Prior CT Improves Deep Learning for Malignancy Risk Estimation of Screening-detected Pulmonary Nodules.

Background Prior chest CT provides valuable temporal information (eg, changes in nodule size or appearance) to accurately estimate malignancy risk. Purpose To develop a deep learning (DL) algorithm that uses a current and prior low-dose CT examination to estimate 3-year malignancy risk of pulmonary nodules. Materials and Methods In this retrospective study, the algorithm was trained using National Lung Screening Trial data (collected from 2002 to 2004), wherein patients were imaged at most 2 years apart, and evaluated with two external test sets from the Danish Lung Cancer Screening Trial (DLCST) and the Multicentric Italian Lung Detection Trial (MILD), collected in 2004-2010 and 2005-2014, respectively. Performance was evaluated using area under the receiver operating characteristic curve (AUC) on cancer-enriched subsets with size-matched benign nodules imaged 1 and 2 years apart from DLCST and MILD, respectively. The algorithm was compared with a validated DL algorithm that only processed a single CT examination and the Pan-Canadian Early Lung Cancer Detection Study (PanCan) model. Results The training set included 10 508 nodules (422 malignant) in 4902 trial participants (mean age, 64 years ± 5 [SD]; 2778 men). The size-matched external test sets included 129 nodules (43 malignant) and 126 nodules (42 malignant). The algorithm achieved AUCs of 0.91 (95% CI: 0.85, 0.97) and 0.94 (95% CI: 0.89, 0.98). It significantly outperformed the DL algorithm that only processed a single CT examination (AUC, 0.85 [95% CI: 0.78, 0.92; P = .002]; and AUC, 0.89 [95% CI: 0.84, 0.95; P = .01]) and the PanCan model (AUC, 0.64 [95% CI: 0.53, 0.74; P < .001]; and AUC, 0.63 [95% CI: 0.52, 0.74; P < .001]). Conclusion A DL algorithm using current and prior low-dose CT examinations was more effective at estimating 3-year malignancy risk of pulmonary nodules than established models that only use a single CT examination. Clinical trial registration nos. NCT00047385, NCT00496977, NCT02837809 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Horst and Nishino in this issue.

Lung carcinoid tumours: histology and Ki-67, the eternal rivalry.

WHO classification of Thoracic Tumours defines lung carcinoid tumours (LCTs) as well-differentiated neuroendocrine neoplasms (NENs) classified in low grade typical (TC) and intermediate grade atypical carcinoids (AC). Limited data exist concerning protein expression and morphologic factors able to predict disease aggressiveness. Though Ki-67 has proved to be a powerful diagnostic and prognostic factor for Gastro-entero-pancreatic NENs, its role in lung NENs is still debated. A retrospective series of 370 LCT from two oncology centers was centrally reviewed. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR-2A, Ascl1, and p53) were studied and correlated with Overall Survival (OS), Cancer-specific survival (CSS) and Disease-free survival (DFS). Carcinoid histology was confirmed in 355 patients: 297 (83.7%) TC and 58 (16.3%) AC. Ki-67 at 3% was the best value in predicting DFS. Ki-67 ≥ 3% tumours were significantly associated with AC histology, stage III-IV, smoking, vascular invasion, tumour spread through air spaces OTP negativity, and TTF-1, Ascl1 and p53 positivity. After adjustment for center and period of diagnosis, both Ki-67 (≥3 versus <3) and histology (AC versus TC) alone significantly added prognostic information to OS and CSS multivariable model with age, stage and OTP; addition of both variables did not provide further prognostic information. Conversely, an improved significance of the DFS prediction model at multivariate analysis was seen by adding Ki-67 (≥3 versus <3, P adj = 0.01) to TC and AC histological distinction, age, lymph node involvement, residual tumour and OTP. Ki-67 ≥ 3% plays a potentially pivotal role in LCT prognosis, irrespective of histological grade.

Ascl1 and OTP tumour expressions are associated with disease-free survival in lung atypical carcinoids.

According to World Health Organization guidelines, atypical carcinoids (ACs) are well-differentiated lung neuroendocrine tumours with 2-10 mitoses/2 mm2 and/or foci of necrosis (usually punctate). Besides morphological criteria, no further tools in predicting AC clinical outcomes are proposed. The aim of this work was to identify novel factors able to predict AC disease aggressiveness and progression. METHODS AND RESULTS: Three hundred-seventy lung carcinoids were collected and centrally reviewed by two expert pathologists. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR2A, Ascl1, p53, and Rb1) were studied and correlated with disease-free survival (DFS) and overall survival (OS). Fifty-eight of 370 tumours were defined as AC. Survival analysis showed that patients with Ascl1 + ACs and those with OTP-ACs had a significantly worse DFS than patients with Ascl1-ACs and OTP + ACs, respectively. Combining Ascl1 and OTP expressions, groups were formed reflecting the aggressiveness of disease (P = 0.0005). Ki-67 ≥10% patients had a significantly worse DFS than patients with Ki-67 <10%. At multivariable analysis, Ascl1 (present versus absent, hazard ratio [HR] = 3.42, 95% confidence interval [CI] 1.35-8.65, P = 0.009) and OTP (present versus absent, HR = 0.26, 95% CI 0.10-0.68, P = 0.006) were independently associated with DFS. The prognosis of patients with Ki-67 ≥10% tended to be worse compared to that with Ki-67 <10%. On the contrary, OTP (present versus absent, HR = 0.28, 95% CI 0.09-0.89, P = 0.03), tumour stage (III-IV versus I-II, HR = 4.25, 95% CI 1.42-12.73, P = 0.01) and increasing age (10-year increase, HR = 1.67, 95% CI 1.04-2.68, P = 0.03) were independently associated with OS. CONCLUSION: This retrospective analysis of lung ACs showed that Ascl1 and OTP could be the main prognostic drivers of postoperative recurrence.

Prognostic Factors across Poorly Differentiated Neuroendocrine Neoplasms: A Pooled Analysis.

INTRODUCTION: Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic and lung NECs and to assess if further prognostic parameters can be isolated. METHODS: A pooled analysis of four NEC retrospective studies was performed to evaluate the prognostic role of Ki-67 cut-off, the overall survival (OS) according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine learning random survival forest (RSF). RESULTS: 422 NECs were analyzed. The most represented tumor site was the colorectum (n = 156, 37%), followed by the lungs (n = 111, 26%), gastroesophageal site (n = 83, 20%; 66 gastric, 79%) and pancreas (n = 42, 10%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III-IV, and colorectal NEC disease. Patients with Ki-67 <55% and mixed/combined morphology had better survival than those with pure morphology. Morphology pure or mixed/combined became irrelevant in NEC survival when Ki-67 was ≥55%. The prognosis of metastatic patients who did not receive any treatment tended to be worse compared to that of the treated group. The prognostic impact of Rb1 immunolabeling appears to be limited when multiple risk factors are simultaneously assessed. CONCLUSION: The most effective parameters to predict OS for NEC patients could be Ki-67, pure or mixed/combined morphology, stage, and site.

Scan-based competing death risk model for re-evaluating lung cancer computed tomography screening eligibility.

BACKGROUND: A baseline computed tomography (CT) scan for lung cancer (LC) screening may reveal information indicating that certain LC screening participants can be screened less, and instead require dedicated early cardiac and respiratory clinical input. We aimed to develop and validate competing death (CD) risk models using CT information to identify participants with a low LC risk and a high CD risk. METHODS: Participant demographics and quantitative CT measures of LC, cardiovascular disease and chronic obstructive pulmonary disease were considered for deriving a logistic regression model for predicting 5-year CD risk using a sample from the National Lung Screening Trial (n=15 000). Multicentric Italian Lung Detection data were used to perform external validation (n=2287). RESULTS: Our final CD model outperformed an external pre-scan model (CD Risk Assessment Tool) in both the derivation (area under the curve (AUC) 0.744 (95% CI 0.727-0.761) and 0.677 (95% CI 0.658-0.695), respectively) and validation cohorts (AUC 0.744 (95% CI 0.652-0.835) and 0.725 (95% CI 0.633-0.816), respectively). By also taking LC incidence risk into consideration, we suggested a risk threshold where a subgroup (6258/23 096 (27%)) was identified with a number needed to screen to detect one LC of 216 (versus 23 in the remainder of the cohort) and ratio of 5.41 CDs per LC case (versus 0.88). The respective values in the validation cohort subgroup (774/2287 (34%)) were 129 (versus 29) and 1.67 (versus 0.43). CONCLUSIONS: Evaluating both LC and CD risks post-scan may improve the efficiency of LC screening and facilitate the initiation of multidisciplinary trajectories among certain participants.

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.

A novel CXCR4 antagonist counteracts paradoxical generation of cisplatin-induced pro-metastatic niches in lung cancer.

Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite experimental evidence of its potential to induce long-term detrimental effects, including the promotion of pro-metastatic microenvironments. In this study, we investigated the interconnected pathways underlying the promotion of cisplatin-induced metastases. In tumor-free mice, cisplatin treatment resulted in an expansion in the bone marrow of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IMs) and an increase in lung levels of stromal SDF-1, the CXCR4 ligand. In experimental lung metastasis assays, cisplatin-induced IMs promoted the extravasation of tumor cells and the expansion of CD133+CXCR4+ metastasis-initiating cells (MICs). Peptide R, a novel CXCR4 inhibitor designed as an SDF-1 mimetic peptide, prevented cisplatin-induced IM expansion, the recruitment of IMs into the lungs, and the promotion of metastasis. At the primary tumor site, cisplatin treatment reduced tumor size while simultaneously inducing tumor release of SDF-1, MIC expansion, and recruitment of pro-invasive CXCR4+ macrophages. Co-recruitment of MICs and CCR2+CXCR4+ IMs to distant SDF-1-enriched sites also promoted spontaneous metastases that were prevented by CXCR4 blockade. In clinical specimens from NSCLC patients SDF-1 levels were found to be higher in platinum-treated samples and related to a worse clinical outcome. Our findings reveal that activation of the CXCR4/SDF-1 axis specifically mediates the pro-metastatic effects of cisplatin and suggest CXCR4 blockade as a possible novel combination strategy to control metastatic disease.

Combining pulmonary and cardiac computed tomography biomarkers for disease-specific risk modelling in lung cancer screening.

OBJECTIVES: Combined assessment of cardiovascular disease (CVD), COPD and lung cancer may improve the effectiveness of lung cancer screening in smokers. The aims were to derive and assess risk models for predicting lung cancer incidence, CVD mortality and COPD mortality by combining quantitative computed tomography (CT) measures from each disease, and to quantify the added predictive benefit of self-reported patient characteristics given the availability of a CT scan. METHODS: A survey model (patient characteristics only), CT model (CT information only) and final model (all variables) were derived for each outcome using parsimonious Cox regression on a sample from the National Lung Screening Trial (n=15 000). Validation was performed using Multicentric Italian Lung Detection data (n=2287). Time-dependent measures of model discrimination and calibration are reported. RESULTS: Age, mean lung density, emphysema score, bronchial wall thickness and aorta calcium volume are variables that contributed to all final models. Nodule features were crucial for lung cancer incidence predictions but did not contribute to CVD and COPD mortality prediction. In the derivation cohort, the lung cancer incidence CT model had a 5-year area under the receiver operating characteristic curve of 82.5% (95% CI 80.9-84.0%), significantly inferior to that of the final model (84.0%, 82.6-85.5%). However, the addition of patient characteristics did not improve the lung cancer incidence model performance in the validation cohort (CT model 80.1%, 74.2-86.0%; final model 79.9%, 73.9-85.8%). Similarly, the final CVD mortality model outperformed the other two models in the derivation cohort (survey model 74.9%, 72.7-77.1%; CT model 76.3%, 74.1-78.5%; final model 79.1%, 77.0-81.2%), but not the validation cohort (survey model 74.8%, 62.2-87.5%; CT model 72.1%, 61.1-83.2%; final model 72.2%, 60.4-84.0%). Combining patient characteristics and CT measures provided the largest increase in accuracy for the COPD mortality final model (92.3%, 90.1-94.5%) compared to either other model individually (survey model 87.5%, 84.3-90.6%; CT model 87.9%, 84.8-91.0%), but no external validation was performed due to a very low event frequency. CONCLUSIONS: CT measures of CVD and COPD provides small but reproducible improvements to nodule-based lung cancer risk prediction accuracy from 3 years onwards. Self-reported patient characteristics may not be of added predictive value when CT information is available.

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis.

BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.

Lung cancer screening by nodule volume in Lung-RADS v1.1: negative baseline CT yields potential for increased screening interval.

OBJECTIVES: The 2019 Lung CT Screening Reporting & Data System version 1.1 (Lung-RADS v1.1) introduced volumetric categories for nodule management. The aims of this study were to report the distribution of Lung-RADS v1.1 volumetric categories and to analyse lung cancer (LC) outcomes within 3 years for exploring personalized algorithm for lung cancer screening (LCS). METHODS: Subjects from the Multicentric Italian Lung Detection (MILD) trial were retrospectively selected by National Lung Screening Trial (NLST) criteria. Baseline characteristics included selected pre-test metrics and nodule characterization according to the volume-based categories of Lung-RADS v1.1. Nodule volume was obtained by segmentation with dedicated semi-automatic software. Primary outcome was diagnosis of LC, tested by univariate and multivariable models. Secondary outcome was stage of LC. Increased interval algorithms were simulated for testing rate of delayed diagnosis (RDD) and reduction of low-dose computed tomography (LDCT) burden. RESULTS: In 1248 NLST-eligible subjects, LC frequency was 1.2% at 1 year, 1.8% at 2 years and 2.6% at 3 years. Nodule volume in Lung-RADS v1.1 was a strong predictor of LC: positive LDCT showed an odds ratio (OR) of 75.60 at 1 year (p < 0.0001), and indeterminate LDCT showed an OR of 9.16 at 2 years (p = 0.0068) and an OR of 6.35 at 3 years (p = 0.0042). In the first 2 years after negative LDCT, 100% of resected LC was stage I. The simulations of low-frequency screening showed a RDD of 13.6-21.9% and a potential reduction of LDCT burden of 25.5-41%. CONCLUSIONS: Nodule volume by semi-automatic software allowed stratification of LC risk across Lung-RADS v1.1 categories. Personalized screening algorithm by increased interval seems feasible in 80% of NLST eligible. KEY POINTS: • Using semi-automatic segmentation of nodule volume, Lung-RADS v1.1 selected 10.8% of subjects with positive CT and 96.87 relative risk of lung cancer at 1 year, compared to negative CT. • Negative low-dose CT by Lung-RADS v1.1 was found in 80.6% of NLST eligible and yielded 40 times lower relative risk of lung cancer at 2 years, compared to positive low-dose CT; annual screening could be preference sensitive in this group. • Semi-automatic segmentation of nodule volume and increased screening interval by volumetric Lung-RADS v1.1 could retrospectively suggest a 25.5-41% reduction of LDCT burden, at the cost of 13.6-21.9% rate of delayed diagnosis.

p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression.

Mutations in the TP53 gene and microenvironmentally driven activation of hypoxia-inducible factor-1 (HIF-1) typically occur in later stages of tumorigenesis. An ongoing challenge is the identification of molecular determinants of advanced cancer pathogenesis to design alternative last-line therapeutic options. Here, we report that p53 mutants influence the tumor microenvironment by cooperating with HIF-1 to promote cancer progression. We demonstrate that in non-small cell lung cancer (NSCLC), p53 mutants exert a gain-of-function (GOF) effect on HIF-1, thus regulating a selective gene expression signature involved in protumorigenic functions. Hypoxia-mediated activation of HIF-1 leads to the formation of a p53 mutant/HIF-1 complex that physically binds the SWI/SNF chromatin remodeling complex, promoting expression of a selective subset of hypoxia-responsive genes. Depletion of p53 mutants impairs the HIF-mediated up-regulation of extracellular matrix (ECM) components, including type VIIa1 collagen and laminin-γ2, thus affecting tumorigenic potential of NSCLC cells in vitro and in mouse models in vivo. Analysis of surgically resected human NSCLC revealed that expression of this ECM gene signature was highly correlated with hypoxic tumors exclusively in patients carrying p53 mutations and was associated with poor prognosis. Our data reveal a GOF effect of p53 mutants in hypoxic tumors and suggest synergistic activities of p53 and HIF-1. These findings have important implications for cancer progression and might provide innovative last-line treatment options for advanced NSCLC.

SDHx and Non-Chromaffin Tumors: A Mediastinal Germ Cell Tumor Occurring in a Young Man with Germline SDHB Mutation.

Background: Mutations in genes encoding one of the subunits of succinate dehydrogenase (SDH) are involved in pheochromocytoma (PHEO) and paraganglioma (PGL) development. Over the last few years, such mutations have also been associated with non-chromaffin tumors. However, immunohistochemistry (IHC) on the tumor tissue and a study on the loss of heterozygosity (LOH) aimed at demonstrating the pathogenic role of SDHx genes have only been employed in a few cases. Case report: We describe the case of a 19-year-old Caucasian man with a germline SDHB mutation, who presented with acne vulgaris resistant to medical treatment. His follow-up for chromaffin tumors was negative, while hormonal tests revealed suppressed gonadotropins with testosterone in the upper range of normality and elevated ß-human chorionic gonadotropin (ß-hCG). At the whole-body enhanced CT scan, a mediastinal lesion suggestive of a germ cell tumor (GCT) was detected. 18FDG-PET (fluorodeoxyglucose-positron emission tomography) imaging showed low glucose metabolism at the mediastinal site. Surgical removal of the mass was uneventful. Pathology confirmed the diagnosis of GCT consisting of cystic teratoma (95%) and seminoma (5%). IHC for SDHB showed normal protein expression, and genetic analysis of the tumor tissue revealed the absence of SDHB LOH. Normalization of the hormonal tests and acne attenuation were achieved after surgery. Conclusion: We report an incidental association of a germinal SDHB mutation and mediastinal GCT in a young Caucasian man. Our paper highlights the importance of IHC and genetic analysis in confirming the etiologic role of SDHx genes in nonchromaffin tumors, thus excluding incidental associations.

Circulating mir-320a promotes immunosuppressive macrophages M2 phenotype associated with lung cancer risk.

miRNAs play a central role in the complex signaling network of cancer cells with the tumor microenvironment. Little is known on the origin of circulating miRNAs and their relationship with the tumor microenvironment in lung cancer. Here, we focused on the cellular source and relative contribution of different cell types to circulating miRNAs composing our risk classifier of lung cancer using in vitro/in vivo models and clinical samples. A cell-type specific expression pattern and topography of several miRNAs such as mir-145 in fibroblasts, mir-126 in endothelial cells, mir-133a in skeletal muscle cells was observed in normal and lung cancer tissues. Granulocytes and platelets are the major contributors of miRNAs release in blood. miRNAs modulation observed in plasma of lung cancer subjects was consistent with de-regulation of the same miRNAs observed during immunosuppressive conversion of immune cells. In particular, activated neutrophils showed a miRNA profile mirroring that observed in plasma of lung cancer subjects. Interestingly mir-320a secreted by neutrophils of high-risk heavy-smokers promoted an M2-like protumorigenic phenotype through downregulation of STAT4 when shuttled into macrophages. These findings suggest a multifactorial and nonepithelial cell-autonomous origin of circulating miRNAs associated with risk of lung cancer and that circulating miRNAs may act in paracrine signaling with causative role in lung carcinogenesis and immunosuppression.

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.

Sulphurous thermal water inhalation impacts respiratory metabolic parameters in heavy smokers.

Sulphurous thermal water inhalations have been traditionally used in the treatment of airway diseases. In vivo and in vitro studies reported that they ameliorate mucus rheology, mucociliary clearance and reduce inflammation. Cigarette smoking induces an inflammatory damage, with consequent remodeling of respiratory airways, which in turn affect pulmonary functions. Despite the anti-inflammatory effects of H2S are clinically documented in several airway inflammatory diseases, data on the effects of sulphurous thermal water treatment on pulmonary function and biomarkers of airways inflammation in smokers are still scant. Therefore, we investigated whether a conventional cycle of sulphurous thermal water inhalation produced changes in markers of respiratory inflammation and function. A cohort of 504 heavy current and former smokers underwent 10-day cycles of sulphurous thermal water inhalation. Pulmonary function and metabolic analyses on exhaled breath condensate were then performed at day 0 and after the 10-day treatment. Spirometric data did not change after spa therapy, while exhaled breath condensate analysis revealed that a single 10-day cycle of sulphurous water inhalation was sufficient to induce a statistically significant increase of citrulline levels along with a decrease in ornithine levels, thus shifting arginine metabolism towards a reduced nitric oxide production, i.e. an anti-inflammatory profile. Overall, sulphurous thermal water inhalation impacts on arginine catatabolic intermediates of airways cells, shifting their metabolic balance towards a reduction of the inflammatory activity, with potential benefits for smokers.

Diagnostic role of circulating extracellular matrix-related proteins in non-small cell lung cancer.

BACKGROUND: Interactions between cancer cells and the surrounding microenvironment are crucial determinants of cancer progression. During this process, bi-directional communication among tumor cells and cancer associated fibroblasts (CAF) regulate extracellular matrix (ECM) deposition and remodeling. As a result of this dynamic process, soluble ECM proteins can be released into the bloodstream and may represent novel circulating biomarkers useful for cancer diagnosis. The aim of the present study was to measure the levels of three circulating ECM related proteins (COL11A1, COL10A1 and SPARC) in plasma samples of lung cancer patients and in healthy heavy-smokers controls and test whether such measurements have diagnostic or prognostic value. METHODS: Gene expression profiling of lung fibroblasts isolated from paired normal and cancer tissue of NSCLC patients was performed by gene expression microarrays. The prioritization of the candidates for the study of circulating proteins in plasma was based on the most differentially expressed genes in cancer associated fibroblasts. Soluble ECM proteins were assessed by western blot in the conditioned medium of lung fibroblasts and by ELISA assays in plasma samples. RESULTS: Plasma samples from lung cancer patients and healthy heavy-smokers controls were tested for levels of COL11A1 and COL10A1 (n = 57 each) and SPARC (n = 90 each). Higher plasma levels of COL10A1 were detected in patients (p ≤ 0.001), a difference that was driven specifically by females (p < 0.001). No difference in COL11A1 levels between patients and controls was found. SPARC levels were also higher in plasma patients than controls (p < 0.001) with good performance in discriminating the two groups (AUC = 0.744). No significant association was observed between plasma proteins levels and clinicopathological features or survival. CONCLUSION: Soluble factors related to proficient tumor-stroma cross-talk are detectable in plasma of primary lung cancer patients and may represent a valuable complementary diagnostic tool to discriminate lung cancer patients from healthy heavy-smokers individuals as shown for the SPARC protein.

Primary sternal tuberculosis mimicking a lytic bone tumor lesion.

Tubercular sternal osteomyelitis is a rare manifestation of tuberculosis. We describe the case of a 51-years-old male patient, presenting with three months history of pain and swelling of the central chest wall, referred to our hospital with clinical diagnosis of chondrosarcoma of the sternum.

European position statement on lung cancer screening.

Lung cancer screening with low-dose CT can save lives. This European Union (EU) position statement presents the available evidence and the major issues that need to be addressed to ensure the successful implementation of low-dose CT lung cancer screening in Europe. This statement identified specific actions required by the European lung cancer screening community to adopt before the implementation of low-dose CT lung cancer screening. This position statement recommends the following actions: a risk stratification approach should be used for future lung cancer low-dose CT programmes; that individuals who enter screening programmes should be provided with information on the benefits and harms of screening, and smoking cessation should be offered to all current smokers; that management of detected solid nodules should use semi-automatically measured volume and volume-doubling time; that national quality assurance boards should be set up to oversee technical standards; that a lung nodule management pathway should be established and incorporated into clinical practice with a tailored screening approach; that non-calcified baseline lung nodules greater than 300 mm3, and new lung nodules greater than 200 mm3, should be managed in multidisciplinary teams according to this EU position statement recommendations to ensure that patients receive the most appropriate treatment; and planning for implementation of low-dose CT screening should start throughout Europe as soon as possible. European countries need to set a timeline for implementing lung cancer screening.

Pleural plaques in lung cancer screening by low-dose computed tomography: prevalence, association with lung cancer and mortality.

BACKGROUND: To report the prevalence of pleural plaques in a lung cancer screening trial by low-dose computed tomography (LDCT) and to test the association with incidence of lung cancer and mortality. METHODS: The LDCT of 2303 screenees were retrospectively reviewed with the specific aim of describing the prevalence and features of pleural plaques. Self-administered questionnaire was used to assess asbestos exposure. Frequency of lung cancer, lung cancer mortality, and overall mortality were detailed according to presence of pleural findings. Statistical analyses included comparison of mean or median, contingency tables, and Cox model for calculation of hazard ratio (HR) and its 95% confidence interval (CI). RESULTS: Among male screenees, 31/1570 (2%) showed pleural abnormalities, 128/1570 (8.2%) disclosed asbestos exposure, 23/31 (74.2%) subjects with pleural plaques consistently denied exposure to asbestos. There was a trend for higher frequency of lung cancer among subjects with pleural plaques (9.7% vs 4.2%). Lung cancer in subjects with pleural plaques was always diagnosed in advanced stage. Subjects with pleural plaques showed HR 5.48 (95% CI 1.61-18.70) for mortality from lung cancer. CONCLUSIONS: Pleural plaques are a risk factor for lung cancer mortality that can be detected in lung cancer screening by LDCT, also in subjects that are not aware of asbestos exposure. TRIAL REGISTRATION: NCT02837809 - Retrospectively registered July 1, 2016 - Enrolment of first participant September 2005.

[Lung cancer screening in high-risk subjects: early detection with LDCT and risk stratification using miRNA-based blood test]. / Screening per il tumore polmonare in soggetti ad alto rischio: diagnosi precoce con TC spirale associata a stratificazione del rischio con miRNA circolanti.

Lung cancer still remains a high mortality disease in the face of developments in diagnostic and therapeutic methods that occurred in the last 20 years. The analysis of the experiences from the first studies - in which chest X-ray (CXR) was adopted, associated or not with sputum cytology - has failed to show a reduction in lung cancer specific mortality. Subsequent screening studies that have introduced the use of low-dose computed tomography (LDCT) have revealed a large number of early-stage lung cancers, thus potentially curable; however, this has not allowed us to demonstrate a decrease in lung cancer-specific mortality. With the results of the American study National Lung ScreeningTrial (NLST), published in 2011, for the first time a lung cancer-specific mortality reduction by 20% thanks to the use of LDCT compared to RXT, was highlighted. However, a false discovery rate of 96.4% was also described with an overdiagnosis that can be up to 78.9% for bronchioalveolar lung cancer. Due to the high sensitivity of LDCT, able to identify a non-calcified pulmonary nodule in one subject on two, it becomes necessary to avail instruments to more accurately identify suspicious nodules. Until some time ago, the possible use of lung tumour markers was not viable in view of the poor organ specificity. The study and development was, then, pushed to organ- and tissue-specific markers such as microRNA (miRNA), noncoding RNA sequences involved in many processes and expression of oncogenic activity of the microenvironment. The use of biomarkers such as circulating miRNA implemented in LDCT screening has highlighted a reduction of 5 times for the rate of false positives, going from 19.4% to 3.7%, with a sensitivity of 87%, a specificity of 81%, and a negative predictive value of 99%. The need to appropriately use the available resources commensurate with the disease to treat will push more and more towards the implementation of LDCT biomarkers based screenings, stable and easily reproducible, as circulating miRNAs, obviating to problems such as false positives, unnecessary procedures of invasive surgery for benign lesions, and optimizing the cost benefit ratios.The development of new specific biomarkers appears to offer new promising prospects.