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1.  Suitability of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration Specimens for Subtyping and Genotyping of Non–Small Cell Lung Cancer 
Rationale: The current management of advanced non–small cell lung cancer (NSCLC) requires differentiation between squamous and nonsquamous subtypes as well as epidermal growth factor receptor (EGFR) mutation status. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used for the diagnosis and staging of lung cancer. However, it is unclear whether cytology specimens obtained with EBUS-TBNA are suitable for the subclassification and genotyping of NSCLC.
Objectives: To determine whether cytology specimens obtained from EBUS-TBNA in routine practice are suitable for phenotyping and genotyping of NSCLC.
Methods: Cytological diagnoses from EBUS-TBNA were recorded from 774 patients with known or suspected lung cancer across five centers in the United Kingdom between 2009 and 2011.
Measurements and Main Results: The proportion of patients with a final diagnosis by EBUS-TBNA in whom subtype was classified was 77% (95% confidence interval [CI], 73–80). The rate of NSCLC not otherwise specified (NSCLC-NOS) was significantly reduced in patients who underwent immunohistochemistry (adjusted odds ratio, 0.50; 95% CI, 0.28–0.82; P = 0.016). EGFR mutation analysis was possible in 107 (90%) of the 119 patients in whom mutation analysis was requested. The sensitivity, negative predictive value, and diagnostic accuracy of EBUS-TBNA in patients with NSCLC were 88% (95% CI, 86–91), 72% (95% CI, 66–77), and 91% (95% CI, 89–93), respectively.
Conclusions: This large, multicenter, pragmatic study demonstrates that cytology samples obtained from EBUS-TBNA in routine practice are suitable for subtyping of NSCLC and EGFR mutation analysis and that the use of immunohistochemistry reduces the rate of NSCLC-NOS.
PMCID: PMC3378660  PMID: 22505743
endobronchial ultrasound; non–small cell lung cancer; adenocarcinoma; EGFR mutation; NSCLC-NOS
2.  Comparison of Epidermal Growth Factor Receptor Mutations between Metastatic Lymph Node Diagnosed by EBUS-TBNA and Primary Tumor in Non-Small Cell Lung Cancer 
PLoS ONE  2016;11(9):e0163652.
Although the use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasing for epidermal growth factor receptor (EGFR) testing in lung cancer, the discordance rate in EGFR mutations between lymph node (LN) samples obtained by EBUS-TBNA and primary tumor (PT) is not well known. Thus, we compared the EGFR mutation status of LN samples obtained by EBUS-TBNA and PTs to estimate the efficacy of using EBUS-TBNA specimens for EGFR testing in advanced, non-squamous, non-small cell lung cancer (NSCLC).
Materials and Methods
Using data of patients from the EBUS-TBNA database (N = 1914) obtained between January 2009 and January 2013, we identified 100 treatment-naïve, advanced, non-squamous NSCLC patients (stage 3 and 4) with matched LN specimens obtained by EBUS-TBNA and PT specimens. Of these, 74 patients with paired specimens were feasible for EGFR mutation analysis, which we performed using a direct sequencing method.
Of the 74 cases, at least one major [exon 19 deleted (19del) and L858R] or minor (T790M, exon 20 insertion, and other point mutations) EGFR mutation was detected in 31 cases (41.9%), which included PT (n = 31, 41.9%) and LN (n = 28, 37.8%) specimens. Major mutations were detected in 25 PT (33.8%, 19del = 13, L858R = 12) and 22 LN (29.8%, 19del = 11, L858R = 11) specimens. The discordance rate in major mutations between matched PT and LN specimens was 4.1% (3/74). Among minor mutations, T790M was detected in LN specimen only in 2 cases with L858R in PT and LN. The discordance rate major and minor EGFR mutations combined between matched PT and LN specimens was 12% (9/74).
We observed a high concordance rate of major EGFR mutations between matched LN specimens sampled by EBUS-TBNA and PTs, suggesting that LN samples obtained by EBUS-TBNA from advanced non-squamous NSCLC patients are effective for use in EGFR mutation testing.
PMCID: PMC5042474  PMID: 27685950
3.  Screening for EGFR and KRAS Mutations in Endobronchial Ultrasound Derived Transbronchial Needle Aspirates in Non-Small Cell Lung Cancer Using COLD-PCR 
PLoS ONE  2011;6(9):e25191.
EGFR mutations correlate with improved clinical outcome whereas KRAS mutations are associated with lack of response to tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Endobronchial ultrasound (EBUS)-transbronchial needle aspiration (TBNA) is being increasingly used in the management of NSCLC. Co-amplification at lower denaturation temperature (COLD)–polymerase chain reaction (PCR) (COLD-PCR) is a sensitive assay for the detection of genetic mutations in solid tumours. This study assessed the feasibility of using COLD-PCR to screen for EGFR and KRAS mutations in cytology samples obtained by EBUS-TBNA in routine clinical practice. Samples obtained from NSCLC patients undergoing EBUS-TBNA were evaluated according to our standard clinical protocols. DNA extracted from these samples was subjected to COLD-PCR to amplify exons 18–21 of EGFR and exons two and three of KRAS followed by direct sequencing. Mutation analysis was performed in 131 of 132 (99.3%) NSCLC patients (70F/62M) with confirmed lymph node metastases (94/132 (71.2%) adenocarcinoma; 17/132 (12.8%) squamous cell; 2/132 (0.15%) large cell neuroendocrine; 1/132 (0.07%) large cell carcinoma; 18/132 (13.6%) NSCL-not otherwise specified (NOS)). Molecular analysis of all EGFR and KRAS target sequences was achieved in 126 of 132 (95.5%) and 130 of 132 (98.4%) of cases respectively. EGFR mutations were identified in 13 (10.5%) of fully evaluated cases (11 in adenocarcinoma and two in NSCLC-NOS) including two novel mutations. KRAS mutations were identified in 23 (17.5%) of fully analysed patient samples (18 adenocarcinoma and five NSCLC-NOS). We conclude that EBUS-TBNA of lymph nodes infiltrated by NSCLC can provide sufficient tumour material for EGFR and KRAS mutation analysis in most patients, and that COLD-PCR and sequencing is a robust screening assay for EGFR and KRAS mutation analysis in this clinical context.
PMCID: PMC3176319  PMID: 21949883
4.  Endobronchial ultrasound in real life: primary diagnosis and mediastinal staging of lung cancer in patients submitted to thoracic surgery 
BMC Pulmonary Medicine  2016;16:101.
Since the first articles published for over 10 years ago, endobronchial ultrasound (EBUS) has gained a strong scientific backing and has been incorporated into routine medical practice in pulmonology and thoracic surgery centers. How is EBUS performing outside the scientific environment, as a diagnostic and mediastinal staging tool in a subset of patients that undergo thoracic surgery, is an interesting question.
This study evaluated consecutive patients who, during the period from January 2010 to August 2012, were submitted to EBUS and later to thoracic surgery. The samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) were compared to surgical samples. The primary endpoint was the proportion of patients with a final diagnosis of non-small cell lung cancer (NSCLC) by EBUS-TBNA correctly subtyped. The secondary endpoint was the negative predictive value (NPV) of EBUS-TBNA for mediastinal staging of lung cancer.
Two hundred eighty seven patients were studied. Considering 84 patients with a final diagnosis of NSCLC by EBUS-TBNA, 79 % (CI 95 % 70.1–87.3) were correctly subclassified. The NPV of EBUS-TBNA for mediastinal staging was 89 % (IC 95 % 84.9–92.7). From a total of 21 false negative cases of mediastinal staging, 16 (76 %) did not undergo positron emission tomography-computed tomography (PET-CT) before the EBUS and in 15 (71 %) the affected lymph node chain was not punctured by EBUS-TBNA. Ten (47 %) patients had only lymph node metastases not directly accessible by the EBUS.
Performed in hospital routine and in patients submitted to thoracic surgery, EBUS-TBNA proved to be a good tool for proper pathological diagnosis of lung cancer. The negative predictive value of 89 % for mediastinal staging of lung cancer is comparable to that reported in previous studies, but the relatively high number of 21 false negative cases points to the need for standardization of routine strategies before, during and after EBUS.
PMCID: PMC4952060  PMID: 27435209
5.  Adequacy of endobronchial ultrasound-guided transbronchial needle aspiration samples processed as histopathological samples for genetic mutation analysis in lung adenocarcinoma 
Molecular and Clinical Oncology  2015;4(1):119-125.
Phenotyping non-small-cell lung cancer is becoming increasingly important with the advent of molecular testing. Tumours harbouring somatic mutations in the gene that encodes for the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) have been found to increase responsiveness to tyrosine kinase inhibitors. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive technique for mediastinal node sampling. The available prospective data on EBUS-TBNA sample suitability for molecular profiling are currently limited. The aim of this prospective study was to evaluate the adequacy of EBUS-TBNA samples for EGFR and anaplastic lymphoma kinase (ALK) genetic mutation analysis in confirmed primary lung adenocarcinomas. We conducted a prospective analysis of 410 consecutive patients referred for EBUS-TBNA between 2010 and 2014. Rapid on-site cytological evaluation was not used. The samples were obtained using 21-gauge (21G) or 22G needles and were prepared as histopathological samples. A total of 91 samples were confirmed as lung adenocarcinomas and 80 of these samples were sent for EGFR mutation analysis. EBUS-TBNA had a diagnostic accuracy of 98.3% for malignancy. EGFR mutation testing was possible in 79/80 cases (98.75%). EGFR mutations were detected in 5/80 (6.3%) samples. ALK gene analysis, which became available during the study period, was requested and successfully performed in 21/21 samples (100%). The total combined genotyping success rate was 100/101 (99.0%). This UK study confirmed the high clinical utility of EBUS-TBNA samples processed as histopathological specimens for EGFR and ALK genotyping in primary lung adenocarcinoma. The needle gauge did not affect genotyping efficacy.
PMCID: PMC4727210  PMID: 26870369
lung cancer; endobronchial ultrasound; disease phenotyping; epidermal growth factor receptor; anaplastic lymphoma kinase
6.  Triple Gene Analysis Using Samples Obtained by Endobronchial Ultrasound-guided Transbronchial Needle Aspiration 
Internal Medicine  2016;55(21):3105-3111.
Objective A mutational analysis of tumor tissue samples is an important part of advanced lung cancer treatment strategies. This study evaluated the efficacy of a triple gene analysis using samples obtained via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA).
Methods Either metastatic lymph nodes or primary lung mass samples obtained by EBUS-TBNA were collected between May 2011 and May 2013. We consecutively analyzed epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK) fusion genes using remnant tissue samples.
Results A total of 109 patients were diagnosed with non-small cell lung cancer (NSCLC). Of these, 70% were adenocarcinoma, 27% squamous cell carcinoma with NSCLC, and 3% were related to other types of lung cancer. EGFR mutations were detected in 23 cases (21.1%), KRAS mutations in 13 cases (11.9%), and ALK fusion genes in 5 cases (4.9%). The ALK fusion genes could not be analyzed in four cases because of insufficient tissue samples remaining after routine histochemistry and an EGFR/KRAS mutation analysis. We found that small biopsy samples from EBUS-TBNA were adequate for performing a triple gene analysis in 97 patients (96%). ALK fusion protein immunohistochemistry (IHC) was 100% consistent with fluorescence in situ hybridization (FISH).
Conclusion Small samples obtained by EBUS-TBNA were found to be sufficient for performing a triple gene analysis following routine histology and IHC. ALK IHC showed a very good concordance with FISH for detecting ALK fusion genes.
PMCID: PMC5140857  PMID: 27803402
EBUS-TBNA; lung cancer; EGFR mutations; KRAS mutations; ALK fusion genes
7.  Re-biopsy by endobronchial ultrasound procedures for mutation analysis of non-small cell lung cancer after EGFR tyrosine kinase inhibitor treatment 
BMC Pulmonary Medicine  2016;16:106.
Re-biopsy for resistant non-small cell lung cancer (NSCLC) after treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is important for selection of better therapy, but there have been no reports about the utility of endobronchial ultrasound (EBUS)-guided procedures for such purpose. The aim of this study was to evaluate the utility of EBUS-guided re-biopsy for resistant NSCLC after treatment with EGFR-TKIs.
From January 2013 to December 2015, 53 consecutive patients who underwent EBUS-guided re-biopsy for mutation analysis of NSCLC after EGFR-TKI treatment were assessed.
Nine patients underwent EBUS-guided transbronchial needle aspiration (EBUS-TBNA) and 44 patients underwent EBUS with a guide sheath (EBUS-GS) transbronchial biopsy. The technical success rates were 100 %. As for mutation analysis, all 9 specimens (100 %) from EBUS-TBNA and 33 specimens (75.0 %) from EBUS-GS were adequate for gene profiling. The remaining 11 specimens from EBUS-GS procedures were inadequate for mutation analysis owing to the absence of tumor component in the sample (n = 6) or insufficient specimen (n = 5). There were no related severe complications.
Re-biopsy by both EBUS-TBNA and EBUS-GS were useful and safe sampling procedures for mutation analysis of EGFR-TKI resistant NSCLC.
PMCID: PMC4960795  PMID: 27457475
EGFR-TKI; EBUS-TBNA; EBUS-GS; T790M; Lung cancer; Re-biopsy
8.  TBNA with and without EBUS: a comparative efficacy study for the diagnosis and staging of lung cancer 
Journal of Thoracic Disease  2014;6(5):416-420.
Conventional transbronchial needle aspiration (TBNA) has been around for over 30 years with sensitivities approaching 70-90%. Recent development of endobronchial ultrasound (EBUS) TBNA demonstrated even higher sensitivities among experts. However EBUS-TBNA is more costly and less available worldwide than conventional TBNA. A comparison study to determine the efficacy of TBNA with and without EBUS in the diagnosis and staging of lung cancer is described.
A total of 287 patients with mediastinal and hilar lymphadenopathy presenting for diagnosis and/or staging of lung cancer at enrolling institutions were included. Equal numbers of punctures were performed at the target lymph node stations using conventional TBNA techniques followed by EBUS-TBNA at the same sites. Patients and puncture sites that were biopsied by both methods and were positive for lung cancer were compared to establish efficacy of each technique on the same patients.
In 253 patients at least one pair of specimens were obtained by conventional TBNA and EBUS-TBNA. In 83 of these patients malignancy was diagnosed. Among the 83 patients with a diagnosis of a malignancy there was no significant difference in the diagnostic yield of conventional TBNA versus EBUS-TBNA. When comparing diagnosis of malignancy for each lymph node sampled, there were a significantly greater number of positive (diagnostic for malignancy) lymph nodes sampled by EBUS-TBNA.
Recommendations for current practice depend on individual centers and bronchoscopist comfort level with TBNA (with or without EBUS). In our study, no significant difference was seen between the techniques for the diagnosis and staging of individual patients.
PMCID: PMC4015015  PMID: 24822097
Bronchoscopy; transbronchial needle aspiration (TBNA); endobronchial ultrasound (EBUS); lung cancer
9.  Usefulness of High Suction Pressure for Sufficient Tissue Collection During Endobronchial Ultrasound Guided Transbronchial Needle Aspiration 
PLoS ONE  2013;8(12):e82787.
The optimal suction pressure during endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) remains to be determined. The aim of this study was to compare suction pressures for performance in collecting sufficient tissue specimens from mediastinal and hilar lymph nodes during EBUS-TBNA.
Retrospective analysis of consecutive patients with mediastinal and hilar lymphadenopathy who underwent EBUS-TBNA over a 3-year period. Results from patients who underwent EBUS-TBNA using a dedicated 20-mL VacLoc (Merit Medical Systems, Inc, South Jordan, UT) syringe (conventional method, group C) were compared with results from patients in whom a disposable 30-mL syringe (high pressure group, group H) was used. The yield for sufficient histologic specimen retrieval and amount of tissue obtained were compared between the 2 groups.
Of 178 patients who underwent EBUS-TBNA, 131 had lung cancer confirmed by EBUS-TBNA: 35 in group C and 96 in group H. There were 7 patients in group C and 6 in group H who received final diagnoses by cytology alone. There were 28 in group C and 90 in group H who were diagnosed by both cytology and histology. There was a statistically significant difference between the groups in terms of the rate of sufficient sampling for histological specimens (p = 0.04). The H group revealed a tissue area approximately twice that of the C group (p = 0.003). There were no major procedure-related complications in either group.
Higher suction pressures with larger syringe volumes during EBUS-TBNA may be useful for safely collecting sufficient tissue specimens.
PMCID: PMC3855538  PMID: 24340058
10.  Impact of the introduction of EBUS on time to management decision, complications, and invasive modalities used to diagnose and stage lung cancer: a pragmatic pre-post study 
BMC Cancer  2016;16:44.
Utilisation of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and guide sheath (EBUS-GS) for diagnosis and staging of lung cancer is gaining popularity, however, its impact on clinical practice is unclear. This study aimed to determine the impact of the introduction of endobronchial ultrasound-guided procedures (EBUS) on time to management decision for lung cancer patients, and on the utilisation of other invasive diagnostic modalities, including CT-guided trans-thoracic needle aspiration (CT-TTNA), bronchoscopy, and mediastinoscopy.
Hospital records of new primary lung cancer patients presenting in 2007 and 2008 (Pre-EBUS cohort) and in 2010 and 2011 (Post-EBUS cohort) were reviewed retrospectively.
The Pre-EBUS cohort included 234 patients. Of the 326 patients in the Post-EBUS cohort, 90 had an EBUS procedure (EBUS-TBNA for 19.0 % and EBUS-GS for 10.4 % of cases). The number of CT-TTNAs and bronchoscopies decreased following the introduction of EBUS (p = 0.015 and p < 0.001 respectively). Of 162 CT-TTNAs, 59 (36 %) resulted in complications compared to 1 complication each for bronchoscopy and EBUS-GS, and no complications from EBUS-TBNA. Fewer complications occurred overall in the Post-EBUS cohort compared to the Pre-EBUS cohort (p = 0.0264). The median time to management decision was 17 days (IQR 24) for the Pre-EBUS and 13 days (IQR 21) for the Post-EBUS cohort (p = 0.07). Within the Post-EBUS cohort, median time to management decision was longer for the EBUS group (n = 90) than the Non-EBUS group (17 days (IQR 29) vs. 10 days (IQR 10), p < 0.001). For half of EBUS-TBNA patients (n = 28, 50.0 %) and EBUS-GS patients (n = 14, 50.0 %), EBUS alone provided sufficient diagnostic and/or staging information; these patients had median time to management decision of 10 days. Regression analysis revealed that the number of imaging events, inpatient, and outpatient visits were significant predictors of time to management decision of >28 days; EBUS was not a predictor of time to management decision.
The introduction of EBUS led to fewer CT-TTNAs and bronchoscopies and did not impact on the time to management decision. EBUS-TBNA or EBUS-GS alone provided sufficient information for diagnosis and/or regional staging in half of the lung cancer patients referred for this investigation.
PMCID: PMC4730595  PMID: 26822160
Lung neoplasms; Diagnostic techniques and procedures; Fine needle aspiration; Bronchoscopy; EBUS; Complication
11.  Endobronchial ultrasound transbronchial needle aspiration: a hybrid method 
Journal of Thoracic Disease  2015;7(Suppl 4):S287-S291.
Conventional transbronchial needle aspiration (cTBNA) was first performed approximately 30 years ago; however TBNA was not widely adopted until the development of endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA). Current EBUS-TBNA needle sizes are limited to 21- and 22-gauge. In order to determine whether a 19-gauge (19G) needle in EBUS-TBNA can further improve the diagnostic yield and simplify the methodology of EBUS-TBNA we developed a hybrid method. Here we report our initial experience in assessing the feasibility of performing EBUS-TBNA using a conventional 19G TBNA needle.
Ten patients with diagnosed or suspected lung cancer with or without lymphadenopathy (LAD) were sampled for diagnostic and/or staging purposes. Patients with suspected benign processes were sampled only for diagnosis. A 19G cTBNA needle was deployed through the working channel of the EBUS bronchoscope. Samples obtained were evaluated for cyto- and histopathologic adequacy.
All 10 patients successfully underwent hybrid 19G EBUS-TBNA. All samples were considered adequate for cyto- and histopathologic evaluation.
Hybrid EBUS-TBNA utilizing a 19G cTBNA needle through an EBUS scope is feasible and may be able to reliably acquire histologic specimens.
PMCID: PMC4700370  PMID: 26807276
EBUS; TBNA; 19-gauge needle; histology; cytology
12.  Contribution of cell blocks obtained through endobronchial ultrasound-guided transbronchial needle aspiration to the diagnosis of lung cancer 
BMC Cancer  2012;12:34.
Conventional smears of samples obtained by endobronchial ultrasound with real-time transbronchial needle aspiration (EBUS-TBNA) have proven useful in lung cancer staging, but the value of additional information from cell-block processing of EBUS-TBNA samples has only been marginally investigated. This study focussed on the contribution of cell block analysis to the diagnostic yield in lung cancer.
Patients referred for lung cancer diagnosis and/or staging by means of EBUS-TBNA were enrolled, the adequacy of the obtained samples for preparing cell blocks was assessed, and the additional pathologic or genetic information provided from cell block analysis was examined.
In 270 lung cancer patients referred for EBUS-TBNA (mean age, 63.3 SD 10.4 years) 697 aspirations were performed. Cell blocks could be obtained from 334 aspirates (47.9%) and contained diagnostic material in 262 (37.6%) aspirates, providing information that was additional to conventional smears in 50 of the 189 samples with smears that were non-diagnostic, corresponding 21 of these blocks to malignant nodes, and allowing lung cancer subtyping of 4 samples. Overall, cell blocks improved the pathologic diagnosis attained with conventional smears in 54 of the 697 samples obtained with EBUS-TBNA (7.7%). Cell blocks obtained during EBUS-TBNA also made epithelial growth factor receptor mutation analysis possible in 39 of the 64 patients with TBNA samples showing metastatic adenocarcinoma (60.1%). Overall, cell blocks provided clinically significant information for 83 of the 270 patients participating in the study (30.7%).
Cell-block preparation from EBUS-TBNA samples is a simple way to provide additional information in lung cancer diagnosis. Analysis of cell blocks increases the diagnostic yield of the procedure by nearly seven per cent and allows for genetic analysis in a sixty per cent of the patients with metastatic adenocarcinoma.
PMCID: PMC3292510  PMID: 22264305
Cell block; Endobronchial ultrasound; Transbronchial needle aspiration; Lung cancer
13.  Endobronchial Ultrasound–guided Transbronchial Needle Aspiration Prevents Mediastinoscopies in the Diagnosis of Isolated Mediastinal Lymphadenopathy 
Rationale: Patients with isolated mediastinal lymphadenopathy (IML) are a common presentation to physicians, and mediastinoscopy is traditionally considered the “gold standard” investigation when a pathological diagnosis is required. Endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) is established as an alternative to mediastinoscopy in patients with lung cancer.
Objective: To determine the efficacy and health care costs of EBUS-TBNA as an alternative initial investigation to mediastinoscopy in patients with isolated IML.
Methods: Prospective multicenter single-arm clinical trial of 77 consecutive patients with IML from 5 centers between April 2009 and March 2011. All patients underwent EBUS-TBNA. If EBUS-TBNA did not provide a diagnosis, then participants underwent mediastinoscopy.
Measurements and Main Results: EBUS-TBNA prevented 87% of mediastinoscopies (95% confidence interval [CI], 77–94%; P < 0.001) but failed to provide a diagnosis in 10 patients (13%), all of whom underwent mediastinoscopy. The sensitivity and negative predictive value of EBUS-TBNA in patients with IML were 92% (95% CI, 83–95%) and 40% (95% CI, 12–74%), respectively. One patient developed a lower respiratory tract infection after EBUS-TBNA, requiring inpatient admission. The cost of the EBUS-TBNA procedure per patient was £1,382 ($2,190). The mean cost of the EBUS-TBNA strategy was £1,892 ($2,998) per patient, whereas a strategy of mediastinoscopy alone was significantly more costly at £3,228 ($5,115) per patient (P < 0.001). The EBUS-TBNA strategy is less costly than mediastinoscopy if the cost per EBUS-TBNA procedure is less than £2,718 ($4,307) per patient.
Conclusions: EBUS-TBNA is a safe, highly sensitive, and cost-saving initial investigation in patients with IML.
Clinical trial registered with (NCT00932854).
PMCID: PMC3423452  PMID: 22652031
endobronchial ultrasound; mediastinal lymphadenopathy; sarcoidosis; tuberculosis; lymphoma
14.  Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of intrathoracic lymph node metastases from extrathoracic malignancies 
Intrathoracic lymph node enlargement is a common finding in patients with extrathoracic malignancies. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a technique that is commonly used for lung cancer diagnosis and staging but that has not been widely investigated for the diagnosis of enlarged mediastinal and lobar lymph nodes in patients with extrathoracic malignancies. We conducted a retrospective study of 117 patients with extrathoracic malignancies who underwent EBUS-TBNA for diagnosis of intrathoracic lymph node enlargement from October 2005 to December 2009 and compared the EBUS-TBNA findings with the final diagnoses. EBUS-TBNA diagnosed mediastinal metastases in 51 of the 117 (43.6 %) cases and gave an alternate diagnosis or ruled out the presence of malignancy in 35 (56.4 %). Fourteen of these 35 patients underwent further surgical investigation, while the remaining 21 had clinical and radiological follow-up for 18 months. No false negatives were found in the surgery group. In the follow-up group, 13 patients had stable or regressive lymphadenopathy, and eight developed clinicoradiological progression and were assumed to have been false negatives by EBUS-TBNA. The sensitivity and negative predictive value of EBUS-TBNA were 86.4 and 75 %, respectively. Immunohistochemical staining (IHC) was performed in 80.4 % of the samples obtained by EBUS-TBNA. In samples obtained from ten patients with metastatic breast cancer, estrogen receptor expression was successfully assessed in eight patients and progesterone receptor and human epidermal growth factor receptor 2 in four. EBUS-TBNA is an accurate procedure for the diagnosis of thoracic lymph node metastases in patients with extrathoracic malignancies and should be an initial diagnostic tool in these patients. Furthermore, EBUS-TBNA can obtain high-quality specimens from metastatic lymph nodes for use in molecular analyses.
PMCID: PMC3616225  PMID: 23196318
Endobronchial ultrasound; Transbronchial needle aspiration; EBUS-TBNA; Mediastinal lymph node metastases; Extrathoracic malignancy; Immunohistochemistry
15.  Endobronchial ultrasound-guided transbronchial needle aspiration for lung cancer staging: early experience in Brazil*,**  
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive, safe and accurate method for collecting samples from mediastinal and hilar lymph nodes. This study focused on the initial results obtained with EBUS-TBNA for lung cancer and lymph node staging at three teaching hospitals in Brazil.
This was a retrospective analysis of patients diagnosed with lung cancer and submitted to EBUS-TBNA for mediastinal lymph node staging. The EBUS-TBNA procedures, which involved the use of an EBUS scope, an ultrasound processor, and a compatible, disposable 22 G needle, were performed while the patients were under general anesthesia.
Between January of 2011 and January of 2014, 149 patients underwent EBUS-TBNA for lymph node staging. The mean age was 66 ± 12 years, and 58% were male. A total of 407 lymph nodes were sampled by EBUS-TBNA. The most common types of lung neoplasm were adenocarcinoma (in 67%) and squamous cell carcinoma (in 24%). For lung cancer staging, EBUS-TBNA was found to have a sensitivity of 96%, a specificity of 100%, and a negative predictive value of 85%.
We found EBUS-TBNA to be a safe and accurate method for lymph node staging in lung cancer patients.
PMCID: PMC4350822  PMID: 25750671
Lung neoplasms; Neoplasm staging; Bronchoscopy; Endoscopic ultrasound-guided fine needle aspiration; Lymph nodes
16.  Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for the Diagnosis of Central Lung Parenchymal Lesions 
Yonsei Medical Journal  2013;54(3):672-678.
The purpose of this study was to evaluate the usefulness of convex probe endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for detecting malignancy in parenchymal pulmonary lesions located adjacent to the central airways.
Materials and Methods
We retrospectively reviewed the diagnostic performance of EBUS-TBNA in consecutive patients with high clinical suspicion of a centrally located primary lung cancer who had undergone EBUS-TBNA at the Samsung Medical Center between May 2009 and June 2011.
Thirty-seven patients underwent EBUS-TBNA for intrapulmonary lesions adjacent to the central airways. Seven lesions were located adjacent to the trachea and 30 lesions were located adjacent to the bronchi. Cytologic and histologic samples obtained via EBUS-TBNA were diagnostic in 32 of 37 (86.4%) of patients. The final diagnosis was lung cancer in 30 patients (7 small cell lung cancer, 23 non-small cell lung cancer), lymphoma in one and malignant fibrous histiocytoma in one patient. The diagnostic sensitivity of EBUS-TBNA in detecting malignancy and detecting both malignancy and benignity was 91.4% and 86.5%, respectively. Two patients experienced minor complications.
EBUS-TBNA is an effective and safe method for tissue diagnosis of parenchymal lesions that lie centrally close to the airways. EBUS-TBNA should be considered the procedure of choice for patients with centrally located lesions without endobronchial involvement.
PMCID: PMC3635626  PMID: 23549813
Bronchoscopy; endobronchial ultrasound; transbronchial needle aspiration; lung cancer; parenchymal lesion
17.  Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of non-lymph node thoracic lesions 
Annals of Thoracic Medicine  2013;8(1):14-21.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has shown excellent diagnostic capabilities for mediastinal and hilar lymphadenopathy. However, its value in thoracic non-lymph node lesions is less clear. This study was designed to assess the value of EBUS-TBNA in distinguishing malignant from benign thoracic non-lymph node lesions.
From October 2009 to August 2011, 552 patients underwent EBUS-TBNA under local anesthesia and with conscious sedation. We retrospectively reviewed 81 of these patients who had tracheobronchial wall-adjacent intrapulmonary or isolated mediastinal non-lymph node lesions. On-site cytological evaluation was not used. Immunohistochemistry (IHC) was performed to distinguish the origin or type of malignancy when necessary.
EBUS-TBNA was performed in 68 tracheobronchial wall-adjacent intrapulmonary and 13 isolated mediastinal non-lymph node lesions. Of the 81 patients, 77 (95.1%, 60 malignancies and 17 benignancies) were diagnosed through EBUS-TBNA, including 57 primary lung cancers, 2 mediastinal tumors, 1 pulmonary metastatic adenocarcinoma, 7 inflammation, 5 tuberculosis, 3 mediastinal cysts, 1 esophageal schwannoma, and 1 focal fibrosis. There were four false-negative cases (4.9%). Of the 60 malignancies, there were 9 (15.0%) which originally had no definite histologic origin or type. Thus, IHC was performed, with 7 (77.8%) being subsequently confirmed. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS-TBNA in distinguishing malignant from benign lesions were 93.4% (60/64), 100% (17/17), 100% (60/60), 81.0% (17/21), and 95.1% (77/81), respectively.
EBUS-TBNA is a safe procedure with a high sensitivity for distinguishing malignant from benign thoracic non-lymph node lesions within the reach of EBUS-TBNA, with IHC usually providing a more definitive diagnosis.
PMCID: PMC3573552  PMID: 23439919
Endobronchial ultrasound; immunohistochemistry; lung cancer; thoracic lesion; transbronchial needle aspiration
18.  Genomic Characterisation of Small Cell Lung Cancer Patient-Derived Xenografts Generated from Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Specimens 
PLoS ONE  2014;9(9):e106862.
Patient-derived xenograft (PDX) models generated from surgical specimens are gaining popularity as preclinical models of cancer. However, establishment of PDX lines from small cell lung cancer (SCLC) patients is difficult due to very limited amount of available biopsy material. We asked whether SCLC cells obtained from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) could generate PDX lines that maintained the phenotypic and genetic characteristics of the primary tumor. Following successful EBUS-TBNA sampling for diagnostic purposes, we obtained an extra sample for cytologic analysis and implantation into the flanks of immunodeficient mice. Animals were monitored for engraftment for up to 6 months. Histopathologic and immunohistochemical analysis, and targeted next-generation re-sequencing, were then performed in both the primary sample and the derivative PDX line. A total of 12 patients were enrolled in the study. EBUS-TBNA aspirates yielded large numbers of viable tumor cells sufficient to inject between 18,750 and 1,487,000 cells per flank, and to yield microgram quantities of high-quality DNA. Of these, samples from 10 patients generated xenografts (engraftment rate 83%) with a mean latency of 104 days (range 63–188). All but one maintained a typical SCLC phenotype that closely matched the original sample. Identical mutations that are characteristic of SCLC were identified in both the primary sample and xenograft line. EBUS-TBNA has the potential to be a powerful tool in the development of new targeting strategies for SCLC patients by providing large numbers of viable tumor cells suitable for both xenografting and complex genomic analysis.
PMCID: PMC4156408  PMID: 25191746
19.  Systematic Endobronchial Ultrasound-guided Mediastinal Staging Versus Positron Emission Tomography for Comprehensive Mediastinal Staging in NSCLC Before Radical Radiotherapy of Non-small Cell Lung Cancer 
Medicine  2016;95(8):e2488.
Despite known limitations of positron emission tomography (PET) for mediastinal staging of non-small cell lung cancer (NSCLC), radiation treatment fields are generally based on PET-identified disease extent. However, no studies have examined the accuracy of FDG-PET/CT on a per-node basis in patients being considered for curative-intent radiotherapy in NSCLC.
In a prospective trial, patients with NSCLC being considered for definitive thoracic radiotherapy (± systemic chemotherapy) underwent minimally invasive systematic mediastinal evaluation with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) following noninvasive staging with integrated PET-CT.
Thirty patients underwent EBUS-TBNA, with TBNA performed from a mean 2.5 lymph node (LN) stations per patient (median 3, range 1–5). Discordant findings between PET-CT and EBUS-TBNA were observed in 10 patients (33%, 95% CI 19%–51%). PET-occult LN metastases were demonstrated by EBUS in 4 patients, whereas a lesser extent of mediastinal involvement, compared with FDG-PET, was demonstrated by EBUS in 6 patients, including 2 patients downstaged from cN3 to pN2. LNs upstaged by EBUS were significantly smaller than nodes downstaged by EBUS, 7.5 mm (range 7–9) versus 12 mm (range 6–21), P = 0.005.
A significant proportion of patients considered for definitive radiotherapy (+/-chemotherapy) undergoing systematic mediastinal evaluation with EBUS-TBNA in this study have an extent of mediastinal NSCLC involvement discordant with that indicated by PET-CT. Systematic EBUS-TBNA may aid in defining the extent of mediastinal involvement in NSCLC patients undergoing radiotherapy. Systematic EBUS-TBNA has the potential to contribute significantly to radiotherapy planning and delivery, by either identifying occult nodal metastases, or demonstrating FDG-avid LNs to be disease-free.
PMCID: PMC4778990  PMID: 26937894
20.  Optimal sequence of tests for the mediastinal staging of non-small cell lung cancer 
Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer and the most difficult to predict. When there are no distant metastases, the optimal therapy depends mainly on whether there are malignant lymph nodes in the mediastinum. Given the vigorous debate among specialists about which tests should be used, our goal was to determine the optimal sequence of tests for each patient.
We have built an influence diagram (ID) that represents the possible tests, their costs, and their outcomes. This model is equivalent to a decision tree containing millions of branches. In the first evaluation, we only took into account the clinical outcomes (effectiveness). In the second, we used a willingness-to-pay of € 30,000 per quality adjusted life year (QALY) to convert economic costs into effectiveness. We assigned a second-order probability distribution to each parameter in order to conduct several types of sensitivity analysis.
Two strategies were obtained using two different criteria. When considering only effectiveness, a positive computed tomography (CT) scan must be followed by a transbronchial needle aspiration (TBNA), an endobronchial ultrasound (EBUS), and an endoscopic ultrasound (EUS). When the CT scan is negative, a positron emission tomography (PET), EBUS, and EUS are performed. If the TBNA or the PET is positive, then a mediastinoscopy is performed only if the EBUS and EUS are negative. If the TBNA or the PET is negative, then a mediastinoscopy is performed only if the EBUS and the EUS give contradictory results. When taking into account economic costs, a positive CT scan is followed by a TBNA; an EBUS is done only when the CT scan or the TBNA is negative.
This recommendation of performing a TBNA in certain cases should be discussed by the pneumology community because TBNA is a cheap technique that could avoid an EBUS, an expensive test, for many patients.
We have determined the optimal sequence of tests for the mediastinal staging of NSCLC by considering sensitivity, specificity, and the economic cost of each test. The main novelty of our study is the recommendation of performing TBNA whenever the CT scan is positive. Our model is publicly available so that different experts can populate it with their own parameters and re-examine its conclusions. It is therefore proposed as an evidence-based instrument for reaching a consensus.
PMCID: PMC4727341  PMID: 26813400
Decision making under uncertainty; Cost-effectiveness analysis in medicine; Probabilistic graphical models; Influence diagrams; Bayesian networks
21.  Endobronchial ultrasound elastography: a new method in endobronchial ultrasound-guided transbronchial needle aspiration 
Journal of Thoracic Disease  2015;7(Suppl 4):S272-S278.
TBNA through the flexible bronchoscope is a 37-year-old technology that utilizes a TBNA needle to puncture the bronchial wall and obtain specimens of peribronchial and mediastinal lesions through the flexible bronchoscope for the diagnosis of benign and malignant diseases in the mediastinum and lung.
Since 2002, the Olympus Company developed the first generation ultrasound equipment for use in the airway, initially utilizing an ultrasound probe introduced through the working channel followed by incoroporation of a fixed linear ultrasound array at the distal tip of the bronchoscope. This new bronchoscope equipped with a convex type ultrasound probe on the tip was subsequently introduced into clinical practice. The convex probe (CP)-EBUS allows real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of mediastinal and hilar lymph nodes. EBUS-TBNA is a minimally invasive procedure performed under local anesthesia that has been shown to have a high sensitivity and diagnostic yield for lymph node staging of lung cancer.
In 10 years of EBUS development, the Olympus Company developed the second generation EBUS bronchoscope (BF-UC260FW) with the ultrasound image processor (EU-M1), and in 2013 introduced a new ultrasound image processor (EU-M2) into clinical practice. FUJI company has also developed a curvilinear array endobronchial ultrasound bronchoscope (EB-530 US) that makes it easier for the operator to master the operation of the ultrasonic bronchoscope. Also, the new thin convex probe endobronchial ultrasound bronchoscope (TCP-EBUS) is able to visualize one to three bifurcations distal to the current CP-EBUS.
The emergence of EBUS-TBNA has also been accompanied by innovation in EBUS instruments. EBUS elastography is, then, a new technique for describing the compliance of structures during EBUS, which may be of use in the determination of metastasis to the mediastinal and hilar lymph nodes. This article describes these new EBUS techniques and reviews the relevant literature.
PMCID: PMC4700375  PMID: 26807274
Endobronchial ultrasound (EBUS); elastography; lung cancer; specimens
22.  Utility of on-site evaluation of endobronchial ultrasound-guided transbronchial needle aspiration specimens 
CytoJournal  2011;8:20.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an integral tool in the diagnosis and staging of malignant tumors of the lung. Rapid on-site evaluation (ROSE) of fine needle aspiration (FNA) samples has been advocated for as a guide for assessing the accuracy and adequacy of biopsy samples. Although ROSE has proven useful for numerous sites and procedures, few studies have specifically investigated its utility in the assessment of EBUS-TBNA specimens. The intention of this study was to explore the utility of ROSE for EBUS-TBNA specimens.
Materials and Methods:
The pathology files at our institution were searched for all EBUS-TBNA cases performed between January 2010 and June 2010. The data points included number of sites sampled per patient, location of site(s) sampled, on-site evaluation performed, preliminary on-site diagnosis rendered, final cytologic diagnosis, surgical pathology follow-up, cell blocks, and ancillary studies performed.
A total of 294 EBUS-TBNA specimens were reviewed and included in the study; 264 of 294 (90%) were lymph nodes and 30 of 294 (10%) were lung mass lesions. ROSE was performed for 140 of 294 (48%) specimens. The on-site and final diagnoses were concordant in 104 (74%) and discordant in 36 (26%) cases. Diagnostic specimens were obtained in 132 of 140 (94%) cases with on-site evaluation and 138 of 154 (90%) without on-site evaluation. The final cytologic diagnosis was malignant in 60 of 132 (45%) cases with ROSE and 46 of 138 (33%) cases without ROSE, and the final diagnosis was benign in 57 of 132 (47%) with ROSE and 82 of 138 (59%) without ROSE. A cell block was obtained in 129 of 140 (92%) cases with ROSE and 136 of 154 (88%) cases without ROSE.
The data demonstrate no remarkable difference in diagnostic yield, the number of sites sampled per patient, or clinical decision making between specimens collected via EBUS-TBNA with or without ROSE. As a result, this study challenges the notion that ROSE is beneficial for the evaluation of EBUS-TBNA specimens.
PMCID: PMC3229807  PMID: 22145008
EBUS-TBNA; endobronchial; on-site; ROSE
23.  Diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration in various lung diseases 
Jornal Brasileiro de Pneumologia  2015;41(5):410-414.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a new method for the diagnosis and staging of lung disease, and its use is increasing worldwide. It has been used as a means of diagnosing lung cancer in its initial stages, and there are data supporting its use for the diagnosis of benign lung disease. The aim of this study was to share our experience with EBUS-TBNA and discuss its diagnostic value.
We retrospectively analyzed the results related to 159 patients who underwent EBUS-TBNA at our pulmonary medicine clinic between 2010 and 2013. We recorded the location and size of lymph nodes seen during EBUS. Lymph nodes that appeared to be affected on EBUS were sampled at least twice. We recorded the diagnostic results of EBUS-TBNA and (for cases in which EBUS-TBNA yielded an inconclusive diagnosis) the final diagnoses after further investigation and follow-up.
We evaluated 159 patients, of whom 89 (56%) were male and 70 (44%) were female. The mean age was 54.6 ± 14.2 years among the male patients and 51.9 ± 11.3 years among the female patients. Of the 159 patients evaluated, 115 (84%) were correctly diagnosed by EBUS. The diagnostic accuracy of EBUS-TBNA was 83% for benign granulomatous diseases and 77% for malignant diseases.
The diagnostic value of EBUS-TBNA is also high for benign pathologies, such as sarcoidosis and tuberculosis. In patients with mediastinal disorders, the use of EBUS-TBNA should be encouraged, primarily because it markedly reduces the need for mediastinoscopy.
PMCID: PMC4635086  PMID: 26578131
Sarcoidosis; Tuberculosis, pulmonary; Lung neoplasms; Bronchoscopy; Mediastinoscopy; Endosonography
24.  Rapid KRAS, EGFR, BRAF and PIK3CA Mutation Analysis of Fine Needle Aspirates from Non-Small-Cell Lung Cancer Using Allele-Specific qPCR 
PLoS ONE  2011;6(3):e17791.
Endobronchial Ultrasound Guided Transbronchial Needle Aspiration (EBUS-TBNA) and Trans-esophageal Ultrasound Scanning with Fine Needle Aspiration (EUS-FNA) are important, novel techniques for the diagnosis and staging of non-small cell lung cancer (NSCLC) that have been incorporated into lung cancer staging guidelines. To guide and optimize treatment decisions, especially for NSCLC patients in stage III and IV, EGFR and KRAS mutation status is often required. The concordance rate of the mutation analysis between these cytological aspirates and histological samples obtained by surgical staging is unknown. Therefore, we studied the extent to which allele-specific quantitative real-time PCR with hydrolysis probes could be reliably performed on EBUS and EUS fine needle aspirates by comparing the results with histological material from the same patient. We analyzed a series of 43 NSCLC patients for whom cytological and histological material was available. We demonstrated that these standard molecular techniques can be accurately applied on fine needle cytological aspirates from NSCLC patients. Importantly, we show that all mutations detected in the histological material of primary tumor were also identified in the cytological samples. We conclude that molecular profiling can be reliably performed on fine needle cytology aspirates from NSCLC patients.
PMCID: PMC3050927  PMID: 21408138
25.  Endobronchial ultrasound elastography strain ratio for mediastinal lymph node diagnosis 
Radiology and Oncology  2015;49(4):334-340.
Ultrasound elastography is an imaging procedure that can assess the biomechanical characteristics of different tissues. The aim of this study was to define the diagnostic value of the endobronchial ultrasound (EBUS) elastography strain ratio of mediastinal lymph nodes in patients with a suspicion of lung cancer. The diagnostic values of the strain ratios were compared with the EBUS brightness mode (B-mode) features of selected mediastinal lymph nodes and with their cytological diagnoses.
Patients and methods
This prospective, single-centre study enrolled patients with an indication for biopsy and mediastinal staging after a non-invasive diagnostic workup of a lung tumour. EBUS with standard B-mode evaluation and elastography with strain ratio measurement were performed before endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA).
Thirty-three patients with 80 suspicious mediastinal lymph nodes were included. Malignant infiltration was confirmed in 34 (42.5%) lymph nodes. The area under the receiver operating characteristic curve for the strain ratio was 0.87 (p < 0.0001). At a strain ratio ≥ 8, the accuracy for malignancy prediction was 86.25% (sensitivity 88.24%, specificity 84.78%, positive predictive value [PPV] 81.08%, negative predictive value [NPV] 90.70%). The strain ratio is more accurate than conventional B-mode EBUS modalities for differentiating between malignant and benign lymph nodes.
EBUS-guided elastography with strain ratio assessment can distinguish malignant from benign mediastinal lymph nodes with greater accuracy than conventional EBUS modalities. This new method may reduce the number of mediastinal EBUS-TBNAs and thus reduce the invasiveness and expense of mediastinal staging in patients with non-small lung cancer (NSCLC).
PMCID: PMC4722923  PMID: 26834519
cancer staging; elastography; endobronchial ultrasound; lung cancer; needle biopsy

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