Asterisk indicates no biopsies of at least lymph node station 4L and
4R and 7.
Annema JT, Versteegh MI, Veseliç M, Welker L, Mauad T, Sont JK, Willems LNA, Rabe KF. Endoscopic Ultrasound Added to Mediastinoscopy for Preoperative Staging
of Patients With Lung Cancer. JAMA. 2005;294(8):931-936. doi:10.1001/jama.294.8.931
Author Affiliations: Divisions of Pulmonary
Medicine (Drs Annema, Mauad, Willems, and Rabe), Cardiothoracic Surgery (Dr
Versteegh), Pathology (Dr Veseliç), and Medical Decision Making (Dr
Sont), Leiden University Medical Center, Leiden, the Netherlands; and Division
of Pulmonary Medicine, Krankenhaus Grosshansdorf, Grosshansdorf, Germany (Dr
Context Up to 40% of thoracotomies performed for non–small cell lung cancer
are unnecessary, predominantly due to inaccurate preoperative detection of
lymph node metastases and mediastinal tumor invasion (T4). Mediastinoscopy
and the novel, minimally invasive technique of transesophageal ultrasound–guided
fine-needle aspiration (EUS-FNA) target different mediastinal lymph node stations.
In addition, EUS can identify tumor invasion in neighboring organs if tumors
are located adjacent to the esophagus.
Objective To investigate the additional value of EUS-FNA to mediastinoscopy in
the preoperative staging of patients with non–small cell lung cancer.
Design, Setting, and Patients Prospective, nonrandomized multicenter trial performed in 1 referral
and 5 general hospitals in the Netherlands. During a 3-year period (2000-2003),
107 consecutive patients with potential resectable non–small cell lung
cancer underwent preoperative staging by both EUS-FNA and mediastinoscopy.
Patients underwent thoracotomy with tumor resection if mediastinoscopy was
negative. Surgical-pathological staging was compared with preoperative findings
and the added benefit of the combined strategy was assessed.
Intervention The EUS-FNA examination was performed as an additional staging test
to mediastinoscopy in all patients.
Main Outcome Measure Detection of mediastinal tumor invasion (T4) and lymph node metastases
(N2/N3) comparing the combined staging by both EUS-FNA and mediastinoscopy
with staging by mediastinoscopy alone.
Results The combination of EUS-FNA and mediastinoscopy identified more patients
with tumor invasion or lymph node metastases (36%; 95% confidence interval
[CI], 27%-46%) compared with either mediastinoscopy alone (20%; 95% CI, 13%-29%)
or EUS-FNA (28%; 95% CI, 19%-38%) alone. This indicated that 16% of thoracotomies
could have been avoided by using EUS-FNA in addition to mediastinoscopy. However,
2% of the EUS-FNA findings were false-positive.
Conclusion These preliminary findings suggest that EUS-FNA, when added to mediastinoscopy,
improves the preoperative staging of lung cancer due to the complementary
reach of EUS-FNA in detecting mediastinal lymph node metastases and the ability
to assess mediastinal tumor invasion.
Up to 40% of thoracotomies performed for non–small cell lung cancer
(NSCLC) are reported to be unnecessary due to imperfect preoperative staging.1,2 Accurate preoperative staging is important
in identifying those patients who will benefit from surgical resection.3,4 Patients with lymph node metastases
(N2/N3) are not considered eligible for surgical resection, except for minimal
N2 disease. All currently available staging techniques, such as computed tomography
(CT) of the thorax, positron emission tomography (PET), transbronchial needle
aspiration, and mediastinoscopy, have limited accuracy in selecting those
lung cancer patients without regional lymph node metastases.5,6
Transesophageal ultrasound–guided fine-needle aspiration (EUS-FNA)
is a minimally invasive and safe technique to sample mediastinal lymph nodes
under real-time conditions and is complementary to mediastinoscopy in its
diagnostic reach.5,7,8 The
EUS-FNA examination has a sensitivity of 88% and a specificity of 91% in analyzing
mediastinal lymph nodes.5,7,8 To
date it is not known how EUS-FNA compares with mediastinoscopy, nor to what
extent the combination of EUS-FNA and mediastinoscopy improves preoperative
Patients with tumors invading the mediastinum, heart, or central vessels
are generally not candidates for surgery. Currently, mediastinal tumor invasion
(T4) is frequently assessed intraoperatively because CT has limited sensitivity
and specificity (<75%) for mediastinal invasion9 and
PET has no value in detecting T4 tumors due to its limited anatomical resolution.
However, in a recent study,10 EUS has demonstrated
a high sensitivity (88%) and specificity (98%) in diagnosing T4 tumors.
In the present prospective study, patients with proven NSCLC who were
candidates for surgical resection were staged by both EUS-FNA and mediastinoscopy.
The EUS-FNA results were used for study purposes only. The primary aim was
to assess whether staging by EUS-FNA in addition to mediastinoscopy improved
preoperative staging compared with staging by mediastinoscopy alone.
Patients with proven NSCLC without signs of distant metastases after
conventional staging and who were scheduled for mediastinoscopy were eligible
for the present study. According to local guidelines, all NSCLC patients who
are surgical candidates are staged by mediastinoscopy regardless of mediastinal
lymph node size on CT scans. Patients were approached by a study physician
and asked to undergo an EUS-FNA examination on a voluntary basis for study
purposes. Candidates for the study were explicitly told that EUS-FNA results
were going to be used for study purposes only and that further treatment decisions
would be based on the results of mediastinoscopy. A single exception was created
in the protocol for patients with an N3 lymph node metastasis confirmed by
EUS-FNA that was not assessed by mediastinoscopy. However, this situation
did not occur once the trial was under way. If the absence of regional lymph
node metastases was confirmed at mediastinoscopy, patients underwent resection
of the lung tumor with complete lymph node dissection. The EUS-FNA examination
was performed separately from mediastinoscopy to assess possible complications
and acquire information about patients’ preference for either staging
technique. The ethical committee of the Leiden University Medical Center (Leiden,
the Netherlands) approved this study. Oral and written informed consent for
study participants was obtained at study entry.
All EUS-FNA examinations were scheduled prior to mediastinoscopy. We
deliberately decided not to randomize the sequence of EUS-FNA and mediastinoscopy
because we wanted to prevent a situation in which all lymph node tissue was
removed by mediastinoscopy, which would prevent EUS-FNA from sampling it.
The EUS-FNA examinations were performed at the Department of Pulmonary Medicine,
Leiden University Medical Center, using a Pentax FG 34 UX echoendoscope (Pentax
GmbH, Hamburg, Germany) with a longitudinal convex ultrasound transducer and
an adjustable ultrasonic frequency of 5, 7.5, or 10 MHz in combination with
a Hitachi EUB 6500 ultrasound scanner (Hitachi Medical Systems Ltd, Reeuwijk,
the Netherlands). The EUS-FNA examination was performed on an outpatient basis
under conscious sedation using 1 to 5 mg of midazolam (intravenously). Lymph
nodes were described, videotaped, and numbered according to the regional lymph
node classification for lung cancer staging.11 Aspiration
of mediastinal lymph nodes was performed under ultrasound guidance from the
esophagus with a 22-gauge needle and vacuum (Hancke/Vilmann type, GIP/Medi-Globe
Inc, Tempe, Ariz). The aspirated material was stained and examined on-site
for adequacy before assessment by an experienced cytopathologist. If the primary
tumor was visible with EUS, the presence or absence of mediastinal tumor invasion
was recorded. Patients were observed for 2 hours after the procedure and were
instructed to contact the hospital if chest or other discomfort occurred.
The EUS-FNA findings were not available to cardiothoracic surgeons.
Cervical mediastinoscopy was considered adequate if it minimally included
biopsies of the left and right lower paratracheal (4L, 4R) and the subcarinal
lymph nodes.7 Pathological examination of resected
mediastinal lymph nodes was performed according to standard procedures (in
lymph nodes <1 cm, sliced once in the midline; in lymph nodes >1 cm, lamination
of the lymph node and staining with hematoxylin-eosin). An experienced pathologist
judged all lymph node biopsies. Surgeons dissected the regional lymph node
stations during thoracotomy.
For both EUS-FNA and mediastinoscopy, microscopic proof of malignancy
was compulsory to stage a lymph node as malignant. For CT, mediastinal lymph
nodes with a short axis (>1 cm) were classified as enlarged. An experienced
radiologist reviewed the CT scans of the chest according to the regional lymph
For CT, the presence or absence of mediastinal tumor invasion was recorded.
Endoscopic ultrasound findings demonstrating tumor invasion to the heart,
large central vessels, or mediastinum equaled tumor stage T4. After both an
EUS-FNA examination and mediastinoscopy, patients’ preference for either
EUS-FNA or mediastinoscopy was assessed by a short questionnaire.
The primary end point of this study was the detection of mediastinal
tumor invasion (T4) or lymph node metastases (N2/N3). The outcomes were reported
as point estimates with 95% confidence intervals (CIs). The reference standard
for the presence or absence of lymph node metastases or tumor invasion was
histological evaluation as performed by both mediastinoscopy and thoracotomy
with lymph node dissection (for those patients in whom no lymph node metastases
were detected by mediastinoscopy) or mediastinoscopy alone (for those patients
with lymph node metastases assessed by mediastinoscopy). In the latter group,
it was judged unethical to verify tumor-positive mediastinoscopic results
by open thoracotomy. We hypothesized that the prevalence of patients with
either mediastinal tumor invasion (T4) or lymph node metastases (N2/N3) was
40% and that mediastinoscopy alone would detect half of these patients (20%).
Due to the complementary reach of EUS-FNA and mediastinoscopy and the fact
that EUS-FNA might assess tumor invasion, we hypothesized that combined staging
by both EUS-FNA and mediastinoscopy would detect 30% of these patients.
For EUS-FNA and mediastinoscopy, separately and in combination, the
sensitivity, specificity, positive predictive value (PPV), negative predictive
value (NPV), and diagnostic accuracy were assessed for the lymph node stations,
which can be reached by either technique as opposed to all existing lymph
node stations. For mediastinoscopy these were stations 2L, 2R, 4L, 4R, and
7 and for EUS-FNA these were stations 3, 4L, 5, 7, 8, and 9. For both CT and
EUS-FNA, the accuracy of mediastinal tumor invasion was assessed. At the end
of the study, to assess interobserver variability quantified by the κ
statistic, CT scans of the chest, lymph node aspirates obtained by EUS-FNA,
and lymph node biopsies obtained by mediastinoscopy were reevaluated by an
independent thoracic radiologist, a cytopathologist, and a pathologist not
involved in the study. All statistical analyses were performed using SPSS
version 12.0 (SPSS Inc, Chicago, Ill).
A total of 108 consecutive patients with proven NSCLC were enrolled
in the study. Eight patients were not evaluable for the primary outcome measure
due to inadequate (n = 4) or cancelled (n = 1) mediastinoscopies,
lack of surgical verification after negative mediastinoscopies due to a proven
distant metastasis (n = 1), a rapidly deteriorating clinical condition
(n = 1), and a treating physician changing his therapeutic strategy
(n = 1) (Figure). Characteristics
of the 100 evaluable patients appear in Table
The combination of EUS-FNA and mediastinoscopy identified more patients
(36%; 95% CI, 27%-46%) with mediastinal tumor invasion (T4) or lymph node
metastases (N2/N3) compared with either mediastinoscopy alone (20%; 95% CI,
13%-29%) or EUS-FNA alone (28%; 95% CI, 19%-38%). The EUS-FNA examination
detected advanced disease in 16% of patients with a negative mediastinoscopy
by assessing lymph node metastases (N2) in 9%, mediastinal tumor invasion
(T4) in 4%, and both mediastinal tumor invasion (T4) and lymph node metastases
(N2) in 3% of patients (Table 2). This
indicated that 16% of thoracotomies could have been avoided by using EUS-FNA
in addition to mediastinoscopy. However, 2% of the EUS-FNA results were false-positive.
The prevalence of lymph node metastases (N2/N3), as assessed after surgery,
in our cohort was 36%. A CT scan of the chest was available with slices of
at least 10 mm and intravenous contrast was used in 87% of patients. Half
of the patients had normal-sized mediastinal lymph nodes. For CT, the sensitivity
of assessing mediastinal lymph node metastases was 69%; specificity, 49%;
PPV, 43%; NPV, 73%; and diagnostic accuracy, 56% (Table 3).
The EUS-FNA examination detected N2 (21%) or N3 (1%) lymph node metastases
in 22 of the 100 patients (Table 2).
In 26 patients, no EUS-guided aspirates of mediastinal lymph node were taken
due to the very small size (<5 mm) or absence of detectable lymph nodes.
Of the 74 patients in whom EUS-guided aspirates of mediastinal lymph nodes
were taken (median number of needle passes: 3; range, 1-7), representative
material was obtained in 66 patients (89%). Patients without detectable nodes
or those with small, sonographic nonsuspicious nodes in which aspirates were
not evaluable also were staged as N0. Of the 36 patients with proven lymph
node metastases (N2/N3), they were located within reach of EUS-FNA in 29 patients
and were confirmed in 22 of these patients. Lymph node metastases that were
missed were located at the stations 4L in 1 patient, 5 in 1 patient, 7 in
4 patients, and 8 in 1 patient. Two subcarinal lymph node metastases assessed
by EUS-FNA were not confirmed by mediastinoscopy and thoracotomy. For EUS-FNA,
the sensitivity of assessing mediastinal lymph nodes was 76%; specificity,
97%; PPV, 92%; NPV, 91%; and diagnostic accuracy, 91% (Table 3). No complications, such as fever, chest pain, or mediastinitis,
occurred during or after EUS-FNA.
Mediastinoscopy detected N2 (17%) or N3 (2%) lymph node metastases in
19 of the 100 patients (Table 2). Of
the 36 patients with lymph node metastases (N2/N3), they were located within
reach of mediastinoscopy in 29 patients and were confirmed in 19 of these
patients. Lymph node metastases that were missed were located at station 4L
in 2 patients and station 7 in 8 patients. In the 10 patients in which mediastinoscopy
was false-negative, biopsy material was obtained from the affected lymph node
station. For mediastinoscopy, the sensitivity of assessing mediastinal lymph
nodes was 66%; specificity, 100%; PPV, 100%; NPV, 88%; and diagnostic accuracy,
90% (Table 3). Six patients reported
hoarseness that occurred immediately after mediastinoscopy.
Lymph node metastases were confirmed in 31 (86%) of 36 patients by either
EUS-FNA or mediastinoscopy (Table 2).
The 5 lymph node metastases that were missed by both techniques were located
at station 4L in 1 patient, 5 in 1 patient, 7 in 2 patients, and 8 in 1 patient.
The combination of EUS-FNA and mediastinoscopy detected more patients with
lymph node metastases (31%; 95% CI, 22%-41%) compared with either mediastinoscopy
alone (19%; 95% CI, 11%-28%) or EUS-FNA alone (22%; 95% CI, 14%-31%). For
the combination of mediastinoscopy and EUS-FNA, the sensitivity of assessing
all regional mediastinal lymph node stations was 86%; specificity, 97%; PPV,
94%; NPV, 93%; and diagnostic accuracy, 93% (Table 3).
The prevalence of mediastinal tumor invasion was 17%. Mediastinal tumor
invasion (T4) was assessed by EUS-FNA in 7 (44%) of the 17 patients based
on invasion in the mediastinum (n = 4), large central vessels (n = 2),
or both (n = 1) (Table 2).
Of the 7 patients with mediastinal tumor invasion (T4) staged by EUS-FNA,
4 were staged T4 by CT as well. The sensitivity of EUS-FNA was 44%; specificity,
100%; PPV, 100%; NPV, 88%; and accuracy, 89%. The sensitivity of CT was 38%;
specificity, 88%; PPV, 38%; NPV, 88%; and accuracy, 79%. One patient was staged
T4 by mediastinoscopy based on tracheal growth of an upper lobe tumor. Previously,
a second bronchoscopy with deep mucosal biopsies did not reveal a tumor.
Because mediastinoscopy yielded positive results in 20% of the patients,
a thoracotomy was performed in 80% of the patients. Of the 80 patients who
underwent thoracotomy (Figure), the
following pathological data were obtained: N2 lymph node metastases in 12
patients (15%); mediastinal tumor invasion (T4) in 8 patients (10%); both
mediastinal tumor invasion (T4) and lymph node metastases (N2) in 3 patients
(3%); both mediastinal tumor invasion (T4) and either small pleural metastases
or satellite nodules in another lobe (M1) in 5 patients (6%); and lymph node
metastases (N2) and either small pleural metastases or satellite nodules in
another lobe (M1) in 2 patients (3%). In 2 patients, the EUS-FNA findings
of lymph node metastases (N2) were not confirmed by surgical-pathological
staging. The pathological staging of the cohort appears in Table 1. Four patients undergoing thoracotomy experienced severe
complications: hypoxia due to cardiac arrest (n = 1), bleeding necessitating
pneumectomy instead of lobectomy (n = 1), bronchopleural fistula
(n = 1), and an irreversible spinal cord paralysis (n = 1).
The interobserver variability in assessing lymph node metastases by
CT yielded a κ of 0.65; for cytology obtained by EUS-FNA, κ =
0.88; and for histology obtained by mediastinoscopy, κ = 1.0. In this
study, 80% of patients preferred EUS-FNA, 10% preferred mediastinoscopy, and
10% had no preference for either technique.
This study demonstrates that preoperative staging by EUS-FNA in addition
to mediastinoscopy identifies more patients with either mediastinal tumor
invasion (T4) or lymph node metastases (N2/N3) compared with staging by mediastinoscopy
alone. The results can be explained by the fact that EUS-FNA and mediastinoscopy
have a complementary reach in assessing regional lymph node stations and in
the ability of EUS-FNA to detect mediastinal tumor invasion. If the EUS-FNA
results had been taken into account in the present study, a thoracotomy could
have been prevented in 1 of 6 patients. Our findings are directly applicable
to clinical practice.
This is the first study, to our knowledge, that prospectively compared
EUS-FNA with mediastinoscopy in the preoperative staging of NSCLC. Additionally,
this is the first study in which positive findings from EUS-FNA were verified
by surgical-pathological findings. New diagnostic tests, such as EUS-FNA,
need to be evaluated against the reference standard to assess their value.
Two patients in this study were overstaged by EUS-FNA because investigators
judged a round, well-defined hypoechoic structure located adjacent to a left
lower lobe tumor as a subcarinal lymph node. Endoscopic ultrasound–guided
biopsies of this structure revealed malignant cells; however, neither mediastinoscopy
nor thoracotomy revealed subcarinal lymph node metastases. In retrospect,
biopsies had been taken from the tumor itself, and the false-positive results
were due to misinterpretation of the EUS-FNA images. We now believe that a
mediastinoscopy should always be performed in patients with lymph nodes located
immediately adjacent to the primary tumor.
Only half of the patients in the present study had enlarged mediastinal
lymph node stations on CT scans. Therefore, it is not surprising that our
sensitivity of 76% in assessing mediastinal lymph nodes by EUS-FNA is a bit
lower than other studies (median, 88%; range, 82%-97%).5,7,8,12,13 This
difference could be explained by the fact that in other studies EUS-FNA was
performed in selected patients with enlarged mediastinal lymph nodes on CT
scans. The prevalence of regional lymph node metastases was around 70% in
a recent review5 compared with the prevalence
of 36% found in this study. We did not select patients on the basis of enlarged
mediastinal lymph nodes, which is a scenario that is in our opinion closer
to clinical reality.
In addition to regional lymph node staging, EUS-FNA identified 7 (44%)
of the 17 patients with T4 tumors invading the mediastinum (n = 4),
large central vessels (n = 2), or both (n = 1). The prevalence
of T4 tumors in the present study was relatively high. With a sensitivity
of 44% and a specificity of 100%, EUS-FNA was more accurate than CT, which
had a sensitivity of only 38% and a specificity of only 88%. The only other
study10 providing data about tumor staging
assessed by EUS reported a sensitivity of 88%; specificity, 98%; PPV, 70%;
and NPV, 99%. However, not all cases of mediastinal tumor invasion (T4) in
that study were verified by surgical-pathological staging.
Surgical-pathological staging is the reference standard for preoperative
lymph node staging. We carefully assessed all mediastinoscopies and excluded
those not performed adequately. The specificity, PPV, NPV, and accuracy of
assessing mediastinal lymph nodes by mediastinoscopy in our study correspond
well with those found in the literature.5,7 However,
the sensitivity of mediastinoscopy in our study (66%) was lower compared with
the pooled sensitivity (81%) of cervical mediastinoscopy reported in a recent
review.5 Although some of these studies reported
sensitivities around 70%, a few large retrospective studies found sensitivities
up to 93%. These data should be judged critically because nothing was mentioned
about the rigidity of lymph node sampling at thoracotomy in the largest study
with 1369 patients and a reported sensitivity of 85%.14 The
key issue is validation of negative mediastinoscopy results. In the other
large study15 of 1259 patients, the reported
sensitivity of 93% for mediastinoscopy was calculated for the superior lymph
nodes only. If we apply that definition to our data, the sensitivity of mediastinoscopy
in our study cohort would increase to 90% because 8 of the 10 missed metastases
were located subcarinally. The dorsal part of lymph node station 7, the most
frequently involved mediastinal station, cannot be reached by mediastinoscopy.14,16 However, due to its position adjacent
to the esophagus, it can be reached by EUS-FNA.
The reported hoarseness, which occurred immediately after mediastinoscopy
in 6% of patients, was possibly due to recurrent nerve paralysis. The morbidity
of mediastinoscopy reported in the literature is 2%.14 The
majority of patients (80%) in our study preferred EUS-FNA compared with mediastinoscopy
because of the absence of general anesthesia and clinical admission.
Some limitations apply to this study. The EUS-FNA examinations were
performed at only 1 academic center with highly experienced clinicians, while
mediastinoscopy and CT were performed at several study sites. The end point
of this study was the assessment of a specific staging end point, the presence
of either mediastinal tumor invasion (T4) or lymph node metastases (N2/N3).
This end point is important because patients with N2/N3 lymph node metastases
(stage IIIA/IIIB) or mediastinal tumor invasion (stage IIIB) are not considered
candidates for surgical resection. The data demonstrate that staging by EUS-FNA
in addition to mediastinoscopy improves preoperative staging significantly.
Although not proven in a randomized design, these data strongly suggest that
additional staging by EUS-FNA reduces unnecessary thoracotomies. The obvious
question that remains is whether the staging of NSCLC by EUS-FNA is another
add-on or a breakthrough in selecting patients for surgical resection.
Staging by EUS-FNA in addition to mediastinoscopy in this study demonstrated
that this combination could have led to the prevention of a thoracotomy in
1 of 6 patients, with an expected impact on patient management comparable
with the addition of PET to mediastinoscopy.2 The
improvement in the preoperative staging due to PET17 and
PET-CT18 has resulted in the recommendation
to use PET in the preoperative workup of NSCLC.3,19 In
the only large comparison study between PET and EUS-FNA, with the identification
of inoperable patients as primary outcome, PET and EUS-FNA had similar sensitivities
(68% and 63%, respectively) and NPVs (64% and 68%, respectively). However,
superior specificity of EUS compared with PET (100% and 72%, respectively)
and a considerably lower expense led researchers in one study20 to
the conclusion that EUS was preferred above PET in preoperative staging to
identify inoperable patients. A new algorithm is needed for mediastinal lymph
node staging in which the place of the following techniques should be defined:
bronchoscopy with transbronchial needle aspiration, endobronchial ultrasound–guided
transbronchial needle aspiration, EUS-FNA, PET, and mediastinoscopy. We advocate
the use of EUS-FNA early in the preoperative staging of NSCLC because EUS-FNA
alone in the present study provided proof of lymph node metastases or mediastinal
tumor invasion in 28% of patients with NSCLC.
Overall, mediastinoscopy and EUS-FNA have inherent limitations and they
should be viewed as complementary in the regional staging of NSCLC. These
preliminary findings suggest that EUS-FNA, a novel, minimally invasive staging
procedure for lung cancer, may improve the preoperative staging due to the
complementary reach of EUS-FNA in detecting mediastinal lymph node metastases
and the ability to assess mediastinal tumor invasion. However, the occurrence
of false-positive EUS-FNA findings in selected cases needs to be further investigated.
Corresponding Author: Jouke T. Annema, MD,
PhD, Department of Pulmonology C3 P, Albinusdreef 2, 2300 RC Leiden University
Medical Center, PO Box 9600, Leiden, the Netherlands (firstname.lastname@example.org).
Author Contributions: Dr Annema had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Annema, Versteegh,
Sont, Willems, Rabe.
Acquisition of data: Annema, Versteegh, Veseliç,
Analysis and interpretation of data: Annema,
Versteegh, Veseliç, Mauad, Sont, Rabe.
Drafting of the manuscript: Annema, Versteegh,
Critical revision of the manuscript for important
intellectual content: Annema, Versteegh, Veseliç, Welker, Sont,
Statistical analysis: Annema, Sont.
Obtained funding: Annema, Rabe.
Administrative, technical, or material support:
Annema, Versteegh, Veseliç, Welker, Mauad, Willems, Rabe.
Study supervision: Rabe.
Financial Disclosures: None reported.
Funding/Support: The research for this article
was supported by a grant from the Leiden University Medical Center. Hitachi
Ultrasound (Reeuwijk, the Netherlands) provided the ultrasound scanner and
echoendoscope on a loan basis.
Role of the Sponsor: The Leiden University
Medical Center had no influence on the design, conduct of the study, or the
IKW Oncology Study Group: E. H. Bel, MD, PhD;
J. J. Brahim, MD; H. Codrington, MD; H. Dik, MD; J. Kersbergen, MD; H. C.
J. van Klink, MD; K. W. Kralingen, MD, PhD; P. Marton, MD; B. Roldaan, MD,
PhD; H. Schreur, MD, PhD; B. Slotema, MD; J. Stolk, MD, PhD; A. Ten Brinke,
MD, PhD; H. P. A. A. van Veen, MD; and T. Wever, MD.
Previous Presentations: Presented in part at
the 97th International Conference of the American Thoracic Society, San Francisco,
Calif, May 22, 2001; 10th World Conference on Lung Cancer, Vancouver, British
Columbia, August 12, 2003; and 100th International Conference of the American
Thoracic Society Conference, Orlando, Fla, May 24, 2004.
Acknowledgment:We thank E. Joekes, MD, and
J. Tjon a Ling, MD (Division of Radiology, Leiden University Medical Center),
for scoring computed tomographic scans; D. Grootendorst, PhD, and F. Rosendaal,
PhD (Division of Clinical Epidemiology, Leiden University Medical Center),
for advice on statistical analyses; and A. van der Mey and W. J. Oudshoorn
(Division of Pulmonary Medicine, Leiden University Medical Center) for computing
and logistical assistance. Drs Joekes and Tjon a Ling received a fee of €900
for their contributions. No compensation was given to Drs Grootendorst and
Rosendaal or to van der Mey and W. J. Oudshoorn.