A prospective, open-label, randomized clinical trial to evaluate the efficacy and safety of remimazolam in patients undergoing EBUS-TBNA: REST trial design.

BACKGROUND: Remimazolam is safe and effective for moderate sedation during flexible bronchoscopy, but its safety and efficacy during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) remains undetermined. The REST trial (NCT06275594) will be a prospective randomized study of remimazolam in patients undergoing EBUS-TBNA with conscious sedation. The primary aim is to evaluate whether remimazolam is safe and effective for moderate sedation during EBUS-TBNA compared to real-world midazolam and on-label midazolam. METHODS: The REST trial will recruit 330 patients from four university hospitals with mediastinal lesions suspected of being lung cancer who are eligible for EBUS-TBNA under moderate sedation. The participants will be randomized into groups using remimazolam, real-world midazolam, and on-label midazolam (US prescribing information dosage) to perform EBUS-TBNA for procedural sedation. The primary endpoint will be procedural success using composite measures. DISCUSSION: The REST trial will prospectively evaluate the efficacy and safety of remimazolam during EBUS-TBNA under moderate sedation. It will provide information for optimizing sedation modalities and contribute to practical benefits in patients undergoing EBUS-TBNA. TRIAL REGISTRATION: ClinicalTrials.gov (NCT06275594). Prospectively registered on 15 February 2024.

Impact of Respiratory Bacterial Findings on Patients with Chronic Pulmonary Aspergillosis.

Background: Distinct bacterial strains may affect the prognosis of patients with chronic respiratory diseases. However, little is known about the clinical significance of respiratory bacteria in patients with chronic pulmonary aspergillosis (CPA), a progressive and debilitating disease caused by Aspergillus spp. Objectives: This study aimed to analyze data obtained from CPA patients and their sputum or bronchial washing samples and investigate the prevalence and composition of respiratory bacteria and clinical implications. Patients and Methods. We retrospectively reviewed the data of patients diagnosed with CPA between March 2019 and February 2023 in a tertiary referral hospital. We assessed the clinical characteristics and overall and pneumonia-specific survival rates of patients with CPA based on the presence of bacteria. Results and Conclusions. We included 142 patients with CPA. The most commonly identified bacteria were Klebsiella pneumoniae (22.5%), followed by Pseudomonas aeruginosa (21.8%) and Escherichia coli (4.2%). Patients with isolated bacteria had a higher prevalence of older age, female sex, diabetes, and a history of extrathoracic malignancy than those without isolated bacteria (P = 0.024, 0.013, 0.021, and 0.034, respectively). Furthermore, over a median follow-up of 11 (4-21) months, the pneumonia-specific mortality rate was 13.4% (19/142), which was higher in patients with isolated bacteria than in those without (P = 0.045, log-rank test). Particularly, patients with the presence of P. aeruginosa had a significantly higher mortality rate from pneumonia than those without the presence of P. aeruginosa (adjusted hazard ratio, 3.34; P = 0.015). In conclusion, CPA patients with isolated bacteria, especially P. aeruginosa, showed higher mortality rates due to pneumonia. Performing tests to identify bacteria in the lower respiratory tract of patients with CPA may be helpful in predicting future prognosis. Further studies are required to validate these findings in diverse ethnic groups.

Increased Lung Cancer Risk and Associated Risk Factors in Tuberculosis Survivors: A Korean Population-Based Study.

BACKGROUND: Few studies have comprehensively evaluated the risk of lung cancer in tuberculosis survivors with consideration of smoking status and chronic obstructive pulmonary disease (COPD). Furthermore, little is known about lung cancer risk factors in tuberculosis survivors. METHODS: This population-based cohort study enrolled tuberculosis survivors (n = 75 467) between 2010 and 2017 and 1:1 age- and sex-matched controls. Subjects were followed up for 1 year from the date of tuberculosis diagnosis to the date of the incident lung cancer, death, or December 2018, whichever came first. The risk of lung cancer was evaluated according to smoking and COPD status. We also evaluated the risk factors for lung cancer and developed an individualized lung cancer prediction model for tuberculosis survivors. RESULTS: During a median follow-up duration of 4.8 years, the incident lung cancer risk was 1.72-fold higher in tuberculosis survivors than in the controls. Among tuberculosis survivors, those who were current smokers with ≥20 pack-years showed the highest risk of lung cancer (adjusted hazard ratio, 6.78) compared with never-smoker, non-tuberculosis-infected controls. tuberculosis survivors with COPD had a higher risk (2.43) than non-COPD, non-tuberculosis-infected controls. Risk factors for lung cancer in tuberculosis survivors were pulmonary tuberculosis, age >60 years, smoking, and the presence of COPD or asthma. The individualized lung cancer risk model showed good discrimination (concordance statistic = 0.827). CONCLUSIONS: Previous tuberculosis infection is an independent risk factor regardless of smoking status or amount and COPD. Closer monitoring of tuberculosis survivors, especially heavy smokers or those with COPD, is needed for early lung cancer diagnosis.

Translation and validation of the Korean version of the clinical frailty scale in older patients.

BACKGROUND: Frailty is a multidimensional syndrome that leads to an increase in vulnerability. Previous studies have suggested that frailty is associated with poor health-related outcomes. For frailty screening, the Clinical Frailty Scale (CFS) is a simple tool that is widely used in various translated versions. We aimed to translate the CSF into Korean and evaluated its contents and concurrent validity. METHODS: Translations and back-translations of the CFS were conducted independently. A multidisciplinary team decided the final CFS-K. Between August 2019 and April 2020, a total of 100 outpatient and inpatient participants aged ≥65 years were enrolled prospectively. The clinical characteristics were evaluated using the CFS-K. The CFS-K scores were compared with those of other frailty screening tools using Pearson's correlation coefficient and Spearman's rank correlation. The area under curve (AUC) for identifying the Eastern Cooperative Oncology Group Performance Status (ECOG PS) grade 3 or more was calculated for the CFS-K and other screening tools. RESULTS: The mean age of the participants was 76.5 years (standard deviation [SD], 7.0), and 63 (63%) participants were male. The mean CFS-K was 4.8 (SD, 2.5). Low body mass index (p = 0.013) and low score on the Korean version of the Mini-Mental State Examination (p < 0.001) were significantly associated with high CFS-K scores, except for those assigned to scale 9 (terminally ill). The CFS-K showed a significant correlation with other frailty screening tools (R = 0.7742-0.9190; p < 0.01), except in the case of those assigned to scale 9 (terminally ill). In comparison with other scales, the CFS-K identified ECOG PS grade 3 or more with the best performance (AUC = 0.99). Patients assigned to scale 9 on the CFS-K (terminally ill) had similar frailty scores to those assigned to scale 4 (vulnerable) or 5 (mildly frail). CONCLUSIONS: In conclusion, the CFS-K is a valid scale for measuring frailty in older Korean patients. The CFS-K scores were significantly correlated with the scores of other scales. To evaluate the predictive and prognostic value of this scale, further larger-scale studies in various clinical settings are warranted.

Comparative Study on the Effect of Cidofovir Treatment for Severe Adenovirus Pneumonia.

BACKGROUND: Adenovirus infection can cause severe pneumonia even in immunocompetent adults. However, there is limited data on the benefits of cidofovir treatment in severe adenovirus pneumonia. The objective of this study was to evaluate the association of cidofovir treatment with clinical improvement in immunocompetent adult patients with severe adenovirus pneumonia. METHODS: We evaluated 22 male patients who admitted to intensive care unit (ICU) with severe adenovirus pneumonia between January 2014 and December 2019. The patients were divided into 2 groups, patients treated with cidofovir or not. Clinical outcomes including time to defervescence and stopping of oxygen supplement, length of stay in ICU and hospital, and the need for mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) were compared between the 2 groups. RESULTS: Among 22 patients, 13 patients (59%) were treated with cidofovir and 9 (41%) were not. The difference in mean time (95% confidence interval [CI]) to defervescence and stopping of oxygen supplement between cidofovir group and no cidofovir group was 2.1 (-5.7 to 10.0) and 1.0 (-14.9 to 16.8) days, respectively. The difference in mean length of stay (95% CI) in ICU and hospital between the 2 groups was 0.2 (-7.1 to 7.5) and -0.4 (-18.3 to 17.5) days, respectively. The differences in proportion of patients requiring MV and ECMO between the 2 groups was 28.2 (-17.4 to 73.8) % and -10.3 (-52.2 to 31.7) %, respectively. CONCLUSIONS: The treatment with cidofovir for severe adenovirus pneumonia in immunocompetent patients did not improve clinical outcomes. Further studies with larger samples with prospective design are warranted.

Clinical Utility of Combined Circulating Tumor Cell and Circulating Tumor DNA Assays for Diagnosis of Primary Lung Cancer.

BACKGROUND/AIM: Although it has been suggested that circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) might be used in a complementary manner in lung cancer diagnosis, limited confirmatory data are available. In this prospective study, we evaluated the diagnostic performance of each assay separately and in combination. PATIENTS AND METHODS: From March 2018 to January 2019, patients with suspected primary lung cancer, who underwent routine lung cancer work-up and peripheral blood sampling, were prospectively enrolled in the study. Epithelial cell adhesion molecule and cytokeratin served as markers of CTCs. In terms of ctDNA analysis, single-nucleotide variants were evaluated via next-generation sequencing. RESULTS: We analyzed 111 patients, including 99 with primary lung cancer and 12 with benign pulmonary disease. The median number of CTCs in 10 ml of blood was 3. The most frequently detected single nucleotide variants of ctDNA were TP53, CDKN2A, and EGFR. The diagnostic sensitivity of conventional tumor marker (combination of carcinoembryonic antigen/CYFRA 21-1/neuron-specific enolase) was 66.7%, while those of the ctDNA and CTC assays were 72.7% and 65.7%, respectively. The sensitivity of the CTC/ctDNA combination (95.0%) was significantly greater than those of the CTC (p<0.001), ctDNA (p<0.001), or conventional tumor marker (p<0.001) alone. Subgroup analysis revealed that the sensitivity of the combination assay was greater than those of the CTC or ctDNA assays alone, regardless of tumor stage or histopathology type. CONCLUSION: The CTC/ctDNA combination assay enhanced the sensitivity of primary lung cancer diagnosis. The combination assay strategy may be clinically useful and could enhance the early detection of lung cancer (ClinicalTrials.gov number: NCT03479099).

Prognostic factors associated with long-term mortality in 1445 patients with nontuberculous mycobacterial pulmonary disease: a 15-year follow-up study.

Limited data are available regarding the prognostic factors for patients with nontuberculous mycobacterial pulmonary disease (NTM-PD). We investigated the prognostic factors associated with long-term mortality in NTM-PD patients after adjusting for individual confounders, including aetiological organism and radiological form.A total of 1445 patients with treatment-naïve NTM-PD who were newly diagnosed between July 1997 and December 2013 were included. The aetiological organisms were as follows: Mycobacterium avium (n=655), M. intracellulare (n=487), M. abscessus (n=129) and M. massiliense (n=174). The factors associated with mortality in NTM-PD patients were analysed using a multivariable Cox model after adjusting for demographic, radiological and aetiological data.The overall 5-, 10- and 15-year cumulative mortality rates for the NTM-PD patients were 12.4%, 24.0% and 36.4%, respectively. On multivariable analysis, the following factors were significantly associated with mortality in NTM-PD patients: old age, male sex, low body mass index, chronic pulmonary aspergillosis, pulmonary or extrapulmonary malignancy, chronic heart or liver disease and erythrocyte sedimentation rate. The aetiological organism was also significantly associated with mortality: M. intracellulare had an adjusted hazard ratio (aHR) of 1.40, 95% CI 1.03-1.91; M. abscessus had an aHR of 2.19, 95% CI 1.36-3.51; and M. massiliense had an aHR of 0.99, 95% CI 0.61-1.64, compared to M. avium Mortality was also significantly associated with the radiological form of NTM-PD for the cavitary nodular bronchiectatic form (aHR 1.70, 95% CI 1.12-2.59) and the fibrocavitary form (aHR 2.12, 95% CI 1.57-3.08), compared to the non-cavitary nodular bronchiectatic form.Long-term mortality in patients with NTM-PD was significantly associated with the aetiological NTM organism, cavitary disease and certain demographic characteristics.

Diagnostic Performance of Radial Probe Endobronchial Ultrasound without a Guide-Sheath and the Feasibility of Molecular Analysis.

BACKGROUND: Radial probe endobronchial ultrasound (R-EBUS), is effective for tissue diagnosis of lung lesions. We evaluated the diagnostic performance of R-EBUS both a guide-sheath and fluoroscopy and identified factors associated with accurate diagnosis. The feasibility of molecular and genetic testing, using specimens obtained by R-EBUS, was also investigated. METHODS: The study retrospectively reviewed 211 patients undergoing R-EBUS without a guide-sheath and fluoroscopy, June 2016-May 2017. After excluding 27 patients of which the target lesion was not reached, 184 were finally included. Multivariate logistic regression was used, to identify factors associated with accurate diagnosis. RESULTS: Among 184 patients, R-EBUS-guided biopsy diagnosed malignancy in 109 patients (59%). The remaining 75 patients (41%) with non-malignant results underwent additional work-ups, and 34 were diagnosed with malignancy. Based on final diagnosis, diagnostic accuracy was 80% (136/170), and sensitivity and specificity for malignancy were 76% (109/143) and 100% (27/27), respectively. In multivariate analysis, peripheral location (adjusted odds ratio [aOR], 3.925; 95% confidence interval [CI], 1.203-12.811; p=0.023), and central position of the probe (aOR, 2.435; 95% CI, 1.424-7.013; p=0.035), were associated with accurate diagnosis of malignancy. Molecular and genetic analyses were successful, in all but one case, with inadequate specimens. CONCLUSION: R-EBUS-guided biopsy without equipment, is effective for tissue diagnosis. Peripheral location and central position of the radial probe, were crucial for accurate diagnosis. Performance of molecular and genetic testing, using samples obtained by R-EBUS, was satisfactory.

Long-term natural history of non-cavitary nodular bronchiectatic nontuberculous mycobacterial pulmonary disease.

BACKGROUND: Information about the natural history of nontuberculous mycobacterial pulmonary disease (NTM-PD) is limited. The purpose of this study was to evaluate the long-term natural history of non-cavitary nodular bronchiectatic NTM-PD and the factors associated with treatment initiation and the frequency of spontaneous sputum culture conversion after diagnosis of NTM-PD. METHODS: We evaluated 1,021 patients with newly diagnosed non-cavitary nodular bronchiectatic NTM-PD caused by Mycobacterium avium complex or M. abscessus between 2003 and 2013. RESULTS: Of 1,021 patients, 562 (55%) initiated antibiotic treatment and 459 (45%) did not. Young age (adjusted hazard ratio [aHR] = 0.99; 95% confidence interval [CI] = 0.98-0.99), low body mass index (aHR = 0.96; 95% CI = 0.93-0.99), previous history of tuberculosis (aHR = 1.23; 95% CI = 1.01-1.50), respiratory complaints such as cough (aHR = 1.36; 95% CI = 1.05-1.75) and sputum production (aHR = 1.47; 95% CI = 1.13-1.91), and high number of involved lobes on high-resolution computed tomography (aHR = 1.22; 95% CI = 1.14-1.31) were associated with treatment initiation. Of 459 patients who did not initiate treatment, 157 (34%) showed spontaneous sputum culture conversion. None of the clinical factors was associated with spontaneous conversion. After spontaneous culture conversion, 26 of 157 (17%) showed redeveloped NTM-PD caused by a species different from the original species. CONCLUSIONS: The natural history of non-cavitary nodular bronchiectatic NTM-PD is variable. After diagnosis, the decision to initiate antibiotic therapy should be individualized based on consideration of the risk factors for disease progression. However, for patients who do not start antibiotic therapy, continuous and lifetime follow-up is recommended to manage underlying bronchiectasis and the possibility of late progression of NTM-PD.

Non-intubated video-assisted thoracoscopic lung biopsy for interstitial lung disease: a single-center experience.

BACKGROUND: The mortality and morbidity associated with video-assisted thoracoscopic (VATS) lung biopsy for interstitial lung disease (ILD) are not negligible. We evaluated whether non-intubated VATS lung biopsy, which avoids intubation and general anesthesia, can be safely performed in ILD subjects. METHODS: This retrospective study compared the incidence of complications and surgical mortality between 25 consecutive intubated subjects and 10 non-intubated subjects (a total of 35 consecutive subjects) at a single institution. RESULTS: No major surgical complications or deaths were reported in either group, and non-intubated VATS biopsies were safely performed in subjects with relatively low carbon monoxide diffusing capacity (P=0.08) or poor American Society of Anesthesiologists physical status scores (ASA) (P=0.02). CONCLUSIONS: These preliminary results suggest that non-intubated VATS lung biopsy is a safe and feasible option in patients with ILD.

Intermittent Antibiotic Therapy for Recurrent Nodular Bronchiectatic Mycobacterium avium Complex Lung Disease.

Intermittent, three-times-weekly oral antibiotic therapy is recommended for the initial treatment of noncavitary nodular bronchiectatic (NB) Mycobacterium avium complex (MAC) lung disease. However, intermittent therapy is not recommended for patients who have been previously treated. We evaluated 53 patients with recurrent noncavitary NB MAC lung disease who underwent antibiotic treatment for ≥12 months with daily therapy (n = 26) or intermittent therapy (n = 27) between January 2008 and December 2015. Baseline characteristics were comparable between daily therapy and intermittent therapy groups. Sputum culture conversion rates did not differ between daily therapy (21/26, 81%) and intermittent therapy (22/27, 82%) groups. Compared to the etiologic organism at the time of previous treatment, recurrent MAC lung disease was caused by the same MAC species in 38 patients (72%) and by a different MAC species in 15 patients (28%). Genotype analysis in patients with sequenced paired isolates revealed that 86% (12/14) of cases with same species recurrence were due to reinfection with a new MAC genotype. In conclusion, most recurrent noncavitary NB MAC lung disease cases were caused by reinfection rather than relapse. Intermittent antibiotic therapy is a reasonable treatment strategy for recurrent noncavitary NB MAC lung disease.

Ipsilateral pleural recurrence after diagnostic transthoracic needle biopsy in pathological stage I lung cancer patients who underwent curative resection.

OBJECTIVES: The relationship between transthoracic needle biopsy (TTNB) and pleural recurrence of cancer after curative lung resection remains unclear. We aimed to assess whether TTNB increases the ipsilateral pleural recurrence (IPR) rate and identify other potential risk factors for pleural recurrence after surgery. MATERIALS AND METHODS: This retrospective study included 392 patients with p-stage I non-small cell lung cancer with solid or part-solid nodules after curative lung resection in 2009-2010. Imbalances among the characteristics were adjusted using an inverse probability-weighted method based on propensity scoring. Multivariate Cox's regression analysis and the Kaplan-Meier method were used to determine independent risk factors for IPR. RESULTS: A total of 243 (62%) patients received TTNB, while 149 (38%) underwent an alternate, or no, diagnostic technique. IPR was significantly more frequent in the TTNB group (p=0.004), while total recurrence was similar between the groups (p=0.098). After applying the weighted model, diagnostic TTNB (hazard ratio [HR], 5.27; 95% confidence interval [CI], 1.49-18.69; p=0.010), microscopic visceral pleural invasion (HR, 2.76; 95% CI, 1.08-7.01; p=0.033) and microscopic lymphatic invasion (HR, 3.25; 95% CI, 1.30-8.10; p=0.012) were associated with an increased frequency of IPR. Among patients who received TTNB, microscopic lymphatic invasion was a risk factor for IPR (HR, 2.74; 95% CI, 1.10-6.79; p=0.030). CONCLUSIONS: The diagnostic TTNB procedure is associated with pleural recurrence but may be unrelated to overall recurrence-free survival in early lung cancer. Moreover, microscopic lymphatic invasion could be a risk factor for pleural recurrence. TTNB should be carefully considered before lung resection and close follow-up to detect if pleural recurrence is needed.

Effect of Rifampin on Thyroid Function Test in Patients on Levothyroxine Medication.

BACKGROUND: Levothyroxine (LT4) and rifampin (RIF) are sometimes used together; however, no clinical studies have assessed the effects of these drugs on thyroid function or the need to adjust LT4 dose. METHODS: We retrospectively reviewed the records of 71 Korean patients who started RIF during LT4 treatment. Clinically relevant cases that required dose adjustment according to the American Thyroid Association (ATA)/American Association of Clinical Endocrinologists (AACE) guidelines were identified, and risk factors of increased LT4 dose were analyzed. RESULTS: After administering RIF, median serum thyroid-stimulating hormone (TSH) level (2.58 mIU/L, interquartile range [IQR] 0.21-7.44) was significantly higher than that before RIF (0.25 mIU/L, IQR, 0.03-2.62; P < 0.001). An increased LT4 dose was required for 50% of patients in the TSH suppression group for thyroid cancer and 26% of patients in the replacement group for hypothyroidism. Risk factor analysis showed that remaining thyroid gland (odds ratio [OR] 9.207, P = 0.002), the time interval between starting RIF and TSH measurement (OR 1.043, P = 0.019), and baseline LT4 dose per kg body weight (OR 0.364, P = 0.011) were clinically relevant variables. CONCLUSIONS: In patients receiving LT4, serum thyroid function test should be performed after starting RIF treatment. For patients with no remnant thyroid gland and those receiving a lower LT4 dose, close observation is needed when starting RIF and TB medication.

Lung cancer with superior vena cava syndrome diagnosed by intravascular biopsy using EBUS-TBNA.

Since superior vena cava syndrome (SVCS) is a critical condition, immediate diagnostic approach and therapy are imperative to avoid potentially life-threatening complications. Here, we report a case of lung cancer with SVCS, which was diagnosed through intravascular tumor biopsy using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). EBUS-TBNA enabled us to obtain tissue sufficient for diagnosis, without significant complications. Prompt diagnosis was followed by appropriate anticancer treatment and improvement in the symptoms. For patients suspected of SVCS and requiring prompt pathologic diagnosis, we can consider EBUS-TBNA to diagnose intravascular or mediastinal tumors and provide an accurate diagnosis.

Warfarin skin necrosis mimicking calciphylaxis in a patient with secondary hyperparathyroidism undergoing peritoneal dialysis.

Warfarin skin necrosis (WSN) is an infrequent complication of warfarin treatment and is characterized by painful ulcerative skin lesions that appear a few days after the start of warfarin treatment. Calciphylaxis also appears as painful skin lesions caused by tissue injury resulting from localized ischemia caused by calcification of small- to medium-sized vessels in patients with end-stage renal disease. We report on a patient who presented with painful skin ulcers on the lower extremities after the administration of warfarin after a valve operation. Calciphylaxis was considered first because of the host factors; eventually, the skin lesions were diagnosed as WSN by biopsy. The skin lesions improved after warfarin discontinuation and short-term steroid therapy. Most patients with end-stage renal disease have some form of cardiovascular disease and some require temporary or continual warfarin treatment. It is important to differentiate between WSN and calciphylaxis in patients with painful skin lesions.