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  • Title: JAK1 Genomic Alteration Associated With Exceptional Response to Siltuximab in Cutaneous Castleman Disease.
    Author: Patel M, Ikeda S, Pilat SR, Kurzrock R.
    Journal: JAMA Dermatol; 2017 May 01; 153(5):449-452. PubMed ID: 28241173.
    Abstract:
    IMPORTANCE: Castleman disease (CD) is an ultrarare, interleukin-6 (IL-6)-driven lymphoproliferative disorder whose underlying molecular alterations are unknown. Siltuximab (anti-IL-6 antibody) is approved for treatment of this disease. To our knowledge, genomic sequencing of CD has not been reported. OBJECTIVE: To investigate and identify molecular aberration(s) that help explain the exceptional response to siltuximab in a patient with cutaneous CD. DESIGN, SETTING, AND PARTICIPANTS: This case study examines data from comprehensive genomic profiling (using targeted next-generation sequencing) of tissue from a patient with cutaneous CD who demonstrated an exceptional response to siltuximab treated at a National Cancer Institute-designated Comprehensive Cancer Center. INTERVENTIONS: Intravenous siltuximab 12 mg/kg every 3 weeks. Tissue from the patient was interrogated by next-generation sequencing (405 genes). Serum was evaluated for IL-6 levels by enzyme-linked immunoassay. MAIN OUTCOMES AND MEASURES: Identification of pretreatment serum IL-6 levels and somatic variants that may explain the exceptional response to siltuximab in this patient with cutaneous CD. RESULTS: Patient pretreatment serum IL-6 levels were normal. Treatment with siltuximab resulted in a complete response lasting 7 years. Next-generation sequencing demonstrated a JAK1V310I missense mutation. Janus Kinase 1 (JAK1) is a crucial signaling component of the IL-6/IL-6 receptor/gp130 machinery. JAK1V310I may induce a conformation change with functional activation effect leading to enhanced sensitivity to the IL-6 ligand. CONCLUSIONS AND RELEVANCE: Our observations suggest that a JAK1 alteration may explain the underlying biology of a patient's cutaneous CD, as well as the patient's exceptional response to siltuximab.
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