Occupational and environmental risk factors for idiopathic pulmonary fibrosis: A case-control study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease of unknown etiology. The aim of this study was to evaluate the environmental and occupational risk factors of IPF. METHODS: This hospital-based, case-control study included 206 patients with IPF selected from the Seoul National University Bundang Hospital Interstitial Lung Disease registry and 167 controls without lung disease. Data on occupation, lifestyle, transportation, and types of environmental and occupational dust exposure were obtained using a questionnaire. IPF diagnosis was confirmed based on the recent guidelines, and the possibility of hypersensitivity pneumonitis was excluded. Multiple logistic regression was performed to determine the risk factors for IPF. RESULTS: After adjusting for age and sex, ever-smokers (odds ratio [OR], 2.35; 95 % confidence interval [CI]: 1.51-3.68) and individuals who smoked more than 30 pack-years (OR, 2.79; 95%CI: 1.70-4.68) showed an increased risk for IPF. Any occupational dust exposure (adjusted OR, 2.08; 95%CI: 1.19-3.72), especially exposure to chemicals (adjusted OR, 3.52; 99%CI: 1.56-9.05), was associated with IPF after adjusting for age, sex, and smoking. CONCLUSIONS: Smoking and occupational dust exposure are associated with an increased risk for IPF. Both factors have dose and duration-dependent relationships with the risk for IPF.

Myeloid-derived suppressor cells in pleural effusion as a diagnostic marker for early discrimination of pulmonary tuberculosis from pneumonia.

Introduction: Tuberculous pleural effusion (TPE) stands as one of the primary forms of extrapulmonary tuberculosis (TB) and frequently manifests in regions with a high prevalence of TB, consequently being a notable cause of pleural effusion in such areas. However, the differentiation between TPE and parapneumonic pleural effusion (PPE) presents diagnostic complexities. This study aimed to evaluate the potential of myeloid-derived suppressor cells (MDSCs) in the pleural fluid as a potential diagnostic marker for distinguishing between TPE and PPE. Methods: Adult patients, aged 18 years or older, who presented to the emergency room of a tertiary referral hospital and received a first-time diagnosis of pleural effusion, were prospectively enrolled in the study. Various immune cell populations, including T cells, B cells, natural killer (NK) cells, and MDSCs, were analyzed in both pleural fluid and peripheral blood samples. Results: In pleural fluid, the frequency of lymphocytes, including T, B, and NK cells, was notably higher in TPE compared to PPE. Conversely, the frequency of polymorphonuclear (PMN)-MDSCs was significantly higher in PPE. Notably, compared to traditional markers such as the neutrophil-to-lymphocyte ratio and adenosine deaminase level, the frequency of PMN-MDSCs emerged as a more effective discriminator between PPE and TPE. PMN-MDSCs demonstrated superior positive and negative predictive values and exhibited a higher area under the curve in the receiver operating characteristic curve analysis. PMN-MDSCs in pleural effusion increased the levels of reactive oxygen species and suppressed the production of interferon-gamma from T cells following nonspecific stimulation. These findings suggest that MDSC-mediated immune suppression may contribute to the pathology of both TPE and PPE. Discussion: The frequency of PMN-MDSCs in pleural fluid is a clinically useful indicator for distinguishing between TPE and PPE.

Understanding the effects of Haemophilus influenzae colonization on bronchiectasis: a retrospective cohort study.

BACKGROUND: Bacterial colonization is an essential aspect of bronchiectasis. Although Haemophilus influenzae is a frequent colonizer in some regions, its clinical impacts are poorly understood. This study aimed to elucidate the impact of H. influenzae colonization in patients with bronchiectasis. METHODS: This retrospective study screened adult patients diagnosed with bronchiectasis at a tertiary referral center between April 1, 2003, and May 16, 2021, in South Korea. Propensity score matching was used to match patients with and without H. influenzae colonization. We assessed the severity of bronchiectasis as per the bronchiectasis severity index, the incidence of exacerbation, differences in lung function, and all-cause mortality. RESULTS: Out of the 4,453 patients with bronchiectasis, 79 (1.8%) were colonized by H. influenzae. After 1:2 propensity score matching, 78 and 154 patients were selected from the H. influenzae colonizer and non-colonizer groups, respectively. Although there were no significant differences between the groups regarding baseline demographics, patients colonized with H. influenzae had a higher bronchiectasis severity index (median 6 [interquartile range 4-8] vs. 4 [2-7], p = 0.002), associated with extensive radiographic involvement (52.2% vs. 37.2%, p = 0.045) and mild exacerbation without hospitalization (adjusted incidence rate ratio 0.15; 95% confidence interval 0.12-0.24). Lung function and mortality rates did not reveal significant differences, regardless of H. influenzae colonization. CONCLUSION: H. influenzae colonization in bronchiectasis was associated with more severe disease and greater incidence of mild exacerbation, but not lung function and mortality. Attention should be paid to patients with bronchiectasis with H. influenzae colonization.

Deep learning-based prognostication in idiopathic pulmonary fibrosis using chest radiographs.

OBJECTIVES: To develop and validate a deep learning-based prognostic model in patients with idiopathic pulmonary fibrosis (IPF) using chest radiographs. METHODS: To develop a deep learning-based prognostic model using chest radiographs (DLPM), the patients diagnosed with IPF during 2011-2021 were retrospectively collected and were divided into training (n = 1007), validation (n = 117), and internal test (n = 187) datasets. Up to 10 consecutive radiographs were included for each patient. For external testing, three cohorts from independent institutions were collected (n = 152, 141, and 207). The discrimination performance of DLPM was evaluated using areas under the time-dependent receiver operating characteristic curves (TD-AUCs) for 3-year survival and compared with that of forced vital capacity (FVC). Multivariable Cox regression was performed to investigate whether the DLPM was an independent prognostic factor from FVC. We devised a modified gender-age-physiology (GAP) index (GAP-CR), by replacing DLCO with DLPM. RESULTS: DLPM showed similar-to-higher performance at predicting 3-year survival than FVC in three external test cohorts (TD-AUC: 0.83 [95% CI: 0.76-0.90] vs. 0.68 [0.59-0.77], p < 0.001; 0.76 [0.68-0.85] vs. 0.70 [0.60-0.80], p = 0.21; 0.79 [0.72-0.86] vs. 0.76 [0.69-0.83], p = 0.41). DLPM worked as an independent prognostic factor from FVC in all three cohorts (ps < 0.001). The GAP-CR index showed a higher 3-year TD-AUC than the original GAP index in two of the three external test cohorts (TD-AUC: 0.85 [0.80-0.91] vs. 0.79 [0.72-0.86], p = 0.02; 0.72 [0.64-0.80] vs. 0.69 [0.61-0.78], p = 0.56; 0.76 [0.69-0.83] vs. 0.68 [0.60-0.76], p = 0.01). CONCLUSIONS: A deep learning model successfully predicted survival in patients with IPF from chest radiographs, comparable to and independent of FVC. CLINICAL RELEVANCE STATEMENT: Deep learning-based prognostication from chest radiographs offers comparable-to-higher prognostic performance than forced vital capacity. KEY POINTS: • A deep learning-based prognostic model for idiopathic pulmonary fibrosis was developed using 6063 radiographs. • The prognostic performance of the model was comparable-to-higher than forced vital capacity, and was independent from FVC in all three external test cohorts. • A modified gender-age-physiology index replacing diffusing capacity for carbon monoxide with the deep learning model showed higher performance than the original index in two external test cohorts.

Cross-Activation of Regulatory T Cells by Self Antigens Limits Self-Reactive and Activated CD8+ T Cell Responses.

The interaction between regulatory T (Treg) cells and self-reactive T cells is a crucial mechanism for maintaining immune tolerance. In this study, we investigated the cross-activation of Treg cells by self-antigens and its impact on self-reactive CD8+ T cell responses, with a focus on the P53 signaling pathway. We discovered that major histocompatibility complex (MHC) I-restricted self-peptides not only activated CD8+ T cells but also induced the delayed proliferation of Treg cells. Following HLA-A*0201-restricted Melan-A-specific (pMelan) CD8+ T cells, we observed the direct expansion of Treg cells and concurrent suppression of pMelan+CD8+ T cell proliferation upon stimulation with Melan-A peptide. Transcriptome analysis revealed no significant alterations in specific signaling pathways in pMelan+CD8+ T cells that were co-cultured with activated Treg cells. However, there was a noticeable upregulation of genes involved in P53 accumulation, a critical regulator of cell survival and apoptosis. Consistent with such observation, the blockade of P53 induced a continuous proliferation of pMelan+CD8+ T cells. The concurrent stimulation of Treg cells through self-reactive TCRs by self-antigens provides insights into the immune system's ability to control activated self-reactive CD8+ T cells as part of peripheral tolerance, highlighting the intricate interplay between Treg cells and CD8+ T cells and implicating therapeutic interventions in autoimmune diseases and cancer immunotherapy.

Phase 1 trial of 4-1BB-based adoptive T-cell therapy targeting human telomerase reverse transcriptase in patients with advanced refractory solid tumors.

BACKGROUND AIMS: Human telomerase reverse transcriptase (hTERT) is an attractive target for anti-cancer therapies. We developed an effective method for generating hTERT-specific CD8+ T cells (hTERT-induced natural T cells [TERTiNTs]) using peripheral blood mononuclear cells (PBMCs) from patients with solid cancers and investigated their feasibility and safety. METHODS: This was a single-center phase 1 trial using a 3 + 3 dose escalation design to evaluate six dose levels of TERTiNTs. PBMCs from each patient were screened using an hTERT peptide panel to select those that stimulated CD8+ T cells. The four most stimulatory peptides were used to produce autologous CD8+ T cells from patients refractory or intolerant to standard therapies. Eligible patients received a single intravenous infusion of TERTiNTs at different dose levels (4 × 108 cells/m2, 8 × 108 cells/m2 and 16 × 108 cells/m2). Pre-conditioning chemotherapy, including cyclophosphamide alone or in combination with fludarabine, was administered to induce lymphodepletion. RESULTS: From January 2014 to October 2019, a total of 24 patients with a median of three prior lines of therapy were enrolled. The most common adverse events were lymphopenia (79.2%), nausea (58.3%) and neutropenia (54.2%), mostly caused by pre-conditioning chemotherapy. The TERTiNT infusion was well tolerated, and dose-limiting toxicities were not observed. None of the patients showed objective responses. Seven patients (30.4%) achieved stable disease with a median progression-free survival of 3.9 months (range, 3.2-11.3). At the highest dose level (16 × 108 cells/m2), four of five patients showed disease stabilization. CONCLUSIONS: The generation of TERTiNTs was feasible and safe and provided an interesting disease control rate in heavily pre-treated cancer patients.

Real-world experience of adverse reactions-necessitated rifampicin-sparing treatment for drug-susceptible pulmonary tuberculosis.

Rifampicin is an important agent for tuberculosis treatment; however, it is often discontinued because of adverse reactions. The treatment regimen then can be administered as that for rifampicin-resistant tuberculosis, which can be toxic. We retrospectively reviewed 114 patients with drug-susceptible pulmonary tuberculosis who discontinued rifampicin due to adverse reactions during an 18 year period at a tertiary referral center, of which 92 (80.7%) exhibited favorable response. Hepatotoxicity was the leading cause of intolerance. Patients with a favorable response were younger and less likely to have comorbidities. The majority of patients were administered four medications during the intensive phase and three to four during the consolidative phase. For those with a favorable response, the median duration of treatment was 10.2 months and the most common intensive regimen was a combination of isoniazid, ethambutol, pyrazinamide, and fluoroquinolone (25%). The most common consolidation regimen was a combination of isoniazid, ethambutol, and fluoroquinolone (22.8%). Among the patients with a favorable response, two (2.2%) experienced recurrence after a follow-up of 3.4 (interquartile range 1.8-6.8) years. For patients with drug-susceptible pulmonary tuberculosis who do not tolerate rifampicin owing to its toxicity, a shorter regimen may be a useful alternative.

Electromagnetic Navigation Bronchoscopy Versus Radial Endobronchial Ultrasound for Diagnosing Lung Cancer: A Propensity Score-Matched Analysis

Introduction: Electromagnetic navigation bronchoscopy (ENB) and radial endobronchial ultrasound (R-EBUS) are advanced imaging-guided bronchoscopy techniques for diagnosing pulmonary lesions. This study aimed to determine the comparative diagnostic yield of sole ENB and R-EBUS under moderate sedation. Methods: We investigated 288 patients who underwent sole ENB (n=157) or sole R-EBUS (n=131) under moderate sedation for pulmonary lesion biopsy between January 2017 and April 2022. After a 1:1 propensity score-matching to control for pre-procedural factors, the diagnostic yield, sensitivity for malignancy, and procedure-related complications between both techniques were compared. Results: The matching resulted in 105 pairs/procedure for analyses with balanced clinical and radiological characteristics. The overall diagnostic yield was significantly higher for ENB than for R-EBUS (83.8% vs. 70.5%, p=0.021). ENB demonstrated a significantly higher diagnostic yield than R-EBUS among those with lesions>20mm in size (85.2% vs. 72.3%, p=0.034), radiologically solid lesions (86.7% vs. 72.7%, p=0.015), and lesions with a class 2 bronchus sign (91.2% vs. 72.3%, p=0.002), respectively. The sensitivity for malignancy was also higher for ENB than for R-EBUS (81.3% vs. 55.1%, p<0.001). After adjusting for clinical/radiological factors in the unmatched cohort, using ENB over R-EBUS was significantly associated with a higher diagnostic yield (odd ratio=3.45, 95% confidence interval=1.75–6.82). Complication rates for pneumothorax did not significantly differ between ENB and R-EBUS. Conclusion: ENB demonstrated a higher diagnostic yield than R-EBUS under moderate sedation for diagnosing pulmonary lesions, with similar and generally low complication rates. Our data indicate the superiority of ENB over R-EBUS in a least-invasive setting. (AU)

Usefulness of the BACES score in nontuberculous mycobacterial pulmonary disease for various clinical outcomes.

A uniform prognostic marker is needed for nontuberculous mycobacterial pulmonary disease (NTM-PD) due to the diverse clinical course. We aimed to seek the utility of the BACES score, originally derived to predict all-cause mortality, for various outcomes. To calculate the BACES score, one point was given for each of the following factors: body mass index < 18.5 kg/m2, age ≥ 65 years, presence of cavities, elevated erythrocyte sedimentation rate, or male sex. The study included 681 patients, of whom 97 (14.2%), 189 (27.7%), 192 (28.2%), 143 (21.0%), 47 (6.9%), and 13 (1.9%) had BACES scores of 0 to 5. Those with greater BACES scores were more likely to experience dyspnea, body weight loss, and anorexia. With severe disease, the risk of disease progression increased while the rate of treatment culture conversion decreased. After adjustment of comorbidities, higher BACES score was independently associated with the risk of mortality from respiratory causes or infection. As a simple and efficient bedside tool for assessing the severity of NTM-PD, the BACES score has the potential to be utilized as a surrogate marker for uniform severity assessment.

Comparison of electromagnetic navigation bronchoscopy and transthoracic needle biopsy for diagnosing bronchus sign-positive pulmonary lesions.

OBJECTIVES: Electromagnetic navigation bronchoscopy (ENB) is an advanced technique for diagnosing peripheral pulmonary lesions, and the bronchus sign is a well-established factor for improving the diagnostic performance. However, ENB is a novel technology compared to the commonly adopted transthoracic needle biopsy (TTNB). There are limited data on the comparison of these techniques for diagnosing bronchus sign-positive lesions. Therefore, we aimed to compare the diagnostic yield and complication rates of ENB and TTNB for diagnosing lung cancer in bronchus sign-positive pulmonary lesions. MATERIALS AND METHODS: We assessed 2,258 individuals who underwent either of the techniques for initial biopsy between September 2016 and May 2022 at a tertiary center in South Korea and analyzed 1,248 participants (153 ENB and 1,095 TTNB cases) with a positive bronchus sign. We performed multivariable logistic regression analyses to evaluate the factors associated with the diagnostic yield, sensitivity for malignancy, and procedure-related complications. In addition, the outcomes were compared between the two techniques after a 1:2 propensity score-matching to control for pre-procedural factors. RESULTS: After adjustments for clinical/radiological factors, performing TTNB over ENB was not significantly associated with a higher diagnostic yield but with a higher risk of pneumothorax (OR = 9.69, 95% CI = 4.15-22.59). Propensity score-matching resulted in 459 participants (153 ENB and 306 TTNB cases) with balanced pre-procedural characteristics. The overall diagnostic yield did not differ significantly between ENB and TTNB (85.0% vs. 89.9%, p = 0.124). The diagnostic yield (86.7% vs. 90.3%, p = 0.280) and sensitivity for malignancy (85.3% vs. 88.8%, p = 0.361) were comparable among patients with a class 2 bronchus sign. However, TTNB demonstrated a significantly higher complication rate of pneumothorax (28.8% vs. 3.9%, p < 0.001) and pneumothorax requiring tube drainage (6.5% vs. 2.0%, p = 0.034) than ENB. CONCLUSION: ENB demonstrated a diagnostic yield comparable with that of TTNB for diagnosing bronchus sign-positive peripheral pulmonary lesions with significantly lower complication rates.

Electromagnetic Navigation Bronchoscopy Versus Radial Endobronchial Ultrasound for Diagnosing Lung Cancer: A Propensity Score-Matched Analysis.

INTRODUCTION: Electromagnetic navigation bronchoscopy (ENB) and radial endobronchial ultrasound (R-EBUS) are advanced imaging-guided bronchoscopy techniques for diagnosing pulmonary lesions. This study aimed to determine the comparative diagnostic yield of sole ENB and R-EBUS under moderate sedation. METHODS: We investigated 288 patients who underwent sole ENB (n=157) or sole R-EBUS (n=131) under moderate sedation for pulmonary lesion biopsy between January 2017 and April 2022. After a 1:1 propensity score-matching to control for pre-procedural factors, the diagnostic yield, sensitivity for malignancy, and procedure-related complications between both techniques were compared. RESULTS: The matching resulted in 105 pairs/procedure for analyses with balanced clinical and radiological characteristics. The overall diagnostic yield was significantly higher for ENB than for R-EBUS (83.8% vs. 70.5%, p=0.021). ENB demonstrated a significantly higher diagnostic yield than R-EBUS among those with lesions>20mm in size (85.2% vs. 72.3%, p=0.034), radiologically solid lesions (86.7% vs. 72.7%, p=0.015), and lesions with a class 2 bronchus sign (91.2% vs. 72.3%, p=0.002), respectively. The sensitivity for malignancy was also higher for ENB than for R-EBUS (81.3% vs. 55.1%, p<0.001). After adjusting for clinical/radiological factors in the unmatched cohort, using ENB over R-EBUS was significantly associated with a higher diagnostic yield (odd ratio=3.45, 95% confidence interval=1.75-6.82). Complication rates for pneumothorax did not significantly differ between ENB and R-EBUS. CONCLUSION: ENB demonstrated a higher diagnostic yield than R-EBUS under moderate sedation for diagnosing pulmonary lesions, with similar and generally low complication rates. Our data indicate the superiority of ENB over R-EBUS in a least-invasive setting.

A prospective study on the long-term storage of sputum and the recovery of nontuberculous mycobacteria.

BACKGROUND: There is little information on the optimal storage conditions for recovery of nontuberculous Mycobacterium spp. (NTM) from refrigerated sputum. OBJECTIVES: We investigated the storage duration that could increase the culture-positive rate of NTM isolates. DESIGN: In this prospective study, we collected NTM isolates and clinical data from patients with repeated culture-positive NTM pulmonary disease (NTM-PD). METHODS: From June 2020 to July 2021, the participants were instructed to randomly collect six sputum samples and immediately store them in a refrigerator at 4°C until the date of their clinic visit. At the outpatient visits, expectorated spot sputum samples were collected. RESULTS: A total of 226 sputum samples were collected from 35 patients. The median duration of refrigeration was 6 days (maximum duration: 36 days). The overall culture-positive rate was 81.6%. While there was a trend for a higher culture positivity rate when stored for ⩽3 weeks, this was not significant compared with those stored for >3 weeks (p = 0.610). According to sputum microscopy, smear-positive sputum was 100% isolated, but smear-negative samples had a culture-positive rate of 77.5%. Similarly, there was no significant association between sputum storage duration and culture positivity (p = 0.511). In addition, the recovery rate of the refrigerated sputum was comparable with the collected spot expectorated sputum (82.6% versus 80.6%, p = 0.795), which is suggestive of the long-term viability of NTM in refrigerated sputum. CONCLUSION: Our data demonstrated the long-term viability of refrigerated NTM, and the culture positivity rate of these samples was comparable with the spot expectorated sputum. These results suggest that implementing sputum refrigeration would enhance convenience in diagnosing and following patients with NTM-PD. PLAIN LANGUAGE SUMMARY: Easy way to diagnose NTM lung diseasesUnder usual circumstances, most patients with suspected NTM submit spontaneously expectorated sputum rather than induced sputum for the purpose of testing the causative organism. By collecting and storing sputum specimens for a longer period than before, it is expected that more sufficient and adequate collection of sputum specimens will be possible.

Correlation of monocyte counts with clinical outcomes in idiopathic nonspecific interstitial pneumonia.

Higher blood monocyte counts are related to worse survival in idiopathic pulmonary fibrosis. However, studies evaluating the association between blood monocyte counts and clinical outcomes of idiopathic nonspecific interstitial pneumonia (iNSIP) are lacking. We evaluated the impact of monocyte counts on iNSIP prognosis. iNSIP patients (n = 126; median age, 60 years; female, n = 64 [50.8%]) diagnosed by surgical lung biopsy were enrolled and categorized into low (monocyte < 600/µL) and high (monocyte ≥ 600/µL) monocyte groups. The median follow-up duration was 53.0 months. After adjusting for age, sex, and smoking history, the annual decline in forced vital capacity (FVC) showed differences between the monocyte groups (Pinteraction = 0.006) (low vs. high; - 28.49 mL/year vs. - 65.76 mL/year). The high-monocyte group showed a worse survival rate (P = 0.01) compared to low monocyte group. The 5-year survival rates were 83% and 72% in the low- and high-monocyte groups, respectively. In the Cox-proportional hazard analysis, older age, male sex, low baseline FVC, and diffusing capacity of the lung for carbon monoxide were independent risk factors for mortality. However, monocyte count (Hazard ratio 1.61, P = 0.126) was not an independent prognostic factor. Although high monocyte count might be associated with faster lung function decline, it could not independently predict survival in iNSIP.

Targeting 4-1BB and PD-L1 induces potent and durable antitumor immunity in B-cell lymphoma.

Introduction: Although PD-1/L1 mAb has demonstrated clinical benefits in certain cancer types, low response rate and resistance remain the main challenges for the application of these immune checkpoint inhibitors (ICIs). 4-1BB is a co-stimulator molecule expressed in T cells, which could enhance T cell proliferation and activation. Herein, the synergetic antitumor effect and underlying mechanism of 4-1BB agonist combined with PD-1/PD-L1 blockade were determined in B-cell lymphoma (BCL). Methods: Subcutaneous transplantation BCL tumor models and metastasis models were established to evaluate the therapeutic effect of PD-L1 antibody and/or 4-1BB agonist in vivo. For the mechanistic study, RNA-seq was applied to analyze the tumor microenvironment and immune-related signal pathway after combination treatment. The level of IFN-γ, perforin, and granzyme B were determined by ELISA and Real-time PCR assays, while tumor-infiltrating T cells were measured by flow cytometry and immunohistochemical analysis. CD4/CD8 specific antibodies were employed to deplete the related T cells to investigate the role CD4+ and CD8+ T cells played in combination treatment. Results: Our results showed that combining anti-PD-L1 ICI and 4-1BB agonists elicited regression of BCL and significantly extended the survival of mice compared to either monotherapy. Co-targeting PD-L1 and 4-1BB preferentially promoted intratumoral cytotoxic lymphocyte infiltration and remodeled their function. RNA-sequence analysis uncovered a series of up-regulated genes related to the activation and proliferation of cytotoxic T lymphocytes, further characterized by increased cytokines including IFN-γ, granzyme B, and perforin. Furthermore, depleting CD8+ T cells not CD4+ T cells totally abrogated the antitumor efficacy, indicating the crucial function of the CD8+ T cell subset in the combination therapy. Discussion: In summary, our findings demonstrated that 4-1BB agonistic antibody intensified the antitumor immunity of anti-PD-1/PD-L1 ICI via promoting CD8+ T cell infiltration and activation, providing a novel therapeutic strategy to BCL.

S-Benproperine, an Active Stereoisomer of Benproperine, Suppresses Cancer Migration and Tumor Metastasis by Targeting ARPC2.

Metastasis, in which cancer cells migrate to other tissues and form new tumors, is a major cause of both cancer death and treatment failure. In a previous study, benproperine (Benp) was identified as a cancer cell migration inhibitor and an inhibitor of actin-related protein 2/3 complex subunit 2 (ARPC2). However, Benp is a racemic mixture, and which stereoisomer is the active isomer remains unclear. In this study, we found that S-Benp is an active isomer and inhibits the migration and invasion of cancer cells much more strongly than R-Benp, with no effect on normal cells. The metastasis inhibitory effect of S-Benp was also verified in an animal model. Validating that inhibitors bind to their targets in cells and tissues has been a very challenging task in drug discovery. The direct interactions between ARPC2 and S-Benp were verified by surface plasmon resonance analysis (SPR), a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). In the mutant study with ARPC2F225A cells, S-Benp did not bind to ARPC2F225A according to CETSA and DARTS. Furthermore, we validated that S-Benp colocalized with ARPC2 in cancer cells and directly bound to ARPC2 in tumor tissues using Cy3-conjugated S-Benp according to CETSA. Finally, actin polymerization assays and immunocytochemistry showed that S-Benp suppressed actin remodeling such as lamellipodium formation. Taken together, our data suggest that S-Benp is an active stereoisomer of Benp and a potential metastasis inhibitor via ARPC2 binding.

Interstitial pneumonitis associated with dasatinib treatment for chronic myeloid leukemia or acute lymphoblastic leukemia: case series and a literature review.

Dasatinib, a tyrosine kinase inhibitor, is usually prescribed for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, some patients may develop an intolerance to this drug over the years. Among various toxicities related to dasatinib, dasatinib-associated interstitial pneumonitis is not reported frequently in the literature yet. Moreover, published studies have reported only few cases of dasatinib-associated pneumonitis, almost exclusively in chronic myeloid leukemia. In this study, we describe three cases of dasatinib-associated interstitial pneumonitis in patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia (a 56-year-old man, a 34-year-old man, and a 46-year-old woman) at our institution. In all three patients, the time from the initiation of dasatinib therapy to the onset of interstitial pneumonitis varied greatly. Among them, one patient underwent a surgical lung biopsy, which revealed chronic granulomatous inflammation without any causative pathogen. In all patients, dasatinib was discontinued after the diagnosis of interstitial pneumonitis, and two patients were treated with systemic steroids. Although infrequent, dasatinib-induced pneumonitis should be considered a possible diagnosis in dasatinib-treated patients with fever and respiratory symptoms. In addition, hematologists and pulmonologists should be aware of this rare but critical toxicity.

The significance of elevated tumor markers among patients with interstitial lung diseases.

The clinical implication of using serum tumor markers in patients with interstitial lung disease (ILD) is inconclusive. In this retrospective study, we analyzed the data of 1176 subjects (294 with ILDs and 882 healthy controls). Eligible patients were who had at least one or more available tumor marker results [carbohydrate antigen (CA) 19-9, CA 125, and carcinoembryonic antigen (CEA)] with no evidence of malignancies or other benign diseases that could be related to the increasing concentration of the values. The healthy controls selected from a health screening program were also screened for the presence of active cancer, and matched at a ratio of 1:3 with age and sex. The proportion of patients with abnormal values in the ILD group (121, idiopathic pulmonary fibrosis (IPF); 173, non-IPF-ILDs) was higher than in the matched control group (CEA, 21.5% vs. 5.5%; CA 19-9, 27.9% vs. 4.0%; CA 125, 36.4% vs. 2.0%). In the multivariable analysis, higher CEA levels were associated with shorter survival after adjusting for age, sex, lung function, and ILD subtypes (hazard ratio: 2.323, 95% confidence interval: 1.271-4.248, P = 0.006). In subgroup analysis, CEA remained a prognostic factor in patients with non-IPF-ILDs, but not in those with IPF.

Impact of body weight change on clinical outcomes in patients with idiopathic pulmonary fibrosis receiving pirfenidone.

There have been limited studies on the association between prognosis and body weight change in patients with idiopathic pulmonary fibrosis (IPF). This single-center retrospective observational study evaluated the impact of weight loss on outcomes in Korean patients with IPF receiving pirfenidone at a tertiary medical institution. We analyzed 215 IPF patients prescribed pirfenidone from January 1st, 2015 to December 31st, 2019. The patients were categorized into maintained weight (MW; weight gain or loss < 5%/year) and reduced weight (RW; weight loss ≥ 5%/year) groups. The mean age was 71.8 years and 175 (81.4%) were male. There were 54 (25.1%) patients in the RW group. All patients showed a decrease in body weight (baseline vs. after 1 year; 64.1 kg vs. 62.8 kg, P < 0.001). Although baseline lung function showed a difference, there was no difference in the rate of change (forced vital capacity [% of predicted]; P = 0.221, diffusing capacity of the lung for carbon monoxide [% of predicted]; P = 0.973). The MW group had a lower risk of all-cause mortality (P < 0.001). Weight loss appeared to be a significant risk factor for mortality in patients with IPF. Not only disease control with antifibrotic agents, but also efforts to prevent weight loss may be necessary.