This study compared the ventilatory variables and computed tomography (CT) features of patients with coronavirus disease 2019 (COVID-19) versus those of patients with pulmonary non–COVID-19-related acute respiratory distress syndrome (ARDS) during the early phase of ARDS. This prospective, observational cohort study of ARDS patients in Taiwan was performed between February 2017 and June 2018 as well as between October 2020 and January 2024. Analysis was performed on clinical characteristics, including consecutive ventilatory variables during the first week after ARDS diagnosis. Analysis was also performed on CT scans obtained within one week after ARDS onset. A total of 222 ARDS patients were divided into a COVID-19 ARDS group (n = 44; 19.8

Background: Substitution of methionine for threonine at codon 790 (T790M) of epidermal growth factor receptor (EGFR) represents the major mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer. We determined the prognostic impact and association of secondary T790M mutations with the outcomes of osimertinib and chemotherapy. Methods: Patients (n = 460) progressing from first-line EGFR-TKI treatment were assessed. Tissue and/or liquid biopsies were used to determine T790M status; post-progression overall survival (OS) was analyzed. Results: Overall, 143 (31.1%) patients were T790M positive, 95 (20.7%) were T790M negative, and 222 (48.2%) had unknown T790M status. T790M status [T790M positive versus T790M negative: hazard ratio (HR) 0.48 (95% confidence interval (CI), 0.32–0.70); p < 0.001, T790M unknown versus T790M negative: HR 1.97 (95% CI, 1.47–2.64); p < 0.001] was significantly associated with post-progression OS. T790M positivity rates were similar for tissue (90/168, 53.6%) and liquid (53/90, 58.9%) biopsies (Fisher’s exact test, p = 0.433). Tumor T790M-positive patients had significantly longer post-progression OS than tumor T790M-negative patients (34.1 versus 17.1 months; log-rank test, p = 8 × 10 −5 ). Post-progression OS was similar between plasma T790M-positive and -negative patients (17.4 versus not reached; log-rank test, p = 0.600). In tumor T790M-positive patients, post-progression OS was similar after osimertinib and chemotherapy [34.1 versus 29.1 months; log-rank test, p = 0.900; HR 1.06 (95% CI, 0.44–2.57); p = 0.897]. Conclusion: T790M positivity predicts better post-progression OS than T790M negativity; tumor T790M positivity has a stronger prognostic impact than plasma T790M positivity. Osimertinib and chemotherapy provide similar OS benefits in patients with T790M-positive tumors.

Real-world clinical experience of using anti-programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) combined with chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer (SCLC) patients has rarely been reported. In this study, we aimed to perform a retrospective multicenter clinical analysis of extensive-stage SCLC patients receiving first-line therapy with anti-PD-L1 ICIs combined with chemotherapy. Between November 2018 and March 2022, 72 extensive-stage SCLC patients receiving first-line atezolizumab or durvalumab in combination with chemotherapy, according to the cancer center databases of Linkou, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals, were retrospectively included in the analysis. Twenty-one patients (29.2%) received atezolizumab and fifty-one (70.8%) received durvalumab. Objective response (OR) and disease control (DC) rates of 59.7% and 73.6%, respectively, were observed with first-line ICI plus chemotherapy. The median progression-free survival (PFS) was 6.63 months (95% confidence interval (CI), 5.25–8.02), and the median overall survival (OS) was 16.07 months (95% CI, 15.12–17.0) in all study patients. A high neutrophil-to-lymphocyte ratio (NLR; >4) and a high serum lactate dehydrogenase (LDH) concentration (>260 UL) were identified as independent unfavorable factors associated with shorter OS in the multivariate analysis. Regarding safety, neutropenia was the most common grade 3 treatment-related adverse event (AE), but no treatment-related deaths occurred in the study patients. First-line anti-PD-L1 ICIs combined with chemotherapy are effective and safe for male extensive-stage SCLC patients. Further therapeutic strategies may need to be developed for patients with unfavorable outcomes (e.g., baseline high NLR and serum LDH level).

Background Cadmium and nickel exposure can cause oxidative stress, induce inflammation, inhibit immune function, and therefore has significant impacts on the pathogenesis and severity of many diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also provoke oxidative stress and the dysregulation of inflammatory and immune responses. This study aimed to assess the potential associations of cadmium and nickel exposure with the severity and clinical outcomes of patients with coronavirus disease 2019 (COVID-19). Methods We performed a retrospective, observational, bicenter cohort analysis of patients with SARS-CoV-2 infection in Taiwan between June 2022 and July 2023. Cadmium and nickel concentrations in blood and urine were measured within 3 days of the diagnosis of acute SARS-CoV-2 infection, and the severity and clinical outcomes of patients with COVID-19 were analyzed. Results A total of 574 patients were analyzed and divided into a severe COVID-19 group (hospitalized patients) ( n = 252; 43.9%), and non-severe COVID-19 group ( n = 322; 56.1%). The overall in-hospital mortality rate was 11.8% ( n = 68). The severe COVID-19 patients were older, had significantly more comorbidities, and significantly higher neutrophil/lymphocyte ratio, C-reactive protein, and interleukin-6 than the non-severe COVID-19 patients (all p < 0.05). Blood and urine cadmium and urine nickel concentrations were significantly higher in the severe COVID-19 patients than in the non-severe COVID-19 patients. Among the severe COVID-19 patients, those in higher urine cadmium/creatinine quartiles had a significantly higher risk of organ failure (i.e., higher APACHE II and SOFA scores), higher neutrophil/lymphocyte ratio, lower PaO 2 /FiO 2 requiring higher invasive mechanical ventilation support, higher risk of acute respiratory distress syndrome, and higher 60-, 90-day, and all-cause hospital mortality (all p < 0.05). Multivariable logistic regression models revealed that urine cadmium/creatinine was independently associated with severe COVID-19 (adjusted OR 1.643 [95% CI 1.060–2.547], p = 0.026), and that a urine cadmium/creatinine value > 2.05 μg/g had the highest predictive value (adjusted OR 5.349, [95% CI 1.118–25.580], p = 0.036). Conclusions Urine cadmium concentration in the early course of COVID-19 could predict the severity and clinical outcomes of patients and was independently associated with the risk of severe COVID-19.

BACKGROUND:Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), shows superior lung cancer treatment efficacy. However, osimertinib-induced severe hypersensitivity, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), is frequently observed in Asian populations and hinders cancer treatment. OBJECTIVE:We investigated the genetic HLA predisposition and immune pathomechanism of osimertinib-induced hypersensitivity. METHODS:We enrolled 17 patients with osimertinib-induced delayed hypersensitivity (seven with severe SJS/TEN and 10 with mild maculopapular exanthema), 98 osimertinib-tolerant subjects, and 2,123 general population controls. We performed HLA genotyping, drug-induced lymphocyte activation test, and surface plasmon resonance assay. RESULTS:HLA-B∗51:02 was present in 83.3% of osimertinib-induced SJS/TEN patients but in only 3.3% of the general population controls (P = 2.8 × 10-7; corrected P = 6.9 × 10-6; odds ratio [OR] = 146), and 0% of osimertinib-tolerant controls (P = 6.5 × 10-8; corrected P = 1.6 × 10-6; OR = 707). The association of HLA-B∗51:01 and HLA-A∗24:02 with osimertinib-induced maculopapular exanthema patients, rather than with osimertinib-tolerant subjects (P = .002, OR = 15.7 for HLA-B∗51:01; and P = .003, OR = 9.5 for HLA-A∗24:02), was identified as a phenotype-specific association. Granulysin, the SJS/TEN-specific cytotoxic protein, was significantly higher in plasma of SJS/TEN patients (39.8 ± 4.5 ng/mL; P < .001) and in in vitro lymphocyte activation test (sensitivity = 83.3%; P < .01) compared with tolerant controls. Patients with osimertinib-induced hypersensitivity appeared to tolerate alternative EGFR-TKIs. Surface plasmon resonance results also confirmed that HLA-B∗51:02 protein has a higher binding affinity for osimertinib and lower or no affinity for other EGFR-TKIs. CONCLUSIONS:HLA-B∗51:02 frequently occurs in Asian populations and is strongly associated with osimertinib-induced SJS/TEN. Our findings suggest HLA-B∗51:02 screening as a preemptive test to reduce osimertinib-induced severe hypersensitivity.

Abstract Background This study aimed to investigate the factors associated with prolonged progression‐free survival (PFS) (>36 months) of advanced non‐small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations treated with first‐line afatinib. Methods We performed a retrospective analysis of data of patients with advanced EGFR‐mutated NSCLC receiving first‐line afatinib at two tertiary care referral centers, Linkou and Kaohsiung Chang Gung Memorial Hospital, in Taiwan between June 2014 and April 2022. Results The data of 546 treatment‐naïve EGFR‐mutated advanced NSCLC patients were analyzed. Median PFS and overall survival were 14.5 months and 27.2 months, respectively. The PFS of 462 patients (84.6%) was less than 36 months and of 84 patients (15.4%) was more than 36 months. The PFS > 36 months group had a significantly higher percentage of patients with uncommon mutations (p = 0.002). The PFS ≤36 months group had significantly higher incidences of bone, liver, and adrenal metastases (all p < 0.05) and a higher rate of multiple distant metastases. Multivariate logistic regression analysis showed that liver metastasis was negatively and independently associated with prolonged PFS (adjusted odds ratio = 0.246 [95% CI: 0.067–0.908], p = 0.035). The median overall survival of the PFS >36 months group was 46.0 months and that of the PFS ≤36 months group was 22.9 months (log‐rank test, p < 0.001). Conclusions We found that EGFR‐mutated NSCLC patients receiving first‐line afatinib were prone to shorter PFS if they had distant organ metastasis, especially liver metastasis.

Nuclear epidermal growth factor receptor (EGFR) has been shown to be correlated with drug resistance and a poor prognosis in patients with cancer. Previously, we have identified a tripartite nuclear localization signal (NLS) within EGFR. To comprehensively determine the functions and underlying mechanism of nuclear EGFR and its clinical implications, we aimed to explore the nuclear export signal (NES) sequence of EGFR that is responsible for interacting with the exportins. We combined in silico prediction with site-directed mutagenesis approaches and identified a putative NES motif of EGFR, which is located in amino acid residues 736-749. Mutation at leucine 747 (L747) in the EGFR NES led to increased nuclear accumulation of the protein via a less efficient release of the exportin CRM1. Interestingly, L747 with serine (L747S) and with proline (L747P) mutations were found in both tyrosine kinase inhibitor (TKI)-treated and -naïve patients with lung cancer who had acquired or de novo TKI resistance and a poor outcome. Reconstituted expression of the single NES mutant EGFRL747P or EGFRL747S, but not the dual mutant along with the internalization-defective or NLS mutation, in lung cancer cells promoted malignant phenotypes, including cell migration, invasiveness, TKI resistance, and tumor initiation, supporting an oncogenic role of nuclear EGFR. Intriguingly, cells with germline expression of the NES L747 mutant developed into B cell lymphoma. Mechanistically, nuclear EGFR signaling is required for sustaining nuclear activated STAT3, but not for Erk. These findings suggest that EGFR functions are compartmentalized and that nuclear EGFR signaling plays a crucial role in tumor malignant phenotypes, leading to tumorigenesis in human cancer.

Gli1-binding proteins identified through mass spectrum.

Description of additional methods and procedures used in the study. Also includes Supplementary References.

Supplementary Materials and Methods

Enzymes from list of Gli1-binding proteins.

Correlation between Gli1 and PRMT1 Levels (S1); Identification of a PRMT1-Methylated Site in Gli1 (S2); Effects of R597 on Gli1 Transcriptional Activity (S3); Tumorigenicity of Wild-Type Gli1 and R597K-Mutated Gli1 (S4); Regulation of Gli1 by PRMT1 Is Independent of SMO/TGF-B/Kras (S5).

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients’ outcome. 553 metastatic EGFR -mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99–1.48]; p = 0.053), ECOG PS 0–1 (HR 0.71 [95% CI 0.54–0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66–0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0–1 (HR 0.41 [95% CI 0.31–0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13–1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02–4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12–0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28–1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR -mutant NSCLC, whereas OS was mainly associated with EGFR subtype.

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.

IntroductionUncommon epidermal growth factor receptor (EGFR) mutations include single and complex mutations. However, the association of the smoking status of patients with uncommon and complex EGFR mutations remains unclear.MethodsThis retrospective study evaluates the spectrum of uncommon EGFR mutations and investigates the influence of smoking status on the frequency of various uncommon EGFR mutations using a multi-institutional medical database.ResultsBetween 2010 and 2019, 5,608 non-small cell lung cancer (NSCLC) patients were analyzed. EGFR mutations were detected in 3,155 (56.3%) patients. Among the 399 (12.6%) patients with uncommon mutations, 198 had single uncommon and 201 complex mutations, including 87 exon 20 insertions, 79 de novo T790M, 70 complex common, and 52 complex uncommon mutations. For comparison, we also included 402 patients with common EGFR mutations. The percentage of ever-smokers was significantly higher in patients with uncommon EGFR mutations than in patients with common EGFR mutations (25.8% vs. 17.4%, p = 0.005). Furthermore, the percentage of ever-smokers was higher in those with a complex mutation than in those with a single uncommon mutation (30.3% vs. 21.2%, p = 0.040). Among patients carrying uncommon EGFR mutations, ever-smokers had significantly more complex uncommon EGFR mutations than never-smokers (22.3% vs. 9.8%, p = 0.002). Among patients carrying G719X, L861Q, and S768I, ever-smokers tended to have complex EGFR mutations more frequently than never-smokers (64.7% vs. 28.7%, 50.0% vs. 18.7%, 88.9% vs. 81.2%, respectively).ConclusionsOur study demonstrates not only a comprehensive spectrum of uncommon EGFR mutations, but also a positive relationship between smoking status and uncommon EGFR mutation frequency, especially complex uncommon EGFR mutations. The results suggest that smoking contributes to the development of complex EGFR mutations.

Extracellular vesicles (EVs) contain abundant extracellular RNA (exRNA), which can be a valuable source of liquid biopsy. However, as various RNA species exist in different types of EVs, lack of detailed characterization of these RNA species and efficient collection methods limits the clinical application of exRNA. In the present study, we measured two mRNAs, CK19 and PCTK1; one lncRNA, MALAT1; and two miRNAs, miR21 and miR155, in different EV fractions separated by differential centrifugation or captured by magnetic beads coated with annexin A5 (ANX beads). The results showed that in a cultured medium, the majority of mRNA and lncRNA exist in larger EVs, whereas miRNA exist in both large and small EVs from the differential centrifugation fractions. All these RNA species exist in ANX beads captured EVs. We then used ANX beads to capture EVs in plasma samples from non-small-cell lung cancer patients and age-matched healthy volunteers. We found that the ANX bead capturing could efficiently improve RNA detection from human plasma, compared with direct extraction of RNA from plasma. Using ANX-bead capturing and reverse transcription and quantitative PCR, we detected significantly higher levels of CK19 mRNA, MALAT1 lncRNA, and miR155 miRNA in the plasma of lung cancer patients. These facts suggested the collection methods strongly affect the results of exRNA measurement from EVs, and that ANX beads can be a useful tool for detecting exRNA from plasma samples in clinical application.

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.

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Background/Aim: Circulating tumor DNA (ctDNA) bears specific mutations derived from tumor cells. The amount of mutant ctDNA may reflect tumor burden. In this study, we detected epidermal growth factor receptor (EGFR) mutations in ctDNA as a monitoring marker for the response of non-small cell lung cancer (NSCLC) patients to tyrosine kinase inhibitors (TKIs). Patients and Methods: Serial plasma samples from eight NSCLC patients during TKI treatment were collected. Libraries with barcoded adapters were constructed from ctDNA of these plasma samples using a PCR-based targeted DNA panel. The libraries were then sequenced for measuring EGFR mutations. In addition, carcinoembryonic antigen (CEA) was also measured in these patients. Results: In six patients who suffered disease progression (PD), five had elevated EGFR mutation reads before PD. In the two patients who did not develop PD, EGFR mutations remained undetectable in their plasma. The CEA levels were higher than the cutoff value in most samples and had a poor correlation with disease status. Conclusion: The mutation count of tumor-specific mutations can be a monitoring marker of TKI treatment in NSCLC patients.

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 β-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.