Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling.

Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer development. COPD induces activation of hypoxia-induced signaling, causing remodeling of surrounding microenvironmental cells also modulating the release and cargo of their extracellular vesicles (EVs). We aimed to evaluate the potential role of circulating EVs from COPD subjects in lung cancer onset. Plasma-EVs were isolated by ultracentrifugation from heavy smoker volunteers with (COPD-EVs) or without (heavy smoker-EVs, HS-EV) COPD and characterized following MISEV guidelines. Immortalized human bronchial epithelial cells (CDK4, hTERT-HBEC3-KT), genetically modified with different oncogenic alterations commonly found in lung cancer (sh-p53, KRASV12), were used to test plasma-EVs pro-tumorigenic activity in vitro. COPD-EVs mainly derived from immune and endothelial cells. COPD-EVs selectively increased the subset of CD133+CXCR4+ metastasis initiating cells (MICs) in HBEC-sh-p53-KRASV12high cells and stimulated 3D growth, migration/invasion, and acquisition of mesenchymal traits. These effects were not observed in HBEC cells bearing single oncogenic mutation (sh-p53 or KRASV12). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transferred from COPD-EVs triggers CXCR4 pathway activation that in turn mediates MICs expansion and acquisition of pro-tumorigenic effects. Indeed, HIF-1α inhibition or CXCR4 silencing prevented the acquisition of malignant traits induced by COPD-EVs alone. Hypoxia recapitulates the effects observed with COPD-EVs in HBEC-sh-p53-KRASV12high cells. Notably, higher levels of HIF-1α were observed in EVs from COPD subjects who subsequently developed cancer compared to those who remained cancer-free. Our findings support a role of COPD-EVs to promote the expansion of MICs in premalignant epithelial cells through HIF-1α-CXCR4 axis activation thereby potentially sustaining lung cancer progression.

Evaluation of Simplified Diet Scores Related to C-Reactive Protein in Heavy Smokers Undergoing Lung Cancer Screening.

The aim of this study was to assess the relationship between adherence to a healthy diet, such as the Mediterranean diet (MedDiet), and C-reactive protein (CRP) in Italian heavy smokers undergoing an LDCT screening program (bioMILD trial), using scores calculated by simple questionnaires. Simple formats of food frequency questionnaires were administered to a sample of 2438 volunteers, and the adherence to a healthy diet was measured by the validated 14-point MEDAS and by two adaptations proposed by us: 17-item revised-MEDAS and 18-item revised-MEDAS. The OR of CRP ≥ 2 mg/L for 1-point increase in 14-point MEDAS score was 0.95 (95% CI 0.91-0.99), for 17-point score was 0.94 (95% CI 0.91-0.98), and for 18-point score was 0.92 (95% CI 0.88-0.97). These inverse associations remained statistically significant also after further adjustment for body mass index. These results showed the efficacy of simplified scores and their relationship with lower levels of CRP in a population of heavy smokers. This suggests that a targeted nutritional intervention might achieve a substantial reduction in CRP levels. The findings will be prospectively tested in a new randomized study on primary prevention during lung cancer screening.

Development of a Molecular Blood-Based Immune Signature Classifier as Biomarker for Risks Assessment in Lung Cancer Screening.

BACKGROUND: Low-dose CT (LDCT) screening trials have shown that lung cancer early detection saves lives. However, a better stratification of the screening population is still needed. In this respect, we generated and prospectively validated a plasma miRNA signature classifier (MSC) able to categorize screening participants according to lung cancer risk. Here, we aimed to deeply characterize the peripheral immune profile and develop a diagnostic immune signature classifier to further implement blood testing in lung cancer screening. METHODS: Peripheral blood mononuclear cell (PBMC) samples collected from 20 patients with LDCT-detected lung cancer and 20 matched cancer-free screening volunteers were analyzed by flow cytometry using multiplex panels characterizing both lymphoid and myeloid immune subsets. Data were validated in PBMC from 40 patients with lung cancer and 40 matched controls and in a lung cancer specificity set including 27 subjects with suspicious lung nodules. A qPCR-based gene expression signature was generated resembling selected immune subsets. RESULTS: Monocytic myeloid-derived suppressor cell (MDSC), polymorphonuclear MDSC, intermediate monocytes and CD8+PD-1+ T cells distinguished patients with lung cancer from controls with AUCs values of 0.94/0.72/0.88 in the training, validation, and lung cancer specificity set, respectively. AUCs raised up to 1.00/0.84/0.92 in subgroup analysis considering only MSC-negative subjects. A 14-immune genes expression signature distinguished patients from controls with AUC values of 0.76 in the validation set and 0.83 in MSC-negative subjects. CONCLUSIONS: An immune-based classifier can enhance the accuracy of blood testing, thus supporting the contribution of systemic immunity to lung carcinogenesis. IMPACT: Implementing LDCT screening trials with minimally invasive blood tests could help reduce unnecessary procedures and optimize cost-effectiveness.

Cytisine Therapy Improved Smoking Cessation in the Randomized Screening and Multiple Intervention on Lung Epidemics Lung Cancer Screening Trial.

INTRODUCTION: Cytisine, a partial agonist-binding nicotine acetylcholine receptor, is a promising cessation intervention. We conducted a single-center, randomized, controlled trial (RCT) in Italy to assess the efficacy and tolerability of cytisine as a smoking cessation therapy among lung cancer screening participants. METHODS: From July 2019 to March 2020, the Screening and Multiple Intervention on Lung Epidemics RCT enrolled 869 current heavy tobacco users in a low-dose computed tomography screening program, with a randomized comparison of pharmacologic intervention with cytisine plus counseling (N = 470) versus counseling alone (N = 399). The primary outcome was continuous smoking abstinence at 12 months, biochemically verified through carbon monoxide measurement. RESULTS: At the 12-month follow-up, the quit rate was 32.1% (151 participants) in the intervention arm and 7.3% (29 participants) in the control arm. The adjusted OR of continuous abstinence was 7.2 (95% confidence interval: 4.6-11.2). Self-reported adverse events occurred more frequently in the intervention arm (399 events among 196 participants) than in the control arm (230 events among 133 participants, p < 0.01). The most common adverse events were gastrointestinal symptoms, comprising abdominal swelling, gastritis, and constipation. CONCLUSIONS: The efficacy and safety observed in the Screening and Multiple Intervention on Lung Epidemics RCT indicate that cytisine, a very low-cost medication, is a useful treatment option for smoking cessation and a feasible strategy to improve low-dose computed tomography screening outcomes with a potential benefit for all-cause mortality.

Single-Cell Phenotypic and Molecular Characterization of Circulating Tumor Cells Isolated from Cryopreserved Peripheral Blood Mononuclear Cells of Patients with Lung Cancer and Sarcoma.

BACKGROUND: The isolation of circulating tumor cells (CTCs) requires rapid processing of the collected blood due to their inherent fragility. The ability to recover CTCs from peripheral blood mononuclear cells (PBMCs) preserved from cancer patients could allow for retrospective analyses or multicenter CTC studies. METHODS: We compared the efficacy of CTC recovery and characterization using cryopreserved PMBCs vs fresh whole blood from patients with non-small cell lung cancer (NSCLC; n = 8) and sarcoma (n = 6). Two epithelial cellular adhesion molecule (EpCAM)-independent strategies for CTC enrichment, based on Parsortix® technology or immunomagnetic depletion of blood cells (AutoMACS®) were tested, followed by DEPArray™ single-cell isolation. Phenotype and genotype, assessed by copy number alterations analysis, were evaluated at a single-cell level. Detection of target mutations in CTC-enriched samples from frozen NSCLC PBMCs was also evaluated by digital PCR (dPCR). RESULTS: The use of cryopreserved PBMCs from cancer patients allowed for the retrospective enumeration of CTCs and their molecular characterization, using both EpCAM-independent strategies that performed equally in capturing CTC. Cells isolated from frozen PBMCs were representative of whole blood-derived CTCs in terms of number, phenotype, and copy number aberration profile/target mutations. Long-term storage (≥3 years) did not affect the efficacy of CTC recovery. Detection of target mutations was also feasible by dPCR in CTC-enriched samples derived from stored PBMCs. CONCLUSIONS: Isolating CTCs from longitudinally collected PBMCs using an unbiased selection strategy can offer a wider range of retrospective genomic/phenotypic analyses to guide patients' personalized therapy, paving the way for sample sharing in multicenter studies.

Circulating extracellular vesicles from individuals at high-risk of lung cancer induce pro-tumorigenic conversion of stromal cells through transfer of miR-126 and miR-320.

BACKGROUND: Extracellular vesicles (EVs) containing specific subsets of functional biomolecules are released by all cell types and analysis of circulating EVs can provide diagnostic and prognostic information. To date, little is known regarding the role of EVs both as biomarkers and potential key players in human lung cancer. METHODS: Plasma EVs were isolated from 40 cancer-free heavy-smokers classified according to a validated 24-microRNA signature classifier (MSC) at high (MSCpos-EVs) or low (MSCneg-EVs) risk to develop lung cancer. EVs origin and functional properties were investigated using in vitro 3D cultures and in vivo models. The prognostic value of miRNAs inside EVs was assessed in training and in validation cohorts of 54 and 48 lung cancer patients, respectively. RESULTS: Different membrane composition, biological cargo and pro-tumorigenic activity were observed in MSCpos vs MSCneg-EVs. Mechanistically, in vitro and in vivo results showed that miR-126 and miR-320 from MSCpos-EVs increased pro-angiogenic phenotype of endothelial cells and M2 polarization of macrophage, respectively. MSCpos-EVs prompted 3D proliferation of non-tumorigenic epithelial cells through c-Myc transfer. Moreover, hypoxia was shown to stimulate the secretion of EVs containing c-Myc from fibroblasts, miR-126-EVs from endothelial cells and miR-320-EVs from granulocytes. Lung cancer patients with higher levels of mir-320 into EVs displayed a significantly shorter overall survival in training [HR2.96] and validation sets [HR2.68]. CONCLUSION: Overall our data provide a new perspective on the pro-tumorigenic role of circulating EVs in high risk smokers and highlight the significance of miR-320-EVs as a new prognostic biomarker in lung cancer patients.

Cotargeting of miR-126-3p and miR-221-3p inhibits PIK3R2 and PTEN, reducing lung cancer growth and metastasis by blocking AKT and CXCR4 signalling.

Lung cancer is the leading cause of cancer-related death worldwide. Late diagnosis and metastatic dissemination contribute to its low survival rate. Since microRNA (miRNA) deregulation triggers lung carcinogenesis, miRNAs might represent an interesting therapeutic tool for lung cancer management. We identified seven miRNAs, including miR-126-3p and miR-221-3p, that are deregulated in tumours compared with normal tissues in a series of 38 non-small-cell lung cancer patients. A negative correlation between these two miRNAs was associated with poor patient survival. Concomitant miR-126-3p replacement and miR-221-3p inhibition, but not modulation of either miRNA alone, reduced lung cancer cell viability by inhibiting AKT signalling. PIK3R2 and PTEN were validated as direct targets of miR-126-3p and miR-221-3p, respectively. Simultaneous miRNA modulation reduced metastatic dissemination of lung cancer cells both in vitro and in vivo through CXCR4 inhibition. Systemic delivery of a combination of miR-126-3p mimic and miR-221-3p inhibitor encapsulated in lipid nanoparticles reduced lung cancer patient-derived xenograft growth through blockade of the PIK3R2-AKT pathway. Our findings reveal that cotargeting miR-126-3p and miR-221-3p to hamper both tumour growth and metastasis could be a new therapeutic approach for lung cancer.

Timeline of SARS-CoV-2 Spread in Italy: Results from an Independent Serological Retesting.

The massive emergence of COVID-19 cases in the first phase of pandemic within an extremely short period of time suggest that an undetected earlier circulation of SARS-CoV-2 might have occurred. Given the importance of this evidence, an independent evaluation was recommended by the World Health Organization (WHO) to test a subset of samples selected on the level of positivity in ELISA assays (positive, low positive, negative) detected in our previous study of prepandemic samples collected in Italy. SARS-CoV-2 antibodies were blindly retested by two independent centers in 29 blood samples collected in the prepandemic period in Italy, 29 samples collected one year before and 11 COVID-19 control samples. The methodologies used included IgG-RBD/IgM-RBD ELISA assays, a qualitative micro-neutralization CPE-based assay, a multiplex IgG protein array, an ELISA IgM kit (Wantai), and a plaque-reduction neutralization test. The results suggest the presence of SARS-CoV-2 antibodies in some samples collected in the prepandemic period, with the oldest samples found to be positive for IgM by both laboratories collected on 10 October 2019 (Lombardy), 11 November 2019 (Lombardy) and 5 February 2020 (Lazio), the latter with neutralizing antibodies. The detection of IgM and/or IgG binding and neutralizing antibodies was strongly dependent on the different serological assays and thresholds employed, and they were not detected in control samples collected one year before. These findings, although gathered in a small and selected set of samples, highlight the importance of harmonizing serological assays for testing the spread of the SARS-CoV-2 virus and may contribute to a better understanding of future virus dynamics.

Unexpected detection of SARS-CoV-2 antibodies in the prepandemic period in Italy.

There are no robust data on the real onset of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and spread in the prepandemic period worldwide. We investigated the presence of SARS-CoV-2 receptor-binding domain (RBD)-specific antibodies in blood samples of 959 asymptomatic individuals enrolled in a prospective lung cancer screening trial between September 2019 and March 2020 to track the date of onset, frequency, and temporal and geographic variations across the Italian regions. SARS-CoV-2 RBD-specific antibodies were detected in 111 of 959 (11.6%) individuals, starting from September 2019 (14%), with a cluster of positive cases (>30%) in the second week of February 2020 and the highest number (53.2%) in Lombardy. This study shows an unexpected very early circulation of SARS-CoV-2 among asymptomatic individuals in Italy several months before the first patient was identified, and clarifies the onset and spread of the coronavirus disease 2019 (COVID-19) pandemic. Finding SARS-CoV-2 antibodies in asymptomatic people before the COVID-19 outbreak in Italy may reshape the history of pandemic.

Improved Prognostic Prediction in Never-Smoker Lung Cancer Patients by Integration of a Systemic Inflammation Marker with Tumor Immune Contexture Analysis.

Almost 25% of lung cancers (LCs) occur in never-smokers. LC inflammatory profile, based on plasma C-reactive protein levels (CRP), predicts mortality, independently by smoking-status. We hypothesized that: CRP could be associated with tumor immune contexture (TIC) in never-smokers and both these two parameters may improve their prognosis. Sixty-eight never-smokers LC patients with high or low CRP were selected. The programmed cell death protein 1 (PD-1) and its ligand (PD-L1), the human leukocyte antigens (HLA-DR and HLA-I), CD8, CD4, CD3, CD33, CD163, and CD68 were evaluated by immunohistochemistry on surgical samples given TIC evaluation. The classification model based on TIC scores was generated by Classification and Regression Tree analysis. Tumor mutational burden was evaluated by targeted next-generation sequencing. Exclusively high CRP (H-CRP) subset showed PD-L1 expression in 35% of LC as well as lower HLA-I and HLA-DR in their stromal cells. CD3, CD4, CD8, HLA-I, HLA-DR tumor cells staining were associated with a "low inflammatory profile" subset. CRP and LC immune profiles drive clinical outcome: 5-year survival 88% against 8% was associated with low and high-risk profiles (p < 0.0001). Clinical outcome prediction in never-smoker LC patients may be improved by both CRP and tumor immune contexture evaluation.

Correction: Circulating microRNA signature as liquid-biopsy to monitor lung cancer in low-dose computed tomography screening.

[This corrects the article DOI: 10.18632/oncotarget.5210.].

Baseline and Postoperative C-reactive Protein Levels Predict Long-Term Survival After Lung Metastasectomy.

BACKGROUND: Blood level of C-reactive protein (CRP) at diagnosis is a well-know prognostic bio-marker in different primary tumors, but its role has not been investigated in resectable lung metastases. The aim of our study is to assess the predictive value of baseline (CRP0) and 3rd postoperative day (CRP3) levels on long-term survival of patients undergoing lung metastasectomy. METHODS: A total of 846 consecutive patients underwent the first pulmonary resection for lung metastases between January 2003 and December 2015, including 611 (72%) single surgical procedures, 235 (28%) multiple metastasectomies, 501 (59%) epithelial primary tumors, 276 (33%) sarcomas, 66 (8%) melanomas, 286 (33.8%) with 0 risk factors (CRP0 ≤ 2 and CRP3 ≤ 84 mg/L) and 560 (66.2%) with ≥ 1 risk factor (CRP0 > 2 and/or CRP3 > 84 mg/L). RESULTS: Cumulative 5-year survival was 57% in patients with low CRP (0 risk factors) versus 43% in high CRP (≥ 1 risk factor, p < 0.0002), 62% versus 50% respectively for epithelial tumors (p < 0.0140), and 51% versus 34% for sarcomas (p < 0.0111). Multivariable Cox analysis confirmed a mortality hazard ratio of 2.5 at 1-year and 1.5 at 5-years in patients with high CRP. CONCLUSIONS: Baseline and postoperative CRP levels predict survival of patients with resectable lung metastases. These data provide a rationale for prospective clinical trials testing the efficacy of anti-inflammatory or immune-modulating agents as "adjuvant" therapy after lung metastasectomy, in patients with elevated pre- and/or postoperative CRP levels.

Effect of Tobacco Smoking Cessation on C-Reactive Protein Levels in A Cohort of Low-Dose Computed Tomography Screening Participants.

Smokers have higher levels of C-Reactive Protein (CRP) compared to never smokers. The role of smoking cessation on CRP is still under debate. Using data from two screening studies conducted in Italy in 2000-2010 on 3050 heavy smokers (including 777 ex-smokers), we estimated multivariate odds ratios (OR) for high CRP (i.e. ≥2 mg/L) according to smoking status. Moreover, in a longitudinal analysis based on 975 current smokers, with a second measurement of CRP after an average study period of 3.4 years, we estimated the changes in CRP according to smoking cessation. Prevalence of high CRP at baseline was 35.8% among ex-smokers and 41.1% among current smokers (significant OR for ex- vs. current smokers: 0.79). After four years since smoking cessation, CRP levels significantly decreased with increasing years of cessation (significant OR for ex-smokers since more than 8 years: 0.55). In the longitudinal analysis, no significant reduction in CRP was found for time since smoking cessation (ORs: 1.21, 1.04, and 0.91 for ex-smokers since 1 year, 2-3 years, and ≥4 years, respectively). In the largest prospective study available so far, we found that smoking cessation has a favourable effect on CRP, but this benefit is not evident in the short-term.

Inflammatory status and lung function predict mortality in lung cancer screening participants.

Low-dose computed tomography (LDCT) screening trials have based their risk selection algorithm on age and tobacco exposure, but never on pulmonary risk-related biomarkers. In the present study, the baseline inflammatory status, measured by C-reactive protein (CRP) level, and lung function, measured by forced expiratory volume in 1 s (FEV1), were tested as independent predictors of all-cause mortality in LDCT-screening participants. Between 2000 and 2010, 4413 volunteers were enrolled in two LDCT-screening trials, with evaluable baseline CRP and FEV1 values: 2037 were included in the discovery set and 2376 were included in the validation set. The effect of low FEV1 or high CRP alone or combined was evaluated by Kaplan-Meier mortality curves and hazard ratio (HR) with 95% confidence interval (CI) by fitting Cox proportional hazards models. The overall mortality risk was significantly higher in participants with FEV1 of up to 90% (HR: 2.13, CI: 1.43-3.17) or CRP more than 2 mg/l (HR: 3.38, CI: 1.60-3.54) and was still significant in the fully adjusted model. The cumulative 10-year probability of death was 0.03 for participants with FEV1 of more than 90% and CRP up to 2 mg/l, 0.05 with only FEV1 of up to 90% or CRP above 2 mg/l, and 0.12 with FEV1 of up to 90% and CRP above 2 mg/l. This predictive performance was confirmed in the two external validation cohorts with 10-year mortality rates of 0.06, 0.12, and 0.14, and 0.03, 0.07, and 0.14, respectively. Baseline inflammatory status and lung function reduction are independent predictors of all-cause long-term mortality in LDCT-screening participants. CRP and FEV1 could be used to select higher-risk individuals for future LDCT screening and preventive programs.

MicroRNA Based Liquid Biopsy: The Experience of the Plasma miRNA Signature Classifier (MSC) for Lung Cancer Screening.

The development of a minimally invasive test, such as liquid biopsy, for early lung cancer detection in its preclinical phase is crucial to improve the outcome of this deadly disease. MicroRNAs (miRNAs) are tissue specific, small, non-coding RNAs regulating gene expression, which may act as extracellular messengers of biological signals derived from the cross-talk between the tumor and its surrounding microenvironment. They could thus represent ideal candidates for early detection of lung cancer. In this work, a methodological workflow for the prospective validation of a circulating miRNA test using custom made microfluidic cards and quantitative Real-Time PCR in plasma samples of volunteers enrolled in a lung cancer screening trial is proposed. In addition, since the release of hemolysis-related miRNAs and more general technical issues may affect the analysis, the quality control steps included in the standard operating procedures are also presented. The protocol is reproducible and gives reliable quantitative results; however, when using large clinical series, both pre-analytical and analytical features should be cautiously evaluated.

Baseline and postoperative C-reactive protein levels predict mortality in operable lung cancer.

BACKGROUND: Higher blood levels of C-reactive protein (CRP) have been associated with shorter survival in patients with cardiovascular, chronic obstructive pulmonary disease and cancer. We investigated the impact of baseline and postoperative CRP levels on survival of patients with operable lung cancer (LC). PATIENTS AND METHODS: CRP values at baseline (CRP0) and 3 days after surgery (CRP3) were measured in a consecutive series of 1750 LC patients who underwent complete resection between 2003 and 2015. Patients were classified as having 0 (N = 593), 1 (N = 658) or 2 (N = 553) risk factors: CRP0 and/or CRP3 values above the respective median value. The effect of higher CRP was evaluated by Kaplan-Meier mortality curves and adjusted hazard ratio (HR) with 95% confidence interval (CI), by fitting Cox proportional hazards models. RESULTS: Cumulative proportions of 5-year survival were 67% for 0 risk factors, 58% for 1 risk factor and 41% for 2 risk factors (P < 0.0001). The overall 5-year mortality risk was significantly higher in patients with 1 risk factor (adjusted hazard ratio [aHR] 1.43 [95% CI 1.14-1.79]), or 2 risk factors (aHR 2.49 [95% CI 1.99-3.11]). A significant impact on survival was observed in each tumour-node-metastasis stage group, and in the subset of non-smokers. Postoperative 30-day mortality was significantly higher in patients with 2 risk factors only (aHR 2.2% versus 0.6%, p < 0.0475). CONCLUSIONS: Baseline and postoperative CRP levels predict immediate and long-term mortality in all stages of operable lung cancer. Patients with higher CRP levels could be candidate to randomised adjuvant trials with anti-inflammatory agents.

Mutational Profile from Targeted NGS Predicts Survival in LDCT Screening-Detected Lung Cancers.

BACKGROUND: The issue of overdiagnosis in low-dose computed tomography (LDCT) screening trials could be addressed by the development of complementary biomarkers able to improve detection of aggressive disease. The mutation profile of LDCT screening-detected lung tumors is currently unknown. METHODS: Targeted next-generation sequencing was performed on 94 LDCT screening-detected lung tumors. Associations with clinicopathologic features, survival, and the risk profile of a plasma microRNA signature classifier were analyzed. RESULTS: The mutational spectrum and frequency observed in screening series was similar to that reported in public data sets, although a larger number of tumors without mutations in driver genes was detected. The 5-year overall survival (OS) rates of patients with and without mutations in the tumors were 66% and 100%, respectively (p = 0.015). By combining the mutational status with the microRNA signature classifier risk profile, patients were stratified into three groups with 5-year OS rates ranging from 42% to 97% (p < 0.0001) and the prognostic value was significant after controlling for stage (p = 0.02). CONCLUSION: Tumor mutational status along with a microRNA-based liquid biopsy can provide additional information in planning clinical follow-up in lung cancer LDCT screening programs.

C-reactive protein level predicts mortality in COPD: a systematic review and meta-analysis.

The prognostic role of baseline C-reactive protein (CRP) in chronic obstructive pulmonary disease (COPD) is controversial. In order to clarify this issue, we performed a systematic review and meta-analysis to assess the predictive effect of baseline CRP level in COPD patients. 15 eligible articles focusing on late mortality in COPD were included in our study. We performed a random-effects meta-analysis, and assessed heterogeneity and publication bias. We pooled hazard ratio (HR) estimates and their 95% confidence intervals on mortality for the comparison between the study-specific highest category of CRP level versus the lowest category. In overall analysis, elevated baseline CRP levels were significantly associated with higher mortality (HR 1.53, 95% CI 1.32-1.77, I2=68.7%, p<0.001). Similar results were observed across subgroups. However, higher mortality risk was reported in studies using a cut-off value of 3 mg·L-1 (HR 1.61, 95% CI 1.12-2.30) and in those enrolling an Asiatic population (HR 3.51, 95% CI 1.69-7.31). Our analysis indicates that baseline high CRP level is significantly associated with higher late mortality in patients with COPD. Further prospective controlled studies are needed to confirm these data.

Baseline C-reactive protein level predicts survival of early-stage lung cancer: evidence from a systematic review and meta-analysis.

PURPOSE: The prognostic impact of baseline C-reactive protein (CRP) in non-small-cell lung cancer (NSCLC) is debated. To evaluate this issue, we performed a systematic review and meta-analysis to explore the role of CRP value in predicting early-stage NSCLC survival. METHODS: Ten articles on early-stage NSCLC were eligible and included in our study. We performed a random-effects meta-analysis and assessed heterogeneity and publication bias. We pooled hazard ratio (HR) estimates and their 95% confidence intervals (CIs) on mortality for the comparison between the study-specific highest category of CRP level versus the lowest one. RESULTS: In overall analysis, elevated pretreatment CRP values were significantly associated with poor overall survival (HR 1.60, 95% CI 1.30-1.97, p<0.001, I2 = 71.9%). Similar results were observed across considered strata. However, higher mortality risk was reported in studies in which CRP was combined with other factors (HR 1.96, 95% CI 1.58-2.45) and in those using a cutoff value of 3 mg/L (HR 1.89, 95% CI 1.52-2.35). CONCLUSIONS: Based on our analysis, baseline high CRP level is significantly associated with poor prognosis in early-stage NSCLC. Further prospective controlled studies are needed to confirm these data.