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.

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.

COVID-19 in patients with pulmonary alveolar proteinosis: a European multicentre study.

Adult PAP patients experience similar #COVID19 rates to the general population, and high rates of hospitalisation and deaths, underscoring their vulnerability and the need for measures to prevent infection. The impact of iGM-CSF must be considered. https://bit.ly/3M0wKnZ.

A mid-term follow-up with a lung ultrasonographic score correlates with the severity of COVID-19 acute phase.

Lung ultrasound (LUS) has rapidly emerged in COVID-19 diagnosis and for the follow-up during the acute phase. LUS is not yet used routinely in lung damage follow-up after COVID-19 infection. We investigated the correlation between LUS score, and clinical and laboratory parameters of severity of SARS-COV-2 damage during hospitalization and at follow-up visit. Observational retrospective study including all the patients discharged from the COVID-19 wards, who attended the post-COVID outpatient clinic of the IRCCS Policlinico San Matteo in April-June 2020. 115 patients were enrolled. Follow-up visits with LUS score measurements were at a median of 38 days (IQR 28-48) after discharge. LUS scores were associated with the length of hospitalization (p < 0.001), patients' age (p = 0.036), use of non-invasive ventilation (CPAP p < 0.001 or HFNC p = 0.018), administration of corticosteroids therapy (p = 0.030), and laboratory parameters during the acute phase (WBC p < 0.001, LDH p < 0.001, CRP p < 0.001, D-dimer p = 0.008, IL-6 p = 0.045), and inversely correlated with lymphocyte count (p = 0.007). We found correlation between LUS score and both LDH (p = 0.001) and the antibody anti-SARS-CoV-2 titers (p value = 0.008). Most of these finding were confirmed by dichothomizing the LUS score (≤ 9 or > 9 points). We found a significantly higher LUS score at the follow-up in the patients with persistent dyspnea (7.00, IQR 3.00-11.00) when compared to eupnoeic patients (3.00, IQR 0-7.00 p < 0.001). LUS score at follow-up visit correlates with more severe lung disease. These findings support the hypothesis that ultrasound could be a valid tool in the follow-up medium-term COVID-19 lung damage.

Mid-term follow-up chest CT findings in recovered COVID-19 patients with residual symptoms.

OBJECTIVES: More than a year has passed since the initial outbreak of SARS-CoV-2, which caused many hospitalizations worldwide due to COVID-19 pneumonia and its complications. However, there is still a lack of information detailing short- and long-term outcomes of previously hospitalized patients. The purpose of this study is to analyze the most frequent lung CT findings in recovered COVID-19 patients at mid-term follow-ups. METHODS: A total of 407 consecutive COVID-19 patients who were admitted to the Fondazione IRCCS Policlinico San Matteo, Pavia and discharged between February 27, 2020, and June 26, 2020 were recruited into this study. Out of these patients, a subset of 108 patients who presented with residual asthenia and dyspnea at discharge, altered spirometric data, positive lung ultrasound and positive chest X-ray was subsequently selected, and was scheduled to undergo a mid-term chest CT study, which was evaluated for specific lung alterations and morphological patterns. RESULTS: The most frequently observed lung CT alterations, in order of frequency, were ground-glass opacities (81%), linear opacities (74%), bronchiolectases (64.81%), and reticular opacities (63.88%). The most common morphological pattern was the non-specific interstitial pneumonia pattern (63.88%). Features consistent with pulmonary fibrosis were observed in 32 patients (29.62%). CONCLUSIONS: Our work showed that recovered COVID-19 patients who were hospitalized and who exhibited residual symptoms after discharge had a slow radiological recovery with persistent residual lung alterations. ADVANCES IN KNOWLEDGE: This slow recovery process should be kept in mind when determining the follow-up phases in order to improve the long-term management of patients affected by COVID-19.

The Plastic Interplay between Lung Regeneration Phenomena and Fibrotic Evolution: Current Challenges and Novel Therapeutic Perspectives.

Interstitial lung diseases (ILDs) are a heterogeneous group of pulmonary disorders characterized by variable degrees of inflammation, interstitial thickening, and fibrosis leading to distortion of the pulmonary architecture and gas exchange impairment. Among them, idiopathic pulmonary fibrosis (IPF) displays the worst prognosis. The only therapeutic options consist of the two antifibrotic drugs, pirfenidone and nintedanib, which limit fibrosis progression but do not reverse the lung damage. The shift of the pathogenetic paradigm from inflammatory disease to epithelium-derived disease has definitively established the primary role of type II alveolar cells, which lose their epithelial phenotype and acquire a mesenchymal phenotype with production of collagen and extracellular matrix (EMC) deposition. Some predisposing environmental and genetic factors (e.g., smoke, pollution, gastroesophageal reflux, variants of telomere and surfactant genes) leading to accelerated senescence set a pro-fibrogentic microenvironment and contribute to the loss of regenerative properties of type II epithelial cells in response to pathogenic noxae. This review provides a complete overview of the different pathogenetic mechanisms leading to the development of IPF. Then, we summarize the currently approved therapies and the main clinical trials ongoing. Finally, we explore the potentialities offered by agents not only interfering with the processes of fibrosis but also restoring the physiological properties of alveolar regeneration, with a particular focus on potentialities and concerns about cell therapies based on mesenchymal stem cells (MSCs), whose anti-inflammatory and immunomodulant properties have been exploited in other fibrotic diseases, such as graft versus host disease (GVHD) and COVID-19-related ARDS.

A Proof-of-Concept Analysis of Plasma-Derived Exosomal microRNAs in Interstitial Pulmonary Fibrosis Secondary to Antisynthetase Syndrome.

Antisynthetase syndrome (ASSD) is an autoimmune disease characterized by the positivity of autoantibodies against different aminoacyl transfer RNA (tRNA) synthetases. Morbidity and mortality of this disease are highly affected by interstitial lung disease (ILD) which is present in about 80% of patients. In this study, we investigated possible differences in 84 immune-related circulating miRNAs between ASSD patients with and without ILD; we enrolled 15 ASSD patients, 11 with ILD (ILD+) and 4 without ILD (ILD-), and 5 patients with idiopathic pulmonary fibrosis (IPF) as an additional control group. All patients were at disease onset and not on therapy at the time of inclusion. Differentially expressed miRNAs were identified in plasma-derived exosomes, using an miRNA PCR array (MIHS-111ZG, Qiagen, Hilden, Germany); miR-30a-5p and miR-29c-3p were upregulated in ASSD-ILD patients compared to patients without lung involvement (adjusted p-value < 0.05). IPF patients showed higher miR-29c-3p expression levels with respect to both ASSD and ASSD-ILD (p = 0.0005), whereas levels of miR-30a-5p were not different. miR-29c-3p and miR-30a-5p are overexpressed in ASSD-ILD+ patients compared with ILD−. These miRNAs are involved in the regulation of inflammation and fibrosis through their action on NF-κB and TGF-ß1. Although the mechanistic role of these miRNAs in ASSD-ILD development has to be elucidated, we suggest that their exosome levels could be useful in identifying patients at risk of ILD.

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.

Electrophysiological evidence of subclinical trigeminal dysfunction in patients with COVID-19 and smell impairment: A pilot study.

Background: Smell and taste disturbances are among the most frequent neurological symptoms in patients with COVID-19. A concomitant impairment of the trigeminal nerve has been suggested in subjects with olfactory dysfunction, although it has not been confirmed with objective measurement techniques. In this study, we explored the trigeminal function and its correlations with clinical features in COVID-19 patients with impaired smell perception using electrophysiological testing. Methods: We enrolled 16 consecutive patients with mild COVID-19 and smell impairment and 14 healthy controls (HCs). Olfactory and gustatory symptoms were assessed with self-reported questionnaires. Electrophysiological evaluation of the masseter inhibitory reflex (MIR) and blink reflex (BR) was carried out to test the trigeminal function and its connections within the brainstem. Results: Masseter inhibitory reflex (MIR) analysis revealed higher latency of ipsilateral and contralateral early silent period in patients when compared with HCs. No significant differences between groups were detected as regards the duration of the early and late silent period. However, several patients showed a prolonged duration of the early silent period. BR evaluation disclosed only an increased amplitude of early components in patients. Conclusions: Patients with COVID-19 and smell impairment show a subclinical trigeminal nerve impairment. Trigeminal alterations mainly involve the oligosynaptic pathway, as a result of either direct viral damage or secondary neuroinflammation of the peripheral trigeminal fibers, whereas the polysynaptic ponto-medullary circuits seem to be spared. The prolonged duration of the early silent period and the increased amplitude of early BR response might reflect a compensatory upregulation of the trigeminal function as a consequence of the olfactory dysfunction.

Sarcopenia in idiopathic pulmonary fibrosis: a prospective study exploring prevalence, associated factors and diagnostic approach.

BACKGROUND: Sarcopenia gained importance in the evaluation of patients with chronic respiratory diseases, including idiopathic pulmonary fibrosis (IPF), since it may impact negatively on clinical outcomes. AIM: Aim of this study is to evaluate the prevalence and factors associated with sarcopenia, defined according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) 2019 definition, and to evaluate the prevalence of the single criteria that define the EWGSOP2 definition (muscle strength, muscle quantity and physical performance), in a cohort of consecutive patients with IPF prospectively followed up in 9 hospitals in Northern Italy between December 2018 and May 2021. METHODS: Enrolled patients underwent an extensive pulmonary and nutritional assessment, including bioelectrical impedance analysis, dynamometry and 4-m gait speed test, both at IPF diagnosis and at 6-month follow-up. RESULTS: Out of the 83 patients (81% males, mean age 72.5 years) with IPF at disease diagnosis enrolled in the study, 19 (22.9%) showed sarcopenia, including 2 (2.4%) with severe sarcopenia, 5 (6.0%) with confirmed sarcopenia and 12 (14.5%) with probable sarcopenia. Sarcopenia was associated with a significantly higher severity of the disease and sedentary lifestyle, while no differences were observed in regards to body mass index, history of weight loss and comorbidities between patients with and without sarcopenia. Out of the 64 patients without sarcopenia at baseline, 16 cases showed alteration of muscle quantity and/or physical performance. In the 51 patients with complete data at 6-month follow-up, there were no cases of severe sarcopenia, 1 case (2.0%) showed confirmed sarcopenia, while the prevalence of probable sarcopenia was 19.6% (10 cases). No differences in regards to antifibrotic treatment received and onset of gastrointestinal side effects were observed between patients with and without sarcopenia at follow-up. CONCLUSIONS: The prevalence of sarcopenia in patients with IPF both at diagnosis and at 6-month follow-up was low but not negligible and was associated with higher severity of the disease and sedentary lifestyle. In IPF patients, a comprehensive diagnostic work-up including all the criteria defining the EWGSOP2 definition might be more useful than a series testing for prompt recognition of nutritional and physical performance abnormalities.

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.

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.

Liposomes Loaded with Everolimus and Coated with Hyaluronic Acid: A Promising Approach for Lung Fibrosis.

Chronic lung allograft dysfunction (CLAD) and interstitial lung disease associated with collagen tissue diseases (CTD-ILD) are two end-stage lung disorders in which different chronic triggers induce activation of myo-/fibroblasts (LFs). Everolimus, an mTOR inhibitor, can be adopted as a potential strategy for CLAD and CTD-ILD, however it exerts important side effects. This study aims to exploit nanomedicine to reduce everolimus side effects encapsulating it inside liposomes targeted against LFs, expressing a high rate of CD44. PEGylated liposomes were modified with high molecular weight hyaluronic acid and loaded with everolimus (PEG-LIP(ev)-HA400kDa). Liposomes were tested by in vitro experiments using LFs derived from broncholveolar lavage (BAL) of patients affected by CLAD and CTD-ILD, and on alveolar macrophages (AM) and lymphocytes isolated, respectively, from BAL and peripheral blood. PEG-LIP-HA400kDa demonstrated to be specific for LFs, but not for CD44-negative cells, and after loading everolimus, PEG-LIP(ev)-HA400kDa were able to arrest cell cycle arrest and to decrease phospho-mTOR level. PEG-LIP(ev)-HA400kDa showed anti-inflammatory effect on immune cells. This study opens the possibility to use everolimus in lung fibrotic diseases, demonstrating that our lipids-based vehicles can vehicle everolimus inside cells exerting the same drug molecular effect, not only in LFs, but also in immune cells.

The Evolving Landscape of the Molecular Epidemiology of Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural lining of the lungs. It has a strong association with exposure to biopersistent fibers, mainly asbestos (80% of cases) and-in specific geographic regions-erionite, zeolites, ophiolites, and fluoro-edenite. Individuals with a chronic exposure to asbestos generally have a long latency with no or few symptoms. Then, when patients do become symptomatic, they present with advanced disease and a worse overall survival (about 13/15 months). The fibers from industrial production not only pose a substantial risk to workers, but also to their relatives and to the surrounding community. Modern targeted therapies that have shown benefit in other human tumors have thus far failed in MPM. Overall, MPM has been listed as orphan disease by the European Union. However, molecular high-throughput profiling is currently unveiling novel biomarkers and actionable targets. We here discuss the natural evolution, mainly focusing on the novel concept of molecular epidemiology. The application of innovative endpoints, quantification of genetic damages, and definition of genetic susceptibility are reviewed, with the ultimate goal to point out new tools for screening of exposed subject and for designing more efficient diagnostic and therapeutic strategies.

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.

Broncho-alveolar inflammation in COVID-19 patients: a correlation with clinical outcome.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19. METHODS: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels. RESULTS: ICU patients showed a marked increase in neutrophils (1.24 × 105 ml- 1, 0.85-2.07), lower lymphocyte (0.97 × 105 ml- 1, 0.024-0.34) and macrophages fractions (0.43 × 105 ml- 1, 0.34-1.62) compared to IMW patients (0.095 × 105 ml- 1, 0.05-0.73; 0.47 × 105 ml- 1, 0.28-1.01 and 2.14 × 105 ml- 1, 1.17-3.01, respectively) (p < 0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p < 0.01, IL8 p < 0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p < 0.1) or antivirals (p < 0.05). CONCLUSIONS: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.

From Interconnection between Genes and Microenvironment to Novel Immunotherapeutic Approaches in Upper Gastro-Intestinal Cancers-A Multidisciplinary Perspective.

Despite the progress during the last decade, patients with advanced gastric and esophageal cancers still have poor prognosis. Finding optimal therapeutic strategies represents an unmet need in this field. Several prognostic and predictive factors have been evaluated and may guide clinicians in choosing a tailored treatment. Data from large studies investigating the role of immunotherapy in gastrointestinal cancers are promising but further investigations are necessary to better select those patients who can mostly benefit from these novel therapies. This review will focus on the treatment of metastatic esophageal and gastric cancer. We will review the standard of care and the role of novel therapies such as immunotherapies and CAR-T. Moreover, we will focus on the analysis of potential predictive biomarkers such as Modify as: Microsatellite Instability (MSI) and PD-L1, which may lead to treatment personalization and improved treatment outcomes. A multidisciplinary point of view is mandatory to generate an integrated approach to properly exploit these novel antiproliferative agents.