State of the Art and New Trends from the Second International StemNet Meeting.

The Second International StemNet (Federation of Stem Cell Research Associations) meeting took place on 18-20 October 2023 in Brescia (Italy), with the support of the University of Brescia and the Zooprophylactic Institute of Lombardy and Emilia Romagna. The program of the meeting was articulated in nine sections: (1) Biomedical Communication in Italy: Critical Aspects; (2) StemNet Next Generation Session; (3) Cell-Free Therapies; (4) Tips and Tricks of Research Valorisation; (5) Stem Cells and Cancer; (6) Stem Cells in Veterinary Applications; (7) Stem Cells in Clinical Applications; (8) Organoids and 3D Systems; (9) induced pluripotent stem cells (iPCS) and Gene Therapy. National and International speakers presented their scientific works, inspiring debates and discussions among the attendees. The participation in the meeting was high, especially because of the young researchers who animated all the sessions and the rich poster session.

Immune Stroma in Lung Cancer and Idiopathic Pulmonary Fibrosis: A Common Biologic Landscape?

Idiopathic pulmonary fibrosis (IPF) identifies a specific entity characterized by chronic, progressive fibrosing interstitial pneumonia of unknown cause, still lacking effective therapies. Growing evidence suggests that the biologic processes occurring in IPF recall those which orchestrate cancer onset and progression and these findings have already been exploited for therapeutic purposes. Notably, the incidence of lung cancer in patients already affected by IPF is significantly higher than expected. Recent advances in the knowledge of the cancer immune microenvironment have allowed a paradigm shift in cancer therapy. From this perspective, recent experimental reports suggest a rationale for immune checkpoint inhibition in IPF. Here, we recapitulate the most recent knowledge on lung cancer immune stroma and how it can be translated into the IPF context, with both diagnostic and therapeutic implications.

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.

The growth of non-solid neoplastic lung nodules is associated with low PD L1 expression, irrespective of sampling technique.

BACKGROUND: Few data are known regarding the molecular features and patterns of growth and presentation which characterize those lung neoplastic lesions presenting as non-solid nodules (NSN). METHODS: We retrospectively reviewed two different cohorts of NSNs detected by CT scan which, after transthoracic fine-needle aspiration (FNA) and core needle biopsy (CNB) received a final diagnosis of malignancy. All the enrolled patients were then addressed to surgical removal of lung cancer nodules or to exclusive radiotherapy. Exhaustive clinical and radiological features were available for each case. RESULTS: In all 62 analysed cases the diagnosis of adenocarcinoma (ADC) was reached. In cytologic samples, EGFR activating mutations were identified in 2 of the 28 cases (7%); no case showed ALK/EML4 or ROS1 translocations. In the histologic samples EGFR activating mutation were found in 4 out of 25 cases (16%). PD-L1 immunostains could be evaluated in 30 cytologic samples, while the remaining 7 did not reach the cellularity threshold for evaluation. TPS was < 1% in 26 cases, > 1% < 50% in 3, and > 50% in 1. All surgical samples showed TPS < 1%. Of the 17 cases that could be evaluated on both samples, 15 were concordantly TPS 0, and 2 showed TPS > 1% < 50 on the biopsy samples. TPS was < 1% in 14 cases, > 1%/< 5% in 4 cases, > 5%/< 50% in 2 cases, > 50% in 1 case. CONCLUSIONS: Overall PD-L1 immunostaining documented the predominance of low/negative TPS, with high concordance in FNA and corresponding surgical samples. It can be hypothesized that lung ADC with NSN pattern and predominant in situ (i.e. lepidic) components represent the first steps in tumor progression, which have not yet triggered immune response, and/or have not accumulated a significant rate of mutations and neoantigen production, or that they belong to the infiltrated-excluded category of tumors. The negative prediction of response to immunomodulating therapy underlines the importance of rapid surgical treatment of these lesions. Notably, cell block cytology seems to fail in detecting EGFR mutations, thus suggesting that this kind of sampling technique should be not adequate in case of DNA direct sequencing.

Radiographic findings in 240 patients with COVID-19 pneumonia: time-dependence after the onset of symptoms.

OBJECTIVE: To analyze the most frequent radiographic features of COVID-19 pneumonia and assess the effectiveness of chest X-ray (CXR) in detecting pulmonary alterations. MATERIALS AND METHODS: CXR of 240 symptomatic patients (70% male, mean age 65 ± 16 years), with SARS-CoV-2 infection confirmed by RT-PCR, was retrospectively evaluated. Patients were clustered in four groups based on the number of days between symptom onset and CXR: group A (0-2 days), 49 patients; group B (3-5), 75 patients; group C (6-9), 85 patients; and group D (> 9), 31 patients. Alteration's type (reticular/ground-glass opacity (GGO)/consolidation) and distribution (bilateral/unilateral, upper/middle/lower fields, peripheral/central) were noted. Statistical significance was tested using chi-square test. RESULTS: Among 240 patients who underwent CXR, 180 (75%) showed alterations (group A, 63.3%; group B, 72%; group C, 81.2%; group D, 83.9%). GGO was observed in 124/180 patients (68.8%), reticular alteration in 113/180 (62.7%), and consolidation in 71/180 (39.4%). Consolidation was significantly less frequent (p < 0.01). Distribution among groups was as follows: reticular alteration (group A, 70.9%; group B, 72.2%; group C, 57.9%; group D, 46.1%), GGO (group A, 67.7%; group B, 62.9%; group C, 71%; group D, 76.9%), and consolidation (group A, 35.5%; group B, 31.4%; group C, 47.8%; group D, 38.5%). Alterations were bilateral in 73.3%. Upper, middle, and lower fields were involved in 36.7%, 79.4%, and 87.8%, respectively. Lesions were peripheral in 49.4%, central in 11.1%, or both in 39.4%. Upper fields and central zones were significantly less involved (p < 0.01). CONCLUSIONS: The most frequent lesions in COVID-19 patients were GGO (intermediate/late phase) and reticular alteration (early phase) while consolidation gradually increased over time. The most frequent distribution was bilateral, peripheral, and with middle/lower predominance. Overall rate of negative CXR was 25%, which progressively decreased over time. KEY POINTS: • The predominant lung changes were GGO and reticular alteration, while consolidation was less frequent. • The typical distribution pattern was bilateral, peripheral, or both peripheral and central and involved predominantly the lower and middle fields. • Chest radiography showed lung abnormalities in 75% of patients with confirmed SARS-CoV-2 infection, range varied from 63.3 to 83.9%, respectively, at 0-2 days and > 9 days from the onset of symptoms.

Lung abscess: the non-conservative management: a narrative review.

Background and Objective: Systemic antibiotics are the best treatment options for lung abscesses. However, up to 37% of lung abscesses do not respond to antibiotics and may require additional interventions. Percutaneous transthoracic tube drainage (PTTD), endoscopic catheter drainage (ECD) and surgical resection are additional options available when first line therapy with systemic antibiotics are unsuccessful. In this narrative review, we summarize all available interventional procedures, techniques, complications, safety, and contraindications. Methods: A literature search was performed using Medline/PubMed from January 1980 to October 2023. Key words: "lung abscess", "pulmonary abscess", "endoscopic drainage", "percutaneous drainage", "tube drainage". Pediatric patients were excluded from this study. Key Content and Findings: PTTD and ECD are fairly safe procedures. Performing PTTD or ECD without delay may shorten the duration of hospital stay. This may lower the burden on health care. Moreover, draining abscesses may relieve discomfort in the clinical symptoms associated with abscesses. The primary factor in choosing ECD over PTTD is the location of the abscess, and the presence of a bronchial airway leading to the abscess for successful ECD. ECD has lower rate of complications and mortality; and similar success rate compared to PTTD. While mortality has been reported with PTTD, ECD appears to be safer according to present data. Conclusions: PTTD and ECD are safe procedures, with low complication rates. ECD has a lower complication rate than PTTD does.

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.

CT and MRI radiomic features of lung cancer (NSCLC): comparison and software consistency.

BACKGROUND: Radiomics is a quantitative approach that allows the extraction of mineable data from medical images. Despite the growing clinical interest, radiomics studies are affected by variability stemming from analysis choices. We aimed to investigate the agreement between two open-source radiomics software for both contrast-enhanced computed tomography (CT) and contrast-enhanced magnetic resonance imaging (MRI) of lung cancers and to preliminarily evaluate the existence of radiomic features stable for both techniques. METHODS: Contrast-enhanced CT and MRI images of 35 patients affected with non-small cell lung cancer (NSCLC) were manually segmented and preprocessed using three different methods. Sixty-six Image Biomarker Standardisation Initiative-compliant features common to the considered platforms, PyRadiomics and LIFEx, were extracted. The correlation among features with the same mathematical definition was analyzed by comparing PyRadiomics and LIFEx (at fixed imaging technique), and MRI with CT results (for the same software). RESULTS: When assessing the agreement between LIFEx and PyRadiomics across the considered resampling, the maximum statistically significant correlations were observed to be 94% for CT features and 95% for MRI ones. When examining the correlation between features extracted from contrast-enhanced CT and MRI using the same software, higher significant correspondences were identified in 11% of features for both software. CONCLUSIONS: Considering NSCLC, (i) for both imaging techniques, LIFEx and PyRadiomics agreed on average for 90% of features, with MRI being more affected by resampling and (ii) CT and MRI contained mostly non-redundant information, but there are shape features and, more importantly, texture features that can be singled out by both techniques. RELEVANCE STATEMENT: Identifying and selecting features that are stable cross-modalities may be one of the strategies to pave the way for radiomics clinical translation. KEY POINTS: • More than 90% of LIFEx and PyRadiomics features contain the same information. • Ten percent of features (shape, texture) are stable among contrast-enhanced CT and MRI. • Software compliance and cross-modalities stability features are impacted by the resampling method.

Bayesian Networks in the Management of Hospital Admissions: A Comparison between Explainable AI and Black Box AI during the Pandemic.

Artificial Intelligence (AI) and Machine Learning (ML) approaches that could learn from large data sources have been identified as useful tools to support clinicians in their decisional process; AI and ML implementations have had a rapid acceleration during the recent COVID-19 pandemic. However, many ML classifiers are "black box" to the final user, since their underlying reasoning process is often obscure. Additionally, the performance of such models suffers from poor generalization ability in the presence of dataset shifts. Here, we present a comparison between an explainable-by-design ("white box") model (Bayesian Network (BN)) versus a black box model (Random Forest), both studied with the aim of supporting clinicians of Policlinico San Matteo University Hospital in Pavia (Italy) during the triage of COVID-19 patients. Our aim is to evaluate whether the BN predictive performances are comparable with those of a widely used but less explainable ML model such as Random Forest and to test the generalization ability of the ML models across different waves of the pandemic.

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.

The Role of Native T1 and T2 Mapping Times in Identifying PD-L1 Expression and the Histological Subtype of NSCLCs.

We investigated the association of T1/T2 mapping values with programmed death-ligand 1 protein (PD-L1) expression in lung cancer and their potential in distinguishing between different histological subtypes of non-small cell lung cancers (NSCLCs). Thirty-five patients diagnosed with stage III NSCLC from April 2021 to December 2022 were included. Conventional MRI sequences were acquired with a 1.5 T system. Mean T1 and T2 mapping values were computed for six manually traced ROIs on different areas of the tumor. Data were analyzed through RStudio. Correlation between T1/T2 mapping values and PD-L1 expression was studied with a Wilcoxon-Mann-Whitney test. A Kruskal-Wallis test with a post-hoc Dunn test was used to study the correlation between T1/T2 mapping values and the histological subtypes: squamocellular carcinoma (SCC), adenocarcinoma (ADK), and poorly differentiated NSCLC (PD). There was no statistically significant correlation between T1/T2 mapping values and PD-L1 expression in NSCLC. We found statistically significant differences in T1 mapping values between ADK and SCC for the periphery ROI (p-value 0.004), the core ROI (p-value 0.01), and the whole tumor ROI (p-value 0.02). No differences were found concerning the PD NSCLCs.

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.

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.

Incidence of Tracheal Stenosis in ICU Hospitalized COVID-19 Patients: Results from a Prospective, Observational, Multicenter Study.

Background: Tracheal stenosis represents a fearsome complication that substantially impairs quality of life. The recent SARS-CoV-2 pandemic increased the number of patients requiring invasive ventilation through prolonged intubation or tracheostomy, increasing the risk of tracheal stenosis. Study design and methods: In this prospective, observational, multicenter study performed in Lombardy (Italy), we have exanimated 281 patients who underwent prolonged intubation (more than 7 days) or tracheostomy for severe COVID-19. Patients underwent CT scan and spirometry 2 months after hospital discharge and a subsequent clinical follow-up after an additional 6 months (overall 8 months of follow-up duration) to detect any tracheal lumen reduction above 1%. The last follow-up evaluation was completed on 31 August 2022. Results: In the study period, 24 patients (8.5%, CI 5.6-12.4) developed tracheal stenosis in a median time of 112 days and within a period of 200 days from intubation. Compared to patients without tracheal stenosis, tracheostomy was performed more frequently in patients that developed stenosis (75% vs 54%, p = 0.034). Tracheostomy and alcohol consumption (1 unit of alcohol per day) increased risk of developing tracheal stenosis of 2.6-fold (p = 0.047; IC 0.99-6.8) and 5.4-fold (p = 0.002; CI 1.9-16), respectively. Conclusions: In a large cohort of patients, the incidence of tracheal stenosis increased during pandemic, probably related to the increased use of prolonged intubation. Patients with histories of prolonged intubation should be monitored for at least 200 days from invasive ventilation in order to detect tracheal stenosis at early stage. Alcohol use and tracheostomy are risk factors for developing tracheal stenosis.

Cancers of unknown primary origin: current perspectives and future therapeutic strategies.

It is widely accepted that systemic neoplastic spread is a late event in tumour progression. However, sometimes, rapidly invasive cancers are diagnosed because of appearance of metastatic lesions in absence of a clearly detectable primary mass. This kind of disease is referred to as cancer of unknown primary (CUP) origin and accounts for 3-5% of all cancer diagnosis. There is poor consensus on the extent of diagnostic and pathologic evaluations required for these enigmatic cases which still lack effective treatment. Although technology to predict the primary tumour site of origin is improving rapidly, the key issue is concerning the biology which drives early occult metastatic spreading. This review provides the state of the art about clinical and therapeutic management of this malignant syndrome; main interest is addressed to the most recent improvements in CUP molecular biology and pathology, which will lead to successful tailored therapeutic options.

Managing Malignant Pleural Mesothelioma in the Age of Personalized Medicine: Where Are We and What Is Still Missing?

Malignant Mesothelioma (MM) is an aggressive neoplasm of the pleural mesothelium, less frequently peritoneal and exceptionally of the vaginal tunic of the testicle and pericardium [...].

Pragmatic Expectancy on Microbiota and Non-Small Cell Lung Cancer: A Narrative Review.

It is well known that lung cancer relies on a number of genes aberrantly expressed because of somatic lesions. Indeed, the lungs, based on their anatomical features, are organs at a high risk of development of extremely heterogeneous tumors due to the exposure to several environmental toxic agents. In this context, the microbiome identifies the whole assemblage of microorganisms present in the lungs, as well as in distant organs, together with their structural elements and metabolites, which actively interact with normal and transformed cells. A relevant amount of data suggest that the microbiota plays a role not only in cancer disease predisposition and risk but also in its initiation and progression, with an impact on patients' prognosis. Here, we discuss the mechanistic insights of the complex interaction between lung cancer and microbiota as a relevant component of the microenvironment, mainly focusing on novel diagnostic and therapeutic objectives.

Idiopathic pulmonary fibrosis and lung cancer: targeting the complexity of the pharmacological interconnection.

INTRODUCTION: Many data already suggested that cancer and IPF are underlined by a number of common pathogenic biologic pathways. However, fewer data regards the interconnections, in terms of synergy or increased toxicities, of drugs used in cancer and IPF. Particularly, how the specific therapy influences the concurrent condition and prognostic factors of response in patients with both lung cancer and IPF are far to be clarified. Similarly, identification of features of IPF patients with higher risk of developing pulmonary adverse events when treated with chemotherapy, immune checkpoint inhibitors, TKIs, or radiotherapy is of primary importance in clinical practice. AREAS COVERED: We will discuss the scientific rationale, based on the extensive analysis of literature data, by consulting several databases for combining anticancer and antifibrotic treatments and for the design of novel therapeutic strategies. The role of immunotherapy in cancer aroused in IPF context will be discussed with specific interested, based on the continuously increasing role of immune checkpoint inhibition against lung tumors. EXPERT OPINION: This work will help to improve knowledge, based on a multidisciplinary perspective, on IPF and cancer patients, which identify an unmet clinical need. A better management during each phase of disease progression will require the design innovative trials and the development of new drugs and molecules both in the oncologic and respiratory medicine pipeline.