Therapeutic efficacy of the novel SHP2 degrader SHP2-D26, alone or in combination, against lung cancer is associated with modulation of p70S6K/S6, Bim and Mcl-1.

SHP2, a protein tyrosine phosphatase, plays a critical role in fully activating oncogenic signaling pathways such as Ras/MAPK downstream of cell surface tyrosine receptors (e.g., EGFR), which are often activated in human cancers, and thus has emerged as an attractive cancer therapeutic target. This study focused on evaluating the therapeutic potential of the novel SHP2 degrader, SHP2-D26 (D26), either alone or in combination, against non-small cell lung cancer (NSCLC) cells. While all tested NSCLC cell lines responded to D26 with IC50s of < 8 µM, a few cell lines (4/14) were much more sensitive than others with IC50s of ≤ 4 µM. There was no clear association between basal levels of SHP2 and cell sensitivities to D26. Moreover, D26 rapidly and potently decreased SHP2 levels in different NSCLC cell lines in a sustained way regardless of cell sensitivities to D26, suggesting that additional factors may impact cell response to D26. We noted that suppression of p70S6K/S6, but not ERK1/2, was associated with cell responses to D26. In the sensitive cell lines, D26 effectively increased Bim levels while decreasing Mcl-1 levels accompanied with the induction of apoptosis. When combined with the third generation EGFR inhibitor, osimertinib (AZD9291), synergistic effects on decreasing the survival of different osimertinib-resistant cell lines were observed with enhanced induction of apoptosis. Although D26 alone exerted moderate inhibition of the growth of NSCLC xenografts, the combination of osimertinib and D26 effectively inhibited the growth of osimertinib-resistant xenografts, suggesting promising efficacy in overcoming acquired resistance to osimertinib.

Overcoming acquired resistance to third-generation EGFR inhibitors by targeting activation of intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation, or both.

Treatment of EGFR-mutant non-small cell lung cancer (NSCLC) with mutation-selective third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib has achieved remarkable success in the clinic. However, the immediate challenge is the emergence of acquired resistance, limiting the long-term remission of patients. This study suggests a novel strategy to overcome acquired resistance to osimertinib and other third-generation EGFR-TKIs through directly targeting the intrinsic apoptotic pathway. We found that osimertinib, when combined with Mcl-1 inhibition or Bax activation, synergistically decreased the survival of different osimertinib-resistant cell lines, enhanced the induction of intrinsic apoptosis, and inhibited the growth of osimertinib-resistant tumor in vivo. Interestingly, the triple-combination of osimertinib with Mcl-1 inhibition and Bax activation exhibited the most potent activity in decreasing the survival and inducing apoptosis of osimertinib-resistant cells and in suppressing the growth of osimertinib-resistant tumors. These effects were associated with increased activation of the intrinsic apoptotic pathway evidenced by augmented mitochondrial cytochrome C and Smac release. Hence, this study convincingly demonstrates a novel strategy for overcoming acquired resistance to osimertinib and other 3rd generation EGFR-TKIs by targeting activation of the intrinsic apoptotic pathway through Mcl-1 inhibition, Bax activation or both, warranting further clinical validation of this strategy.

Identification of tumor microenvironment-based genes associated with acquired resistance to EGFR Tyrosine Kinase Inhibitor in Lung Adenocarcinoma.

Background: The tumor microenvironment evidently affects treatment response and clinical outcome. This study aims to construct a tumor microenvironment-based crosstalk between immunotherapy and epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in lung adenocarcinoma. Methods: We used ESTIMATE algorithm to calculate stromal and immune scores. Differentially expressed genes (DEGs) were extracted based on the comprehensive analysis of immune score groups and EGFR-TKI resistance samples. The independent prognostic value of the five selected genes was assessed by univariate/multivariate Cox regression analysis, survival analysis and the receiver operating characteristic (ROC) curve. Correlation analysis was performed using Spearman's rho value through TIMER 2.0. Results: The Kaplan-Meier survival curve show that patients with higher immune scores have significantly better overall survival. We identified 1328 DEGs from immune score groups and 806 DEGs from the EGFR-TKI resistance cohort GSE123066. A total of 19 co-regulated genes were found, and the Cox regression model produced a significant statistical prognosis for five genes (CENPF, CYSLTR1, GLDN, PIGR and SCGB3A1). Multivariate Cox regression analysis showed that the selected five gene signatures could be used as independent prognostic indicators. Furthermore, GSEA and correlation analysis demonstrated that CENPF was positively correlated to the signalling pathway which related to EGFR-TKI resistance and the well-known bypass gene. Conclusion: Our findings indicate that CENPF, CYSLTR1, GLDN, PIGR and SCGB3A1 are independent prognostic biomarkers associated with acquired EGFR-TKI resistance and tumor immune cell infiltration in lung adenocarcinoma, and CENPF may be a potential target that can improve immunotherapy efficacy and overcome the acquired EGFR-TKI resistance.

Systemic Immune-Inflammation Index Is a Prognostic Factor for Breast Cancer Patients After Curative Resection.

BACKGROUND: The preoperative systemic immune-inflammation index (SII) is correlated with prognosis in several malignancies. The aim of this study was to investigate the prognosis value of SII in patients with resected breast cancer. MATERIALS AND METHODS: A total of 784 breast cancer patients who underwent surgical resection were consecutively investigated. The optimal cutoff value of SII was evaluated using the receiver operating characteristic (ROC) curve. The collection of SII with clinicopathological characteristic and prognosis was further evaluated. RESULTS: The optimal cutoff value for SII in the prediction of survival was 514 according to ROC curve analysis. A high SII was significantly correlated with younger age (P = 0.037), PR status (P < 0.001), and HER2 status (P = 0.035). Univariate analysis revealed that SII (P < 0.001), T-stage (P < 0.001), lymph node involvement post-surgery (P = 0.024), and histological grade (P < 0.001) were significantly related to DFS, and SII (P < 0.001), T-stage (P = 0.003), lymph node involvement post-surgery (P = 0.006), and histological grade (P < 0.001) were significantly associated with OS. In multivariate analysis, a high SII was an independent worse prognostic factor for DFS (HR, 4.530; 95% CI, 3.279-6.258; P < 0.001) and OS (HR, 3.825; 95% CI, 2.594-5.640; P < 0.001) in all the enrolled patients. Furthermore, subgroup analysis of molecular subtype revealed that SII was significantly associated with prognosis in all subtypes. CONCLUSION: Preoperative SII is a simple and useful prognostic factor for predicting long-term outcomes for breast cancer patients undergoing surgery.

Membrane-Associated RING-CH 8 Functions as a Novel PD-L1 E3 Ligase to Mediate PD-L1 Degradation Induced by EGFR Inhibitors.

Expression of programmed death-ligand 1 (PD-L1) on cancer cells is a critical mechanism contributing to immunosuppression and immune escape. PD-L1 expression may also affect therapeutic outcomes of epidermal growth factor receptor (EGFR)-targeted therapy (e.g., with osimertinib/AZD9291) against EGFR-mutant non-small cell lung cancers (NSCLC) and can even be altered during the treatment albeit with largely undefined mechanisms. This study primarily focuses on elucidating the mechanism by which osimertinib induces PD-L1 degradation in addition to validating osimertinib's effect on decreasing PD-L1 expression in EGFR-mutant NSCLC cells and tumors. Osimertinib and other EGFR inhibitors effectively decreased PD-L1 levels primarily in EGFR-mutant NSCLCs and xenografted tumors. Osimertinib not only decreased PD-L1 mRNA expression, but also prompted proteasomal degradation of PD-L1 protein, indicating both transcriptional and posttranslational mechanisms accounting for osimertinib-induced reduction of PD-L1. Knockdown of ß-TrCP or inhibition of GSK3 failed to prevent PD-L1 reduction induced by osimertinib. Rather, knockdown of membrane-associated RING-CH 8 (MARCH8) that encodes a membrane-bound E3 ubiquitin ligase rescued osimertinib-induced PD-L1 reduction. Furthermore, manipulation of MARCH8 expression accordingly altered PD-L1 degradation rate. Critically, MARCH8 interacted with PD-L1 through its N-terminal region and also ubiquitinated PD-L1 in cells. Collectively, these results strongly suggest that MARCH8 is a previously undiscovered E3 ubiquitin ligase responsible for PD-L1 degradation including osimertinib-induced PD-L1 degradation, establishing a novel connection between MARCH8 and PD-L1 regulation. IMPLICATIONS: This study has demonstrated a previously undiscovered function of MARCH8 in mediating PD-L1 degradation induced by EGFR inhibitors in EGFR-mutant NSCLC cells, establishing a novel connection between MARCH8 and PD-L1 regulation.

Comprehensive analysis of competitive endogenous RNA associated with immune infiltration in lung adenocarcinoma.

To identify the prognostic biomarker of the competitive endogenous RNA (ceRNA) and explore the tumor infiltrating immune cells (TIICs) which might be the potential prognostic factors in lung adenocarcinoma. In addition, we also try to explain the crosstalk between the ceRNA and TIICs to explore the molecular mechanisms involved in lung adenocarcinoma. The transcriptome data of lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) database, and the hypergeometric correlation of the differently expressed miRNA-lncRNA and miRNA-mRNA were analyzed based on the starBase. In addition, the Kaplan-Meier survival and Cox regression model analysis were used to identify the prognostic ceRNA network and TIICs. Correlation analysis was performed to analysis the correlation between the ceRNA network and TIICs. In the differently expressed RNAs between tumor and normal tissue, a total of 190 miRNAs, 224 lncRNAs and 3024 mRNAs were detected, and the constructed ceRNA network contained 5 lncRNAs, 92 mRNAs and 10 miRNAs. Then, six prognostic RNAs (FKBP3, GPI, LOXL2, IL22RA1, GPR37, and has-miR-148a-3p) were viewed as the key members for constructing the prognostic prediction model in the ceRNA network, and three kinds of TIICs (Monocytes, Macrophages M1, activated mast cells) were identified to be significantly related with the prognosis in lung adenocarcinoma. Correlation analysis suggested that the FKBP3 was associated with Monocytes and Macrophages M1, and the GPI was obviously related with Monocytes and Macrophages M1. Besides, the LOXL2 was associated with Monocytes and Activated mast cells, and the IL22RA1 was significantly associated with Monocytes and Macrophages M1, while the GPR37 and Macrophages M1 was closely related. The constructed ceRNA network and identified Monocytes, Macrophages M1 and activated Mast cells are all prognostic factors for lung adenocarcinoma. Moreover, the crosstalk between the ceRNA network and TIICs might be a potential molecular mechanism involved.

Effects of clinicopathological factors on prognosis of young patients with resected breast cancer.

ABSTRACT: This study aims to analyze the relationship between clinicopathological characteristics and survival in young patients (≤35 years old) with resected breast cancer.A total of 173 cases were included in this study. The clinicopathological factors potentially associated with prognosis were evaluated. Furthermore, we categorized patients into different groups to evaluate the prognosis according to hormone receptor status or important risk factors.Younger age (≤30 years) was an independent predictor for poor disease-free survival (DFS) and overall survival (OS). Besides, PR negative status, tumor grade, and advanced lymph nodes postsurgery were independent prognostic factors of DFS, while PR negative status and advanced lymph nodes postsurgery were independent prognostic factors of OS. For hormone receptor-positive patients, people with ER+ or PR+ and HER2-/+ showed poorer prognosis than the other 2 levels. Risk factor grouping based on the ER, PR, HER2, Ki-67 status, tumor grade, and lymph nodes postsurgery showed that patients in highest score group received the poorest prognosis. Grading system based on the hormone status or the risk factor grouping may offer a useful approach to assess which subgroups of young breast cancer present poorer prognosis.

Artesunate exhibits synergistic anti-cancer effects with cisplatin on lung cancer A549 cells by inhibiting MAPK pathway.

BACKGROUND: Artesunate (ART) has been used extensively as anti-malarial drugs worldwide. Besides, it has also been reported to have anti-cancer activities. This study was aimed to explore the anti-cancer activity of ART in combination with cisplatin (CIS) on A549 cells. METHODS: Cells were cultured with different concentrations of ART and/or CIS for 24, 48, or 72 h to test the anti-proliferative effects by CCK-8 assay. Colony formation assay and EdU staining were also performed. TUNEL staining was used to illustrate the morphologic changes. Cell cycle and apoptosis were determined by flow cytometry assay, and Western blot analysis was conducted to detect the expression of apoptosis- and proliferation-related proteins. Caspase activities were determined by colorimetric assay kit. Moreover, the synergistic effect of ART with CIS in A549 cell xenograft model was also determined. RESULTS: ART significantly inhibited cell proliferation in dose- and time-dependent manners. Collectively, the combination treatment remarkably decreased colony formation rates and increased the rates of TUNEL-positive cells compared with mono-treatment. Mechanistically, the combination treatment influenced the expression of Bcl-2, Bax, p-P53, Caspase-3/7, Caspase-9, CyclinB1, P34, P21, and synergistically regulated the activity of P38/JNK/ERK1/2 MAPK pathway. In mice A549 xenograft tumors, the combination strategy significantly increased the anti-cancer efficacy of ART and CIS alone, consistent with the in vitro observations. CONCLUSIONS: ART exhibited significant anti-tumor effect on A549 cells and this efficiency could be enhanced by combination with CIS.

The combination of platelet count and lymphocyte to monocyte ratio is a prognostic factor in patients with resected breast cancer.

Many inflammation indicators have been reported to be related with patient outcomes in various cancers. Previous studies have evaluated the combination of platelet (PLT) and lymphocyte to monocyte ratio (COP-LMR) as a systemic inflammatory marker for prognostication in lung cancer, yet its prognostic role among breast cancer patients remains unclear.In the present study, a total of 409 breast cancer patients with surgical resection were retrospectively investigated. The receiver operating characteristic (ROC) curve was used to choose the optimal cut-off value of PLT and lymphocyte to monocyte ratio (LMR). Patients were classified into 3 groups according to the score of COP-LMR, and its relationship with various clinicopathological factors and breast cancer prognosis were further evaluated.The ROC curve analysis showed that COP-LMR had a higher area under the ROC curve for the prediction of 5-year disease-free survival and overall survival than PLT or LMR alone. Multivariable analysis showed that an elevated COP-LMR was an independent predictor of poor disease-free survival (P = .032) and overall survival (P = .005). Subgroup analysis revealed that COP-LMR was still significantly associated with prognosis in both luminal A and luminal B subtypes.Preoperative COP-LMR is a potential prognostic factor in breast cancer patients who underwent surgery.

Controlling Nutritional Status (CONUT) score is a prognostic factor in patients with resected breast cancer.

The present study aimed to determine the correlation between controlling nutritional status (CONUT) and prognosis in resected breast cancer patients. Totally, 861 breast cancer patients with surgical resection in West China Hospital of Sichuan University between 2007 and 2010 were included. The relationship between CONUT and various clinicopathological factors as well as prognosis was evaluated. The results showed that the optimal cutoff value for CONUT to predict the 5-year survival was 3 and CONUT had a higher area under the ROC curve (AUC) for 5-year disease free survival (DFS) and overall survival (OS) prediction compared with the neutrophil lymphocyte ratio (NLR) and prognostic nutritional index (PNI). High CONUT was significantly correlated with older age, lymph node involvement, advanced T-stage, and surgery type. In the multivariate analysis, CONUT-high patients had worse DFS and OS, when compared with CONUT-low patients. In conclusion, preoperative CONUT is a useful marker for predicting long term outcomes in breast cancer patients after curative resection.

Nm23-H1 inhibits lung cancer bone-specific metastasis by upregulating miR-660-5p targeted SMARCA5.

BACKGROUND: Nm23-H1 gene has been found to be an inhibitor of tumor metastasis in lung cancer. MicroRNAs (miRNAs) play key roles in tumor metastasis through multiple signaling pathways. This study explored whether the nm23-H1 gene could inhibit invasion and metastasis of lung cancer cells by regulating miRNA-660-5p targets. METHODS: Quantitative real-time PCR (qRT-PCR) and western blots were used to measure the expression of nm23-H1 and miR-660-5p of various human lung cancer cell lines. Cell counting kit-8 (CCK-8), wound-healing and transwell assay were carried out to assess cell proliferation, migration and invasion of each cell line. Xenograft were applied to determine in vivo effects of miR-660-5p among nude mice. Luciferase assay and western blot were performed to determine the target gene of miR-660-5p. RESULTS: We found that high expression of nm23-H1 correlated with decreased miRNA-660-5p expression. Inhibiting miR-660-5p suppressed lung cancer cells progression significantly in vitro, whereas overexpression of miR-660-5p facilitated tumor growth and bone metastasis in vivo. In addition, as the potential target gene of miR-660-5p, SMARCA5 overexpression in vitro suppressed tumor progression and osteolytic metastasis associated RANKL signaling, which is congruent with the effect of nm23-H1 on the lung cancer cells. CONCLUSION: Nm23-H1 inhibits tumor progression and bone-specific metastasis of lung cancer by regulating miR-660-5p/SMARCA5/RANKL axis, which indicates the related genes may serve as potential targets for the treatment of human lung cancer. KEY POINTS: Significant findings of the study High expression of nm23-H1 correlated with decreased miRNA-660-5p expression. Further, downregulation of miR-660-5p significantly suppressed the tumor progression and bone-specific metastasis of lung cancer cells. What this study adds This is the first study to show an inverse association between nm23-H1 and miR-660-5p, and confirm that nm23-H1 inhibits tumor progression and bone-specific metastasis of lung cancer by regulating miR-660-5p/SMARCA5/RANKL axis.

Prognostic Value of Ki-67 in Patients With Resected Triple-Negative Breast Cancer: A Meta-Analysis.

Background: Ki-67 is a widely used marker of tumor proliferation, but the prognostic value of ki-67 in triple-negative breast cancer (TNBC) has not been comprehensively reviewed. This meta-analysis was conducted to evaluate the association between ki-67 expression and survival of patients with resected TNBC. Materials and Methods: Relevant studies, evaluating the prognostic impact of pretreatment ki-67 in resected TNBC patients, were identified from PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and Cochrane Library until March 14, 2019. Hazard ratios (HRs) with 95% confidence intervals (CI) were calculated as effect values for disease-free survival (DFS) and overall survival (OS). Results: In present meta-analysis, 35 studies with 7,716 enrolled patients were eligible for inclusion. Pooled results showed that a high ki-67 expression was significantly associated with poor DFS (HR = 1.73, 95% CI: 1.45-2.07, p < 0.001) and poor OS (HR = 1.65, 95% CI: 1.27-2.14, p < 0.001) in resected TNBC. In the subgroup analysis, when a cutoff of Ki-67 staining ≥40% was applied, the pooled HR for DFS and OS was 2.30 (95% CI 1.54-3.44, p < 0.001) and 2.95 (95% CI 1.67-5.19, p < 0.001), respectively. Conclusion: A high Ki-67 expression is a poor prognostic factor of resected TNBC. The cut-off of ki-67 ≥40% is associated with a greater risk of recurrence and death compared with lower expression rates, despite the Ki-67 threshold with the greatest prognostic significance is as yet unknown.

Prognostic significance of nuclear Yes-associated protein 1 in patients with nonsmall cell lung cancer: A systematic review and meta-analysis.

BACKGROUND: Nuclear Yes-associated protein 1 (YAP1) has often been regarded as an adverse prognostic indicator in various tumors. Recent studies have associated YAP1 with unfavorable prognosis in nonsmall cell lung cancer (NSCLC). However, due to small sample sizes, the prognostic value of nuclear YAP1 in NSCLC patients is not well understood. In the present study, we evaluated the prognostic role of nuclear YAP1 in NSCLC patients via a systematic review and meta-analysis. METHODS: We searched the PubMed, EMBASE, Cochrane, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang Databases for papers investigating the prognostic significance of nuclear YAP1 expression in NSCLC patients. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were calculated with reference to overall survival (OS) and progression-free survival (PFS) of NSCLC patients to provide synthesized estimates of the effects of nuclear YAP1 expression. RESULTS: Among 414 cases, higher nuclear YAP1 expression presented as a predictive factor of poorer OS (HR = 1.52; 95% CI: 1.11-2.08; P = .01; I = 0.0%) and decreased PFS (HR = 2.11; 95% CI: 1.52-2.93; P < .001; I = 44.2%) in NSCLC patients. Subgroup analysis revealed shortened OS (HR = 1.63; 95% CI: 1.14-2.34; P = .007; I = 0.0%) and worse PFS (HR = 2.25; 95% CI: 1.53-3.30; P < .001; I = 0.0%) in patients from Asia with higher nuclear YAP1 expression. Prognosis was also worse in patients with III-IV stage cancer (PFSHR = 2.09; 95% CI: 1.45-3.01; P < .001; I = 58.1%) and in patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) (OS HR = 1.59; 95% CI: 1.00-2.51; P = .048; I = 15.5%, and PFS HR = 2.35, 95% CI: 1.62-3.42; P < .001; I = 0.0%). CONCLUSION: High expression of nuclear YAP1 was associated with shorter survival outcome in patients with NSCLC.

Villi development core-related gene expression associated with lung squamous cancer prognosis.

Similarities between embryonic development and tumorigenesis are reflected in biological behavior and gene expression. Although the gene signature during development and the clinical phenotype of different cancers show certain correlation pattern, the correlation between early embryo development and cancer remains largely unexplored. To compare the gene expression profile between development and cancer, our study analyzed the gene expression of chorionic villi samples at different gestational ages (6, 7, 8, 9, 10, 40 weeks) obtained from gene expression omnibus (GEO) datasets using correlation test. Then the villi development-related genes that gradually showed a positive correlation (upregulated) (n = 394) or negative correlation (downregulated) (n = 325) with time were used to construct protein-protein interaction (PPI) networks. Three subnetworks among the gradually upregulated genes and 3 subnetworks among the downregulated genes were identified using the molecular complex detection (MCODE) plugin in Cytoscape software. The most significant GO terms for villi-correlated genes were immune, inflammatory response and cell division. These gene clusters were also dysregulated in lung squamous cell carcinoma (SCC). Moreover the prognostic value of the gene clusters was then analyzed with TCGA lung SCC data, which showed 4 clusters that were associated with prognosis. Our results demonstrate the gene expression similarity between development and lung SCC and identified development-associated gene clusters that could contain prognostic information for lung SCC patients.

The Prognostic Role of MET Protein Expression Among Surgically Resected Non-small Cell Lung Cancer Patients: A Meta-Analysis.

Objectives: MET protein expression has been reported to be in relevance with the survival of NSCLC patients in various studies, yet the results were inconsistent. The purpose of our study set out to determine the prognostic role of both c-MET and p-MET expression among NSCLC that underwent surgical resection. Methods: Data were obtained from retrospective cohort studies by searching on PubMed, Cochrane Library, EMBASE and Web of Science, and a meta-analysis was performed to assess the prognostic role of MET expression among NSCLC. Results: Totally 18 literatures including 5,572 surgically resected NSCLC cases staged I-IV were included for data synthesis. The positive rate of c-MET and p-MET was 1,753/4,315 and 135/1,257. The pooled hazard ratios (HRs) regarding c-MET and p-MET expression for overall survival (OS) was 1.623 (95% CI: 1.176-2.240, p = 0.003) and 1.710 (95% CI: 0.823-3.533, p = 0.15), respectively. Subgroup analysis results on Asian (HR = 2.115, p < 0.001), adenocarcinoma (HR = 2.220, p < 0.001) and rabbit polyclonal antibodies (HR = 2.107, p < 0.001) etc. were also indicative. Conclusion: C-MET over-expression among NSCLC patients that underwent surgical resection is a prognostic factor that indicated adverse survival on OS. Whereas, p-met didn't appear to have an impact on the prognosis of NSCLC. The studies are need and the topic could be re-valued by then.

CDK4/6 Inhibitors in Combination With Hormone Therapy for HR+/HER2- Advanced Breast Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: This meta-analysis of randomized controlled trials aimed to comprehensively assess the efficacy and toxicity of cyclin-dependent kinase (CDK) 4/6 inhibitors in advanced breast cancer (ABC) with hormone-receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) disease. METHODS: We performed a systematical search using Cochrane Library, PubMed, Embase, and Web of Science up to March 2018. Only phase 2 and 3 randomized clinical trials assessing the efficacy and toxicity of the combination regimen of CDK4/6 inhibitors plus hormone therapy compared with hormone therapy alone were eligible for this meta-analysis. The pooled analyses of relative risk (RR) and hazard ratio were carried out by Stata software. RESULTS: A total of 7 randomized controlled trials including 3854 patients with HR+/HER2- ABC were included in this meta-analysis. The pooled hazard ratio for progression-free survival was 0.54 (95% confidence interval, 0.49-0.59; P < .001), and the pooled RR for the objective response rate in all intent-to-treat patients was 1.51 (95% confidence interval, 1.26-1.81; P < .001). The pooled RRs for all grade adverse events (AEs) and grade 3/4 AEs were 1.07 (95% confidence interval, 1.03-1.11; P < .001) and 2.81 (95% confidence interval, 2.54-3.11; P < .001), respectively. However, to investigate the influence of CDK4/6 inhibitors on overall survival, sufficient follow-up is still needed. CONCLUSION: CDK4/6 inhibitors plus hormone therapy can significantly prolong the progression-free survival of patients with HR+/HER2- ABC and improve the objective response rate compared to conventional hormone therapy alone. The combined regimen results in a higher risk of AEs, especially grade 3/4 AEs.

The prognostic role of programmed cell death-ligand 1 expression in non-small cell lung cancer patients: An updated meta-analysis.

BACKGROUND: Programmed cell death-ligand 1 (PD-L1) seemed to be associated with the outcomes of non-small cell lung cancer. However the prognostic role of PD-L1 expression among NSCLC remained unclear and inconsistent. The aim of the study set out to evaluate the correlation between PD-L1 expression and the prognosis of patients that developed NSCLC. METHODS: Identified literatures were extracted of various electronic databases and a meta-analysis was performed to evaluate the prognostic role of PD-L1 among NSCLC patients. RESULTS: Totally 25 studies from 11 countries containing 5861 patients were included in the meta-analysis. The pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were 1.176 (95% CI: 1.016-1.361, P = 0.029) and 1.170 (95% CI: 0.984-1.392, P = 0.076), respectively. High PD-L1 expression on NSCLC tissue was also related with worse OS among Asian patients (HR = 1.381, 95% CI: 1.127-1.629, P = 0.002), adenocarcinomas (HR = 1.899, 95% CI: 1.306-2.762, P = 0.001) and poor PFS in non-Asian patients (HR = 1.695, 95% CI: 1.158-2.480, P = 0.002). Sensitivity analysis indicated that removal of any particular included literature won't affect the pooled results. Publication bias among the studies was not significant neither. CONCLUSIONS: PD-L1 expression is a prognostic factor related with poor survival among patients that developed NSCLC.

Microvessel density as a prognostic factor in esophageal squamous cell cancer patients: A meta-analysis.

BACKGROUND: To date, literature has emerged that shows contradictory results about the prognostic role of microvessel density (MVD) in esophageal squamous cell cancer (ESCC). The aim of the study set out to evaluate the correlation between MVD and the prognosis of ESCC. METHODS: Identified publications from various databases were obtained and reviewed. A meta-analysis was performed to evaluate the prognostic role of MVD among ESCC patients. RESULTS: A total of 11 eligible studies containing 891 ESCC cases were included in the meta-analysis. The pooled hazard ratio for overall survival was 2.39 (95% confidence interval 1.92-2.96, P < .001). Heterogeneity among the studies was not significant, and publication bias was not found. Subgroup analyses were also performed on different issues, such as districts, antibodies, and median age. CONCLUSION: High MVD is a prognostic factor among ESCC that indicated worse prognosis in these patients. More studies are needed, and through abundant evidence, the topic could be re-evaluated by then.

The accuracy of 18F-FDG PET/CT in predicting the pathological response to neoadjuvant chemotherapy in patients with breast cancer: a meta-analysis and systematic review.

OBJECTIVES: The aim of this meta-analysis was to evaluate the accuracy of 18F-FDG PET/CT in predicting the pathological response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients. METHODS: PubMed, Embase, the Cochrane Library (Central), and the Web of Science (SCI-Expanded) were systematically searched to identify pertinent studies. The methodologic quality of the included studies was assessed by the Quality Assessment of Diagnostic Accuracy Studies-2. The Spearman correlation coefficient was used to explore the existence of a threshold effect. Heterogeneity was assessed by the likelihood ratio I 2 index. RESULTS: The pooled values calculated with a mixed-effects model for the sensitivity, specificity and diagnostic odds ratio with 95% confidence intervals were 81.9% (76.0-86.6%), 79.3% (72.1-85.1%) and 17.35 (10.98-27.42), respectively. CONCLUSIONS: 18F-FDG PET/CT has a moderate accuracy in predicting the pathological response during the early process of NAC in breast cancer patients. To increase the role of 18F-FDG PET/CT in monitoring the therapy response, future prospective studies are needed to explore how chemotherapy regimens and different subtypes affect the levels of glucose metabolism. KEY POINTS: • This meta-analysis assesses the role of PET/CT in breast cancer during NAC. • Pathological responses were based on both primary tumour and lymph node. • 18 F-FDG PET/CT has a moderate accuracy in predicting the pathological response.