Zhaofei Pang

The efficacy and potential predictive factors of PD-1/PD-L1 blockades in epithelial carcinoma patients: a systematic review and meta analysis

Background This systematic analysis aims to assess the efficacy of PD-1/PD-L1 blockades compared with non-PD-1/PD-L1 therapy and investigate the potential predictive factors in epithelial carcinoma patients. Results A total of 11 trials with 6716 patients of melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) were included. The pooled HRs (95%CI) were 0.67 (0.62, 0.73), p < 0.001 for OS and 0.66 (0.57, 0.76), p < 0.001 for PFS. In subgroup analyses, HRs were 0.58 (0.50, 0.66), p < 0.001 in PD-L1 ≥ 1% group, 0.75 (0.63, 0.89), p = 0.001 in PD-L1 < 1% group for OS and 0.59 (0.48, 0.72), p < 0.001 in PD-L1 ≥ 1% group, 0.80 (0.59, 1.07), p = 0.136 in PD-L1 < 1% group for PFS. The p values of pooled HRs for OS in different age, sex and ECOG score groups were less than 0.001. In NSCLC patients, aggregated HRs for OS were 1.40 (0.92, 2.12), p = 0.114 in EGFR mutant group and 0.88 (0.59, 1.32), p = 0.536 in never smokers. Methods A systematic search from January 2010 to April 2016 was conducted for eligible clinical trials. Based on the data of hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS), we assessed the pooled HRs and proposed the subgroup analyses. Conclusions PD-1/PD-L1 blockades prolonged OS and PFS in epithelial carcinoma patients. PD-L1 expression was a predictive factor for PFS but not predictive for OS. Age, sex and ECOG score were excluded to predict any of the efficacy endpoints. Smoking history and EGFR wild type were associated with extended OS in NSCLC patients.

The Prognostic Value of PLR in Lung Cancer, a Meta-analysis Based on Results from a Large Consecutive Cohort

Recently, many studies have been conducted to explore prognostic value of platelet to lymphocyte ratio (PLR) for patients with lung cancer, while the results remain controversial. We collected pretreatment, clinicopathological and follow-up data of 1388 lung cancer patients receiving surgery between 2006 and 2011 in our hospital, and reviewed relevant articles from Embase, Pubmed, Web of science databases, then performed a meta-analysis to clarify the relationship between PLR and prognosis of lung cancer patients. Finally, 11 articles with our study were included, results indicated elevated PLR was negatively related to overall survival (HR = 1.33, 95% CI: 1.10–1.62), but not related to progress-free survival (HR = 1.21, 95% CI: 0.97–1.49). Subgroup analysis suggested high PLR was correlated with poor survival in non-small cell lung cancer (HR = 1.43, 95% CI: 1.14–1.78), but not in small cell lung cancer (HR = 1.10, 95% CI: 0.76–1.58). Besides, for patients treated by chemotherapy or radiotherapy (HR = 1.66, 95% CI: 1.15–2.38) and patients in late stage (HR = 1.41, 95% CI: 1.19–1.68), PLR had significantly prognostic value. Additionally, the result was significant for patients when cut-off value of PLR was between 150 and 200 (HR = 1.47, 95% CI: 1.18–1.82). In Conclusion, this meta-analysis revealed that elevated PLR was associated with poor prognosis in lung cancer.

Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy

Background Prognostic studies of insulin-like growth factor-1 receptor(IGF-1R) inhibitors in cancer therapy had promising results in infratests, which exhibited that IGF-1R signalling was crucial in cancer cells growth. However, the conclusion of later clinical trials revealed a dim future for IGF-1R inhibitors to treat cancer. We conducted this analysis to figure out how IGF-1R inhibitors acted in clinical cancer therapy. Material and Methods We searched up-to-date studies about the single agent of IGF-1R inhibitors or combination with other therapies in solid tumor. Five IGF-1R anti-agents were involved. The primary endpoint was progression-free survival (PFS). The secondary endpoint was overall survival (OS). Result 17studies were enrolled. The results was not significant in overall survival (I2=37.1%, P=0.080, HR=1.08, 95% CI=0.97-1.21) and in progression-free survival (I2=0.0%, P=0.637, HR=1.05, 95% CI=0.98-1.12). OS for dalotuzumab, breast cancer, colorectal cancer, and PFS for prostate cancer even indicated harmful effects. Conclusion So far, anti-IGF-1R mono-antibodies did not make significant differences in solid tumor prognosis. On the contrary, pessimistic effects were shown in the dalotuzumab, breast cancer, colorectal cancer and prostate cancer subgroups. Further studies of IGF-1R anti-agents were needed, but unwarranted in unselected patients by predictive biomarkers.

Prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma

Purpose Gastric carcinoma (GC) is a highly aggressive cancer and one of the leading causes of cancer-related deaths worldwide. Histopathological evaluation pertaining to invasiveness is likely to provide additional information in relation to patient outcome. In this study, we aimed to evaluate the prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma. Materials and methods Hematoxylin and eosin-stained slides generated from 296 gastric adenocarcinoma patients with full clinical and pathological and follow-up information were systematically reviewed. The patients were grouped on the basis of tumor budding, single cell invasion, large cell invasion, mitotic count, and fibrosis. The association between histopathological parameters, different classification systems, and overall survival (OS) was statistically analyzed. Results Among the 296 cases that were analyzed, high-grade tumor budding was observed in 49.0% (145) of them. Single cell invasion and large cell invasion were observed in 62.8% (186) and 16.9% (50) of the cases, respectively. Following univariate analysis, patients with high-grade tumor budding had shorter OS than those with low-grade tumor budding (hazard ratio [HR]: 2.260, P<0.001). Similarly, the OS of patients with single cell invasion and large cell invasion was reduced (single cell invasion, HR: 3.553, P<0.001; large cell invasion, HR: 2.466, P<0.001). Following multivariate analysis, tumor budding and single cell invasion were observed to be independent risk factors for gastric adenocarcinoma (P<0.05). According to the Lauren classification, patients with intestinal-type adenocarcinoma had better outcomes than those with diffuse-type adenocarcinoma (HR: 2.563, P<0.001). Conclusion Tumor budding and single cell invasion in gastric adenocarcinoma are associated with an unfavorable prognosis.

Down-regulation of long non-coding RNA MEG3 indicates an unfavorable prognosis in non-small cell lung cancer: Evidence from the GEO database

Long non-coding RNA (lncRNA) MEG3 (maternally expressed gene 3) is an imprinted gene that suppresses cells growth in various tumors. However, the association between MEG3 expression and prognosis in non-small cell lung cancer (NSCLC) has not been fully investigated. Seven datasets with 1144 patients were obtained from Gene Expression Omnibus (GEO) database (Affymetrix U133 Plus 2.0 platform). Association between MEG3 and other variables was tested using the chi-squared test. Kaplan-Meier survival analysis was carried out to explore the association between MEG3 expression and overall survival (OS)/progression free survival (PFS). Results of univariate and multivariate Cox regression analysis were represented in HR and 95%CI form. Summarized results and publication bias were showed by forest plots and funnel plots respectively. Differential expression of MEG3 was related to stage (GSE31210OS and GSE31210PFS), histology (GSE29013OS and GSE29013PFS) and gender (GSE29013PFS). In summary, low MEG3 expression was associated with shorter long-term survival time in several datasets (GSE3141 (p=0.039), GSE30219 (p=0.008) for OS and GSE30219 (p=0.048) for PFS). We found that MEG3 was an independent prognostic factor in GSE30219 for PFS (HR 0.666, 95%CI 0.458-0.969, p=0.033). The summarized results suggested that low MEG3 expression was a poor prognostic factor in NSCLC (HR=0.77, 95%CI 0.63-0.95). Specifically, the association between low MEG3 expression and poor prognosis was markedly significant in younger patients (≤60years old) (HR0.602, 95%CI 0.417-0.867, p=0.007). These findings indicate that MEG3 could be a novel prognostic factor for NSCLC patients.

PKD1 is downregulated in non-small cell lung cancer and mediates the feedback inhibition of mTORC1-S6K1 axis in response to phorbol ester

Protein kinase D1 (PKD1) is increasingly implicated in multiple biological and molecular events that regulate the proliferation or invasiveness in several cancers. However, little is known about the expression and functions of PKD1 in non-small cell lung cancer (NSCLC). In the present study, 34 pairs of human NSCLC and matched normal bronchiolar epitheliums were enrolled and evaluated for PKD1 expression by quantitative real-time PCR. We showed that PKD1 was downregulated in 26 of 34 cancer tissues in comparison with matched normal epitheliums. Moreover, patients with venous invasion or lymph node metastasis showed significant lower expression of PKD1. Exposure of NSCLC A549 and H520 cells to the PKD family inhibitor kb NB 142-70(Kb), at concentrations that inhibited PKD1 activation, strikingly potentiated S6K1 phosphorylation at Thr(389) and S6 phosphorylation at Ser(235/236) in response to phorbol ester (PMA). Knockdown of PKD1 with siRNAs strikingly enhanced S6K1 phosphorylation whereas constitutively active PKD1 resulted in the S6K1 activity inhibition. Furthermore, the PI3K inhibitors LY294002, BKM120 and MEK inhibitors U0126, PD0325901 blocked the enhanced S6K1 activity induced by Kb. Collectively, our results identify decreased expression of the PKD1 as a marker for NSCLC and the loss of PKD1 expression increases the malignant potential of NSCLC cells. This may be due to the function of PKD1 as a negative regulator of mTORC1-S6K1. Our results suggest that re-expression or activation of PKD1 might serve as a potential therapeutic target for NSCLC treatment.

Optimal managements of stage IIIA (N2) non-small cell lung cancer patients: a population-based survival analysis

Background This study aimed to investigate the optimal management of stage IIIA (cN2) non-small cell lung cancer (NSCLC) patients and determine potential predictive factors. Methods We extracted patients diagnosed as NSCLC stage IIIA (cN2) between 2004 and 2011 from Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and lung cancer-specific survival (LCSS) were compared among patients given different clinical managements by Kaplan-Meier method. Other variables such as age, sex and tumor size were analyzed to explore the factors associated with outcomes. Results A total of 98,700 IIIA-cN2 NSCLC patients were identified from SEER database. Survival of patients treated with surgery was better than that of patients treated by radiotherapy alone (P<0.001). Radiation prior to surgery significantly improved the survival in comparison with surgery alone (P<0.001). In the subgroups of OS analysis, age >65 (P=0.902), adenocarcinoma (P=0.279), tumor size ≤3 cm (P=0.170), well differentiated (P=0.360) patients, preoperative radiotherapy improved survival insignificantly compared with surgery alone. Conclusions Preoperative radiation with surgery had the most encouraging survival outcomes in stage IIIA-cN2 NSCLC patients compared with radiation or surgery alone. No significant outcome improvement was shown between postoperative radiotherapy (PORT) and surgery alone.

Survival Outcomes for Patients with Surgical and Non-Surgical Treatments in Stages I-III Small-Cell Lung Cancer

Objectives: Chemotherapy and radiation therapy are the standard treatments for patients with small-cell lung cancer (SCLC). However, recent studies suggest that patients with limited stage (I-III) SCLC may benefit from surgical treatment. This study was performed to evaluate the survival outcomes of surgery for stage I-III SCLC. Methods: This analysis used data from the Surveillance, Epidemiology, and End Results (SEER) database. All stage I-III (excluding N3 and Nx) SCLC patients received a diagnosis between 2004 and 2014. Overall survival (OS) and lung cancer-specific survival (LCSS) were determined by Kaplan-Meier analysis and compared using the log-rank test. A Cox proportional hazard model identified relevant survival variables. Results: A total of 4,780 histologically confirmed patients were identified from the SEER database, comprising 1,018 patients (21.3%) with stage I disease; 295 (6.2%) with stage II; and 3,467 (72.5%) with stage III disease. Among all of the patients, 520 had been treated with surgery, the majority (n = 344; 66.2%) of whom had stage I disease. The hazard ratio (HR) for OS and LCSS, in patients who underwent surgery, according to stage were as follows: OS, 0.369 and LCSS, 0.335 in stage I; OS, 0.549 and LCSS, 0.506 in stage II; and OS, 0.477 and LCSS, 0.456 in stage III (all p < 0.001). Patients who underwent surgery had significantly better OS, and lobectomy was associated with the best outcome. Conclusions: Surgical resection was associated with significantly improved OS outcomes and should be considered in the management of stage I-III SCLC.

Appropriate surgical modalities for stages T2a and T2b in the eighth TNM classification of lung cancer

Patients with tumors of 3 to 5 cm were divided into stages T2a (3 to 4 cm) and T2b (4 to 5 cm) based on the 8th tumor-node-metastasis staging system for lung cancer. The objective of our study was to explore appropriate surgical modalities for the new stages, T2a and T2b. We selected 6,996 node-negative non-small-cell lung cancer patients with tumor sizes of 3 to 5 cm, diagnosed between 2009 and 2013, from the Surveillance, Epidemiology, and End Results (SEER) program. The Pearson