade. The predictive value provided for HCC patients by the ALBI grade is comparable to that of the CP grade; however, it can also surpass CP grade by greatly reducing subjectivity and further subdividing CP A patients into several different groups, thus improving the prognosis judgment and helping to inform clinicians' optimal decision-making. The application of the ALBI grade into currently used HCC staging systems such as the Barcelona Clinic Liver Cancer (BCLC) staging system, the Cancer of the Liver Italian Program (CLIP) staging system, and the Japan Integrated Staging (JIS) score, etc., as well as newly produced systems like the ALBI-PLT grade, the ALBI and progression disease (ALBI-PD) grade and Modified Intermediate Stage of Liver Cancer (MICAN) criteria, greatly elevates prognostic power.

Comparison of radiofrequency ablation combined with sorafenib or sorafenib alone in patients with ECOG performance score 1: identifying optimal candidates.

BACKGROUND: Sorafenib has been recommended as the first-line treatment and shown to prolong the median overall survival (OS) of patients with advanced unresectable hepatocellular carcinoma (HCC). Recently, a growing number of earlier studies showed the application of radiofrequency ablation (RFA) plus sorafenib in patients diagnosed at the advanced-stage HCC. This study aimed to compare the outcomes of RFA plus sorafenib versus sorafenib alone and identify prognostic factors related to OS for BCLC stage C patients with PS 1 but without vascular invasion or extrahepatic spread. METHODS: A total of 276 consecutive patients in BCLC stage C with PS 1 but without vascular invasion or extrahepatic spread were enrolled in this retrospective study. Survival analyses were performed using the Kaplan-Meier analysis, and the log-rank test examined the statistical differences between the transarterial chemoembolization (TACE) and sorafenib groups. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic factors for OS. RESULTS: Based on the Kaplan-Meier curves, patients treated with RFA plus sorafenib showed better OS than those undergoing sorafenib, with respective OS at 1, 3 and 5 years (84.0%, 43.1%, 22.8% vs. 55.6%, 29.6%, 4.8%, Log-rank P<0.001). The univariate analysis and multivariate analysis showed that tumor size, tumor number, treatment method, albumin, bilirubin, and the Child-Pugh score were associated with OS. According to the subgroups analyses based on the tumor size and tumor number, there were significant differences in OS among overall subsets except in patients with tumor number ≥4 between RFA plus sorafenib and sorafenib therapy. CONCLUSIONS: RFA plus sorafenib provided better prognostic performance than sorafenib, which should be suggested as an alternative treatment modality compared with sorafenib for BCLC stage C patients with PS 1 but without vascular invasion or extrahepatic spread.

Identifying optimal candidates for liver resection or transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Recommended as the first-line treatment for advanced unresectable hepatocellular carcinoma (HCC), sorafenib has been shown to prolong median overall survival (OS) for patients. However, advanced HCC sees high heterogeneity across patient groups. Recently, a growing number of studies have indicated surgical resection and transarterial chemoembolisation (TACE) to perform well in patients with portal vein tumor thrombosis (PVTT). The aim of this study was to compare the outcomes of liver resection and TACE and to identify prognostic factors related to OS for BCLC stage C patients with performance status (PS) 1 who have a single tumor but no vascular invasion or extrahepatic spread. METHODS: A total of 323 consecutive patients in BCLC stage C with PS 1 who had only one tumor and no vascular invasion or extrahepatic spread were enrolled in this retrospective study, regardless of tumor size. Survival analyses were performed using the Kaplan-Meier analysis, and statistical differences between the TACE and sorafenib groups were examined by the log-rank test. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic factors for OS. RESULTS: Based on the Kaplan-Meier curves, patients treated with surgical resection showed a better OS than those who underwent TACE, with OS at 1, 3, and 5 years (85.7%, 48.8%, and 33.3% vs. 66.6%, 21.8%, and 13.4%, respectively; log-rank P<0.001). Univariate and multivariate analyses demonstrated that tumor size, albumin, bilirubin, Child-Pugh score, and treatment method were significant prognostic factors for OS. According to the subgroup analyses based on tumor size, there were significant differences in OS among overall subsets between patients who underwent hepatectomy and those who underwent TACE therapy. CONCLUSIONS: Liver resection had a better prognostic performance than TACE and should be put forward as an alternative treatment modality to TACE for BCLC stage C patients with PS 1 who have a single tumor and no vascular invasion or extrahepatic spread.

Identifying optimal candidates of transarterial chemoembolization (TACE) vs. sorafenib in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Sorafenib has been recommended as the first-line treatment and shown to prolong median overall survival (OS) of patients with advanced unresectable hepatocellular carcinoma (HCC). Recently, a growing amount of research has supported the application of transarterial chemoembolization (TACE) in patients with advanced-stage HCC. The aim of this study was to compare the outcomes of TACE and sorafenib and identify the prognostic factors related to OS for Barcelona Clinic Liver Cancer (BCLC) stage C patients with PS 1 but without vascular invasion or extrahepatic spread. METHODS: A total of 323 consecutive patients in BCLC stage C with PS 1 but without vascular invasion or extrahepatic spread were enrolled in this retrospective study. Survival analyses were performed using the Kaplan-Meier analysis, and the statistical differences between the TACE and sorafenib groups were examined by the log-rank test. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic factors for OS. RESULTS: Based on the Kaplan-Meier curves, patients treated with TACE showed a better OS than those undergoing sorafenib, with respective OS at 1, 3, and 5 years (67.7%, 41.5%, 23.2% vs. 55.6%, 29.6%, 4.8%; log-rank P=0.002). The univariate analysis indicated that tumor size, tumor number, and treatment method, along with platelet (PLT), white blood cell (WBC), and α-fetoprotein (AFP) count, were associated with OS. The multivariate analysis demonstrated that tumor size, tumor number, and treatment method were significant prognostic factors for OS. According to the subgroups analyses based on the tumor size and tumor number, there were significant differences in OS among overall subsets between TACE and sorafenib therapy. CONCLUSIONS: TACE provided better prognostic performance than sorafenib and should be suggested as an alternative treatment modality to sorafenib for BCLC stage C patients with PS 1 but without vascular invasion or extrahepatic spread.

The diagnostic value of the combination of Golgi protein 73, glypican-3 and alpha-fetoprotein in hepatocellular carcinoma: a diagnostic meta-analysis.

BACKGROUND: Alpha-fetoprotein (AFP) has been extensively applied in clinical practice to detect and predict postoperative outcomes of patients with hepatocellular carcinoma (HCC). However, due to its low sensitivity and specificity, its efficacy has been questioned. Recently, novel serum biomarkers including Golgi protein 73 (GP73) and glypican-3 (GPC-3) have shown a better discriminatory ability than AFP in detecting early HCC. The results of the combined use of GP73, GPC-3 and AFP in the diagnosis of HCC remain inconclusive. This investigation aimed to evaluate the discriminatory ability of GP73, GPC-3 and AFP to jointly identify HCC using the statistical methods of meta-analysis. METHODS: Comprehensive database searches of, Web of Science, the Cochrane Library, Embase, the Chinese Biomedical Literature Database, and the China National Knowledge Infrastructure were performed for literature dated up to 1 November, 2019. Studies relating to the diagnostic accuracy of the combination of GP73, GPC-3 and AFP in the identification of HCC were included. A random-effects model was used to pool sensitivity, specificity, the positive and negative likelihood ratios [positive likelihood ratio (PLR) and negative likelihood ratio (NLR), respectively], and the diagnostic odds ratio (DOR). We applied the Fagan nomogram to assess the clinical utility of joint detection. The overall detection accuracy was determined using summary receiver operating characteristic curve (SROC) analysis. Meta-regression analysis of heterogeneity publication bias was analyzed with Stata (version 12.0). RESULTS: Our meta-analysis focused on 12 studies involving 919 patients with HCC and 1,549 non-HCC patients. Sensitivity, specificity, PLR, NLR and DOR for joint detection, were 0.91 (95% CI: 0.87-0.94), 0.84 (95% CI: 0.77-0.89), 5.83 (95% CI: 4.05-8.40), 0.10 (95% CI: 0.07-0.15), 57.51 (95% CI: 35.92-92.08), respectively, when pooled, and the area under the SROC curve was 0.95. CONCLUSIONS: Current evidence indicates that GP73, GPC-3 and AFP exhibit much better accuracy for the diagnosis of HCC when used in combination rather than alone or in pairs.

Comparison of albumin-bilirubin grade versus Child-Pugh score in predicting the outcome of transarterial chemoembolization for hepatocellular carcinoma using time-dependent ROC.

BACKGROUND: The Child-Pugh score has been used extensively to assess hepatic function and predict post-treatment outcomes in patients with hepatocellular carcinoma (HCC). Recently, the albumin-bilirubin (ALBI) grade has been put forward as an objective method of evaluating liver function and predicting overall survival (OS) in HCC patients. Transarterial chemoembolization (TACE) is considered to be effective in prolonging OS among intermediate-stage HCC patients. This study aimed to explore and compare the performance of ALBI grade and Child-Pugh score in predicting outcomes for HCC patients who underwent TACE. METHODS: There were a total of 221 consecutive HCC patients enrolled in this study, all of whom received TACE and were enrolled retrospectively. The Kaplan-Meier method and time-dependent receiver operating curves (ROC) were used to estimate the discriminatory ability and survival prediction accuracy of ALBI grade and Child-Pugh score in predicting postoperative OS. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic factors for OS. RESULTS: Of the patients enrolled in the study, 106 (48.0%) were ALBI grade 1 and 115 (52.0%) were ALBI grade 2. Overall survival differed significantly between patients with ALBI-1 and ALBI-2 [hazard ratio (HR), 3.032; 95% CI, 2.019-4.555, P<0.001]. With regard to Child-Pugh scores, 160 (72.4%) patients had a score of A5 and 61 (27.6%) had a score of A6. There was also a difference in overall survival between patients with Child-Pugh-A5 and Child-Pugh-A6 (HR, 1.548; 95% CI, 1.066-2.247, P=0.022). In multivariate analyses, both ALBI grade and Child-Pugh score could significantly stratify the patients with different OS (HR, 2.994 and 1.545, P<0.001 and P=0.026 for ALBI grade and Child-Pugh score, respectively). Furthermore, time-dependent ROC analysis and its subgroup analyses demonstrated that the ALBI grade had a better discriminatory ability than Child-Pugh score in predicting survival. CONCLUSIONS: In stratifying prognosis for HCC patients who had received TACE therapy, the ALBI grade provided better prognostic performance and discrimination of liver function than Child-Pugh score. These results suggest that ALBI grade could provide an alternative liver function grading system for stratification of patients with HCC.

Efficacy evaluation of the combination therapy of sorafenib and transarterial chemoembolization for unresectable HCC: a systematic review and meta-analysis of comparative studies.

BACKGROUND: Sorafenib and transarterial chemoembolization (TACE) are the standard treatments recommended by guidelines for unresectable hepatocellular carcinoma (HCC). Although previous studies have shown the combination therapy of sorafenib and TACE to be safe, there is no consensus regarding its efficacy. This systematic review and meta-analysis, which was based on the findings of comparative clinical trials, was conducted to provide up-to-date and comprehensive information about the efficacy of combination therapy versus TACE monotherapy in unresectable HCC. METHODS: Multiple databases were systematically reviewed to screen studies through particular inclusion criteria. Hazard ratio (HR) with 95% confidence intervals (95% CIs) was collected and analyzed by Revman 5.3 in a fixed or random effects meta-analysis model. Adverse events (AEs) were also evaluated. RESULTS: This review ultimately included 14 comparative studies focused on combination therapy versus TACE monotherapy. Of these: 5 studies conducted TACE plus sorafenib versus TACE with placebo; 9 studies provided overall survival (OS) in combination groups which ranged from 10.3 to 29.7 months; and 10 studies provided time to progression (TTP) in combination groups which ranged from 2.6 to 10.8 months. The disease control rate (DCR) in combination groups ranged from 9.7% to 89.2% in 7 of the studies. After performing a random effects meta-analysis model, our study showed that OS (HR =0.65, 95% CI: 0.54-0.79, P<0.0001) and TTP (HR =0.72, 95% CI: 0.59-0.88, P=0.001) have been significantly improved in the combination therapy group when compared with the TACE monotherapy group. AEs mainly included hand-foot skin reaction (HFSR), fatigue and diarrhea and the majority of these were in grade 1 or grade 2. CONCLUSIONS: Combination therapy has significant advantages over TACE monotherapy in terms of improving TTP and OS.