Cancers

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19 pages, 2925 KiB

Open AccessArticle

Comprehensive Serum Glycopeptide Spectra Analysis Combined with Machine Learning for Early Detection of Lung Cancer: A Case–Control Study

by Koji Yamazaki, Shigeto Kawauchi, Masaki Okamoto, Kazuhiro Tanabe, Chihiro Hayashi, Mikio Mikami and Tetsuya Kusumoto

Cancers 2025, 17(9), 1474; https://doi.org/10.3390/cancers17091474 - 27 Apr 2025

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Abstract

Background: Lung cancer is among the most prevalent and fatal cancers worldwide. Traditional diagnostic methods, such as computed tomography, are not ideal for screening due to their high cost and radiation exposure. In contrast, blood-based diagnostics, as non-invasive approaches, are expected to reduce [...] Read more.

Background: Lung cancer is among the most prevalent and fatal cancers worldwide. Traditional diagnostic methods, such as computed tomography, are not ideal for screening due to their high cost and radiation exposure. In contrast, blood-based diagnostics, as non-invasive approaches, are expected to reduce patient burden, thereby increasing screening participation and ultimately improving survival rates. However, conventional tumor markers have shown limited effectiveness in early detection. Methods: We recruited 199 patients with lung cancer and 590 healthy volunteers. Nine tumor markers (CEA, CA19-9, CYFRA, AFP, PSA, CA125, CA15-3, SCC antigen, and NCC-ST439) were analyzed, along with enriched glycopeptides (EGPs) derived from serum proteins using liquid chromatography–mass spectrometry. Machine learning models, including decision trees and deep learning approaches, were employed to develop a predictive model for accurately distinguishing lung cancer from healthy controls based on tumor markers and EGP profiles. Results: We found that α1-antitrypsin with fully sialylated biantennary glycan, attached to asparagine 271 (AT271-FSG), and α2-macroglobulin with fully sialylated biantennary glycan, attached to asparagine 70 (MG70-FSG), could significantly distinguish between patients with lung cancer and healthy individuals. Comprehensive Serum Glycopeptide Spectra Analysis (CSGSA), integrating nine conventional tumor markers and 1688 EGPs using a machine learning model, enhanced diagnostic accuracy and achieved an ROC-AUC score of 0.935. It also identified stage I cases with an ROC-AUC of 0.914, indicating the possibility of early-stage detection. The PPV reached 2.8%, which was sufficient for practical application. Conclusions: This method represents a significant advancement in cancer diagnostics, combining multiple biomarkers with cutting-edge machine learning to improve the early detection of lung cancer. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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18 pages, 928 KiB

Open AccessArticle

Soluble PD-L1 and Serum Vascular Endothelial Growth Factor-B May Independently Predict Prognosis in Patients with Advanced Non-Small Cell Lung Cancer Treated with Pembrolizumab

by Eleni Kokkotou, Dimitra Grapsa, Anna Papadopoulou, Stylianos Gaitanakis, Petros Bakakos, Garyfallia Poulakou, Paraskevi Moutsatsou and Konstantinos Syrigos

Cancers 2025, 17(3), 421; https://doi.org/10.3390/cancers17030421 - 27 Jan 2025

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Abstract

Background: Previous preclinical data have shown that the dynamic cross-talk between abnormal tumor vasculature and immune cell factors in the tumor microenvironment may exert a critical role in the progression and treatment resistance of non-small cell lung cancer (NSCLC). In the clinical setting, [...] Read more.

Background: Previous preclinical data have shown that the dynamic cross-talk between abnormal tumor vasculature and immune cell factors in the tumor microenvironment may exert a critical role in the progression and treatment resistance of non-small cell lung cancer (NSCLC). In the clinical setting, a variety of blood-based angiogenesis- and immune-related factors are being increasingly investigated as potential biomarkers of prognosis or treatment response in immunotherapy-treated NSCLC. We herein aimed to evaluate the clinical relevance of the peripheral blood levels of vascular endothelial growth factor-A and -B (VEGF-A and VEGF-B, respectively), soluble programmed cell death-1 (sPD-1), and programmed cell death-ligand 1 (sPD-L1) in patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs). Methods: Consecutive patients with advanced-stage, non-oncogene-addicted NSCLC, eligible to receive ICIs at the Oncology Unit of Sotiria Athens General Hospital, were prospectively recruited. A group of sex- and age-matched healthy controls was also enrolled for the evaluation of the potential diagnostic significance of the examined biomarkers. Serum levels of all biomarkers were measured using ELISA, both before and after treatment, and were correlated with standard clinicopathological features of patients, treatment response, progression-free survival (PFS), and overall survival (OS). Results: A total of 55 patients and 16 healthy controls were included in the final analysis. The mean age of patients and controls was 66.5 years (SD = 8.0 years) and 65.4 years (SD = 9.1 years), respectively. The majority of patients (65.5%) received pembrolizumab in combination with chemotherapy, while the remaining patients received pembrolizumab monotherapy. ROC curve analysis showed that VEGFB and sPD-1 were the only markers with a significant diagnostic value. Higher pre-treatment values of sPD-L1 (HR = 1.68; p = 0.040) and sPD-1 (HR = 10.96; p = 0.037) as well as higher post-treatment values of VEGF-B (HR = 2.99; p = 0.049) were all significantly associated with a reduced OS in univariate Cox regression analysis. The adverse prognostic significance of higher pre-treatment values of sPD-L1 (HR = 2.10; p = 0.014) and higher post-treatment values of VEGFB (HR = 3.37; p = 0.032) was further confirmed in multivariate analysis. Conclusions: Our study results suggest that serum levels of sPD-L1 and VEGF-B may independently predict prognosis in ICI-treated advanced-stage NSCLC. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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12 pages, 574 KiB

Open AccessArticle

Allostatic Load, Cigarette Smoking, and Lung Cancer Risk

by Yufan Guan, Jie Shen, Kai Zhang, Bernard F. Fuemmeler and Hua Zhao

Cancers 2024, 16(18), 3235; https://doi.org/10.3390/cancers16183235 - 23 Sep 2024

Viewed by 1513

Abstract

Background: Allostatic load (AL) is a biomarker of chronic stress associated with various chronic diseases. No study has evaluated the relationship between AL and lung cancer risk. Methods: To address this gap, we analyzed the association between AL and the development of lung [...] Read more.

Background: Allostatic load (AL) is a biomarker of chronic stress associated with various chronic diseases. No study has evaluated the relationship between AL and lung cancer risk. Methods: To address this gap, we analyzed the association between AL and the development of lung cancer in 344,380 participants from the UK Biobank. Results: During the follow-up period from 2006 to 2020, 2517 participants were diagnosed with incident lung cancer. Participants who developed lung cancer had significantly higher AL compared to cancer-free controls (mean: 3.49 vs. 2.87, p < 0.001). In the multivariate analysis, a marginally significant association was observed between higher AL and increased lung cancer risk (per one AL unit: Hazard Ratio [HR] = 1.02, 95% Confidence Interval [CI]: 0.99, 1.04). In the categorical analysis, individuals with high AL (AL > 2) had a 15% higher risk of lung cancer compared to those with low AL (AL ≤ 2) (HR = 1.15, 95% CI: 1.05, 1.25). Stratified analyses revealed that this increased risk was only observed in former (HR = 1.38, 95% CI: 1.06, 1.43) and current smokers (HR = 1.25, 95% CI: 1.10, 1.42) but not in never-smokers (HR = 0.93, 95% CI: 0.74, 1.17). Moreover, we found that demographics, socioeconomics, and other health behaviors could modify the risk association. Finally, among cigarette smoking-related variables, a significant trend of increasing AL was observed with higher pack-years, longer smoking duration, earlier age of smoking initiation, and later age of smoking cessation. Conclusions: These findings suggest that higher AL is associated with an increased risk of lung cancer. The results need to be further confirmed in additional studies. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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23 pages, 6728 KiB

Open AccessArticle

Novel DNA Repair Inhibitors Targeting XPG to Enhance Cisplatin Therapy in Non-Small Cell Lung Cancer: Insights from In Silico and Cell-Based Studies

by Rita Manguinhas, Patrícia A. Serra, Nuno Gil, Rafael Rosell, Nuno G. Oliveira and Rita C. Guedes

Cancers 2024, 16(18), 3174; https://doi.org/10.3390/cancers16183174 - 16 Sep 2024

Viewed by 1333

Abstract

NSCLC is marked by low survival and resistance to platinum-based chemotherapy. The XPG endonuclease has emerged as a promising biomarker for predicting the prognosis of cisplatin-treated patients and its downregulation having been reported to increase cisplatin efficacy. This study presents an integrated strategy [...] Read more.

NSCLC is marked by low survival and resistance to platinum-based chemotherapy. The XPG endonuclease has emerged as a promising biomarker for predicting the prognosis of cisplatin-treated patients and its downregulation having been reported to increase cisplatin efficacy. This study presents an integrated strategy for identifying small molecule inhibitors of XPG to improve cisplatin therapy in NSCLC. A structure-based virtual screening approach was adopted, including a structural and physicochemical analysis of the protein, and a library of small molecules with reported inhibitory activities was retrieved. This analysis identified Lys84 as a crucial residue for XPG activity by targeting its interaction with DNA. After molecular docking and virtual screening calculations, 61 small molecules were selected as potential XPG inhibitors, acquired from the ChemBridge database and then validated in H1299 cells, a NSCLC cell line exhibiting the highest ERCC5 expression. The MTS assay was performed as a first screening approach to determine whether these potential inhibitors could enhance cisplatin-induced cytotoxicity. Overall, among the eight compounds identified as the most promising, three of them revealed to significantly increase the impact of cisplatin. The inherent cytotoxicity of these compounds was further investigated in a non-tumoral lung cell line (BEAS-2B cells), which resulted in the identification of two non-cytotoxic candidates to be used in combination with cisplatin in order to improve its efficacy in NSCLC therapy. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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10 pages, 653 KiB

Open AccessArticle

Recurrence Rates and Patterns after Radical Resection of Lung Carcinoids

by Erika Askildsen, Patrick Soldath, Seppo W. Langer, Mikkel Andreassen, Ulrich Knigge and René Horsleben Petersen

Cancers 2024, 16(17), 2978; https://doi.org/10.3390/cancers16172978 - 27 Aug 2024

Viewed by 1157

Abstract

Atypical lung carcinoid (AC) is widely accepted to recur more often after radical resection than typical lung carcinoid (TC). However, their recurrence rates have never been compared in a multi-state competing risks model. We retrospectively reviewed files from patients with AC and TC [...] Read more.

Atypical lung carcinoid (AC) is widely accepted to recur more often after radical resection than typical lung carcinoid (TC). However, their recurrence rates have never been compared in a multi-state competing risks model. We retrospectively reviewed files from patients with AC and TC who had been radically resected at our European Neuroendocrine Tumor Society Center of Excellence between 2009 and 2020. We estimated the recurrence rates between the AC and TC patients counting unrelated death as a competing event using Aalen–Johansen estimates and compared them using a multi-state Cox model. Finally, we analyzed all AC and TC recurrences as to resection type, pathological stage, resection margin, recurrence site, and time to recurrence. The study included 217 patients, of whom 194 had TC and 23 had AC. The median follow-up was 9.4 years. The AC patients experienced recurrence at a higher rate (hazard ratio [HR] 16.0, 95% confidence interval [CI] 5.3–47.9, p < 0.001). Correspondingly, the 5- and 10-year recurrence rates were 18% and 32% for AC and merely 1.0% and 2.4% for TC. In patients without nodal involvement, AC recurred at a considerably higher rate (HR 41.2, 95% CI 8.7–194.8, p < 0.001) than TC. In both AC and TC, most recurrences were distant and occurred in patients with a resection margin less than 2 cm. We conclude that AC recurs more often than TC, even in patients without nodal involvement at surgery, suggesting that all AC patients regardless of their pathological stage should undergo close follow-up care after surgery. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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16 pages, 4538 KiB

Open AccessArticle

Clinical Importance of Grading Tumor Spread through Air Spaces in Early-Stage Small-Lung Adenocarcinoma

by Jeong Hyeon Lee, Younggjn Kang, Seojin Kim, Youggi Jung, Jae Ho Chung, Sungho Lee and Eunjue Yi

Cancers 2024, 16(12), 2218; https://doi.org/10.3390/cancers16122218 - 14 Jun 2024

Viewed by 1246

Abstract

This study aimed to identify the clinical manifestation and implications according to the grading of tumor spread through air spaces in early-stage small (≤2 cm) pathological stage I non-mucinous lung adenocarcinomas. Medical records of patients with pathological stage I tumors sized ≤2 cm [...] Read more.

This study aimed to identify the clinical manifestation and implications according to the grading of tumor spread through air spaces in early-stage small (≤2 cm) pathological stage I non-mucinous lung adenocarcinomas. Medical records of patients with pathological stage I tumors sized ≤2 cm were retrospectively reviewed and analyzed. The furthest distance of the spread through air spaces from the tumor margin was measured on a standard-length scale (mm). Enrolled patients were categorized into spread through air spaces (STAS) (−) and STAS (+), and STAS (+) was subdivided according to its furthest distance as follows: STAS (+)-L (<2 mm) and STAS (+)-H (≥2 mm). Risk factors for STAS (+) included papillary predominant subtype (p = 0.027), presence of micropapillary patterns (p < 0.001), and EGFR (p = 0.039). The overall survival of the three groups did not differ significantly (p = 0.565). The recurrence-free survival of STAS (+)-H groups was significantly lower than those of STAS (−) and STAS (+)-L (p < 0.001 and p = 0.039, respectively). A number of alveolar spaces were definite risk factors for STAS (+)-H groups (p < 0.001), and male gender could be one (p = 0.054). In the patient group with small (≤2 cm) pathological stage I lung adenocarcinomas, the presence of STAS ≥ 2 mm was related to significantly lower recurrence-free survival. For identifying definite risk factors for the presence of farther STAS, more precise analysis from a larger study population should be undertaken. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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12 pages, 4335 KiB

Open AccessArticle

Bronchopleural Fistula after Lobectomy for Lung Cancer: How to Manage This Life-Threatening Complication Using Both Old and Innovative Solutions

by Antonio Mazzella, Monica Casiraghi, Clarissa Uslenghi, Riccardo Orlandi, Giorgio Lo Iacono, Luca Bertolaccini, Gianluca Maria Varano, Franco Orsi and Lorenzo Spaggiari

Cancers 2024, 16(6), 1146; https://doi.org/10.3390/cancers16061146 - 14 Mar 2024

Cited by 3 | Viewed by 2215

Abstract

Backgrounds: Our goal is to evaluate the correct management of broncho-pleural fistula (BPF) after lobectomy for lung cancer. Methods: We retrospectively reviewed our 25-years’ experience and reported our strategies and our diagnostic algorithm for the management of post-lobectomy broncho-pleural fistula. Results: Five thousand [...] Read more.

Backgrounds: Our goal is to evaluate the correct management of broncho-pleural fistula (BPF) after lobectomy for lung cancer. Methods: We retrospectively reviewed our 25-years’ experience and reported our strategies and our diagnostic algorithm for the management of post-lobectomy broncho-pleural fistula. Results: Five thousand one hundred and fifty (5150) patients underwent lobectomy for lung cancer in the period between 1998 and 2023. A total of 44 (0.85%) out of 5150 developed post-operative BPF. In 11 cases, BPF was solved by non-invasive treatment. In nine cases, direct surgical repair of the bronchial stump allowed BPF resolution. In 14 cases, a completion intervention was performed. In six cases, we performed open window thoracostomy (OWT) after lobectomy; in two cases, the BPF was closed by percutaneous injection of an n-butyl cyanoacrylate glue mixture. In two cases, no surgical procedure was performed because of the clinical status of the patient at the time of fistula developing. Thirty-day and ninety-day mortality from fistula onset was, respectively, 18.2% (eight patients) and 22.7% (ten patients). Thirty-day and ninety-day mortality after completion pneumonectomy (12 patients) was, respectively, 8.3% (one patient) and 16.6% (two patients). Conclusions: The correct management of BPF depends on various factors: timing of onset, size of the fistula, anatomic localization, and the general condition of the patient. In the case of failure of various initial therapeutic approaches, completion intervention or OWT could be considered. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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Review

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43 pages, 2417 KiB

Open AccessReview

Targeting Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer: Beyond PD-1/PD-L1 Monoclonal Antibodies

by Nicolas Roussot, Courèche Kaderbhai and François Ghiringhelli

Cancers 2025, 17(5), 906; https://doi.org/10.3390/cancers17050906 - 6 Mar 2025

Cited by 1 | Viewed by 1344

Abstract

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immunotherapy targeting the PD-1/PD-L1 axis has revolutionized treatment, providing durable responses in a subset of patients. However, with fewer than 50% of patients achieving significant benefits, there is a critical need [...] Read more.

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immunotherapy targeting the PD-1/PD-L1 axis has revolutionized treatment, providing durable responses in a subset of patients. However, with fewer than 50% of patients achieving significant benefits, there is a critical need to expand therapeutic strategies. This review explores emerging targets in immune checkpoint inhibition beyond PD-1/PD-L1, including CTLA-4, TIGIT, LAG-3, TIM-3, NKG2A, and CD39/CD73. We highlight the biological basis of CD8 T cell exhaustion in shaping the antitumor immune response. Novel therapeutic approaches targeting additional inhibitory receptors (IR) are discussed, with a focus on their distinct mechanisms of action and combinatory potential with existing therapies. Despite significant advancements, challenges remain in overcoming resistance mechanisms and optimizing patient selection. This review underscores the importance of dual checkpoint blockade and innovative bispecific antibody engineering to maximize therapeutic outcomes for NSCLC patients. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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19 pages, 25647 KiB

Open AccessReview

Incidental Findings in Lung Cancer Screening

by Yenpo Lin, Khulan Khurelsukh, I-Gung Li, Chen-Te Wu, Yi-Ming Wu, Gigin Lin, Cheng-Hong Toh and Yung-Liang Wan

Cancers 2024, 16(14), 2600; https://doi.org/10.3390/cancers16142600 - 20 Jul 2024

Cited by 2 | Viewed by 3066 | Correction

Abstract

While low-dose computed tomography (LDCT) for lung cancer screening (LCS) has been recognized for its effectiveness in reducing lung cancer mortality, it often simultaneously leads to the detection of incidental findings (IFs) unrelated to the primary screening indication. These IFs present diagnostic and [...] Read more.

While low-dose computed tomography (LDCT) for lung cancer screening (LCS) has been recognized for its effectiveness in reducing lung cancer mortality, it often simultaneously leads to the detection of incidental findings (IFs) unrelated to the primary screening indication. These IFs present diagnostic and management challenges, potentially causing unnecessary anxiety and further invasive diagnostic procedures for patients. This review article provides an overview of IFs encountered in LDCT, emphasizing their clinical significance and recommended management strategies. We categorize IFs based on their anatomical locations (intrathoracic–intrapulmonary, intrathoracic–extrapulmonary, and extrathoracic) and discuss the most common findings. We highlight the importance of utilizing guidelines and standardized reporting systems by the American College of Radiology (ACR) to guide appropriate follow-ups. For each category, we present specific IF examples, their radiologic features, and the suggested management approach. This review aims to provide radiologists and clinicians with a comprehensive understanding of IFs in LCS for accurate assessment and management, ultimately enhancing patient care. Finally, we outline a few key aspects for future research and development in managing IFs. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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Other

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17 pages, 1172 KiB

Open AccessSystematic Review

Methylation Biomarkers of Lung Cancer Risk: A Systematic Review and Meta-Analysis

by Jacopo Dolcini, Manuela Chiavarini, Giorgio Firmani, Kasey J. M. Brennan, Andres Cardenas, Andrea A. Baccarelli and Pamela Barbadoro

Cancers 2025, 17(4), 690; https://doi.org/10.3390/cancers17040690 - 18 Feb 2025

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Abstract

Background: Lung cancer (LC) is the leading cause of cancer deaths worldwide among both men and women, and represents a major public health challenge. DNA methylation (DNAm) has shown potential in identifying individuals at higher risk of LC, but the overall evidence [...] Read more.

Background: Lung cancer (LC) is the leading cause of cancer deaths worldwide among both men and women, and represents a major public health challenge. DNA methylation (DNAm) has shown potential in identifying individuals at higher risk of LC, but the overall evidence has not been systematically evaluated. This review and meta-analysis aims to evaluate and summarize existing research on the association between blood DNAm levels and LC risk. Methods: Searches were conducted in PubMed, Web of Science, and Scopus for studies published until February 2024, following PRISMA and MOOSE guidelines. Eleven studies met the eligibility criteria. Results: Using a random effects model, our pooled analysis showed a significant association between increased DNAm levels and LC risk (OR 1.24, 95% CI 1.10–1.39; I² = 93.90%, p = 0.0001). Stratifying the results by study design showed a stronger association in two prospective cohort studies (OR 1.61; 95% CI 1.36–1.90; I² = 14.42%, p = 0.32), while case–control studies showed a weaker association (OR 1.05; 95% CI 0.99–1.11; I² = 70.57%, p = 0.0001). Sensitivity analyses indicated that omitting individual studies did not significantly alter the LC risk estimates. Conclusions: These findings suggest that higher blood DNAm levels are associated with an increased risk of LC, especially in long-term cohort studies. Further research is recommended to explore the potential of DNAm as a screening biomarker for LC and to clarify the role of other influencing factors. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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3 pages, 2563 KiB

Open AccessCorrection

Correction: Lin et al. Incidental Findings in Lung Cancer Screening. Cancers 2024, 16, 2600

by Yenpo Lin, Khulan Khurelsukh, I-Gung Li, Chen-Te Wu, Yi-Ming Wu, Gigin Lin, Cheng-Hong Toh and Yung-Liang Wan

Cancers 2025, 17(1), 41; https://doi.org/10.3390/cancers17010041 - 26 Dec 2024

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Abstract

The affiliation for K [...] Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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21 pages, 2340 KiB

Open AccessSystematic Review

Leucocyte Telomere Length and Lung Cancer Risk: A Systematic Review and Meta-Analysis of Prospective Studies

by Roberto Fabiani, Manuela Chiavarini, Patrizia Rosignoli and Irene Giacchetta

Cancers 2024, 16(18), 3218; https://doi.org/10.3390/cancers16183218 - 21 Sep 2024

Cited by 2 | Viewed by 1153

Abstract

Although numerous epidemiological studies are available, the relationship between leukocyte telomere length (LTL) and lung cancer risk is still controversial. This systematic review and meta-analysis, performed according to the PRISMA statement and MOOSE guidelines, aims to summarize the evidence and calculate the risk [...] Read more.

Although numerous epidemiological studies are available, the relationship between leukocyte telomere length (LTL) and lung cancer risk is still controversial. This systematic review and meta-analysis, performed according to the PRISMA statement and MOOSE guidelines, aims to summarize the evidence and calculate the risk of lung cancer associated with LTL. The literature search was performed on PubMed, Web of Science, and Scopus databases through May 2024. A random-effects model was used to calculate the pooled risk. Heterogeneity was assessed using I² and Cochran’s Q statistic. Begg’s and Egger’s tests were used to detect publication bias. Based on 8055 lung cancer cases and 854,653 controls (nine prospective studies), longer LTL was associated with a significant 42% increment in all types of lung cancer risk (OR 1.42, 95% CI 1.24–1.63). The effect was even more evident for adenocarcinomas (OR 1.98, 95% CI 1.69–2.31), while no association was observed for squamous cell carcinoma (OR 0.87, 95% CI 0.72–1.06). Significantly, no association was found for current smokers (OR 1.08, 95% CI 0.90–1.30), while it remained high for both never-smokers (OR 1.92, 95% CI 1.62–2.28) and former smokers (OR 1.34, 95% CI 1.11–1.62). No significant publication bias was evidenced. Longer LTL is associated with an increment in lung cancer risk particularly in never-smoker subjects. Full article

(This article belongs to the Special Issue Lung Cancer: From Mechanisms of Action and Risk Factors in Disease Onset to Management)

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