Non-bacterial thrombotic endocarditis in ROS1-rearranged lung cancer: a report of two cases
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PROVIDER: S-EPMC10891407 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Non-bacterial thrombotic endocarditis is a rare condition characterized by the formation of thrombotic vegetations on heart valve leaflets, leading to valvular dysfunction, heart failure and thromboembolic events. It is known to be associated with other diseases and some cases remain undiagnosed or can be diagnosed in the postmortem analysis. Surgical excision of the mass may be necessary to prevent further embolic events and other complications. In this article, we report a young patient with non-bacterial thrombotic endocarditis, whose medical history was significant for primary hypoparathyroidism and a positive family history of coagulation disorders.
| S-EPMC11538929 | biostudies-literature
Project description:BackgroundNon-bacterial thrombotic endocarditis (NBTE) is a rare condition, usually observed in association with malignancy, lupus erythematosus, or antiphospholipid syndrome. Diagnosis of NBTE remains a challenge as patients are often asymptomatic up to their first thromboembolic event. While there is no randomized data available for the guidance of treatment in NBTE, effective anticoagulation remains the main focus in the management of affected patients.Case summaryA 44-year-old female patient without a significant medical history presented to the emergency department with a new numbness of her right hand. Magnetic resonance imaging scans facilitated the diagnosis of supratentorial stroke. Within the next 3 months, the patient had multiple thromboembolic events, including multiple strokes, pulmonary embolism, and renal/splenic infarction. Echocardiographic examination revealed large, transient vegetations of the aortic valve with concomitant aortic regurgitation. In addition, an incidental, pulmonary non-small-cell adenocarcinoma was found during the diagnostic work-up. Infective endocarditis was excluded by several negative blood cultures and missing signs of infection. Hence, the diagnosis of NBTE secondary to malignancy was made.DiscussionWe present a rare case of NBTE in the context of pulmonary adenocarcinoma. The adequate treatment of malignancy and effective anticoagulation are the main treatment options.
| S-EPMC7047059 | biostudies-literature
Project description:BackgroundChromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET.MethodsWe enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays.ResultsThe objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.ConclusionsIn this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
| S-EPMC4264527 | biostudies-literature
Project description:Behçet disease (BD) is a form of widespread vasculitis that involves both arteries and veins. Cardiac involvement in BD is exceedingly rare and can present as a form of non-bacterial- thrombotic-endocarditis (NBTE). A 54-year-old man with Behçet disease was admitted to our hospital after presenting with abdominal pain and fever. He had been recently discharged from a hospital in another country with the diagnosis of infective endocarditis of the mitral valve and mycotic embolization to the superior mesenteric artery. At presentation, oral and genital ulcers were present, raising the suspicion of a flare of BD. Transesophageal echocardiography showed a small vegetation on the anterior leaflet of the mitral valve. Blood cultures results were negative. Computed tomography of the abdomen showed extensive inferior vena cava thrombosis. The aneurysm and thrombotic phenomena were interpreted as related to BD: the vegetation on the mitral valve was diagnosed as NBTE of which BD is a recognized cause. With corticosteroid and anticoagulant therapy, the patient's symptoms steadily improved. NBTE is a rare manifestation of BD; differential diagnosis with infective endocarditis can be challenging and should be focused on identifying predisposing conditions. The mainstay of treatment in NBTE is medical therapy with anticoagulation and treatment of the underlying disease. <Learning objective: Cardiac involvement in the setting of Behçet Disease (BD) is rare and several different manifestations are described (intracardiac thrombus, non-infective endocarditis, myocarditis, pericarditis, endomyocardial fibrosis, coronary arteritis). Non-bacterial thrombotic endocarditis (NBTE) is also a rare finding which can happen in the setting of BD. Its prevalence is unknown and evidence is derived only from scarce case reports.The role of BD as a potential cause of NBTE must be acknowledged to avoid potential misdiagnosis.>.
| S-EPMC8758554 | biostudies-literature
Project description:C-ros oncogene 1 receptor tyrosine kinase (ROS1) rearrangement has been detected in patients with advanced non-small cell lung cancer (NSCLC). Although ROS1 tyrosine kinase inhibitors (TKIs) provide a survival benefit for patients with ROS1-rearranged advanced NSCLC, subsequent therapy remains limited. Small cell transformation is an important mechanism of drug resistance in epidermal growth factor receptor-mutant NSCLC. However, its significance in mediating ROS1 resistance has not been determined yet. Here, we present the case of a 63-year-old man with ROS1-rearranged advanced NSCLC who had disease progression with small cell transformation of the mediastinal lymph node after 8 months of treatment with crizotinib. More importantly, fluorescence in situ hybridization of post-progression tumor biopsy demonstrated retention of ROS1 rearrangement. Tissue biopsy remains indispensable for patients who acquire resistance to ROS1 TKIs.
| S-EPMC8590892 | biostudies-literature
Project description: Not available
| S-EPMC4801313 | biostudies-literature
Project description:Entrectinib is a pan-tyrosine-kinase inhibitor that targets oncogenic rearrangements in NTRK, ROS1 and ALK. The combined results of two clinical trials demonstrated the efficacy of entrectinib in ROS1-rearranged NSCLC. Because the development of drug resistance is inevitable, it would be helpful to determine the mechanisms of entrectinib resistance in a ROS1-rearranged tumor model so that future therapeutic strategies can be developed. Here, we characterized the molecular basis of resistance in entrectinib-resistant ROS1-rearranged HCC78 cells (HCC78ER cells). These cells were analyzed by next-generation sequencing and genetic profiling, which revealed the acquisition of KRAS G12C and the amplification of KRAS and FGF3. However, there were no secondary mutations in the ROS1 kinase domain. We also found that sustained ERK activation was involved in entrectinib resistance, and that combined treatment with selumetinib resensitized HCC78ER cells to entrectinib in cell viability and colony formation assays. Our data suggest that activation of the RAS signaling pathway can cause entrectinib resistance in ROS1-rearranged NSCLC, and is unlikely to be overcome by sequential single agent ROS1-targeting strategies against such tumors. Instead, co-targeting ROS1 and MEK may be an effective strategy for overcoming entrectinib resistance in ROS1-rearranged NSCLC.
| S-EPMC7066105 | biostudies-literature
Project description:ROS proto-oncogene 1 (ROS1) rearrangements occur in 0.9-2.6% of patients with non small cell lung cancer (NSCLC), conferring sensitivity to treatment with specific tyrosine-kinase inhibitors (TKI). Crizotinib, a first-generation TKI, was the first target-therapy approved for the first-line treatment of ROS1-positive NSCLC. Recently, entrectinib, a multitarget inhibitor with an anti-ROS1 activity 40 times more potent than crizotinib and better activity on the central nervous system (CNS), received approval for treatment-naive patients. After a median time-to-progression of 5.5-20 months, resistance mechanisms can occur, leading to tumor progression. Therefore, newer generation TKI with greater potency and brain penetration have been developed and are currently under investigation. This review summarizes the current knowledge on clinicopathological characteristics of ROS1-positive NSCLC and its therapeutic options.
| S-EPMC10380455 | biostudies-literature
Project description:ROS1-rearranged (also known as ROS1 fusion-positive) non-small-cell lung cancer is an uncommon but distinct molecular subgroup seen in approximately 1-2% of cases. Oncogene addiction due to constitutive ROS1 tyrosine kinase activation has allowed development of molecularly targeted therapies with remarkable anti-tumor activity. Both crizotinib and entrectinib, multitargeted tyrosine kinase inhibitors (TKIs) have now received approval by the FDA for treatment of patients with advanced ROS1-rearranged lung cancers; however, the clinical efficacy and safety of these drugs have been derived from expansion cohorts of single-arm phase I or basket clinical trials with relatively small populations of this clinically and molecularly distinct subgroup. Both drugs lead to high objective response rates (approximately 70-80%) and have manageable side effects, although only entrectinib has potent intracranial efficacy. Lorlatinib is an oral brain-penetrant ALK/ROS1 TKI with activity in both TKI-naïve and some crizotinib-resistant settings (albeit with limited potency against the crizotinib/entrectinib-resistant ROS1-G2032R mutation). We describe cases of advanced ROS1-rearranged lung cancer receiving crizotinib, entrectinib, and/or lorlatinib in first and later line treatment settings to dissect the current state of evidence supporting management decisions for these patients. The next generation ROS1 TKIs (repotrectinib and DS-6051b), owing to their broad activity against kinase mutations including ROS1-G2032R in preclinical studies, hold promise to transform the current treatment paradigm and permit even further gains with regards to long-term outcomes in this subset of patients.
| S-EPMC7410006 | biostudies-literature
Project description:Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC). However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22-q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer.
| S-EPMC3572153 | biostudies-literature