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.
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.
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 KRAS G12D 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 KRAS G12D 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.
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.
Background: Pleural effusions (PE) most commonly signal either pleural-disseminated infection or cancer. Simple and rapid diagnostic markers of pleural malignancy at patients' admission that streamline diagnostic, treatment, and research efforts remain unidentified. The objective of the study was to identify and validate predictors of malignancy of PE at admission. Methods: A prospective cohort of 360 patients with PE from different etiologies was recruited between 2013 and 2017 (ClinicalTrials.Gov NCT03319472). Data collected within 4 hours of admission included history, chest X-ray, and blood/pleural fluid cell counts and biochemistry. Binary regression and receiver-operator analyses using malignancy as the target were used to develop the malignancy of pleural effusion in the emergency department (MAPED) score. MAPED was retrospectively validated in a separate cohort (n = 241). Results: Five variables emerged from binary regression as independent predictors of malignant PE. Receiver-operator curves determined optimal cut-offs and repeat binary regression of thresholded variables identified hazard ratios for development of the weighted MAPED score. Age > 55 years and X-ray PE size > 50% of lung field (2 hazard points each), unilateral effusion, pleural fluid neutrophils < 10%, and PF protein > 3.5 g/dL (1 hazard point each) were used to compile MAPED (scoring 0-7 points), which yielded an area under curve of 0.824 (P < 10-23) in the derivation cohort and 0.677 (P = 2 x 10-6) in the validation cohort. Conclusion: MAPED can identify malignant PE within 4 hours of admission with 75% accuracy and can be a useful clinical and research tool.
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)(2015)(2016)(2017)(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.
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