EGFR Oncogenic Mutations in NSCLC Impair Macrophage Phagocytosis and Mediate Innate Immune Evasion Through Up-Regulation of CD47.

INTRODUCTION: EGFR-mutated NSCLC is characterized by an immunosuppressive microenvironment that confers limited clinical effectiveness to anti-PD-1 or PD-L1 antibodies. Despite the discouraging outcomes of immunotherapy, novel immune checkpoints are constantly emerging, among which the specific vulnerability for therapeutic intervention in the context of EGFR-mutated NSCLC remains unresolved. METHODS: Data sets of patient- and cell line-levels were used for screening and mutual validation of association between EGFR mutation and a panel of immune checkpoint-related genes. Regulatory mechanism was elucidated through in vitro manipulation of EGFR signaling pathway and evaluated by immunoblot analysis, quantitative polymerase chain reaction, flow cytometry, immunofluorescence staining, and chromatin immunoprecipitation. In vivo investigation of different therapeutic strategies were conducted using both immunocompetent and immunodeficient mouse models. RESULTS: Among all screened immune checkpoints, CD47 emerged as the candidate most relevant to EGFR activation. Mechanistically, EGFR mutation constitutively activated downstream ERK and AKT pathways to respectively up-regulate the transcriptional factors c-Myc and NF-κB, both of which structurally bound to the promotor region of CD47 and actively transcribed this "don't eat me" signal. Impaired macrophage phagocytosis was observed on introduction of EGFR-sensitizing mutations in NSCLC cell line models, whereas CD47 blockade restored the phagocytic capacity and augmented tumor cell killing in both in vitro and in vivo models. Remarkably, the combination of anti-CD47 antibody with EGFR tyrosine kinase inhibitor revealed an additive antitumor activity compared with monotherapy of either antitumor agent in both immunocompetent and adaptive immunity-deficient mouse models. CONCLUSIONS: EGFR-sensitizing mutation facilitates NSCLC's escape from innate immune attack through up-regulating CD47. Combination therapy incorporating CD47 blockade holds substantial promise for clinical translation in developing more effective therapeutic approaches against EGFR-mutant NSCLC.

The efficacy of first-line chemotherapy in recurrent or metastatic nasopharyngeal carcinoma: a systematic review and meta-analysis.

BACKGROUND: The standard first-line chemotherapy for patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) has not been well established. We conducted a pooled meta-analysis to evaluate the efficacy of commonly used first-line chemotherapy in this disease. METHODS: Electronic databases including PubMed, Embase, and Corchrane library were searched for eligible literatures. Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS) were pooled with the 95% confidence interval (CI) using R software. RESULTS: Totally 973 patients were available for analysis from 14 phase II single arm clinical trials and 2 phase III randomized clinical trials. Four regimens were identified including 5-fluorouracil plus platinum (FP), gemcitabine plus platinum (GP), taxanes plus platinum (TP), and triplet combination regimen. Of these four regimens, triplet combination regimen demonstrated best short-term efficacy with a highest ORR (0.74; 95% CI, 0.62-0.87), DCR (0.91; 95% CI, 0.87-0.95), and 6-month PFS rate (0.83; 95% CI, 0.75-0.91), while 1-year OS rate (0.74; 95% CI, 0.61-0.87) was a little lower than TP regimen. Meanwhile, TP regimen showed best prognosis with a highest 1-year OS rate of 0.79 (95% CI, 0.65-0.92) and pretty good short-term efficacy with an ORR of 0.60 (95% CI, 0.48-0.72) and a DCR of 0.92 (95% CI, 0.86-0.98) comparable with triplet combination therapy. FP regimen had the lowest ORR (0.52; 95% CI, 0.38-0.65) and 1-year OS rate (0.63; 95% CI, 0.57-0.69). Efficacy of GP regimen fell between FP and TP regimens with an ORR of 0.54 (95% CI, 0.38-0.65), a DCR of 0.85 (95% CI, 0.71-0.93), a 6-month PFS rate of 0.69 (95% CI, 0.60-0.78) and a 1-year OS rate of 0.71 (95% CI, 0.61-0.80). CONCLUSIONS: Among four commonly used first-line chemotherapy regimens for R/M NPC, triplet combination regimen showed best short-term efficacy but failed to improve prognosis. TP regimen demonstrated fairly good short-term efficacy and best long-term efficacy, followed by GP regimen, while FP regimen was the lowest.

Chemotherapy Near the End of Life for Chinese Patients with Solid Malignancies.

INTRODUCTION: There are increasing concerns about the negative impacts of chemotherapy near the end of life (EOL). There is discrepancy among different countries about its use, and little is known about the real-world situation in China. PATIENTS AND METHODS: This retrospective study was conducted at six representative hospitals across China. Adult decedents with a record of advanced solid cancer and palliative chemotherapy were consecutively screened from 2010 through 2014. The prevalence of EOL chemotherapy within the last 1 month of life was set as the primary outcome. The correlations among EOL chemotherapy, clinicopathological features, and overall survival (OS) were investigated. RESULTS: A total of 3,350 decedents who had had cancer were consecutively included; 2,098 (62.6%) were male and the median age was 56 years (range, 20-88). There were 177 (5.3%), 387 (11.6%), and 837 (25.0%) patients who received EOL chemotherapy within the last 2 weeks, 1 month, and 2 months of life, respectively. We identified inferior OS (median OS, 7.1 vs. 14.2 months; hazard ratio, 1.37; 95% confidence interval [CI], 1.23-1.53; p < .001), more intensive treatments (e.g., admitted to intensive care unit [ICU] in the last month of life, received cardiopulmonary resuscitation and invasive ventilation support), and hospital death (odds ratio, 1.53; 95% CI, 1.14-2.06; p = .005) among patients who received continued chemotherapy within the last month compared with those who did not. However, subgroup analyses indicated that receiving oral agents correlated with fewer ICU admissions and lower rates of in-hospital death. CONCLUSION: This study showed that EOL chemotherapy is commonly used in China. Intravenous chemotherapy at the EOL significantly correlated with poor outcomes and the role of oral anticancer agents warrants further investigation. The Oncologist 2017;22:53-60Implications for Practice: The role of chemotherapy toward the end of life (EOL) in patients with solid cancers is debatable. This article is believed to be the first to report the current prevalence of EOL chemotherapy in China. This study found that, compared with oral anticancer agents, intravenous chemotherapy at the EOL was significantly associated with poor outcomes. Therefore, the role of oral anticancer agents at the EOL stage deserves further investigation.

Efficacy of Addition of Antiangiogenic Agents to Taxanes-Containing Chemotherapy in Advanced Nonsmall-Cell Lung Cancer: A Meta-Analysis and Systemic Review.

Preclinical researches indicated a potential synergistic effect of taxanes-containing chemotherapy (TCC) and antiangiogenic agents (AAs) on the treatment of advanced nonsmall-cell lung cancer (NSCLC). The advantage of adding AA to TCC in the real world remains confusing. We summarized the current evidences from relevant phase II/III randomized controlled trials (RCTs) by performing this meta-analyses.Electronic databases were searched for eligible literatures. The primary endpoint was overall survival (OS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were calculated using RevMan 5.2.A total of 14 phase II/III RCTs involving 9703 participants were included. Compared to standard TCC, the addition of AA was associated with the significant better OS (HR 0.92, 95% CI 0.87-0.97, P = 0.002), prolonged progression-free survival (HR 0.79, 95% CI 0.71-0.87, P < 0.00001), superior response rate (risk ratio [RR] 1.69, 95% CI 1.47-1.95, P < 0.0001), and disease control rate (RR 1.19, 95% CI 1.08-1.32, P < 0.00001). Subgroup analyses indicated that patient treated with monoclonal antibodies (HR 0.89, 95% CI 0.82-0.96, P = 0.02) as well as application in second-line (HR 0.91, 95% CI 0.85-0.96, P = 0.02) acquired significant OS improvement. Other clinical factors directing significant OS improvement by the combination strategy included nonsquamous cancer (P = 0.002), nonsmokers (P = 0.0005), and female (P = 0.02). Toxicities were greater but generally mild or moderate in the combination group, and were mostly manageable.In summary, the addition of AAs to TCC could improve prognosis of advanced NSCLC. Furthermore, proper selection of patient population and AAs is crucial for clinical trials design and clinical practice in the future.

The Efficacy of Combining EGFR Monoclonal Antibody With Chemotherapy for Patients With Advanced Nonsmall Cell Lung Cancer: A Meta-Analysis From 9 Randomized Controlled Trials.

Although epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) have been proved synergistic effect when combined with cytotoxic agents for advanced nonsmall cell lung cancer (NSCLC), the results of relevant clinical trials remain controversial. The purpose of this meta-analysis was to assess the advantage and toxicity profile of chemotherapy plus EGFR-mAbs versus chemotherapy alone for patients with NSCLC.We rigorously searched electronic databases for eligible studies reporting EGFR-mAbs combined with chemotherapy versus chemotherapy alone for patients with advanced NSCLC. The primary outcome was overall survival (OS). Pooled results were calculated using proper statistical methods.Nine phase II/III randomized controlled trials involved a total of 4949 participants were included. In general, compared with chemotherapy alone, the addition of EGFR-mAbs significantly improved OS (hazard ratio [HR] = 0.91, 95% confidence interval [CI]: 0.86-0.97, P = 0.006), progression-free survival (HR = 0.83, 95% CI: 0.87-0.98, P = 0.01), response rate (odd ratio [OR] = 1.28, 95% CI: 1.12-1.47, P = 0.0003), and disease control rate (OR = 1.17, 95% CI: 1.01-1.36, P = 0.04). Subgroup analysis showed that apparent OS benefit present in patients with squamous NSCLC (HR = 0.83, 95% CI: 0.74-0.93, P = 0.001), and those treatment-naive population (HR = 0.88, 95% CI: 0.82-0.95, P = 0.0006). Several manageable adverse events were markedly increased by EGFR-mAbs, such as acne-like rash, infusion reactions, and diarrhea. The risk for some ≥Grade 3 toxicities, such as leukopenia, febrile neutropenia, and thromboembolic events were slightly increased by the addition of EGFR-mAbs. In general, the toxicities of the combination strategy were tolerable and manageable.The addition of EGFR-mAbs to chemotherapy provided superior clinical benefit along with acceptable toxicities to patients with advanced NSCLC, especially those harboring squamous cancer and treatment-naive. Further validation in front-line investigation, proper selection of the potential benefit population by tumor histology, and development of prognostic biomarkers are warranted for future research and clinical application of EGFR-mAbs.

Roles of immunohistochemical staining in diagnosing pulmonary squamous cell carcinoma.

BACKGROUND: Differentiating morphologic features based on hematoxylin-eosin (HE) staining is the most common method to classify pathological subtypes of non-small-cell lung cancer (NSCLC). However, its accuracy and inter-observer reproducibility in pathological diagnosis of poorly differentiated NSCLC remained to be improved. MATERIALS AND METHODS: We attempted to explore the role of immunohistochemistry (IHC) staining in diagnosing pulmonary squamous cell carcinoma (SQCC) with poorly differentiated features by HE staining or with elevated serum adenocarcinoma-specific tumor markers (AD-TMs). We also compared the difference of epidermal growth factor receptor (EGFR) mutation rate between patients with confirmed SQCC and those with revised pathological subtype. Logistic regression analyses were used to test the association between different factors and diagnostic accuracy. RESULTS: A total of 132 patients who met the eligible criteria and had adequate specimens for IHC confirmation were included. Pathological revised cases in poor differentiated subgroup, biopsy samples and high-level AD-TMs cases were more than those with high/moderate differentiation, surgical specimens and normal-level AD-TMs. Moreover, biopsy sample was a significant factor decreasing diagnostic accuracy of pathological subtype (OR, 4.037; 95% CI 1.446-11.267, p=0.008). Additionally, EGFR mutation rate was higher in patients with pathological diagnostic changes than those with confirmed SQCC (16.7% vs 4.4%, p=0.157). CONCLUSIONS: Diagnosis based on HE staining only might cause pathological misinterpretation in NSCLC patients with poor differentiation or high-level AD-TMs, especially those with biopsy samples. HE staining and IHC should be combined as pathological diagnostic standard. The occurrence of EGFR mutations in pulmonary SQCC might be overestimated.

ABO blood group, Epstein-Barr virus infection and prognosis of patients with non-metastatic nasopharyngeal carcinoma.

BACKGROUND: A prior study showed blood type A/AB to be associated with an increased risk of nasopharyngeal carcinoma (NPC) compared to subjects with blood type O. However, the relationship between ABO blood groups and prognosis of NPC patients is still questionable. In addition, whether Epstein-Barr virus (EBV) infection is associated with prognosis of NPC patients with different ABO blood groups is unclear. MATERIALS AND METHODS: We conducted univariate and multivariable Cox regression analyses based on a consecutive cohort of 1,601 patients to investigate the above issues. RESULTS: There was no significant difference in overall survival (OS) between different ABO blood groups (p=0.629), neither between A vs. non-A blood groups (p=0.895) nor AB vs. non-AB blood group (p=0.309) in univariate analyses and after adjusting for other factors. Interaction tests revealed that high immunoglobulin A against Epstein-Barr virus viral capsid antigen (VcA-IgA) level was associated with a favorable prognosis in male patients with UICC stage II disease who had an A blood type (p=0.008), compared with those with non-A blood type. In addition, male patients with an A blood group with a high blood lymphocyte level showed a tendency towards better survival in UICC stage III (p=0.096). CONCLUSIONS: ABO blood group status is not associated with the prognosis of patients with NPC. Additionally, blood group A male NPC patients with high VcA-IgA level or high blood lymphocyte counts might be correlated with a favorable prognosis in UICC stage II or III, respectively.

Artificial neural networks based on principal component analysis input selection for clinical pattern recognition analysis.

Two clinical data sets were applied for pattern recognition in order to discover the correlation between urinary nucleoside profiles and tumours. One data set contains 168 clinical urinary samples, of which 84 specimens are from female thyroid cancer patients (malignant tumour group), and the other samples were collected from healthy women (normal group). However, 168 clinical urinary samples comprised the second data set, too. In all the specimens, each number of the samples for both uterine cervical cancer patients (malignant tumour group) and healthy females (normal group) is 60, and the other 48 samples were collected from uterine myoma patients (benign tumour group). For the two data sets, the separation and quantitative determination of the clinical urinary nucleosides were performed by capillary electrophoresis (CE). The pattern recognition was achieved applying multiple layer perceptron artificial neural networks (MLP ANN) based on conjugate gradient descent training algorithm. Moreover, applying the proposed principal component analysis (PCA) input selection scheme to MLP ANN, the accuracy rate of the pattern recognition was improved to some extent (or without any deterioration) even by much simpler structure of MLP ANN. The study showed that MLP ANN based on PCA input selection was a promising tool for pattern recognition.

Modeling of the relationship between electroosmotic flow and separation parameters in capillary zone electrophoresis using artificial neural networks and experimental design.

The prediction of migration time of electroosmotic flow (EOF) marker was achieved by applying artificial neural networks (ANN) model based on principal component analysis (PCA) and standard normal distribution simulation to the input variables. The voltage of performance, the temperature in the capillary, the pH and the ionic strength of background electrolytes (BGE) were applied as the input variables to ANN. The range of the performance voltage studied was from 15 to 27kV, and that of the temperature in the capillary was from 20 to 30 degrees C. For the pH values studied, the range was from 5.15 to 8.04. The range of the ionic strength investigated in this paper was from 0.040 to 0.097. The prediction abilities of ANN with different pre-processing procedure to the input variables were compared. Under the same performance conditions, the average prediction error of the migration time of the EOF marker was 5.46% with RSD = 1.76% according to 10 parallel runs of the optimized ANN structure by the proposed approach, and that of the 10 parallel predictions of the optimal ANN structure for the different performance conditions was 12.95% with RSD = 2.29% according to the proposed approach. The study showed that the proposed method could give better predicted results than other approaches discussed.

The study of the relationship between the new topological index A(m) and the gas chromatographic retention indices of hydrocarbons by artificial neural networks.

The newly developed topological indices A(m1)-A(m3) and the molecular connectivity indices (m)X were applied to multivariate analysis in structure-property correlation studies. The topological indices calculated from the chemical structures of some hydrocarbons were used to represent the molecular structures. The prediction of the retention indices of the hydrocarbons on three different kinds of stationary phase in gas chromatography can be achieved applying artificial neural networks and multiple linear regression models. The results from the artificial neural networks approach were compared with those of multiple linear regression models. It is shown that the predictive ability of artificial neural networks is superior to that of multiple linear regression method under the experimental conditions in this paper. Both the topological indices (2)X and A(m1) can improve the predicted results of the retention indices of the hydrocarbons on the stationary phase studied.