Survival Outcomes In Hepatocellular Carcinoma Patients Research Articles

Survival Outcome and Prognostic Factors Among Patients With Hepatocellular Carcinoma: A Hospital-Based Study

Background: Hepatocellular carcinoma (HCC) is a leading cancer with very high incidence and mortality and low survival rate in Vietnam and worldwide. This study aimed to investigate the survival outcome and its prognostic factors among HCC patients. Methods: This is a retrospective descriptive study on patients newly diagnosed with HCC at Hanoi Oncology Hospital, Vietnam from January 2018 to December 2020. Overall survival (OS) was calculated by the Kaplan-Meier method. Log-rank test and Cox regression were used to investigate the association among patients’ OS and their diagnosis and treatment factors. Results: A total of 674 patients were included. The median OS was 10.0 months. The survival rates at 6, 12, 24, and 36 months were 57.3%, 46.6%, 34.8%, and 29.7%, respectively. The initial performance status (PS), Child-Pugh score, and Barcelona Clinic Liver Cancer (BCLC) stage at the time of diagnosis are prognostic factors of HCC OS. A total of 451 (66.8%) patients have died, most of them (375 equally 83.1%) died at home, and only 76 (16.9%) died at hospital. Hepatocellular carcinoma patients living in the rural area more likely died at home than those living in the urban area (85.9% vs 74.8%, P = .007). Conclusions: Hepatocellular carcinoma has a poor prognosis with low OS. Performance status, Child-Pugh score, and BCLC stage were the independent prognostic factors for the survival outcome of HCC patients. The fact that most HCC patients died at home suggested that home-based hospice care needs to be paid special attention.

Integrated analysis of ferroptosis-related gene signature for overall survival prediction in Asian patients with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent types of cancers in Asia. Accumulating evidence suggests that ferroptosis is a non-apoptotic form of cell death, and has played an important role in cancer biology. Based on the manually curated ferroptosis-related gene set and TCGA-LIHC dataset of Asian patients, we used DESeq2, Kaplan-Meier analysis, and univariate Cox regression to identify differentially expressed ferroptosis-related genes with significantly prognostic capacity. A risk signature was constructed based on the selected genes for predicting the survival of HCC patients in Asia. The survival prediction accuracy was confirmed by the time-dependent receiver operating characteristic (ROC) curve analysis. Gene set variation analysis (GSVA) was used to explore the functional associations of the signature. Ferroptosis potential index (FPI) and xCell algorithm was applied to quantify ferroptosis and immune cell infiltration, respectively. Two independent datasets from the GEO and the ICGC database were used for external validation. The ferroptosis-related signature could accurately predict the survival outcomes of HCC patients in Asian (p value < 0.0001). We showed that the signature was an independent factor and was beneficial in elevating risk stratification of current clinicopathologic features, such as the amount of alpha-fetoprotein (AFP) and residual tumor classification. Functional characterization showed that critical processes in tumorigenesis belonged to the high-risk groups, for example inflammatory response, which may be the main driver of HCC. The high-risk group had higher FPIs and infiltrations of macrophages and T-helper cells than the low-risk group. Furthermore, two independent cohorts confirmed the prognostic value of our signature. Overall, our results demonstrated potential application of ferroptosis-related genes as independent biomarkers in Asian HCC patients. Targeting ferroptosis may be clinically useful beyond known clinicopathological factors and provide benefit in immunotherapy.

LncRNA THAP9-AS1 highly expressed in tissues of hepatocellular carcinoma and accelerates tumor cell proliferation

BackgroundLong noncoding RNAs (lncRNAs) are emerging as significant regulators of cancer development. The purposes of study were to analyze the expression levels of long noncoding RNA THAP9-AS1 (THAP9-AS1) in hepatocellular carcinoma (HCC) tissue samples and cell lines, evaluate the clinical significance of THAP9-AS1 in predicting the survival prognosis of HCC patients, and explore the biological function of THAP9-AS1 in regulating tumor progression of HCC. MethodsThe expression of THAP9-AS1 was determined by quantitative real-time PCR. The determination of HCC cell proliferation was performed using cell counting kit-8 assay. Chi-square test was used to reveal the relationship between THAP9-AS1 and clinicopathological data of HCC patients. Kaplan-Meier method, log-rank test were used to perform analyze the relationship between THAP9-AS1 and prognostic survival in HCC patients. Cox regression was used to evaluate the abilities of THAP9-AS1 to predict survival outcomes in HCC patients. ResultsThe expression of THAP9-AS1 were markedly upregulated in HCC tissue and cells. THAP9-AS1 expression was correlated with tumor size, tumor node metastasis (TNM) stage. High THAP9-AS1 expression was associated with poor prognostic survival in HCC patients. THAP9-AS1 was an independent prognostic factor for HCC patients. Overexpression of THAP9-AS1 promoted HCC cell proliferation, silencing THAP9-AS1 inhibited HCC cell proliferation. ConclusionAberrantly highly expressed THAP9-AS1 in HCC tissues and cells was associated with tumor size, TNM stage and poor survival prognosis, and promoted HCC cell proliferation. THAP9-AS1 had the potential to serve as independent prognostic biomarker for HCC patients and provide a novel target for HCC patients’ prognostic treatment.

Surgical Resection of a Recurrent Hepatocellular Carcinoma with Portal Vein Thrombosis: Is It a Good Treatment Option? A Case Report and Systematic Review of the Literature.

Background: Hepatocellular carcinoma (HCC) is the sixth most frequent diagnosed tumor worldwide and the third leading cause of cancer related death. According to the EASL Guidelines, HCC with portal vein tumor thrombosis (PVTT) is classified as an advanced stage (BCLC stage C) and the only curative option is represented by systemic therapy. Therefore, treatment of HCC patients with PVTT remains controversial and debated. In this paper, we describe the case of a 66-year-old man with a recurrent HCC with PVTT who underwent surgical resection. A systematic review of the literature, comparing surgical resection with other choices of treatment in HCC patients with PVTT, is reported. Methods: A systematic review of the literature regarding all prospective and retrospective studies comparing the survival outcomes of HCC patients with PVTT treated with surgical resections (SRs) or other non-surgical treatments (n-SRs) has been conducted. Case presentation: A 66-year-old Caucasian man with a history of Hepatitis C Virus (HCV) related liver cirrhosis and previous hepatocellular carcinoma of the VI segment treated with percutaneous ethanol infusion (PEI) seven years before presented to our clinics. A new nodular hypoechoic lesion in the VI hepatic segment was demonstrated on follow-up ultrasound examination. A hepatospecific magnetic resonance imaging (MRI) scan confirmed also the presence of a 18 × 13 mm nodular lesion in the V hepatic segment with satellite micronodules associated with V–VIII sectoral portal branch thrombosis. The case was then discussed at the multidisciplinary team meeting, and it was decided to perform a right hepatectomy. The postoperative course was regular and uneventful, and the discharge occurred seven days after the surgery. At eight-month follow-up, there was no clinical nor radiological evidence of neoplastic recurrence, with well-preserved liver function (Child-Pugh A5). Results: Nine studies were included in the review. Median Overall Survaival (OS) ranged from 8.2 to 30 months for SRs patients and from 7 to 13.3 for n-SRs patients. In SR patients, one-year survival ranged from 22.7% to 100%, two-year survival from 9.8% to 100%, and three-year survival from 0% to 71%. In n-SRs patients, one-year survival ranged from 11.8% to 77.6%, two-year survival from 0% to 47.8%, and three-year survival from 0% to 20.9%. Conclusion: The present systematic literature review and the case presented demonstrated the efficacy of surgery as a first-line treatment in well-selected HCC patients with PVTT limited or more distal to the right and left portal branches. However, further studies, particularly randomized trials, need to be conducted in future to better define the surgical indications.

Multi-omics data integration for hepatocellular carcinoma subtyping with multi-kernel learning.

Hepatocellular carcinoma (HCC) is a leading malignant liver tumor with high mortality and morbidity. Patients at the same stage can be defined as different molecular subtypes associated with specific genomic disorders and clinical features. Thus, identifying subtypes is essential to realize efficient treatment and improve survival outcomes of HCC patients. Here, we applied a regularized multiple kernel learning with locality preserving projections method to integrate mRNA, miRNA and DNA methylation data of HCC patients to identify subtypes. We identified two HCC subtypes significantly correlated with the overall survival. The patient 3-years mortality rates in the high-risk and low-risk group was 51.0% and 23.5%, respectively. The high-risk group HCC patients were 3.37 times higher in death risk compared to the low-risk group after adjusting for clinically relevant covariates. A total of 196 differentially expressed mRNAs, 2,151 differentially methylated genes and 58 differentially expressed miRNAs were identified between the two subtypes. Additionally, pathway activity analysis showed that the activities of six pathways between the two subtypes were significantly different. Immune cell infiltration analysis revealed that the abundance of nine immune cells differed significantly between the two subtypes. We further applied the weighted gene co-expression network analysis to identify gene modules that may affect patients prognosis. Among the identified modules, the key module genes significantly associated with prognosis were found to be involved in multiple biological processes and pathways, revealing the mechanism underlying the progression of HCC. Hub gene analysis showed that the expression levels of CDK1, CDCA8, TACC3, and NCAPG were significantly associated with HCC prognosis. Our findings may bring novel insights into the subtypes of HCC and promote the realization of precision medicine.

Endoplasmic Reticulum Stress-Related Signature for Predicting Prognosis and Immune Features in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) with cancer cells under endoplasmic reticulum (ER) stress has a poor prognosis. This study is aimed at discovering credible biomarkers for predicting the prognosis of HCC based on ER stress-related genes (ERSRGs). We constructed a novel four-ERSRG prognostic risk model, including PON1, AGR2, SSR2, and TMCC1, through a series of bioinformatic approaches, which can accurately predict survival outcomes in HCC patients. Higher risk scores were linked to later grade, recurrence, advanced TNM stage, later T stage, and HBV infection. In addition, 20 fresh frozen tumors and normal tissues from HCC patients were collected and used to validate the genes expressed in the signature by qRT-PCR and immunohistochemical (IHC) assays. Moreover, we found the ER stress-related signature could reflect the infiltration levels of different immune cells in the tumor microenvironment (TME) and forecast the efficacy of immune checkpoint inhibitor (ICI) treatment. Finally, we created a nomogram incorporating this ER stress-related signature. In conclusion, our constructed four-gene risk model associated with ER stress can accurately predict survival outcomes in HCC patients, and the model's risk score is associated with the poor clinical classification.

A Novel Epithelial-Mesenchymal Transition Gene Signature Correlated With Prognosis, and Immune Infiltration in Hepatocellular Carcinoma

Background: Although many genes related to epithelial-mesenchymal transition (EMT) have been explored in hepatocellular carcinoma (HCC), their prognostic significance still needs further analysis. Methods: Differentially expressed EMT-related genes were obtained through the integrated analysis of 4 Gene expression omnibus (GEO) datasets. The univariate Cox regression and Lasso Cox regression models are utilized to determine the EMT-related gene signature. Based on the results of multivariate Cox regression, a predictive nomogram is established. Time-dependent ROC curve and calibration curve are used to show the distinguishing ability and consistency of the nomogram. Finally, we explored the correlation between EMT risk score and immune immunity. Results: We identified a nine EMT-related gene signature to predict the survival outcome of HCC patients. Based on the EMT risk score’s median, HCC patients in each dataset were divided into high and low-risk groups. The survival outcomes of HCC patients in the high-risk group were significantly worse than those in the low-risk group. The prediction nomogram based on the EMT risk score has better distinguishing ability and consistency. High EMT risk score was related to immune infiltration. Conclusion: The nomogram based on the EMT risk score can reliably predict the survival outcome of HCC patients, thereby providing benefits for medical decisions.

The nociceptin receptor promotes autophagy through NF-kB signaling and is transcriptionally regulated by E2F1 in HCC

Opioids and their receptors are involved in cancer progression. However, the roles of the nociceptin receptor (NOP) and its antagonist (JTC801) in hepatocellular carcinoma (HCC) are poorly understood. The prognostic value of NOP expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human HCC cohort. The biological role and mechanism of NOP in HCC tumor growth were determined in vitro and in vivo. We found that NOP was associated with the clinicopathological features and survival outcomes of HCC patients. NOP overexpression promoted HCC growth in vitro and in vivo. Mechanistically, NOP activated NF-kB signaling to promote autophagy, which inhibited apoptosis, in HCC cells. An inhibitor of autophagy, 3-MA, and an inhibitor of NF-kB, JSH-23, attenuated the function of NOP in HCC. E2F1 was identified as a transcription factor of NOP. The oncogenic role of NOP was positively regulated by E2F1. Furthermore, JTC801, a selective antagonist of NOP, abolished the function of NOP by inhibiting NF-kB signaling and autophagy. Our study demonstrates that NOP is an oncogene in HCC. We provide a potential therapeutic candidate and prognostic predictor for HCC. JTC801 could become a potential drug for HCC therapy.

NLRC3 High Expression Represents a Novel Predictor for Positive Overall Survival Correlated With CCL5 and CXCL9 in HCC Patients.

NLRC3 (NLR family caspase recruitment domain containing 3) has been reported as a factor of inhibiting inflammatory responses. It’s role in HCC (hepatocellular carcinoma) is still unknown. In this study we firstly used the GEO (Gene Expression Omnibus) database and mIHC (multiple immunohistochemical analysis) with TMAs (tumor tissue microarrays) of HCC patients to evaluate NLRC3 levels. The tumor-bearing mouse models were also established with NLRC3 over-expressing and knock-down Hepal-6 cells to assess its effect. The data showed high NLRC3 expression was related with favorable overall survival (P=0.0386) and disease-free survival (P=0.0458). In addition, NLRC3 expression showed a positive correlation between CD8+ T cells infiltration. In vivo, NLRC3-overexpressing Hepal-6 tumors showed increased CD8+ T cell infiltration. NLRC3-knockdown Hepa1-6 tumors displayed decreased CD8+ T cell infiltration. At the same time, we also found the positive correlations between NLRC3 and CCL5 (C-C motif chemokine ligand 5, P<0.0001, R2 = 0.2372) as well as CXCL9 (C-X-C motif chemokine ligand 9, P<0.0001, R2 = 0.2338) expressions. So NLRC3 high expression represents a novel predictor for positive survival outcomes in HCC patients, and NLRC3 is involved in CD8+ T cell infiltration, which is correlated with increased CCL5 and CXCL9 in TME (tumor microenvironment). This study implies that boosting NLRC3 is a promising treatment to enhance survival in HCC patients.

Association of Preoperative Coagulability With Incidence and Extent of Portal Vein Tumor Thrombus and Survival Outcomes in Hepatocellular Carcinoma After Hepatectomy: A Large-Scale, Multicenter Study.

BackgroundOccurrence of portal vein tumor thrombus (PVTT) worsens the outcomes of hepatocellular carcinoma (HCC) and imparts high economic burden on society. Patients with high risks of having hypercoagulation are more likely to experience thrombosis. Herein, we examined how preoperative international normalized ratio (INR) was related to the incidence and extent of PVTT, and associated with survival outcomes in HCC patients following R0 liver resection (LR).MethodsPatients with HCC and PVTT were enrolled from six major hospitals in China. The overall survival (OS) and recurrence-free survival (RFS) rates of individuals with different INR levels were assessed with Cox regression analysis as well as Kaplan-Meier method.ResultsThis study included 2207 HCC patients, among whom 1005 patients had concurrent PVTT. HCC patients in the Low INR group had a significantly higher incidence of PVTT and more extensive PVTT than the Normal and High INR groups (P<0.005). Of the 592 HCC subjects who had types I/II PVTT following R0 LR, there were 106 (17.9%), 342 (57.8%) and 144 (24.3%) patients in the High, Normal and Low INR groups, respectively. RFS and OS rates were markedly worse in patients in the Low INR group relative to those in the Normal and High INR groups (median RFS, 4.87 versus 10.77 versus 11.40 months, P<0.001; median OS, 6.30 versus 11.83 versus 12.67 months, P<0.001).ConclusionPreoperative INR influenced the incidence and extent of PVTT in HCC. Particularly, patients with HCC and PVTT in the Low INR group had worse postoperative prognosis relative to the High and Normal INR groups.

Distant survival for patients undergoing surgery using volatile versus IV anesthesia for hepatocellular carcinoma with portal vein tumor thrombus: a retrospective study

BackgroundWhether anesthesia type is associated with the surgical outcome of Hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) remains to be determined. This study aims to investigate the impact of volatile inhalational anesthesia (INHA) versus total IV anesthesia (TIVA) on the survival outcomes in HCC patients with PVTT.MethodsA cohort of in-patients whom were diagnosed of HCC with PVTT in Eastern Hepatobiliary Surgery Hospital, Shanghai, China, from January 1, 2008 to December 24, 2012 were identified. Surgical patients receiving the INHA and TIVA were screened out. The overall survival (OS), recurrence-free survival (RFS) and several postoperative adverse events were compared according to anesthesia types.ResultsA total of 1513 patients were included in this study. After exclusions are applied, 263 patients remain in the INHA group and 208 in the TIVA group. Patients receiving INHA have a lower 5-year overall survival rate than that of patients receiving TIVA [12.6% (95% CI, 9.0 to 17.3) vs. 17.7% (95% CI, 11.3 to 20.8), P = 0.024]. Results of multivariable Cox-regression analysis also identify that INHA anesthesia is significantly associated with mortality and cancer recurrence after surgery compare to TIVA, with HR (95%CI) of 1.303 (1.065, 1.595) and 1.265 (1.040, 1.539), respectively. Subgroup analysis suggested that in more severe cancer patients, the worse outcome related to INHA might be more significant.ConclusionThis retrospective analysis identifies that TIVA is associated with better outcomes compared with INHA. Future prospective studies clinical and translational studies are required to verify this difference and investigate underlying pathophysiology.

Characterization of Hepatocellular Carcinoma Cell Lines Using a Fractionation-Then-Sequencing Approach Reveals Nuclear-Enriched HCC-Associated lncRNAs.

Background: Advances in sequencing technologies have greatly improved our understanding of long noncoding RNA (lncRNA). These transcripts with lengths of >200 nucleotides may play significant regulatory roles in various biological processes. Importantly, the dysregulation of better characterized lncRNAs has been associated with multiple types of cancers, including hepatocellular carcinoma (HCC). There are many studies on altered lncRNA expression levels, very few, however, have focused on their subcellular localizations, from which accumulating evidences have indicated their close relationships to lncRNA functions. A transcriptome-wide investigation of the subcellular distributions of lncRNAs might thus provide new insights into their roles and functions in cancers. Results: In this study, we subjected eight patient-derived HCC cell lines to subcellular fractionation and independently sequenced RNAs from the nuclear and cytoplasmic compartments. With the integration of tumor and tumor-adjacent RNA-seq datasets of liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas (TCGA), de novo transcriptome assembly and differential expression analysis were conducted successively and identified 26 nuclear-enriched HCC-associated lncRNAs shared between the HCC samples and the TCGA datasets, including the reported cancer driver PXN-AS1. The majority of nuclear-enriched HCC-associated lncRNAs were associated with the survival outcomes of HCC patients, exhibited characteristics similar to those of many experimentally supported HCC prognostic lncRNAs, and were co-expressed with protein-coding genes that have been linked to disease progression in various cancer types. Conclusion: We adopted a fractionation-then-sequencing approach on multiple patient-derived HCC samples and identified nuclear-enriched, HCC-associated lncRNAs that could serve as important targets for HCC diagnosis and therapeutic development. This approach could be widely applicable to other studies into the disease etiologies of lncRNA.

MIR22HG As A Tumor Suppressive lncRNA In HCC: A Comprehensive Analysis Integrating RT-qPCR, mRNA-Seq, And Microarrays.

IntroductionMIR22HG has a reported involvement in the tumorigenesis of a variety of cancers, including hepatocellular carcinoma (HCC). However, the exact molecular mechanism of MIR22HG in HCC has not been clarified.MethodsIn the present study, we integrated data from in-house RT-qPCR, RNA-sequencing, microarray, and literature studies to conduct a comprehensive evaluation of the clinico-pathological and prognostic significance of MIR22HG in an extremely large group of HCC samples. We also explored the potential mechanism of MIR22HG in HCC by analyzing the alteration profiles of MIR22HG in HCC to predict transcription factors (TFs) that may interact with MIR22HG and to annotate the biological functions of genes co-expressed with MIR22HG. MIR22HG expression was also compared in HCC nude mice xenografts before and after a treatment with nitidine chloride.ResultsWe found that MIR22HG was downregulated in HCC and that this downregulation correlated with the malignant phenotype of HCC. Comprehensive analysis of the prognostic impact of MIR22HG in HCC revealed a beneficial effect of MIR22HG on the survival outcome of HCC patients. Seven cases of MIR22HG deep deletion occurred in 360 of the cancer genome atlas (TCGA) provisional HCC samples. A total of 22 MIR22HG-TF-mRNA triplets in HCC were predicted by the lncRNAmap. Co-expressed genes of MIR22HG, identified by weighted correlation network analysis (WGCNA), mainly participated in the pathways involving osteoclast differentiation, chemokine signaling pathways, and hematopoietic cell lineage. In vivo experiments demonstrated that nitidine chloride could stimulate MIR22HG expression in HCC xenografts.ConclusionIn summary, MIR22HG may play a tumor-suppressive role in HCC by coordinating with predicted TFs and co-expressed genes, such as NLRP3, CSF1R, SIGLEC10, and ZEB2, or by being controlled by nitidine chloride.

4-1BB Delineates Distinct Activation Status of Exhausted Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma.

Background and AimsTargeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8+ T cells (CD8+ tumor‐infiltrating lymphocytes [TILs]) and its association with distinct T‐cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC).Approach and ResultsTumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8+ TILs. 4‐1BB expression was almost exclusively detected on CD8+ T cells in the tumor—especially on programmed death 1 (PD‐1)high cells and not PD‐1int and PD‐1neg cells. Compared to PD‐1int and 4‐1BBnegPD‐1high CD8+ TILs, 4‐1BBposPD‐1high CD8+ TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1high CD8+ TILs, 4‐1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T‐cell activation.Conclusion4‐1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.

744P - Predictive value of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) In hepatocellular carcinoma (HCC) patients treated with nivolumab (N)

BackgroundCurrently there are no recognized or validated biomarkers to identify HCC patients(pts) likely to benefit from N. Several studies have established the inverse relationship between inflammation-based scores such as NLR, PLR and survival in other solid tumours treated with immunotherapy. We evaluated the relationship between NLR and PLR and survival outcomes in HCC pts treated with N at Mount Sinai Hospital. MethodsOne hundred and four HCC pts treated between June 2016 and July 2018 were identified. NLR=Absolute neutrophil count/ Absolute lymphocyte count (ALC) and was calculated pretreatment and at 6-8 weeks after 3 doses (Posttreatment) of N. PLR=Platelet count/ALC. Kaplan-Meier analysis and the log-rank test were used to calculate and compare Overall and Progression free survival (OS, PFS) between NLR <5 vs≥5 and among PLR tertiles. ResultsMedian age was 66 (29-89) years. Median treatment duration was 26 (2-149) weeks. Child Pugh score (CPS, N=96) was A in 64 (66%) and B in 32 (33%) pts. Barcelona Clinic Liver Cancer (BCLC) stage was B in 21 (20%) and C in 83 (80%) pts. Median follow-up time was 17 months (95% CI (15.7, 20.7). NLR was <5 in 64 (62%) pts pretreatment and 59 (60%) pts post treatment. NLR<5 was associated with improved OS compared to NLR≥5 both pretreatment (23 Vs 10 months, P=0.0037) and post treatment (35 Vs 9 months, P<0.0001). Survival also differed significantly among PLR tertiles (Table), with median OS for the lowest post treatment tertile not yet reached. Median PFS differed significantly between pre (16 Vs 5 months, P=0.0217) and post (35 Vs 5 months, P=0.0002) treatment NLR. PLR was not significantly associated with PFS. In a multivariable model, port treatment PLR and NLR were significantly associated with OS.Table744PTablePretreatment PLR groupN(%)OS (months)< 11936(36)35P=0.0495>= 119 & < 22432(31)10>= 22433(33)15Post treatment PLR group< 12635(35)Not ReachedP=0.0126>= 126 & < 22931(31)19>= 22933(33)10 ConclusionsThis study suggests that lower NLR and PLR levels may predict better survival outcomes in HCC patients treated with N. The potential role of NLR and PLR as early predictors of immunotherapy outcomes in HCC pts warrants further evaluation. Legal entity responsible for the studyMount Sinai Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Preoperative serum ferritin is an independent prognostic factor for liver cancer after hepatectomy

Background and aimsSerum ferritin (SF) may have a close relationship with the tumor. But no study has investigated the prognostic value of SF in hepatocellular carcinoma (HCC) patients receiving curative resection yet. Aim of this study is to explore the role of preoperative SF in survival outcomes of such patients. MethodsWe retrospectively analyzed 427 HCC patients who received curative hepatic resection in our medical center. Significant clinical and pathological data along with the association between SF and clinicopathological parameters were compared and analyzed. The prognostic significance of SF was determined by Kaplan-Meier analysis and the Cox proportional hazards regression model. ResultsThe optimal cut-off value of SF for overall survival (OS) was 267 ng/ml. Preoperative SF level could predict OS (P = 0.001, HR = 1.651, 95%CI: 1.213–2.247) and recurrence-free survival (RFS) (P < 0.001, HR = 1.570, 95%CI: 1.221–2.018) independent of other prognostic factors. Patients with a low SF were more likely to have both favorable OS and RFS (both P < 0.001), and vice versa. The 1-, 3-, and 5-year OS and RFS rates were 91.4%, 80.1%, 71.7%, and 78.0%, 53.0%, 47.3% in low SF group, and 91.6%, 60.2%, 45.2%, and 61.3%, 36.4%, 29.0% in high SF group, respectively. ConclusionsPreoperative SF was a simple, inexpensive, convenient and reliable prognostic factor that could predict survival outcomes in HCC patients who received radical hepatic resection.

High PGAM5 expression induces chemoresistance by enhancing Bcl-xL-mediated anti-apoptotic signaling and predicts poor prognosis in hepatocellular carcinoma patients

Hepatocellular carcinoma (HCC) is the one of most common and deadly cancers, and is also highly resistant to conventional chemotherapy treatments. Mitochondrial phosphoglycerate mutase/protein phosphatase (PGAM5) regulates mitochondrial homeostasis and cell death, however, little is known about its roles in cancer. The aim of this study was to explore the clinical significance and potential biological functions of PGAM5 in hepatocellular carcinoma. For the first time, our results show that PGAM5 is significantly upregulated in HCC compared with corresponding adjacent noncancerous hepatic tissues and high PGAM5 expression is an independent predictor of reduced survival times in both univariate and multivariate analyses. Additionally, in vivo and in vitro studies showed that depleting PGAM5 expression inhibited tumor growth and increased the 5-fluorouracil sensitivity of HCC cells. Conversely, restoring PGAM5 expression in PGAM5-knockdown cells dramatically enhanced HCC cell resistance to 5-fluorouracil. Importantly, we demonstrated that the mechanism of 5-fluorouracil resistance conferred to HCC cells by PGAM5 was via inhibiting BAX- and cytochrome C-mediated apoptotic signaling by interacting and stabilizing Bcl-xL. Consistently, in the same cohorts of HCC patient tissues, Bcl-xL expression was positively correlated with PGAM5, and together predicted poor prognoses. In Conclusion, Our data highlight the molecular etiology and clinical significance of PGAM5 in HCC. Targeting the novel signaling pathway mediated by PGAM5/Bcl-xL may represent a new therapeutic strategy to improve the survival outcomes of HCC patients.

Prognostic role of neutrophil-to-lymphocyte ratio in unresectable hepatocellular cancer patients treated with trans-arterial chemoembolization

The neutrophil-to-lymphocyte ratio (NLR), a useful biomarker, reflects systemic inflammation responses which are closely associated with the prognosis of various malignancies. Nevertheless, the prognostic significance of NLR in patients with hepatocellular carcinoma (HCC) undergoing trans-arterial chemoembolization (TACE) remains controversial. The study was designed to determine the prognostic value of NLR in survival outcomes of HCC patients receiving TACE by systematical review of present literature. Medline, Embase, Web of Science and Cochrane library databases were searched according to a pre-specified inclusive strategy to identify studies concerning survival in HCC patients receiving TACE with high or low pre- or post-TACE NLR. An electronic Excel table was used to extract epidemiological information, clinical pathological characteristics as well as primary outcome data. Initially, 598 relevant articles were selected, of which, 13 articles including 1,648 unresectable HCC patients undergoing TACE were ultimately enrolled. Our review and meta-analysis demonstrated that a high pre-TACE NLR reflected unfavorable overall survival (OS) [pooled hazard ratio (HR): 1.53, pooled 95% confidence interval (CI): 1.29–1.78, P 0.05) and tumor response (P=0.088). A high post-TACE NLR was closely associated with metastasis (OR: 1.57, 95% CI: 0.732–3.382, P=0.246), but not with time to progression (TTP) (P=0.18) and tumor response (P=0.229), and controversial role with OS (P value: 0.001 vs . 0.342). The NLR change trend between pre-and post-TACE was not correlated with either tumor response to TACE (P=0.89) or hepatic progression (P=0.55), whereas its prognostic role with OS was also controversial (P>0.05 or <0.05). As a convenient, inexpensive and easily available inflammatory biomarker, NLR harbored its important value in prognostic prediction in patients with unresectable HCC undergoing TACE. However, the association of the changing trends of NLR and NLR at different stages with different prognostic endpoints in HCC patients undergoing TACE was still in controversy, therefore further large-scale, prospective studies are needed to confirm these findings.

Should transarterial chemoembolization be given before or after intensity-modulated radiotherapy to treat patients with hepatocellular carcinoma with portal vein tumor thrombus? a propensity score matching study.

Background and ObjectiveTo compare the survival outcomes of patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) who received transarterial chemoembolization (TACE) before or after intensity-modulated radiotherapy (IMRT).MethodsDuring the study period, the survival outcomes of HCC patients with PVTT who underwent TACE before (TACE-RT) or after IMRT (RT-TACE) were compared. Using propensity score matching (PSM), matched pairs of patients were compared.ResultsThere were 76 patients in the TACE-RT group and 36 patients in the RT-TACE group. Using a 2:1 matching, 75 patients were included into this study after PSM: 50 patients in the TACE-RT group and 25 patients in the RT-TACE group. Before PSM, patients in the RT-TACE group showed significantly better survival when compared with the TACE-RT group (median survival, 13.2 months vs.7.4 months; P = 0.014) for patients with main trunk PVTT, and after PSM, the corresponding median survival was 13.2 months vs.7.4 months (P = 0.020). When compared with TACE-RT, RT-TACE had a significantly lower rate of worsening in liver function (9.5% vs. 33.3%, P = 0.044) for patients with main trunk PVTT.ConclusionsFor HCC patients with main trunk PVTT, IMRT followed by TACE yielded better survival outcomes and liver function when compared to TACE followed by IMRT.

NEK2 promotes hepatocellular carcinoma migration and invasion through modulation of the epithelial-mesenchymal transition.

Never in mitosis gene-A (NIMA)-related expressed kinase 2 (NEK2) has been recently reported to play a role in tumor progression, drug resistance and tumorigenesis. However, little is known about the effects of NEK2 in hepatocellular carcinoma (HCC) metastasis and the underlying mechanism. NEK2 expression levels were examined by immunochemistry, qRT-PCR and western blot analyses in HCC cell lines and HCC tissues. A Transwell assay was used to determine the migration and invasion capacity of NEK2-silenced or NEK2-overexpressing HCC cells. Cell proliferation was investigated by MTT [(3-(4,5)-dimethylthiazol(-z-y1)-3,5-di-phenytetrazolium bromide] assay. The expression levels of epithelial-mesenchymal transition (EMT) markers in NEK2-silenced or NEK2-overexpressing HCC cells were examined by western blot analyses and qRT-PCR. The correlations between NEK2 expression and clinicopathological characteristics were further analyzed. Gene microarray was further used to analyze the effect of NEK2 expression on downstream cell signals. Our study showed that NEK2 was overexpressed in human HCC (37.84%; 98/259). NEK2 overexpression was significantly associated with liver non-capsulation and predicted poor survival outcomes in HCC patients after hepatectomy. In addition, NEK2 significantly enhanced HCC cell invasive ability. Mechanistically, we found that the epithelial-mesenchymal transition (EMT) plays a pivotal role in the NEK2-mediated promotion of HCC cell invasion. Furthermore, we provided evidence that signaling through the Wnt, NF-κB, focal adhesion, VEGF, Hippo and p53 pathways may be downstream of NEK2. Our findings highlight the importance of NEK2 in HCC metastasis and suggest that NEK2 is a reliable prognostic marker for HCC patients after hepatectomy.