Clinical and financial impact of immune checkpoint inhibitors following platinum chemotherapy in patients with advanced or metastatic non-small cell lung cancer: a nationwide population-based study.

Background: Although various studies have demonstrated that the clinical efficacy of immune checkpoint inhibitors (ICIs) improves the prognosis of patients with non-small cell lung cancer (NSCLC), studies on the financial aspects based on large population-based data are needed. This study aimed to analyze the differences in medical expenses and the effect of ICIs on the prognosis of patients with advanced or metastatic NSCLC. Methods: Patients newly diagnosed with stage IIIB or IV NSCLC who received palliative chemotherapy between 2013 and 2020 were selected from the nationwide database of the population covered by the Korean National Health Insurance Service. Interrupted time-series analysis was performed to evaluate the effects of subsequent ICI use after platinum-based cytotoxic chemotherapy (CC) on overall mortality. Progression-free survival and medical expenditure were also assessed. Results: In the final study population, 2,485 and 4,812 patients were included in the ICI and non-ICI groups, respectively. ICI treatment significantly lowered the risk of death [adjusted hazard ratio, 0.79; 95% confidence interval (CI): 0.75-0.84]. And the ICI-treated patients were less likely to experience disease progression (adjusted odds ratios, 0.92; 95% CI: 0.85-0.99). Furthermore, after the introduction of ICIs, both total and cancer-related medical expenses per capita showed an increasing trend [ß: $4.56K, standard error (SE): $0.27K, P<0.0001 and ß: $4.54K, SE: $0.27K, P<0.0001, respectively]. Conclusions: Subsequent ICI use after platinum-based CC improved the overall survival rate of patients with advanced NSCLC. With the increasing burden of individual medical expenses, further research is required to identify patients for whom ICI treatment may be effective.

SARS-CoV-2-Infected Pregnant Woman Requiring 38 Days of Extracorporeal Membrane Oxygenation Experiences Rectal Ulcer Bleeding: A Case Report.

Pregnancy has been shown to be associated with an adverse clinical course and symptomatic patients with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Extracorporeal membrane oxygenation (ECMO) is rarely used in pregnant or postpartum women with severe coronavirus disease 2019 (COVID-19). Here, we report the rare case of a pregnant woman diagnosed with SARS-CoV-2 infection placed on ECMO postpartum who subsequently received treatment for active rectal ulcer bleeding. Despite being placed on ECMO for 38 days and receiving a massive transfusion of 95 packs of red blood cells, she recovered and was discharged on hospital day 112. ECMO can be used in most patients with severe COVID-19, including pregnant patients, although potential coagulopathy complications must be considered.

: Short-term effects of exposure to particulate matter on hospital admissions for asthma and chronic obstructive pulmonary disease.

We investigated the effects of particulate matter (PM) factors on hospitalization rates for asthma and chronic obstructive pulmonary disease (COPD). We obtained data on pollutants-PM10, PM2.5-in Seoul, South Korea. We also investigated data for asthma and COPD exacerbation that required hospitalization from 2006 to 2016. We used a time-stratified case-crossover design and generalized additive models with log transformation to assess adjusted risk, and conditional logistic regression was performed to analyze these data. Our study showed that PM10 and PM2.5, on different best lag days, were associated with increased risks of COPD or asthma hospitalization. The odds ratios (ORs) for each per-unit increase in PM10 and PM2.5 were higher in patients with male asthma (PM10: OR, 1.012; 95% confidence interval [CI], 1.008-1.016 and PM2.5: OR, 1.015; 95% CI, 1008-1.023), preschool asthma (PM10: OR, 1.015; 95% CI, 1.006-1.015 and PM2.5: OR, 1.015; 95% CI, 1.009-1.024), male COPD (PM10: OR, 1.012; 95% CI, 1.005-1.019 and PM2.5: OR, 1.013; 95% CI, 1.000-1.026), and senior COPD (PM10: OR, 1.016; 95% CI, 1.008-1.024 and PM2.5: OR, 1.022; 95% CI, 1.007-1.036). Increasing PM levels increased hospitalizations for asthma and COPD. Additionally, the consequences may be different according to age and sex, and PM2.5 may have a more significant effect on airway disease patients than PM10.

ABT-737, a BH3 Mimetic, Enhances the Therapeutic Effects of Ionizing Radiation in K-ras Mutant Non-Small Cell Lung Cancer Preclinical Model.

PURPOSE: Tumor radioresistance and dose-limiting toxicity restrict the curative potential of radiotherapy, requiring novel approaches to overcome the limitations and augment the efficacy. Here, we investigated the effects of signal transducer and activator of transcription 3 (STAT3) activation and autophagy induction by irradiation on antiapoptotic proteins and the effectiveness of the BH3 mimetic ABT-737 as a radiosensitizer using K-ras mutant non-small cell lung cancer (NSCLC) cells and a KrasG12D:p53fl/fl mouse (KP mouse) model. MATERIALS AND METHODS: A549 and H460 cells were irradiated, and the expression of Bcl-2 family proteins, JAK/STAT transcriptional pathway, and autophagic pathway were evaluated by immunoblotting. The radiosensitizing effects of ABT-737 were evaluated using A549 and H460 cell lines with clonogenic assays and also by a KP mouse model with microcomputed tomography and immunohistochemistry. RESULTS: In A549 and H460 cells and mouse lung tissue, irradiation-induced overexpression of the antiapoptotic molecules Bcl-xL, Bcl-2, Bcl-w, and Mcl-1 through JAK/STAT transcriptional signaling induced dysfunction of the autophagic pathway. After treatment with ABT-737 and exposure to irradiation, the number of surviving clones in the cotreatment group was significantly lower than that in the group treated with radiation or ABT-737 alone. In the KP mouse lung cancer model, cotreatment with ABT-737 and radiation-induced significant tumor regression; however, body weight changes in the combination group were not significantly different, suggesting that combination treatment did not cause systemic toxicity. CONCLUSION: These findings supported the radiosensitizing activity of ABT-737 in preclinical models, and suggested that clinical trials using this strategy may be beneficial in K-ras mutant NSCLC.

Event Prediction Model Considering Time and Input Error Using Electronic Medical Records in the Intensive Care Unit: Retrospective Study.

BACKGROUND: In the era of artificial intelligence, event prediction models are abundant. However, considering the limitation of the electronic medical record-based model, including the temporally skewed prediction and the record itself, these models could be delayed or could yield errors. OBJECTIVE: In this study, we aim to develop multiple event prediction models in intensive care units to overcome their temporal skewness and evaluate their robustness against delayed and erroneous input. METHODS: A total of 21,738 patients were included in the development cohort. Three events-death, sepsis, and acute kidney injury-were predicted. To overcome the temporal skewness, we developed three models for each event, which predicted the events in advance of three prespecified timepoints. Additionally, to evaluate the robustness against input error and delays, we added simulated errors and delayed input and calculated changes in the area under the receiver operating characteristic curve (AUROC) values. RESULTS: Most of the AUROC and area under the precision-recall curve values of each model were higher than those of the conventional scores, as well as other machine learning models previously used. In the error input experiment, except for our proposed model, an increase in the noise added to the model lowered the resulting AUROC value. However, the delayed input did not show the performance decreased in this experiment. CONCLUSIONS: For a prediction model that was applicable in the real world, we considered not only performance but also temporal skewness, delayed input, and input error.

Development and validation of a prognostic model for early triage of patients diagnosed with COVID-19.

We developed a tool to guide decision-making for early triage of COVID-19 patients based on a predicted prognosis, using a Korean national cohort of 5,596 patients, and validated the developed tool with an external cohort of 445 patients treated in a single institution. Predictors chosen for our model were older age, male sex, subjective fever, dyspnea, altered consciousness, temperature ≥ 37.5 °C, heart rate ≥ 100 bpm, systolic blood pressure ≥ 160 mmHg, diabetes mellitus, heart disease, chronic kidney disease, cancer, dementia, anemia, leukocytosis, lymphocytopenia, and thrombocytopenia. In the external validation, when age, sex, symptoms, and underlying disease were used as predictors, the AUC used as an evaluation metric for our model's performance was 0.850 in predicting whether a patient will require at least oxygen therapy and 0.833 in predicting whether a patient will need critical care or die from COVID-19. The AUCs improved to 0.871 and 0.864, respectively, when additional information on vital signs and blood test results were also used. In contrast, the protocols currently recommended in Korea showed AUCs less than 0.75. An application for calculating the prognostic score in COVID-19 patients based on the results of this study is presented on our website ( https://nhimc.shinyapps.io/ih-psc/ ), where the results of the validation ongoing in our institution are periodically updated.

Body mass index as a predictor of mortality in bronchiectasis: A nationwide population-based study.

INTRODUCTION: The prognosis of bronchiectasis is not well known. The purpose of this study was to evaluate the association between body mass index (BMI) and mortality in bronchiectasis using a large nationwide population-based cohort. MATERIAL AND METHODS: Using the National Health Insurance Service-Health Screening Cohort in Korea, individuals with bronchiectasis were identified from 2004 to 2006 and monitored for up to 10 years. Mortality in bronchiectasis was analyzed based on a BMI score <18.5 kg/m2 (underweight), 1.85-22.9 kg/m2 (normal weight), 23.0-24.9 kg/m2 (overweight), and >25.0 kg/m2 (obese). RESULTS: A total of 2769 individuals with bronchiectasis were included. The underweight, normal weight, overweight, and obese accounted for 5.1%, 40.4%, 25.4%, and 29.3% of all patients with bronchiectasis, respectively. Compared to normal weight, underweight in bronchiectasis was associated with increased all-cause mortality (hazard ratio [HR] = 2.60; 95% confidence interval [CI] = 1.92-3.54), while obese was associated with decreased all-cause mortality (HR = 0.71; 95% CI = 0.55-0.93). This relationship between BMI and mortality was more prominent in respiratory disease-related mortality. CONCLUSIONS: BMI is a predictor of mortality in bronchiectasis. Underweight is associated with increased mortality among individuals with bronchiectasis while obese is associated with decreased mortality.

Clinical outcomes of difficult-to-wean patients with ventilator dependency at intensive care unit discharge.

BACKGROUND: Ventilator-dependent patients in the intensive care unit (ICU) who are difficult to wean from invasive mechanical ventilation (IMV) have been increasing in number. However, data on the clinical outcomes of difficult-to-wean patients are lacking. We aimed to evaluate clinical outcomes in patients discharged from the ICU with tracheostomy and ventilator dependency. METHODS: We retrospectively investigated clinical course and survival in patients requiring home mechanical ventilation (HMV) with a tracheostomy and difficulty weaning from IMV during medical ICU admission from September 2013 through August 2016 at Severance Hospital, Yonsei University, Seoul, Korea. RESULTS: Of 84 difficult-to-wean patients who were started on HMV in the medical ICU, 72 survived, were discharged from the ICU, and were included in this analysis. HMV was initiated after a median of 23 days of IMV, and the successful weaning rate was 46% (n=33). In-hospital mortality rate was significantly lower in the successfully weaned group than the unsuccessfully weaned group (0% vs. 23.1%, respectively; P=0.010). Weaning rates were similar according to primary diagnosis, but high body mass index (BMI), low Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score at ICU admission, and absence of neuromuscular disease were associated with weaning success. After a median follow-up of 4.6 months (range, 1-27 months) for survivors, 3-month (n=64) and 6-month (n=59) survival rates were 82.5% and 72.2%, respectively. Survival rates were higher in the successfully weaned group than the unsuccessfully weaned group at 3 months (96.4% vs. 69.0%; P=0.017) and 6 months (84.0% vs. 62.1%; P=0.136) following ICU discharge. CONCLUSIONS: In summary, 46% of patients who started HMV were successfully weaned from the ventilator in general wards. High BMI, low APACHE II score, and absence of neuromuscular disease were factors associated with weaning success.

Methionyl-tRNA Synthetase is a Useful Diagnostic Marker for Lymph Node Metastasis in Non-Small Cell Lung Cancer.

PURPOSE: Identification of lymph node (LN) metastasis in non-small cell lung cancer (NSCLC) is critical for disease staging and selection of therapeutic modalities. Sometimes it is not possible to obtain LN core tissue by endobronchial ultrasound-guided transbronchial needle aspirate (EBUS-TBNA), resulting in low diagnostic yield. MATERIALS AND METHODS: In this study, 138 specimens were collected from 108 patients who underwent EBUS-TBNA under the suspicion of LN metastasis of NSCLC. Diagnostic yields of anti-CD45 and anti-methionyl-tRNA synthetase (MRS), immunofluorescent (IF) staining on cytology specimens were compared with those of conventional cytology and positron emission tomography-computed tomography (PET-CT). RESULTS: MRS was strongly expressed in NSCLC cells metastasized to LNs, but weakly expressed in cells at the periphery of the LN germinal center. The majority of cells were CD20 positive, although a few cells were either CD3 or CD14 positive, indicating that CD45 staining is required for discrimination of non-malignant LN constituent cells from NSCLC cells. When the diagnostic efficacy of MRS/CD45 IF staining was evaluated using 138 LN cellular aspirates from 108 patients through EBUS-TBNA, the sensitivity was 76.7% and specificity was 90.8%, whereas those of conventional cytology test were 71.8% and 100.0%, respectively. Combining the results of conventional cytology testing and those of PET-CT showed a sensitivity and specificity of 71.6% and 100%, and the addition of MRS/CD45 dual IF data to this combination increased sensitivity and specificity to 85.1% and 97.8%, respectively. CONCLUSION: MRS/CD45 dual IF staining showed good diagnostic performance and may be a good tool complementing conventional cytology test for determining LN metastasis of NSCLC.

Prevalence, incidence, and mortality of nontuberculous mycobacterial infection in Korea: a nationwide population-based study.

BACKGROUND: Epidemiologic characteristics of nontuberculous mycobacterial (NTM) disease remain largely unknown. The objective of this study was to evaluate incidence, prevalence, and mortality of NTM infection in a large nationwide population-based cohort in Korea. METHODS: Data of the National Health Insurance Service database, an extensive health-related database including most Korean residents, were used. Adults with a primary diagnosis of NTM as determined by International Classification of Disease-Tenth Revision coding (A31) were identified between 2003 and 2016. Incidence, prevalence, and mortality of NTM infection were analyzed. RESULTS: A total of 46,194 individuals had a primary diagnosis of NTM infection. Their mean age was 55.8 years. Of these subjects, 61.1% were females. Annual age-adjusted incidence and prevalence of NTM infection tended to increase rapidly from 2003 to 2016. Age-adjusted incidence and prevalence was 17.9 and 33.3 per 100,000 population in 2016. The incidence and prevalence were higher in females and the elderly. The 5-year mortality rate in the population with NTM infection was 17.8%. The standardized mortality ratio of patients with NTM infection to the general population was 2.16 (95% confidence interval: 2.10 to 2.22). CONCLUSIONS: This large population-based study showed that the incidence and prevalence of NTM infection in Korea increased rapidly from 2003 to 2016. They were higher in women and the elderly. The mortality rate in the population with NTM infection was higher than that in the general population.

Therapeutic effects of the novel Leucyl-tRNA synthetase inhibitor BC-LI-0186 in non-small cell lung cancer.

OBJECTIVE: Leucyl-tRNA synthetase (LRS) is an aminoacyl-tRNA synthetase catalyzing ligation of leucine to its cognate tRNA and is involved in the activation of mTORC1 by sensing cytoplasmic leucine. In this study, the usefulness of LRS as a therapeutic target of non-small cell lung cancer (NSCLC) and the anticancer effect of the LRS inhibitor, BC-LI-0186, was evaluated. METHODS: LRS expression and the antitumor effect of BC-LI-0186 were evaluated by immunohistochemical staining, immunoblotting, and live cell imaging. The in vivo antitumor effect of BC-LI-0186 was evaluated using Lox-Stop-Lox (LSL) K-ras G12D mice. RESULTS: LRS was frequently overexpressed in NSCLC tissues, and its expression was positively correlated with mTORC1 activity. The guanosine-5'-triphosphate (GTP) binding status of RagB was related to the expression of LRS and the S6K phosphorylation. siRNA against LRS inhibited leucine-mediated mTORC1 activation and cell growth. BC-LI-0186 selectively inhibited phosphorylation of S6K without affecting phosphorylation of AKT and leucine-mediated co-localization of Raptor and LAMP2 in the lysosome. BC-LI-0186 induced cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3 and increase of p62 expression, showing that it has the autophagy-inducing property. BC-LI-0186 has the cytotoxic effect at nanomolar concentration and its GI50 value was negatively correlated with the degree of LRS expression. BC-LI-0186 showed the antitumor effect, which was comparable with that of cisplatin, and mTORC1 inhibitory effect in a lung cancer model. CONCLUSIONS: BC-LI-0186 inhibits the noncanonical mTORC1-activating function of LRS. These results provide a new therapeutic strategy for NSCLC and warrant future clinical development by targeting LRS.

Usefulness of Bronchoscopic Rebiopsy of Non-Small Cell Lung Cancer with Acquired Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor.

Background: Approximately 50% of non-small cell lung cancer (NSCLC) patients with acquired resistance to EGFR-TKI harbor the EGFR mutation T790M. The recent development and wide use of third-generation EGFR-TKIs targeting T790M-mutant NSCLCs have increased the importance of rebiopsy after EGFR-TKI failure. We aimed to investigate the advantages of flexible bronchoscopy as a rebiopsy method and the prevalence of and factors affecting the T790M mutation after EGFR-TKI failure. Methods: We investigated 139 patients who had undergone bronchoscopic rebiopsy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) between Sep 2014 and Jul 2016. Results: Among the 139 patients, bronchoscopic rebiopsy yielded successful pathological diagnoses in 102 (73.4%). Among them, 41 patients with EGFR-mutant lung adenocarcinoma and EGFR-TKI progression were selected for an investigation of T790M mutation prevalence at rebiopsy. The initial EGFR mutations were exon 19 del (56.1%), L858R or L861Q (34.1%), and others (9.8%). The most common rebiopsy method was transbronchial lung biopsy (41.5%), followed by EBUS-TBNA (26.8%) and endobronchial biopsy (19.5%). The median interval to T790M emergence was the longest among cases with exon 19 deletion (14.1 months), followed by exon 21 L858R or L861Q (11.3 months) and other rare EGFR mutations (2.9 months). The T790M mutation was identified in 18 (43.9%) patients, and exon 19 del was the most significant factor affecting T790M mutation development (hazard ratio: 6.875, P = 0.014). Conclusions: Bronchoscopy was more useful than other rebiopsy approaches. The T790M emergence rate was highest in cases with exon 19 deletion, likely as a consequence of long-term EGFR-TKI exposure.

Prevalence and Impact of Diabetes Mellitus Among Patients with Active Pulmonary Tuberculosis in South Korea.

OBJECTIVE: South Korea has an increasing prevalence of diabetes and a relatively high burden of tuberculosis. We aimed to determine the prevalence of diabetes in patients with active pulmonary tuberculosis (PTB) and examine the effect of diabetes on tuberculosis treatment outcomes. SETTING AND DESIGN: Data from patients ≥30 years diagnosed with and treated for PTB between January 2010 and December 2012 at Severance Hospital, a 2000-bed tertiary referral hospital in Seoul, South Korea, were analyzed and compared with data from a contemporaneous general population sample extracted from KNHANES V. RESULTS: Diabetes prevalence was 24.2% (252/1044) among patients with PTB and 11.6% (1700/14,655) among controls. Diabetes [odds ratios (OR) 2.56, 95% confidence interval (CI) 1.56-4.21, P < 0.001], male sex (OR 1.93, 95% CI 1.08-3.44, P = 0.027), and cavitary disease (OR 2.08, 95% CI 1.29-3.35, P = 0.003) were significant risk factors for 2-month culture positivity. Diabetes was the only factor associated with unsuccessful treatment outcomes (OR 1.67, 95% CI 1.03-2.70, P = 0.039). CONCLUSION: The prevalence of diabetes was markedly higher in patients with PTB than in a sample of the general South Korean population. Diabetes may delay sputum conversion and adversely affect treatment outcomes; detection and management of diabetes in patients with PTB is crucial.

A Case of Extensive IgG4-Related Disease Presenting as Massive Pleural Effusion, Mediastinal Mass, and Mesenteric Lymphadenopathy in a 16-Year-Old Male.

IgG4-related disease is an immune-mediated fibro-inflammatory disease, characterized by lymphoplasmacytic infiltration composed of IgG4-positive plasma cells of various organs with elevated circulating levels of IgG4. This disease is now reported with increasing frequency and usually affects middle-aged men. Massive pleural effusion in children is an uncommon feature in IgG4-related disease. Here, we report a case of a 16-year-old male patient with extensive IgG4-related disease presenting with massive pleural effusion, mediastinal mass, and mesenteric lymphadenopathy.

Repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex improves probabilistic category learning.

Traditionally, it has been thought that probabilistic category learning, one of the implicit memory functions, is dependent on the basal ganglia. However, there is growing evidence indicating the involvement of the dorsolateral prefrontal cortex (DLPFC) in probabilistic category learning. In order to identify the causal role of DLPFC in probabilistic category learning, we investigated whether repetitive transcranial magnetic stimulation (rTMS) over the left DLPFC influences the learning ability in healthy subjects using the weather prediction task (WPT). Application of 10 Hz rTMS over the left DLPFC induced significant improvement in the total hit rate during the total trials of the WPT, compared with sham stimulation. Specifically, the improvement was significant in the early and late learning blocks of the WPT, but not in the intermediate block of learning. These results indicate that the left DLPFC may play an important role in probabilistic category learning, possibly by influencing not only on embodied information application in late stage of the learning but also on memory encoding for working memory demands in early stage of the learning via frontostriatal and frontohippocampal circuits, respectively. They also may lend support to the possibility that rTMS can improve implicit learning ability in patients with basal ganglia disorders.