Zinc deficiency associated with cutaneous toxicities induced by epidermal growth factor receptor tyrosine kinase inhibitor therapy in patients with lung adenocarcinoma.

PURPOSE: Cutaneous toxicities are common adverse effects following epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. Zinc deficiency causes diverse diseases, including skin toxicities. Therefore, this study aimed to investigate the role of zinc deficiency in patients with EGFR-TKI-induced skin toxicities. EXPERIMENTAL DESIGN: This retrospective study enrolled 269 patients with diverse skin disorders who visited our hospital between January 2016 and December 2017. The skin toxicity severities and plasma zinc levels of 101 EGFR-TKI-treated cancer patients were analysed and compared with those of 43 non-EGFR-TKI-treated cancer patients and 125 patients without cancer but presenting cutaneous manifestations. Additionally, the role of zinc in erlotinib-induced skin eruptions was established in a 14-day-murine model. Clinical features were further evaluated following systemic zinc supplementation in EGFR-TKI-treated cancer patients. RESULTS: EGFR-TKI-treated patients demonstrated severe cutaneous manifestations and a significant decrease in plasma zinc levels than those of the control groups. The serum zinc level and Common Terminology Criteria for Adverse Events (CTCAE) 5.0 grading of EGFR-TKI-induced skin toxicities showed a significant negative correlation (r = -0.29; p < 0.0001). Moreover, erlotinib treatment decreased the plasma zinc levels and induced periorificial dermatitis in rats confirming zinc deficiency following EGFR-TKI treatment. Zinc supplementation to the EGFR-TKI-treated cancer patients showed a significant decrease in the CTCEA grading (p < 0.0005 for mucositis and p < 0.0.0001 for all other cases) after 8 weeks. CONCLUSIONS: Skin impairment following EGFR-TKI therapy could be ameliorated through zinc supplementation. Thus, zinc supplementation should be considered for cancer patients undergoing EGFR-TKI therapy.

Integrative Omics Analysis Reveals Soluble Cadherin-3 as a Survival Predictor and an Early Monitoring Marker of EGFR Tyrosine Kinase Inhibitor Therapy in Lung Cancer.

PURPOSE: EGFR tyrosine kinase inhibitors (EGFR-TKI) benefit patients with advanced lung adenocarcinoma (ADC) harboring activating EGFR mutations. We aimed to identify biomarkers to monitor and predict the progression of patients receiving EGFR-TKIs via a comprehensive omic analysis. EXPERIMENTAL DESIGN: We applied quantitative proteomics to generate the TKI resistance-associated pleural effusion (PE) proteome from patients with ADC with or without EGFR-TKI resistance. Candidates were selected from integrated genomic and proteomic datasets. The PE (n = 33) and serum (n = 329) levels of potential biomarkers were validated with ELISAs. Western blotting was applied to detect protein expression in tissues, PEs, and a cell line. Gene knockdown, TKI treatment, and proliferation assays were used to determine EGFR-TKI sensitivity. Progression-free survival (PFS) and overall survival (OS) were assessed to evaluate the prognostic values of the potential biomarkers. RESULTS: Fifteen proteins were identified as potential biomarkers of EGFR-TKI resistance. Cadherin-3 (CDH3) was overexpressed in ADC tissues compared with normal tissues. CDH3 knockdown enhanced EGFR-TKI sensitivity in ADC cells. The PE level of soluble CDH3 (sCDH3) was increased in patients with resistance. The altered sCDH3 serum level reflected the efficacy of EGFR-TKI after 1 month of treatment (n = 43). Baseline sCDH3 was significantly associated with PFS and OS in patients with ADC after EGFR-TKI therapy (n = 76). Moreover, sCDH3 was positively associated with tumor stage in non-small cell lung cancer (n = 272). CONCLUSIONS: We provide useful marker candidates for drug resistance studies. sCDH3 is a survival predictor and real-time indicator of treatment efficacy in patients with ADC treated with EGFR-TKIs.

Combined serum biomarkers in the noninvasive diagnosis of complicated parapneumonic effusions and empyema.

BACKGROUND: We previously demonstrated that the pleural levels of proteins (neutrophil gelatinase-associated lipocalin/NGAL, calprotectin, bactericidal permeability-increasing/BPI, azurocidin 1/AZU-1) were valuable markers for identifying complicated PPE (CPPE). Herein, this study was performed to evaluate whether these proteins are useful as serological markers for identifying CPPE and empyema. METHODS: A total of 137 participates were enrolled in this study. The levels of NGAL, calprotectin, BPI and AZU-1 were measured in serum and pleural fluid by enzyme-linked immunosorbent assay. We also characterized the diagnostic values of these markers between different groups. RESULTS: The serum levels of NGAL, calprotectin, and BPI in PPE patients were significantly higher than those in transudates, noninfectious exudates, and healthy controls. The area under the curve (AUC) values of NGAL, calprotectin, and BPI for distinguishing PPE from transudates or noninfectious exudates were around 0.861 to 0.953. In PPE group, serum NGAL and calprotectin levels were significantly elevated in patients with CPPE and empyema than in those with UPPE, whereas the serum BPI levels were similar between these two groups. In CPPE and empyema patients, the serum NGAL showed a positive correlation with the pleural fluid NGAL (r = 0.417, p <  0.01). When combined with serum CRP, the sensitivity and specificity of serum calprotectin for identifying CPPE and empyema were the highest at 73.52% and 80.55%, respectively. CONCLUSIONS: We concluded that serum calprotectin and NGAL were adjuvant serological markers for CPPE and empyema diagnosis. Patients present with pneumonia and pleural effusion signs in the chest x-ray and the combination of serum calprotectin and CRP constitutes a more highly sensitive and specific assay for identifying CPPE and empyema.