Therapeutic Strategies to Improve the Treatment of Pleural Mesothelioma.

Pleural mesothelioma is a rare neoplastic disease with aggressive features. Patient survival is poor due to the lack of early symptoms and the absence of effective therapeutic strategies. The development of pleural mesothelioma is mainly associated with asbestos exposure and related chronic inflammation. From a molecular-based perspective, this disease is a heterogeneous tumor lacking actionable alterations. The median overall survival of patients affected by this tumor does not exceed 16 months from diagnosis. Molecular and biochemical approaches have shown that this disease is characterized by resistance to drug-induced apoptosis associated with the activation of cell survival pathways and expression of anti-apoptotic proteins. Thus, there is an urgent need to develop efficient and safe therapeutic strategies. Here, we review the pharmacological options available for the treatment of this disease with specific reference to the antitumor agents used in systemic therapies. In addition, novel pharmacological approaches, such as drug delivery tools, to improve pleural mesothelioma treatment are discussed.

Phenotypes and Serum Biomarkers in Sarcoidosis.

Sarcoidosis is a multisystem disease, which is diagnosed on a compatible clinical presentation, non-necrotizing granulomatous inflammation in one or more tissue samples, and exclusion of alternative causes of granulomatous disease. Considering its heterogeneity, numerous aspects of the disease remain to be elucidated. In this context, the identification and integration of biomarkers may hold significance in clinical practice, aiding in appropriate selection of patients for targeted clinical trials. This work aims to discuss and analyze how validated biomarkers are currently integrated in disease category definitions. Future studies are mandatory to unravel the diverse contributions of genetics, socioeconomic status, environmental exposures, and other sociodemographic variables to disease severity and phenotypic presentation. Furthermore, the implementation of transcriptomics, multidisciplinary approaches, and consideration of patients' perspectives, reporting innovative insights, could be pivotal for a better understanding of disease pathogenesis and the optimization of clinical assistance.

Diagnostic delay in bronchiectasis: an Italian perspective.

It takes ∼3.5 years to reach a diagnosis of bronchiectasis from onset of symptoms: the long patient's journey in Italy https://bit.ly/46XMWAz.

Exacerbation Burden in COPD and Occurrence of Mortality in a Cohort of Italian Patients: Results of the Gulp Study.

Objective: To describe the burden of moderate to severe exacerbations and all-cause mortality; the secondary objectives were to analyze treatment patterns and changes over follow-up. Design: Observational, multicenter, retrospective, cohort study with a three year follow-up period. Setting: Ten Italian academic secondary- and tertiary-care centers. Participants: Patients with a confirmed diagnosis of COPD referring to the outpatient clinics of the participating centers were retrospectively recruited. Primary and Secondary Outcome Measures: Annualized frequency of moderate and severe exacerbations stratified by exacerbation history prior to study enrollment. Patients were classified according to airflow obstruction, GOLD risk categories, and divided in 4 groups: A = no exacerbations; B = 1 moderate exacerbation; C = 1 severe exacerbation; D = ≥2 moderate and/or severe exacerbations. Overall all-cause mortality stratified by age, COPD category, and COPD therapy. A logistic regression model assessed the association of clinical characteristics with mortality. Results: 1111 patients were included (73% males), of which 41.5% had a history of exacerbations. As expected, the proportion of patients experiencing ≥1 exacerbation during follow-up increased according to pre-defined study risk categories (B: 79%, C: 84%, D: 97.4%). Overall, by the end of follow-up, 45.5% of patients without a history of exacerbation experienced an exacerbation (31% of which severe), and 13% died. Deceased patients were significantly older, more obstructed and hyperinflated, and more frequently active smokers compared with survivors. Severe exacerbations were more frequent in patients that died (23.5%, vs 10.2%; p-value: 0.002). Chronic heart failure and ischemic heart disease were the only comorbidities associated with a higher odds ratio (OR) for death (OR: 2.2, p-value: 0.001; and OR: 1.9, p-value: 0.007). Treatment patterns were similar in patients that died and survivors. Conclusion: Patients with a low exacerbation risk are exposed to a significant future risk of moderate/severe exacerbations. Real life data confirm the strong association between mortality and cardiovascular comorbidities in COPD.

Quantification of circulating alpha-1-antitrypsin polymers associated with different SERPINA1 genotypes.

OBJECTIVES: Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin (AAT), the major serine protease inhibitor in plasma. Reduced AAT levels are associated with elevated risk of developing emphysema mainly due to uncontrolled activity of neutrophil elastase in the lungs. The prevalent Z-AAT mutant and many rare pathogenic AAT variants also predispose to liver disease due to their accumulation as polymeric chains in hepatocytes. Part of these polymers are secreted into the bloodstream and could represent biomarkers of intra-hepatic accumulation. Moreover, being inactive, they further lower lung protection against proteases. Aim of our study is to accurately quantify the percentage of circulating polymers (CP) in a cohort of subjects with different SERPINA1 genotypes. METHODS: CP concentration was measured in plasma or Dried Blood Spot (DBS) by a sensitive sandwich ELISA based on capture by the polymer-specific 2C1 monoclonal antibody. RESULTS: CP were significantly elevated in patients with the prevalent PI*SZ and PI*ZZ genotypes, with considerable intra-genotype variability. Notably, higher percentage of polymers was observed in association with elevated C-reactive protein. CP levels were also increased in carriers of the Mmalton variant, and of Mprocida, I, Plowell and Mherleen in heterozygosity with Z-AAT. CONCLUSIONS: These findings highlight the importance of implementing CP quantification in a clinical laboratory. Indeed, the variable amount of CP in patients with the same genotype may correlate with the variable severity of the associated lung and liver diseases. Moreover, CP can reveal the polymerogenic potential of newly discovered ultrarare AAT variants.

Does pulmonary endarterectomy improve the clinical conditions of patients with chronic thromboembolic pulmonary disease without pulmonary hypertension?

To verify whether the new hemodynamic definition of pulmonary hypertension (PH) has any implication in treatment of Chronic Thrombo-Embolic Pulmonary Disease (CTEPD) patients without PH, we retrospectively analysed the clinical and functional changes determined by pulmonary endarterectomy (PEA) in 63 CTEPD patients without PH who underwent surgery at our center, comparing those in whom the hemodynamic diagnosis of PH met recent guideline recommendations versus those in whom the diagnosis only met previous hemodynamic thresholds. The results show that the vast majority of CTEPD patients without PH operated at our center would now be defined as chronic thromboembolic pulmonary hypertension (CTEPH) patients. PEA did not result in any improvement in exercise capacity nor in right ventricular function or lung function test in patients with mean pulmonary artery pressure (mPAP) ≤ 20 mm Hg and pulmonary vascular resistance (PVR) ≤ 2 WU; on the contrary, hemodynamic parameters, exercise capacity, right ventricular function and lung function significantly improved in patients with mPAP between 21 and 24 mm Hg.

Inhaled recombinant GM-CSF reduces the need for whole lung lavage and improves gas exchange in autoimmune pulmonary alveolar proteinosis patients.

RATIONALE: Whole lung lavage (WLL) is a widely accepted palliative treatment for autoimmune pulmonary alveolar proteinosis (aPAP) but does not correct myeloid cell dysfunction or reverse the pathological accumulation of surfactant. In contrast, inhaled recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) is a promising pharmacological approach that restores alveolar macrophage functions including surfactant clearance. Here, we evaluate WLL followed by inhaled rGM-CSF (sargramostim) as therapy of aPAP. METHODS: 18 patients with moderate-to-severe aPAP were enrolled, received baseline WLL, were randomised into either the rGM-CSF group (receiving inhaled sargramostim) or control group (no scheduled therapy) and followed for 30 months after the baseline WLL. Outcome measures included additional unscheduled "rescue" WLL for disease progression, assessment of arterial blood gases, pulmonary function, computed tomography, health status, biomarkers and adverse events. Patients requiring rescue WLL were considered to have failed their assigned intervention group. RESULTS: The primary end-point of time to first rescue WLL was longer in rGM-CSF-treated patients than controls (30 versus 18 months, n=9 per group, p=0.0078). Seven control patients (78%) and only one rGM-CSF-treated patient (11%) required rescue WLL, demonstrating a 7-fold increase in relative risk (p=0.015). Compared to controls, rGM-CSF-treated patients also had greater improvement in peripheral arterial oxygen tension, alveolar-arterial oxygen tension difference, diffusing capacity of the lungs for carbon monoxide and aPAP biomarkers. One patient from each group withdrew for personal reasons. No serious adverse events were reported. CONCLUSIONS: This long-term, prospective, randomised trial demonstrated inhaled sargramostim following WLL reduced the requirement for WLL, improved lung function and was safe in aPAP patients. WLL plus inhaled sargramostim may be useful as combined therapy for aPAP.

Spirometric patterns in young and middle-aged adults: a 20-year European study.

BACKGROUND: Understanding the natural history of abnormal spirometric patterns at different stages of life is critical to identify and optimise preventive strategies. We aimed to describe characteristics and risk factors of restrictive and obstructive spirometric patterns occurring before 40 years (young onset) and between 40 and 61 years (mid-adult onset). METHODS: We used data from the population-based cohort of the European Community Respiratory Health Survey (ECRHS). Prebronchodilator forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were assessed longitudinally at baseline (ECRHS1, 1993-1994) and again 20 years later (ECRHS3, 2010-2013). Spirometry patterns were defined as: restrictive if FEV1/FVC≥LLN and FVC<10th percentile, obstructive if FEV1/FVC

Early life exposures contributing to accelerated lung function decline in adulthood - a follow-up study of 11,000 adults from the general population.

Background: We aimed to assess whether exposure to risk factors in early life from conception to puberty continue to contribute to lung function decline later in life by using a pooled cohort comprising approx. 11,000 adults followed for more than 20 years and with up to three lung function measurements. Methods: Participants (20-68 years) in the ECRHS and NFBC1966 cohort studies followed in the periods 1991-2013 and 1997-2013, respectively, were included. Mean annual decline in maximum forced expired volume in 1 s (FEV1) and forced vital capacity (FVC) were main outcomes. Associations between early life risk factors and change in lung function were estimated using mixed effects linear models adjusted for sex, age, FEV1, FVC and height at baseline, accounting for personal smoking. Findings: Decline in lung function was accelerated in participants with mothers that smoked during pregnancy (FEV1 2.3 ml/year; 95% CI: 0.7, 3.8) (FVC 2.2 ml/year; 0.2, 4.2), with asthmatic mothers (FEV1 2.6 ml/year; 0.9, 4.4) (FEV1/FVC 0.04 per year; 0.04, 0.7) and asthmatic fathers (FVC 2.7 ml/year; 0.5, 5.0), and in women with early menarche (FVC 2.4 ml/year; 0.4, 4.4). Personal smoking of 10 pack-years contributed to a decline of 2.1 ml/year for FEV1 (1.8, 2.4) and 1.7 ml/year for FVC (1.3, 2.1). Severe respiratory infections in early childhood were associated with accelerated decline among ever-smokers. No effect-modification by personal smoking, asthma symptoms, sex or cohort was found. Interpretation: Mothers' smoking during pregnancy, parental asthma and early menarche may contribute to a decline of FEV1 and FVC later in life comparable to smoking 10 pack-years. Funding: European Union's Horizon 2020; Research Council of Norway; Academy of Finland; University Hospital Oulu; European Regional Development Fund; Spanish Ministry of Science and Innovation; Generalitat de Catalunya.

Pleural Mesothelioma: Treatable Traits of a Heterogeneous Disease.

Pleural mesothelioma is an aggressive disease with diffuse nature, low median survival, and prolonged latency presenting difficulty in prognosis, diagnosis, and treatment. Here, we review all these aspects to underline the progress being made in its investigation and to emphasize how much work remains to be carried out to improve prognosis and treatment.

Severe Asthma Network Italy Definition of Clinical Remission in Severe Asthma: A Delphi Consensus.

Severe asthma affects about 10% of the population with asthma and is characterized by low lung function and a high count of blood leukocytes, mainly eosinophils. Various definitions are used in clinical practice and in the literature to identify asthma remission: clinical remission, inflammatory remission, and complete remission. This work highlights a consensus for asthma remission using a Delphi method. In the context of the Severe Asthma Network Italy, which accounts for 57 severe asthma centers and more than 2,200 patients, a board of six experts drafted a list of candidate statements in a questionnaire, which has been revised to minimize redundancies and ensure clear and consistent wording for the first round (R1) of the analysis. Thirty-two statements were included in the R1 questionnaire and then submitted to a panel of 80 experts, which used a 5-point Likert scale to measure agreement regarding each statement. Then, an interim analysis of R1 data was performed, and items were discussed and considered to produce a consistent questionnaire for round 2 (R2) of the analysis. Then, the board set the R2 questionnaire, which included only important topics. Panelists were asked to vote on the statements in the R2 questionnaire afterward. During R2, the criteria of complete clinical remission (the absence of the need for oral corticosteroids, symptoms, exacerbations or attacks, and pulmonary function stability) and those of partial clinical remission (the absence of the need for oral corticosteroids, and two of three criteria: the absence of symptoms, exacerbations or attacks, and pulmonary stability) were confirmed. This Severe Asthma Network Italy Delphi analysis defined a valuable and independent tool that is easy to use, to test the efficacy of different treatments in patients with severe asthma enrolled into the SANI registry.

Smart Sensors and Microtechnologies in the Precision Medicine Approach against Lung Cancer.

BACKGROUND AND RATIONALE: The therapeutic interventions against lung cancer are currently based on a fully personalized approach to the disease with considerable improvement of patients' outcome. Alongside continuous scientific progresses and research investments, massive technologic efforts, innovative challenges, and consolidated achievements together with research investments are at the bases of the engineering and manufacturing revolution that allows a significant gain in clinical setting. AIM AND METHODS: The scope of this review is thus to focus, rather than on the biologic traits, on the analysis of the precision sensors and novel generation materials, as semiconductors, which are below the clinical development of personalized diagnosis and treatment. In this perspective, a careful revision and analysis of the state of the art of the literature and experimental knowledge is presented. RESULTS: Novel materials are being used in the development of personalized diagnosis and treatment for lung cancer. Among them, semiconductors are used to analyze volatile cancer compounds and allow early disease diagnosis. Moreover, they can be used to generate MEMS which have found an application in advanced imaging techniques as well as in drug delivery devices. CONCLUSIONS: Overall, these issues represent critical issues only partially known and generally underestimated by the clinical community. These novel micro-technology-based biosensing devices, based on the use of molecules at atomic concentrations, are crucial for clinical innovation since they have allowed the recent significant advances in cancer biology deciphering as well as in disease detection and therapy. There is an urgent need to create a stronger dialogue between technologists, basic researchers, and clinicians to address all scientific and manufacturing efforts towards a real improvement in patients' outcome. Here, great attention is focused on their application against lung cancer, from their exploitations in translational research to their application in diagnosis and treatment development, to ensure early diagnosis and better clinical outcomes.

Performance of an AI algorithm during the different phases of the COVID pandemics: what can we learn from the AI and vice versa.

Background: Artificial intelligence (AI) has proved to be of great value in diagnosing and managing Sars-Cov-2 infection. ALFABETO (ALL-FAster-BEtter-TOgether) is a tool created to support healthcare professionals in the triage, mainly in optimizing hospital admissions. Methods: The AI was trained during the pandemic's "first wave" (February-April 2020). Our aim was to assess the performance during the "third wave" of the pandemics (February-April 2021) and evaluate its evolution. The neural network proposed behavior (hospitalization vs home care) was compared with what was actually done. If there were discrepancies between ALFABETO's predictions and clinicians' decisions, the disease's progression was monitored. Clinical course was defined as "favorable/mild" if patients could be managed at home or in spoke centers and "unfavorable/severe" if patients need to be managed in a hub center. Results: ALFABETO showed accuracy of 76%, AUROC of 83%; specificity was 78% and recall 74%. ALFABETO also showed high precision (88%). 81 hospitalized patients were incorrectly predicted to be in "home care" class. Among those "home-cared" by the AI and "hospitalized" by the clinicians, 3 out of 4 misclassified patients (76.5%) showed a favorable/mild clinical course. ALFABETO's performance matched the reports in literature. Conclusions: The discrepancies mostly occurred when the AI predicted patients could stay at home but clinicians hospitalized them; these cases could be handled in spoke centers rather than hubs, and the discrepancies may aid clinicians in patient selection. The interaction between AI and human experience has the potential to improve both AI performance and our comprehension of pandemic management.

Long-term residential exposure to air pollution and risk of chronic respiratory diseases in Italy: The BIGEPI study.

Long-term exposure to air pollution has adverse respiratory health effects. We investigated the cross-sectional relationship between residential exposure to air pollutants and the risk of suffering from chronic respiratory diseases in some Italian cities. In the BIGEPI project, we harmonised questionnaire data from two population-based studies conducted in 2007-2014. By combining self-reported diagnoses, symptoms and medication use, we identified cases of rhinitis (n = 965), asthma (n = 328), chronic bronchitis/chronic obstructive pulmonary disease (CB/COPD, n = 469), and controls (n = 2380) belonging to 13 cohorts from 8 Italian cities (Pavia, Turin, Verona, Terni, Pisa, Ancona, Palermo, Sassari). We derived mean residential concentrations of fine particulate matter (PM10, PM2.5), nitrogen dioxide (NO2), and summer ozone (O3) for the period 2013-2015 using spatiotemporal models at a 1 km resolution. We fitted logistic regression models with controls as reference category, a random-intercept for cohort, and adjusting for sex, age, education, BMI, smoking, and climate. Mean ± SD exposures were 28.7 ± 6.0 µg/m3 (PM10), 20.1 ± 5.6 µg/m3 (PM2.5), 27.2 ± 9.7 µg/m3 (NO2), and 70.8 ± 4.2 µg/m3 (summer O3). The concentrations of PM10, PM2.5, and NO2 were higher in Northern Italian cities. We found associations between PM exposure and rhinitis (PM10: OR 1.62, 95%CI: 1.19-2.20 and PM2.5: OR 1.80, 95%CI: 1.16-2.81, per 10 µg/m3) and between NO2 exposure and CB/COPD (OR 1.22, 95%CI: 1.07-1.38 per 10 µg/m3), whereas asthma was not related to environmental exposures. Results remained consistent using different adjustment sets, including bi-pollutant models, and after excluding subjects who had changed residential address in the last 5 years. We found novel evidence of association between long-term PM exposure and increased risk of rhinitis, the chronic respiratory disease with the highest prevalence in the general population. Exposure to NO2, a pollutant characterised by strong oxidative properties, seems to affect mainly CB/COPD.

Comparison among populations with severe and intermediate alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease.

BACKGROUND: Severe alpha1-antitrypsin (AAT) deficiency (AATD) is associated with a high risk of airflow obstruction and emphysema. The risk of lung disease in those with intermediate AAT deficiency is unclear. Our aims were to compare pulmonary function, time of onset of symptoms, and indicators of quality of life among patients with severe AATD (PI*ZZ), patients with intermediate AATD (PI*MZ) from the Italian Registry of AATD with a chronic obstructive pulmonary disease (COPD) cohort of patients without AATD (PI*MM). METHODS: We considered a total of 613 patients: 330 with the PI*ZZ genotype, 183 with the PI*MZ genotype and 100 with the PI*MM genotype. Radiological exams, pulmonary function test, and measurement of quality of life have been performed on all cohorts of patients. RESULTS: The three populations differ significantly in terms of age at COPD/AATD diagnosis (P=0.00001), respiratory function (FEV1, FVC, DLCO P<0.001), quality of life (P=0.0001) and smoking history (P<0.0001). PI*ZZ genotype had 24.9 times a higher likelihood of developing airflow obstruction. The MZ genotype is not associated with a significant early risk of airflow obstruction. CONCLUSIONS: The comparison of populations with PI*ZZ, MZ and MM genotypes allows to delineate the role of alpha1-antitrypsin deficiency on respiratory function and on the impact on quality of life, in relation to other risk factors. These results highlight the crucial role of primary and secondary prevention on smoking habits in PI*MZ subjects and the importance of an early diagnosis.

Practical dietary advices for subjects with alpha-1 antitrypsin deficiency.

Congenital alpha-1 antitrypsin deficiency (AATD) is a rare inherited disorder caused by the mutation of the SERPINA1 gene on chromosome 14. At pulmonary level, AAT deficiency leads to an increased risk of chronic obstructive pulmonary disease (COPD) and emphysema, starting from the third-fourth decade of life. At hepatic level, some variants of the allelic, in particular PI*Z, cause a conformational change of the AAT molecule, which polymerizes within the hepatocytes. Excessive hepatic accumulation of these abnormal molecules can lead to liver disease in both adults and children, with clinical presentation ranging from cholestatic jaundice in the newborn to abnormal blood indices of liver function in children and adults, up to fatty liver, cirrhosis and hepatocarcinoma. Nutritional interventions in AATD aim to provide the necessary calories, stop protein catabolism, prevent and treat malnutrition as in the case of common COPD, and even take into account any liver disease that is a distinctive trait, compared to common COPD. Actually, there is a lack of formal research regarding the effects of specific nutritional recommendations in patients with AATD, proper eating habits may help to preserve lung and liver function. For practical dietary advice in patients with AATD and COPD, recently a food pyramid proposal has been published. It has been observed that there is a marked overlap between AATD liver disease and obesity-related liver disease, suggesting shared molecular basis and, therefore, similar nutritional strategies. In this narrative review dietary advice for all possible stages of liver disease have been reported.

Comprehensive Clinical Diagnostic Pipelines Reveal New Variants in Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed disorder associated with mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (AAT). Severe AATD can manifest as pulmonary emphysema and progressive liver disease. Besides the most common pathogenic variants S (E264V) and Z (E342K), many rarer genetic variants of AAT have been found in patients and in the general population. Here we report a panel of new SERPINA1 variants, including 4 null and 16 missense alleles, identified among a cohort of individuals with suspected AATD whose phenotypic follow-up showed inconclusive or atypical results. Because the pathogenic significance of the missense variants was unclear purely on the basis of clinical data, the integration of computational, biochemical, and cellular studies was used to define the associated risk of disease. Established pathogenicity predictors and structural analysis identified a panel of candidate damaging mutations that were characterized by expression in mammalian cell models. Polymer formation, intracellular accumulation, and secretory efficiency were evaluated experimentally. Our results identified two AAT mutants with a Z-like polymerogenic severe deficiency profile (Smilano and Mcampolongo) and three milder variants (Xsarezzo, Pdublin, and Ctiberias). Overall, the experimentally determined behavior of the variants was in agreement with the pathogenicity scores of the REVEL (an ensemble method for predicting the pathogenicity of rare missense variants) predictor, supporting the utility of this bioinformatic tool in the initial assessment of newly identified amino acid substitutions of AAT. Our study, in addition to describing 20 new SERPINA1 variants, provides a model for a multidisciplinary approach to classification of rare AAT variants and their clinical impact on individuals with rare AATD genotypes.