Role of CCR1/5/7 in hepatocellular carcinoma: a study on prognostic evaluation, molecular subtyping, and association with immune infiltration.

This study aims to assess the prognostic value of the C-C motif chemokine receptor (CCR) gene family in hepatocellular carcinoma (HCC) and its relationship with immune infiltration and molecular subtypes of HCC. The evaluation of the GSE14520 dataset and TCGA database confirmed the prognostic significance of CCR. Building upon the correlation between CCR1, CCR5, and CCR7 and favorable prognosis, we further validated the prognostic importance of CCR1, CCR5, and CCR7 in ICGC database and an independent cohort from Guangxi autonomous region. Then, we constructed a risk prognosis model. Additionally, we observed significant positive correlations between CCR1, CCR5, and CCR7 and the infiltration of B cells, T cells, and macrophages in HCC. Subsequently, we conducted CCK assays, Transwell assays, and colony formation assays to evaluate the molecular biological functions of CCR1, CCR5, and CCR7. These experiments further confirmed that upregulation of CCR1, CCR5, and CCR7 can individually inhibit the proliferation, migration, and stemness of HCC cells. By analyzing the relationship between expression levels and tumor mutation frequency, we discovered that patients with high CCR1 expression were more likely to be classified as non-proliferative HCC. Similar conclusions were observed for CCR5 and CCR7. The association of CCR1, CCR5, and CCR7 with the molecular subtypes of HCC suggests that they may serve as intermediary molecules linking immune status and molecular subtypes in HCC. In summary, CCR1, CCR5, and CCR7 have the potential to serve as prognostic biomarkers for HCC and regulate HCC progression by influencing immune cell infiltration.

Prognostic value of geriatric nutritional risk index and prognostic nutritional index in hepatocellular carcinoma.

BACKGROUND: The geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI) are considered prognostic factors for several cancers. This study aimed to investigate the relationship between the GNRI and PNI for survival outcomes in patients with hepatocellular carcinoma (HCC). METHODS: We retrospectively analyzed 1666 patients with HCC who underwent hepatectomy. Restricted cubic spline regression was used to analyze the relationship between the GNRI and PNI for recurrence and mortality. Cox proportional hazards regression analysis was used to evaluate the risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Interaction analysis was performed to investigate the comprehensive effects of the GNRI, PNI, and subgroup parameters on the prognosis of patients with HCC. RESULTS: The risks of death and recurrence decreased rapidly and gradually stabilized as the GNRI and PNI scores increased. Patients with lower GNRI and PNI scores had significantly shorter OS and RFS rates than those with higher scores. Multivariate analysis showed that high GNRI [HR and 95%CI = 0.77 (0.70-0.85), P < 0.001] and PNI [HR and 95%CI = 0.77 (0.70-0.86), P < 0.001] scores were associated with decreased mortality risk. This trend was maintained by confounding variables in adjusted models despite partial interactions with clinical factors. The combined GNRI and PNI analysis showed that HCC patients with high GNRI and PNI had longer OS and RFS. CONCLUSIONS: The GNRI and PNI showed good survival predictions in patients with HCC. Combining the GNRI with PNI may help predict the prognosis of patients (age>18 years) with HCC after hepatectomy.

Sarcosine dehydrogenase as an immune infiltration-associated biomarker for the prognosis of hepatocellular carcinoma.

This study was aimed to investigate the prognostic value and clinical significance of sarcosine dehydrogenase (SARDH) in hepatocellular carcinoma (HCC) and to explore the underlying mechanisms. The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), HPA and CPTAC databases were adopted to analyze the expression of SARDH mRNA and protein between normal liver tissue and HCC, and examine their relationship with clinicopathological features. Kaplan-Meier analysis, Cox regression, as well as nomogram were adopted to explore the prognostic value of SARDH in HCC. Gene Ontology (GO), Kyoto Gene and Genome Encyclopedia (KEGG) together with Gene Set Enrichment Analysis (GSEA) were adopted to analyze the molecular mechanisms and biological functions of SARDH in HCC; while MethSurv, STRING, GeneMANIA, TIMER database data and single-sample gene set enrichment analysis (ssGSEA) algorithm were used for other bioinformatic analysis. Furthermore, immunohistochemistry was used to verify the expression of SARDH. Compared to normal liver tissue, SARDH expression was markedly lower in HCC. A lower SARDH expression was linked with Pathologic T stage (T3&T4), pathologic stage (Stage III&IV), and histologic grade (G3&4), which further indicates worse prognosis. Besides, results of bioinformatic analysis proved that SARDH expression was correlated with immune infiltration. In addition, SARDH hypermethylation was related to a poorer prognosis. SARDH expression was related to several key genes in the Ferroptosis pathway.

Hepatic Artery Infusion Chemotherapy Sequential Hepatic Artery Embolization Combined with Operation in the Treatment of Recurrent Massive Hepatocellular Carcinoma Achieved Pathological Complete Response: A Case Report.

Hepatocellular carcinoma (HCC) recurrence, which encompasses both true recurrence resulting from cancer spread and de novo tumors developing within the same cancer-prone liver, presents a complication in approximately 70% of cases within a 5-year timeframe. The efficacy of neoadjuvant therapy for recurrence after hepatectomy for hepatocellular carcinoma is still unclear. We report a case of recurrent massive advanced hepatocellular carcinoma with pathological complete remission was treated by continuous hepatic arterial infusion chemotherapy (HAIC) and sequential transcatheter arterial embolization (TAE) combined with secondary operation. One month after resection, the patient recurred (massive type 141mm×76mm). After 4 times of HAIC sequential TAE conversion therapy, the tumor shrank significantly (70mm×29mm), alpha-fetoprotein(AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels decreased significantly, residual liver volume[left half liver accounted for 39.85% of standard liver volume(left half liver + right anterior lobe) accounted for 80.17% of standard liver volume] and Indocyanine green 15-minute retention(ICG R15 8.0%) complies with surgical requirement.The second operation was performed, and the tumor was completely resected after hepatic blood flow occlusion Requirement. The postoperative pathological results showed complete remission (PCR) of the tumor, and no recurrence was found during the follow-up of 16 months. In this case, HAIC sequential TAE conversion therapy has good short-term effect on patients with postoperative recurrence of hepatocellular carcinoma, tumor burden is significantly reduced, the second surgery pathology achieves complete remission, safety and tolerance, it is worthy of study and promotion.

Dual transformation therapy for giant hepatocellular carcinoma: Two case reports and review of literature.

BACKGROUND: In the translational therapy of giant hepatocellular carcinoma (HCC), hepatic arterial infusion chemotherapy (HAIC) combined with anti-PD-1 immunotherapy and tyrosine kinase inhibitors (TKI) after laparoscopic portal vein ligation (PVL) is extremely rare. This is a dual conversion therapy that combines surgery and oncology. Here, we report two cases of successful surgical completion after dual conversion therapy. CASE SUMMARY: We report that a 54-year-old man and a 69-year-old woman were diagnosed with primary HCC combined with hepatitis B cirrhosis (case 2 also combined with fatty liver) on physical examination. Due to the insufficient residual liver volume assessed before surgery, laparoscopic right PVL was performed, followed by HAIC combined with anti-PD-1 immunotherapy and TKI. Finally, surgical resection was successfully completed, and pathology confirmed that the tumor was mostly necrotic (90%) in one case, and no live tumor tissue was found in the other case. CONCLUSION: In the process of surgical transformation, our treatment plan takes into account the control and transformation of oncology at the same time, which is expected to provide more opportunities for radical hepatectomy and improve the prognosis of patients with large liver cancer.

Outer dynein arm docking complex subunit 2 polymorphism rs7893462 modulates hepatocellular carcinoma susceptibility and can serve as an overall survival biomarker for hepatitis B virus-related hepatocellular carcinoma after hepatectomy: a cohort study with a long-term follow-up.

BACKGROUND: Genetic variants of outer dynein arm docking complex subunit 2 (ODAD2) have been reported to be closely associated with primary ciliary dyskinesia and colorectal cancer in previous studies, but the association of genetic variants of ODAD2 with hepatocellular carcinoma (HCC) has not been reported. METHODS: We enrolled 80 healthy subjects and 468 Guangxi hepatitis B virus (HBV)-related HCC patients in this study. A case-control study method was used to explore the association of different ODAD2-rs7893462 genotypes with hepatocarcinogenesis. A comprehensive survival analysis was used to explore the association of rs7893462 with the prognosis of HBV-related HCC in Guangxi. RESULTS: Through a case-control study, we observed that patients carrying the G allele of rs7893462 had a markedly increased susceptibility to hepatocarcinogenesis (odds ratio = 1.712, 95% confidence interval = 1.032-2.839, P = 0.037). We found that there were significant prognosis differences among three different genotypes of rs7893462. Nomogram analysis suggested that the contribution of rs7893462 polymorphisms to the prognosis of HBV-related HCC was second only to the BCLC stage. Stratified survival analysis suggested that the AG genotype of rs7893462 was an independent prognostic risk factor for HBV-related HCC. Joint effect survival analysis also observed that the AG genotype of rs7893462 combined with clinical parameters could significantly identify HBV-related HCC patients with different prognostic outcomes more accurately, and the AG genotype was also observed to be independent of clinical factors in HBV-related HCC survival. CONCLUSION: The ODAD2-rs7893462 polymorphisms can be used as an independent prognostic indicator of HBV-related HCC overall survival and are significantly associated with susceptibility to hepatocarcinogenesis.

Case Report: A case of hepatocellular carcinoma with aberrant right hepatic artery treated with transarterial chemoembolization and infusion chemotherapy separately to bilobar lesion combining with systemic therapies and sequential hepatectomy.

Background: Hepatocellular carcinoma (HCC) with a dismal prognosis is the second most deadly malignancy globally. Surgery is believed to be a curative approach. Nevertheless, there is still a considerable probability of postoperative recurrence. Most patients present in advanced stages with a surgically and oncologically unresectable disease. Systemic medicines are increasingly important to downstage the disease and further improve survival. Case summary: A 67-year-old Chinese man with uncontrolled hepatitis B was discovered to have liver masses with abnormal serum vitamin K absence or antagonist-II (PIVKA-II) level during checkup for upper abdominal discomfort. Abdominal multiphase computerized tomography (CT) and gadoxetate disodium-enhanced magnetic resonance imaging (MRI) showed the bulky bilobar HCCs of Barcelona Clinic Liver Cancer stage B and China Liver Cancer Staging stage IIa. Furthermore, the aberrant right hepatic artery (RHA) originates from the superior mesenteric artery. Due to the location being adjacent to important vasculatures and massive size of the right-sided lesion, curative resection appears to be challenging. To achieve a favorable surgical margin, repeated hepatic arterial infusion chemotherapy (HAIC) was adopted through the variant RHA, while transarterial chemoembolization (TACE) was delivered to the left lobe to arrest tumor growth. Furthermore, sintilimab plus lenvatinib served as the sequential systemic therapy. After 5 months of conversion treatment, the partial response with a decreased serum PIVKA-II level was attained. The R0 hepatectomy was then performed without postoperative complications. The immunohistochemistry and next-generation sequencing results suggested that the two-side HCCs existing tumor heterogeneity were not completely consistent. The patient continues to be without evidence of disease. Conclusion: Our case highlights a favorable outcome in a man with bilobar bulky HCC after undergoing the comprehensive therapeutic schedule that includes personalized intervention and systemic drug therapy. In terms of conversion therapy, our case provides a secure and practical reference for managing unresectable bilobar HCC coexisting with the aberrant hepatic artery.

Nucleoporin 107 is a prognostic biomarker in hepatocellular carcinoma associated with immune infiltration.

OBJECTIVE: To assess the diagnostic value and clinical significance of nucleoporin 107 (NUP107) in hepatocellular carcinoma (HCC), and explore the possible mechanisms. METHODS: The transcriptomic and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) and GEO databases. Tissue specimens were collected from HCC patients in the Guangxi area. According to the expression levels and prognostic characteristics of NUP107, ROC curves and nomogram models were constructed using the R package. RESULTS: NUP107 was highly expressed in 26 human cancers including HCC, and was associated with advanced HCC staging and worse prognosis. NUP107 showed satisfactory ability to predict the prognosis of HCC patients (AUC >0.8). Results of gene set enrichment analysis (GSEA) further showed that NUP107 was mainly associated with cell cycle-related pathways such as the cell cycle, DNA replication, G2M checkpoint, E2F target, and mitotic spindle. In addition, NUP107 was also associated with immune infiltration in HCC and showed significant positive correlation with immune checkpoints (PD-L1 and TIM-3).

Massive Hepatocellular Carcinoma with Situs Inversus Totalis Achieved a Complete Response Following Camrelizumab Plus Apatinib and Combined with Two-Stage Hepatectomy: A Case Report.

Situs inversus totalis (SIT) is a rare congenital condition in which abdominal and thoracic organs are transposed from normal positions. Two-stage hepatectomy (TSH) combined with translational therapy for hepatocellular carcinoma (HCC) with SIT has been rarely reported. We report a 41-year-old man with giant hepatocellular carcinoma (71 mm × 55 mm × 51 mm) whose future residual liver (FLR) and standard liver volume (SLV) ratio at first diagnosis was 37.4%. Preoperative volume assessment of portal vein ligation (PVL) revealed inadequate hypertrophy of FLR. After a multidisciplinary group discussion (MDT), the patient decided to follow conversion therapy. Three months later, ratio of the FLR/SLV increased from 37.4% to 71% after operation, which met the surgical requirements. Second hepatectomy, right lobectomy was successful. There was no recurrence after six months of follow-up. In our case, conversion therapy appears to be effective in maintaining residual liver hyperplasia, reducing tumor load, and preventing tumor progression in patients with large HCC during TSH.

Comprehensive analysis of LILR family genes expression and tumour-infiltrating immune cells in early-stage pancreatic ductal adenocarcinoma.

Leucocyte immunoglobulin-like receptors (LILRs) are closely related to tumourigenesis, but their clinical value in early-stage pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy remains unknown. Kaplan-Meier and Cox proportional hazards regression models is used to investigate the association between LILR expression and prognosis in tumour biopsies and peripheral blood mononuclear cells. Risk score was calculated for each patient based on the prognostic model. DAVID, STRING, GeneMANIA, and GSEA were used to conduct pathway and functional analyses. The CIBERSORT algorithm is used to analyse tumour-infiltrating immune cells. Survival analysis showed that high levels of LILRA4 (p = 0.006) and LILRB4 (p = 0.04) were significantly associated with better overall survival. High levels of LILRA2 (p = 0.008) and LILRB4 (p = 0.038) were significantly associated with better relapse-free survival. JAK-STAT signalling pathway, regulation of T cell activation, regulation of the immune effector process, and tumour necrosis factor superfamily cytokine production were involved in molecular mechanisms that affected poor prognoses in the high-risk group in GSEA. CIBERSORT demonstrated that the high-risk group had significantly higher infiltrating fraction of memory-activated CD4 T cells and activated NK cells and lower fraction of resting dendritic cells and neutrophils. LILRB4 plays crucial roles in affecting the clinical outcomes of early-stage PDAC.

A novel Peng's test in reducing bile leakage after partial hepatectomy for hepatocellular carcinoma: From an animal study to a clinical cohort Propensity score matching comparative study.

BACKGROUND: Bile leakage (BL) is a common complication of partial hepatectomy for hepatocellular carcinoma (HCC). However, various intraoperative approaches to detect BL have not been widely accepted owing to uncertainty in their treatment effectiveness and complexity of use. MATERIALS AND METHODS: A novel BL-detection approach (Peng's test) was developed in a swine model to determine the pressures generated in the gallbladder and common bile duct (CBD) during the test. A comparative study was then conducted on a prospective cohort of patients using Peng's test versus a retrospective historical cohort patient group using the White Gauze test in partial hepatectomy for HCC. Propensity score matching (PSM) was performed in a 1:1 ratio to balance confounding factors. RESULTS: The maximum pressures with methylene blue injection in the gallbladder and CBD without Pringle's maneuver in the four swines were 103.8 ± 11.8 and 42.3 ± 6.1, respectively. After Pringle's maneuver, 32.0 ± 6.8 mL methylene blue injection led to a maximum pressure in the CBD of 85.3 ± 9.5 cmH2O. The pressures in CBD were 25.8 ± 3.3 and 86.0 ± 9.9 cmH2O when BL appeared at small bile ducts and around the ligation sites, respectively. Of the 206 patients enrolled in the historical control group, 31 (15.0%) developed BL, while of the 54 patients in the study group, only 1 developed grade A BL. The number of BL detected by the routine white gauze test in the control group was significantly lower than that in the study group (Z = -3.002, P = 0.003). After PSM, the incidence of BL in the control group and grade B/C BL was 20.4% and 11.1%, respectively. The corresponding incidences in the study group were 1.9% (χ2 = 7.594, P = 0.006) and 0% (P = 0.027), respectively. The length of hospital stay in the study group was significantly reduced (Z = -6.048, P < 0.001). CONCLUSION: Peng's test for intraoperative BL detection is safe and effective in reducing BL after hepatectomy.

Graft versus host disease after liver transplantation following radiotherapy for the treatment of hepatocellular carcinoma: A case report and literature review.

Graft versus host disease after solid organ transplantation is very rare. This article reports a case of graft versus host disease after liver transplantation following targeted therapy and radiotherapy for the treatment of hepatocellular carcinoma. The patient developed a symptomatic skin rash and pancytopenia 13 days after surgery, which was confirmed as graft versus host disease after liver transplantation by histopathology and fluorescence in situ hybridization. Early diagnosis of graft versus host disease after solid organ transplantation is difficult and often delayed due to nonspecific manifestations that overlap with other diseases. Currently, the treatment of graft versus host disease after liver transplantation occurs by either strengthening the immune suppression or weakening the immune suppression; however, there is no unified standard treatment strategy. We found that in addition to age, gender, and human leukocyte antigen type, preoperative radiotherapy is a likely risk factor for graft versus host disease after liver transplantation.

TSLP protects against sepsis-induced liver injury by inducing autophagy via activation of the PI3K/Akt/STAT3 pathway.

BACKGROUND: Liver injury is the main factor in multiple organ failure caused by sepsis. Thymic stromal lymphopoietin (TSLP) is derived from epithelial cells and plays an important role in inflammation, allergies and cancer. The role of TSLP in sepsis-induced liver injury (SILI) is unclear. The purpose of this study was to investigate the effect of TSLP on sepsis-induced liver injury and to clarify the mechanism. METHODS: Wild-type (WT) mice and TSLPR knockout (TSLPR-/-) mice were subjected to cecal ligation and puncture (CLP) to generate a SILI model. Liver injury was assessed by measuring the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), histologic liver injury scores, hepatocyte death, and liver inflammatory factors. Signal pathways were explored in vivo to identify possible mechanisms for TSLP in SILI. RESULTS: The expression of TSLP and TSLPR increased during SILI. Deletion of TSLPR exacerbated liver injury in terms of serum ALT, AST, histologic liver injury scores, and liver inflammatory factors. Compared with controls, administration of exogenous recombinant mouse TSLP reduced liver injury in WT mice during SILI, but failed to reduce liver injury in TSLPR-/- mice. TSLP induced autophagy in hepatocytes during SILI. Mechanistically, Akt and STAT3 were activated in WT mice during SILI. The opposite results were observed in TSLPR-/- mice. In addition, the protective effects of TSLP in WT mice were blocked by PI3K inhibitor, LY294002, during SILI. CONCLUSION: These results suggest that TSLP can improve liver injury caused by sepsis and its specific mechanism may be related to inducing autophagy through the PI3K/Akt/STAT3 signaling pathway.

Clinical Significance and Potential Mechanisms of ATP Binding Cassette Subfamily C Genes in Hepatocellular Carcinoma.

The purpose of this investigation was to assess the diagnostic and prognostic significance of ATP binding cassette subfamily C (ABCC) genes in hepatocellular carcinoma (HCC). The Student t-test was used to compare the expression level of ABCCs between HCC and paraneoplastic tissues. Receiver operating characteristic curve (ROC) analysis was applied for diagnostic efficiency assessment. The Kaplan-Meier method and Cox proportional hazards model were respectively applied for survival analysis. Genes with prognostic significance were subsequently used to construct prognostic models. From the perspective of genome-wide enrichment analysis, the mechanisms of prognosis-related ABCC genes were attempted to be elaborated by gene set enrichment analysis (GSEA). It was observed in the TCGA database that ABCC1, ABCC4, ABCC5, and ABCC10 were significantly upregulated in tumor tissues, while ABCC6 and ABCC7 were downregulated in HCC tissues. Receiver operating characteristic analysis revealed that ABCC7 might be a potential diagnostic biomarker in HCC. ABCC1, ABCC4, ABCC5, and ABCC6 were significantly related to the prognosis of HCC in the TCGA database. The prognostic significance of ABCC1, ABCC4, ABCC5, and ABCC6 was also observed in the Guangxi cohort. In the Guangxi cohort, both polymerase chain reaction and IHC (immunohistochemical) assays demonstrated higher expression of ABCC1, ABCC4, and ABCC5 in HCC compared to liver tissues, while the opposite was true for ABCC6. GSEA analysis indicated that ABCC1 was associated with tumor differentiation, nod-like receptor signal pathway, and so forth. It also revealed that ABCC4 might play a role in HCC by regulating epithelial-mesenchymal transition, cytidine analog pathway, met pathway, and so forth. ABCC5 might be associated with the fatty acid metabolism and KRT19 in HCC. ABCC6 might impact the cell cycle in HCC by regulating E2F1 and myc. The relationship between ABCC genes and immune infiltration was explored, and ABCC1,4,5 were found to be positively associated with infiltration of multiple immune cells, while ABCC6 was found to be the opposite. In conclusion, ABCC1, ABCC4, ABCC5, and ABCC6 might be prognostic biomarkers in HCC. The prognostic models constructed with ABCC1, ABCC4, ABCC5, and ABCC6 had satisfactory efficacy.

Gender disparity in hepatocellular carcinoma recurrence after curative hepatectomy.

INTRODUCTION AND OBJECTIVES: Whether there is gender disparity in the recurrence of hepatocellular carcinoma (HCC) has been not fully addressed. This study aimed to investigate the impact of gender on HCC recurrence following curative hepatectomy. PATIENTS AND METHODS: This retrospective cohort study included 1087 patients with HCC (917 males, 170 females) who underwent curative hepatectomy. Cox regression models were constructed to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the risk parameters associated with HCC recurrence. In the sensitivity analysis, subgroup analysis, and propensity score matching (PSM) analysis were used. Logistic regression models were used to assess the odds ratio (OR) and 95% CI of the risk parameters related to early and late recurrence. RESULTS: Male patients showed significantly higher risk for HCC recurrence than females, in both multivariate Cox regression analysis (HR [95% CI] = 1.480 [1.084-2.020], P = 0.014) and PSM analysis (HR [95% CI] = 1.589 [1.093-2.312], P = 0.015). Higher risk of HCC recurrence was again found in males in the subgroup analysis, but the effect of male versus female gender on HCC recurrence did not depend on any selected subgroups (all P for interaction > 0.05). Gender was an independent risk factor for early recurrence (OR [95% CI] = 1.864 [1.215-2.936], P = 0.006), but not for late recurrence. CONCLUSIONS: There is gender disparity in the recurrence of patients with HCC after curative hepatectomy: males had a higher risk for HCC recurrence than females.

CYP2C8 Suppress Proliferation, Migration, Invasion and Sorafenib Resistance of Hepatocellular Carcinoma via PI3K/Akt/p27kip1 Axis.

BACKGROUND: Cytochrome P450 2C8 (CYP2C8) gene is one of the members of the cytochrome P450 enzymes (CYPs) gene family. The aim of this study was to reveal the function of CYP2C8 in hepatocellular carcinoma (HCC) and its effect on the sorafenib resistance. METHODS: Differential expression analysis in multiple HCC datasets all suggested that CYP2C8 expression was significantly decreased in HCC tissues, compared with para-carcinoma liver tissues. The expression level of CYP2C8 was subsequently compared between HCC tissues and para-carcinoma liver tissues of 70 patients form Guangxi, China, with the result consistent with the above. Survival analysis and ROC analysis indicated that CYP2C8 was equipped with satisfactory diagnostic and prognostic value in HCC. To examine the effect of CYP2C8 on the malignant phenotype of HCC cells, stable transcriptional cell lines with CYP2C8 over-expression were established, and then Cell Counting Kit-8 (CCK8) assay, colony formation assay, cell cycle assay, cell invasion assay and wound healing assay were performed. RESULTS: The results of aforementioned assays suggested that CYP2C8 over-expression restricted the proliferation, clonality, migration, invasion and cell cycle of HCC cells but had no significant effect on cell apoptosis. The enrichment analysis in terms of sequencing data of HCC cell lines with stable CYP2C8 over-expression suggested that CYP2C8 might be related to PI3K/Akt/p27Kip1 axis. The inhibition of CYP2C8 over-expression on PI3K/Akt/p27Kip1 axis was subsequently demonstrated with Western blot assay. In the rescue experiment, it was observed that both P27 inhibitor and PI3K agonist counteracted the repressed malignant phenotype caused by CYP2C8 over-expression, which further demonstrated that CYP2C8 played a role in HCC cells via PI3K/Akt/p27Kip1 axis. DISCUSSION: The results demonstrated that CYP2C8 enhances the anticancer activity of sorafenib in vitro assays and in tumor xenograft model, with Ki-67 down-regulation and PI3K/Akt/p27Kip1 axis inhibition. In conclusion, these findings hinted that CYP2C8 restricted malignant phenotype and sorafenib resistance in HCC via PI3K/Akt/p27kip1 axis.

Intraoperative Indocyanine Green Retention Test of Left Hemiliver in Decision-Making for Patients With Hepatocellular Carcinoma Undergoing Right Hepatectomy.

Introduction: The aim of this study was to select qualified patients with hepatocellular carcinoma (HCC) who underwent right hepatectomy (RH) via intraoperative indocyanine green retention test at 15 min (ICG-R15) of the left hemiliver, which prevents severe posthepatectomy liver failure (PHLF). Methods: Twenty HCC patients who were preoperatively planned to undergo RH were enrolled. Intraoperative ICG-R15 of left hemiliver was measured after the right Glissonean pedicle was completely blocked. Patients then underwent RH if intraoperative ICG-R15 was ≤ 10%. Otherwise, patients underwent staged RH (SRH), either associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) or portal vein ligation (PVL), followed by stage-2 RH. The comparison group consisted of patients with a ratio of standard left liver volume (SLLV) of > 40% and preoperative ICG-R15 ≤ 10% who underwent RH. The clinical outcomes of these two groups were compared. Results: Of the 20 patients, six underwent stage-1 RH, six underwent ALPPS, five underwent PVL followed by stage-2 RH, and three failed to proceed to stage-2 RH after PVL. No significant differences were found among the 17 patients who underwent stage-1 or stage-2 RH in the study group, the 19 patients in the comparison group, the 11 patients in the stage-2 RH group, and the six patients in the stage-1 RH group in incidences of PHLF, postoperative complications, hospital stay, and HCC recurrence within 1 year after RH. Compared with the stage-1 ALPPS group, the mean operative time and blood loss of the stage-1 PVL group were significantly less (p <0.001 and p = 0.022, respectively). The stage-1 PVL group had a significantly longer waiting-time (43.4 vs. 14.0 days, p = 0.016) than the stage-1 ALPPS group to proceed to stage-2 RH. After stage-2 RH, tumor recurrence within 1 year was 20% (1/5) in patients after PVL and 50% (3/6) after stage-1 ALPPS. Conclusions: Intraoperative ICG-R15 ≤ 10% of left hemiliver was valuable in intraoperative decision-making for patients who were planned to undergo RH. There is a possibility that stage-1 PVL might help to select patients with more favorable biological behavior to undergo stage-2 RH.

Efficacy and biomarker exploration of camrelizumab combined with apatinib in the treatment of advanced primary liver cancer: a retrospective study.

This study was to explore the efficacy and safety of camrelizumab combined with apatinib in patients with advanced liver cancer. Moreover, the relationship between peripheral blood parameters and tumor response rate was also investigated. Patients with unresectable or recurrent primary liver cancer (PLC) who received treatment from July 2019 to July 2020 in the First Affiliated Hospital of Guangxi Medical University were included in this single-center retrospective study. The patients were treated with camrelizumab (200 mg, intravenous q2w) plus apatinib (250 mg, oral qd) until the occurrence of disease progression or unbearable toxicity. All the patients underwent blood routine test and detection of lactate dehydrogenase and serum albumin levels before treatment. The primary endpoints were objective response rate (ORR) and disease control rate (DCR). This study included a total of 45 patients. The overall ORR was 33.3% [95% confidence interval (CI),19.0-47.7] and the overall DCR was 57.8% (95% CI, 42.8-72.8). The ORR and DCR were higher in the first-line treatment than those in the second-line treatment (ORR: 45.5% vs. 21.7%, DCR: 63.6% vs. 52.3%). Median progression-free survival in the second-line treatment was 10.5 months (95% CI, 7.9-13.1, P = 0.022). Adverse events occurred in 39 (86.7%) patients. Grade 3/4 adverse reactions occurred in 7 (15.6%) patients. One patient (4.3%) was terminated from treatment due to adverse events. One patient (4.3%) died, which was potentially associated with adverse events. Subgroup analysis indicated that the remission rate in patients with high lymphocyte to monocyte ratio (H-LMR) was higher than that in patients with low lymphocyte to monocyte ratio (L-LMR) (56.25% vs. 25.93%, P = 0.047), and the remission rate in patients with high Prognostic Nutritional Index (H-PNI) was higher than that in patients with low Prognostic Nutritional Index (L-PNI) (66.7% vs. 26.5%, P = 0.046). Camrelizumab combined with apatinib in the treatment of PLC showed encouraging clinical efficacy, with tolerable toxicities. Levels of PNI and LMR may serve as predictors of the prognosis of advanced PLC patients who receive immunotherapy combined with targeted therapy.

SOX4 as biomarker in hepatitis B virus-associated hepatocellular carcinoma.

Background: Hepatitis B virus infection is associated with liver disease, including cancers. In this study, we assessed the power of sex-determining region Y (SRY)-related high-mobility group (HMG)-box 4(SOX4) gene to predict the clinical course of hepatocellular carcinoma (HCC). Methods: To evaluate the differential expression of SOX4 and its diagnostic and prognostic potential in HCC, we analyzed the GSE14520 dataset. Stratified analysis and joint-effect analysis were done using SOX4 and clinical factor. We then designed a nomogram for predicting the clinical course of HCC. Differential SOX4 expression and its correlation with tumor stage as well as its diagnostic and prognostic value were analyzed on the oncomine and GEPIA websites. Gene set enrichment analysis was explored as well as candidate gene ontology and metabolic pathways modulated by in SOX4 HCC. Results: Our analysis revealed that the level of SOX4 was significantly upregulated in tumor issue (P <0.001). This observation was validated through oncomine dataset and MERAV analysis (all P <0.05). Diagnostic receiver operating characteristic (ROC) analysis of SOX4 suggested it has diagnostic potential in HCC (GSE14520 dataset: P <0.001, area under curve (AUC) = 0.782; Oncomine: (Wurmbach dataset) P = 0.002, AUC = 0.831 and (Mas dataset) P <0.001, AUC = 0.947). In addition, SOX4 exhibited high correlation with overall survival of HBV-associated HCC (adjusted P = 0.004, hazard ratio (HR) (95% confidence interval (CI)) = 2.055 (1.261-3.349) and recurrence-free survival (adjusted P = 0.008, HR (95% CI) = 1.721 (1.151-2.574). These observations which were verified by GEPIA analysis for overall survival (P = 0.007) and recurrence-free survival (P= 0.096). Gene enrichment analysis revealed that affected processes included lymphocyte differentiation, pancreatic endocrine pathways, and insulin signaling pathway. SOX4 prognostic value was evaluated using nomogram analysis for HCC 1, 3, and 5-year, survival. Conclusion: Differential SOX4 expression presents an avenue of diagnosing and predicting clinical course of HCC. In HCC, SOX4 may affect TP53 metabolic processes, lymphocyte differentiation and the insulin signaling pathway.

UXT antisense RNA 1 sever as a novel prognostic long non-coding RNA in early stage pancreatic ductal adenocarcinoma patients after receiving pancreaticoduodenectomy.

Objective: The principal objective of this project was to investigate the prognostic value of UXT antisense RNA 1 (UXT-AS1) in pancreatic ductal adenocarcinoma (PDAC), as well as its biological function mechanisms and the screening of targeted drugs using The Cancer Genome Atlas (TCGA) PDAC genome-wide RNA sequencing (RNA-seq) dataset. Methods: We used TCGA 112 early stage PDAC patients to screen the prognostic value of UXT-AS1. Biological functions and mechanisms of UXT-AS1 were investigated by co-expression analysis, differentially expressed genes (DEGs) and gene set enrichment analysis, while targeted drug screening was investigated by connectivity Map (CMap). Results: By analyzing the dataset from TCGA cohort, we found that UXT-AS1 was significantly up-regulated in pancreatic cancer tissues. Multivariate survival analysis demonstrated that PDAC patients with high UXT-AS1 expression had an unfavourable prognosis (adjusted P=0.033, HR=1.830, 95%CI=1.051-3.188). Genome-wide co-expression analysis and gene set enrichment analysis suggested that UXT-AS1 may act as a pivotal part in PDAC by participating in nuclear factor kappa beta, regulation of tumor necrosis factor, cell adhesion, T cell receptor signaling pathway, and numerous immune-related biological processes and signaling pathways. Functional enrichment analysis of DEGs between high- and low-UXT-AS1 expression groups suggested that these DEGs were significant enriched in B cell receptor complex, response to drug chemical carcinogenesis and drug metabolism-cytochrome P450. CMap analysis revealed that quipazine and terazosin may be targeted drugs for UXT-AS1 in PDAC. Conclusion: Our current study has identified UXT-AS1 as a novel biomarker for the prognosis of early stage PDAC. We also clarified its biological functional mechanisms and identified two targeted drugs of UXT-AS1 in PDAC.