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Background: Lung cancer is one of the tumor types with highest incidence of thromboembolic events (TE), especially adenocarcinoma subtype. ROS1 rearrangements confer higher risk of TE. Non-bacterial thrombotic endocarditis (NBTE) is a rare event, frequently diagnosed on autopsy. Clinical suspicion is key to reach the diagnosis and start early treatment of the underlying cause and anticoagulation in order to improve patients' outcomes. Case Description: Here we present two cases of NBTE in patients with ROS1-rearranged lung cancer with different clinical debuts. A 42-year-old woman presented initial tetraplegia and impaired level of consciousness, and the other patient, a 54-year-old man, was diagnosed of stroke with sensitive loss of left body. Both were diagnosed of NBTE, confirmed by the finding of cardiac vegetation on echocardiogram and no microorganisms found on blood cultures. Both responded well to targeted therapy with lorlatinib and crizotinib and anticoagulation with heparin. Conclusions: NBTE is an infrequent disease which can cause severe neurological symptoms that impair quality of life, performance status and survival. Early clinical suspicion in patients with higher risk of TEs such as patients with rearrangements of ROS1 gene is of essence. Adequate management of underlying disease and anticoagulation may impact in the recovery of symptoms.
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INTRODUCTION: Neoadjuvant and adjuvant immune checkpoint blockade (ICB) have recently become standard of care in resectable non-small cell lung cancer (NSCLC). Yet, biomarkers that inform patients who benefit from this approach remain largely unknown. Here, we interrogated the tumor immune microenvironment (TIME) in early-stage NSCLC patients that underwent up-front surgery. METHODS: A total of 185 treatment-naïve patients with early-stage NSCLC, that underwent up-front surgical treatment between 2006 and 2018 at Hospital del Mar were included. 124 lung adenocarcinomas (LUADs), and 61 squamous cell carcinoma (LUSCs) were included in a tissue microarray. Immunohistochemistry for CD3, CD4, CD8, CD68, CD80, CD103, FOXP3, PD-1, PD-L1, PD-L2 and HLA class II were evaluated by digital image analysis (QuPath software). TIME was categorized into four groups using PD-L1 expression in tumor cells (<1 % or ≥1 %) and tumor resident memory (CD103+) immune cells (using the median as cut-off). We explored the association between different TIME dimensions and patient's clinicopathological features and outcomes. RESULTS: We found increased levels of T cell markers (CD3+, CD4+, CD8+ cells), functional immune markers (FOXP3+ cells) as well as, higher HLA-II tumor membrane expression in LUADs compared to LUSCs (p < 0.05 for all). In contrast, LUSCs displayed higher percentage of intratumor macrophages (CD68+ cells) as well as, higher PD-L1 and PD-L2 tumor membrane expression (p < 0.05 for all). Unsupervised analysis revealed three different tumor subsets characterized by membrane tumor expression of PD-L1, PD-L2 and HLA-class II. Enrichment of T cells (CD3+, CD8+ cells), regulatory T cells (FOXP3+ cells) and macrophages (CD68+ cells) was observed in the CD103+/PD-L1+ group (p < 0.05 for all). Multivariate analysis showed that infiltration by CD103+ immune cells was associated with improved OS (p = 0.009). CONCLUSIONS: TIME analysis in resected NSCLC highlighted differences by histology, PD-L1 expression and molecular subgroups. Biomarker studies using IHC might aid to individually tailor adjuvant treatment in early-stage NSCLC.
