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.

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.

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.

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.

CT Scan-Guided Fine Needle Aspiration Cytology for Lung Cancer Diagnosis through the COVID-19 Pandemic: What We Have Learned.

BACKGROUND AND RATIONALE: Novel coronavirus-related disease (COVID-19) has profoundly influenced hospital organization and structures worldwide. In Italy, the Lombardy Region, with almost 17% of the Italian population, rapidly became the most severely affected area since the pandemic beginning. The first and the following COVID-19 surges significantly affected lung cancer diagnosis and subsequent management. Much data have been already published regarding the therapeutic repercussions whereas very few reports have focused on the consequences of the pandemic on diagnostic procedures. METHODS: We, here, would like to analyze data of novel lung cancer diagnosis performed in our Institution in Norther Italy where we faced the earliest and largest outbreaks of COVID-19 in Italy. RESULTS: We discuss, in detail, the strategies developed to perform biopsies and the safe pathways created in emergency settings to protect lung cancer patients in subsequent therapeutic phases. Quite unexpectedly, no significant differences emerged between cases enrolled during the pandemic and those before, and the two populations were homogeneous considering the composition and diagnostic and complication rates. CONCLUSIONS: By pointing out the role of multidisciplinarity in emergency contexts, these data will be of help in the future for designing tailored strategies to manage lung cancer in a real-life setting.

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.

Smoking Habit and Respiratory Function Predict Patients' Outcome after Surgery for Lung Cancer, Irrespective of Histotype and Disease Stage.

BACKGROUND: Growing evidence suggests that sublobar resections offer more favorable outcomes than lobectomy in early-stage lung cancer surgery. However, a percentage of cases that cannot be ignored develops disease recurrence irrespective of the surgery performed with curative intent. The goal of this work is thus to compare different surgical approaches, namely, lobectomy and segmentectomy (typical and atypical) to derive prognostic and predictive markers. PATIENTS AND METHODS: Here we analyzed a cohort of 153 NSCLC patients in clinical stage TNM I who underwent pulmonary resection surgery with a mediastinal hilar lymphadenectomy from January 2017 to December 2021, with an average follow-up of 25.5 months. Partition analysis was also applied to the dataset to detect outcome predictors. RESULTS: The results of this work showed similar OS between lobectomy and typical and atypical segmentectomy for patients with stage I NSCLC. In contrast, lobectomy was associated with a significant improvement in DFS compared with typical segmentectomy in stage IA, while in stage IB and overall, the two treatments were similar. Atypical segmentectomy showed the worst performance, especially in 3-year DFS. Quite unexpectedly, outcome predictor ranking analysis suggests a prominent role of smoking habits and respiratory function, irrespective of the tumor histotype and the patient's gender. CONCLUSIONS: Although the limited follow-up interval cannot allow conclusive remarks about prognosis, the results of this study suggest that both lung volumes and the degree of emphysema-related parenchymal damage are the strongest predictors of poor survival in lung cancer patients. Overall, these data point out that greater attention should be addressed to the therapeutic intervention for co-existing respiratory diseases to obtain optimal control of early lung cancer.

Inhaled corticosteroids and risk of osteoporosis in late-middle-aged subjects: a multicenter European cohort study.

BACKGROUND: Inhaled corticosteroids have been widely used for the regular treatment of asthma and chronic obstructive pulmonary diseases (COPD) over the past few decades. To date, studies investigating the effects of inhaled corticosteroids (ICS) on bone in populations including asthma and COPD patients, show conflicting results. The skeletal effects of ICS remain poorly understood. We assessed the association between ICS exposure and self-reported osteoporosis diagnosis in a European cohort study. METHODS: The analysis was carried out by using clinical and questionnaire data available for subjects participating in the ECRHS III (European Community Respiratory Health Survey) with age >55 years. RESULTS: Among the 3004 enrolled subjects, 245 were ICS users with an exposure ≥12 months. Osteoporosis was reported by 16 subjects in the ICS group (6.5%) and by 167 in the not exposed group (6.1%). The adjusted risk of osteoporosis in ICS users (≥12 months) was not greater in exposed subjects when compared with the unexposed ones (OR=1.02, 95CI%: 0.51, 2.03). The same result was observed even when considering in the analysis a longer exposure to the ICS use (≥36.5 months, the median ICS exposure for all subjects). History of COPD, use of oral corticosteroids, Body Mass Index, smoking and physical activity did not show any evidence of an association with osteoporosis. CONCLUSIONS: Our study did not show any significant association between long- term ICS use and self-reported diagnosis of osteoporosis in subjects aged >55 years. To explore the real effect of ICS on bone status, further studies are needed, especially in the long-term ICS exposure.

Eosinophilic cationic protein (ECP) in the clinical work-up of chronic cough.

BACKGROUND: Chronic cough is a common symptom, addressed in the clinical setting by empirical treatment together with some laboratory investigations. The aim of the present study was to investigate the value of testing eosinophilic cationic protein (ECP) serum levels combined with other diagnostic procedures and empirical treatment in the diagnostic workup of chronic cough. METHODS: In this study, we evaluated 194 patients with chronic cough. No subject had received any anti-inflammatory treatment before clinical evaluation, and none was an active smoker. ECP was measured with a commercially available fluoroenzyme immunoassay and results were expressed as µg/L. RESULTS: The analysis of variance showed that mean ECP level differs among the various diagnosis categories (P<0.001). Mean ECP level was significantly higher in asthmatic patients, particularly in the active disease. CONCLUSIONS: Serum ECP concentration could represent a useful biomarker in the clinical work-up of chronic cough, managing to differentiate asthma from other chronic disorders.

Serum Aspergillus-specific IgE, IgG and IgG4 immunoglobulins assessment in the work-up of invasive pulmonary aspergillosis: a prospective cohort study.

BACKGROUND: Positive microbiological fungal culture from bronchoalveolar-lavage-fluid (BAL) for Aspergillus or tissue biopsy and the detection of high levels of Aspergillus Galactomannan (GM) are commonly considered standard for diagnosing Invasive Pulmonary Aspergillosis (IPA). However, Aspergillus infection induces both cellular and humoral immune responses, characterized by the production of specific immunoglobulins, which can be easily detected in serum and accurately measured. This study hypothesized that Aspergillus-specific IgE, IgG, including IgG4, assays could be adopted as a rapid preliminary screening tool in patients with suspected Aspergillus-related lung disease in order to help in the identification of patients who require more invasive procedures (bronchoscopy, biopsy). METHODS: We prospectively stored 447 serum specimens of patients admitted for suspected IPA from 1 January 2010 to 31 July 2021. Serum total IgE and serum IgE, IgG and IgG4 specific for Aspergillus fumigatus and Aspergillus niger were determined for each sample. In addition, bronchoscopy with BAL for microbiologic culture and Aspergillus Galactomannan (GM) antigen were performed in all patients. RESULTS: Patients with IPA, diagnosed by detection of a positive BAL culture for Aspergillus and/or a positive GM, showed higher serum levels of specific Aspergillus fumigatus and Aspergillus niger immunoglobulins. Serum-specific Aspergillus fumigatus IgG at a cut-off of 22.6 mgA/L showed the highest sensitivity in predicting IPA, though quite moderate (AUC 0.62). Nonetheless, the simultaneous presence of values below the cut-off of Aspergillus IgE, IgG and IgG4 showed a negative predictive value greater than 90% both towards positive BAL culture and positive GM. CONCLUSIONS: In patients with suspected IPA, Aspergillus-specific immunoglobulins assay could be tested as a preliminary screening tool to support more invasive procedures, i.e. BAL.

Fifteen-Year Surveillance of LTR Receiving Pre-Emptive Therapy for CMV Infection: Prevention of CMV Disease and Incidence of CLAD.

The efficacy of pre-emptive therapy in the prevention of cytomegalovirus (CMV) disease and the potential association of CMV infection with the occurrence of chronic lung allograft dysfunction (CLAD) was evaluated in 129 lung transplant recipients receiving pre-emptive therapy based on pp65-antigenemia or CMV-DNA in the blood and in the bronchoalveolar lavage. Seventy-one (55%) patients received pre-emptive ganciclovir/valganciclovir (GCV/VGCV) for CMV infection for a median of 28 (9-191) days. Possible CMV disease occurred in six (5%) patients and was healed after the GCV/VGCV therapy. The cumulative incidence of CLAD was 38% and 54% at 5 and 10 years. Acute rejection and CMV load in the blood (but not in the lung) were independent predictors of the occurrence of CLAD. Pre-emptive therapy is highly effective in preventing CMV disease in lung recipients and does not induce a superior incidence of CLAD compared to what reported for other cohorts of patients who received an extended antiviral prophylaxis.

Improving the Laboratory Diagnosis of M-like Variants Related to Alpha1-Antitrypsin Deficiency.

Alpha1-antitrypsin (AAT) is a serine protease inhibitor that is encoded by the highly polymorphic SERPINA1 gene. Mutations in this gene can lead to AAT deficiency (AATD), which is associated with an increased risk of lung and/or liver disease. On the basis of electrophoretic migration, AAT variants are named with capital letters; M (medium) signifies the normal protein. Among pathological variants, the M-like ones represent a heterogeneous group of rare allelic variants that exhibit the same electrophoretic pattern as the M wild-type protein, which makes them difficult to detect with routine methods. In order to avoid their misdiagnosis, the present study defines and validates effective methods for the detection of two pathogenic M-like variants, Mwurzburg and Mwhitstable. Comparison of protein phenotypes using isoelectric focusing of samples that presented the Mwurzburg variant, as revealed by exons 5 sequencing, identified a particular electrophoretic pattern amenable to the Mwurzburg protein. The specific phenotyping pattern was retrospectively validated, thus enabling the detection of 16 patients with Mwurzburg variant among the subjects already tested but not sequenced according to our diagnostic algorithm. The Mwhitstable allele was detected by intron 4 sequencing of SERPINA1 gene. Mwurzburg and Mwhitstable are often misdiagnosed and the introduction of diagnostic improvements can help the clinical management, especially in patients with established lung disease without any other reported risk factors.

Clinical manifestations of a new alpha-1 antitrypsin genetic variant: Q0parma.

Alpha-1 antitrypsin deficiency is an autosomal, codominant disorder caused by mutations of the SERPINA1 gene. Several mutations of SERPINA1 have been described associated with the development of pulmonary emphysema and/or chronic liver disease and cirrhosis. Here, we report a very rare PI*Q0parma variant identified for the first time in an Italian family originally from the city of Parma in Northern Italy.

The oncogenic landscape of the idiopathic pulmonary fibrosis: a narrative review.

Background and Objective: Translational research is a source of continuous innovation in medicine, more particularly for clinical research on new treatment modalities in idiopathic pulmonary fibrosis (IPF) patients. However, the heterogeneity of the disease is well recognized, and different pathological and molecular settings have been identified. The molecular mechanisms by which IPF proceeds in time and space remains poorly understood. Although some IPF features are reminiscent of cancer, the dynamics of malignant divergent clonal selective pressure and heterogeneity clearly differ from those occurring in IPF. This is reflected in the absence of patient proper selection and stratification to biological agents (pirfenidone, nintedanib) which limit therapeutic efficacy. Consequently, increased costs are related to the clinical management of advanced IPF patients. Steady collaboration and fluid communication between pneumo-oncologists, radiologists and molecular biologists is a clear priority for the correct interpretation of tests and the definition of effective personalized strategies against this orphan disease. The present work aims at providing the most relevant hints shared by cancer and IPF. Methods: A systematic literature review was performed to identify all relevant data. The examined databases were Scopus, Web of Science, Cochrane, Google Scholar, and PubMed. The last search was run on January 5, 2022. We have primarily conducted separated research for lung cancer, IPF, genetics, epigenetics, surgery in IPF and cancer. Key Content and Findings: The data here presented mainly focus on gene mutations, epigenetics and novel therapeutic approaches. Moreover, epidemiology, prognostic variables and in new treatment strategies adopted in patients with IPF and lung cancer are discussed as well. Conclusions: Overall, the findings of this narrative review will be of help in defining the key molecular features that could applied in IPF setting with promising rationale to improve therapy and to better manage those cases carrying IPF and cancer concomitantly.

A mini-whole lung lavage to treat autoimmune pulmonary alveolar proteinosis (PAP).

BACKGROUND: PAP is an ultra-rare respiratory syndrome characterized by the accumulation of surfactant within the alveoli. Whole lung lavage (WLL) is the current standard of care of PAP, however it is not a standardized procedure and the total amount of fluid used to wash each lung is still debated. Considering ICU hospitalization associated risks, a "mini-WLL" with anticipated manual clapping and reduced total infusion volume and has been proposed in our center. The aim of the study is to retrospectively analyze the efficacy of mini-WLL compared to standard WLL at the Pavia center. METHODS: 13 autoimmune PAP patients eligible for WLL were included: 7 patients were admitted to mini-WLL (9 L total infusion volume for each lung) and 6 patients underwent standard WLL (14 L of infusion volume). Functional data (VC%, FVC%, TLC%, DLCO%) and alveolar-arterial gradient values (A-aO2) were collected at the baseline and 1, 3, 6, 12, 18 months after the procedure. RESULTS: A statistically significant improvement of VC% (p = 0.013, 95%CI 3.49-30.19), FVC% (p = 0.016, 95%CI 3.37-32.09), TLC% (p = 0.001, 95%CI 7.38-30.34) was observed in the mini-WLL group in comparison with the standard WLL group, while no significant difference in DLCO% and A-aO2 mean values were reported. CONCLUSION: Mini-WLL has demonstrated higher efficacy in ameliorating lung volumes, suggesting that a lower infusion volume is sufficient to remove the surfactant accumulation and possibly allows a reduced mechanical insult of the bronchi walls and the alveoli. However, no statistically significant differences were found in terms of DLCO% and Aa-O2.

Machine Learning-based Voice Assessment for the Detection of Positive and Recovered COVID-19 Patients.

Many virological tests have been implemented during the Coronavirus Disease 2019 (COVID-19) pandemic for diagnostic purposes, but they appear unsuitable for screening purposes. Furthermore, current screening strategies are not accurate enough to effectively curb the spread of the disease. Therefore, the present study was conducted within a controlled clinical environment to determine eventual detectable variations in the voice of COVID-19 patients, recovered and healthy subjects, and also to determine whether machine learning-based voice assessment (MLVA) can accurately discriminate between them, thus potentially serving as a more effective mass-screening tool. Three different subpopulations were consecutively recruited: positive COVID-19 patients, recovered COVID-19 patients and healthy individuals as controls. Positive patients were recruited within 10 days from nasal swab positivity. Recovery from COVID-19 was established clinically, virologically and radiologically. Healthy individuals reported no COVID-19 symptoms and yielded negative results at serological testing. All study participants provided three trials for multiple vocal tasks (sustained vowel phonation, speech, cough). All recordings were initially divided into three different binary classifications with a feature selection, ranking and cross-validated RBF-SVM pipeline. This brough a mean accuracy of 90.24%, a mean sensitivity of 91.15%, a mean specificity of 89.13% and a mean AUC of 0.94 across all tasks and all comparisons, and outlined the sustained vowel as the most effective vocal task for COVID discrimination. Moreover, a three-way classification was carried out on an external test set comprised of 30 subjects, 10 per class, with a mean accuracy of 80% and an accuracy of 100% for the detection of positive subjects. Within this assessment, recovered individuals proved to be the most difficult class to identify, and all the misclassified subjects were declared positive; this might be related to mid and short-term vocal traces of COVID-19, even after the clinical resolution of the infection. In conclusion, MLVA may accurately discriminate between positive COVID-19 patients, recovered COVID-19 patients and healthy individuals. Further studies should test MLVA among larger populations and asymptomatic positive COVID-19 patients to validate this novel screening technology and test its potential application as a potentially more effective surveillance strategy for COVID-19.

Local Therapies and Modulation of Tumor Surrounding Stroma in Malignant Pleural Mesothelioma: A Translational Approach.

Malignant Pleural Mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated with asbestos exposure and still lacking effective therapies. Modern targeted biological strategies that have revolutionized the therapy of other solid tumors have not had success so far in the MPM. Combination immunotherapy might achieve better results over chemotherapy alone, but there is still a need for more effective therapeutic approaches. Based on the peculiar disease features of MPM, several strategies for local therapeutic delivery have been developed over the past years. The common rationale of these approaches is: (i) to reduce the risk of drug inactivation before reaching the target tumor cells; (ii) to increase the concentration of active drugs in the tumor micro-environment and their bioavailability; (iii) to reduce toxic effects on normal, non-transformed cells, because of much lower drug doses than those used for systemic chemotherapy. The complex interactions between drugs and the local immune-inflammatory micro-environment modulate the subsequent clinical response. In this perspective, the main interest is currently addressed to the development of local drug delivery platforms, both cell therapy and engineered nanotools. We here propose a review aimed at deep investigation of the biologic effects of the current local therapies for MPM, including cell therapies, and the mechanisms of interaction with the tumor micro-environment.