Spirometric Transition of at Risk Individuals and Risks for Progression to Chronic Obstructive Pulmonary Disease in General Population.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a dynamic disease with a high socioeconomic burden. Using data collected prospectively from the general population, we examined factors related to the transition of at-risk individuals to COPD. METHODS: We used the Korean Genome Epidemiology Study (KoGES) database, defining pre-COPD based on respiratory symptoms and radiological abnormalities suggestive of COPD; the preserved ratio impaired spirometry (PRISm) was defined as a forced expiratory volume in 1s (FEV1)/forced vital capacity ratio≥70% and FEV1<80%, as predicted by spirometry. We determined group differences in the rate of lung function decline, risk of future airflow obstruction (AFO). RESULTS: The study included 4762 individuals, and longitudinal analysis revealed distinct trends in pulmonary function indicators. Compared to the normal group, the pre-COPD group showed a more rapid decline in lung function, while the PRISm group showed a slower decline. In the pre-COPD and PRISm groups, 4.4% and 3.5%, and 13.6% and 10.8%, respectively, of patients had progressed to COPD at the first and second visits. Pre-COPD and PRISm contributed to an earlier time to first AFO, but consideration of comorbid cardiovascular disease weakened this relationship in the PRISm group. Multivariate logistic regression showed that pre-COPD and PRISm are significant risk factors for future development of COPD (OR 1.80, p<0.001; OR 4.26, p<0.001, respectively). CONCLUSION: Pre-COPD and PRISm patients showed different trends in lung function changes over time and both were significant risk factors for future development of COPD.

Clinical significance of chronic bronchitis in different racial groups.

BACKGROUNDS: Limited data are available on racial differences in the clinical features of chronic bronchitis (CB) patients with chronic obstructive pulmonary disease (COPD). In this study, we aimed to compare clinical features among CB patients of different races. We also analyzed the clinical significance of CB, defined classically and based on the COPD Assessment Test (CAT), to validate the CAT-based definition. METHODS: We analyzed patient data extracted from the Korean COPD Subgroup Study (KOCOSS) cohort (2012-2021) and US Genetic Epidemiology of COPD (COPDGene) study (2008-2011). We compared clinical characteristics among CB and non-CB patients of three different races using two CB definitions. RESULTS: In this study, 3,462 patients were non-Hispanic white (NHW), 1,018 were African American (AA), and 1,793 were Asian. The proportions of NHW, AA, and Asian patients with CB according to the classic definition were 27.4%, 20.9%, and 10.7%, compared with 25.2%, 30.9%, and 23.0% according to the CAT-based definition, respectively. The risk of CB prevalence was highest in NHW and lowest in Asian COPD patients. Among all races, CB patients were more likely to be current smokers, have worse respiratory symptoms and poorer health-related quality of life (HrQoL), and to have decreased lung function and exercise capacity. Most of these characteristics showed similar associations with the outcomes between the two definitions of CB. A binominal regression model revealed that CB patients of all races had an increased risk of future exacerbations according to both CB definitions, except for Asian patients with classically defined CB. CONCLUSIONS: The presence of CB was associated with worse respiratory symptoms, HrQoL, exercise capacity and lung function, and more exacerbations, regardless of race or CB definition. The CAT-based definition may be more useful for assessing the risk of future exacerbations in Asian COPD patients.

Enhancing Identification of High-Risk cN0 Lung Adenocarcinoma Patients Using MRI-Based Radiomic Features.

Purpose: To develop an MRI-based radiomics model to predict high-risk pathologic features for lung adenocarcinoma: micropapillary and solid pattern (MPsol), spread through air space (STAS), and poorly differentiated patterns. Materials and Methods: As a prospective study, we screened clinical N0 lung cancer patients who were surgical candidates and had undergone both 18F-fluorodeoxyglucose (FDG) positron emission tomography-CT (PET/CT) and chest CT from August 2018 to January 2020. We recruited patients meeting our proposed imaging criteria indicating high-risk, that is, poorer prognosis of lung adenocarcinoma, using CT and FDG PET/CT. If possible, these patients underwent an MRI examination from which we extracted 77 radiomics features from T1-contrast-enhanced and T2-weighted images. Additionally, patient demographics, SUVmax (maximum standardized uptake value) on FDG PET/CT, and the mean ADC value on DWI, were considered together to build prediction models for high-risk pathologic features. Results: Among 616 patients, 72 patients met the imaging criteria for high-risk lung cancer and underwent lung MRI. The MR-eligible group showed a higher prevalence of nodal upstaging (29.2% vs. 4.2%, p<0.001), vascular invasion (6.5% vs. 2.1%, p=0.011), high-grade pathologic features (p<0.001), worse 4-year disease free survival (p<0.001) compared with non-MR-eligible group. The prediction power for MR-based radiomics model predicting high-risk pathologic features was good, with mean area under the receiver operating curve (AUC) value measuring 0.751-0.886 in test sets. Adding clinical variables increased the predictive performance for MPsol and the poorly differentiated pattern using the 2021 grading system (AUC 0.860 and 0.907, respectively). Conclusion: Our imaging criteria can effectively screen high-risk lung cancer patients and predict high-risk pathologic features by our MR-based prediction model using radiomics.

U-Shape Pillar Strip for 3D Cell-Lumped Organoid Model (3D-COM) Mimicking Lung Cancer Hypoxia Conditions in High-Throughput Screening (HTS).

Hypoxia is a representative tumor characteristic associated with malignant progression in clinical patients. Engineered in vitro models have led to significant advances in cancer research, allowing for the investigation of cells in physiological environments and the study of disease mechanisms and processes with enhanced relevance. In this study, we propose a U-shape pillar strip for a 3D cell-lumped organoid model (3D-COM) to study the effects of hypoxia on lung cancer in a high-throughput manner. We developed a U-pillar strip that facilitates the aggregation of PDCs mixed with an extracellular matrix to make the 3D-COM in 384-plate array form. The response to three hypoxia-activated prodrugs was higher in the 3D-COM than in the 2D culture model. The protein expression of hypoxia-inducible factor 1 alpha (HIF-1α) and HIF-2α, which are markers of hypoxia, was also higher in the 3D-COM than in the 2D culture. The results show that 3D-COM better recapitulated the hypoxic conditions of lung cancer tumors than the 2D culture. Therefore, the U-shape pillar strip for 3D-COM is a good tool to study the effects of hypoxia on lung cancer in a high-throughput manner, which can efficiently develop new drugs targeting hypoxic tumors.

Clinical Characteristics and Frequency of Chronic Obstructive Pulmonary Disease Exacerbations in Korean Patients: Findings From the KOCOSS Cohort 2012-2021.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) exert a substantial burden on patients and healthcare systems; however, data related to the frequency of AECOPD in the Korean population are limited. Therefore, this study aimed to describe the frequency of severe, and moderate or severe AECOPD, as well as clinical and demographic characteristics of patients with chronic obstructive pulmonary disease (COPD) in South Korea. METHODS: Data from patients aged > 40 years with post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ≤ 70% of the normal predicted value from the Korea COPD Subgroup Study database were analyzed (April 2012 to 2021). The protocol was based on the EXAcerbations of COPD and their OutcomeS International study. Data were collected retrospectively for year 0 (0-12 months before study enrollment) based on patient recall, and prospectively during years 1, 2, and 3 (0-12, 13-24, and 25-36 months after study enrollment, respectively). The data were summarized using descriptive statistics. RESULTS: Data from 3,477 Korean patients (mean age, 68.5 years) with COPD were analyzed. Overall, most patients were male (92.3%), former or current smokers (90.8%), had a modified Medical Research Council dyspnea scale score ≥ 1 (83.3%), and had moderate airflow limitation (54.4%). The mean body mass index (BMI) of the study population was 23.1 kg/m², and 27.6% were obese or overweight. Hypertension was the most common comorbidity (37.6%). The mean blood eosinophil count was 226.8 cells/µL, with 21.9% of patients having ≥ 300 cells/µL. A clinically insignificant change in FEV1 (+1.4%) was observed a year after enrollment. Overall, patients experienced a mean of 0.2 severe annual AECOPD and approximately 1.1 mean moderate or severe AECOPD. Notably, the rates of severe AECOPD remained generally consistent over time. Compared with patients with no exacerbations, patients who experienced severe exacerbations had a lower mean BMI (21.7 vs. 23.1 kg/m²; P < 0.001) and lower lung function parameters (all P values < 0.001), but reported high rates of depression (25.5% vs. 15.1%; P = 0.044) and anxiety (37.3% vs. 16.7%; P < 0.001) as a comorbidity. CONCLUSION: Findings from this Korean cohort of patients with COPD indicated a high exacerbation burden, which may be attributable to the unique characteristics of the study population and suboptimal disease management. This highlights the need to align clinical practices with the latest treatment recommendations to alleviate AECOPD burden in Korea. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05750810.

The Effects of National Insurance Coverage Expansion and Genetic Counseling's Role on BRCA1/2 Mutation Tests in Breast Cancer Patients.

PURPOSE: This study aims to evaluate the impact of South Korea's national insurance coverage (NIC) expansion and the addition of genetic counselors on BRCA1/2 mutation testing rates in breast cancer patients. MATERIALS AND METHODS: A retrospective review was conducted at the Samsung Medical Center (SMC), dividing patients into three groups: pre-NIC expansion, post-NIC expansion, and post-extra genetic counselor involvement. The number of BRCA1/2 tests performed and the detection rates among newly diagnosed and follow-up patients, particularly focusing on triple-negative breast cancer (TNBC) cases, were analyzed. RESULTS: Post-NIC expansion, there was a significant increase in BRCA1/2 testing rates, with a gradual rise in detection rates while maintaining statistical significance. TNBC patients under 60 experienced substantial increases in testing rates. The number of follow-up patients recalled for testing also rose significantly after the extra genetic counselor involvement. Additionally, NIC expansion increased insurance coverage for TNBC patients, enhancing accessibility to testing. CONCLUSION: The study highlights the positive impact of NIC expansion and genetic counselor involvement on BRCA1/2 mutation testing rates and subsequent patient management. Addressing financial barriers to testing and incorporating genetic counseling significantly improve patient outcomes. This model provides a potential strategy for enhancing early detection and personalized treatment for breast cancer patients with BRCA1/2 mutations, contributing to global cancer management efforts.

Prediction of TKI response in EGFR-mutant lung cancer patients-derived organoids using malignant pleural effusion.

Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy. PDOs are ideal models for precision oncologists. However, their practical application in guiding timely clinical decisions remains challenging. This study focused on patients with advanced EGFR-mutated non-small cell lung cancer and employed a cancer organoid-based diagnosis reactivity prediction (CODRP)-based precision oncology platform to assess the efficacy of EGFR inhibitor treatments. CODRP was employed to evaluate EGFR-tyrosine kinase inhibitors (TKI) drug sensitivity. The results were compared to those obtained using area under the curve index. This study validated this index by testing lung cancer-derived organoids in 14 patients with lung cancer. The CODRP index-based drug sensitivity test reliably classified patient responses to EGFR-TKI treatment within a clinically suitable 10-day timeline, which aligned with clinical drug treatment responses. This approach is promising for predicting and analyzing the efficacy of anticancer, ultimately contributing to the development of a precision medicine platform.

Practice guidelines for managing extrahepatic biliary tract cancers.

Backgrounds/Aims: Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Methods: Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. Results: In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. Conclusions: The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.

Predicting Postoperative Lung Function in Patients with Lung Cancer Using Imaging Biomarkers.

There have been previous studies conducted to predict postoperative lung function with pulmonary function tests (PFTs). Computing tomography (CT) can quantitatively measure small airway walls' thickness, lung volume, pulmonary vessel volume, and emphysema area, which reflect the severity of respiratory diseases. These measurements are considered imaging biomarkers. This study aimed to predict postoperative lung function with imaging biomarkers. A retrospective analysis of 79 patients with lung cancer who had undergone lung surgery was completed. Postoperative lung function measured by forced expiratory volume in one second (FEV1) was defined as an outcome. Preoperative clinico-pathological parameters and imaging biomarkers representing airway walls' thickness, severity of emphysema, total lung volume, and pulmonary vessel volume were measured quantitatively in chest CT by an automated segmentation software, AVIEW COPD. Pi1 was defined as the first percentile along the histogram of lung attenuation that represents the degree of emphysema. Wafw was defined as the airway thickness, which was calculated by the full-width at half-maximum method. Logistic and linear regressions were used to assess these variables. If the actual postoperative FEV1 was higher than the postoperative FEV1 projected by a formula, the group was considered to be preserved. Among the 79 patients, 16 of the patients were grouped as a non-preserved group, and 63 of them were grouped as a preserved group. The patients in the preserved FEV1 group had a higher vessel volume than the non-preserved group. Pi1 and Wafw were independent predictors of postoperative lung function. Imaging biomarkers can be considered significant variables in predicting postoperative lung function in patients with lung cancer.

Role of invasive mediastinal nodal staging in survival outcomes of patients with non-small cell lung cancer and without radiologic lymph node metastasis: a retrospective cohort study.

Background: Lung cancer diagnostic guidelines advocate for invasive mediastinal nodal staging (IMNS), but the survival benefits of this approach in patients with non-small cell lung cancer (NSCLC) without radiologic evidence of lymph node metastasis (rN0) remain uncertain. We aimed to investigate the impact of IMNS in patients with rN0 NSCLC by comparing the long-term survival between patients who underwent IMNS and those who did not (non-IMNS). Methods: In this retrospective cohort study, we included patients with NSCLC but without radiologic evidence of lymph node metastasis from the Registry for Thoracic Cancer Surgery and the clinical data warehouse at the Samsung Medical Centre, Republic of Korea between January 2, 2008 and December 31, 2016. We compared the 5-year overall survival (OS) rate as the primary outcome after propensity score matching between the IMNS and non-IMNS groups. The age, sex, performance statue, tumor size, centrality, solidity, lung function, FDG uptake in PET-CT, and histological examination of the tumor before surgery were matched. Findings: A total of 4545 patients (887 in the IMNS group and 3658 in the non-IMNS group) who received curative treatment for NSCLC were included in this study. By the mediastinal node dissection, the overall incidence of unforeseen mediastinal node metastasis (N2) was 7.2% (317/4378 patients). Despite the IMNS, 67% of pathological N2 was missed (61/91 patients with unforeseen N2). Based on propensity score matching, 866 patients each for the IMNS and non-IMNS groups were assigned. There was no significant difference in 5-year OS and recurrence-free survival (RFS) between two groups: 5-year OS was 73.9% (95% confidence interval, CI: 71%-77%) for IMNS and 71.7% (95% CI: 68.6%-74.9%; p = 0.23), for non-IMNS (hazard ratio, HR 0.90, 95% CI: 0.77-1.07), while 5-year RFS was 64.7% (95% CI: 61.5%-68.2%) and 67.5% (95% CI: 64.3%-70.9%; p = 0.35 (HR 1.08, 95% CI: 0.92-1.27), respectively. Moreover, the timing and locations of recurrence were similar in both groups. Interpretation: IMNS might not be required before surgery for patients with NSCLC without LN suspicious of metastasis. Further randomised trials are required to validate the findings of the present study. Funding: None.

Prognostic Value of Radiomic Analysis Using Pre- and Post-Treatment 18F-FDG-PET/CT in Patients with Laryngeal Cancer and Hypopharyngeal Cancer.

BACKGROUND: The prognostic value of conducting 18F-FDG PET/CT imaging has yielded different results in patients with laryngeal cancer and hypopharyngeal cancer, but these results are controversial, and there is a lack of dedicated studies on each type of cancer. This study aimed to evaluate whether combining radiomic analysis of pre- and post-treatment 18F-FDG PET/CT imaging features and clinical parameters has additional prognostic value in patients with laryngeal cancer and hypopharyngeal cancer. METHODS: From 2008 to 2016, data on patients diagnosed with cancer of the larynx and hypopharynx were retrospectively collected. The patients underwent pre- and post-treatment 18F-FDG PET/CT imaging. The values of ΔPre-Post PET were measured from the texture features. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select the most predictive features to formulate a Rad-score for both progression-free survival (PFS) and overall survival (OS). Kaplan-Meier curve analysis and Cox regression were employed to assess PFS and OS. Then, the concordance index (C-index) and calibration plot were used to evaluate the performance of the radiomics nomogram. RESULTS: Study data were collected for a total of 91 patients. The mean follow-up period was 71.5 mo. (8.4-147.3). The Rad-score was formulated based on the texture parameters and was significantly associated with both PFS (p = 0.024) and OS (p = 0.009). When predicting PFS, only the Rad-score demonstrated a significant association (HR 2.1509, 95% CI [1.100-4.207], p = 0.025). On the other hand, age (HR 1.116, 95% CI [1.041-1.197], p = 0.002) and Rad-score (HR 33.885, 95% CI [2.891-397.175], p = 0.005) exhibited associations with OS. The Rad-score value showed good discrimination when it was combined with clinical parameters in both PFS (C-index 0.802-0.889) and OS (C-index 0.860-0.958). The calibration plots also showed a good agreement between the observed and predicted survival probabilities. CONCLUSIONS: Combining clinical parameters with radiomics analysis of pre- and post-treatment 18F-FDG PET/CT parameters in patients with laryngeal cancer and hypopharyngeal cancer might have additional prognostic value.

Oncologic Outcomes of Immediate Breast Reconstruction in the Setting of Neoadjuvant Chemotherapy: A Long-term Follow-up Study of a Matched Cohort.

PURPOSE: Despite the increasing use of immediate breast reconstruction (IBR), its oncologic safety in the setting of neoadjuvant chemotherapy (NACT) needs to be comprehensively clarified in breast cancer management. The objective of the present study was to analyze the oncologic safety of IBR following NACT. METHODS: In total, 587 patients with breast cancer who underwent a total mastectomy (TM) with IBR after NACT between 2008 and 2017 at a single institution were retrospectively reviewed. The reviewed patients with IBR following skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM) were matched 1:3 to patients who underwent TM alone after NACT. Matching variables included age, clinical T and N stages before NACT, response to NACT, pathologic T and N stages, and molecular subtypes. RESULTS: After propensity score matching, 95 patients who underwent IBR following SSM/NSM after NACT (IBR group) and 228 patients who underwent TM alone after NACT (TM group) were selected. The median follow-up period was 73 (range, 5-181) months after matching. After matching, there were no significant differences between the two groups in 5-year locoregional recurrence-free survival (88.8% vs. 91.2%, p = 0.516), disease-free survival (67.3% vs. 76.6%, p = 0.099), distant metastasis-free survival (71.9% vs. 81.9%, p = 0.057), or overall survival (84.1% vs. 91.5, p = 0.061) rates. In multivariate analyses, conducting IBR was not associated with increased risks for locoregional recurrence, any recurrence, distant metastasis, or overall death. CONCLUSION: Our findings suggest that IBR following SSM/NSM elicits comparable long-term oncologic outcomes to those of TM alone in the setting of NACT.

Pulmonary Rehabilitation Is Associated With Decreased Exacerbation and Mortality in Patients With COPD: A Nationwide Korean Study.

BACKGROUND: Poor uptake to pulmonary rehabilitation (PR) is still challenging around the world. There have been few nationwide studies investigating whether PR impacts patient outcomes in COPD. We investigated the change of annual PR implementation rate, medical costs, and COPD outcomes including exacerbation rates and mortality between 2015 and 2019. RESEARCH QUESTION: Does PR implementation improve outcomes in patients with COPD in terms of direct cost, exacerbation, and mortality? STUDY DESIGN AND METHODS: Data of patients with COPD extracted from a large Korean Health Insurance Review and Assessment service database (2015-2019) were analyzed to determine the trends of annual PR implementation rate and direct medical costs of PR. Comparison of COPD exacerbation rates between pre-PR and post-PR, and the time to first exacerbation and mortality rate according to PR implementation, were also assessed. RESULTS: Among all patients with COPD in South Korea, only 1.43% received PR. However, the annual PR implementation rate gradually increased from 0.03% to 1.4% during 4 years, especially after health insurance coverage commencement. The direct medical cost was significantly higher in the PR group than the non-PR group, but the costs in these groups showed decreasing and increasing trends, respectively. Both the incidence rate and frequency of moderate-to-severe and severe exacerbations were lower during the post-PR period compared with the pre-PR period. The time to the first moderate-to-severe and severe exacerbations was longer in the PR group than the non-PR group. Finally, PR implementation was associated with a significant decrease in mortality. INTERPRETATION: We concluded that health insurance coverage increases PR implementation rates. Moreover, PR contributes toward improving outcomes including reducing exacerbation and mortality in patients with COPD. However, despite the well-established benefits of PR, its implementation rate remains suboptimal.

Neoadjuvant Nivolumab Therapy for Esophageal Squamous Cell Carcinoma: A Single-Arm, Phase II Study.

PURPOSE: Programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors have shown efficacy in metastatic esophageal squamous cell carcinoma (ESCC) therapy. However, data is still limited regarding neoadjuvant immunotherapy for operable ESCC. MATERIALS AND METHODS: Patients with clinical stage T2 or T3 and N0 ESCC received three cycles of nivolumab therapy every two weeks before surgical resection. The primary endpoint is major pathologic responses (MPR) rate (≤ 10% of residual viable tumor [RVT]). RESULTS: Total 20 patients completed the planned nivolumab therapy. Among them, 17 patients underwent surgery as protocol, showing MPR in two patients (MPR rate, 11.8%), including one pathologic complete response, on conventional pathologic response evaluation. Pathologic response was re-evaluated using the immune-related pathologic response criteria based on immune-related RVT (irRVT). Three patients were classified as immunologic major pathologic response (iMPR; ≤ 10% irRVT, iMPR rate: 17.6%), five as pathologic partial response (> 10% and < 90% irRVT), and nine as pathologic nonresponse (≥ 90% irRVT). The combined positive score (CPS) for PD-L1 in the baseline samples was predictable for iMPR, with the probability as 37.5% in CPS ≥ 10 (3/8) and 0% in CPS < 10 (0/9). CONCLUSION: Although the efficacy of neoadjuvant nivolumab therapy was modest in unselected ESCC patients, further researches on neoadjuvant immunotherapy are necessary in patients with PD-L1 expressed ESCC.

Associations between depression and anxiety index and frequency of acute exacerbation in chronic obstructive pulmonary disease.

BACKGROUND: Comorbidities of chronic obstructive pulmonary disease (COPD) influence clinical characteristics and prognosis. OBJECTIVES: This study compared the clinical characteristics and exacerbation rate of COPD according to the presence of depression or anxiety. DESIGN: This study used data from The Korea COPD Subgroup Study (KOCOSS) cohort, a nationwide prospective cohort from 54 medical centers, between April 2012 and 2019. METHODS: Depression and anxiety were diagnosed with the Beck Depression Inventory and Beck Anxiety Inventory. Negative binomial regression analysis was performed to analyze the frequency of exacerbations in depressed patients and anxiety. Differences in lung function trajectory according to presence of depression/anxiety were analyzed using a linear mixed model. RESULTS: In all, 2147 patients were enrolled. Depressed patients or anxiety had lower lung function, higher modified Medical Research Council (mMRC) grade, St. George Respiratory Questionnaire (SGRQ) score, and COPD assessment test score, and higher rates of exacerbation in the past year than those without depression/anxiety. Depressed patients had a higher frequency of moderate to severe exacerbations [Incidence Rate Ratio (IRR): 1.57, CI: 1.17-2.11, p = 0.002] and those with anxiety had higher frequencies of moderate to severe (IRR: 1.52, CI: 1.03-2.27, p = 0.038) and severe exacerbations (IRR: 2.13, CI: 1.09-4.15, p = 0.025) during 1-year follow-up compared to those without these comorbidities. The differences in the change in annual forced expiratory volume in 1 seconds (FEV1) over 3 years according to the presence of depression or anxiety were not statistically significant. CONCLUSION: Depressed and anxious patients showed increased respiratory symptoms and exacerbation rate as well as reduced health-related quality of life, whereas there were no significant differences in changes in lung function between groups with and without depression/anxiety.

Synthesis and Evaluation of [18F]SiFA-Conjugated Ligands for Fibroblast Activation Protein Imaging.

In recent years, fibroblast activation protein (FAP) has emerged as an important target for the diagnosis and therapy of various tumors due to its high expression on the cell surface of cancer-associated fibroblasts, which are the major components of the tumor stroma. In this study, we synthesized and evaluated 18F-labeled FAP inhibitors (FAPIs) for FAP imaging. Two silicon fluoride acceptor (SiFA)-conjugated FAPIs were synthesized: one containing a γ-carboxy-l-glutamic acid (Gla) residue (1) and another containing two Gla residues (2). Both ligands exhibited high binding affinities for FAP. 18F/19F exchange reactions on both ligands were performed in the presence of 2% water. This resulted in the formation of radioligands [18F]1 and [18F]2 in high radiochemical yields. Radioligand [18F]2, with a more favorable partition coefficient, was selected for the U87MG cell binding study, and the results showed FAP-specific binding of the radioligand to the cells. An ex vivo biodistribution study in U87MG tumor-bearing mice 60 min after injection demonstrated a 5.8-fold higher tumor accumulation of [18F]2 than that of [18F]1. Furthermore, PET and ex vivo biodistribution studies of [18F]2 in U87MG tumor-bearing mice showed high and persistent tumor uptake over time, which was significantly blocked by the preinjection of FAPI-04. Our results indicate that [18F]SiFA-(Gla)2-conjugated FAPI ([18F]2) has the potential for FAP imaging.

Risk adjustment model for tuberculosis compared to non-tuberculosis mycobacterium or latent tuberculosis infection: Center for Personalized Precision Medicine of Tuberculosis (cPMTb) cohort database.

BACKGROUND: The Center for Personalized Precision Medicine of Tuberculosis (cPMTb) was constructed to develop personalized pharmacotherapeutic systems for tuberculosis (TB). This study aimed to introduce the cPMTb cohort and compare the distinct characteristics of patients with TB, non-tuberculosis mycobacterium (NTM) infection, or latent TB infection (LTBI). We also determined the prevalence and specific traits of polymorphisms in N-acetyltransferase-2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) phenotypes using this prospective multinational cohort. METHODS: Until August 2021, 964, 167, and 95 patients with TB, NTM infection, and LTBI, respectively, were included. Clinical, laboratory, and radiographic data were collected. NAT2 and SLCO1B1 phenotypes were classified by genomic DNA analysis. RESULTS: Patients with TB were older, had lower body mass index (BMI), higher diabetes rate, and higher male proportion than patients with LTBI. Patients with NTM infection were older, had lower BMI, lower diabetes rate, higher previous TB history, and higher female proportion than patients with TB. Patients with TB had the lowest albumin levels, and the prevalence of the rapid, intermediate, and slow/ultra-slow acetylator phenotypes were 39.2%, 48.1%, and 12.7%, respectively. The prevalence of rapid, intermediate, and slow/ultra-slow acetylator phenotypes were 42.0%, 44.6%, and 13.3% for NTM infection, and 42.5%, 48.3%, and 9.1% for LTBI, respectively, which did not differ significantly from TB. The prevalence of the normal, intermediate, and lower transporter SLCO1B1 phenotypes in TB, NTM, and LTBI did not differ significantly; 74.9%, 22.7%, and 2.4% in TB; 72.0%, 26.1%, and 1.9% in NTM; and 80.7%, 19.3%, and 0% in LTBI, respectively. CONCLUSIONS: Understanding disease characteristics and identifying pharmacokinetic traits are fundamental steps in optimizing treatment. Further longitudinal data are required for personalized precision medicine. TRIAL REGISTRATION: This study registered ClinicalTrials.gov NO. NCT05280886.

Cancer organoid-based diagnosis reactivity prediction (CODRP) index-based anticancer drug sensitivity test in ALK-rearrangement positive non-small cell lung cancer (NSCLC).

BACKGROUND: Recently, cancer organoid-based drug sensitivity tests have been studied to predict patient responses to anticancer drugs. The area under curve (AUC) or IC50 value of the dose-response curve (DRC) is used to differentiate between sensitive and resistant patient's groups. This study proposes a multi-parameter analysis method (cancer organoid-based diagnosis reactivity prediction, CODRP) that considers the cancer stage and cancer cell growth rate, which represent the severity of cancer patients, in the sensitivity test. METHODS: On the CODRP platform, patient-derived organoids (PDOs) that recapitulate patients with lung cancer were implemented by applying a mechanical dissociation method capable of high yields and proliferation rates. A disposable nozzle-type cell spotter with efficient high-throughput screening (HTS) has also been developed to dispense a very small number of cells due to limited patient cells. A drug sensitivity test was performed using PDO from the patient tissue and the primary cancer characteristics of PDOs were confirmed by pathological comparision with tissue slides. RESULTS: The conventional index of drug sensitivity is the AUC of the DRC. In this study, the CODRP index for drug sensitivity test was proposed through multi-parameter analyses considering cancer cell proliferation rate, the cancer diagnosis stage, and AUC values. We tested PDOs from eight patients with lung cancer to verify the CODRP index. According to the anaplastic lymphoma kinase (ALK) rearrangement status, the conventional AUC index for the three ALK-targeted drugs (crizotinib, alectinib, and brigatinib) did not classify into sensitive and resistant groups. The proposed CODRP index-based drug sensitivity test classified ALK-targeted drug responses according to ALK rearrangement status and was verified to be consistent with the clinical drug treatment response. CONCLUSIONS: Therefore, the PDO-based HTS and CODRP index drug sensitivity tests described in this paper may be useful for predicting and analyzing promising anticancer drug efficacy for patients with lung cancer and can be applied to a precision medicine platform.