Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene and occur almost absolutely in carcinomas arising in non-smokers. Crizotinib, the first inhibitor of anaplastic lymphoma kinase (ALK), ROS1 and c-Met receptor kinase, has been used in the treatment of ALK-positive non-small cell lung cancer. Side effects of crizotinib mostly consist of grade 1-2 gastrointestinal events (nausea, vomiting, diarrhea and constipation), grade 1-2 edema and fatigue; grade 1 visual disorders, rare cases of elevated liver enzymes and pneumonitis. We are presenting a case of adenocarcinoma of lung, who progressed on first-line chemotherapy and received crizotinib as second line therapy for 9 months. Patient has very good partial response to crizotinib and had some side effects of crizotinib like nausea, vomiting, diarrhea, fatigue, asthenia and anorexia, asymptomatic transaminitis in the first 2 to 3 weeks of therapy and managed symptomatically. But after 9 months, he developed sudden onset left sided vision loss. On fundoscopic examination he was found to have "cherry red spot" and fundus flourescein angiography revealed central retinal artery occlusion (CRAO). After 15 days of vision loss patient developed pleural effusion, and pleural fluid cytology was positive for malignant cells. Visual symptoms are very well known in the literature as side effects of crizotinib, but CRAO is not yet been documented. As this patient is not having any prothrombotic state like diabetes, hypertension, atherosclerosis, hyperhomocysteinemia or any genetic disorders except malignancy. Hypercoagulability disorders are known to be commonly associated with a variety of cancer types including lung cancer. This appears to be a sign of early crizotinib resistance in this patient because there was no history of prior hypercoagulable state. To the best of our knowledge this is the first case report in the world literature, as CRAO presenting as a sign of crizotinib resistance in an adenocarcinoma of lung patient who was on crizotinib.
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PMID:Central retinal artery occlusion, an early sign of crizotinib resistance in an alk positive adenocarcinoma of lung: A rare case report. 2760 84

Receptor tyrosine kinases (RTKs) bearing oncogenic mutations in EGFR, ALK and ROS1 occur in a significant subset of lung adenocarcinomas. Tyrosine kinase inhibitors (TKIs) targeting tumor cells dependent on these oncogenic RTKs yield tumor shrinkage, but also a variety of adverse events. Skin toxicities, hematological deficiencies, nausea, vomiting, diarrhea, and headache are among the most common, with more acute and often fatal side effects such as liver failure and interstitial lung disease (ILD) occurring less frequently. In normal epithelia, RTKs regulate tissue homeostasis. For example, EGFR maintains keratinocyte homeostasis while MET regulates processes associated with tissue remodeling. Previous studies suggest that the acneiform rash occurring in response to EGFR inhibition is a part of an inflammatory response driven by pronounced cytokine and chemokine release and recruitment of distinct immune cell populations. Mechanistically, blockade of EGFR causes a Type I interferon (IFN) response within keratinocytes and in carcinoma cells driven by this RTK. This innate immune response within the tumor microenvironment (TME) involves increased antigen presentation and effector T cell recruitment that may participate in therapy response. This TKI-mediated release of inflammatory suppression represents a novel tumor cell vulnerability that may be exploited by combining TKIs with immune-oncology (IO) agents that rely on T-cell inflammation for efficacy. However, early clinical data indicate that combination therapies enhance the frequency and magnitude of the more acute adverse events, especially pneumonitis, hepatitis, and pulmonary fibrosis. Further preclinical studies to understand TKI mediated inflammation and crosstalk between normal epithelial cells, cancer cells, and the TME are necessary to improve treatment regimens for patients with RTK-driven carcinomas.
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PMID:Linking tyrosine kinase inhibitor-mediated inflammation with normal epithelial cell homeostasis and tumor therapeutic responses. 3065 89