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.

Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab.

The impact of an initial skeletal-related event (SRE) and denosumab adjuvant treatment on the survival outcome of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with bone metastasis remains unclear. This retrospective study included 400 metastatic EGFR-mutated NSCLC patients. Among 190 bone metastasis patients, 61 had initial SREs and 73 received denosumab. We analyzed patient characteristics, SRE-free survival (SRE-FS), and overall survival (OS). In metastatic EGFR-mutated NSCLC, bone metastasis was associated with a poorer OS (21.7 vs. 33.0 months; p < 0.001). Bone metastasis patients with initial SREs at diagnosis had an even shorter OS, compared with those without initial SRE (15.4 vs. 23.6 months; p = 0.026). Denosumab reduced SRE incidence (hazard ratio (HR) 0.57 (95% confidence interval (CI) 0.34−0.94; p = 0.027) and was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). A multivariate analysis demonstrated that denosumab treatment was correlated with a lower incidence of SRE (HR 0.61 (95% CI 0.37−0.98); p = 0.042) and better OS (HR 0.60 (95% CI 0.41−0.88); p = 0.008). In subgroup analyses, denosumab prolonged SRE-FS (HR 0.36 (95% CI 0.19−0.79); p = 0.009) in patients without initial SREs and was related to a better OS (25.3 vs. 12.9 months; p = 0.016) in patients with initial or pre-existing SREs. Osteonecrosis of the jaw was diagnosed in two patients (2.74%) receiving denosumab. Our study confirmed the association between initial SREs and a worse outcome and provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.

Using betaxolol for the prevention of paronychia induced by epidermal growth factor receptor inhibitors: a case-control cohort study.

BACKGROUND: High rates of posttreatment discomfort, infection, recurrence, and increased time to return to work have been noted after nail plate avulsion resulting from epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)-induced paronychia, which may even interrupt the course of treatment for EGFR-TKI therapy. Thus, we conducted this study to determine how effectively a topical ß-blocker, betaxolol, prevents EGFR-TKI-induced paronychia. METHODS: This case-control cohort study included a total of 131 non-small-cell lung cancer patients. The prevention group comprised 40 patients treated with topical betaxolol 0.25% solution to prevent paronychia while they received EGFR-TKI therapy. The control group comprised 91 patients who did not preventively use topical betaxolol 0.25% solution while receiving EGFR-TKI therapy. The patients' age, gender, antineoplastic regimen, duration of antineoplastic treatment before the appearance of lesions, number of involved digits (fingernails or toenails) with lesions, grading of paronychia, and pain score were recorded. RESULTS: In terms of the cumulative incidence of paronychia, significant differences (P < 0.01) were noted at both the 2nd and 3rd months after starting EGFR-TKIs. Furthermore, the average visual analogue scale scores were 3.125 and 6.29 in the prevention group and control group, respectively (P < 0.01). The average grades of paronychia were 1.5 and 2.12 in the prevention group and control group, respectively (P < 0.01). The average numbers of involved digits were 2.25 (range: 1-5 digits) in the prevention group and 3.03 (range: 1-7) in the control group (P = 0.07). CONCLUSIONS: Preventively using topical betaxolol can significantly decrease the incidence, VAS score, and grading of EGFR-TKI-induced paronychia.

Effects of tyrosine kinase inhibitor therapy on skin toxicity and skin-related quality of life in patients with lung cancer: An observational study.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is the primary treatment option for patients with non-small cell lung cancer (NSCLC). However, one of the major adverse effects associated with this therapy is skin toxicity, which impacts the patient's quality of life. This study aimed to describe the severities and locations of skin toxicity, and to analyze their association with the quality of life in patients with advanced NSCLC who received EGFR-TKI therapy as first-line treatment.This cross-sectional and correlation study was conducted at a tertiary medical center in northern Taiwan between July 2015 and March 2016. Skin toxicity was assessed and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). The Skindex-16 scale was used to measure the skin disease-related quality of life.A total of 146 NSCLC patients who received EGFR-TKI therapy within the first 3 months of diagnosis were included in this study; 93.2% of these patients experienced skin toxicities. Approximately 70% of the patients developed xerosis and pruritus, while 50% had papulopustular eruptions and paronychia. The mean skin symptom impact score was 5.38 (standard deviation = 2.65). The skin-related quality of life varied widely among the participants but remained acceptable (mean score = 13.96, standard deviation = 16.55). Skin symptoms correlated significantly with poor quality of life (r = 0.50, P < .001). Younger patients and those treated with afatinib were the most affected, reporting the poorest quality of life. Patients who required EGFR-TKI dose reduction had experienced more severe skin symptoms than had patients who did not require it (7.35 vs 5.01, P < .001).Skin toxicity related to EGFR-TKI treatment impacts the quality of life in patients with NSCLC. During the treatment period, skin assessment and tailored management should be incorporated into the daily care plan.

Psychological profiles of excluded living liver donor candidates: An observational study.

Living donor liver transplantation has advantages over deceased organ liver transplantation. However, the living liver donor candidates must be carefully assessed before surgery. Candidates may be excluded for various reasons. The purpose of this study was to evaluate the psychological profiles of excluded living liver donor candidates according to the reason for exclusion.A descriptive and cross-sectional study was conducted. Donor candidates were invited to participate if they were at least 20 years of age, related biologically or by marriage to the recipient (within 5 degrees), and had undergone living donor evaluation. Among the 338 participants recruited from August 2013 to December 2015, 116 were excluded for the following reasons: a medical condition (n = 35), failure to be chosen (n = 63), or withdrawal from the selection process (n = 18). The psychological profiles of these 3 exclusion groups were evaluated.There were no significant group differences in age, sex, education level, religion, marital status, and consanguinity (P > .05). The withdrawal group had fewer recipients with an hepatitis B virus infection than did the other groups (χ = 9.28, P = .01). Additionally, compared with the unchosen group, the withdrawal group had lower intimacy with the recipient (F = 5.32, P = .006) and higher ambivalence (F = 5.53, P = .005). In terms of family relationship parameters, the withdrawal group had lower family cohesion than the medical condition and unchosen groups (F = 4.44, P = .01), lower family expressiveness than the medical condition group (F = 3.76, P = .03), and higher family conflict than the medical condition and unchosen groups (F = 7.05, P = .001). The withdrawal group also had lower emotional social support than the medical condition group (F = 3.55, P = .03). There were no significant group difference in motivation, expectations, donation-related concerns, informational social support, value social support, instrumental social support, and health-related quality of life.The living donor candidates who withdrew from the selection process had obvious ambivalence, poorer family relationships, and insufficient emotional social support. The transplantation team should respect the autonomy of the candidate's decision and mitigate the impact of the donation decision on living liver donor candidates.

Response to afatinib in treatment-naïve patients with advanced mutant epidermal growth factor receptor lung adenocarcinoma with brain metastases.

BACKGROUND: Brain metastases are observable in 20-40% of non-small cell lung cancer patients, but standard treatments for such metastases may be intolerable to some. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were found to be effective against mutant-EGFR lung adenocarcinomas, but data regarding their effectiveness, especially for the second-generation EGFR-TKI afatinib, is limited. This study compared key outcomes for afatanib monotherapy versus afatinib combined with whole-brain radiotherapy (WBRT) in treatment-naïve lung adenocarcinoma patients harboring EGFR mutations. METHODS: A retrospective review of 28 brain metastatic lung adenocarcinoma patients treated between June 2014 and December 2016 was conducted; 17 were treated with WBRT and maintenance afatinib therapy, while 11 received afatinib monotherapy. RESULTS: The patients were predominantly female (n = 17, 60.7%) and non-smokers (78.6%). Almost all the patients (89.3%) had an Eastern Cooperative Oncology Group performance status of 0-2. The EGFR mutation type consisted of the del19 mutation in 57.1% of the patients (n = 16), while L858R mutations were found in 42.9% (n = 12). The mean number of brain metastases (6.1 ± 5.0) was higher among the patients treated with afatinib monotherapy, while the mean size of the largest brain metastasis (19.0 ± 10.5mm) was greater in the afatinib combined with WBRT group. The objective response rates for the afatinib monotherapy and combination therapy groups were 81.8% and 88.2%, respectively. However, the monotherapy group exhibited a significantly higher complete response rate for intracranial lesions (63.6% vs. 17.6%, p = 0.02), and there were no significant differences between the two treatment groups in overall survival or time to treatment failure. CONCLUSION: Afatinib can provide therapeutic efficacy and a good response rate in treatment-naïve mutant-EGFR lung adenocarcinoma patients with brain metastases regardless of whether or not they also receive radiotherapy.

Morphology and Gene Expression Screening with Morpholinos in Zebrafish Embryos.

High-throughput screening with a loss-of-function strategy is a logical and efficient way to identify novel genes involved in biological processes of interest. In zebrafish, morpholinos have been developed as a convenient tool to knock down gene expression. Here, we describe procedures for systematic screening using morpholinos in zebrafish to identify novel deubiquitylases involved in convergent extension during gastrulation. In this example, we examine candidates based on embryonic morphology and molecular signals of whole mount in situ hybridization assay.

New classes of mind bomb-interacting proteins identified from yeast two-hybrid screens.

Notch signaling pathway defines an evolutionarily conserved mechanism in cell-fate determination in a broad spectrum of developmental processes through local cell interactions. mind bomb (mib) encodes an E3 ubiquitin ligase that is involved in Notch activation through Delta ubiquitylation and internalization. To further dissect the function of Mib, two yeast two-hybrid screens for zebrafish Mib/Mib2-binding proteins with different strategies have been performed. 81 putative interesting proteins were discovered and classified into six groups: ubiquitin proteasome pathway, cytoskeleton, trafficking, replication/transcription/translation factors, cell signaling and others. Confirmed by coimmunoprecipitation (Co-IP), Mib interacted with four tested proteins: ubiquitin specific protease 1 (Usp1), ubiquitin specific protease 9 (Usp9), tumor-necrosis-factor-receptor-associated factor (TRAF)-binding domain (Trabid)/zinc finger, RAN-binding domain containing 1 (Zranb1) and hypoxia-inducible factor 1, alpha subunit inhibitor (Hif1an)/factor inhibiting HIF 1 (Fih-1). Usp1, Usp9, Trabid and Fih-1 also bound to zebrafish Mib2, a Mib homolog with similar structural domains and functions. Both Mib and Mib2 can ubiquitylate Trabid and Fih-1, indicating a potential regulating role of Mib and Mib2 on Trabid and Fih-1 and, furthermore, the possible involvement of Notch signaling in hypoxia-regulated differentiation, tumorigenesis and NF-κB pathway. Finally, functions of confirmed Mib/Mib2-interacting proteins are collated, summarized and hypothesized, which depicts a regulating network beyond Notch signaling.

Temporal control of nuclear envelope assembly by phosphorylation of lamin B receptor.

The nuclear envelope of metazoans disassembles during mitosis and reforms in late anaphase after sister chromatids have well separated. The coordination of these mitotic events is important for genome stability, yet the temporal control of nuclear envelope reassembly is unknown. Although the steps of nuclear formation have been extensively studied in vitro using the reconstitution system from egg extracts, the temporal control can only be studied in vivo. Here, we use time-lapse microscopy to investigate this process in living HeLa cells. We demonstrate that Cdk1 activity prevents premature nuclear envelope assembly and that phosphorylation of the inner nuclear membrane protein lamin B receptor (LBR) by Cdk1 contributes to the temporal control. We further identify a region in the nucleoplasmic domain of LBR that inhibits premature chromatin binding of the protein. We propose that this inhibitory effect is partly mediated by Cdk1 phosphorylation. Furthermore, we show that the reduced chromatin-binding ability of LBR together with Aurora B activity contributes to nuclear envelope breakdown. Our studies reveal for the first time a mechanism that controls the timing of nuclear envelope reassembly through modification of an integral nuclear membrane protein.