Junyu Long

PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy

Gastrointestinal (GI) malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.

Identification of hub genes involved in the development of hepatocellular carcinoma by transcriptome sequencing

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The aim of this study was to identify underlying hub genes and dysregulated pathways associated with the development of HCC using bioinformatics analysis. Differentially expressed protein-coding genes were subjected to transcriptome sequencing in 11 pairs of liver cancer tissue and matched adjacent non-cancerous tissue. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, followed by protein-protein interaction (PPI) network construction. Hub genes were identified via centralities analysis and verified using published datasets. In total, 720 significantly differentially expressed protein-coding genes were identified in the samples, including 335 upregulated genes and 385 downregulated genes. The upregulated genes were significantly enriched in cell adhesion, biological adhesion and cell-cell adhesion GO terms under biological process (BP). Conversely, the downregulated genes were significantly enriched in embryonic organ morphogenesis, embryonic organ development and embryonic morphogenesis. The KEGG pathway analysis showed that the upregulated genes were enriched in ECM-receptor interaction and focal adhesion pathways. Furthermore, the downregulated genes were enriched in the ErbB, VEGF and MAPK signaling pathways. The PPI network and centralities analysis suggested that ITGA2 and 12 alternate genes were significant hub genes. These findings improve current understanding of the molecular mechanisms underlying HCC development and may be helpful in identifying candidate molecular biomarkers for use in diagnosing, treating and monitoring the prognosis of HCC.

Prognostic significance of combined preoperative fibrinogen and CA199 in gallbladder cancer patients

AIM To investigate the prognostic value of the combination of preoperative plasma fibrinogen and CA199 in patients with gallbladder carcinoma (GBC). METHODS The clinicopathological data of 154 GBC patients were retrospectively reviewed after surgery. A receiver operating characteristic (ROC) curve was plotted to verify the optimum cut-off values for plasma fibrinogen and CA199. Univariate and multivariate survival analyses were performed to identify the factors associated with GBC prognosis. Based on the HRs calculated via multivariate survival analyses, patients with elevated plasma fibrinogen and CA199 levels were allocated a score of 2.1; those with an elevated plasma fibrinogen level only were allocated a score of 1, those with an elevated CA199 level only were allocated a score of 1.1, and those with neither of these abnormalities were allocated a score of 0. RESULTS ROC curve analysis showed that the optimum cut-off values for preoperative plasma fibrinogen and CA199 were 3.47 g/L and 25.45 U/mL, respectively. Multivariate analysis indicated that elevated preoperative plasma fibrinogen and CA199 levels were significantly correlated with worse overall survival (OS) (HR = 1.711, 95%CI: 1.114-2.627, P = 0.014, and HR = 1.842, 95%CI: 1.111-3.056, P = 0.018). When we combined these two parameters, the area under the ROC curve increased from 0.735 (for preoperative plasma fibrinogen only) and 0.729 (for preoperative CA199 only) to 0.765. When this combined variable was added to the multivariate analysis, the combination of plasma fibrinogen and CA199 (P < 0.001), resection margin (P < 0.001) and TNM stage (P = 0.010) were independent prognostic factors for GBC. CONCLUSION The combination of plasma fibrinogen and CA199 may serve as a more efficient independent prognostic biomarker for postoperative GBC patients than either parameter alone.

Prognostic significance of the fibrinogen-to-albumin ratio in gallbladder cancer patients

AIM To investigate the prognostic role of fibrinogen-to-albumin ratio (FAR) on patients with gallbladder cancer (GBC) in this study. METHODS One hundred and fifty-four GBC patients were retrospectively analyzed, who received potentially curative cholecystectomy in our institute from March 2005 to December 2017. Receiver operating characteristic curve (ROC curve) was used to determine the optimal cut-offs for these biomarkers. In addition, Kaplan-Meier survival analysis as well as multivariate analysis were applied for prognostic analyses. RESULTS ROC curve revealed that the optimal cut-off value for FAR was 0.08. FAR was significantly correlated with age (P = 0.045), jaundice (P < 0.001), differentiation (P = 0.002), resection margin status (P < 0.001), T stage (P < 0.001), TNM stage (P < 0.001), and CA199 (P < 0.001) as well as albumin levels (P < 0.001). Multivariate analysis indicated that the resection margin status [hazard ratio (HR): 2.343, 95% confidence interval (CI): 1.532-3.581, P < 0.001], TNM stage (P = 0.035), albumin level (HR = 0.595, 95%CI: 0.385-0.921, P = 0.020) and FAR (HR: 2.813, 95%CI: 1.765-4.484, P < 0.001) were independent prognostic factors in GBC patients. CONCLUSION An elevated preoperative FAR was significantly correlated with unfavorable overall survival in GBC patients, while an elevated preoperative albumin level was a protective prognostic factor for patients with GBC. The preoperative FAR could be used to predict the prognosis of GBC patients, which was easily accessible, cost-effective and noninvasive.

Prognostic impact of the red cell distribution width in esophageal cancer patients: A systematic review and meta-analysis

AIM To clarify the previous discrepant conclusions, we performed a meta-analysis to evaluate the prognostic value of red cell distribution width (RDW) in esophageal cancer (EC). METHODS We searched the PubMed, EMBASE, Web of Science and Cochrane Library databases to identify clinical studies, followed by using STATA version 12.0 for statistical analysis. Studies that met the following criteria were considered eligible: (1) Studies including EC patients who underwent radical esophagectomy; (2) studies including patients with localized disease without distant metastasis; (3) studies including patients without preoperative neoadjuvant therapy; (4) studies including patients without previous antiinflammatory therapies and with available preoperative laboratory outcomes; (5) studies reporting association between the preoperative RDW and overall survival (OS)/disease-free survival (DFS)/cancer-specific survival (CSS); and (6) studies published in English. RESULTS A total of six articles, published between 2015 and 2017, fulfilled the selection criteria in the end. Statistical analysis showed that RDW was not associated with the prognosis of EC patients, irrespective of OS/CSS [hazard ratio (HR) = 1.27, 95% confidence interval (CI): 0.97-1.57, P = 0.000] or DFS (HR = 1.42, 95%CI: 0.96-1.88, P = 0.000). Subgroup analysis indicated that elevated RDW was significantly associated with worse OS/CSS of EC patients when RDW > 13% (HR = 1.45, 95%CI: 1.13-1.76, P = 0.000), when the patient number ≤ 400 (HR = 1.45, 95%CI: 1.13-1.76, P = 0.000) and when the study type was retrospective (HR = 1.42, 95%CI : 1.16-1.69, P = 0.000). CONCLUSION Contrary to our general understanding, this meta-analysis revealed that RDW cannot serve as an indicator of poor prognosis in patients with EC. However, it may still be a useful predictor of unfavorable prognosis using an appropriate cut-off value.

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.

Prognostic significance of the platelet-to-lymphocyte ratio in ovarian cancer: a meta-analysis

Background: Recent studies have shown that the pretreatment measurement of the peripheral platelet-to-lymphocyte ratio (PLR) is an independent predictor of poor prognosis of various types of malignancies. However, the relationship between the pretreatment PLR and the prognosis of ovarian cancer remains largely undefined. A meta-analysis was conducted to investigate the prognostic significance of PLR in patients with ovarian cancer. n Methods: We searched the PubMed, Embase and Web of Science databases to collect eligible studies, followed by application of STATA version 12.0 for statistical analysis. Results: Eight studies enrolling 1,636 patients were ultimately included in this meta-analysis. As a result, an elevated PLR was significantly correlated with poor OS [hazard ration (HR) =5.95, 95% confidence interval (CI): 4.35–8.14, P=0.000] in patients with ovarian cancer. Moreover, subgroup analyses revealed that an elevated PLR was able to predict poor OS when the cut-off value was near 200 (HR =6.78, 95% CI: 4.50–10.21, P Conclusions: This meta-analysis revealed that the pretreatment PLR with different cut-off values could be utilized as a negative prognostic indicator in patients with ovarian cancer undergoing various treatments.

Hypertension and risk of cholangiocarcinoma: a systematic review and meta-analysis

Background: Hypertension has been demonstrated to enhance the risk of cholangiocarcinoma (CCC) by several researches, which, however, still remains controversial. To this end, a systematic review and meta-analysis was performed to further investigate the association between hypertension and CCC risk. Methods: We searched PubMed, EMBASE, ISI Web of Science to collect relevant researches published before November 2017. Afterwards, random effects model proposed by DerSimonian and Laird was employed to determine the correlation between hypertension and CCC risk. Results: Nine articles, comprising 2,016 patients with CCC and 199,812 healthy controls, were finally enrolled in our study. Our findings failed to support the correlation between hypertension and elevated risk of CCC among these heterogeneous studies [summary odds ratio (OR), 0.87; 95% confidence interval (CI), 0.57–1.17; I 2 =79.5%]. In subgroup analysis following separation of intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC), hypertension also failed to harbor a correlation with elevated risk of ECC (OR, 0.74; 95% CI, 0.42–1.37) and ICC (OR, 1.07; 95% CI, 0.43–1.71). n Conclusions: Hypertension did not harbor any correlation with elevated risk of CCC.

A four-gene-based prognostic model predicts overall survival in patients with hepatocellular carcinoma

With the development of new advances in hepatocellular carcinoma (HCC) management and noninvasive radiological techniques, high‐risk patient groups such as those with hepatitis virus are closely monitored. HCC is increasingly diagnosed early, and treatment may be successful. In spite of this progress, most patients who undergo a hepatectomy will eventually relapse, and the outcomes of HCC patients remain unsatisfactory. In our study, we aimed to identify potential gene biomarkers based on RNA sequencing data to predict and improve HCC patient survival. The gene expression data and clinical information were acquired from The Cancer Genome Atlas (TCGA) database. A total of 339 differentially expressed genes (DEGs) were obtained between the HCC (n = 374) and normal tissues (n = 50). Four genes (CENPA, SPP1, MAGEB6 and HOXD9) were screened by univariate, Lasso and multivariate Cox regression analyses to develop the prognostic model. Further analysis revealed the independent prognostic capacity of the prognostic model in relation to other clinical characteristics. The receiver operating characteristic (ROC) curve analysis confirmed the good performance of the prognostic model. Then, the prognostic model and the expression levels of the four genes were validated using the Gene Expression Omnibus (GEO) dataset. A nomogram comprising the prognostic model to predict the overall survival was established, and internal validation in the TCGA cohort was performed. The predictive model and the nomogram will enable patients with HCC to be more accurately managed in trials testing new drugs and in clinical practice.

Metabolic syndrome and the risk of cholangiocarcinoma: a hospital-based case–control study in China

Background Metabolic syndrome is regarded as a risk factor for hepatocellular carcinoma. However, no research has been conducted to investigate the association between metabolic syndrome and cholangiocarcinoma (CCA), especially in the Chinese population. Herein, a hospital-based case–control study was carried out in China to explore the association between metabolic syndrome and CCA risk. Patients and methods In this study, 303 CCA patients (136 intrahepatic cholangiocarcinoma [ICC] and 167 extrahepatic cholangiocarcinoma [ECC]) were included, who were observed at Peking Union Medical College Hospital (PUMCH), from 2002 to 2014. Healthy controls were randomly selected from the database of PUMPH Health Screening Center. We retrospectively extracted metabolic syndrome and other possible risk factors from clinical records, followed by investigation of the relationship with CCA via calculation of ORs and 95% CIs using logistic regression analysis. Results Metabolic syndrome was significantly and positively correlated with all CCA subtypes, with adjusted ORs (AORs) of 0.35 (95% CI =0.29–0.42) and 0.29 (95% CI =0.19–0.44) for ICC and ECC, respectively (both P<0.001). Dyslipoproteinemia harbored a stronger relationship with ICC (OR =3.16; 95% CI =2.12–4.71) than ECC (OR =1.87; 95% CI =1.27–2.77), whereas hypertension harbored a stronger association with ECC (OR =3.09; 95% CI =2.09–4.58) than ICC (OR =2.06; 95% CI =1.32–3.21). Obesity was related to both ICC and ECC, with similar ORs, while diabetes was only related to ICC (OR =4.59; 95% CI =2.78–7.58), but not ECC (OR =0.97; 95% CI =0.49–1.94). Conclusion Metabolic syndrome was significantly related to a 1.86-fold elevated CCA risk.