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.

Carbon confined GeO2 hollow spheres for stable rechargeable Na ion batteries.

Germanium (Ge) based nanomaterials are regarded as promising high-capacity anode materials for Na ion batteries, but suffer fast capacity fading problems caused by the alloying/de-alloying reactions of Na-Ge. Herein, we report a new method for preparing highly dispersed GeO2 by using molecular-level ionic liquids (ILs) as carbon sources. In the obtained GeO2@C composite material, GeO2 exhibits hollow spherical morphology and is uniformly distributed in the carbon matrix. The as-prepared GeO2@C exhibits improved Na ion storage performances including high reversible capacity (577 mA h g-1 at 0.1C), rate property (270 mA h g-1 at 3C), and high capacity retention (82.3% after 500 cycles). The improved electrochemical performance could be attributed to the unique nanostructure of GeO2@C, the synergistic effect between GeO2 hollow spheres and the carbon matrix ensures the anode material effectively alleviates the volume expansion and the particle agglomeration problems.

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.

Impact of Home Parenting Environment on Cognitive and Psychomotor Development in Children Under 5 Years Old: A Meta-Analysis.

This study aims to evaluate the relationship between home parenting environment and the cognitive and psychomotor development in children under 5 years old by using meta-analysis. A systematic search of the Chinese and English databases including Pubmed, Embase, the Cochrane Library, CNKI, Weipu, Wanfang, and CBMdisc databases from January 1, 1990, to July 31, 2021, was performed. Articles concerning the relationship between home parenting environment and the cognitive and psychomotor development in children under 5 years old were included. Review Manager 5.4 was used for meta-analysis. Subgroup analysis in terms of age and region were performed. A total of 12 articles were included, including 11 in English and 1 in Chinese. Meta-analysis showed that there was significant relationship between home parenting environment and the cognitive and psychomotor development of children (r = 0.31; r = 0.21). Subgroup analysis showed that correlation between home parenting environment and the cognitive and psychomotor development of children was stronger in children over 18 months compared to those under 17 months [(r = 0.33, r = 0.21) vs. (r = 0.28, r = 0.17)]. The converted summary r value between home parenting environment and cognitive development in developing and developed countries was both 0.32. Conclusively, there is a positive correlation between the home parenting environment and the cognitive and psychomotor development of children under 5 years old. Improving the home parenting environment of children is beneficial to promote their early development.

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.

Comprehensive Analysis of the PD-L1 and Immune Infiltrates of m6A RNA Methylation Regulators in Head and Neck Squamous Cell Carcinoma.

Because most studies have focused on the intrinsic carcinogenic pathways of tumors, the underlying role of N6-methyladenosine (m6A) methylation in tumor immune microenvironment (TIME) remains elusive. Herein, we systematically explored the correlations of prominent m6A regulators with PD-L1 and immune infiltrates in 769 head and neck squamous cell carcinomas (HNSCCs; The Cancer Genome Atlas [TCGA] cohort, n = 499; GSE65858 cohort, n = 270). The PD-L1 expression evidently associated with m6A regulators. Two molecular subtypes (cluster1/2) were identified by consensus clustering for 15 m6A regulators. The cluster2 preferentially associated with favorable prognosis, upregulated PD-L1 expression, higher immunoscore, and distinct immune cell infiltration. The hallmarks of G2M checkpoint, mTORC1 signaling, and PI3K/AKT/mTOR signaling were remarkably enriched in the cluster1. A prognostic risk score was constructed using seven m6A regulator-associated signatures that represented an independent prognosis factor for HNSCC. Patients with low-risk score exhibited higher immunoscore and upregulated PD-L1 expression than patients with high-risk score. Consistently, m6A regulators showed the same influence on immune modulation and survival in external GSE65858 cohort. Further analysis revealed that m6A regulator-based signatures were implicated in TIME and their copy-number alterations dynamically affected the abundance of tumor-infiltrating immune cells. Collectively, our study elucidated the important role of m6A methylation in TIME of HNSCC. The proposed m6A regulator-based signatures might serve as crucial mediators of TIME in HNSCC, representing promising therapeutic targets in improving immunotherapeutic efficacy.

Comparison of the benefits of celecoxib combined with anticancer therapy in advanced non-small cell lung cancer: A meta-analysis.

Background: Studies have reported that advanced NSCLC benefits from celecoxib combined with systematic treatment. However, the optimal combination with different treatments remains unclear. A meta-analysis was conducted to explore treatment combinations. Methods: We searched the relevant literature via PubMed, EMBASE, the Cochrane Library and PMC. The data for the overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse effects were obtained. Subgroup analysis was performed according to the treatment pattern. Statistical analyses were carried out using Review Manager 5.3 software. Results: A total of 18 eligible studies were included, with 1178 advanced NSCLC patients. Subgroup analysis revealed that celecoxib combined with chemotherapy or tyrosine kinase inhibitors (TKIs) significantly increased the ORR, with no significant difference between the two groups. Celecoxib combined with chemotherapy improved OS-6 (OR=0.65, 95% CI 0.59-0.71, P<0.001), while OS-6 was not changed with celecoxib combined with TKIs (OR=0.53, 95% CI 0.31-0.73, P=0.82). Differences were apparent between the chemotherapy and TKIs regarding OS-6 (P=0.0392). Celecoxib combined with chemotherapy significantly prolonged OS-12 (OR=0.39, 95% CI 0.33-0.45, P<0.001). In terms of OS-12, there was no significant improvement when celecoxib was combined with radiotherapy or TKIs. Celecoxib combined with chemotherapy or TKIs significantly improved PFS-6 and PFS-12, with no obvious difference in terms of PFS between the two groups. Additionally, celecoxib combined with chemotherapy or TKI treatment increased the incidence of adverse events, with no significant differences between the two groups. Conclusions: Celecoxib combined with chemotherapy or TKIs improved the ORR, with no significant differences between the two groups. In terms of OS, celecoxib combined with chemotherapy was superior to TKIs or radiotherapy. Accordingly, celecoxib combined with chemotherapy increased hematological toxicity and cardiovascular events.

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.

CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter.

Rationale: Chemoresistance frequently occurs in patients with small cell lung cancer (SCLC) and leads to a dismal prognosis. However, the mechanisms underlying this process remain largely unclear. Methods: The effects of chromodomain Y-like (CDYL) on chemoresistance in SCLC were determined using Western blotting, immunohistochemistry, cell counting kit-8 assays, flow cytometry, and tumorigenicity experiments, and the underlying mechanisms were investigated using mRNA sequencing, chromatin immunoprecipitation-qPCR, electrophoretic mobility shift assays, co-immunoprecipitation, GST pull down assays, bisulfite sequencing PCR, ELISA, and bioinformatics analyses. Results: CDYL is expressed at high levels in chemoresistant SCLC tissues from patients, and elevated CDYL levels correlate with an advanced clinical stage and a poor prognosis. Furthermore, CDYL expression is significantly upregulated in chemoresistant SCLC cells. Using gain- and loss-of-function methods, we show that CDYL promotes chemoresistance in SCLC in vitro and in vivo. Mechanistically, CDYL promotes SCLC chemoresistance by silencing its downstream mediator cyclin-dependent kinase inhibitor 1C (CDKN1C). Further mechanistic investigations showed that CDYL recruits the enhancer of zeste homolog 2 (EZH2) to regulate trimethylation of lysine 27 in histone 3 (H3K27me3) at the CDKN1C promoter region and promotes transcriptional silencing. Accordingly, the EZH2 inhibitor GSK126 de-represses CDKN1C and decreases CDYL-induced chemoresistance in SCLC. Principal conclusions: Based on these results, the CDYL/EZH2/CDKN1C axis promotes chemoresistance in SCLC, and these markers represent promising therapeutic targets for overcoming chemoresistance in patients with SCLC.

Identification of aberrantly methylated differentially expressed genes in breast cancer by integrated bioinformatics analysis.

BACKGROUND: Abnormal DNA methylation has been demonstrated to drive breast cancer tumorigenesis. Thus, this study aimed to explore differentially expressed biomarkers driven by aberrant methylation in breast cancer and explore potential pathological mechanisms using comprehensive bioinformatics analysis. METHODS: Gene microarray datasets of expression (GSE45827) and methylation (GSE32393) were extracted from the Gene Expression Omnibus database. Abnormally methylated differentially expressed genes (DEGs) were obtained by overlapping datasets. Functional enrichment analysis of screened genes and protein-protein interaction (PPI) networks were executed with the Search Tool for the Retrieval of Interacting Genes database. PPI networks were visualized, and hub genes were screened using Cytoscape software. The results were further verified using Oncomine and The Cancer Genome Atlas (TCGA) databases. Finally, the genetic alterations and prognostic roles of hub genes were analyzed. RESULTS: In total, we found 18 hypomethylated upregulated oncogenes and 21 hypermethylated downregulated tumor suppressor genes (TSGs). These genes were mainly linked to the biological process categories of cellular component movement and cellular metabolism as well as nuclear factor-κB (NF-κB) and ataxia telangiectasia mutated (ATM) signaling pathways. Six hub genes were identified: three hypomethylated upregulated oncogenes (BCL2, KIT, and RARA) and three hypermethylated downregulated TSGs (ATM, DICER1, and DNMT1). The expression and methylation status of hub genes validated in Oncomine and TCGA databases were significantly altered and were consistent with our findings. Downregulation of BCL2, KIT, ATM, and DICER1 was closely associated with shorter overall survival in breast cancer patients. In addition, the expression levels of ATM and DICER1 were significantly distinct among different subgroups of clinical stages, molecular subtypes, and histological types. CONCLUSIONS: Our study reveals possible methylation-based DEGs and involved pathways in breast cancer, which could provide novel insights into underlying pathogenesis mechanisms. Abnormally methylated oncogenes and TSGs, especially ATM and DICER1, may emerge as novel biomarkers and therapeutic targets for breast cancer in the future.

Efficacy and safety of osimertinib in treating EGFR-mutated advanced NSCLC: A meta-analysis.

Osimertinib is the only Food and Drug Administration-approved third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI). A meta-analysis was performed to aggregate the mixed results of published clinical trials to assess the efficacy and safety of osimertinib. A systematic search of the PubMed, Web of Science, and Cochrane Library electronic databases was performed to identify eligible literature. The primary endpoints were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and adverse events (AEs). A total of 3,086 advanced nonsmall cell lung cancer (NSCLC) patients from 11 studies have been identified. The aggregate efficacy parameters for treatment-naïve patients with EGFR-TKI-sensitizing mutations are as follows: ORR 79% (95% CI 75-84%), DCR 97% (95% CI 95-99%), 6-month PFS 83% (95% CI 80-87%), and 12-month PFS 64% (95% CI 59-69%). The aggregate efficacy parameters for advanced NSCLC harboring T790M mutations after earlier-generation EGFR-TKI therapy are as follows: ORR 58% (95% CI 46-71%), DCR 80% (95% CI 63-98%), 6-month PFS 63% (95% CI 58-69%), and 12-month PFS 32% (95% CI 17-47%). EGFR-TKI-naïve patients with EGFR-positive mutations tend to have longer median PFS than EGFR-TKI-pretreated counterparts (19.17 vs. 10.58 months). The most common AEs were diarrhea and rash, of which the pooled incidences were 44 and 42%, respectively. Generally, osimertinib is a favorable treatment option for previously treated T790M mutation-positive advanced NSCLC as well as a preferable therapy for untreated EGFR mutation-positive advanced NSCLC. Additionally, osimertinib is well tolerated by most patients.

Efficacy and Safety of Ipilimumab plus Chemotherapy for Advanced Lung Cancer: A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related deaths worldwide, with poor prognosis in advanced lung cancer patients. Platinum-based chemotherapy has always been a first-line treatment for the majority of advanced lung cancer patients, but its long-term survival benefit is limited. Ipilimumab is an immune drug that targets the CTLA-4 protein in T cells. Therefore, we evaluated the efficacy and safety of adding ipilimumab to simple chemotherapy for patients with advanced lung cancer. We searched literatures in PubMed, Web of Science, EMBASE, the Cochrane Library and cliniclatrials.gov. The primary end points of this assessment were overall survival (OS), progression-free survival (PFS) and immune-related PFS(irPFS) of lung cancer patients. Other end points were objective response rate (ORR), disease control rate (DCR) and safety. The results of this study will be presented by the risk ratio (RR) of the endpoints and the 95% confidence interval (CI) of the various effect sizes. And when the p value is less than 0.05, we think there is a statistical difference. Finally, 6 RCTs and 2,037 patients including 953 with advanced or recurrent non-small cell lung cancer (NSCLC) and 1084 with extensive-disease small-cell lung cancer (ED-SCLC) were identified. Among them, 1089 received immunochemotherapy, and 948 patients received chemotherapy alone. Immunochemotherapy can't improve OS (6months: risk ratio (RR)=0.97 P=0.11; 1year: RR=1.05 P=0.36), ORR (RR=1.00 P=0.95) and DCR (RR=0.92, 95%CI 0.85-1.00, P=0.04) of patients with lung cancer compared to pure chemotherapy, but it can improve the PFS (6months: RR=1.16 P=0.02; 1year: RR=1.39 P=0.02) and 6months-irPFS(RR=1.60 P=0.004). However, due to the addition of ipilimumab, the immune-related toxicities are more apparent in immunochemotherapy group.

Systematic review and meta-analysis of the benefit of celecoxib in treating advanced non-small-cell lung cancer.

BACKGROUND: The clinical benefit of a selective cyclooxygenase-2 inhibitor, celecoxib, combined with anticancer therapy in advanced non-small-cell lung cancer (NSCLC) remains unclear. A meta-analysis was performed to address the efficacy and safety of celecoxib in patients with advanced NSCLC. MATERIALS AND METHODS: Three databases, including PubMed, EMBASE, and the Cochrane Library, were systematically searched for available literature until March 1, 2018. Data on tumor response rates, one-year survival, overall survival, progression-free survival, and toxicities were extracted from the included randomized clinical trials. Subgroup analysis was carried out according to the line of treatment. Review Manager 5.3 software was applied to conduct the meta-analysis. RESULTS: A total of 7 randomized controlled trials involving 1,559 patients with advanced NSCLC were enrolled for analysis. The pooled overall response rate (ORR) of celecoxib added to systemic therapy was not significantly improved (risk ratio [RR] =1.14, 95% CI =0.96-1.35, P=0.13). Additionally, no differences were observed between the celecoxib and placebo groups regarding 1-year survival (RR =0.99, 95% CI =0.88-1.12, P=0.91). Subgroup analysis showed that adding celecoxib to the first-line treatment significantly improved the ORR (RR =1.21, 95% CI =1.01-1.44, P=0.04) and partial response rate (RR =1.26, 95% CI =1.01-1.58, P=0.04). The aggregated Kaplan-Meier analysis found no significant difference between celecoxib and placebo regarding the 5-year overall survival (median, 12.9 vs 12.5 months, P=0.553) and 5-year progression-free survival (median, 7.4 vs 7.2 months, P=0.641). The increased RR of leukopenia (RR =1.25, 95% CI =1.03-1.50) and thrombocytopenia (RR =1.39, 95% CI =1.11-1.75) indicated that celecoxib increased hematologic toxicities (grade ≥III). However, celecoxib did not increase the related risks of thrombosis or embolism (RR =1.26, 95% CI =0.66-2.39) and cardiac ischemia (RR =1.16, 95% CI =0.39-3.44). CONCLUSION: Celecoxib had no benefit on survival indices for advanced NSCLC but improved the ORR of first-line treatment. Additionally, celecoxib increased the rate of hematologic toxicities without increasing the risk of cardiovascular events.

Adjuvant chemoradiotherapy versus radiotherapy alone in high-risk endometrial cancer: A systematic review and meta-analysis.

BACKGROUND: The benefits of adjuvant chemoradiotherapy (CRT) for high-risk endometrial cancer (HREC) in International Federation of Gynecology and Obstetrics (FIGO) stages I-III remain controversial. A systematic review and meta-analysis was conducted to evaluate the clinical effectiveness and safety of postoperative CRT over radiotherapy (RT) alone, exclusively for patients with HREC for the following key endpoints: overall survival (OS), progression-free survival (PFS), the local recurrence rate, the distant metastasis rate, cancer-specific survival (CSS), grade III/IV acute and late toxicities, and the small bowel obstruction rate. METHODS: Five databases, namely, PubMed, EMBASE, Cochrane Library, Web of Science and ClinicalTrials.gov, were systematically explored and supplemented by manual searching to identify relevant studies published before Dec 9, 2017. Only prospective randomized controlled trials (RCTs) conducted for HREC comparing CRT and RT alone after surgery were included. All statistical analyses were performed using RevMan Version 5.3 software. RESULTS: Six eligible trials involving 2105 patients were identified for the final meta-analysis (CRT: n = 1064; RT: n = 1041). No statistically significant differences were evident between the CRT and RT groups regarding OS (n = 2105, RR = 1.02, 95% CI 0.98-1.06, P = 0.40). Additionally, no differences were apparent in terms of the local recurrence rate (n = 690, RR = 0.48, 95% CI 0.19-1.18, P = 0.11) or distant metastasis rate (n = 1445, RR = 0.94, 95% CI 0.72-1.23, P = 0.67). However, CRT significantly prolonged overall five-year PFS (80.2% vs. 74.5%, +5.7%; RR = 1.08, P = 0.005) and five-year CSS (86.1% vs. 79.0%, +7.1%; RR = 1.09, P = 0.03). A higher incidence of grade III/IV toxicities (P < 0.00001) was evident with CRT, while grade III/IV late toxicities and the small bowel obstruction rate were not significantly different between the two groups. CONCLUSIONS: For patients with endometrial cancers with stage I-III risk factors, adjuvant CRT can significantly improve PFS and CSS compared with RT. With the exception of increased acute toxicities, CRT is well accepted and tolerated in HREC patients.

A de novo 1.38 Mb duplication of 1q31.1 in a boy with hemifacial microsomia, anophthalmia, anotia, macrostomia, and cleft lip and palate.

We reported a 2-year-old boy with developmental delay, mild mental retardation, and severe craniofacial malformation, including facial asymmetry with hypoplasia of the left zygoma, maxilla, and mandible, and left anophthalmia and anotia. A genome-wide screen revealed a 1.38 Mb duplication on chromosome 1q31.1, which was absent in his parents and 27 healthy controls. The duplication region contains two Refseq genes, PLA2G4A and C1orf99, which have not been reported to be implicated in craniofacial malformation. Functional studies of these genes and additional clinical analysis are necessary to elucidate the pathogenesis of craniofacial malformation.