Medical treatment of pleural infection: antibiotic duration and corticosteroid usefulness.

The data about the optimal duration of antibiotics and the usefulness of corticosteroids in the management of parapneumonic effusion and pleural infection are scarce. Two randomised controlled trials evaluating short antibiotic courses (ODAPE and SLIM) and another trial assessing the benefit from corticosteroid use (STOPPE) in this setting were recently published. The aim of this journal club is to present these trials and discuss their significance and limitations. ODAPE compared the efficacy and safety of a short (2 weeks) versus an extended (3 weeks) course of amoxicillin-clavulanate in community-acquired complicated parapneumonic effusions, while SLIM compared the efficacy and safety of short (14-21 days) versus longer (28-42 days) antibiotic courses in patients with community- or hospital-acquired pleural infection. STOPPE assessed the benefit from dexamethasone use in patients with community-acquired pneumonia and concomitant pleural effusion. Both ODAPE and SLIM found that shorter antibiotic courses produce less adverse events while being equally efficacious to the longer courses in a subgroup of patients, such as those with pleural infection that is stabilised with only medical treatment and does not require surgery. In contrast, STOPPE found no benefit from the use of dexamethasone in unselected patients with pneumonia and pleural effusion. Due to the significant limitations of these trials, further studies are required to confirm these findings. Commentary on: Hassan M, et al. The Short versus Long Antibiotic Course for Pleural Infection Management (SLIM) randomised controlled open-label trial. ERJ Open Res 2023; 9: 00635-2022.Porcel JM, et al. Two vs. three weeks of treatment with amoxicillin-clavulanate for stabilized community-acquired complicated parapneumonic effusions. A preliminary non-inferiority, double-blind, randomized, controlled trial. Pleura Peritoneum 2020; 5: 20190027.Fitzgerald DB, et al. Steroid Therapy and Outcome of Parapneumonic Pleural Effusions (STOPPE): a pilot randomized clinical trial. Am J Respir Crit Care Med 2022; 205: 1093-1101.

MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma.

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.

CSF1/CSF1R signaling mediates malignant pleural effusion formation.

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.

KRAS signaling in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.

CSF1/CSF1R Axis Blockade Limits Mesothelioma and Enhances Efficiency 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.

Bacteriology, antibiotic resistance and risk stratification of patients with culture-positive, community-acquired pleural infection.

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.

MTH1 favors mesothelioma progression and mediates paracrine rescue of bystander endothelium from oxidative damage.

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.

Lung nodules: A comprehensive review on current approach and management.

In daily clinical practice, radiologists and pulmonologists are faced with incidental radiographic findings of pulmonary nodules. Deciding how to manage these findings is very important as many of them may be benign and require no further action, but others may represent early disease and importantly early-stage lung cancer and require prompt diagnosis and definitive treatment. As the diagnosis of pulmonary nodules includes invasive procedures which can be relatively minimal, such as bronchoscopy or transthoracic aspiration or biopsy, but also more invasive procedures such as thoracic surgical biopsies, and as these procedures are linked to anxiety and to cost, it is important to have clearly defined algorithms for the description, management, and follow-up of these nodules. Clear algorithms for the imaging protocols and the management of positive findings should also exist in lung cancer screening programs, which are already established in the USA and which will hopefully be established worldwide. This article reviews current knowledge on nodule definition, diagnostic evaluation, and management based on literature data and mainly recent guidelines.

Mediastinal staging by videomediastinoscopy in clinical N1 non-small cell lung cancer.

VAM(LA) has adequate sensitivity to be considered as the approach of choice for preoperative mediastinal staging in the subgroup of early-stage operable NSCLC patients http://ow.ly/42Wn30m78Zw.

Myeloid-derived interleukin-1ß drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion.

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-1ß. Indeed, IKKα is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-κB signaling. IL-1ß fuels addiction of mutant KRAS to IKKα resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1ß-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-1ß, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance.

Asbestos and the lung: highlights of a detrimental relationship.

Novel aspects of the pathogenesis of asbestos-related diseases are still coming to light http://ow.ly/EPDa30e8JqK.