Influence of TP53 mutation on efficacy and survival in advanced EGFR-mutant non-small cell lung cancer patients treated with third-generation EGFR tyrosine kinase inhibitors.

TP53 comutation is related to poor prognosis of non-small cell lung cancer. However, there is limited study focusing on the structural influence of TP53 mutation on third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. We retrospectively analyzed the clinical and molecular data of patients treated with third-generation EGFR-TKIs in two independent cohorts. A total of 117 patients from the Sun Yat-sen University Cancer Center (SYSUCC) and 141 patients from the American Association for Cancer Research Project GENIE database were included. In the SYSUCC cohort, TP53 comutations were found in 59 patients (50.4%) and were associated with poor median progress-free survival (mPFS) and median overall survival (mOS). The additional subtype analysis found that TP53 mutation in the alpha-helix region had shorter mOS compared with those with TP53 mutations in other regions in the SYSUCC cohort (mOS, 12.2 vs. 21.7 months; p = 0.027). Similar findings were confirmed in the GENIE cohort. Specifically, the presence of TP53 mutation in the alpha-helix region was an independent negative predictive factor for PFS [hazard ratio (HR) 2.05(1.01-4.18), p = 0.048] and OS [HR 3.62(1.60-8.17), p = 0.002] in the SYSUCC cohort. TP53 mutation in alpha-helix region was related to inferior clinical outcomes in patients treated with third-generation EGFR-TKIs.

PQR309, a dual PI3K/mTOR inhibitor, synergizes with gemcitabine by impairing the GSK-3ß and STAT3/HSP60 signaling pathways to treat nasopharyngeal carcinoma.

End-stage nasopharyngeal carcinoma (NPC) has unsatisfactory survival. The limited benefit of chemotherapy and the scarcity of targeted drugs are major challenges in NPC. New approaches to treat late-stage NPC are urgently required. In this study, we explored whether the dual PI3K/mTOR inhibitor, PQR309, exerted a favorable antineoplastic effect and sensitized the response to gemcitabine in NPC. We observed that PI3K expression was positive and elevated in 14 NPC cell lines compared with that in normal nasopharygeal cell lines. Patients with NPC with higher PI3K levels displayed poorer prognosis. We subsequently showed that PQR309 alone effectively decreased the viability, invasiveness, and migratory capability of NPC cells and neoplasm development in mice xenograft models, and dose-dependently induced apoptosis. More importantly, PQR309 remarkably strengthened the anti-NPC function of gemcitabine both in vivo and in vitro. Mechanistically, PQR309 sensitized NPC to gemcitabine by increasing caspase pathway-dependent apoptosis, blocking GSK-3ß and STAT3/HSP60 signaling, and ablating epithelial-mesenchyme transition. Thus, targeting PI3K/mTOR using PQR309 might represent a treatment option to promote the response to gemcitabine in NPC, and provides a theoretical foundation for the study of targeted drugs combined with chemotherapy for NPC.

The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation.

The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from "cold" to "hot" and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.

Predictive value of immunotherapy-induced inflammation indexes: dynamic changes in patients with nasopharyngeal carcinoma receiving immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have achieved substantial advancements in clinical care. However, there is no strong evidence for identified biomarkers of ICIs in NPC. METHODS: In this retrospective study, 284 patients were enrolled into a training or validation cohort. Inflammatory indexes based on peripheral blood parameters were evaluated, including the systemic immune-inflammation index (SII), the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), the lymphocyte-to-C-reactive protein ratio (LCR), and the lymphocyte-monocyte ratio (LMR). The optimum cut-off value for patient stratification was identified using X-tile. The Kaplan-Meier method and Cox's proportional regression analyses were used to identify prognostic factors. RESULTS: Immunotherapy significantly changed the levels of SII, NLR, PLR, LCR and LMR in NPC patients. Patients with lower SII, NLR, and PLR, as well as those with higher LCR and LMR, before immunotherapy had superior PFS (all p < 0.05). Moreover, PFS in the decreased SII, reduced NLR and increased LMR group was significantly longer than in the opposite group (all p < 0.05). Both univariate and multivariate analyses validated that baseline SII and LMR, and the immunotherapy-related SII reduction and LMR elevation were independent prognostic factors for PFS in advanced NPC patients receiving ICIs. CONCLUSIONS: Immune checkpoint inhibitor treatments significantly changed the levels of SII, NLR, PLR, LCR and LMR in NPC patients treated with immunotherapy. A lower baseline SII and a higher baseline LMR, and a reduction in SII and an elevation in LMR after immunotherapy are favorable factors for predicting survival among advanced NPC patients.

There is no strong evidence for identified biomarkers of immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC).Lower baseline SII and higher baseline LMR were related to better PFS. The dynamic changes of SII and LMR were independent prognostic factors for the survival of NPC patients receiving ICIs.Neutrophils, platelets, lymphocytes, and monocytes can be used as cheap and valuable biomarkers for predicting tumor response in NPC on immunotherapy.

Novel prognostic model predicts overall survival in colon cancer based on RNA splicing regulation gene expression.

Colon cancer is the third most common cancer and the second leading cause of cancer-related death worldwide. Dysregulated RNA splicing factors have been reported to be associated with tumorigenesis and development in colon cancer. In this study, we interrogated clinical and RNA expression data of colon cancer patients from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) database. Genes regulating RNA splicing correlated with survival in colon cancer were identified and a risk score model was constructed using Cox regression analyses. In the risk model, RNA splicing factor peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1) is correlated with a good survival outcome, whereas Cdc2-like kinase 1(CLK1), CLK2, and A-kinase anchor protein 8-like (AKAP8L) with a bad survival outcome. The risk model has a good performance for clinical prognostic prediction both in the TCGA cohort and the other two validation cohorts. In the tumor microenvironment (TME) analysis, the immune score was higher in the low-risk group, and TME-related pathway gene expression was also higher in low-risk group. We further verified the mRNA and protein expression levels of these four genes in the adjacent nontumor, tumor, and liver metastasis tissues of colon cancer patients, which were consistent with bioinformatics analysis. In addition, knockdown of AKAP8L can suppress the proliferation and migration of colon cancer cells. Animal studies have also shown that AKAP8L knockdown can inhibit tumor growth in colon cancer in vivo. We established a prognostic risk model for colon cancer based on genes related to RNA splicing regulation and uncovered the role of AKAP8L in promoting colon cancer progression.

Predictive Value of High Preoperative Serum Total Protein and Elevated Hematocrit in Patients with Non-Small-Cell Lung Cancer after Radical Resection.

BACKGROUND: The relationship between the dynamic alterations of nutritional indexes before and after surgery, and the prognosis of non-small-cell lung cancer (NSCLC) after radical surgery are unclear. Methods: This study enrolled 100 NSCLC patients in stages I-III who received radical surgery. The preoperative and postoperative 6-month levels of nine nutrition-related indicators were assessed in patients. Survival was analyzed using Kaplan-Meier curves as well as Cox regression models. RESULTS: Patients had better disease-free survival (DFS) with baseline total protein (TP) >76.66 g/L (75% vs. 50%, P = .027), baseline albumin (ALB) >37.7 g/L (60% vs. 26.7%, P = .002), baseline albumin to globulin ratio (AGR) >1.31 (63.5% vs. 40.5%, P = .006), or baseline globulin (GLOB) <31.42 g/L (39.4% vs. 62.7%, P = .037). Moreover, patients with increased hematocrit (HCT) (69.8% vs. 43.9% P = .013) and mean corpuscular volume (MCV) (73.2% vs. 42.4%, P = .014) at the postoperative 6-month examination had superior DFS. Cox proportional hazards regression analyses demonstrated that age >65 years, adenocarcinoma (pathological type), higher baseline TP, and post-surgery elevated HCT independently predicted favorable DFS. CONCLUSION: Lower baseline TP and decreased postoperative HCT levels are independent predictors of prognosis in NSCLC following radical surgical procedures.

HIF-1α inhibition promotes the efficacy of immune checkpoint blockade in the treatment of non-small cell lung cancer.

The response to immune checkpoint inhibitors (ICIs) monotherapy remains unsatisfactory in patients with NSCLC. Thus, combining ICIs with other potential modalities is of great significance to enhance the response of single drug alone. Here, we identified that HIF-1α inhibition was capable of promoting anti-tumor immunity in NSCLC. We applied NSCLC cell lines and mouse models to evaluate the synergy of combined HIF-1α inhibition and PD-1 blockade on tumor growth and the function of tumor infiltrating lymphocytes (TILs). Public datasets were utilized to investigate patients' prognosis based on expressions of HIF-1α and LOXL2 as well as EMT-associated markers and CD8+ TILs. Moreover, we explored the correlation between HIF-1α and LOXL2 levels and CD8+ TILs in tumor samples from patients with NSCLC by immunohistochemistry, as well as their association to patients' survival. In vitro, PX-478, an HIF-1α inhibitor, promoted tumor cell apoptosis induced by T cells when combined with ICIs. Furthermore, mice treated with PX-478 and anti-PD-1 antibodies exhibited a marked delay in tumor growth and prolonged survival, which correlated with increased TILs and granzyme B secretion. Besides, patients with high HIF-1α expression exhibited high levels of EMT-related markers and low TILs, indicating an immunosuppressive phenotype. Mechanistically, we observed that HIF-1α inhibition suppressed the EMT phenotypes induced by hypoxia and further alleviated tumor immunosuppression, which was related to blockage of HIF-1α/LOXL2 signaling pathway. In summary, we identified that HIF-1α inhibition could synergize with anti-PD-1 to impair tumor growth in vitro and in vivo. Our data suggest that HIF-1α inhibitors represent a promising treatment to enhance anti-tumor immunity and provide preclinical rationale to evaluate the combination of ICIs with HIF-1α inhibition clinically in NSCLC.

Predictive value of a reduction in the level of high-density lipoprotein-cholesterol in patients with non-small-cell lung cancer undergoing radical resection and adjuvant chemotherapy: a retrospective observational study.

BACKGROUND: Cancer patients often exhibit chemotherapy-associated changes in serum lipid profiles, however, their prognostic value before and after adjuvant chemotherapy on survival among non-small-cell lung cancer (NSCLC) patients is unknown. METHODS: NSCLC patients undergoing radical resection and subsequent adjuvant chemotherapy from 2013 to 2017 at Sun Yat-sen University Cancer Center were retrospectively reviewed. Fasted serum lipid levels were measured before and after chemotherapy. The optimal lipid cut-off values at baseline and fluctuation were determined using X-tile™. The fluctuations in serum lipid levels and disease-free survival (DFS) were assessed. RESULTS: Serum cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, apolipoprotein (Apo) A-I, and ApoB all significantly increased after adjuvant chemotherapy. X-tile determined 1.52 mmol/L of HDL-C and 0.74 g/L of ApoB as the optimal cut-off values before chemotherapy. Patients with HDL-C ≥ 1.52 mmol/L (median DFS: not reached vs. 26.30 months, P = 0.0005) and a decreased HDL-C level after adjuvant chemotherapy (median DFS: 80.43 vs. 26.12 months, P = 0.0204) had a longer DFS. An HDL-C level that increased by ≥ 0.32 mmol/L after chemotherapy indicated a worse DFS. A high baseline ApoB level were associated with a superior DFS. In the univariate analysis and the multivariate Cox analyses, a high baseline HDL-C level and a HDL-C reduction after adjuvant chemotherapy were independent indicators for superior DFS. High baseline HDL-C was related to N0-1 stage (χ2 = 6.413, P = 0.011), and HDL-C fluctuation was significantly correlated with specific chemotherapy regimens (χ2 = 5.002, P = 0.025). CONCLUSIONS: Adjuvant chemotherapy increased various lipid levels in resected NSCLC patients. A higher HDL-C level before chemotherapy and a reduced HDL-C level after adjuvant chemotherapy were independent predictors of longer DFS in patients with curable NSCLC.

Lymphocyte activating gene 3 protein expression in nasopharyngeal carcinoma is correlated with programmed cell death-1 and programmed cell death ligand-1, tumor-infiltrating lymphocytes.

BACKGROUND: Immunotherapy has shown promising efficacy in patients with nasopharyngeal carcinoma (NPC). Lymphocyte activating 3 gene (LAG-3) represents a significant immune target, however, its relationship with NPC remains unclear. This study aimed to evaluate LAG-3 expression in NPC and its association with CD3+ tumor-infiltrating lymphocytes (TILs), Granzyme B (GZMB), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) expression. METHODS: A total of 182 patients with NPC from Sun Yat-sen University Cancer Center, China, were included in this retrospective study. LAG-3 expression in 15 NPC cell lines and LAG-3, CD3+ TILs, GZMB, PD-L1 and PD-1 in clinical samples were estimated using immunohistochemistry. The Chi-square test was used to estimate the association between LAG-3, other biomarkers, and clinical characteristics. Survival analysis was performed using the Kaplan-Meier method and the Cox regression model. RESULTS: LAG-3 was negatively expressed in all of the 15 NPC cell lines, whereas, 147 patients with NPC (80.8%) exhibited high LAG-3 expression on TILs from tumor tissues. Male patients and those who were EBV-positive presented higher LAG-3 expression. Correlation analyses showed that LAG-3 expression was related to PD-1 expression on TILs, as well as, PD-L1 expression on tumor cells (TCs) and TILs. Both the univariate and multivariate Cox models indicated that pathological type III (P = 0.036), higher LAG-3 on TILs (P < 0.001), higher PD-L1 on TCs (P = 0.027), and higher PD-1 on TILs (P < 0.001) were associated with poorer disease-free survival (DFS). However, lower PD-L1 expression on TILs was related to superior DFS only in the univariate Cox analyses (P = 0.002). CONCLUSION: Higher LAG-3 and PD-1 on TILs, and higher PD-L1 expression on TCs, and pathological type III were identified as independent risk factors for poorer DFS in NPC patients. Our data demonstrate that LAG-3 is a promising inhibitory receptor that may play an important role in anti-NPC therapy.

Gemcitabine and APG-1252, a novel small molecule inhibitor of BCL-2/BCL-XL, display a synergistic antitumor effect in nasopharyngeal carcinoma through the JAK-2/STAT3/MCL-1 signaling pathway.

Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis, with an unfavorable response to palliative chemotherapy. Unfortunately, there are few effective therapeutic regimens. Therefore, we require novel treatment strategies with enhanced efficacy. The present study aimed to investigate the antitumor efficacy of APG-1252-M1, a dual inhibitor of BCL-2/BCL-XL, as a single agent and combined with gemcitabine. We applied various apoptotic assays and used subcutaneous transplanted NPC model to assess the in vitro and in vivo antitumor activity. Moreover, phospho-tyrosine kinase array was used to investigate the combined therapy's potential synergistic mechanism. In addition, further validation was performed using immunohistochemistry and western blotting. In vitro, we observed that APG-1252-M1 had moderate antitumor activity toward NPC cells; however, it markedly improved gemcitabine's ability to promote NPC cell apoptosis and suppress invasion, migration, and proliferation. Specifically, APG-1252 plus gemcitabine exhibited even remarkable antitumor activity in vivo. Mechanistically, the drug combination synergistically suppressed NPC by activating caspase-dependent pathways, blocking the phospho (p)-JAK-2/STAT3/MCL-1 signaling pathway, and inhibiting epithelial-mesenchymal transition. In conclusion, the results indicated that the combination of APG-1252 and gemcitabine has synergistic anticancer activities against NPC, providing a promising treatment modality for patients with NPC.

Anticancer bispecific antibody R&D advances: a study focusing on research trend worldwide and in China.

BACKGROUND: The bispecific antibody (bsAbs) research around the world has undergone great changes. We analyzed the global trend of bsAbs research and compared the differences in clinical research of bsAbs between China and worldwide. METHODS: BsAbs research clinical trials information was retrieved through the online open-resource clinical trial registration platform. Research information including organizations, identity numbers, locations, phases, participating centers, conditions, status, enrollment, targets, spectrums of mechanism of action (MOA), and start date was collected. Clinical trials were divided into two categories based on the attributes of pharmaceutical companies (international or China-initiated or involved). RESULTS: From 1997 to 2020, 272 clinical trials regarding bsAbs research were retrieved. Twenty-nine percent of the studies were contributed by companies from Chinese institutions, which followed the USA and ranked second. The clinical trials of bsAbs are mainly concentrated on phase I (n = 161), phase I/II (n = 54), and phase II (n = 51), and the number of phase III trials is still rare (n = 4). Tumor species distribution analysis shows that there are significantly higher focuses on gastric cancer (n = 18), esophageal/gastroesophageal junction cancer (n = 16), bladder cancer (n = 10), biliary malignant tumor (n = 8), nasopharyngeal cancer (n = 6), and thymic cancer (n = 2) in China. BsAbs target and spectrums of MOA analysis showed that international companies mainly focus on bsAbs with CD3-based (n = 63) target with MOA of T-cell redirection, while researches in China pay more attention to PD-1 (n = 9)/PD-L1 (n = 7) axises with MOA of double immune checkpoint blocking. CONCLUSION: Global bsAbs research increased rapidly during the 1997 to 2020 period. The developed countries in America and Europe are leading the trend of bsAbs research. Anticancer bsAbs clinical research in China is booming and chasing after the world trend.

The cross-sectional study of hepatic lipase SNPs and plasma lipid levels.

By the combination of meta-analysis, the data of the 1,000 Genomes Project Phase 3, and the promoter sequence of hepatic lipase (LIPC), we performed the cross-sectional study to explore the associations of four variants (rs1077835; rs1077834; rs1800588 [C-514T], and rs2070895 [G-250A]) in LIPC promoter with plasma lipid levels. Our results indicate that the first and the next three of the four SNPs are, respectively, reported to be associated with the decreased and increased HDL-c level. Meta-analysis of 87 studies with 101,988 participants indicates that HDL-c level in rs1800588 (C-514T) (pooled mean difference = 0.03, 95%CI (0.03, 0.04), p < .001) and rs2070895 (G-250A) (pooled mean difference = 0.07, 95%CI (0.05, 0.09), p < .001) is higher in allele T or A carriers. Similarly, LDL-c, TC, TG, and BMI levels are generally increased in T or A alleles carriers. We failed to conduct the meta-analysis of rs1077835 and rs1077834 due to the limited previous reports. Data from the 1,000 Genomes indicate that the allele frequencies of the four SNPs in total or subpopulations are almost equal to each other. The paired value r 2 and D' of the four SNPs are larger than 0.8, which indicate the linkage disequilibrium of the four variants. The analysis of LIPC promoter indicate that C-514T and G-250A are, respectively, located in transcriptional factor binding sites of USF1and Pbx1b, which may partly explain the effect of the two SNPs on the decreased LIPC activity in the alleles carriers and the corresponding increased plasma lipids hydrolyzed by LIPC. These results may help us to better understand the different effects of the four SNPs on the plasma lipid levels among subpopulations and offer clues for future clinical treatment of dyslipidemia-related diseases.

Multi-targeted tyrosine kinase inhibitors as third-line regimen in advanced non-small cell lung cancer: a network meta-analysis.

BACKGROUND: Four multi-targeted tyrosine kinase inhibitors (TKIs) including apatinib, anlotinib, fruquintinib and lenvatinib are currently available as third-line regimen for advanced non-small cell lung cancer (NSCLC) patients who failed at least two lines of systemic therapy. Limited evidence was provided to demonstrate the general efficacy and safety profile of these drugs as third-line treatment approach for NSCLC. METHODS: Eligible literature was searched from electronic database. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), treatment related adverse event (TRAE), treatment related adverse event grade 3-5 (TRAE3-5), hypertension, proteinuria, hand-foot skin reaction (HFSR), elevated ALT/AST, nausea and vomiting, diarrhea were synthetically extracted. Multiple-treatments comparisons (MTCs) based on a Bayesian consistency model integrated the efficacy and toxicity outcomes. Rank probabilities of each regimen were assessed and clustered by the surface under the cumulative ranking curve. RESULTS: Five phase II/III randomized trials involving 915 advanced NSCLC patients were enrolled. MTCs showed that four multi-targeted TKIs shared equivalent efficacy in terms of outcome measures, of which anlotinib stood out in ORR (OR =39.26; 95% CI: 2.36-2,748.06), DCR (OR =8.69; 95% CI: 1.70-50.18) and PFS (HR =0.27; 95% CI: 0.10-0.78) when compared with placebo plus BSC. No significantly differences were observed among these TKIs and placebo with respect to OS, TRAE and TRAE 3-5. Fruquintinib and lenvatinib may relate to high rate of HFSR while anlotinib may relate to hypertension. CONCLUSIONS: Multi-targeted TKIs (apatinib, anlotinib, fruquintinib and lenvatinib) with acceptable efficacy and safety profile were options for advanced NSCLC in third-line setting.

Correction to: The imbalance in the complement system and its possible physiological mechanisms in patients with lung cancer.

Following publication of the original article [1], it was noticed that Fig. 3c was omitted from the final published article.

The imbalance in the complement system and its possible physiological mechanisms in patients with lung cancer.

BACKGROUND: The clinical and experimental evidences for complement-cancer relationships are solid, whereas an epidemiological study reporting the imbalance of complement system in patients is still lacking. METHODS: Using publicly available databases, we jointly compared the levels of complement components in plasma and lung cancer tissues. With iTRAQ proteomics, quantitative RT-PCR and western blotting, we analysed the differences in complement levels in lung cancer tissues and normal control tissues. Complement components are mainly synthesized by the liver and secreted into the blood. Using paired co-cultures of human normal QSG-7701 hepatocytes with lung cancer cells (A549, LTEP-α-2 or NCI-H1703) or human normal bronchial epithelial (HBE) cells, we examined the effects of lung cancer cells on complement synthesis and secretion in QSG-7701 hepatocytes. RESULTS: An integrated analysis of transcriptome and proteome datasets from 43 previous studies revealed lower mRNA and protein levels of 25 complement and complement-related components in lung cancer tissues than those in normal control tissues; conversely, higher levels of complement proteins were detected in plasma from patients than those in healthy subjects. Our iTRAQ proteome study identified decreased and increased levels of 31 and 2 complement and complement-related proteins, respectively, in lung cancer tissues, of which the reduced levels of 10 components were further confirmed using quantitative RT-PCR and western blotting. Paired co-cultures of QSG-7701 hepatocytes with A549, LTEP-α-2, NCI-H1703 or HBE cells indicated that lung cancer cells increased complement synthesis and secretion in QSG-7701 cells compared to HBE cells. CONCLUSIONS: The opposite associations between the levels of complement and complement-related components in lung cancer tissues and plasma from patients that have been repeatedly reported by independent publications may indicate the prevalence of an imbalance in the complement system of lung cancer patients. The possible mechanism of the imbalance may be associated not only with the decreased complement levels in lung cancer tissues but also the concurrent lung cancer tissue-induced increase in hepatocyte complement synthesis and plasma secretion in patients. And the imbalance should be accompanied by a suppression of complement-dependent immunity in lung cancer tissues coupled with a burden of complement immunity in the circulation of patients.

Pemetrexed/carboplatin plus gefitinib as a first-line treatment for EGFR-mutant advanced nonsmall cell lung cancer: a Bayesian network meta-analysis.

BACKGROUND: First-line treatments for nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations have been evaluated in various clinical trials. However, it remains unclear which is the optimal treatment. METHODS: A Bayesian network meta-analysis was used to assess the efficacy and safety profile of gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, erlotinib plus bevacizumab and pemetrexed/carboplatin, or pemetrexed alone plus gefitinib. Literature was sourced from electronic databases. Data regarding objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs), treatment-related adverse event grades 3-5 (TRAE 3-5), specific TRAEs [diarrhea, rash, and elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT)] were extracted. The regimens were then ranked using the surface under the cumulative ranking curve (SUCRA). RESULTS: A total of 19 studies involving 4607 EGFR-mutant NSCLC patients were analyzed. In regards to efficacy, pemetrexed/carboplatin (PC) plus gefitinib was superior in ORR and OS to chemotherapy and first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). All the TKI-based regimens had equivalent DCR and PFS. Patients with the L858R mutation treated with PC plus gefitinib achieved a better outcome than most EGFR TKI-related groups (except osimertinib) in the PFS subgroup. In regards to safety, no statistical significance for TRAEs was observed among the eight treatments. In regards to SUCRA, PC plus gefitinib ranked first in terms of PFS, OS, and TRAE grades 3-5. CONCLUSIONS: Pemetrexed/carboplatin plus gefitinib is a promising treatment option for EGFR-mutant NSCLC patients in the first-line setting.

Association Between Complement Factor C2/C3/CFB/CFH Polymorphisms and Age-Related Macular Degeneration: A Meta-Analysis.

BACKGROUND: Several previous studies have assessed the contribution of polymorphisms in genes encoding the complement factors C2/C3/CFB/CFH with the risk of age-related macular degeneration (AMD), however the results have been inconsistent. We conducted a meta-analysis to systematically review the potential association between complement factor polymorphisms and AMD. METHODS: Studies that investigated associations between C2 (rs547154 and rs9332739), C3 (rs1047286), CFB (rs4151667 and rs641153), and CFH (rs551397 and rs2274700) polymorphisms and AMD were identified by searching PubMed, EMBASE, Web of Science, and Cochrane Library databases for articles published prior to January 1, 2018. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to evaluate the association between these polymorphisms and AMD using Stata 12.0 software. Q and I2 statistics were used to evaluate between-study heterogeneity. Publication bias analyses were conducted using Begg's test. We also conducted an ethnic subgroup analysis. RESULTS: A total of 53 studies that included data for 53,774 patients and 56,973 healthy controls were evaluated. The pooled ORs for rs551397, rs2274700, rs4151667, rs641153, rs1047286, rs9332739, and rs547154 in the heterozygote model were 0.53 (95% CI: 0.45-0.61), 0.53 (95% CI: 0.40-0.70), 0.54 (95% CI: 0.46-0.63), 0.48 (95% CI: 0.4-0.57), 1.42 (95% CI: 1.22-1.66), 0.5 (95% CI: 0.45-0.56), and 0.52 (95% CI: 0.43-0.62), respectively. CONCLUSION: Our findings from this analysis confirmed the protective role of C2/CFB/CFH polymorphisms in the development of AMD, but showed that the single nucleotide polymorphism in C3 was a high-risk factor for AMD. The racial analysis results suggested that the effect of variant alleles was stronger in Caucasians than Asians.