[Recurrence of a Giant Emphysematous Bulla After Bullectomy:Report of a Case].

A 38-year-old male, he was diagnosed with a giant pulmonary bulla occupying 2/3 of the right thoracic cavity on chest computed tomography( CT). The preoperative pulmonary function was unfavorable, so bullectomy of right upper lobe with video-assisted thoracoscopic surgery( VATS) was performed. The outpatient follow-up was completed at 6 months after surgery. However, one year and eleven months postoperatively, the patient returned to the clinic complaining of dyspnea. Chest X-ray and CT showed a recurrence of a giant emphysematous bulla in the right upper lobe. Two years and three months after the initial surgery, the recurrent giant bulla was resected by right upper lobectomy with VATS. About four years after the reoperation, no recurrence of giant pulmonary bulla has been seen. Although there are some reports on surgical treatment and results of giant pulmonary bulla, there are few reports on recurrent cases, so we report this case.

A 65-Year-Old Man With Massive Hemoptysis.

CASE PRESENTATION: A 65-year-old man experienced a cough and mild hemoptysis suddenly one morning. He was prescribed tranexamic acid and carbazochrome salicylate by the local clinic at the first visit, and his hemoptysis stopped. However, 2 days later, he experienced recurrent hemoptysis that was prolonged intermittently. He had slight dyspnea and chest discomfort, but no other symptoms, such as sputum, fever, or chest pain. He was referred to our hospital for further assessment of hemoptysis. He had experienced mild hemoptysis of unknown causes 8 years earlier without recurrence until this episode. He had bronchial asthma that was treated with an inhaled corticosteroid and hypertension and hyperuricemia that were untreated with medication. He had no known allergies or family history of lung disease. He did not smoke. The patient denied alcohol consumption, any recent travel, or exposure to TB.

Leptin-producing monocytes in the airway submucosa may contribute to asthma pathogenesis.

BACKGROUND: Obesity leads to an increase in the incidence and severity of asthma. Adipokines, such as leptin, secreted by adipocytes induce systemic inflammation, causing airway inflammation. We previously reported that leptin activates both inflammatory and structural cells, including lung fibroblasts. However, little is known about the differential leptin expression and responsiveness to leptin in asthmatic individuals and healthy controls (HC). In this study, we investigated the expression and origin of leptin in asthmatic airways. We also compared the effect of leptin on asthmatic and HC fibroblasts. METHODS: Lung specimens from asthmatic and non-asthmatic patients were analyzed by immunohistochemical staining using anti-leptin and anti-CD163 antibodies. Leptin mRNA and protein levels in human monocytes were detected by real-time PCR and western blotting and ELISA, respectively. We used flow cytometry to analyze asthmatic and HC lung fibroblasts for leptin receptor (Ob-R) expression. Further, we determined cytokine levels using cytometric bead array and ELISA and intracellular phosphorylation of specific signaling molecules using western blotting. RESULTS: Asthma specimens displayed accumulation of leptin-positive inflammatory cells, which were also positive for CD163, a high-affinity scavenger receptor expressed by monocytes and macrophages. Leptin expression was observed at both transcript and protein levels in human blood-derived monocytes. No significant differences were observed between asthmatic and HC lung fibroblasts in Ob-R expression, cytokine production, and intracellular phosphorylation of p38 mitogen-activated protein kinase. CONCLUSIONS: Our findings reveal similar responsiveness of control and asthmatic fibroblasts to leptin. However, the accumulation of inflammatory leptin-producing monocytes in the airway may contribute to the pathogenesis of asthma.

Impact of lung cancer surgery on comorbid Mycobacterium avium complex lung disease-A case series.

The number of cases with Mycobacterium avium and Mycobacterium intracellulare lung diseases (Mycobacterium avium complex lung disease [MACLD]) are increasing globally. Lung cancer can sometimes present as a comorbidity with MACLD; however, the clinical presentation and outcomes of comorbid MACLD following lung cancer resection remain unclear. Therefore, we retrospectively assessed 17 patients with MACLD undergoing lung cancer resection to determine the impact of lung cancer surgery on comorbid MACLD. Of the 17 patients, Mycobacterium avium and Mycobacterium intracellulare were present in 15 and 2 patients, respectively; 14 patients had stage I lung cancer and underwent lobectomy. Ten patients were postoperatively observed for MACLD without any further intervention, five patients underwent additional resection for conspicuous MACLD lesions, and the remaining two patients underwent complete resection for MACLD and lung cancer within the same lobe followed by rifampicin, ethambutol, and clarithromycin (RECAM) therapy. Seven patients exhibited postoperative MACLD exacerbation, six of whom developed exacerbation in the operated ipsilateral residual lobes. Six of these seven patients received RECAM, three of whom (43%) subsequently exhibited improvement. Attention should be paid to MACLD exacerbation during postoperative follow-up, especially in ipsilateral lobes. Although RECAM therapy may be beneficial in alleviating MACLD exacerbation, further investigation is warranted to validate these results.

Identification of ANXA2 on epithelial cells as a new receptor for secretory IgA using immunoprecipitation and mass spectrometry.

Secretory immunoglobulin A plays an important role in the protection against exogenous pathogens and antigens, but it has also been reported to have pathogenic potential. We previously found that secretory immunoglobulin A accumulated in the peripheral lungs during idiopathic pulmonary fibrosis and that transferrin receptor/CD71 was partially involved in secretory immunoglobulin A-induced inflammatory cytokine production in A549 cells. This study aimed to identify the receptor responsible for the induction of cytokine production by secretory immunoglobulin A-stimulated airway epithelial cells. To this end, immunoprecipitation followed by time-of-flight mass spectrometry and peptide mass fingerprinting were performed and Annexin A2 was detected as a novel receptor for secretory immunoglobulin A. Enzyme-linked immunosorbent assay demonstrated binding of secretory immunoglobulin A to Annexin A2, and flow cytometry showed robust expression of Annexin A2 on the surface of BEAS-2B cells, A549 cells, and normal human bronchial/tracheal epithelial cells. Experiments in A549 cells using Annexin A2 small interfering RNA and neutralizing antibodies suggested that Annexin A2 was partially involved in the production of interleukin-8/CXCL8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 induced by secretory immunoglobulin A. Immunohistochemistry using lung sections revealed clear expression of Annexin A2 on airway epithelial cells, although the staining remained equivalent in idiopathic pulmonary fibrosis, asthma, and healthy control lungs. In conclusion, we identified that Annexin A2 expressed in airway epithelial cells is a novel receptor for secretory immunoglobulin A, which is involved in cytokine synthesis.

Serum total IgE may be a biomarker among chronic pulmonary aspergillosis patients with elevated serum total IgE levels: A cohort study with pathological evaluations.

High serum total immunoglobulin E (IgE) levels have been reported in chronic pulmonary aspergillosis (CPA). However, researchers have not verified if they reflect the disease activity. We aimed to compare the serum total IgE levels in CPA cases with high serum IgE during an exacerbation or when stable and examined the IgE expression patterns in the lesions via immunofluorescence staining. From April 2016 to September 2019, we extracted CPA cases with elevated serum total IgE levels based on the criteria of the Infectious Diseases Society of America. We retrospectively analyzed serum total IgE levels and other parameters and eventually extracted 32 cases. The patients' serum total IgE levels were significantly higher in the exacerbation period than in the stable period (P < .0001). The median rate of change was 1.76 times (quartile 1.41-3.25). In addition, we used surgical specimens of CPA cases with high serum total IgE levels, normal serum total IgE CPA cases, and control surgical specimens and performed immunofluorescence staining with IgE, mast cell tryptase, CD138, and 4,6-diamidino-2-phenylindole. We observed multiple mast cells and plasma cells in the CPA cases regardless of the serum total IgE level. In contrast, multiple IgE-positive cells co-stained with tryptase were observed in CPA cases with high serum total IgE levels. This finding suggested that serum total IgE could serve as a biomarker for evaluating disease severity. Immunofluorescence staining suggested that IgE may play a role in pathogenesis through activation of mast cells by cross-linking in cases of CPA with high serum total IgE levels. LAY SUMMARY: High serum total IgE levels are common in chronic pulmonary aspergillosis. This novel study indicated that serum total IgE is a possible biomarker of the disease activity in the aforementioned condition. Immunofluorescence staining indicated a possible role of IgE in disease pathogenesis.

The accuracy and clinical impact of the morphological identification of Aspergillus species in the age of cryptic species: A single-centre study.

BACKGROUND: Aspergillus spp. is identified morphologically without antifungal susceptibility tests (ASTs) in most clinical laboratories. The aim of this study was to examine the clinical impact of the morphological identification of Aspergillus spp. to ensure the adequate clinical management of Aspergillus infections. PATIENTS/METHODS: Aspergillus isolates (n = 126) from distinct antifungal treatment-naïve patients with aspergillosis were first identified morphologically, followed by species-level identification via DNA sequencing. An AST for itraconazole (ITC) and voriconazole (VRC) was performed on each Aspergillus isolate. RESULTS: Based on the genetic test results, morphology-based identification was accurate for >95% of the isolates at the species sensu lato level although the test concordance of Aspergillus spp. with low detection rates was low. The rates of cryptic species were found to be 1.2% among the isolates of A. fumigatus complex and 96.8% in the A. niger complex. Cryptic species with lower susceptibilities to antifungal drugs than sensu stricto species among the same Aspergillus section were as follows: The A. lentulus (n = 1) isolates had low susceptibilities to azoles among the A. fumigatus complex species (n = 86), and A. tubingensis isolates (n = 18) exhibited lower susceptibility to azoles among the A. niger complex species (n = 31). CONCLUSION: Diagnostic accuracy was high at the A. fumigatus and A. niger complex level. However, in the presence of cryptic species, a solely morphological identification was insufficient. Particularly, ITC and VRC might be inappropriate for aspergillosis treatment when the A. niger complex is identified morphologically because it is possible that the Aspergillus isolate is A. tubingensis.

Diaphragmatic hernia during treatment of lung cancer harboring an EGFR mutation.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line treatment for patients with nonsmall-cell lung cancer harboring EGFR mutations. We report a 65-year-old Japanese woman with nonsmall-cell lung cancer taking an EGFR-TKI who visited the emergency department with acute nausea and vomiting. Imaging studies demonstrated an incarcerated diaphragmatic hernia. Urgent diagnostic surgery revealed a gap in the diaphragm acting as a hernial orifice, where a metastatic tumor was detected. We consider that regression of the diaphragmatic metastasis by EGFR-TKI therapy resulted in perforation of the diaphragm, causing the diaphragmatic hernia. Gastrointestinal adverse events, e.g. nausea, vomiting and diarrhea, are common during EGFR-TKI treatment. However, this case suggests that in patients with diaphragmatic metastasis, we should consider the rare possibility of diaphragmatic perforation and a subsequent hernia.

High detection rate of azole-resistant Aspergillus fumigatus after treatment with azole antifungal drugs among patients with chronic pulmonary aspergillosis in a single hospital setting with low azole resistance.

The prevalence of azole-resistant Aspergillus fumigatus (ARAF) among chronic pulmonary aspergillosis (CPA) patients treated with azoles in Japan is unknown. The aim of this study was to determine the detection rate of ARAF in isolates from CPA patients who were treated with azoles for varying durations. The potential mechanism of acquiring resistance was examined by sequencing cyp51A and hmg1, two genes associated with ARAF. A. fumigatus isolates (n = 120) were collected from CPA patients (n = 104) between February 2012 and February 2019, at National Hospital Organization Tokyo National Hospital. The isolates were tested for susceptibility to the azole drugs itraconazole (ITCZ) and voriconazole (VRCZ). The detection rate of ARAF among all isolates was 8.3% (n = 10). Of the 10 resistant isolates, eight were ITCZ-resistant and five were VRCZ-resistant. Among 47 isolates obtained from 36 CPA patients who were treated with ITCZ (for an average of 256 days) and/or VRCZ (for an average of 29 days), the resistance rates were 17.0% and 10.6%, respectively. In addition, 46.2% of 13 isolates obtained from CPA patients with ongoing azole treatment at the time of antifungal therapy failure were resistant to azoles. Among the 10 ARAF isolates, a point mutation was detected in cyp51A in seven isolates and in hmg1 in two isolates. ARAF was detected at a high rate in CPA patients, particularly in those with ongoing long-term azole treatment, at the time of azole antifungal therapy failure.

Aspergillus fumigatus can acquire azole resistance during long-term treatment with azole drugs in patients with chronic pulmonary aspergillosis (CPA). The aim of this study was to determine the detection rate of azole-resistant A. fumigatus (ARAF) in isolates from CPA patients who had been treated with azoles. In addition, a potential mechanism of acquiring resistance was examined by sequencing cyp51A and hmg1, two genes associated with ARAF. A. fumigatus isolates (n = 120) were collected from CPA patients (n = 104). The isolates were tested for susceptibility to the azole drugs itraconazole (ITCZ) and voriconazole (VRCZ). The detection rate of ARAF from all isolates was 8.3% (n = 10). Greater than 10% of the 47 isolates obtained from 36 CPA patients who had been treated with azoles exhibited resistance. Furthermore, 46.2% of 13 isolates obtained from CPA patients with ongoing azole treatment at the time of antifungal therapy failure were resistant to azoles. Among the 10 ARAF isolates, a point mutation was detected in cyp51A in seven isolates and in hmg1 in two isolates. ARAF was detected at a high rate in CPA patients undergoing long-term azole treatment at the time of antifungal therapy failure.

Migrated coil expectorated 12 years after embolization of pulmonary arteriovenous malformation, due probably to abscess formation around the coil.

Pulmonary arteriovenous malformations (PAVMs) are rare vascular structures providing direct capillary-free communications between pulmonary arteries and veins. Embolotherapy is indicated as a front-line therapy. We report an unusual long-term complication of coil embolization for a 44-year-old woman with hereditary hemorrhagic telangiectasia (HHT) who had repeatedly undergone the procedures for her PAVMs. She expectorated the coil which had been placed 12 years earlier and migrated to the bronchus according to the chest radiogram and bronchoscopy. Histology of the resected lung segment suggested the cavity communicating with the bronchus was the consequence of abscess formation around the coils. Even after technically successful embolization to PAVMs, long term follow-up should be necessary paying attention to the symptoms and imaging to avoid massive hemoptysis and subsequent emergency surgery.

Mediastinal metastasis from ovarian serous carcinoma 29 years after initial treatment.

Ovarian cancer is a critically lethal gynecologic malignancy. More than 80% of patients with ovarian cancer have relapses within 5 years after initial treatment. However, recurrence from ovarian cancer more than 20 years later is extremely rare. We report a case of a 67-year-old female with mediastinal metastasis from ovarian cancer 29 years after initial gynecologic surgery and chemotherapy.

Pulmonary resection for nontuberculous mycobacterial pulmonary disease: outcomes and risk factors for recurrence.

OBJECTIVES: As the number of patients with nontuberculous mycobacterial pulmonary disease (NTMPD) increases, surgical treatment to control disease becomes more important. However, postoperative outcomes and predictors of recurrence have been insufficiently evaluated. METHODS: We retrospectively investigated 100 patients with NTMPD who underwent pulmonary resection from 2009 to 2016 at our institution. Clinical data of patients with and without postoperative recurrence were statistically compared. Recurrence was defined as microbiological re-identification or computed tomography findings highly suspicious for relapse after excluding other diseases. Recurrence-free survival was calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test. Predictive factors were evaluated using univariate and multivariate analyses. RESULTS: Nine patients experienced recurrence. A significant difference in recurrence-free survival was detected between patients with and without a positive preoperative sputum culture (P = 0.000942). Moreover, patients with a positive preoperative sputum smear (≥ 2 +) had a significantly higher recurrence rate than those who did not (P = 0.000216). Multivariate analysis revealed that preoperative sputum smear (≥ 2 +) is an independent risk factor for recurrence after pulmonary resection for NTMPD (odds ratio, 7.38; 95% confidential interval, 1.29-42.2; P = 0.024). CONCLUSIONS: NTM discharge might have an impact on postoperative recurrence of NTMPD patients without residual cavitary lesions. Preoperative NTM discharge should be minimized by optimizing medical therapy before surgical treatment to improve the postoperative course. Intensive follow-up and prolonged postoperative medical therapy should be considered for patients without a sufficient reduction in bacterial discharge before pulmonary resection.

Species identification, antifungal susceptibility, and clinical feature association of Aspergillus section Nigri isolates from the lower respiratory tract.

Species of Aspergillus section Nigri are generally identified by molecular genetics approaches, whereas in clinical practice, they are classified as A. niger by their morphological characteristics. This study aimed to investigate whether the species of Aspergillus section Nigri isolated from the respiratory tract vary depending on clinical diagnosis. Forty-four Aspergillus section Nigri isolates isolated from the lower respiratory tracts of 43 patients were collected from February 2012 to January 2017 at the National Hospital Organization (NHO) Tokyo National Hospital. Species identification was carried out based on ß-tubulin gene analysis. Drug susceptibility tests were performed according to the Clinical and Laboratory Standards Institute (CLSI) M38 3rd edition, and the clinical characteristics were retrospectively reviewed. A. welwitschiae was isolated most frequently, followed by A. tubingensis. More than half of the A. tubingensis isolates exhibited low susceptibility to azoles in contrast to only one A. welwitschiae isolate. Approximately three quarters of the patients from whom A. welwitschiae was isolated were diagnosed with colonization, whereas more than half the patients from whom A. tubingensis was isolated were diagnosed with chronic pulmonary aspergillosis (CPA). More attention needs to be given to the drug choice for patients with CPA with Aspergillus section Nigri infection because A. tubingensis, which was found to be frequently azole-resistant, was the most prevalent in these patients.

Recent trends in the incidence of latent tuberculosis infection in Japanese patients with lung cancer: A small retrospective study.

Active tuberculosis is an important complication in Japanese lung cancer patients. We studied the generation-wise trend of latent tuberculosis infection (LTBI) among lung cancer patients. We analyzed background data including birth year, lung cancer status, and interferon-gamma release assay (IGRA) data of lung cancer patients who were admitted to National Hospital Organization Tokyo National Hospital from 2010 to 2016. Of the 1450 cases, 7 showed active tuberculosis and 45 had previous tuberculosis. Of the remaining 1398 patients, 795 underwent IGRAs and 120 (15%) of them were found to have LTBI. Patients with LTBI were older (p = 0.0005), and the proportion of smokers was also higher in this group (p = 0.0159) than among those without LTBI. LTBI incidence decreased from 33% among patients born in the 1920s to 21%, 15%, 9.8%, and 5.1% among those born in the 1930s, 1940s, 1950s, and after 1960, respectively. A significant decrease in the smoking adjusted risk ratio was also observed with every generation (p < 0.0001). Our study suggests that the total number of patients with active tuberculosis comorbid with lung cancer will greatly decrease in the future in Japan. However, owing to recent improvements in lung cancer prognosis due to advances in cancer medication, careful monitoring for active tuberculosis development may be required in lung cancer patients with LTBI.

Competing Risk Analysis in Lung Cancer Patients Over 80 Years Old Undergoing Surgery.

BACKGROUND: This study aimed to analyze cause-specific mortality in lung cancer patients over 80 years old undergoing surgery. METHODS: This retrospective, multi-institutional analysis included patients aged ≥ 80 years who underwent radical surgery for primary lung cancer from January 1998 to December 2015. Preoperative clinical data, surgical results, survival, and cause of death were evaluated. Competing risk analysis for cause-specific mortality was performed. RESULTS: Of the 337 patients (median age 82 years) enrolled and analyzed, 68.1% were male. There were 52 and 44 cancer-specific and non-cancer-specific deaths, respectively. On competing risk regression analysis, non-cancer-specific deaths were significantly associated with male sex (hazard ratio [HR]: 3.06, 95% confidence interval [CI]: 1.02-9.12, p = 0.046), coronary artery disease (HR: 2.49, 95% CI: 2.49 [1.14-5.47], p = 0.02), interstitial pneumonia (HR: 3.58, 95% CI: 1.73-7.40, p < 0.001), and pathological stage III (HR: 3.83, 95% CI: 1.44-10.13, p = 0.007). In contrast, cancer-specific deaths were significantly associated with limited resection (HR: 1.99, 95% CI: 1.02-3.89, p = 0.04) and pathological stage III (HR: 3.13, 95% CI: 1.44-6.80, p = 0.004). The 5-year cumulative incidences of lung cancer-specific and non-cancer-specific deaths were 18.0% and 15.9%, respectively. CONCLUSIONS: Prognostic factors for non-cancer-specific death were different from those of cancer-specific death, except for pathological stage. Each prognostic factor should be considered when deciding surgical indication and procedure and monitoring for pulmonary events during outpatient follow-up.

The influence of comorbidity on the postoperative survival in elderly (≥ 75 years old) with lung cancer.

OBJECTIVES: We conducted a multi-institutional prospective observational study of elderly patients (≥ 75 years-old) with resected non-small cell lung cancer. In this report, we have followed the cohorts for 2 years after surgery and examined both the influence of preoperative comorbidity [Adult Comorbidity Evaluation-27 (ACE-27) index] on the postoperative survival and the change in the Karnofsky Performance Status (KPS). METHODS: From March 2014 to April 2015, 264 patients were prospectively registered from 22 hospitals affiliated with the National Hospital Organization. The mean age at the time of surgery was 79.3 years (range 75-90 years), and 41% of the patients were ≥ 80 years of age. A total of 26% underwent sublobar resection. The study endpoints were the postoperative overall survival (OS), its prognostic factors, and the changes in the postoperative KPS. RESULTS: The 2-year OS was 85.3% (95% confidence interval 80.4-89.1%). Male gender, age ≥ 80, a smoking history, grade 2 of ACE-27, and an advanced disease stage were significantly poor prognostic factors for the OS in the univariate risk analysis. The multivariate analysis showed that male gender, age ≥ 80, an advanced disease stage and sublobar resection were significantly poor prognostic factors for the OS. In comparison with the preoperative KPS, no marked decline was observed in the postoperative chorological change of KPS. CONCLUSIONS: In the surgical treatment of elderly patients, the comorbidity as assessed by the ACE-27 index might affect the postoperative survival, and therefore should be taken into accounts in the preoperative evaluation of the surgical indications.

Risk factors for postoperative complications and long-term survival in lung cancer patients older than 80 years.

OBJECTIVES: The number of octogenarian lung cancer patients undergoing radical surgery has been increasing recently. However, knowledge regarding the risk factors for postoperative complications and reliable predictive factors for long-term survival is limited. This study aimed to investigate the risk factors of postoperative complications, and reliable prognostic factors, in lung cancer patients older than 80 years. METHODS: Lung cancer patients aged 80 years or older who underwent radical surgery were retrospectively studied; a multi-institutional analysis was conducted from January 1998 to December 2015. Preoperative and postoperative clinical data, including age, gender, smoking history, body mass index, respiratory function, Charlson Comorbidity Index, Glasgow Prognostic Score, surgical procedure, cancer histology, clinical and pathological stage, surgical result and survival time, were collected. RESULTS: A total of 337 patients, comprising 216 (64.1%) men and 121 (35.9%) women were enrolled. The median age was 82 (range 80-92) years. Of the 337 patients, 205 (60.8%) had preoperative comorbidities. Postoperative complications were observed in 119 (35.3%) patients; postoperative mortalities occurred in 6 (1.8%) patients. Univariate and multivariate analyses showed that male gender (P = 0.01) and operation time (P = 0.047) were associated with postoperative complications; in contrast, pathological Stage III (P < 0.001), male gender (P = 0.01), Charlson Comorbidity Index ≥2 (P = 0.03) and Glasgow Prognostic Score = 1/2 (P = 0.04) were independent prognostic factors for overall survival. CONCLUSIONS: The risk factors for postoperative complications (male gender and operation time) and the predictive factors affecting long-term survival (male gender, Charlson Comorbidity Index, Glasgow Prognostic Score and P-stage) should be taken into account for the effective management of patients older than 80 years with lung cancer, undergoing surgery.

TBX4 is involved in the super-enhancer-driven transcriptional programs underlying features specific to lung fibroblasts.

Lung fibroblasts participate in the pathogenesis of respiratory diseases, including lung cancer and pulmonary fibrosis. Although fibroblasts are ubiquitous constituents of various organs, their cellular diversity among different organs has been poorly characterized. Here, we aimed to investigate the distinct gene signature of lung fibroblasts that represents its pulmonary origin and the underlying gene regulatory networks. Promoter-level differential expression analysis by cap analysis of gene expression (CAGE) sequencing revealed distinct gene expression patterns of fibroblasts derived from different anatomical sites and identified 88 coding genes with higher expression in lung fibroblasts relative to other fibroblasts. Multiple key transcription factors important for lung mesenchyme development, including the T-box transcription factors TBX2, TBX4, and TBX5 were enriched in this lung-specific signature and were associated with super-enhancers. TBX4 showed highly specific expression in lung fibroblasts and was required for cell proliferation and collagen gel contraction capacity. Transcriptome analysis revealed that TBX4 could broadly regulate fibroblast-related pathways and partly contribute to super-enhancer-mediated transcriptional programs. Of pathological importance, lung fibroblast-specific genes were globally downregulated in lung cancer-associated fibroblasts (CAFs). Notably, TBX2, TBX4, and TBX5 were downregulated and hypermethylated in lung CAFs, suggesting an association between epigenetic silencing of these factors and phenotypic alteration of lung fibroblasts in cancer. Our study highlights the importance of T-box transcription factors, especially TBX4, and super-enhancers in the roles of lung fibroblasts in pulmonary physiology and pathogenesis.

Relationship Between Lung Cancer and Mycobacterium Avium Complex Isolated Using Bronchoscopy.

INTRODUCTION: The incidence of Mycobacterium avium complex (MAC)-positive respiratory specimen cultures and MAC lung disease (MACLD) is increasing worldwide. This retrospective study aimed to assess the association between MAC culture-positive bronchoscopy specimens and lung cancer. MATERIALS AND METHODS: The medical records of 1382 untreated lung cancer patients between 2003 and 2011 were collected using our hospital database. Of them, records for 1258 that had undergone bronchoscopy together with sampling for mycobacterial culture were reviewed. Patient characteristics were compared between those with MAC-positive/other nontuberculous mycobacteria (NTM)-negative bronchial washings and those with MAC-negative/other NTM-negative bronchial washings. Patients with MAC-positive lung cancer were cross-sectionally divided into MACLD and non-MACLD groups, and their features were assessed. Follow-up data for patients with lung cancer but without MACLD were reviewed for subsequent development of MACLD. RESULTS: Of the 1258 patients with lung cancer, 25 (2.0%) had MAC-positive/other NTM-negative bronchial washings. The proportion of women (52% vs 30%; P = 0.0274) and patient age (72 years vs 69 years; P = 0.0380) were significantly higher in the MAC-positive/other NTM-negative lung cancer group (n = 25) than in the MAC-negative/other NTM-negative lung cancer group (n = 1223). There were 10 patients with lung cancer and MACLD and 15 without MACLD; significant differences in patient characteristics were not found between the two groups, and none of the 15 patients without MACLD subsequently developed MACLD. CONCLUSION: MAC culture-positive bronchial washing is positively associated with lung cancer. Female sex and advanced age, but not lung cancer characteristics, were found to be associated with MAC infection in patients with lung cancer.