Purpose: This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage epidermal growth factor receptor (EGFR)+ non–small cell lung cancer (NSCLC) who received sequential afatinib and osimertinib and to compare the outcomes with other second-line regimens (comparator group). Materials and Methods: In this updated report, the existing medical records were reviewed and rechecked. TOT and OS were updated and analyzed according to clinical features using the Kaplan-Meier method and log-rank test. TOT and OS were compared with those of the comparator group, in which most patients received pemetrexed-based treatments. A multivariable Cox proportional hazard model was used to evaluate features that could affect survival outcomes. Results: The median observation time was 31.0 months. The follow-up period was extended to 20 months. A total of 401 patients who received first-line afatinib were analyzed (166 with T790M+ and second-line osimertinib, and 235 with unproven T790M and other second-line agents). Median TOTs on afatinib and osimertinib were 15.0 months (95% confidence interval [CI], 14.0 to 16.1) and 11.9 months (95% CI, 8.9 to 14.6), respectively. The median OS in the osimertinib group was 54.3 months (95% CI, 46.7 to 61.9), much longer than that in the comparator group. In patients who received osimertinib, the OS was longest with Del19+ (median, 59.1; 95% CI, 48.7 to 69.5). Conclusion This is one of the largest real-world studies reporting the encouraging activity of sequential afatinib and osimertinib in Asian patients with EGFR+ NSCLC who acquired the T790M mutation, particularly Del19+.

Purpose: Although osimertinib is the standard-of-care treatment of epidermal growth factor receptor (EGFR) T790M mutation–positive non–small cell lung cancer, real-world evidence on the efficacy of osimertinib is not enough to reflect the complexity of the entire course of treatment. Herein, we report on the use of osimertinib in patients with EGFR T790M mutation–positive non–small cell lung cancer who had previously received EGFR tyrosine kinase inhibitor (TKI) treatment in Korea. Materials and Methods: Patients with confirmed EGFR T790M after disease progression of prior EGFR-TKI were enrolled and administered osimertinib 80 mg daily. The primary effectiveness outcome was progression-free survival, with time-to-treatment discontinuation, treatment and adverse effects leading to treatment discontinuation, and overall survival being the secondary endpoints. Results: A total of 558 individuals were enrolled, and 55.2% had investigator-assessed responses. The median progression-free survival was 14.2 months (95% confidence interval [CI], 13.0 to 16.4), and the median time-to-treatment discontinuation was 15.0 months (95% CI, 14.1 to 15.9). The median overall survival was 36.7 months (95% CI, 30.9 to not reached). The benefit with osimertinib was consistent regardless of the age, sex, smoking history, and primary EGFR mutation subtype. However, hepatic metastases at the time of diagnosis, the presence of plasma EGFR T790M, and the shorter duration of prior EGFR-TKI treatment were poor predictors of osimertinib treatment. Ten patients (1.8%), including three with pneumonitis, had to discontinue osimertinib due to severe adverse effects. Conclusion Osimertinib demonstrated its clinical effectiveness and survival benefit for EGFR T790M mutation–positive in Korean patients with no new safety signals.

Background: Recent reports have suggested that pneumonitis is a rare complication following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).However, its clinical features and outcomes are not well known. The aim of this study was to identify the clinical characteristics and outcomes of patients with vaccine-associated pneumonitis following vaccination against SARS-CoV-2. Methods: In this nationwide multicenter survey study, questionnaires were distributed to pulmonary physicians in referral hospitals. They were asked to report cases of development or exacerbation of interstitial lung disease (ILD) associated with the coronavirus disease 2019 vaccine. Vaccine-associated pneumonitis was defined as new pulmonary infiltrates documented on chest computed tomography within 4 weeks of vaccination and exclusion of other possible etiologies. Results: From the survey, 49 cases of vaccine-associated pneumonitis were identified between February 27 and October 30, 2021. After multidisciplinary discussion, 46 cases were analyzed. The median age was 66 years and 28 (61%) were male. The median interval between vaccination and respiratory symptoms was 5 days. There were 20 (43%), 17 (37%), and nine (19%) patients with newly identified pneumonitis, exacerbation of pre-diagnosed ILD, and undetermined pre-existing ILD, respectively. The administered vaccines were BNT162b2 and ChAdOx1 nCov-19/AZD1222 each in 21 patients followed by mRNA-1273 in three, and Ad26.COV2.S in one patient. Except for five patients with mild disease, 41 (89%) patients were treated with corticosteroid. Significant improvement was observed in 26 (57%) patients including four patients who did not receive treatment. However, ILD aggravated in 9 (20%) patients despite treatment. Mortality was observed in eight (17%) patients. Conclusion These results suggest pneumonitis as a potentially significant safety concern for vaccines against SARS-CoV-2. Clinical awareness and patient education are necessary for early recognition and prompt management. Additional research is warranted to identify the epidemiology and characterize the pathophysiology of vaccine-associated pneumonitis.

Purpose: With the identification of epidermal growth factor receptor (EGFR) mutations in non–small cell lung cancer (NSCLC) cells, EGFR–tyrosine kinase inhibitors (TKIs) are being used widely as the first-line of treatment in NSCLC. These inhibitors block auto-phosphorylation of activated EGFR by competing with ATP binding and mediate EGFR degradation independent of exogenous epidermal growth factor, which is associated with the mutation variants of EGFR. However, the precise mechanisms underlying the TKI-mediated EGFR degradation are still unclear. Materials and Methods: To examine the physiological roles of miR-4487 and ubiquitin-specific peptidase 37 (USP37) in gefitinib-mediated EGFR degradation in NSCLC cells, multiple NSCLC cell lines were applied. The level of EGFR expression, apoptosis marker and autophagic flux were determined by western blot. Expression level of miR-4487 and cell cycle arrest was analyzed by TaqMan assay and flow cytometry respectively. Results: We found that gefitinib mediates EGFR degradation under normal culture conditions, and is dependent on autophagic flux and the mutation variants of EGFR. Gefitinib reduced expression levels of USP37, which mediated EGFR degradation similar to gefitinib. Our results also showed a gefitinib-mediated increase in endogenous miR-4487 level and presented evidence for the direct targeting of USP37 by miR-4487, resulting in the sequential enhancement of ubiquitination, autophagy, and EGFR degradation. Thus, the depletion of USP37 and overexpression of miR-4487 led to an increase in gefitinib-mediated apoptotic cell death. Conclusion These data suggest that miR-4487 is a potential target for treating NSCLC, and miR-4487/USP37-regulated EGFR degradation is a determinant for developing gefitinib resistance.

Background: There has been no comparison of the determinants of admission route between acute ischemic stroke (AIS) and acute myocardial infarction (AMI). We examined whether factors associated with direct versus transferred-in admission to regional cardiocerebrovascular centers (RCVCs) differed between AIS and AMI. Methods: Using a nationwide RCVC registry, we identified consecutive patients presenting with AMI and AIS between July 2016 and December 2018. We explored factors associated with direct admission to RCVCs in patients with AIS and AMI and examined whether those associations differed between AIS and AMI, including interaction terms between each factor and disease type in multivariable models. To explore the influence of emergency medical service (EMS) paramedics on hospital selection, stratified analyses according to use of EMS were also performed. Results: Among the 17,897 and 8,927 AIS and AMI patients, 66.6% and 48.2% were directly admitted to RCVCs, respectively. Multivariable analysis showed that previous coronary heart disease, prehospital awareness, higher education level, and EMS use increased the odds of direct admission to RCVCs, but the odds ratio (OR) was different between AIS and AMI (for the first 3 factors, AMI > AIS; for EMS use, AMI < AIS). EMS use was the single most important factor for both AIS and AMI (OR, 4.72 vs. 3.90). Hypertension and hyperlipidemia increased, while living alone decreased the odds of direct admission only in AMI;additionally, age (65–74 years), previous stroke, and presentation during non-working hours increased the odds only in AIS. EMS use weakened the associations between direct admission and most factors in both AIS and AMI. Conclusions Various patient factors were differentially associated with direct admission to RCVCs between AIS and AMI. Public education for symptom awareness and use of EMS is essential in optimizing the transportation and hospitalization of patients with AMI and AIS.

Idiopathic interstitial pneumonia (IIP) is a histologically identifiable pulmonary disease without a known cause that usually infiltrates the lung interstitium. IIP is largely classified into idiopathic pulmonary fibrosis, idiopathic non-specific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease (ILD), cryptogenic organizing pneumonia, desquamative interstitial pneumonia, and acute interstitial pneumonia. Each of these diseases has a different prognosis and requires specific treatment, and a multidisciplinary approach that combines chest high-resolution computed tomography (HRCT), histological findings, and clinical findings is necessary for their diagnosis. Diagnosis of IIP is made based on clinical presentation, chest HRCT findings, results of pulmonary function tests, and histological findings. For histological diagnosis, video-assisted thoracoscopic biopsy and transbronchial lung biopsy are used. In order to identify ILD associated with connective tissue disease, autoimmune antibody tests may also be necessary. Many biomarkers associated with disease prognosis have been recently discovered, and future research on their clinical significance is necessary. The diagnosis of ILD is difficult because patterns of ILD are both complicated and variable. Therefore, as with other diseases, accurate history taking and meticulous physical examination are crucial.
Biomarkers ; Biopsy ; Classification ; Connective Tissue Diseases ; Cryptogenic Organizing Pneumonia ; Diagnosis ; Idiopathic Interstitial Pneumonias ; Idiopathic Pulmonary Fibrosis ; Lung ; Lung Diseases ; Lung Diseases, Interstitial ; Physical Examination ; Prognosis ; Respiratory Function Tests ; Thorax

Idiopathic interstitial pneumonia (IIP) is a histologically identifiable pulmonary disease without a known cause that usually infiltrates the lung interstitium. IIP is largely classified into idiopathic pulmonary fibrosis, idiopathic non-specific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease (ILD), cryptogenic organizing pneumonia, desquamative interstitial pneumonia, and acute interstitial pneumonia. Each of these diseases has a different prognosis and requires specific treatment, and a multidisciplinary approach that combines chest high-resolution computed tomography (HRCT), histological findings, and clinical findings is necessary for their diagnosis. Diagnosis of IIP is made based on clinical presentation, chest HRCT findings, results of pulmonary function tests, and histological findings. For histological diagnosis, video-assisted thoracoscopic biopsy and transbronchial lung biopsy are used. In order to identify ILD associated with connective tissue disease, autoimmune antibody tests may also be necessary. Many biomarkers associated with disease prognosis have been recently discovered, and future research on their clinical significance is necessary. The diagnosis of ILD is difficult because patterns of ILD are both complicated and variable. Therefore, as with other diseases, accurate history taking and meticulous physical examination are crucial.

PURPOSE: We investigated the clinical characteristics of patients who developed thyroid dysfunction and evaluated the risk factors for hypothyroidism following radiotherapy and chemotherapy in pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). METHODS: The medical records of 66 patients (42 males) treated for medulloblastoma (n=56) or PNET (n=10) in childhood between January 2000 and December 2014 at Seoul National University Children’s Hospital were retrospectively reviewed. A total of 21 patients (18 high-risk medulloblastoma and 3 PNET) underwent high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) RESULTS: During the median 7.6 years of follow-up, 49 patients (74%) developed transient (n=12) or permanent (n=37) hypothyroidism at a median 3.8 years of follow-up (2.9–4.6 years). Younger age ( < 5 years) at radiation exposure (P=0.014 vs. ≥9 years) and HDCT (P=0.042) were significantly predictive for hypothyroidism based on log-rank test. However, sex, type of tumor, and dose of craniospinal irradiation (less vs. more than 23.4 Gy) were not significant predictors. Cox proportional hazard model showed that both younger age (< 5 years) at radiation exposure (hazard ratio [HR], 3.1; vs. ≥9 years; P=0.004) and HDCT (HR, 2.4; P=0.010) were significant predictors of hypothyroidism. CONCLUSIONS: Three-quarters of patients with pediatric medulloblastoma or PNET showed thyroid dysfunction, and over half had permanent thyroid dysfunction. Thus, frequent monitoring of thyroid function is mandatory in all patients treated for medulloblastoma or PNET, especially, in very young patients and/or high-risk patients recommended for HDCT/ASCR.
Craniospinal Irradiation ; Drug Therapy ; Follow-Up Studies ; Humans ; Hypothyroidism ; Medical Records ; Medulloblastoma* ; Neuroectodermal Tumors, Primitive* ; Pediatrics ; Proportional Hazards Models ; Radiation Exposure ; Radiotherapy ; Retrospective Studies ; Risk Factors ; Seoul ; Stem Cells ; Thyroid Gland* ; Thyroid Hormones

OBJECTIVETo examinie the synergistic effects of Banxia Xiexin Decoction (, Known as Banhasasim-tang in Korean) extract (BXDE) on cisplatin-induced cytotoxicity in the A549 human lung cancer cell lines.

METHODSA549 cells were treated with varying concentrations (50-200 μg/mL) of cisplatin and BXDE alone or in combination for 96 h. We used 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan assay and flow cytometry to analyze cell viability and apoptosis, respectively.

RESULTSThe exposure of cells to cisplatin and BXDE alone or in combination decreased cell viability dose- and time-dependently (P<0.05), which was found to be mediated by the apoptotic pathway as confirmed by the increase in the annexin V/propidium iodide- stained cell population and a ladder pattern of discontinuous DNA fragments. Furthermore, the apoptosis was inhibited by the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (z-VAD-FMK).

CONCLUSIONSBXDE significantly potentiated apoptotic effects of cisplatin in A549 cells. Moreover, apoptosis induced by BXDE might be the pivotal mechanism mediating its chemopreventative action against cancer.

A549 Cells ; Apoptosis ; drug effects ; Apoptosis Regulatory Proteins ; metabolism ; Caspase Inhibitors ; pharmacology ; Cisplatin ; pharmacology ; DNA Fragmentation ; drug effects ; Humans ; Plant Extracts ; pharmacology

PURPOSE: Following legal reform in 2013, the annual number of asylum seekers entering South Korea has increased from 1,143 in 2012 to 5,711 in 2015. We interviewed six African refugee mothers of young children regarding their health needs and barriers to access maternal child health services. METHODS: We recruited mothers who had visited a clinic for immigrants between July 2013 and August 2015. Participants were African refugee women, aged over 18 years, who had given birth in Korea within the previous 5 years and had come to Korea over a year before recruitment. Interview questions examined participants' experiences in pregnancy and childbirth and concerns regarding their child's health status. Initial data analysis involved all researchers' immersion in the entire collection of transcripts. We then noted recurrent topics and themes and identified similar issues. RESULTS: At the time of giving birth, 5 participants were asylum seekers and one had undocumented status. The following barriers impeded their access to maternal child healthcare: socioeconomic factors (unstable social identity, low economic status, difficulty obtaining health insurance), language barriers (lack of linguistically appropriate health information, limited access to translation services), and cultural barriers (religious and cultural differences). Weak social support also hindered access to healthcare soon after migration; however, social links with the community emerged as a key coping strategy following settlement. CONCLUSION: We identified barriers to maternal and child healthcare and coping strategies among African refugee mothers in Korea. Future research should assess refugees' health status and improve health access and literacy among refugee mothers.
Child ; Communication Barriers ; Delivery of Health Care* ; Emigrants and Immigrants ; Female ; Health Services Accessibility ; Humans ; Immersion ; Infant ; Korea* ; Literacy ; Maternal-Child Health Services ; Mothers* ; Parturition ; Pregnancy ; Refugees* ; Social Identification ; Socioeconomic Factors ; Statistics as Topic