EJ

Olntmncrmftli8dBgsns

DA

1d

(B)US-Guided Pulmonary Interventionsouke T. Annema, MD, PhD

Transesophageal ultrasound-guided fine needle aspiration (EUS-FNA) enables minimallyinvasive tissue sampling of mediastinal lymph nodes. There is convincing evidence thatEUS-FNA is an accurate method for mediastinal staging of patients with non small cell lungcancer (NSCLC), and therefore EUS-FNA provides an alternative for surgical evaluation ofthe mediastinum. Due to the complementary reach in analyzing different mediastinalregions, additional staging by EUS-FNA to mediastinoscopy improves preoperative stagingof NSCLC and therefore reduces the number of futile thoracotomies. Preliminary datasuggest an important role for EUS-FNA in the assessment of mediastinal tumor invasion aswell as mediastinal restaging after prior chemo (radiation) therapy. For interstitial lungdiseases, EUS-FNA has been demonstrated to be an accurate method in diagnosingsarcoidosis. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a novel diagnostic method by which mediastinal, hilar, and intrapulmonary nodescan be aspirated under real-time ultrasound control from the trachea or main bronchi.EBUS-TBNA can be performed in an ambulatory setting and has been proven to be accuratein mediastinal staging of patients with NSCLC. Like EUS-FNA, EBUS-TBNA is an alterna-tive for mediastinoscopy. EUS-FNA and EBUS-TBNA have a complementary reach forvarious mediastinal nodal stations, and recent studies indicate that complete and accuratelocoregional staging of NSCLC can be achieved by the combination of EUS-FNA andEBUS-TBNA.Tech Gastrointest Endosc 9:25-31 © 2007 Elsevier Inc. All rights reserved.

Keywords EUS-FNA, EBUS-TBNA, pulmonary

dm

EPTgnana1tbtaG-sgocr

n a daily basis, chest physicians and thoracic surgeonsare faced with the challenge to evaluate mediastinal

esions. Due to the high incidence of lung cancer, 170,000ew cases in the USA1 and 1.3 million worldwide,2 medias-inal staging of non small cell lung cancer (NSCLC) compro-ises by far the largest subset of patients in which mediasti-al analysis is indicated. Although imaging methods such asomputed tomography (CT) and positron emission tomog-aphy (PET) provide detailed information regarding size andetabolic activity of mediastinal nodes,3 tissue samples are

requently needed for accurate nodal assessment.4 Therefore,o date, mediastinoscopy is frequently performed for regionalung cancer staging in those cases in which tissue verifications indicated. Although mediastinoscopy has a sensitivity of1% and excellent specificity (100%),5 it has limitations in itsiagnostic reach, is invasive, and requires clinical admission.y 1995, it was reported that transesophageal ultrasound-uided fine needle aspiration (EUS-FNA), originally de-igned for the analysis and staging of gastrointestinal malig-ancies, had a high diagnostic potential for mediastinaltaging of lung cancer.6 In the following section, the proce-

ivision of Pulmonary Medicine, Leiden University Medical Center, Leiden.ddress reprint requests to Jouke Annema, MD, PhD, Department of Pulmonol-

ogy C3 P, Albinusdreef 2, PO Box 9600, 2300 RC Leiden University Medical

uCenter, Leiden, The Netherlands.E-mail: j.t.annema@lumc.nl

096-2883/07/$-see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.tgie.2006.11.012

ure, indications, limitations, and impact on patient manage-ent of EUS-FNA in pulmonary medicine will be discussed.

US-FNA: Instruments androcedural Technique

he same linear array ultrasonic equipment that is used inasteroenterology is utilized for the assessment of mediasti-al lesions. For accurate mediastinal analysis, tissue samplesre required, and therefore linear and not radial equipment iseeded. Various ultrasonic endoscopes that are commerciallyvailable (for instance Pentax FG 34UX, or Olympus GF UC40 P) are equipped with curved linear array ultrasoundransducers that transmit ultrasound waves with frequenciesetween 5 and 10 MHz parallel to the axis of the scope andherefore permit a real-time controlled aspiration.7 For thectual tissue sampling, various needle types (Vizeon, Medi-lobe 222 480, Wilson-Cook Echo tip -1-22 or Olympus NA

10J-10) and sizes (19-, 22-, 25-gauge) are available, buttudies almost exclusively have been performed with 22-auge needles. The use of suction is under debate,8 and for anptimal yield, five needle passes are advised.9 Rapid on-siteytology (ROSE) is advocated to obtain optimal yield.10 Foregional lung cancer staging, the Mountain classification is

sed (Fig. 1).11

25

ciaAgcumtp

n2LF2nadt(

aging m

26 J.T. Annema

Patients are investigated in left lateral position underonscious sedation using midazolam. Initially, the scopes introduced into the stomach from where the celiacxis, celiac nodes, and left adrenal gland can be inspected.

thorough mediastinal staging is performed by 360 de-ree rotations of the echoendoscope at intervals of 3 to 4m proceeding from the gastroesophageal junction to thepper esophageal sphincter. Using this technique,ediastinal nodes can be detected in following regions:

he pulmonary ligament (stations 9R and 9L), the lower

Figure 1 Regional lung cancer st

araesophageal area (stations 8R and 8L), the subcari- p

al area (station 7), paratracheal to the left (station 4L, Fig., LN1), the aorto-pulmonary window (station 5, Fig. 2,N2), and the para-aortal region (station 6) (Hawes RH,ockens P: Endosonography 2006, p 57-72, ISBN1-4160-953-2). The latter two lymph node stations often can-ot be aspirated due to the interposition of the pulmonaryrtery and aorta (Fig. 2, LN2). EUS has limitations inetecting the lower paratracheal nodes on the right (sta-ion 4R) (Fig. 3) as well as the upper paratracheal stations2R and 2L), unless they are grossly enlarged, due to the

ap, according to Mountain.11

resence of air in the trachea.

EMibnsT(i(efmsmmg

irjmEapitawad9bnf

ttmdc

Fl(w

Fr

Fnn

Fti

Pulmonary interventions 27

US-FNA Resultsediastinal staging of lung cancer is beyond doubt the main

ndication for EUS-FNA. The vast majority of studies haveeen performed in selected patients with enlarged mediasti-al nodes at chest CT. The accuracy of EUS-FNA in thisubset of patients ranges between 91% and 100%.10,12-21

hree studies evaluated the role of EUS-FNA in patients withsuspected) lung cancer without signs of mediastinal nodalnvolvement at chest CT. The lower accuracy of EUS-FNArange 76% to 89%)22-24 might be explained by samplingrrors, technical difficulty to sample small nodes, or just theact that the nodes have not been aspirated due to their nor-

al sonographic appearance.22-25 Evaluating patients withuspected mediastinal involvement at positron emission to-ography (PET) by EUS-FNA has been proposed as a mini-ally invasive and accurate (range 77-97%) staging strate-

y.26-28 Staging by EUS-FNA in addition to mediastinoscopy

igure 2 EUS image, demonstrating a left-sided lower paratrachealymph node located between the esophagus (Es), pulmonary arteryPA), and the aorta (AO) (Station 4L, LN1) and an aorta-pulmonaryindow node located lateral from the aorta (Station 5, LN2).

igure 3 Computed tomogram (CT) of the chest demonstrating a

ight-sided paratracheal lymph node (LN, station 4R). i

mproves preoperative staging due to the complementaryeach of various mediastinal nodal stations.29,30 EUS has ma-or impact on patient management, as 70% of scheduled

ediastinoscopies can be prevented by EUS-FNA.10,12,16

US-FNA has also been suggested for mediastinal restagingfter induction chemo (radiation) therapy,31,32 and thereforerovides an alternative for remediastinoscopy. Besides target-

ng mediastinal nodes, intrapulmonary tumors can be de-ected and aspirated by EUS-FNA, provided they are locateddjacent to the esophagus (Fig. 4). In two studies in patientsith a centrally located intrapulmonary mass without medi-

stinal involvement at chest CT, EUS-FNA (after a prior non-iagnostic bronchoscopy) was able to establish a diagnosis in7% and 100% of patients.33,34 If intrapulmonary tumors cane detected at EUS, the presence or absence of mediasti-al29,35 or aortic36 invasion (Fig. 5) can be assessed success-ully.

EUS-FNA also has an important role in assessing medias-inal metastases in patients with (previous) extra thoracicumors and radiological suspicion of mediastinal involve-ent.37,38 EUS-FNA is expected to be incorporated in theiagnostic workup of patients with sarcoidosis—the mostommon cause of interstitial lung disorder—a disease in

igure 4 Real-time EUS-guided aspiration of a squamous cell carci-oma of the lung (T) located adjacent to the esophagus (Es). (N,eedle; L, compromised lung tissue.)

igure 5 Adenocarcinoma of the left upper lobe (T) located adjacento the aorta (Ao). On EUS, there are no signs of tumor invasion (T4)n the aorta. (L, compromised lung tissue.) (Color version of figure

s available online.)

wcnTpapi

(MFborncaoclv1iidpolinsHleT

tmaib

EPT(iq3sbsssao

alttmnwtaulbvF

a

FOo

28 J.T. Annema

hich mediastinal nodes are frequently affected. Bronchos-opy with TBNA and peripheral lung biopsies have a diag-ostic yield in assessing granulomas in 65% of patients.39,40

he disadvantages of peripheral lung biospies are the risk ofneumothoraces and hemoptysis. Three studies have evalu-ted the role of EUS-FNA in diagnosing sarcoidosis and re-orted a yield of noncaseating granulomas without necrosis

n 82% to 94% of patients.41-43

EBUS)-TBNA in Pulmonaryedicine

lexible bronchoscopy allows inspection of the airways andiopsying of endobronchial lesions. In case tissue samplingf mediastinal lymph nodes is indicated, they can be aspi-ated by transbronchial needle aspiration (TBNA).44 As theseodes cannot be identified during conventional bronchos-opy, the actual aspiration is “blind” (Fig. 6) and the site ofspiration is selected based on the CT scan (Fig. 3). The yieldf TBNA varies widely (range 39-78%) as reported by a re-ent meta-analysis and is critically dependent on the preva-ence of mediastinal metastases in the population under in-estigation.45 Unfortunately, TBNA is only performed by0% to 30% of bronchoscopists,46,47 and the main reason for

ts limited use is the absence of real-time needle monitor-ng.48 The first attempt to overcome this problem was theevelopment of endobronchial ultrasound (EBUS) minirobes. These probes can be inserted in the working channelf a bronchoscope, and after inflation of a water-filled bal-oon, provide a 360° ultrasound image in a plane surround-ng the ultrasound transducer. After localizing the targetode, the ultrasound probe has to be removed and using theame working channel, a “blind” TBNA can be performed.49

erth and coworkers demonstrated that TBNA after EBUSocalization improved diagnostic yield in all nodal stations,xcept in the subcarinal area, compared with conventionalBNA.50 By the end of 2003, Krasnik and coworkers reported

igure 6 Endobronchial view demonstrating a transbronchial needle

ospiration (TBNA) of a paratracheal node.

he first experiences with an EBUS-TBNA scope, which per-itted real-time ultrasound-guided transbronchial needle

spiration of mediastinal nodes.51 As real-time EBUS-TBNAs a promising future technique, it will be discussed in detailelow.

BUS-TBNA: Instruments androcedural Technique

he EBUS-TBNA bronchoscope (Olympus BF 160F-OL8)Fig. 7) has an outer diameter of 6.9 mm and incorporated atts distal end is a curved linear ultrasound transducer (fre-uency 7.5 MHz, scanning range 50 degrees) as well as a5-degree forward oblique optical system. A 22-gauge needleystem (Olympus NA-201SX-4022) can be attached to theronchoscope (Fig. 8). After adjustment of the length of theheath, a needle can be inserted in a plane parallel to thecanning direction (Fig. 7), thus permitting a real-time ultra-ound controlled aspiration. The distal end of the needle hasn echogenic dimpled tip (Fig. 9) that improves its visibilityn ultrasound images.EBUS-TBNA can be performed in an ambulatory setting,

nd most investigators use conscious sedation with midazo-am.52-54 Before the examination, the oropharynx is anesthe-ized with a lidocaine spray. After the (oral) introduction ofhe ultrasonic bronchoscope, the trachea and right and leftain bronchus can be inspected. To visualize the mediastinalodes, the ultrasound transducer has to make firm contactith the tracheo/bronchial wall. A balloon option is available,

o increase surface contact between ultrasound transducernd the tracheal wall, but in the majority of cases, goodltrasound images can be obtained without use of the bal-

oon. A Doppler system is available to detect flow, which cane helpful in the discrimination between solid lesions andascular structures (Fig. 10). After adjustment of the length

igure 7 Curved linear array EBUS-TBNA scope (Olympus BF 160F-L8) with a 22-gauge needle. (Color version of figure is availablenline.)

f the sheath, a real-time controlled aspiration of a lymph

ndfiiafwat11ab

EAlnsmpissmpHl

sspma9

CEasrslodElEwpglt

F(fl

F(

FT

F2

Pulmonary interventions 29

ode can be performed. In case a cartilage ring is encountereduring TBNA, the scope is moved a little bit up or down tond an intercartilage space. After positioning of the needle

nto the node (Fig. 11), the stylet of the needle is removednd suction is applied. After moving the needle back andorth several times, suction is removed and the needle isithdrawn.52,53 EBUS can visualize the upper (stations 2R

nd 2L) and lower (stations 4R and 4L) paratracheal nodes,he subcarinal area (station 7), as well as the hilar (stations0R and 10L) and intrapulmonary nodes (stations 11R and1L). In addition to lymph nodes, centrally located tumorsbutting the larger airways and undetectable by conventionalronchoscopy can be identified by EBUS.51

BUS-TBNA Resultsfter the initial report in 2003,51 3 medium-sized53-55 and 1

arge study52 have been performed, all addressing mediasti-al lymph node staging in patients with (suspected) non-mall cell lung cancer. In a study of 70 patients with enlargedediastinal nodes at chest CT, Yasafuku and coworkers re-orted a sensitivity, specificity and, accuracy for EBUS-TBNA

n assessing mediastinal nodes of 96%, 100%, and 97%, re-pectively.53 In a subsequent study of 105 patients with non-mall cell lung cancer, 29 mediastinoscopies, 8 thoracoto-ies, 4 thoracoscopies, and 9 CT-guided lung biopsies wererecluded due to EBUS-TBNA findings.54 Very recently,erth and colleague studied 502 patients with (suspected)

ung cancer and enlarged mediastinal nodes and reported a

igure 8 Needle system (Olympus NA-201SX-4022) and EBUS-BNA scope.

igure 9 Sheath with 22-gauge EBUS-TBNA needle (Olympus NA-

n01SX-4022). Notice the echogenic dimpled tip.

ensitivity of 94% and a specificity of 100% for mediastinaltaging.52 The same author evaluated EBUS-TBNA in 100atients without signs of mediastinal lymph node enlarge-ent (�10 mm short axis) on CT. The sensitivity, specificity,

nd accuracy of EBUS-TBNA in this subset of patients were2%, 100%, and 96%, respectively.55

linical PerspectivesUS-FNA and EBUS-TBNA are accurate, minimally invasive,nd safe diagnostic methods for mediastinal staging of non-mall cell lung cancer. It has to be realized that the diagnosticeach of both methods in assessing various mediastinal nodaltations is complementary.56 The role of mediastinoscopy inung cancer staging is issue of debate due to the introductionf ultrasonic endoscopic methods.57 Surgical staging by me-iastinoscopy can be prevented to a large extent by bothUS12-16 and EBUS.54 The concept of complete endoscopic

ung cancer staging by the combination of EUS-FNA andBUS-TBNA has been postulated by Vilman and colleagues,ho reported an accuracy of 100% in a small study of 33atients.58 These findings were confirmed by Wallace and hisroup, who presented data on 84 patients with (suspected)ung cancer who all underwent bronchoscopy with conven-ional TBNA, EBUS-TBNA, and EUS-FNA in 1 ambulatory

igure 10 EBUS image demonstrating a paratracheal lymph nodeLN) adjacent to the pulmonary artery (PA) (notice the Dopplerow).

igure 11 Real- time EBUS-guided transbronchial needle aspirationTBNA) of a right-sided paratracheal node (LN, station 4R). (N,

eedle.)

sEF((sbarfbliwtbAr

CIEmrms

R

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

2

T

MMHDASMD

� t indica

30 J.T. Annema

etting. The sensitivity of mediastinal staging for combinedUS-FNA � EBUS-TBNA (97%) was superior to either EUS-NA � TBNA (95%), EBUS-TBNA � TBNA combined89%), and EUS (89%), EBUS (83%) or conventional TBNA43%) alone (Wallace MD, Endoscopy 2006, 38, p4, ab-tract). It has to be realized that EUS and EBUS results haveeen obtained by a selected group of dedicated investigators,nd it remains to be seen whether the reported accuracyemains high after large-scale implementation. In the nearuture, both EUS-FNA and EBUS-TBNA beyond doubt wille implemented in diagnostic and (re) staging strategies for

ung cancer (Table 1). As a result, the need for surgical stag-ng and the number of exploratory and futile thoracotomiesill be reduced. For extra thoracic malignancies that metas-

asize to the mediastinal nodes, EUS and possible EBUS cane of value in confirming or excluding mediastinal spread.side from its role in (lung) cancer, EUS is expected to play a

ole in diagnosing sarcoidosis41-43 and cysts.59

onclusionsn conclusion, by now there is substantial evidence that bothUS-FNA and EBUS-TBNA are accurate and safe diagnosticethods for the analysis of mediastinal lymph nodes. For

egional staging of lung cancer and evaluation of mediastinalasses, it is expected that EUS-FNA and EBUS-TBNA will

ubstitute surgical methods to a large extent.

eferences1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Can-

cer J Clin 49:8-31, 19992. Parkin DM: Global cancer statistics in the year 2000. Lancet Oncol

2:533-543, 20013. Toloza EM, Harpole L, McCrory DC: Noninvasive staging of nonsmall

cell lung cancer: a review of the current evidence. Chest 123:137S-146S, 2003 (suppl)

4. Silvestri GA, Tanoue LT, Margolis ML, et al: The noninvasive staging ofnonsmall cell lung cancer: the guidelines. Chest 123:147S-156S, 2003(suppl)

5. Toloza EM, Harpole L, Detterbeck F, et al: Invasive staging of nonsmallcell lung cancer: a review of the current evidence. Chest 123:157S-166S, 2003 (suppl)

6. Pedersen BH, Vilmann P, Folke K, et al: Endoscopic ultrasonographyand real-time guided fine-needle aspiration biopsy of solid lesions ofthe mediastinum suspected of malignancy. Chest 110:539-544, 1996

7. Vilmann P: Endoscopic ultrasonography-guided fine-needle aspirationbiopsy of lymph nodes. Gastrointest Endosc 43:S24-S29, 1996

8. Wallace MB, Kennedy T, Durkalski V, et al: Randomized controlledtrial of EUS-guided fine needle aspiration techniques for the detectionof malignant lymphadenopathy. Gastrointest Endosc 54:441-447,

able 1 Indications for EUS-FNA and EBUS-TBNA in Pulmon

Indications in Pulmonary Medicine

ediastinal staging of lung cancerediastinal restagingilar lymph node stagingiagnosing lung tumours located adjacent the esophagusssessing mediastial tumor invasion (T4)uspected left adrenal mass in lung cancer patientsediastinal staging of extra thoracic tumorsiagnosing sarcoidosis

�, strong evidence available; �, some evidence available; �, no

2001 2

9. Leblanc JK, Ciaccia D, Al Assi MT, et al: Optimal number of EUS-guided fine needle passes needed to obtain a correct diagnosis. Gastroi-ntest Endosc 59:475-481, 2004

0. Tournoy KG, Praet MM, Van Maele G, et al: Esophageal endoscopicultrasound with fine-needle aspiration with an on-site cytopathologist:high accuracy for the diagnosis of mediastinal lymphadenopathy. Chest128:3004-3009, 2005

1. Mountain CF, Dresler CM: Regional lymph node classification for lungcancer staging. Chest 111:1718-1723, 1997

2. Annema JT, Versteegh MI, Veselic M, et al: Endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of lung can-cer and its impact on surgical staging. J Clin Oncol 23:8357-8361,2005

3. Fritscher-Ravens A, Sriram PV, Bobrowski C, et al: Mediastinal lymph-adenopathy in patients with or without previous malignancy: EUS-FNA-based differential cytodiagnosis in 153 patients. Am J Gastroen-terol 95:2278-2284, 2000

4. Fritscher-Ravens A: Endoscopic ultrasound evaluation in the diagnosisand staging of lung cancer. Lung Cancer 41:259-267, 2003

5. Gress FG, Hawes RH, Savides TJ, et al: Endoscopic ultrasound-guidedfine-needle aspiration biopsy using linear array and radial scanningendosonography. Gastrointest Endosc 45:243-250, 1997

6. Larsen SS, Krasnik M, Vilmann P, et al: Endoscopic ultrasound guidedbiopsy of mediastinal lesions has a major impact on patient manage-ment. Thorax 57:98-103, 2002

7. Savides TJ, Perricone A: Impact of EUS-guided FNA of enlarged medi-astinal lymph nodes on subsequent thoracic surgery rates. GastrointestEndosc 60:340-346, 2004

8. Silvestri GA, Hoffman BJ, Bhutani MS, et al: Endoscopic ultrasoundwith fine-needle aspiration in the diagnosis and staging of lung cancer.Ann Thorac Surg 61:1441-1445, 1996

9. Wallace MB, Silvestri GA, Sahai AV, et al: Endoscopic ultrasound-guided fine needle aspiration for staging patients with carcinoma of thelung. Ann Thorac Surg 72:1861-1867, 2001

0. Wiersema MJ, Vazquez-Sequeiros E, Wiersema LM: Evaluation of me-diastinal lymphadenopathy with endoscopic US-guided fine-needle as-piration biopsy. Radiology 219:252-257, 2001

1. Williams DB, Sahai AV, Aabakken L, et al: Endoscopic ultrasoundguided fine needle aspiration biopsy: a large single centre experience.Gut 44:720-726, 1999

2. Fernandez-Esparrach G, Gines A, Belda J, et al: Transesophageal ultra-sound-guided fine needle aspiration improves mediastinal staging inpatients with nonsmall cell lung cancer and normal mediastinum oncomputed tomography. Lung Cancer 54:35-40, 2006

3. Leblanc JK, Devereaux BM, Imperiale TF, et al: Endoscopic ultrasoundin non-small cell lung cancer and negative mediastinum on computedtomography. Am J Respir Crit Care Med 171:177-182, 2005

4. Wallace MB, Ravenel J, Block MI, et al: Endoscopic ultrasound in lungcancer patients with a normal mediastinum on computed tomography.Ann Thorac Surg 77:1763-1768, 2004

5. Annema JT, Rabe KF: Lung cancer patients with small nodes on CT:what’s the next step? Endoscopy 38:S77-S80, 2006 (suppl 1)

6. Annema JT, Hoekstra OS, Smit EF, et al: Toward a minimally invasivestaging strategy in NSCLC: analysis of PET positive mediastinal lesionsby EUS-FNA. Lung Cancer 44:53-60, 2004

dicine

EUS EBUS

� � � �� ?� �

� � �� �� �� ?

� � ?

ted; ?, possible future indication, studies are ongoing.

ary Me

7. Eloubeidi MA, Cerfolio RJ, Chen VK, et al: Endoscopic ultrasound-

2

2

3

3

3

3

3

3

3

3

3

3

4

4

4

4

4

4

4

4

4

4

5

5

5

5

5

5

5

5

5

5

Pulmonary interventions 31

guided fine needle aspiration of mediastinal lymph node in patientswith suspected lung cancer after positron emission tomography andcomputed tomography scans. Ann Thorac Surg 79:263-268, 2005

8. Kramer H, van Putten JW, Post WJ, et al: Oesophageal endoscopicultrasound with fine needle aspiration improves and simplifies thestaging of lung cancer. Thorax 59:596-601, 2004

9. Annema JT, Versteegh MI, Veselic M, et al: Endoscopic ultrasoundadded to mediastinoscopy for preoperative staging of patients with lungcancer. JAMA 294:931-936, 2005

0. Eloubeidi MA, Tamhane A, Chen VK, et al: Endoscopic ultrasound-guided fine-needle aspiration in patients with nonsmall cell lung cancerand prior negative mediastinoscopy. Ann Thorac Surg 80:1231-1239,2005

1. Annema JT, Veselic M, Versteegh MI, et al: Mediastinal restaging: EUS-FNA offers a new perspective. Lung Cancer 42:311-318, 2003

2. Varadarajulu S, Eloubeidi M: Can endoscopic ultrasonography-guidedfine-needle aspiration predict response to chemoradiation in nonsmallcell lung cancer? A pilot study. Respiration 73:213-220, 2006

3. Annema JT, Veselic M, Rabe KF: EUS-guided FNA of centrally locatedlung tumours following a nondiagnostic bronchoscopy. Lung Cancer48:357-361, 2005

4. Varadarajulu S, Hoffman BJ, Hawes RH, et al: EUS-guided FNA of lungmasses adjacent to or abutting the esophagus after unrevealing CT-guided biopsy or bronchoscopy. Gastrointest Endosc 60:293-297,2004

5. Varadarajulu S, Schmulewitz N, Wildi SF, et al: Accuracy of EUS instaging of T4 lung cancer. Gastrointest Endosc 59:345-348, 2004

6. Schroder C, Schonhofer B, Vogel B: Transesophageal echographic de-termination of aortic invasion by lung cancer. Chest 127:438-442,2005

7. Fritscher-Ravens A, Sriram PV, Topalidis T, et al: Endoscopic ultra-sonography-guided fine-needle cytodiagnosis of mediastinal metasta-ses from renal cell cancer. Endoscopy 32:531-535, 2000

8. Kramer H, Koeter GH, Sleijfer DT, et al: Endoscopic ultrasound-guidedfine-needle aspiration in patients with mediastinal abnormalities andprevious extrathoracic malignancy. Eur J Cancer 40:559-562, 2004

9. Gilman MJ, Wang KP: Transbronchial lung biopsy in sarcoidosis. Anapproach to determine the optimal number of biopsies. Am Rev RespirDis 122:721-724, 1980

0. Koonitz CH, Joyner LR, Nelson RA: Transbronchial lung biopsy via thefiberoptic bronchoscope in sarcoidosis. Ann Intern Med 85:64-66,1976

1. Annema JT, Veselic M, Rabe KF: Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of sarcoidosis. Eur Respir J 25:405-409, 2005

2. Fritscher-Ravens A, Sriram PV, Topalidis T, et al: Diagnosing sarcoid-osis using endosonography-guided fine-needle aspiration. Chest 118:928-935, 2000

3. Wildi SM, Judson MA, Fraig M, et al: Is endosonography guided fine

needle aspiration (EUS-FNA) for sarcoidosis as good as we think?Thorax 59:794-799, 2004

4. Wang KP, Brower R, Haponik EF, et al: Flexible transbronchial needleaspiration for staging of bronchogenic carcinoma. Chest 84:571-576,1983

5. Holty JE, Kuschner WG, Gould MK: Accuracy of transbronchial needleaspiration for mediastinal staging of nonsmall cell lung cancer: a meta-analysis. Thorax 60:949-955, 2005

6. Smyth CM, Stead RJ: Survey of flexible fibreoptic bronchoscopy in theUnited Kingdom. Eur Respir J 19:458-463, 2002

7. Haponik EF, Shure D: Underutilization of transbronchial needle aspi-ration: experiences of current pulmonary fellows. Chest 112:251-253,1997

8. Wang KP: Continued efforts to improve the sensitivity of transbron-chial needle aspiration. Chest 114:4-5, 1998

9. Herth FJ, Becker HD, Ernst A: Ultrasound-guided transbronchial nee-dle aspiration: an experience in 242 patients. Chest 123:604-607, 2003

0. Herth F, Becker HD, Ernst A: Conventional versus endobronchial ul-trasound-guided transbronchial needle aspiration: a randomized trial.Chest 125:322-325, 2004

1. Krasnik M, Vilmann P, Larsen SS, et al: Preliminary experience with anew method of endoscopic transbronchial real time ultrasound guidedbiopsy for diagnosis of mediastinal and hilar lesions. Thorax 58:1083-1086, 2003

2. Herth FJ, Eberhardt R, Vilmann P, et al: Real-time, endobronchialultrasound-guided, transbronchial needle aspiration: a new method forsampling mediastinal lymph nodes. Thorax 61:795-798, 2006

3. Yasufuku K, Chiyo M, Sekine Y, et al: Real-time endobronchial ultra-sound-guided transbronchial needle aspiration of mediastinal and hilarlymph nodes. Chest 126:122-128, 2004

4. Yasufuku K, Chiyo M, Koh E, et al: Endobronchial ultrasound guidedtransbronchial needle aspiration for staging of lung cancer. Lung Can-cer 50:347-354, 2005

5. Herth FJ, Ernst A, Eberhardt R, et al: Endobronchial ultrasound-guidedtransbronchial needle aspiration of lymph nodes in the radiologicallynormal mediastinum. Eur Respir J 28:910-914, 2006

6. Herth FJ, Lunn W, Eberhardt R, et al: Transbronchial versus trans-esophageal ultrasound-guided aspiration of enlarged mediastinallymph nodes. Am J Respir Crit Care Med 171:1164-1167, 2005

7. Rusch VW: Mediastinoscopy: an endangered species? J Clin Oncol23:8283-8285, 2005

8. Vilmann P, Krasnik M, Larsen SS, et al: Transesophageal endoscopicultrasound-guided fine-needle aspiration (EUS-FNA) and endobron-chial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy: a combined approach in the evaluation of mediastinallesions. Endoscopy 37:833-839, 2005

9. Wildi SM, Fickling WE, Day TA, et al: Endoscopic ultrasonography inthe diagnosis and staging of neoplasms of the head and neck. Endos-

copy 36:624-630, 2004