PRMT5-PAK1 Signaling Participates in Metastasis and Is Associated With Poor Prognosis in Human Esophageal Carcinoma.

BACKGROUND/AIM: Protein arginine methyltransferase 5 (PRMT5), a member of the arginine methyltransferases, is an enzyme catalyzing the methylation of arginine residuals of histones and non-histone proteins to serve as one of many critical posttranslational modifications (PTMs). Phosphorylated P21-activated kinase 1 (p-PAK1), a serine/threonine protein kinase family member, is a cytoskeletal protein that plays a critical role in metastasis. We examined the expression of PRMT5 and PAK1 in esophageal squamous cell carcinoma (ESCC) and evaluated the correlation between PRMT5/p-PAK1 and both clinicopathological parameters and prognosis of ESCC patients. MATERIALS AND METHODS: 106 tumor tissues collected from ESCC patients were assessed for PRMT5 and PAK1 expression using immunohistochemistry. Pearson's correlation and Kaplan-Meier analysis were used to estimate the correlation with the clinicopathological parameters and effect on patient survival. Western blot analysis was used to determine the PRMT5/p-PAK1 protein expression. The wound healing assay was performed to assess the effect of PRMT5 on the migration of ESCC cells. RESULTS: PRMT5 is upregulated in ESCC and the level of PRMT5 is correlated with metastasis and can serve as an independent prognostic factor for overall survival (OS). PRMT5 knockdown remarkably inhibited ESCC cell migration with concomitantly reduced levels of phosphorylated PAK1 (p-PAK1) but not total PAK1. Kaplan-Meier analysis showed that the OS of the subgroup of patients with PRMT5high/p-PAK1high is remarkably shorter than those of other subgroups (i.e., PRMT5high/p-PAK1low, PRMT5low/p-PAK1low and PRMT5low/p-PAK1high). CONCLUSION: PRMT5-PAK1 signaling participates in ESCC metastasis and can predict patients' outcomes.

Bioinformatics Analysis and Screening of Potential Target Genes Related to the Lung Cancer Prognosis.

OBJECTIVE: Several genes have been validated as molecular targets for gene therapy in lung cancer. We screened target genes that affect survival of patients with lung cancer. METHODS: Data on gene expression in normal lung tissues/lung adenocarcinoma (LUAD) samples were acquired from Genotype-Tissue Expression (GTEx)/The Cancer Genome Atlas (TCGA) databases and merged to expand the sample size, followed by differential analysis of the merged expression data and acquisition of differentially expressed genes. Survival and simple Cox analyses were used to screen for genes affecting LUAD survival. Protein-protein interaction/multivariable Cox analyses were utilized, and a risk model was established. Candidate genes expression levels in cancer/paracancerous tissues of lung cancer patients, and BEAS-2B/A549/HCC95 cells were measured by RT-qPCR/Western blot. Survival analysis of candidate genes was conducted in LUAD samples collected from TCGA. RESULTS: Among 947 genes differentially expressed in LUAD, 151 were correlated with patient survival, and 116 might act as risk factors for LUAD. The 7 identified candidate genes (TOP2A, TK1, KIF4A, ANLN, KIF2C, ASF1B, CCNB1) were high-risk genes playing possible roles in LUAD. These genes were differentially expressed in lung cancer and were associated with TNM stages (III - IV)/differentiation grade/lymph node metastasis/distant metastasis, which affected lung cancer patient survival. CONCLUSION: P2A, TK1, KIF4A, ANLN, KIF2C, ASF1B and CCNB1 were highly-expressed in LUAD/lung squamous cell carcinoma (LUSC) and correlated with LUAD patient survival. This study contributes to better understanding of the prognostic regulation mechanism in LUAD and the screening of target genes for clinical treatment.

The genomic characteristics of RET fusion positive tumors in Chinese non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Approximately 1-2% of non-small cell lung cancer (NSCLC) patients harbor RET (rearranged during transfection) fusions. The oncogenic RET fusions could lead to constitutive kinase activation and oncogenesis. METHODS: 1746 Chinese NSCLC patients were analyzed in this study. Tumor tissues were collected, and were formalin fixed, paraffin-embedded (FFPE) and archived. Peripheral blood (PB) samples were also collected from each patient as control. In addition, we selected 17 of them for cfDNA NGS testing and 14 tumor samples for immunohistochemistry testing using PD-L1 rabbit monoclonal antibody, clones 28-8 (Abcam, Cambridge, UK). RESULTS: Of the 1746 NSCLC cases, RET rearrangements were identified in 25 cases (1.43%) with locally advanced or metastatic NSCLC, of which 20 (80%) were female. We found that 14 out of 25 patients had an KIF5B-RET fusion, with KIF5B exon15-RET exon12, KIF5B exon23-RET exon12, and KIF5B exon24-RET exon11 detected in 14, 3, and 1 patients, respectively. We also identified one novel RET fusion partner PLCE1 and 4 intergenic-breakpoint fusions. CONCLUSION: In this study, using the hybrid capture based next generation sequencing (NGS) techniques, we revealed the genomic profiling for the patients with RET fusion-positive NSCLC. To the best of our knowledge, this is the first study that exhibited the detailed breakpoints of Chinese NSCLC patients with RET rearrangement, and we found a novel new partner PLCE1. The results provided genomic information for patients with RET fusion which is significant for personalized clinical management in the era of precision medicine.

Clinical Significance and Immune Landscape of Recurrence-Associated Ferroptosis Signature in Early-Stage Lung Adenocarcinoma.

BACKGROUND: The prevalence of patients newly diagnosed with early-stage lung adenocarcinoma (LUAD) is growing alongside significant advances in screening approaches. This study aimed to construct ferroptosis-related gene score (FRGscore) for predicting recurrence, explore immune-molecular characteristics, and determine the benefit of immunotherapy in distinct ferroptosis-based patterns and FRGscore-defined subgroups. METHODS: A total of 1,085 early-stage LUAD patients from four independent cohorts were included. Consensus clustering analysis was performed using 217 co-expressed FRGs to explore different ferroptosis-mediated patterns. An FRG scoring system was established to predict relapse, quantify ferroptosis-mediated patterns, and evaluate the response to immunotherapy in individual patients based on Lasso-penalized and stepwise Cox regression analyses. Immune landscape involving multiple parameters was further evaluated, stratified by cluster subtypes and FRGscore subgroups. RESULTS: Two ferroptosis-mediated patterns were identified and verified, which were characterized by significantly distinct prognosis and immune profiles. Analyses of immune characteristics showed that identified ferroptosis patterns were characterized as immune-inflamed phenotype and immune-exhausted phenotype. The FRG scoring model based on 11 FRG-derived signatures panel classified patients into the FRGscore-high and FRGscore-low subgroups. Significantly longer recurrence-free survival (RFS) and overall survival (OS) were observed in the FRGscore-low subgroup. FRGscore-low patients were characterized by higher tumor mutational burden (TMB), immunoscore, immunophenoscore, and PD-L1 expression level and were associated with lower Tumor Immune Dysfunction and Exclusion (TIDE) score, whereas the opposite was observed in FRGscore-high patients. Immune-active pathways were remarkably enriched in the FRGscore-low subgroup. This scoring model remained highly predictive of prognosis across different clinical, molecular, and immune subgroups. Further analysis indicated that FRGscore-low patients exhibited higher response to anti-PD-1/PD-L1 immunotherapy and better clinical benefits based on two independent immunotherapy cohorts. CONCLUSION: The proposed FRGscore could highly distinguish the recurrence patterns and molecular and immune characteristics and could predict immunotherapy prognosis, potentially representing a powerful prognostic tool for further optimization of individuated treatment and management strategies in early-stage LUAD.

Apatinib Combined with Irinotecan in the Treatment of Advanced Small-Cell Esophageal Carcinoma: A Case Report.

Chemotherapy is the mainstay of treatment for advanced small cell esophageal carcinoma (SCEC) characterized by poor prognosis. Preclinical studies demonstrated that apatinib has the potential to enhance the efficacy of conventional chemotherapeutic drugs and reverse multidrug resistance (MDR). This report described the application of apatinib combined with irinotecan as the third-line treatment for advanced SCEC in a 54-year-old male patient. His symptoms of upper abdominal pain and distension were ameliorated notably after the combination therapy. Computed tomography (CT) examination revealed the treatment efficacy was partial response (PR). The progression-free survival (PFS) and overall survival (OS) were 12.5 months and 28 months, respectively. The treatment-related toxicity was manageable. Apatinib combined with chemotherapy may serve as a new treatment choice for advanced SCEC patients. However, further studies should be conducted to confirm the therapeutic value of this combination regimen in advanced SCEC.

Integrative stemness characteristics associated with prognosis and the immune microenvironment in esophageal cancer.

BACKGROUND: Cancer stem cells (CSCs) induces tumor metastasis and recurrence. However, the role of CSCs in molding the tumor immune microenvironment (TIME) is largely inexplicit. This study aimed to comprehensively characterize the stemness of esophageal cancer (EC) and correlate the stemness patterns with TIME. METHODS: A trained stemness index model was used to score EC patients based on the one-class logistic regression (OCLR) machine-learning algorithm. Gene expression-based stemness index (mRNAsi) and DNA methylation-based stemness index (mDNAsi) were calculated for integrative analyses of EC stemness in the training cohort (n = 182) and validation cohort (n = 179). Intrinsic stemness patterns were estimated to determine its association with clinical features, biological pathways, prognosis, and potential inhibitors. Additionally, the dynamic interplay between EC stemness and TIME was integrally characterized. RESULTS: Analyses of EC stemness and clinical characteristics indicated that higher-stage and metastatic tumors featured more dedifferentiated phenotypically. Univariate and multivariate Cox regression analyses revealed that mRNAsi was significantly associated with overall survival (OS) of EC patients, whereas no relationship was observed between mDNAsi and OS. Notably, prolonged OS was observed with esophageal squamous cell carcinoma (ESCC) in low versus high mRNAsi groups, whereas the OS was equivalent between the two groups for esophageal adenocarcinoma (ESAD). The mRNAsi may thus recapitulate prognostic molecular subgroups of EC. The prognostic model comprising 14 stemness signatures was constructed using combined Cox and Lasso regression analyses which effectively distinguished individual survival of ESCC in two cohorts. Nevertheless, no significant differences in OS was observed when the same prognostic model of ESCC was applied to ESAD. Gene Set Enrichment Analysis (GSEA) of selected stemness signatures indicated that ESCC stemness is involved in immune-related pathways. Furthermore, ESCC stemness and stemness-related signatures were associated with tumor-infiltrating immune cells, immunoscore, and PD-L1 expression. Compounds specific to the selected stemness signatures were detected using the CMap database. CONCLUSION: This study determined integrated characteristics of EC stemness. The identified mRNAsi-based signatures conferred with the predictive ability of personalized ESCC prognosis and highlighted the potential targets for CSC-mediated immunotherapy. Analyses of the interface between ESCC stemness and TIME may help in predicting the efficacy of CSC-specific immunotherapy and provide insight into combinatorial therapy by targeting ESCC stem cells and TIME.

Optimal timing of antiviral therapy for patients with malignant tumor who presented with hepatitis B reactivation during chemotherapy and/or immunosuppressive therapy.

Background: Hepatitis B virus (HBV) reactivation may occur with chemotherapy and/or immunotherapy. Antiviral prophylaxis is recommended for all patients who are hepatitis B surface antigen (HBsAg)-positive during chemotherapy and/or immunosuppressive therapy. However, the optimal timing of antiviral therapy before chemotherapy and/or immunosuppressive therapy is not fully elucidated. Patients and methods: We retrospectively evaluated 446 HBsAg-positive patients who underwent chemotherapy and/or immunosuppressive therapy. The cumulative rates of HBV reactivation were evaluated using the Kaplan-Meier method and were compared using the log-rank test. The risk factors of HBV reactivation were examined via univariate and multivariate analyses using the Cox proportional hazards model. Results: The cumulative HBV reactivation rates of patients who received antiviral therapy before chemotherapy and/or immunosuppressive therapy were significantly lower than those of patients who received antiviral therapy after chemotherapy and/or immunosuppressive therapy (P = 0.002). The incidence of HBV reactivation was significantly different between patients who received antiviral therapy at least 1 day before chemotherapy and/or immunosuppressive therapy and those who did not (P = 0.006). No significant difference was observed in the HBV reactivation rates between patients who received antiviral therapy at least 2 days (P = 0.310), 3 days (P = 0.494), and 1 week (P = 0.655) before chemotherapy and/or immunosuppressive therapy and those who did not. The multivariate Cox proportional hazards model showed that women had a lower risk of developing HBV reactivation than men (P = 0.025). The use of the prophylactic antiviral agent entecavir, compared with lamivudine and telbivudine, was associated with the decreased risk of developing HBV reactivation (P = 0.002). Conclusion: HBsAg-positive patients who received preemptive antiviral therapy after chemotherapy and/or immunosuppressive therapy had a high risk of developing HBV reactivation. However, it is not necessary for patients to receive antiviral therapy at least 1 week before chemotherapy and/or immunosuppressive therapy.

Prognostic Value of Site-Specific Metastases and Surgery in De Novo Stage IV Triple-Negative Breast Cancer: A Population-Based Analysis.

BACKGROUND This retrospective study aimed to evaluate the prognostic roles of distant metastatic patterns in de novo metastatic triple-negative breast cancer to explore the roles of surgery on the primary tumor and to characterize the prognostic factors of organ-specific metastasis. MATERIAL AND METHODS Data were obtained from the Surveillance, Epidemiology, and End Results program. Kaplan-Meier analyses and log-rank tests were employed to compare survival outcomes among variables. The Cox proportional hazards model was used to assess risk factors for survival. The key endpoints were overall survival and breast cancer-specific survival. RESULTS A total of 1888 patients were eligible. Distant metastatic site displayed a significant prognostic impact on survival. Using liver metastasis as the reference, overall survival was higher for bone (hazard ratio [HR] 0.770, 95% confidence interval [CI] 0.634-0.935, P=0.008) and lung (HR 0.747, 95% CI 0.612-0.911, P=0.004) metastases. Using patients with brain metastasis as the reference, patients with bone (HR 0.516, 95% CI 0.392-0.680, P<0.001), lung (HR 0.500, 95% CI 0.379-0.661, P<0.001) or liver (HR 0.670, 95% CI 0.496-0.905, P=0.009) metastases exhibited better overall survival. Single-site metastatic patients who received surgery for the primary tumor had more favorable overall survival (P<0.001) and breast cancer-specific survival (P<0.001) than those who did not. Additionally, age, insurance status, chemotherapy, and surgery affected overall survival for patients with isolated bone metastasis; chemotherapy, and surgery affected overall survival for patients with isolated lung metastasis; and insurance status, chemotherapy, and surgery affected overall survival for patients with isolated liver metastasis. CONCLUSIONS Our study verified the specific prognostic significance of distant metastatic site for metastatic triple-negative breast cancer at diagnosis. Surgery on the primary tumor significantly improved survival for patients with single distant metastasis. The identified prognostic factors contributed to evaluating the prognoses for distant metastatic triple-negative breast cancer patients.