Patients with resectable lung cancer were assigned to neoadjuvant pembrolizumab or placebo plus chemotherapy and adjuvant pembrolizumab or placebo. Two-year event-free survival was 62.4% with ...pembrolizumab and 40.6% with placebo.
Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. ...In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.
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•NETs in tissue and blood are markers of poor prognosis in numerous solid cancers.•Tumor-derived factors and microbial infections induce NETosis.•NETs promote tumor growth and ...progression.•NETs enhance metastasis by tumor cell mobility, adhesion and dormant cell awakening.•NETs are promising therapeutic targets in cancer.
Neutrophil extracellular traps (NET) are the extracellular release of decondensed chromatin and granules known for their role in host defense against foreign pathogens. However, a novel and predominantly pro-tumorigenic role of NETs in cancer is emerging. Tumors induce NET formation through the secretion of an array of tumor and infection-derived factors. NET deposition favors tumor cell proliferation, immunosuppression and cancer-associated thrombosis. Moreover, NETs enhance metastasis by contributing to epithelial-to-mesenchymal transition. A mesenchymal transition in tumor cells potentiates their migratory and invasive abilities. Circulating NETs capture circulating tumor cells and increase vascular permeability, thereby promoting tumor cell intravasation and establishment of micrometastasis. NETs present in pre-metastatic niches serve as cytokines in the recruitment of tumor cells through CCDC25. Through NET-mediated laminin remodelling, dormant cells are reawakened favoring metastatic growth. Moreover, post-operative infection results in high NET deposition and exacerbates post-surgical cancer progression and recurrence. Anti-NET therapies are in use for autoimmune diseases and are now being investigated in the context of cancer. The hope is that anti-NET therapies may synergize with existing anti-cancer therapy to increase rate of response given their multi-faceted interplay in several domains of cancer progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Single-cell technologies have revealed the complexity of the tumour immune microenvironment with unparalleled resolution
. Most clinical strategies rely on histopathological stratification of tumour ...subtypes, yet the spatial context of single-cell phenotypes within these stratified subgroups is poorly understood. Here we apply imaging mass cytometry to characterize the tumour and immunological landscape of samples from 416 patients with lung adenocarcinoma across five histological patterns. We resolve more than 1.6 million cells, enabling spatial analysis of immune lineages and activation states with distinct clinical correlates, including survival. Using deep learning, we can predict with high accuracy those patients who will progress after surgery using a single 1-mm
tumour core, which could be informative for clinical management following surgical resection. Our dataset represents a valuable resource for the non-small cell lung cancer research community and exemplifies the utility of spatial resolution within single-cell analyses. This study also highlights how artificial intelligence can improve our understanding of microenvironmental features that underlie cancer progression and may influence future clinical practice.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Despite advances in cancer treatment, metastasis remains today the main cause of cancer death. Local control through complete surgical resection of the primary tumor continues to be a key principle ...in cancer treatment. However, surgical interventions themselves lead to adverse oncologic outcomes and are associated with significantly increased rates of metastasis. Neutrophils through release of neutrophil extracellular traps (NETs) in response to infections were shown to be able to capture circulating cancer cells, and in doing so, support the development of metastatic disease. To be able to intervene on this process, understanding the exact molecular nature of these mechanisms is crucial. We therefore hypothesize and demonstrate that beta1-integrin is an important factor mediating the interactions between circulating tumor cells and NETs. We show that beta1-integrin expression on both cancer cells and NETs is important for the adhesion of circulating tumor cells to NETs both in vitro and in vivo. Using a murine model of intra-abdominal sepsis to mimic the postoperative inflammatory environment, we show that beta1-integrin expression is upregulated in the context of inflammation in vivo. Ultimately, we show that this increased early cancer cell adhesion to NETs in vivo and this effect is abrogated when mice are administered DNAse 1. Our data therefore sheds light on the first molecular mechanism by which NETs can trap circulating tumor cells (CTCs), broadening our understanding of this process. What's new? Surgical removal of tumors can increase inflammation. When neutrophils respond to inflammatory signals, they sometimes form web-like projections called "neutrophil extracellular traps" (NETs). These NETs are able to enhance metastasis, because they bind circulating tumor cells (CTCs) and cause them to adhere to distant organs. In our study, the authors found that beta1-integrins play an essential role in the interaction between NETs and tumor cells. Then, they found that hepatic adhesion of CTCs in mice could be significantly reduced by blocking beta1-integrins. These results suggest that targeting beta1-integrins may help to reduce metastases.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The suboptimal survival outcomes for patients with operable lung cancer continue for our patients and represent a clear unmet need.2 The US Food and Drug Administration's guidelines recommend overall ...survival, progression-free survival or disease-free survival, and objective tumour response rates for the approval of drugs in the setting of non-small-cell lung cancer (NSCLC). Even disease-free survival is increasing in complexity as a measure of efficacy, with what constitutes being disease free rapidly evolving through blood-based biomarkers of minimal or molecular residual disease.3 In response to these challenges, most neoadjuvant clinical trials for operable NSCLC were developed with pathological response as an independent or coprimary endpoint.4,5 As of July 14, 2021, ten phase 3 trials for NSCLC in the neoadjuvant setting are ongoing, of which six include pathological complete or major response as a coprimary or independent primary endpoint. Beyond the use of pathological complete response to predict overall survival, some might argue that surgical resection might not be necessary because no viable tumour is left, which was one of the arguments for definitive chemoradiotherapy without surgery in locally advanced lung cancer.7 Although surgical resection remains a key step to assure locoregional control, determining whether pathological complete response is truly complete will be key to the design of future trials that could obviate patient exposure to the risks and function-depleting effects of local therapy, whether via surgery, radiotherapy, or other novel local therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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