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RSC Advances Jun 2021The chemical characterization of the extract of the aerial parts of afforded two oxetane containing lignans, paronychiarabicine A (1) and B (2), and one new...
The chemical characterization of the extract of the aerial parts of afforded two oxetane containing lignans, paronychiarabicine A (1) and B (2), and one new megastigmane, paronychiarabicastigmane A (3), alongside a known lignan (4), eight known phenolic compounds (5-12), one known elemene sesquiterpene (13) and one steroid glycoside (14). The chemical structures of the isolated compounds were constructed based upon the HRMS, 1D, and 2D-NMR results. The absolute configurations were established NOESY experiments as well as experimental and TDDFT-calculated electronic circular dichroism (ECD). Utilizing molecular docking, the binding scores and modes of compounds 1-3 towards the SARS-CoV-2 main protease (M), papain-like protease (PL), and RNA-dependent RNA polymerase (RdRp) were revealed. Compound 3 exhibited a promising docking score (-9.8 kcal mol) against SARS-CoV-2 M by forming seven hydrogen bonds inside the active site with the key amino acids. The reactome pathway enrichment analysis revealed a correlation between the inhibition of and genes (identified as the main targets of megastigmane treatment) and significant inhibition of SARS-CoV-1 viral replication in infected Vero E6 cells. Our results manifest a novel understanding of genes, proteins and corresponding pathways against SARS-CoV-2 infection and could facilitate the identification and characterization of novel therapeutic targets as treatments of SARS-CoV-2 infection.
PubMed: 35479905
DOI: 10.1039/d1ra02486h -
Lung Cancer (Amsterdam, Netherlands) Jun 2022Alternation of osimertinib and afatinib is a potential approach to overcome osimertinib resistance and to allow complementation of drug efficacy without compromising...
Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L).
INTRODUCTION
Alternation of osimertinib and afatinib is a potential approach to overcome osimertinib resistance and to allow complementation of drug efficacy without compromising safety in patients with epidermal growth factor receptor gene (EGFR)-mutated non-small cell lung cancer (NSCLC).
METHODS
Treatment-naive patients with stage IV NSCLC harboring an activating EGFR mutation (L858R or exon-19 deletion) were enrolled. Alternating cycles of osimertinib at 80 mg/day for 8 weeks followed by afatinib at 20 mg/day for 8 weeks were administered. The primary end point was 12-month progression-free survival (PFS) probability.
RESULTS
Forty-six patients were enrolled and treated with study therapy. The 12-month PFS probability was 70.2% (60% confidence interval [CI], 63.9-75.6%; 95% CI, 54.2-81.5%), which did not meet the primary end point. After a median follow-up time of 25.7 months, the median PFS was 21.3 months (95% CI, 16.3 months-not reached). The overall response rate was 69.6% (95% CI, 54.2-82.3%). The most common treatment-related adverse events (any grade or grade ≥ 3, respectively) were diarrhea (73.9%, 4.3%), rash acneiform (63.0%, 2.2%), and paronychia (52.2%, 0%). Five cases of pneumonitis, two of grade 2 and thres of grade 3, were apparent, all of which developed during osimertinib treatment. Exploratory evaluation of circulating tumor DNA suggested that coexisting TP53 mutations did not influence PFS for the alternating therapy.
CONCLUSIONS
Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR- mutated advanced NSCLC did not meet its primary end point, despite the encouraging efficacy and safety profile of this treatment strategy.
Topics: Acrylamides; Afatinib; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Genes, erbB-1; Humans; Indoles; Lung Neoplasms; Mutation; Pyrimidines
PubMed: 35477147
DOI: 10.1016/j.lungcan.2022.04.004 -
JAMA Dermatology May 2022This case series investigates the characteristics of epidermal growth factor receptor inhibitor–induced nail changes and usefulness of the gutter method.
Usefulness of Noninvasive Management With the Gutter Method for Epidermal Growth Factor Receptor Inhibitor-Induced Paronychia, Pyogenic Granuloma-Like Lesion, and Ingrown Nail.
This case series investigates the characteristics of epidermal growth factor receptor inhibitor–induced nail changes and usefulness of the gutter method.
Topics: ErbB Receptors; Granuloma, Pyogenic; Humans; Nails, Ingrown; Paronychia; Protein Kinase Inhibitors
PubMed: 35416917
DOI: 10.1001/jamadermatol.2022.0725 -
Thoracic Cancer May 2022Dacomitinib is the second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC). EGFR-TKIs are...
Clinical efficacy of dacomitinib in rechallenge setting for patients with epidermal growth factor receptor mutant non-small cell lung cancer: A multicenter retrospective analysis (TOPGAN2020-02).
BACKGROUND
Dacomitinib is the second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC). EGFR-TKIs are often re-administered in Japan after the disease progression prior EGFR-TKI. There is little evidence of dacomitinib in rechallenge setting. This study evaluated clinical outcomes of dacomitinib in rechallenge setting.
METHODS
Patients who received dacomitinib for advanced EGFR-mutant NSCLC who had progressed after EGFR-TKI in nine institutions in Japan were included in the analyses.
RESULTS
In total, 43 patients were analyzed. The median progression-free survival (PFS) was 4.3 months (95% confidence interval [CI], 2.5-5.6). The overall survival (OS) was 10.5 months (95% CI, 7.4-not reached). The overall response rate was 25.5% (95% CI, 13.1-33.7). Subset analysis indicated that patients with EGFR exon 21 L858R showed longer PFS than those with EGFR exon 19 deletion (5.8 vs. 4.1 months) (p = 0.018). The most common adverse events leading to dose modification were diarrhea, paronychia, rash, and oral mucositis.
CONCLUSION
In the real practice in Japan, dacomitinib showed a worthwhile treatment option for NSCLC patients with EGFR mutation after failure of previous EGFR-TKI. The benefit was especially pronounced in patients with the exon 21 mutation.
Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Quinazolinones; Treatment Outcome
PubMed: 35415873
DOI: 10.1111/1759-7714.14415 -
Skin Appendage Disorders Mar 2022Buerger disease, or thromboangiitis obliterans, is an inflammatory and occlusive process involving small and medium size arteries and veins, which generally affects the...
INTRODUCTION
Buerger disease, or thromboangiitis obliterans, is an inflammatory and occlusive process involving small and medium size arteries and veins, which generally affects the lower limbs of young adult male with the habit of smoking.
CASE PRESENTATION
This paper reports 2 patients who developed nail lesions as the first sign of Buerger disease.
CONCLUSION
Signs and symptoms of Buerger's disease are secondary to the inflammatory process and arterial occlusion which results in severe ischemia. Involvement of nails is not common, but we found 2 different clinical features which have not been previously reported in the literature: chronic paronychia, and proximal leukonychia or onycholysis and nail bed erosion.
PubMed: 35415181
DOI: 10.1159/000518982 -
The Journal of International Medical... Mar 2022Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are the first-line treatment for -mutant non-small cell lung cancer. Toxicities...
Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are the first-line treatment for -mutant non-small cell lung cancer. Toxicities related to EGFR-TKIs include skin rash, paronychia, and diarrhea, which in some cases can lead to dose reductions or treatment interruptions. Herein, we report the case of a 51-year-old woman affected by advanced adenocarcinoma harboring an exon 19 deletion in the gene, who was treated with second-generation EGFR-TKI following a scheduled gradual dose reduction to better manage toxicities. Following prescription labeling, treatment was initiated at a dose of 40 mg daily. After a few months, the dose was reduced to 30 mg daily owing to grade 3 skin toxicity. A metabolic complete tumor response was observed after 1 year of treatment, then therapy was continued at 20 mg daily, enabling disease stabilization. In conclusion, low dose afatinib was effective in an -mutant non-small cell lung cancer patient who required dose reductions to better manage toxicities.
Topics: Afatinib; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Genes, erbB-1; Humans; Lung Neoplasms; Middle Aged; Mutation
PubMed: 35291829
DOI: 10.1177/03000605211058864 -
Annals of Medicine Dec 2022Nail conditions are not only aesthetic concerns, and nail changes may be a clue to an underlying systemic diseases or infection. Without timely treatment, nail diseases... (Review)
Review
Nail conditions are not only aesthetic concerns, and nail changes may be a clue to an underlying systemic diseases or infection. Without timely treatment, nail diseases can continue to worsen and significantly impair performance of daily activities and reduce quality of life. Examination of the nails is essential at every medical visit, and may uncover important findings. Brittle nail syndrome, onychomycosis, paronychia, nail psoriasis, longitudinal melanonychia, Beau's lines, onychomadesis and retronychia are common nail disorders seen in clinical practice. These conditions stem from infectious, inflammatory, neoplastic and traumatic aetiologies. Though each nail condition presents with its own distinct characteristics, the clinical findings may overlap between different conditions, resulting in misdiagnosis and treatment delays. Patients can present with nail plate changes (e.g. hyperkeratosis, onycholysis, pitting), discolouration, pain and inflammation. The diagnostic work-up of nail disease should include a detailed history and clinical examination of all 20 nail units. Dermoscopy, diagnostic imaging and histopathologic and mycological analyses may be necessary for diagnosis. Nail findings concerning for malignancy should be promptly referred to a dermatologist for evaluation and biopsy. Nail disease management requires a targeted treatment approach. Treatments include topical and/or systemic medications, discontinuation of offending drugs or surgical intervention, depending on the condition. Patient education on proper nail care and techniques to minimize further damage to the affected nails is also important. This article serves to enhance familiarity of the most common nail disorders seen in clinical practice. It will highlight the key clinical manifestations, systematic approaches to diagnosis and treatment options for each nail condition to improve diagnosis and management of nail diseases, as well as patient outcomes.Key messagesNail disease is not only a cosmetic issue, as nail changes can indicate the presence of a serious underlying systemic disease, infection or malignancy.Nail pain and changes associated with NP are physically and emotionally distressing and may contribute to functional impairment and diminished quality of life.LM is a hallmark sign of subungual melanoma and this finding warrants further investigation to rule out malignancy.
Topics: Humans; Nail Diseases; Nails; Neoplasms; Psoriasis; Quality of Life
PubMed: 35238267
DOI: 10.1080/07853890.2022.2044511 -
Frontiers in Oncology 2022Epidermal growth factor receptor (EGFR) inhibitors are widely used to treat various types of cancers such as non-small cell lung cancer, head and neck cancer, breast... (Review)
Review
Epidermal growth factor receptor (EGFR) inhibitors are widely used to treat various types of cancers such as non-small cell lung cancer, head and neck cancer, breast cancer, pancreatic cancer. Adverse reactions such as skin toxicity, interstitial lung disease, hepatotoxicity, ocular toxicity, hypomagnesemia, stomatitis, and diarrhea may occur during treatment. Because the EGFR signaling pathway is important for maintaining normal physiological skin function. Adverse skin reactions occurred in up to 90% of cancer patients treated with EGFR inhibitors, including common skin toxicities (such as papulopustular exanthemas, paronychia, hair changes) and rare fatal skin toxicities (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis). This has led to the dose reduction or discontinuation of EGFR inhibitors in the treatment of cancer. Recently, progress has been made about research on the skin toxicity of EGFR inhibitors. Here, we summarize the mechanism of skin toxicity caused by EGFR inhibitors, measures to prevent severe fatal skin toxicity, and provide reference for medical staff how to give care and treatment after adverse skin reactions.
PubMed: 35223483
DOI: 10.3389/fonc.2022.804212 -
Translational Cancer Research Apr 2021Epidermal growth factor receptor (EGFR) inhibitors, as a first-line drug treatment in the EGFR-sensitive mutation of advanced non-small-cell lung cancer (NSCLC), has...
Epidermal growth factor receptor (EGFR) inhibitors, as a first-line drug treatment in the EGFR-sensitive mutation of advanced non-small-cell lung cancer (NSCLC), has been used in a wide variety of malignancies. These therapies have various troublesome side effects including diarrhea, stomatitis, mucositis, rash, dry skin and paronychia which may impact a patient's clinical outcome in addition to their beneficial effects. Here, we report a rare case of a 69-year-old male having advanced NCSLC treated with gefitinib, who developed EGFR tyrosine kinase inhibitor (TKI)-related multiple ulcers accompanied by bleeding. After a detailed examination and multidisciplinary discussion, we have learnt that early identification of gastrointestinal (GI) bleeding and blood in urine is due to targeted drugs rather than other causes such as ulcer and stones. Good results have also been achieved by reducing drug dosage under close observation. So far, the patient has been followed up for 15 months, and his condition remained stable. Up to now, there is no case of such severe side effect having been found, and no guidelines recommended for handling such adverse events. Through clinical case sharing, early recognition and proactive management are particularly important in order to minimize appropriately the effect of these adverse events. The whole course of a disease can be vividly illustrated through a case report, so as to provide more effective guiding principles for clinicians.
PubMed: 35116516
DOI: 10.21037/tcr-20-3420 -
Clinical Cancer Research : An Official... Apr 2022EGFR pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen...
PURPOSE
EGFR pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen presentation during anti-PD-1 monotherapy in humans remain unknown. We hypothesized that afatinib, an irreversible EGFR tyrosine kinase inhibitor, would improve outcomes in patients treated with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) by promoting antigen presentation and immune activation in the tumor microenvironment.
PATIENTS AND METHODS
The ALPHA study (NCT03695510) was a single-arm, Phase II study with Simon's 2-stage design. Afatinib and pembrolizumab were administered to patients with platinum-refractory, recurrent, or metastatic HNSCC. The primary endpoint was the objective response rate (ORR). The study applied gene expression analysis using a NanoString PanCancer Immune Profiling Panel and next-generation sequencing using FoundationOne CDx.
RESULTS
From January 2019 to March 2020, the study enrolled 29 eligible patients. Common treatment-related adverse events were skin rash (75.9%), diarrhea (58.6%), and paronychia (44.8%). Twelve patients (41.4%) had an objective partial response to treatment. The median progression-free survival was 4.1 months, and the median overall survival was 8.9 months. In a paired tissue analysis, afatinib-pembrolizumab were found to upregulate genes involved in antigen presentation, immune activation, and natural killer cell-mediated cytotoxicity. Unaltered methylthioadenosine phosphorylase and EGFR amplification may predict the clinical response to the therapy.
CONCLUSIONS
Afatinib may augment pembrolizumab therapy and improve the ORR in patients with HNSCC. Bioinformatics analysis suggested the enhancement of antigen presentation machinery in the tumor microenvironment.
Topics: Afatinib; Antibodies, Monoclonal, Humanized; Carcinoma, Squamous Cell; ErbB Receptors; Head and Neck Neoplasms; Humans; Neoplasm Recurrence, Local; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment
PubMed: 35046059
DOI: 10.1158/1078-0432.CCR-21-3025