• EGFR-tyrosine kinase inhibitor
• Osimertinib
• UPLC-MS/MS
• concentration determination

• ALK+
• ROS1+
• SAF-189s
• exposure–response relationship
• non-small cell lung cancer
• population pharmacokinetics

• Adjuvant treatment
• Lung neoplasms
• Neoadjuvant treatment
• Perioperative treatment
• Targeted therapy

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/surgery
• ErbB Receptors/genetics
• ErbB Receptors/antagonists & inhibitors
• Lung Neoplasms/genetics
• Lung Neoplasms/drug therapy
• Lung Neoplasms/surgery
• Mutation
• Molecular Targeted Therapy
• Protein Kinase Inhibitors/therapeutic use

• epidermal growth factor receptor mutation status
• non-small-cell lung cancer
• real-word evidence
• relapse
• survival
• treatment

• lung cancer
• cancer

• Humans
• Brain Neoplasms/drug therapy
• Brain Neoplasms/genetics
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Crizotinib/pharmacology
• Crizotinib/therapeutic use
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Protein Kinase Inhibitors/therapeutic use
• Anaplastic Lymphoma Kinase

• National Natural Science Foundation of China (National Science Foundation of China)

• QT prolongation
• cardiac electrophysiology
• delayed conduction
• ion channel
• osimertinib

• National Natural Science Foundation of China

• Adjuvant therapies
• epidermal growth factor receptor (EGFR)
• epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs)
• non-small cell lung cancer (NSCLC)
• postoperative

• P30 CA008748 NCI NIH HHS

• Gamma Knife
• brain metastasis
• radiosurgery
• surgical cavity
• survival
• tumor control

• EGFR
• Gamma Knife
• brain metastasis
• epidermal growth factor receptor
• mutations
• oncology
• stereotactic radiosurgery
• survival
• tumor control
• tyrosine kinase inhibitor

• gefitinib
• osimertinib
• severe stomatitis

To broadly review the modern management of brain metastases.

Brain metastases are the commonest neurological manifestation of cancer and a major cause of morbidity in cancer patients. Brain metastases are increasing in frequency, as a result of longer life expectancy of cancer patients, more sensitive methods for brain metastasis detection and an ageing population. The proportional incidence of brain metastases according to cancer of origin, from greatest to least, is lung cancer, melanoma, renal, breast and colorectal cancers. Patients with lung cancer and melanoma are most likely to have brain metastases at diagnosis. Brain metastases cause a variety of symptoms, depending on their size and location, whether they cause mass effect and oedema, compression of the brain parenchyma, or focal neurological deficits. The major differential diagnoses of brain metastases include primary tumours and vascular/inflammatory lesions. Prognosis is dependent on the site, number and volume of lesions, the patients’ performance status, age and the activity and extent of extracranial disease.

English literature articles in PubMed from 1950 to June 2021 were reviewed. Article bibliographies provided further references.

Treatment of brain metastasis patients has moved from considering them as a homogenous population of patients, to individualised treatment. In those brain metastases patients of satisfactory performance status with a solitary lesion, especially one in a non-eloquent/accessible area causing significant mass effect and/or raised intracranial pressure or for whom the diagnosis is in doubt (histology needed), surgical resection is usually the treatment of choice. For multiple brain metastases, radiotherapy with or without systemic therapies are usually employed. For relatively fit patients with limited numbers of brain metastases (e.g., 4 or less), stereotactic radiosurgery is standard of care. Current clinical trials are testing the efficacy of stereotactic treatment alone for >4 brain metastases (although it is increasingly used for such patients in many centres) as well as integration of local therapies with targeted and immunological therapies in appropriately selected cases. In certain circumstances, cranial irradiation can be omitted.

• Brain
• metastases
• radiotherapy
• surgery
• targeted therapies

• EGFR mutation
• afatinib
• erlotinib
• gefitinib
• real-world effectiveness

Cancer patients account for 15% of all admissions to intensive care unit (ICU) and 5% will experience a critical illness resulting in ICU admission. Mortality rates have decreased during the last decades because of new anticancer therapies and advanced organ support methods. Since early critical care and organ support is associated with improved survival, timely identification of the onset of clinical signs indicating critical illness is crucial to avoid delaying. This article focused on relevant and current information on epidemiology, diagnosis, and treatment of the main clinical disorders experienced by critically ill cancer patients.

• Acute respiratory failure
• Cancer
• Cardiotoxicity
• Chemotherapy
• Critical care
• Infection
• Mechanical ventilation
• Neutropenia
• Postoperative
• Sepsis

• Genome sequencing
• Immune checkpoint inhibitors
• Non-small cell lung carcinoma

• B7-H1 Antigen/genetics
• Brain Neoplasms/genetics
• Brain Neoplasms/secondary
• Brain Neoplasms/surgery
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/secondary
• Carcinoma, Non-Small-Cell Lung/surgery
• Combined Modality Therapy
• ErbB Receptors/genetics
• High-Throughput Nucleotide Sequencing/methods
• Humans
• Immune Checkpoint Inhibitors/therapeutic use
• Immunotherapy
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Male
• Middle Aged
• Mutation/genetics
• Neurosurgical Procedures/methods
• Smoking

Osimertinib has demonstrated efficacy against stable or asymptomatic central nervous system (CNS) metastases of epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in phase 2 and 3 clinical trials that allowed prior CNS radiotherapy. However, the efficacy of osimertinib only or the optimal treatment combination or sequence of radiotherapy has not been investigated. A 74-year-old woman diagnosed with T4N1M1c Stage IVB lung adenocarcinoma with EGFR mutation presented with a left upper lobe mass and multiple bilateral lung metastases. A total of more than 20 asymptomatic multiple brain metastases with a maximum diameter of 12 mm were diagnosed simultaneously. Osimertinib was administered as first-line treatment. Whole brain radiotherapy was deferred because she had no neurological symptoms. After 5 weeks, the multiple brain metastases disappeared completely, together with the response in the lung lesions. This case demonstrated that first-line treatment with osimertinib could even achieve complete remission of multiple brain metastases comprising as many as twenty lesions of EGFR-mutated NSCLC without radiation therapy. Radiation therapy for brain metastases can be deferred or even withheld. A new treatment strategy for EGFR mutated NSCLC with CNS metastases should be investigated using osimertinib, especially regarding optimal combination or sequence of radiotherapy.

• ALK NSCLC
• alectinib
• costs
• crizotinib
• economic evaluation
• metastasis CNS

• Epidermal growth factor receptor
• Gamma knife radiosurgery
• Non-small cell lung cancer
• Progression-free survival

• ALK-TKI
• adverse events
• brain metastases
• lung adenocarcinoma
• radiotherapy

• Adenocarcinoma of Lung/genetics
• Adenocarcinoma of Lung/pathology
• Adenocarcinoma of Lung/therapy
• Adult
• Aged
• Anaplastic Lymphoma Kinase/antagonists & inhibitors
• Anaplastic Lymphoma Kinase/genetics
• Antineoplastic Agents/adverse effects
• Biomarkers, Tumor
• Brain Neoplasms/genetics
• Brain Neoplasms/secondary
• Brain Neoplasms/therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/pathology
• Carcinoma, Non-Small-Cell Lung/therapy
• Chemoradiotherapy/adverse effects
• Cranial Irradiation/adverse effects
• Crizotinib/adverse effects
• Drug-Related Side Effects and Adverse Reactions/etiology
• ErbB Receptors/genetics
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Gene Rearrangement
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Lung Neoplasms/therapy
• Male
• Middle Aged
• Mutation
• Prognosis
• Radiodermatitis/etiology
• Retrospective Studies

• ALK
• ceritinib
• non-small cell lung cancer
• resistance

Background: Response Evaluation Criteria in Solid Tumors (RECIST) has been widely utilized to evaluate new therapeutic strategies in cancer. However, RECIST fails to assess the heterogeneity of response in highly active therapies. Depth of response (DepOR), defined as the maximum percentage change in tumor size compared with baseline, may provide a new strategy to evaluate disease response. In the present study, we studied the association between DepOR and progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI).

Methods: Advanced NSCLC patients harboring EGFR driver mutation (L858R or exon 19 deletion) treated with EGFR-TKI from August 2014 to July 2017 from two sites were retrospetively collected for analysis. Patients were divided into four groups by DepOR (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, Q4 = 76-100%). Kaplan-Meier curves were plotted for PFS against DepOR and the hazard ratio (HR) was determined through univariable and multivariable cox regression models.

Results: In total, 265 patients were included for analysis. The number of patients in Group Q1-Q4 were 91 (34.3%), 73 (27.5%), 65 (24.5%) and 36 (13.6%), respectively. A greater DepOR was significantly associated with a longer PFS (Log-rank P<0.0001). The HRs (95% CI) for PFS comparing patients with different DepOR status were 0.58 (0.42-0.80) for Q2, 0.49 (0.35-0.69) for Q3, and 0.33 (0.22-0.50) for Q4, all compared with patients in Q1. DepOR as a continuous variable was also associated with prolonged PFS (HR, 0.20; 95% CI, 0.13-0.33; P<0.001). Additionally, in the multivariable cox regression model, abnormal LDH, brain metastasis and male were found to be associated with worse PFS outcomes (P<0.05).

Conclusion: A greater DepOR is significantly associated with PFS benefit in advanced NSCLC treated with EGFR-TKI, suggesting that it may be a useful clinical outcome to evaluate the response of targeted therapy.

• DepOR
• EGFR-TKI
• NSCLC
• targeted therapy

• brain metastasis
• genomic
• neurocognition
• stereotactic radiosurgery
• targeted therapy
• whole brain radiation therapy

• Brain Neoplasms/pathology
• Brain Neoplasms/therapy
• Disease Management
• Humans
• Neoplasm Metastasis/therapy
• Radiosurgery
• Radiotherapy/trends
• Therapeutics/adverse effects
• Therapeutics/trends

Central nervous system (CNS) metastasis is one of the serious complications of epidermal growth factor receptor (EGFR)‐mutant lung cancer, which arises due to poor penetration of the brain–blood barrier by EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Although osimertinib, a third‐generation EGFR‐TKI, has efficacy against CNS metastases, further treatment modalities are still needed as some of these lesions do not respond to osimertinib, or undergo progression after an initial response to this drug if radiotherapy has already been conducted. Here, we investigated the efficacy of water‐soluble erlotinib (NUFS‐sErt) against these metastases. This agent was synthesized using a nano‐particulation platform technology utilizing fat and supercritical fluid (NUFS™) to resolve the low solubility problem that typically prevents the creation of injectable forms of EGFR‐TKIs. The average NUFS‐sErt particle size was 236.4 nm, and it showed time‐dependent dissolution in culture media. The effects of NUFS‐sErt were similar to those of conventional erlotinib in terms of inhibiting the proliferation of EGFR‐mutant lung cancer cells and suppressing EGFR signaling. In an intraperitoneal xenograft model of HCC827 cells, intraperitoneal administration of NUFS‐sErt produced a dose‐dependent inhibition of tumor growth and enhanced survival rate. Notably, the injection of NUFS‐sErt into the brain ventricle caused significant tumor growth inhibition in an intracranial xenograft model. Hence, our current findings indicate that NUFS‐sErt is a novel, water‐soluble form of erlotinib that can be administered using intraventricular or intrathecal injections. The target cases would be patients with a progressive CNS metastasis and no other therapeutic options. This drug could also be given intravenously to patients with swallowing difficulties or an inability to ingest due to a medical condition.

• EGFR-TKI
• NUFS-sErt
• brain metastasis
• lung cancer
• nano-particulation

Non-small cell lung cancer (NSCLC) is one of the most deadly cancers with poor prognosis. Recent findings suggested that the lncRNA HOTAIR played an important role in tumorigenesis and metastasis. In the present study, HOTAIR was highly expressed in NSCLC tumor tissues and cell lines (H1299, H23, H292, and A549). Downregulation of HOTAIR suppressed cell proliferation and invasion, while it promoted apoptosis of NSCLC cells. The targeting relationship between HOTAIR and miR-613 was first revealed by bioinformatics prediction. miR-613 was found to be lowly expressed in NSCLC tumor tissues and cell lines. Knockdown of HOTAIR increased the expression of miR-613 significantly, and cotransfection with miR-613 inhibitor reversed this increase, indicating that the expression of miR-613 was negatively regulated by HOTAIR. The targeting relationship between HOTAIR and miR-613 was further confirmed through the luciferase report assay. Moreover, the cotransfection of HOTAIR shRNA and miR-613 inhibitor counteracted the tumor inhibition effects of HOTAIR shRNA through promoting cell proliferation and invasion while suppressing apoptosis in NSCLC cells, suggesting that the HOTAIR/miR-613 axis was involved in tumorigenesis and metastasis of NSCLC. In vivo experiments revealed that knockdown of HOTAIR decreased tumor growth and invasion and increased apoptosis and miR-613 expression. In conclusion, our study indicated that downregulation of HOTAIR suppressed tumorigenesis and metastasis of NSCLC via upregulating the expression of miR-613. The HOTAIR/miR-613 axis might provide a new potential therapeutic strategy for NSCLC treatment.

• autophagy
• carcinoma, non-small-cell lung
• claudin-1

• A549 Cells
• Apoptosis/drug effects
• Autophagy/drug effects
• Autophagy-Related Protein-1 Homolog/metabolism
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/pathology
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Cisplatin/pharmacology
• Claudin-1/genetics
• Claudin-1/metabolism
• Drug Resistance, Neoplasm/drug effects
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Silencing/drug effects
• Humans
• Inhibitory Concentration 50
• Intracellular Signaling Peptides and Proteins/metabolism
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Phosphorylation/drug effects
• Protein Biosynthesis/drug effects
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Transcription, Genetic/drug effects
• Up-Regulation/drug effects

• Brain metastases
• Disease-specific graded prognostic assessment
• EGFR mutation
• Leptomeningeal index
• Non-small cell lung cancer
• Prognostic index
• Stereotactic radiosurgery
• Whole brain radiotherapy