Guidelines for Manufacturing and Application of Organoids: Lung

The objective of standard guideline for utilization of human lung organoids is to provide the basic guidelines required for the manufacture, culture, and quality control of the lung organoids for use in non-clinical efficacy and inhalation toxicity assessments of the respiratory system. As a first step towards the utilization of human lung organoids, the current guideline provides basic, minimal standards that can promote development of alternative testing methods, and can be referenced not only for research, clinical, or commercial uses, but also by experts and researchers at regulatory institutions when assessing safety and efficacy.

Immune Evasion of G-CSF and GM-CSF in Lung Cancer / 결핵및호흡기질환

Tumor immune evasion is a complex process that involves various mechanisms, such as antigen recognition restriction, immune system suppression, and T cell exhaustion. The tumor microenvironment contains various immune cells involved in immune evasion. Recent studies have demonstrated that granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induce immune evasion in lung cancer by modulating neutrophils and myeloid-derived suppressor cells. Here we describe the origin and function of G-CSF and GM-CSF, particularly their role in immune evasion in lung cancer. In addition, their effects on programmed death-ligand 1 expression and clinical implications are discussed.

Contemporary Strategies: Incorporating Immunotherapy into Stage 3 Non-small Cell Lung Cancer Treatment / 결핵및호흡기질환

Stage 3 non-small cell lung cancer (NSCLC) exhibits significant diversity, making it challenging to define an optimal treatment. A collaborative multidisciplinary approach is essential in crafting individualized treatments. Previously, targeted therapies and immunotherapies were commonly used to treat patients with advanced and metastatic lung cancer. Such treatments are now being extended to individuals considered surgery, as well as patients once considered unsuitable for surgery. These changes have increased surgical success and substantially reduced postoperative recurrence. However, the possibility of severe adverse effects from immunotherapy can deter some patients from performing surgery. It is essential to carefully explore the clinical traits and biomarkers of patients who may benefit the most from immunotherapy, and patients for whom immunotherapy should not be prescribed. In summary, it’s crucial to effectively integrate the latest immunotherapy in treating stage 3 NSCLC patients, thereby increasing their opportunities for surgical intervention, and ensuring they receive the best possible care.

Evolution of the Stethoscope: Advances with the Adoption of Machine Learning and Development of Wearable Devices / 결핵및호흡기질환

The stethoscope has long been used for the examination of patients, but the importance of auscultation has declined due to its several limitations and the development of other diagnostic tools. However, auscultation is still recognized as a primary diagnostic device because it is non-invasive and provides valuable information in real-time. To supplement the limitations of existing stethoscopes, digital stethoscopes with machine learning (ML) algorithms have been developed. Thus, now we can record and share respiratory sounds and artificial intelligence (AI)-assisted auscultation using ML algorithms distinguishes the type of sounds. Recently, the demands for remote care and non-face-to-face treatment diseases requiring isolation such as coronavirus disease 2019 (COVID-19) infection increased. To address these problems, wireless and wearable stethoscopes are being developed with the advances in battery technology and integrated sensors. This review provides the history of the stethoscope and classification of respiratory sounds, describes ML algorithms, and introduces new auscultation methods based on AI-assisted analysis and wireless or wearable stethoscopes.

Awareness and Use of Complementary and Alternative Medicine in Korean Lung Cancer Patients / 결핵및호흡기질환

Background@#Complementary and alternative medicine (CAM) has been used frequently, and its use continues to increase in lung cancer patients, despite insufficient scientific of its efficacy. To investigate this situation, we analyzed the current awareness and use of CAM in Korean lung-cancer patients. Methods: This prospective survey–based study was performed at seven medical centers in South Korea between August and October 2019. The survey assessed general patient characteristics and the awareness and use of CAM. We analyzed differences in the clinical parameters of patients aware and not aware of CAM and of CAM non-users and users. @*Results@#Of the 434 patients included in this study, 68.8% responded that they were aware of CAM and 30.9% said they had experienced it. In univariate analysis, the patients aware of CAM were younger with poor performance status, had advanced-stage lung cancer, received more systemic therapy, and received concurrent chemoradiation therapy (CCRT). By multiple logistic regression, younger age, poor performance status, advanced stage, and prior CCRT were identified as independent risk factors for CAM awareness. There were no significant differences in the general characteristics and cancer-associated clinical parameters of CAM non-users and users. @*Conclusion@#Specific clinical parameters were associated with patients’ awareness of CAM, although there were no significantly different characteristics between CAM users and non-users.

Transthoracic Needle Biopsy: How to Maximize Diagnostic Accuracy and Minimize Complications / 결핵및호흡기질환

Although transthoracic needle biopsy (TTNB) was introduced for lung biopsy about 40 years ago, it is still mainstay of pathologic diagnosis in lung cancer, because it is relatively inexpensive and can obtain tissue regardless of the tumor-bronchus relationship. With several technological advances, proceduralists can perform TTNB more safely and accurately. Utilizing ultrasound-guided biopsy for peripheral lesions in contact with the pleura and rapid onsite evaluation during the procedure are expected to make up the weakness of TTNB. However, due to the inherent limitations of the percutaneous approach, the incidence of complications such as pneumothorax or bleeding is inevitably higher than that of other lung biopsy techniques. Thorough understating of each biopsy modality and additional technique are fundamental for maximizing diagnostic accuracy and minimizing the complications.

Transthoracic Needle Biopsy: How to Maximize Diagnostic Accuracy and Minimize Complications / 결핵및호흡기질환

Although transthoracic needle biopsy (TTNB) was introduced for lung biopsy about 40 years ago, it is still mainstay of pathologic diagnosis in lung cancer, because it is relatively inexpensive and can obtain tissue regardless of the tumor-bronchus relationship. With several technological advances, proceduralists can perform TTNB more safely and accurately. Utilizing ultrasound-guided biopsy for peripheral lesions in contact with the pleura and rapid onsite evaluation during the procedure are expected to make up the weakness of TTNB. However, due to the inherent limitations of the percutaneous approach, the incidence of complications such as pneumothorax or bleeding is inevitably higher than that of other lung biopsy techniques. Thorough understating of each biopsy modality and additional technique are fundamental for maximizing diagnostic accuracy and minimizing the complications.

Vitamin D-Cathelicidin Axis: at the Crossroads between Protective Immunity and Pathological Inflammation during Infection

Vitamin D signaling plays an essential role in innate defense against intracellular microorganisms via the generation of the antimicrobial protein cathelicidin. In addition to directly binding to and killing a range of pathogens, cathelicidin acts as a secondary messenger driving vitamin D-mediated inflammation during infection. Recent studies have elucidated the biological and clinical functions of cathelicidin in the context of vitamin D signaling. The vitamin D-cathelicidin axis is involved in the activation of autophagy, which enhances antimicrobial effects against diverse pathogens. Vitamin D studies have also revealed positive and negative regulatory effects of cathelicidin on inflammatory responses to pathogenic stimuli. Diverse innate and adaptive immune signals crosstalk with functional vitamin D receptor signals to enhance the role of cathelicidin action in cell-autonomous effector systems. In this review, we discuss recent findings that demonstrate how the vitamin D-cathelicidin pathway regulates autophagy machinery, protective immune defenses, and inflammation, and contributes to immune cooperation between innate and adaptive immunity. Understanding how the vitamin D-cathelicidin axis operates in the host response to infection will create opportunities for the development of new therapeutic approaches against a variety of infectious diseases.

Baseline Serum Interleukin-6 Levels Predict the Response of Patients with Advanced Non-small Cell Lung Cancer to PD-1/PD-L1 Inhibitors

Although various studies on predictive markers in the use of PD-1/PD-L1 inhibitors are in progress, only PD-L1 expression levels in tumor tissues are currently used. In the present study, we investigated whether baseline serum levels of IL-6 can predict the treatment response of patients with advanced non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors. In our cohort of 125 NSCLC patients, the objective response rate (ORR) and disease control rate (DCR) were significantly higher in those with low IL-6 (<13.1 pg/ml) than those with high IL-6 (ORR 33.9% vs. 11.1%, p=0.003; DCR 80.6% vs. 34.9%, p<0.001). The median progression-free survival was 6.3 months (95% confidence interval [CI], 3.9–8.7) in the low IL-6 group, significantly longer than in the high IL-6 group (1.9 months, 95% CI, 1.6–2.2, p<0.001). The median overall survival in the low IL-6 group was significantly longer than in the high IL-6 group (not reached vs. 7.4 months, 95% CI, 4.8–10.0). Thus, baseline serum IL-6 levels could be a potential biomarker for predicting the efficacy and survival benefit of PD-1/PD-L1 inhibitors in NSCLC.

COVID-19 Patients Upregulate Toll-like Receptor 4-mediated Inflammatory Signaling That Mimics Bacterial Sepsis

Background@#Observational studies of the ongoing coronavirus disease 2019 (COVID-19) outbreak suggest that a ‘cytokine storm’ is involved in the pathogenesis of severe illness.However, the molecular mechanisms underlying the altered pathological inflammation in COVID-19 are largely unknown. We report here that toll-like receptor (TLR) 4-mediated inflammatory signaling molecules are upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls (HC). @*Methods@#A total of 48 subjects including 28 COVID-19 patients (8 severe/critical vs. 20 mild/ moderate cases) admitted to Chungnam National University Hospital, and age/sex-matched 20 HC were enrolled in this study. PBMCs from the subjects were processed for nCounter Human Immunology gene expression assay to analyze the immune related transcriptome profiles. Recombinant proteins of severe acute respiratory syndrome coronavirus-2 (SARSCoV-2) were used to stimulate the PBMCs and monocyte-derived macrophages, and real-time polymerase chain reaction was performed to quantify the mRNA expressions of the proinflammatory cytokines/chemokines. @*Results@#Among the most highly increased inflammatory mediators in severe/critically ill patients, S100A9, an alarmin and TLR4 ligand, was found as a noteworthy biomarker, because it inversely correlated with the serum albumin levels. We also observed that recombinant S2 and nucleocapsid proteins of SARS-CoV2 significantly increased proinflammatory cytokines/chemokines and S100A9 in human primary PBMCs. @*Conclusion@#These data support a link between TLR4 signaling and pathological inflammation during COVID-19 and contribute to develop therapeutic approaches through targeting TLR4-mediated inflammation.

The Ability of the Acute Physiology and Chronic Health Evaluation (APACHE) IV Score to Predict Mortality in a Single Tertiary Hospital / 대한중환자의학회지

BACKGROUND: The Acute Physiology and Chronic Health Evaluation (APACHE) II model has been widely used in Korea. However, there have been few studies on the APACHE IV model in Korean intensive care units (ICUs). The aim of this study was to compare the ability of APACHE IV and APACHE II in predicting hospital mortality, and to investigate the ability of APACHE IV as a critical care triage criterion. METHODS: The study was designed as a prospective cohort study. Measurements of discrimination and calibration were performed using the area under the receiver operating characteristic curve (AUROC) and the Hosmer-Lemeshow goodness-of-fit test respectively. We also calculated the standardized mortality ratio (SMR). RESULTS: The APACHE IV score, the Charlson Comorbidity index (CCI) score, acute respiratory distress syndrome, and unplanned ICU admissions were independently associated with hospital mortality. The calibration, discrimination, and SMR of APACHE IV were good (H = 7.67, P = 0.465; C = 3.42, P = 0.905; AUROC = 0.759; SMR = 1.00). However, the explanatory power of an APACHE IV score >93 alone on hospital mortality was low at 44.1%. The explanatory power was increased to 53.8% when the hospital mortality was predicted using a model that considers APACHE IV >93 scores, medical admission, and risk factors for CCI >3 coincidentally. However, the discriminative ability of the prediction model was unsatisfactory (C index <0.70). CONCLUSIONS: The APACHE IV presented good discrimination, calibration, and SMR for hospital mortality.

The Ability of the Acute Physiology and Chronic Health Evaluation (APACHE) IV Score to Predict Mortality in a Single Tertiary Hospital / 대한구급학회지

BACKGROUND: The Acute Physiology and Chronic Health Evaluation (APACHE) II model has been widely used in Korea. However, there have been few studies on the APACHE IV model in Korean intensive care units (ICUs). The aim of this study was to compare the ability of APACHE IV and APACHE II in predicting hospital mortality, and to investigate the ability of APACHE IV as a critical care triage criterion. METHODS: The study was designed as a prospective cohort study. Measurements of discrimination and calibration were performed using the area under the receiver operating characteristic curve (AUROC) and the Hosmer-Lemeshow goodness-of-fit test respectively. We also calculated the standardized mortality ratio (SMR). RESULTS: The APACHE IV score, the Charlson Comorbidity index (CCI) score, acute respiratory distress syndrome, and unplanned ICU admissions were independently associated with hospital mortality. The calibration, discrimination, and SMR of APACHE IV were good (H = 7.67, P = 0.465; C = 3.42, P = 0.905; AUROC = 0.759; SMR = 1.00). However, the explanatory power of an APACHE IV score >93 alone on hospital mortality was low at 44.1%. The explanatory power was increased to 53.8% when the hospital mortality was predicted using a model that considers APACHE IV >93 scores, medical admission, and risk factors for CCI >3 coincidentally. However, the discriminative ability of the prediction model was unsatisfactory (C index <0.70). CONCLUSIONS: The APACHE IV presented good discrimination, calibration, and SMR for hospital mortality.

Metachronous Primary Carcinoid Tumor and Spindle Cell Carcinoma of the Lung

Spindle cell carcinoma (SpCC) of the lung is extremely rare, with an incidence of less than 0.5% among all lung malignancies. Neuroendocrine tumors are frequently associated with secondary primary malignancies. Here, we report a case of metachronous SpCC that occurred after treatment of a primary carcinoid tumor of the lung. The SpCC mass was successfully removed by lobectomy. In immunohistochemical analyses, the tissues were positive for cytokeratin 7 and vimentin.

The Usefulness of Intensivist-Performed Bedside Drainage of Pleural Effusion via Ultrasound-Guided Pigtail Catheter / 대한구급학회지

BACKGROUND: There has been little data reporting the usefulness of intensivist-performed bedside drainage of pleural effusion via ultrasound (US)-guided pigtail catheter. The objective of this study is to clarify the usefulness and safety of these methods in comparison with radiologist-performed procedures. METHODS: Data of patients with pleural effusion treated with US-guided pigtail catheter drainage were analyzed. All procedures were performed from September 2012 to September. 2013 by a well-trained intensivist or radiologist. RESULTS: Pleural effusion was drained in 25 patients in 33 sessions. A radiologist performed 21 sessions, and an intensivist performed 12 sessions. Procedures during mechanical ventilation were performed in 15 (71.4%) patients by a radiologist and in 10 (83.3%) by an intensivist (p = 0.678). The success rate was not significantly different in radiologist- and intensivist-performed procedures, 95.2% (20/21) and 83.3% (10/12), respectively (p = 0.538). The average duration for procedures (including in-hospital transfer) was longer in radiologist-performed cases (p = 0.001). Although the results are limited because of the small population size, aggravation of oxygenation, CO2 retention, and decrease of mean arterial blood pressure were not statistically different in the groups. Pigtail-associated complications including hemothorax, pneumothorax, hepatic perforation, empyema, kink in the catheter, and subcutaneous hematoma were not found. CONCLUSIONS: Intensivist-performed bedside drainage of pleural effusion via ultrasound (US)-guided pigtail catheter is useful and safe and may be recommended in some patients in an intensive care unit.