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Simple Summary: The role of MTH1 in the tumor-related immune responses in mesothelioma remains unknown. We hypothesized that MTH1 regulates immune responses and enhances the efficacy of anti-PD-L1 immunotherapy. We focused on central immune players such as tumor-associated macrophages. MTH1 inhibition enhances M1 macrophage polarization, stimulates CD8 fitness and promotes the activation of DC. Combining anti-PD-L1 immunotherapy with MTH1 inhibitor impairs mesothelioma tumor growth and mesothelioma-associated pleural effusion accumulation more effectively compared to each monotherapy. Background: MTH1 protects tumor cells and their supporting endothelium from lethal DNA damage triggered by oxidative stress in the tumor microenvironment, thus promoting tumor growth. The impact of MTH1 on the tumor-related immune compartment remains unknown. We hypothesized that MTH1 regulates immune fitness and therefore enhances the activity of currently used immunotherapeutic regimens. Methods: Our hypotheses were validated in two syngeneic murine mesothelioma models using the clinically relevant MTH1 inhibitor, karonudib. We also examined the effect of combined MTH1 and PD-L1 blockade in mesothelioma progression, focusing on the main immune players. Results: Karonudib administration enhances M1 macrophage polarization, stimulates CD8 expansion and promotes the activation of DC and T cells. Combined administration of PD-L1 and MTH1 inhibitors impairs mesothelioma tumor growth and mesothelioma-associated pleural effusion accumulation more effectively compared to each monotherapy. Conclusions: Combined MTH1 and PD-L1 inhibition holds promise for the successful clinical management of mesothelioma. [ABSTRACT FROM AUTHOR]

Byline: Konstantinos. Loverdos, Andreas. Fotiadis, Chrysoula. Kontogianni, Marianthi. Iliopoulou, Mina. Gaga In daily clinical practice, radiologists and pulmonologists are faced with incidental radiographic findings of pulmonary nodules. Deciding how to [...]

Although emergency endotracheal intubation and mechanical ventilation (MV) are undoubtedly a life-saving intervention, deciding when and whom to support remains challenging. Common indications include respiratory failure, shock, coma and operative procedures that require analgesia and sedation. Endotracheal intubation is well known for its potential difficulty and mechanical ventilation is associated with complications that may aggravate the critically ill patient. Although MV is used in intensive care units in order to maintain adequate gas exchange and decrease the work of breathing, these goals may be difficult to achieve if there is no proper interaction between patient and ventilator (patient-ventilator asynchrony). Therefore, it is important that clinicians suspect, recognize and resolve appropriately any adverse consequence associated with this intervention. Finally, with the widespread use of mechanical ventilation, ethical challenges arise; patients with terminal illnesses can be kept alive, with little to no prospect of having their underlying condition cured or improved. Of paramount importance is for chronically ill patients to partake in the decision to institute or withhold MV after being appropriately informed for its indications and limitations. [ABSTRACT FROM AUTHOR]

Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers. While we previously identified KRAS mutations as molecular culprits of MPE formation, the underlying mechanism remained unknown. Here, we determine that non-canonical IKKα-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1β. Indeed, IKKα is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-κB signaling. IL-1β fuels addiction of mutant KRAS to IKKα resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1β-mediated NF-κB induction in KRAS-mutant tumor cells, as well as their resulting MPE-competence, can only be blocked by co-inhibition of both KRAS and IKKα, a strategy that overcomes drug resistance to individual treatments. Hence we show that mutant KRAS facilitates IKKα-mediated responsiveness of tumor cells to host IL-1β, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance. [ABSTRACT FROM AUTHOR]

Malignant pleural effusion (MPE) is a common complication of advanced malignancies, particularly lung and breast cancer. The survival time of patients with MPE is often short, with poor quality of life. The pleural space normally contains a thin film of fluid that is regulated by the balance between production from systemic blood vessel filtration and lymphatic absorption. Tumourinduced disturbances of the pleural fluid production and clearance processes result in the development of MPE. Until recently the specific mechanisms underlying pleural fluid accumulation were poorly defined because studies of MPE pathogenesis were limited by a lack of animal models that could reproduce the pathobiology of human MPE. During the past decade, various research groups have established experimental models that mimic human pleural malignancies, including mice models that require either immunocompromised or immunocompetent mice for propagation of human or murine cancer induced-MPE, respectively. The experimental modelling of MPE has provided new insight into the biological behaviour of tumour cells and tumour-host interactions in the pleural cavity, paving the way for improved management of this end-stage condition. [ABSTRACT FROM AUTHOR]

Simple Summary: CSF1/CSF1R signaling mediates tumor-associated macrophages recruitment and M2 polarization. M2 TAMs are dominant immune populations infiltrating mesothelioma tumors. We evaluated the role of CSF1/CSF1R axis blockade in tumor-infiltrating immune subsets. We also examined the effect of combined anti-CSF1R and anti-PDL1 treatment in mesothelioma progression. We show that CSF1R inhibition impedes mesothelioma progression, abrogates infiltration of TAMs, facilitates an M1 anti-tumor phenotype and activates tumor dendritic and CD8+ T cells. We also show that this inhibitor was able to significantly improve the effectiveness of anti-PDL1 immunotherapy. Colony-Stimulating Factor 1 (CSF1)/Colony-Stimulating Factor Receptor 1 (CSF1R) signaling orchestrates tumor-associated macrophage (TAM) recruitment and polarization towards a pro-tumor M2 phenotype, the dominant phenotype of TAMs infiltrating mesothelioma tumors. We hypothesized that CSF1/CSF1R inhibition would halt mesothelioma growth by targeting immunosuppressive M2 macrophages and unleashing efficient T cell responses. We also hypothesized that CSF1/CSF1R blockade would enhance the efficacy of a PDL1 inhibitor which directly activates CD8+ cells. We tested a clinically relevant CSF1R inhibitor (BLZ945) in mesothelioma treatment using syngeneic murine models. We evaluated the role of CSF1/CSF1R axis blockade in tumor-infiltrating immune subsets. We examined the effect of combined anti-CSF1R and anti-PDL1 treatment in mesothelioma progression. CSF1R inhibition impedes mesothelioma progression, abrogates infiltration of TAMs, facilitates an M1 anti-tumor phenotype and activates tumor dendritic and CD8+ T cells. CSF1R inhibition triggers a compensatory PD-1/PDL1 upregulation in tumor and immune cells. Combined CSF1R inhibitor with an anti-PDL1 agent was more effective in retarding mesothelioma growth compared to each monotherapy. In experimental mesotheliomas, CSF1R inhibition abrogates tumor progression by limiting suppressive myeloid populations and enhancing CD8+ cell activation and acts synergistically with anti-PDL1. [ABSTRACT FROM AUTHOR]

Malignant pleural effusion (MPE) is an incurable common manifestation of many malignancies. Its formation is orchestrated by complex interactions among tumor cells, inflammatory cells, and the vasculature. Tumor-associated macrophages present the dominant inflammatory population of MPE, and M2 macrophage numbers account for dismal prognosis. M2 polarization is known to be triggered by CSF1/CSF1 receptor (CSF1R) signaling. We hypothesized that CSF1R+ M2 macrophages favor MPE formation and could be therapeutically targeted to limit MPE. We generated mice with CSF1R-deficient macrophages and induced lung and colon adenocarcinoma-associated MPE. We also examined the therapeutic potential of a clinically relevant CSF1R inhibitor (BLZ945) in lung and colon adenocarcinoma-induced experimental MPE. We showed that CSF1R+ macrophages promoted pleural fluid accumulation by enhancing vascular permeability, destabilizing tumor vessels, and favoring immune suppression. We also showed that CSF1R inhibition limited MPE in vivo by reducing vascular permeability and neoangiogenesis and impeding tumor progression. This was because apart from macrophages, CSF1R signals in cancer-associated fibroblasts leading to macrophage inflammatory protein 2 secretion triggered the manifestation of suppressive and angiogenic properties in macrophages upon CXCR2 paracrine activation. Pharmacological targeting of the CSF1/CSF1R axis can therefore be a vital strategy for limiting MPE.

Background: Community-acquired pleural infection (CAPI) is a growing health problem worldwide. Although most CAPI patients recover with antibiotics and pleural drainage, 20% require surgical intervention. The use of inappropriate antibiotics is a common cause of treatment failure. Awareness of the common causative bacteria along with their patterns of antibiotic resistance is critical in the selection of antibiotics in CAPI-patients. This study aimed to define CAPI bacteriology from the positive pleural fluid cultures, determine effective antibiotic regimens and investigate for associations between clinical features and risk for death or antibiotic-resistance, in order to advocate with more invasive techniques in the optimal timing., Methods: We examined 158 patients with culture positive, CAPI collected both retrospectively (2012-2013) and prospectively (2014-2018). Culture-positive, CAPI patients hospitalized in six tertiary hospitals in Greece were prospectively recruited (N=113). Bacteriological data from retrospectively detected patients were also used (N=45). Logistic regression analysis was performed to identify clinical features related to mortality, presence of certain bacteria and antibiotic resistance., Results: Streptococci, especially the non-pneumococcal ones, were the most common bacteria among the isolates, which were mostly sensitive to commonly used antibiotic combinations. RAPID score (i.e., clinical score for the stratification of mortality risk in patients with pleural infection; parameters: renal, age, purulence, infection source, and dietary factors), diabetes and CRP were independent predictors of mortality while several patient co-morbidities (e.g., diabetes, malignancy, chronic renal failure, etc.) were related to the presence of certain bacteria or antibiotic resistance., Conclusions: The dominance of streptococci among pleural fluid isolates from culture-positive, CAPI patients was demonstrated. Common antibiotic regimens were found highly effective in CAPI treatment. The predictive strength of RAPID score for CAPI mortality was confirmed while additional risk factors for mortality and antibiotic resistance were detected., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-2786). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Oxidative stress and inadequate redox homeostasis is crucial for tumor initiation and progression. MTH1 (NUDT1) enzyme prevents incorporation of oxidized dNTPs by sanitizing the deoxynucleoside triphosphate (dNTP) pool and is therefore vital for the survival of tumor cells. MTH1 inhibition has been found to inhibit the growth of several experimental tumors, but its role in mesothelioma progression remained elusive. Moreover, although MTH1 is nonessential to normal cells, its role in survival of host cells in tumor milieu, especially tumor endothelium, is unclear. We validated a clinically relevant MTH1 inhibitor (Karonudib) in mesothelioma treatment using human xenografts and syngeneic murine models. We show that MTH1 inhibition impedes mesothelioma progression and that inherent tumoral MTH1 levels are associated with a tumor's response. We also identified tumor endothelial cells as selective targets of Karonudib and propose a model of intercellular signaling among tumor cells and bystander tumor endothelium. We finally determined the major biological processes associated with elevated MTH1 gene expression in human mesotheliomas.