IV segment portal vein reconstruction in split-liver transplantation with extended right grafts.

BACKGROUND: Liver transplantation is one of the most effective treatments for end-stage liver disease. Split liver transplantation (SLT) can effectively improve the utilization efficiency of grafts. However, split liver transplantation still faces shortcomings and is not widely used in surgery. How to improve the effective transplantation volume of split liver transplantation and promote the postoperative recovery of patients has important clinical significance. METHODS: In our study, the donor's liver was split into the extended right graft and left lateral sector, and the IV segment occur ischemia. To guarantee the functional graft size, and avoid complications, we reconstructed the IV segment portal vein and left portal vein. And we analyzed the operation time, intraoperative bleeding, liver function, and postoperative complications. RESULTS: In our research, 14 patients underwent IV segment portal vein reconstruction, and 8 patients did not undergo vascular reconstruction. We found that the ischemic area of the IV segment decreased significantly after IV segment portal vein reconstruction. We found that there was no significant difference in operation time and postoperative complications between the patients of the groups. There were significant differences in ALT on the 1st day and albumin on the 6th day after the operation. CONCLUSION: It indicates that IV segment reconstruction in SLT surgery can alleviate the graft ischemic and promote the recovery of liver function after the operation. And, IV segment reconstruction as a novel operating procedure may be widely used in SLT.

A model integrated fibrinogen and D-dimer for prediction of hepatocellular carcinoma recurrence following liver transplantation: a multicentre study.

BACKGROUND: We aimed to investigate whether D-dimer and fibrinogen levels could predict prognosis of patients with hepatocellular carcinoma (HCC) following liver transplantation. METHODS: From January 2015 to January 2020, we conducted a study on patients with hepatitis B-related liver cancer. Two hundred seventy (270) liver transplant recipients were recruited. Considering D-dimer and plasma fibrinogen levels, a model was established to predict liver cancer recurrence following liver transplantation. Subsequent verification was performed on a validation cohort of 295 recipients from two other hospitals. RESULTS: Elevated D-dimer and plasma fibrinogen levels demonstrated independent correlation between overall survival and tumour-free survival among patients with HCC who underwent liver transplantation. Those who had preoperative fibrinogen ≥2.27 g/L had significantly reduced overall survival and tumour-free survival than those who had preoperative fibrinogen <2.27 g/L, in the discovery cohort. Recipients with increased risk had preoperative plasma D-dimer ≥2400 µg/L. The model was: Y= logit (P) =0.91* fibrinogen concentration +0.967* D-dimer +0.585* alpha-fetoprotein +1.623* Milan criteria +0.68* microvascular invasion -3.159. At a cut-off score of -1.524, the validation cohort had area under curve values of 0.764 and 0.828 respectively; analysis of this data optimised predictive performance for overall and tumour-free survival. CONCLUSIONS: For patients who have undergone liver transplantation for HCC, preoperative D-dimer and fibrinogen levels independently predicted key outcomes such as overall survival and tumour-free survival.

Long-term outcomes of deceased donor liver transplantation in hepatocellular carcinoma patients with portal vein tumor thrombus: A multicenter study.

BACKGROUND: The incidence of portal vein tumor thrombus (PVTT) has been reported to be as high as approximately 10%-40% in patients with hepatocellular carcinoma (HCC). The long-term prognosis of deceased donor liver transplantation (DDLT) in HCC patients with PVTT remains unknown. METHODS: Data of 961 HCC patients who underwent DDLT between 2015 and 2018 in six centers were analyzed. Based on the Milan criteria (MC) and Cheng's classification of PVTT, the patients were divided into 4 groups: within MC, beyond MC without PVTT, type 1 PVTT, and type 2 PVTT groups. RESULTS: 489 (50.9%) were within the MC, 296 (30.8%) beyond the MC but without PVTT, 83 (8.6%) type 1 PVTT, and 93 (9.7%) type 2 PVTT. Kaplan-Meier analysis showed that type 1 or 2 PVTT patients with alpha-fetoprotein (AFP) ≤ 100 ng/mL had overall survival (OS) similar to that of patients within the MC (P = 0.957), and superior OS (P = 0.003 and 0.009) and recurrence-free survival (RFS) (P = 0.038 and <0.001) than those of patients beyond the MC and PVTT patients with AFP > 100 ng/mL. Multivariable Cox-regression analysis identified type 1 and 2 PVTT to be independent risk factor for RFS [hazard ratio (HR) 1.523 95% confidence interval (CI) 1.162-1.997, P = 0.002], but not for OS (HR 1.283, 95%CI 0.922-1.786, P = 0.139). CONCLUSION: HCC patients with type 1 or 2 PVTT may be acceptable candidates for DDLT. To achieve better outcomes, preoperative AFP levels should be seriously considered when selecting patients with PVTT for DDLT.

Correlation Analysis of Pleural Effusion and Lung Infection After Liver Transplantation.

BACKGROUND: The aim was to probe the association of pleural effusion with lung infection in patients with liver transplantation and to provide a theoretical foundation for preventing, diagnosing, and remedying pulmonary complications after liver transplantation. METHODS: Our team harvested clinical data of patients undergoing orthotopic allogeneic liver transplantation complicated with pleural effusion after surgery in our institution from May 2018 to July 2019. Based on whether puncture drainage was needed, patients were allocated to either control group or observation group. The differences in pleural effusion depth, lung function, lung infection, serum inflammatory factor levels and 6-month survival before and after surgery were compared. Finally, ROC curves were constructed for dissecting the correlation of pleural effusion with lung infection. RESULTS: On day 3 after surgery, (1) pleural effusion depth of the observation group was 5.70 ± 1.20 cm, which was saliently greater than that of control group (p < 0.05); (2) in comparison to control group, lung function indexes FVC, FEV1.0, MVV, and PaO2 of observation group declined (all p < 0.05); (3) sputum culture evinced that the lung infection rates of the control group and observation group were 17.24% and 71.70%, respectively, and the observation group harbored brilliantly higher infection rate (p < 0.05); (4) in comparison to the control group, IL-6, IL-8, and TNF-α in observation group were increased (p < 0.05); (5) AUC of pleural effusion depth and lung infection was 0.849, 0.805, and 0.853, respectively on days 1, 2, and 3 after surgery. CONCLUSIONS: A positive correlation existed between pleural effusion and lung infection after liver transplantation. When patients have persistent pleural effusion, the incidence of lung infection should be prevented and reduced.

Identification and validation of a novel immune-related signature associated with macrophages and CD8 T cell infiltration predicting overall survival for hepatocellular carcinoma.

BACKGROUND: Although the effects of macrophages and CD8 T cell infiltration on clinical outcome have been widely reported, the association between immunity-associated gene with them for hepatocellular carcinoma (HCC) remains unclear. MATERIALS AND METHODS: The ssGSEA served for quantifying the macrophages as well as CD8 T cell infiltration in the HCC samples obtained from TCGA database. Kaplan-Meier (KM) survival assay was used to determine the associations between macrophages and CD8 T cell infiltration with OS. LASSO Cox regressive method assisted in developing an immune gene signature as well as building a risk score. The performance was evaluated by the time-dependent ROC together with the KM survival analysis. The ICGC database were adopted for external verification. CIBERSORT was applied to the correlation analysis on the immune-related signature and the immunocyte infiltration. GSEA were employed exploring the underlying molecular mechanisms. RESULTS: Increased CD8+ T cell infiltration was associated with longer OS, whereas a greater infiltration of macrophages was related to shorter OS. There were 398 differential expression genes (DEGs) between the high- and low infiltration groups with the "edgeR" package. An prognostic signature consisted of 10 immune genes was built in TCGA and examined in ICGC. The uniform cutoff (0.927) was adopted for separating sufferers into the high-risk (HR) and low-risk (LR) groups. The ROC curves revealed that the AUC data for this signature predicting 1, 2, 3, 4 and 5 year were all above 0.7 in both TCGA and ICGC cohort and patients in the HR group exhibited an evidently weaker prognostic results compared with the LR group. The HR group presented evidently greater Tregs and Macrophage M0 relative to the LR group, whereas the LR group saw the enrichment of CD8 T cells. CONCLUSION: The immune signature associated with macrophages as well as CD8 T cell infiltration has reliable prognostic and predictive value for HCC patients.

EHMT2 promotes the pathogenesis of hepatocellular carcinoma by epigenetically silencing APC expression.

BACKGROUND: Hepatocellular carcinoma (HCC), the second leading cause of cancer death worldwide, alone accounts for over half (466,100) of new cancer cases and 422,100 deaths based on the average year incidence rates of 2009 to 2011 in China. Due to unclear and complex underlying mechanisms for HCC development, effective therapy for HCC is still unavailable. The Wnt-ß-catenin pathway is a critical contributor of HCC pathogenesis: 40-70% of HCCs from patients harbor the nuclear accumulation of ß-catenin protein. However, the mechanisms for ß-catenin activation are not fully understood. METHODS: The deletion of EHMT2 in Hep3B and Huh1 cells was achieved by transiently transfecting cells with pX459 plasmids, which carry EHMT2 specific small guide RNA (sgRNA) sequences for Cas9 protein. All experiments were performed in triplicate and repeated more than three times. RESULTS: In the present study, we observed that EHMT2 (but not EHMT1) mRNA and protein levels were significantly elevated in HCC compared with normal controls. Next, the results of Ki67 staining, as well as MTT, soft-agar and xenograft assays, in wild-type and EHMT2-/- Hep3B and Huh1 cancer stem cells collectively revealed that the elevation of EHMT2 expression is required for the tumorigenesis of HCC. Meanwhile, we found that elevated EHMT2 expression contributes to the activation of Wnt-ß-catenin signaling: deletion of EHMT2 in Hep3B or Huh1 cells promoted the cytoplasmic localization of ß-catenin and restrained the expression of Wnt-ß-catenin signaling targets such as Myc, CCND1, MMP-7, etc. We demonstrated that EMHT2 directly mediates the H3K9me2 methylation of the APC promoter to epigenetically silence its expression. More intriguingly, our findings also showed that UNC0642, a specific inhibitor of EHMT2, exhibits anti-tumorigenesis effects in HCC both in vitro and in vivo, which were largely abolished by deletion of EHMT2 or overexpression of APC in Hep3B and Huh1 cells. CONCLUSION: Altogether, our observations emphasize that the EHMT2-APC axis is a critical contributor to Wnt-ß-catenin pathway activation in HCC, and UNC0642 may be a potential candidate for target drug treatment of HCC.

Construction and Validation of a Reliable Six-Gene Prognostic Signature Based on the TP53 Alteration for Hepatocellular Carcinoma.

BACKGROUND: The high mutation rate of TP53 in hepatocellular carcinoma (HCC) makes it an attractive potential therapeutic target. However, the mechanism by which TP53 mutation affects the prognosis of HCC is not fully understood. MATERIAL AND APPROACH: This study downloaded a gene expression profile and clinical-related information from The Cancer Genome Atlas (TCGA) database and the international genome consortium (ICGC) database. We used Gene Set Enrichment Analysis (GSEA) to determine the difference in gene expression patterns between HCC samples with wild-type TP53 (n=258) and mutant TP53 (n=116) in the TCGA cohort. We screened prognosis-related genes by univariate Cox regression analysis and Kaplan-Meier (KM) survival analysis. We constructed a six-gene prognostic signature in the TCGA training group (n=184) by Lasso and multivariate Cox regression analysis. To assess the predictive capability and applicability of the signature in HCC, we conducted internal validation, external validation, integrated analysis and subgroup analysis. RESULTS: A prognostic signature consisting of six genes (EIF2S1, SEC61A1, CDC42EP2, SRM, GRM8, and TBCD) showed good performance in predicting the prognosis of HCC. The area under the curve (AUC) values of the ROC curve of 1-, 2-, and 3-year survival of the model were all greater than 0.7 in each independent cohort (internal testing cohort, n = 181; TCGA cohort, n = 365; ICGC cohort, n = 229; whole cohort, n = 594; subgroup, n = 9). Importantly, by gene set variation analysis (GSVA) and the single sample gene set enrichment analysis (ssGSEA) method, we found three possible causes that may lead to poor prognosis of HCC: high proliferative activity, low metabolic activity and immunosuppression. CONCLUSION: Our study provides a reliable method for the prognostic risk assessment of HCC and has great potential for clinical transformation.

Construction and Validation of a Universal Applicable Prognostic Signature for Gastric Cancer Based on Seven Immune-Related Gene Correlated With Tumor Associated Macrophages.

BACKGROUND: Tumor-associated macrophages (TAMs) play a critical role in the progression of malignant tumors, but the detailed mechanism of TAMs in gastric cancer (GC) is still not fully explored. METHODS: We identified differentially expressed immune-related genes (DEIRGs) between GC samples with high and low macrophage infiltration in The Cancer Genome Atlas datasets. A risk score was constructed based on univariate Cox analysis and Lasso penalized Cox regression analysis in the TCGA cohort (n=341). The optimal cutoff determined by the 5-year time-dependent receiver operating characteristic (ROC) curve was considered to classify patients into groups with high and low risk. We conducted external validation of the prognostic signature in four independent cohorts (GSE84437, n=431; GSE62254, n=300; GSE15459, n=191; and GSE26901, n=109) from the Gene Expression Omnibus (GEO) database. RESULTS: The signature consisting of 7 genes (FGF1, GRP, AVPR1A, APOD, PDGFRL, CXCR4, and CSF1R) showed good performance in predicting overall survival (OS) in the 5 independent cohorts. The risk score presented an obviously positive correlation with macrophage abundance (cor=0.7, p<0.001). A significant difference was found between the high- and low-risk groups regarding the overall survival of GC patients. The high-risk group exhibited a higher infiltration level of M2 macrophages estimated by the CIBERSORT algorithm. In the five independent cohorts, the risk score was highly positively correlated with the stromal cell score, suggesting that we can also evaluate the infiltration of stromal cells in the tumor microenvironment according to the risk score. CONCLUSION: Our study developed and validated a general applicable prognostic model for GC from the perspective of TAMs, which may help to improve the precise treatment strategy of GC.

Development and Validation of a Novel Metabolic-Related Signature Predicting Overall Survival for Pancreatic Cancer.

Recently, growing evidence has revealed the significant effect of reprogrammed metabolism on pancreatic cancer in relation to carcinogenesis, progression, and treatment. However, the prognostic value of metabolism-related genes in pancreatic cancer has not been fully revealed. We identified 379 differentially expressed metabolic-related genes (DEMRGs) by comparing 178 pancreatic cancer tissues with 171 normal pancreatic tissues in The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression project (GTEx) databases. Then, we used univariate Cox regression analysis together with Lasso regression for constructing a prognostic model consisting of 15 metabolic genes. The unified risk score formula and cutoff value were taken into account to divide patients into two groups: high risk and low risk, with the former exhibiting a worse prognosis compared with the latter. The external validation results of the International Cancer Genome Consortium (IGCC) cohort and the Gene Expression Omnibus (GEO) cohort further confirm the effectiveness of this prognostic model. As shown in the receiver operating characteristic (ROC) curve, the area under curve (AUC) values of the risk score for overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS) were 0.871, 0.885, and 0.886, respectively. Based on the Gene Set Enrichment Analysis (GSEA), the 15-gene signature can affect some important biological processes and pathways of pancreatic cancer. In addition, the prognostic model was significantly correlated with the tumor immune microenvironment (immune cell infiltration, and immune checkpoint expression, etc.) and clinicopathological features (pathological stage, lymph node, and metastasis, etc.). We also built a nomogram based on three independent prognostic predictors (including individual neoplasm status, lymph node metastasis, and risk score) for the prediction of 1-, 3-, and 5-year OS of pancreatic cancer, which may help to further improve the treatment strategy of pancreatic cancer.

Development and Validation of a Metabolic-related Prognostic Model for Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Growing evidence suggests that metabolic-related genes have a significant impact on the occurrence and development of hepatocellular carcinoma (HCC). However, the prognostic value of metabolic-related genes for HCC has not been fully revealed. METHODS: mRNA sequencing and clinical data were obtained from The Cancer Genome Atlas and the GTEx Genotype-Tissue Expression comprehensive database. Differentially expressed metabolic-related genes in tumor tissues (n=374) and normal tissues (n=160) were identified by the Wilcoxon test. Time-dependent receiver operating characteristic curve analysis, univariate multivariate Cox regression analysis and Kaplan-Meier survival analysis were used to evaluate the predictive effectiveness and independence of the prognostic model. Two independent cohorts (International Cancer Genome Consortiums and GSE14520) were applied to verify the prognostic model. RESULTS: Our study included a total of 793 patients with HCC. We constructed a risk score consisting of five metabolic-genes (BDH1, RRM2, CYP2C9, PLA2G7, and TXNRD1). For the overall survival rate, the low-risk group had a considerably higher rate than the high-risk group. Univariate and multivariate Cox regression analyses indicated that the risk score was an independent predictor for the prognosis of HCC. CONCLUSIONS: We constructed and validated a novel prognostic model, which may provide support for the precise treatment of HCC.

Development and Validation of a Robust Immune-Related Prognostic Signature for Gastric Cancer.

BACKGROUND: An increasing number of reports have found that immune-related genes (IRGs) have a significant impact on the prognosis of a variety of cancers, but the prognostic value of IRGs in gastric cancer (GC) has not been fully elucidated. METHODS: Univariate Cox regression analysis was adopted for the identification of prognostic IRGs in three independent cohorts (GSE62254, n = 300; GSE15459, n = 191; and GSE26901, n = 109). After obtaining the intersecting prognostic genes, the three independent cohorts were merged into a training cohort (n = 600) to establish a prognostic model. The risk score was determined using multivariate Cox and LASSO regression analyses. Patients were classified into low-risk and high-risk groups according to the median risk score. The risk score performance was validated externally in the three independent cohorts (GSE26253, n = 432; GSE84437, n = 431; and TCGA, n = 336). Immune cell infiltration (ICI) was quantified by the CIBERSORT method. RESULTS: A risk score comprising nine genes showed high accuracy for the prediction of the overall survival (OS) of patients with GC in the training cohort (AUC > 0.7). The risk of death was found to have a positive correlation with the risk score. The univariate and multivariate Cox regression analyses revealed that the risk score was an independent indicator of the prognosis of patients with GC (p < 0.001). External validation confirmed the universal applicability of the risk score. The low-risk group presented a lower infiltration level of M2 macrophages than the high-risk group (p < 0.001), and the prognosis of patients with GC with a higher infiltration level of M2 macrophages was poor (p = 0.011). According to clinical correlation analysis, compared with patients with the diffuse and mixed type of GC, those with the Lauren classification intestinal GC type had a significantly lower risk score (p = 0.00085). The patients' risk score increased with the progression of the clinicopathological stage. CONCLUSION: In this study, we constructed and validated a robust prognostic signature for GC, which may help improve the prognostic assessment system and treatment strategy for GC.

Eight-gene prognostic signature associated with hypoxia and ferroptosis for gastric cancer with general applicability.

Aims: To investigate the prognostic significance of hypoxia- and ferroptosis-related genes for gastric cancer (GC). Materials & methods: We extracted data on 259 hypoxia- and ferroptosis-related genes from The Cancer Genome Atlas and identified the differentially expressed genes between normal (n = 32) and tumor (n = 375) tissues. A risk score was established by univariate Cox regression analysis and LASSO penalized Cox regression analysis. Results: The risk score contained eight genes showed good performance in predicting overall survival and relapse-free survival in GC patients in both the training cohort (The Cancer Genome Atlas, n = 350) and the testing cohorts (GSE84437, n = 431; GSE62254, n = 300; GSE15459, n = 191; GSE26253, n = 432). Conclusion: The eight-gene signature may help to the improve the prognostic risk classification of GC.

Mutation profile and its correlation with clinicopathology in Chinese hepatocellular carcinoma patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer worldwide. Although many studies have focused on oncogene characteristics, the genomic landscape of Chinese HCC patients has not been fully clarified. METHODS: A total of 165 HCC patients, including 146 males and 19 females, were enrolled. The median age was 55 years (range, 27-78 years). Corresponding clinical and pathological information was collected for further analysis. A total of 168 tumor tissues from these patients were selected for next-generation sequencing (NGS)-based 450 panel gene sequencing. Genomic alterations including single nucleotide variations (SNV), short and long insertions and deletions (InDels), copy number variations, and gene rearrangements were analyzed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. The top quartile of HCC was classified as TMB high. RESULTS: A total of 1,004 genomic alterations were detected from 258 genes in 168 HCC tissues. TMB values were identified in 160 HCC specimens, with a median TMB of 5.4 Muts/Mb (range, 0-28.4 Muts/Mb) and a 75% TMB of 7.7 Muts/Mb. The most commonly mutated genes were TP53, TERT, CTNNB1, AXIN1, RB1, TSC2, CCND1, ARID1A, and FGF19. SNV was the most common mutation type and C:G>T:A and guanine transformation were the most common SNVs. Compared to wild-type patients, the proportion of Edmondson grade III-IV and microvascular invasion was significantly higher in TP53 mutated patients (P<0.05). The proportion of tumors invading the hepatic capsule was significantly higher in TERT mutated patients (P<0.05). The proportion of Edmondson grade I-II, alpha fetoprotein (AFP) <25 µmg/L, and those without a history of hepatitis B was significantly higher in CTNNB1 mutated patients (P<0.05). CTNNB1 mutations were associated with TMB high in HCC patients (P<0.05). Based on correlation analysis, the mutation of TP53 was independently correlated with microvascular invasion (P=0.002, OR =3.096) and Edmondson grade III-IV (P=0.008, OR =2.613). The mutation of TERT was independently correlated with tumor invasion of the liver capsule (P=0.001, OR =3.030), and the mutation of CTNNB1 was independently correlated with AFP (<25 µmg/L) (P=0.009, OR =3.414). CONCLUSIONS: The most frequently mutated genes of HCC patients in China were TP53, TERT, and CTNNB1, which mainly lead to the occurrence and development of HCC by regulating the P53 pathway, Wnt pathway, and telomere repair pathway. There were more patients with microvascular invasion and Edmondson III-IV grade in TP53 mutated patients and more patients with hepatic capsule invasion in TERT mutated patients, while in CTNNB1 mutated patients, there were more patients with Edmondson I-II grade, AFP <25 µmg/L, and a non-hepatitis B background. Also, the TMB values were significantly higher in CTNNB1 mutated patients than in wild type patients.

WITHDRAWN: Correlation analysis of pleural effusion and lung infection after liver transplantation.

Ahead of Print article withdrawn by publisher. The paper entitled "Correlation analysis of pleural effusion and lung infection after liver transplantation " by Chuanshen XU et al., which was published online on April 23, 2021, has been withdrawn by the Publisher due to double publication; the authors submitted for evaluation the same paper to more than one journal at the same time, which caused the double publication.

Immunotherapeutic strategy based on anti-OX40L and low dose of IL-2 to prolong graft survival in sensitized mice by inducing the generation of CD4+ and CD8+ Tregs.

Alloreactive memory cells play a critical role after a second transplant and are difficult to suppress. This study investigated the effect of an immunotherapeutic strategy that combines anti-OX40L, rapamycin (Rapa), and a low dose of IL-2 in a memory cell-based adoptive model. In this model, the median survival time (MST) of the grafts of the combined treatment group was significantly extended compared to that of the control group and other treatment groups. A similar effect was observed regarding a reduction in memory T cells (Tm) and inflammatory cytokines production. Also, the percentages of Foxp3+ regulatory T cells (Tregs) increased in our model. In addition, mounting evidence has shown CD8+CD122+ T cells are also Tregs. We found that the group of CD8+CD122+PD1+ T cells was markedly increased in the combined treatment group, especially in the graft. We further demonstrated that CD8+CD122+PD1+ T cells could suppress activated T cells. Our data suggest that anti-OX40L combined with Rapa and a low dose of IL-2 can suppress Tm, modulate CD4 and CD8 Tregs, and induce long-term heart allograft survival in sensitized mice.

Eleven immune-gene pairs signature associated with TP53 predicting the overall survival of gastric cancer: a retrospective analysis of large sample and multicenter from public database.

BACKGROUND: Growing attention have been paid to the relationship between TP53 and tumor immunophenotype, but there are still lacking enough search on the field of gastric cancer (GC). MATERIALS AND METHODS: We identified differential expressed immune-related genes (DEIRGs) between the TP53-altered GC samples (n = 183) and without TP53-altered GC samples (n = 192) in The Cancer Genome Atlas and paired them. In the TCGA cohort (n = 350), a risk score was determined through univariate and multivariate cox regression and Lasso regression analysis. Patients were divided into two groups, high-risk and low-risk, based on the median risk score. Four independent cohorts (GSE84437,n = 431; GSE62254, n = 300; GSE15459, n = 191; GSE26901, n = 100) from the Gene Expression Omnibus (GEO) database were used to validate the reliability and universal applicability of the model. RESULTS: The signature contained 11 gene pairs showed good performance in predicting progression-free survival (PFS), disease-free survival (DFS), disease special survival (DSS), and the overall survival (OS) for GC patients in the TCGA cohort. The subgroup analysis showed that the signature was suitable for GC patients with different characteristics. The signature could capable of distinguish GC patients with good prognosis and poor prognosis in all four independent external validation cohorts. The high- and low-risk groups differed significantly in the proportion of several immune cell infiltration, especially for the T cells memory resting, T cells memory activated and follicular helper, and Macrophage M0, which was also related to the prognosis of GC patients. CONCLUSION: The present work proposed an innovative system for evaluating the prognosis of gastric cancer. Considering its stability and general applicability, which may become a widely used tool in clinical practice.

Temperature Plays an Essential Regulatory Role in the Tumor Immune Microenvironment.

In recent years, emerging immunotherapy has been included in various malignant tumor treatment standards. Temperature has been considered to affect different pathophysiological reactions such as inflammation and cancer for a long time. However, in tumor immunology research, temperature is still rarely considered a significant variable. In this review, we discuss the effects of room temperature, body temperature, and the local tumor temperature on the tumor immune microenvironment from multiple levels and perspectives, and we discuss changes in the body's local and whole-body temperature under tumor conditions. We analyze the current use of ablation treatment-the reason for the opposite immune effect. We should pay more attention to the therapeutic potential of temperature and create a better antitumor microenvironment that can be combined with immunotherapy.

TSC2 Mutations Were Associated with the Early Recurrence of Patients with HCC Underwent Hepatectomy.

PURPOSE: To explore the value of Tuberous sclerosis complex 2 (TSC2) mutations in evaluating the early recurrence of hepatocellular carcinoma (HCC) patients underwent hepatectomy. PATIENTS AND METHODS: A total of 183 HCC patients were enrolled. Next-generation sequencing was performed on tumor tissues to analyze genomic alterations, tumor mutational burden and variant allele fraction (VAF). The associations between TSC2 mutations and recurrence rate within 1 year, RFS and OS after hepatectomy were analyzed. RESULTS: Our results showed that TSC2 mutation frequency in HCC was 12.6%. Compared to patients without TSC2 mutation, the proportion of microvascular invasion (MVI) and Edmondson grade III-IV was significantly higher in patients with a TSC2 mutation (p<0.05). The VAF of mutated TSC2 was higher in patients with maximum diameter of tumor >5cm or MVI than that of other patients (p<0.05). The frequency of TP53 mutation was significantly higher in patients with a TSC2 mutation than those without TSC2 mutation (p=0.003). Follow-up analysis showed that patients with a TSC2 mutation had significantly higher recurrence rate within 1 year (p=0.015) and poorer median recurrence-free survival (RFS) (p=0.010) than patients without TSC2 mutation. TSC2 mutations did not significantly affect overall survival of patients (p=0.480). The multivariate analysis results showed that the Barcelona Clinic Liver Cancer (BCLC) B-C stage, TSC2 mutations and preoperative serum alpha-fetoprotein level ≥400µg/L were independently associated with recurrence within 1 year after hepatectomy (HR=8.628, 95% CI: 3.836-19.405, p=0.000; HR=3.885, 95% CI: 1.295-11.653, p=0.015; HR=2.327, 95% CI: 1.018-5.323, p=0.045; respectively), and poorer RFS after hepatectomy (HR=3.070, 95% CI: 1.971-4.783, p=0.000; HR=1.861, 95% CI: 1.061-3.267, p=0.030; HR=1.715, 95% CI: 1.093-2.693, p=0.019; respectively). CONCLUSION: TSC2 mutations were significantly associated with MVI in liver para-carcinoma tissue and Edmondson grade III-IV in patients with HCC and were independently associated with recurrence within 1 year and poorer RFS after hepatectomy. The TSC2 mutation may be a potential predictor for early recurrence in HCC patients underwent hepatectomy.

Clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma.

BACKGROUND: The goal of this study is to disclose the clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma. METHODS: A total of 86 Chinese patients were enrolled in this study. A panel of 579 pan-cancer genes was sequenced for the qualified samples from these patients. Driver genes, actionability, and tumor mutational burden were inferred and compared to a cohort of Western patients. RESULTS: Totally, 36 and 12 driver genes were identified in the Chinese and Western cohorts, respectively. Of them, seven driver genes (IDH1, KRAS, TP53, BAP1, PBRM1, ARID1A, and NRAS) were shared by the two cohorts. Four driver genes (SPTA1, ARID2, TP53, and GATA1) were found significantly correlated with the tumor mutational burden. For both cohorts, half of the patients had actionable mutations. The two cohorts shared the most actionable genes but differed much in their frequency. Though KRAS mutations were at the first and second actionable rank respectively for the Chinese and Western populations, they were still at a relatively low level of actionable evidence. CONCLUSIONS: The study on the clinical significance of genomic alterations directs the future development of precision medicine for intrahepatic cholangiocarcinoma treatment.

Eight-gene metabolic signature related with tumor-associated macrophages predicting overall survival for hepatocellular carcinoma.

BACKGROUND: In recent years, the relationship between tumor-associated macrophages (TAMs) and solid tumors has become a research hotspot. This study aims to explore the close relationship of TAMs with metabolic reprogramming genes in hepatocellular carcinoma (HCC) to provide new methods of treatment for HCC. METHODS: The study selected 343 HCC patients with complete survival information (survival time > = 1 month) in the Cancer Genome Atlas (TCGA) as study subjects. Kaplan-Meier survival analysis assisted in determining the relationship between macrophage infiltration and overall survival (OS), and Pearson correlation tests were used to identify metabolic reprogramming genes (MRGs) associated with tumor macrophage abundance. Lasso regression algorithms were used on prognosis-related MRGs identified by Kaplan-Meier survival analysis and univariate Cox regression analysis to construct a risk score; another independent cohort (including 228 HCC patients) from the International Cancer Genome Consortium (ICGC) was used to verify prognostic signature externally. RESULTS: A risk score composed of 8 metabolic genes could accurately predict the OS of a training cohort (TCGA) and a testing cohort (ICGC). The risk score could be widely used for people with different clinical characteristics, and it is a predictor that is independent of other clinical factors that affect prognosis. As expected, compared with the low-risk group, the high-risk group exhibited an obviously higher macrophage abundance, together with a positive correlation between the risk score and the expression levels of three commonly used immune checkpoints (PD1, PDL1, and CTLA4). CONCLUSION: Our study constructed and validated a novel eight-gene signature for predicting HCC patient OS, which may contribute to clinical treatment decisions.