Sustained Effectiveness of Benralizumab in Naïve and Biologics-Experienced Severe Eosinophilic Asthma Patients: Results from the ANANKE Study.

Purpose: Severe eosinophilic asthma (SEA) patients often present overlapping inflammatory features rendering them eligible for multiple biologic therapies; switching biologic treatment is a strategy adopted to optimize asthma control when patients show partial or no response to previous biologics. Patients and Methods: ANANKE is a retrospective, multicenter Italian study (NCT04272463). Here, we outline the characteristics and long-term clinical outcomes in naïve-to-biologics and biologics-experienced patients treated with benralizumab for up to 96 weeks. Bio-experienced patients were split into omalizumab and mepolizumab subsets according to the type of biologic previously used. Results: A total of 124 (76.5%) naïve and 38 (23.5%) bio-experienced patients were evaluated at index date; 13 patients (34.2%) switched from mepolizumab, 21 patients (55.3%) switched from omalizumab, and four patients (10.5%) received both biologics. The mepolizumab subset was characterized by the longest SEA duration (median of 4.6 years), the highest prevalence of chronic rhinosinusitis with nasal polyposis (CRSwNP) (76.5%), and the greatest oral corticosteroid (OCS) daily dosage (median of 25 mg prednisone equivalent). The omalizumab group showed the highest severe annual exacerbation rate (AER) (1.70). At 96 weeks, treatment with benralizumab reduced any and severe AER by more than 87% and 94%, respectively, across all groups. Lung function was overall preserved, with major improvements observed in the mepolizumab group, which also revealed a 100% drop of the median OCS dose. Asthma Control Test (ACT) score improved in the naïve group while its increment was more variable in bio-experienced patients; among these, a marked difference was noticed between omalizumab and mepolizumab subsets (median ACT score of 23.5 and 18, respectively). Conclusion: Benralizumab promotes durable and profound clinical benefits in naïve and bio-experienced groups, indicating that a nearly complete depletion of eosinophils is highly beneficial in the control of SEA, independently of previous biologic use.

Tracheal atypical solitary carcinoid in a so called "difficult asthma": a diagnostic challenge.

This report describes the case of a 46-year-old non-smoker housewife. She presented to our attention having a diagnosis of "difficult asthma" from another center in the previous two years. She had no allergies and had not been exposed to an excessive amount of noxious stimuli. Her chronic respiratory symptoms (dyspnea on exertion with wheezing) remained uncontrolled despite maximal anti-asthmatic inhaled therapy. An HRCT scan was performed to further investigate other pulmonary diseases that mimic asthma. It revealed a pedunculated endotracheal lesion with regular borders that obstructed 90% of the tracheal lumen. The lesion was removed via rigid bronchoscopy with laser endobronchial; histological examination revealed the presence of atypical carcinoid. Atypical carcinoids are a rare subtype of neuroendocrine lung tumor that accounts for 2% of all thoracic malignancies. They frequently arise from the central airways and cause obstructive symptoms such as coughing, wheezing, chest pain, or recurrent obstructing pneumonia, which is caused by central airway obstruction. Clinical onset is gradual and characterized by non-specific symptoms, which frequently result in misdiagnosis. As a result, in a young patient with progressive dyspnea, chronic cough, and wheezing that is not responding to anti-asthmatic treatment, second-level investigations are required and may lead to a definite diagnosis, allowing the appropriate course of treatment to begin.

Long-term effectiveness of benralizumab in severe eosinophilic asthma patients treated for 96-weeks: data from the ANANKE study.

BACKGROUND: The efficacy of benralizumab has been broadly demonstrated in severe eosinophilic asthma (SEA), but only few real-life studies evaluated its long-term effects. Here we present novel data from the ANANKE study in which a large cohort of SEA patients was treated for up to 96 weeks. METHODS: ANANKE (NCT04272463) is an observational retrospective Italian study investigating the key characteristics of SEA patients (collected during the 12 months prior to benralizumab initiation) and the clinical outcomes during benralizumab treatment (annual exacerbation rate [AER], lung function, asthma control, OCS use, healthcare resource utilization). A post hoc analysis was also conducted in groups of patients based on history of previous biologic therapy (bio-experienced versus naïve patients). Analyses were descriptive only. RESULTS: Before benralizumab initiation, evaluable SEA patients (N = 162, 61.1% females, mean age 56.0 ± 12.7) showed a median blood eosinophil count (BEC) of 600 cells/mm3 (IQR: 430-890). Patients experienced frequent exacerbations (annualized exacerbation rate [AER]: 4.10, severe AER: 0.98), with impaired lung function and poor asthma control (median ACT score: 14) despite 25.3% reported oral corticosteroid (OCS) use. Nasal polyposis was present in 53.1% patients; 47.5% patients were atopic. After 96 weeks since the start of benralizumab, nearly 90% patients were still on treatment; benralizumab dramatically decreased exacerbations (AER: - 94.9%; severe AER: - 96.9%), improved respiratory parameters (median increase in pre-bronchodilator forced expiratory volume [pre-BD FEV1]: + 400 mL) and asthma control (median ACT score: 23) while eliminating OCS in 60% patients. Importantly, benralizumab effects were either maintained or progressively improved over time, accompanied by a nearly complete depletion of BEC. Benralizumab reduced AER both in naïve (any AER: - 95.9%; severe AER: - 97.5%) and bio-experienced patients (any AER: - 92.4%; severe AER: - 94.0%). CONCLUSIONS: Profound and sustained improvements in all asthma outcomes were observed with benralizumab. The correct identification of patients' eosinophilic-driven asthma phenotype was essential to ensure the achievement of such remarkable results. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04272463.

Benralizumab in Patients With Severe Eosinophilic Asthma With and Without Chronic Rhinosinusitis With Nasal Polyps: An ANANKE Study post-hoc Analysis.

Background: Severe eosinophilic asthma (SEA) in the presence of chronic rhinosinusitis with nasal polyps (CRSwNP) indicates the presence of a more extensive eosinophilic inflammation. Post-hoc analyses from a pivotal clinical trial have demonstrated the enhanced efficacy of benralizumab on asthma outcomes in patients with CRSwNP as a comorbidity. Methods: This is a post-hoc analysis from the Italian multi-center observational retrospective ANANKE study. Patients were divided into two groups based on self-reported CRSwNP. Baseline clinical and laboratory features in the 12 months prior to benralizumab prescription were collected. Data of change over time of blood eosinophils, annualized exacerbations rates (AER), asthma control, lung function, oral corticosteroids (OCS) use, and benralizumab discontinuation were collected during the observation period. Results: At baseline, the 110 patients with CRSwNP were less frequently female (50.9% vs 74.2%) and obese (9.1% vs. 22.6%) with higher eosinophils (605 vs. 500 cells/mm3) and OCS use when compared to patients without CRSwNP. Similar reductions of AER were seen (-95.8% vs. -91.5% for any exacerbation and -99.1% vs. -92.2% for severe exacerbations in patients with and without CRSwNP, respectively). During benralizumab treatment, comorbid SEA+CRSwNP was associated with a lower risk of any exacerbation (p = 0.0017) and severe exacerbations (p = 0.025). After a mean ± SD exposure of 10.3 ± 5.0 months, half of the SEA+CRSwNP patients eliminated OCS use. No discontinuation for safety reasons was recorded. Conclusions: This study helped to confirm the baseline clinical features that distinguish patients with and without CRSwNP being prescribed benralizumab. Numerically enhanced OCS reduction and lower exacerbation risk were observed in patients with SEA and comorbid CRSwNP treated with benralizumab.

Club Cell Loss as a Feature of Bronchiolization in ILD.

Background: Distal airway metaplasia may precede honeycombing in progressive fibrosing interstitial lung disease (ILD). The SCGB1A1+ bronchiolar-specific club cell may play a role in this aberrant regenerative process. Objective: To assess the presence of club cells in the small airways of patients suffering from ILD. Methods: Small airways (internal diameter <2 mm) in lung samples [surgical lung biopsy (SLB) and/or transbronchial lung cryobiopsy (TBLC)] from 14 patients suffering from ILD and 10 controls were morphologically assessed and stained for SCGB1A1. SCGB1A1 was weighted by epithelial height as a marker of airway generation (SCGB1A1/EH). Correlations between clinical, functional, and high-resolution CT (HRCT) prognostic factors and histomorphometry were assessed. Results: Small airways from samples with ILD patterns were significantly less dense in terms of SCGB1A1+ cells [0.064 (0.020-0.172)] as compared to controls' sample's small airways [0.393 (0.082-0.698), p < 0.0001]. Usual interstitial pneumonia (UIP) patterns most frequently contained small airways with limited or absent SCGB1A1 expression (SCGB1A1/EH <0.025): UIP (18/33; 55%) as compared with non-UIP patterns (4/31; 13%) or controls (0/29; 0%): p < 0.0001. In addition, correlations with HRCT indicated a significant negative relationship between SCGB1A1 and bronchiectasis as a feature of bronchiolization (Rho -0.63, p < 0.001) and a positive relationship with both forced vital capacity (FVC) and Hounsfield unit (HU)-distribution pattern in kurtosis (Rho 0.38 and 0.50, respectively, both p < 0.001) as markers of fibrotic changes. Conclusion: Compared with controls, the small airways of patients with ILD more often lack SCGB1A1, especially so in UIP. Low densities of SCGB1A1-marked cells correlate with bronchiectasis and fibrotic changes. Further research investigating SCGB1A1 staining as a pathological feature of the bronchiolization process is merited.

COVID-19 pneumonia in lung transplant recipients: Report of 2 cases.

Coronavirus disease 2019 (COVID-19) has been declared pandemic since March 2020. In Europe, Italy was the first nation affected by this infection. We report anamnestic data, clinical features, and therapeutic management of 2 lung transplant recipients with confirmed COVID-19 pneumonia. Both patients were in good clinical condition before the infection and were receiving immunosuppression with calcineurin inhibitors (CNI), mycophenolate mofetil, and corticosteroids. Whereas mycophenolate mofetil was withdrawn in both cases, CNI were suspended only in the second patient. The first patient always maintained excellent oxygen saturation throughout hospitalization with no need for additional oxygen therapy. He was discharged with a satisfactory pulmonary function and a complete resolution of radiological and clinical findings. However, at discharge SARS-CoV-2 RNA could still be detected in the nasopharyngeal swab and in the stools. The second patient required mechanical ventilation, had a progressive deterioration of his clinical conditions, and had a fatal outcome. Further insight into SARS-CoV-2 infection is eagerly awaited to improve the outcome of transplant recipients affected by COVID-19 pneumonia.

A Trained Pulmonologist Can Reliably Assess Endosonography-Derived Lymph Node Samples during Rapid On-Site Evaluation.

BACKGROUND: The widespread use of rapid on-site evaluation is hampered by constraints related to time and resources, inadequate reimbursement, and evidence from randomized trials that show a lack of increase in diagnostic yield and specimen adequacy associated with its usage. OBJECTIVE: We aimed to verify whether a pulmonologist can assess endosonography-derived lymph node samples after a comprehensive and reproducible training provided by a specialist pathologist. METHODS: Prospective, observational trial structured in three phases. In the first (training) phase, a pathologist critically evaluated the smears from 150 archival endosonography cases with a pulmonologist. In the second (test) phase, the pulmonologist was asked to assess 50 archival endosonography-derived samples. In the last (real-life) phase, the pulmonologist classified the samples from 200 patients during the endosonography. The overall agreement between pulmonologist and pathologist (gold standard), assessed through κ-statistics, was the primary outcome. The agreement for the identification of specific cytological categories was the secondary outcome. RESULTS: The overallagreement between pulmonologist and pathologist was 84% (κ0.765, 95% CI 0.732-0.826) in the test phase and 89.7% (κ 0.844, 95% CI 0.799-0.881) in the real-life phase. The agreement for specific cytological categories was 92.7% (95% CI 0.824-0.980) for inadequate samples, 90.3% (95% CI 84.5-94.5%) for reactive lymphadenopathies, 90.5% (95% CI 0.845-0.946) for malignancy, and 73% (95% CI 0.515-0.897) for granulomatous samples. CONCLUSIONS: A trained pulmonologist can reliably assess adequacy and malignancy for endosonography-derived samples, which could be useful in institutions where a cytopathologist/cytotechnician is not available regularly.

Poor Concordance between Sequential Transbronchial Lung Cryobiopsy and Surgical Lung Biopsy in the Diagnosis of Diffuse Interstitial Lung Diseases.

Rationale: The diagnostic concordance between transbronchial lung cryobiopsy (TBLC)-versus surgical lung biopsy (SLB) as the current gold standard-in interstitial lung disease (ILD) cases requiring histology remains controversial. Objectives: To assess diagnostic concordance between TBLC and SLB sequentially performed in the same patients, the diagnostic yield of both techniques, and subsequent changes in multidisciplinary assessment (MDA) decisions. Methods: A two-center prospective study included patients with ILD with a nondefinite usual interstitial pneumonia pattern (on high-resolution computed tomography scan) confirmed at a first MDA. Patients underwent TBLC immediately followed by video-assisted thoracoscopy for SLB at the same anatomical locations. After open reading of both sample types by local pathologists and final diagnosis at a second MDA (MDA2), anonymized TBLC and SLB slides were blindly assessed by an external expert pathologist (T.V.C.). Kappa-concordance coefficients and percentage agreement were computed for: TBLC versus SLB, MDA2 versus TBLC, MDA2 versus SLB, and blinded pathology versus routine pathology. Measurements and Main Results: Twenty-one patients were included. The median TBLC biopsy size (longest axis) was 7 mm (interquartile range, 5-8 mm). SLB biopsy sizes averaged 46.1 ± 13.8 mm. Concordance coefficients and percentage agreement were: TBLC versus SLB: κ = 0.22 (95% confidence interval [CI], 0.01-0.44), percentage agreement = 38% (95% CI, 18-62%); MDA2 versus TBLC: κ = 0.31 (95% CI, 0.06-0.56), percentage agreement = 48% (95% CI, 26-70)%; MDA2 versus SLB: κ = 0.51 (95% CI, 0.27-0.75), percentage agreement = 62% (95% CI, 38-82%); two pneumothoraces (9.5%) were recorded during TBLC. TBLC would have led to a different treatment if SLB was not performed in 11 of 21 (52%) of cases. Conclusions: Pathological results from TBLC and SLB were poorly concordant in the assessment of ILD. SLBs were more frequently concordant with the final diagnosis retained at MDA.

Competence in transbronchial cryobiopsy.

Over the last decade transbronchial lung cryobiopsy (TBLC) has proven to be an "innovative application" of an "old procedure" for the histologic diagnosis of diffuse interstitial lung diseases (DILDs). Thus, the technique of TBL cryobiopsy is now adopted for diagnostic purposes, transbronchially in peripheral airways to sample lung parenchyma, whereas this same technique was traditionally employed in the past for therapeutic purposes, essentially for the management of malignant obstruction of central airways. When patients with interstitial lung diseases (ILDs) need histopathological data in their diagnostic pathway, this bioptic approach could be a valid alternative to surgical lung biopsy, that is still the gold standard at the moment. TBL cryobiopsy has a good safety profile, its sensitivity and specificity appear good overall in idiopathic pulmonary fibrosis. In the last ten years, many papers have been published about this procedure defining modalities by which cryobiopsy should be performed. These studies have shown that TBL cryobiopsy is feasible, it allows to obtain larger lung parenchymal specimens (3 times larger than "classic" transbronchial biopsies), characterized by unaltered and artefact-free morphology, and it represents a safe and poorly invasive diagnostic tool for the histologic diagnosis of ILDs. The technical aspects are really important, and they still need a complete standardization. TBL cryobiopsy should be part of an equipment of the modern interventional pulmonologist, who should know indications and contraindications of this methodic and the technical aspects of the procedure. This is a complex procedure requiring to be performed by endoscopists working in specialized centers with specific knowledge of DILDs, and a multidisciplinary approach, which represent pre-requisites for admission to training in this procedure.

Competence in navigation and guided transbronchial biopsy for peripheral pulmonary lesions.

Options for non-surgical tissue diagnosis of the peripheral nodule include CT scan-guided TTNA, fluoroscopy-guided bronchoscopy, radial endobronchial ultrasound (EBUS), electromagnetic navigation bronchoscopy (ENB), and virtual bronchoscopy navigation (VBN). For physicians who choose to pursue non-surgical biopsy, the decision to perform CT scan-guided or ultrasound-guided TTNA, conventional bronchoscopy or bronchoscopy guided by EBUS, ENB, or VBN will depend on a number of factors. CT scan-guided TTNA is preferable for nodules located near the chest wall or for deeper lesions, provided that there is no need to go through the fissures and there is no surrounding emphysema. Ultrasound-guided TTNA requires contact between the lesion and the costal pleura. Bronchoscopic techniques are preferable for nodules ≥2 cm located near a patent bronchus, or in individuals at high risk for pneumothorax following TTNA. In most other situations, operator experience should guide the decision. Trainees must possess a perfect knowledge of anatomy and be fully competent in the interpretation of imaging (CT with contrast medium and PET) and have a thorough knowledge of navigation technology in all its complexities. Practical training can be performed on animal, cadaver or plastic models. In the last years, to improve diagnostic yield, navigational bronchoscopy has attracted significant attention.

Competence in endosonographic techniques.

Endobronchial ultrasound (EBUS) has revolutionized the field of bronchoscopy because it allows to observe peribronchial structures and distal peripheral lung lesions. The use of EBUS was first described by Hurte and Hanrath in 1992. EBUS technology exists in two forms: radial and convex transducer probes. The radial EBUS probe has a 20-MHZ (12-30 MHz available) rotating transducer that can be inserted together with or without a guide sheath through the working channel (2.0-2.8 mm) of a standard flexible bronchoscope. The transducer rotates and produces a 360-degree circular image around the central position of the probe. There are two types of radial EBUS probes: "peripheral" probes, used to identify parenchymal lung lesions, and "central" probes, with balloon sheaths, used for the assessment of airway walls and peribronchial lymph nodes.

Endobronchial ultrasound-guided transbronchial needle aspiration with the flexible 19-gauge needle.

INTRODUCTION AND OBJECTIVES: Endosonography has become standard of care in the diagnostic work-up of mediastinal lymphadenopathy and peribronchial lung lesions, but its success rate in some specific settings/conditions may be hampered by limited needle flexibility and size. We report on our initial experience with the 19G Flex needle, characterized by larger size and greater flexibility as compared with the currently available cytology needles. METHODS: Retrospective review of prospectively collected data on the first 13 consecutive patients submitted to endosonography with the 19G Flex needle. Patients were included if they had: (a) suspicion of a histologically complex disease (ie, lymphoma); (b) suspicion of an advanced lung cancer possibly requiring extensive genotyping; (c) a lesion whose sampling with a 22G needle had failed because of lack of visibility when the needle was loaded into the scope. RESULTS: The 13 patients enrolled had a mean age of 58.15 ± 17 years and a male to female ratio of 8:5. Target lesions (mean size 18.6 ± 6.4 mm) were lymphadenopathies (9 patients), lung lesions (3 patients) and a pleural nodule (1 patient). Histology core/s and a definite diagnosis (adenocarcinoma, 4 cases; lymphoma, 2; mesothelioma, 2, metastases from extrathoracic tumors, 2; non-small-cell lung cancer not otherwise specifiable, 1; small cell carcinoma, 1; sarcoidosis, 1) were obtained in 100% of patients. A single case of self-resolving bleeding was the only complication we observed. CONCLUSIONS: Preliminary results obtained with the dedicated Flex 19G needle are promising, as sample size/quality is satisfactory and the needle influence on scope flexibility is minimal.

Features and outcome of familial idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathicpulmonary fibrosis (IPF) has a sporadic occurrence in most instances,but can also occasionally occur in familial form. While clinicalfeatures of sporadic IPF are well defined, clinical presentation,complications, and outcome of familial IPF are still undefined. Thisretrospective study was undertaken to establish clinical parametersand survival time in a consecutive series of patients with familialIPF and to establish whether the phenomenon of anticipation could beobserved. METHODS: 30 patients had received a diagnosis of familial IPF at ourinstitution over the period from January 2005 and December 2011; in7 of them there was a parent-child relation.Clinical features and patient outcome were analyzed and contrasted toa well characterized cohort of 127 patients with non familial IPF. RESULTS: there was no significant difference in presenting symptoms and theoverall outcomes were quite similar in the two groups, but thefamilial group was much more enriched for females and we found astatistically significant lower age at onset in the youngergenerations (mean age 57,8 years versus 74,2 years, p 0,001). Acuteexacerbations, IPF progression and lung cancer were more frequent inthe familial IPF group as a cause of death (p < 0,005). CONCLUSION: familial IPF seems indistinguishable from sporadic IPF with respectto most clinical and physiologic findings; however the age of onsetwas slightly lower among the familial cases than in the sporadiccases of IPF and the phenomenon of anticipation could be observed.

Transbronchial lung cryobiopsy in the diagnosis of fibrotic interstitial lung diseases.

BACKGROUND: Histology is a key element for the multidisciplinary diagnosis of fibrotic diffuse parenchymal lung diseases (f-DPLD) when the clinical-radiological picture is nondiagnostic. Transbronchial lung cryobiopsy (TBLC) have been shown to be useful for obtaining large and well-preserved biopsies of lung parenchyma, but experience with TBLC in f-DPLD is limited. OBJECTIVES: To evaluate safety, feasibility and diagnostic yield of TBLC in f-DPLD. METHOD: Prospective study of 69 cases of TBLC using flexible cryoprobe in the clinical-radiological setting of f-DPLD with nondiagnostic high resolution computed tomography (HRCT) features. SAFETY: pneumothorax occurred in 19 patients (28%). One patient (1.4%) died of acute exacerbation. Feasibility: adequate cryobiopsies were obtained in 68 cases (99%). The median size of cryobiopsies was 43.11 mm(2) (range, 11.94-76.25). Diagnostic yield: among adequate TBLC the pathologists were confident ("high confidence") that histopathologic criteria sufficient to define a specific pattern in 52 patients (76%), including 36 of 47 with UIP (77%) and 9 nonspecific interstitial pneumonia (6 fibrosing and 3 cellular), 2 desquamative interstitial pneumonia/respiratory bronchiolitis-interstitial lung disease, 1 organizing pneumonia, 1 eosinophilic pneumonia, 1 diffuse alveolar damage, 1 hypersensitivity pneumonitis and 1 follicular bronchiolitis. In 11 diagnoses of UIP the pathologists were less confident ("low confidence"). Agreement between pathologists in the detection of UIP was very good with a Kappa coefficient of 0.83 (95% CI, 0.69-0.97). Using the current consensus guidelines for clinical-radiologic-pathologic correlation 32% (20/63) of cases were classified as Idiopathic Pulmonary Fibrosis (IPF), 30% (19/63) as possible IPF, 25% (16/63) as other f-DPLDs and 13% (8/63) were unclassifiable. CONCLUSIONS: TBLC in the diagnosis of f-DPLD appears safe and feasible. TBLC has a good diagnostic yield in the clinical-radiological setting of f-DPLD without diagnostic HRCT features of usual interstitial pneumonia. Future studies should consider TBLC as a potential alternative to SLBx in f-DPLD.

MMP-7 and fcDNA serum levels in early NSCLC and idiopathic interstitial pneumonia: preliminary study.

A non-invasive test to facilitate the diagnosis of non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF) is still not available and represents an important goal. Forty-eight patients with stage I NSCLC, 45 with IPF, 30 with other idiopathic interstitial pneumonias (IIPs) including idiopathic non-specific interstitial pneumonia (NSIP) and chronic hypersensitivity pneumonitis (HP), 35 with diffuse non-malignant disease and 30 healthy donors were enrolled onto the study. Free circulating (fc)DNA and MMP-7 levels were evaluated by Real Time PCR and ELISA, respectively. Median fcDNA levels were similar in NSCLC (127 ng/mL, range 23.6-345 ng/mL) and IPF (106 ng/mL, range 22-224 ng/mL) patients, and significantly lower in IIPs patients, in individuals with other diseases and in healthy donors (p < 0.05). Conversely, median MMP-7 values were significantly higher in IPF patients (9.10 ng/mL, range 3.88-19.72 ng/mL) than in those with NSCLC (6.31 ng/mL, range 3.38-16.36 ng/mL; p < 0.0001), NSIP (6.50 ng/mL, range 1.50-22.47 ng/mL; p = 0.007), other diseases (5.41 ng/mL, range 1.78-15.91, p < 0.0001) or healthy donors (4.35 ng/mL, range 2.45-7.23; p < 0.0001). Serum MMP-7 levels seem to be capable of distinguishing IPF patients from those with any other lung disease. fcDNA levels were similar in NSCLC and IPF patients, confirming its potential role as a biomarker, albeit non-specific, for the differential diagnosis of NSCLC.