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Journal ArticleDOI

Five-Year Survival After Endosonography vs Mediastinoscopy for Mediastinal Nodal Staging of Lung Cancer

13 Sep 2016-JAMA (American Medical Association)-Vol. 316, Iss: 10, pp 1110-1112

TL;DR: If mediastinal staging is improved, more patients should receive optimal treatment and might survive longer and the current post hoc analysis evaluated survival in ASTER.
Abstract: Five-Year Survival After Endosonography vs Mediastinoscopy for Mediastinal Nodal Staging of Lung Cancer Lung cancer accounts for the highest cancer-related mortality rate worldwide.1 Accurate mediastinal nodal staging is crucial in the management of non–small cell lung cancer (NSCLC) because it directs therapy and has prognostic value.2,3 The Assessment of Surgical Staging vs Endosonographic Ultrasound in Lung Cancer (ASTER) trial compared mediastinoscopy (surgical staging) with an endosonographic staging strategy (which combined the use of endobronchial and transesophageal ultrasound followed by mediastinoscopy if negative).4 The endosonographic strategy was significantly more sensitive for diagnosing mediastinal nodal metastases than surgical staging (94% endosonographic strategy vs 79% surgical strategy). If mediastinal staging is improved, more patients should receive optimal treatment and might survive longer. The current post hoc analysis evaluated survival in ASTER.
Topics: Mediastinoscopy (73%), Lung cancer (54%), Endoscopic ultrasound (53%), Mediastinum (51%)

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Copyright 2016 American Medical Association. All rights reserved.
Letters
RESEARCH LETTER
Five-Year Survival After Endosonography
vs Mediastinoscopy for Mediastinal Nodal Staging
of Lung Cancer
Lung cancer accounts for the highest cancer-related mortal-
ity rate worldwide.
1
Accurate mediastinal nodal staging is cru-
cial in the management of non–small cell lung cancer (NSCLC)
because it directs therapy and has prognostic value.
2,3
The Assessment of Surgical Staging vs Endosonographic
Ultrasound in Lung Cancer (ASTER) trial compared mediasti-
noscopy (surgical staging) with an endosonographic staging
strategy (which combined the use of endobronchial and trans-
esophageal ultrasound fol-
lowed by mediastinoscopy if
negative).
4
The endosono-
graphic strategy was signifi-
cantly more sensitive for diagnosing mediastinal nodal me-
tastases than surgical staging (94% endosonographic strategy
vs 79% surgical strategy).
If mediastinal staging is improved, more patients should
receive optimal treatment and might survive longer. The cur-
rent post hoc analysis evaluated survival in ASTER.
Methods | At inclusion in ASTER, all participants provided
written informed consent; the current analysis was either
approved or waived by the involved ethical committees. Of
241 patients with potentially resectable NSCLC, 123 were ran-
domized to endosonographic staging and 118 to surgical stag-
ing in 4 tertiary referral centers in Leiden (the Netherlands),
Ghent and Leuven (Belgium), and Cambridge (United
Kingdom) between February 2007 and April 2009.
4
Surgical-
pathological staging was the reference standard for mediasti-
nal nodal assessment.
Between June 30, 2015, and October 15, 2015, survival
data were obtained through patient records, death registers,
or contact with general practitioners (trial protocol in the
Supplement).
The proportion of survivors at 5 years for both staging
strategies and odds ratios (ORs) with 95% CIs were calcu-
lated. Kaplan-Meier analysis was performed and hazard
ratios were calculated to compare survival between the strat-
egies, adjusting for mediastinal nodal metastases in a Cox
proportional hazards model. Survival for patients with no
date of death were censored on the date last known to be
alive. The assumption of proportional hazard was tested and
met. Subgroup analysis was performed for patients with
nodal stages N2/N3 and N0/N1. Data were analyzed using
SPSS Statistics (IBM), version 22.0.
Results | Survival data at 5 years were obtained for 237 of 241 pa-
tients (98%); 2 patients in both groups were lost to follow-up.
There were 182 men (77%) with a mean age at randomization
of 65 years (SD, 9). Detailed patient characteristics were previ-
ously reported.
4
The prevalence of mediastinal nodal metasta-
ses was 54% in the endosonographic strategy group and 44%
in the surgical strategy group.
Survival at 5 years was 35% (42 of 121 patients) for the
endosonographic strategy vs 35% (41 of 116 patients) for the
surgical strategy (OR, 0.97 [95% CI, 0.57-1.66]) (Table). The
estimated median survival was 31 months (95% CI, 21-41)
for the endosonographic strategy vs 33 months (95% CI,
23-43) for the surgical strategy (adjusted hazard ratio, 0.98
[95% CI, 0.73-1.32]) (Figure).
In the subgroup with N2/N3 metastases, survival was
17% (11 of 64 patients) in the endosonographic strategy vs
19% (10 of 52 patients) in the surgical strategy (OR, 0.87
[95% CI, 0.34-2.25]). In the subgroup with N0/N1 metasta-
ses, survival was 54% (31 of 57 patients) for the endosono-
Supplemental content at
jama.com
Table. Survival Among Patients With Lung Cancer in the
Endosonographic vs the Surgical (Mediastinoscopy) Staging Strategies
a
Survival at 5 Years
No./Total No. (%) Odds Ratio (95% CI)
Overall
Endosonographic
staging
42/121 (35)
0.97 (0.57-1.66)
Surgical staging 41/116 (35)
N2/N3
Endosonographic
staging
11/64 (17) 0.87 (0.34-2.25)
Surgical staging 10/52 (19)
N0/N1
Endosonographic
staging
31/57 (54)
1.27 (0.62-2.60)
Surgical staging 31/64 (48)
Estimated Survival
Duration,
Median (95% CI), mo
Unadjusted Mortality,
Hazard Ratio
(95% CI)
b
Overall
Endosonographic
staging
31 (21-41)
1.04 (0.77-1.40)
Surgical staging 33 (23-43)
N2/N3
Endosonographic
staging
21 (15-27)
1.04 (0.70-1.55)
Surgical staging 22 (15-27)
N0/N1
Endosonographic
staging
72 (38-106)
0.91 (0.57-1.44)
Surgical staging 57 (30-84)
a
The endosonographic staging strategy combined the use of endobronchial
and transesophageal ultrasound, followed by mediastinoscopy if negative.
b
Adjusted for mediastinal nodal metastases status (N0/1 vs N2/3), the mortality
hazard ratio was 0.98 (95% CI, 0.73-1.32).
1110 JAMA September 13, 2016 Volume 316, Number 10 (Reprinted) jama.com
Copyright 2016 American Medical Association. All rights reserved.
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graphic strategy vs 48% (31 of 64 patients) for the surgical
strategy (OR, 1.27 [95% CI, 0.62-2.60]).
Discussion | No survival difference was found 5 years follow-
ing randomization to an endosonographic or surgical stag-
ing strategy for patients with NSCLC. Since the original
results of ASTER were published, clinical guidelines on lung
cancer management underwent major revisions and now
advocate endosonography instead of mediastinoscopy as
the initial step for mediastinal nodal staging.
2,3
The endo-
sonographic strategy is more accurate, less invasive, and
reduces unnecessary thoracotomies.
4
Data from a recent randomized trial show prolonged
survival in patients who underwent endosonography com-
pared with conventional staging.
5
However, most patients
in the latter group underwent bronchoscopy instead of
mediastinoscopy.
Why did improved mediastinal staging not lead to
improved survival? Missing data occurred in less than 2%
and therefore are an unlikely source of bias. However,
ASTER was powered to detect a difference in diagnostic sen-
sitivity, not survival, as reflected by the wide confidence
intervals. If a survival difference between the strategies
exists, it is likely to be small and a larger sample size may be
needed to detect it. However, randomized trials to detect a
survival difference based on staging strategy are not likely
to be conducted as the endosonographic strategy is now
advised in clinical guidelines.
2,3
Jolanda C. Kuijvenhoven, MD
Daniël A. Korevaar, MD
Kurt G. Tournoy, MD, PhD
Thomas L. A. Malfait, MD
Christophe Dooms, MD, PhD
Robert C. Rintoul, FRCP, PhD
Jouke T. Annema, MD, PhD
Author Affiliations: Depar tment of Respiratory Medicine, Academic Medical
Center, Amsterdam, the Netherlands (Kuijvenhoven, Annema); Department of
Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical
Center, Amsterdam, the Netherlands (Korevaar); Department of Respiratory
Medicine, Onze-Lieve-Vrouw Hospital, Aalst, Belgium (Tournoy); Department of
Respiratory Medicine, University Hospital Ghent, Ghent, Belgium (Malfait);
Department of Respiratory Medicine, Leuven University Hospitals, Leuven,
Belgium (Dooms); Papworth Clinical Trials Unit Collaboration, Papworth
Hospital, Cambridge, United Kingdom (Rintoul).
Corresponding Author: Jouke T. Annema, MD, PhD, Department of Respiratory
Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam,
the Netherlands (j.t.annema@amc.uva.nl).
Author Contributions: Dr Kuijvenhoven 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.
Concept and design: Kuijvenhoven, Tournoy, Annema.
Acquisition, analysis, or interpretation of data: All Authors.
Drafting of the manuscript: Kuijvenhoven, Korevaar, Tournoy, Annema.
Critical revision of the manuscript for important intellectual content: Tournoy,
Malfait, Dooms, Rintoul, Annema.
Statistical analysis: Kuijvenhoven, Korevaar, Tournoy.
Administrative, technical, or material support: Malfait.
Study supervision: Tournoy, Annema.
No additional contributions: Dooms, Rintoul.
Conflict of Interest Disclosures: All authors have completed and submitted the
ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Annema reports
receiving material and financial support for educational endobronchial and
esophageal ultrasound courses from Hitachi, Pentax, COOK and Symbionix to the
department of respiratory medicine at his institution. Dr Rintoul reports receiving
financial support for educational endobronchial and esophageal ultrasound
courses from Olympus to his institution. No other disclosures were reported.
Funding/Support: The ASTER trial was supported by local support for data
collection at Ghent University Hospital, the Zorgprogramma Oncologie Gent,
and by the National Institute for Health Research Cambridge Biomedical
Research Centre (Dr Rintoul). Data collection in Papworth Hospital was
supported by the UK National Health Service R&D Health Technology
Assessment Program (project No. 06/302/216). No specific funding
was sought for this post hoc analysis.
Role of the Funder/Sponsor: The funders of the original ASTER trial had no role
in the design and conduct of this post hoc analysis; collection, management,
analysis, and interpretation of the data; preparation, review, or approval of the
manuscript; and decision to submit the manuscript for publication.
Trial Registration: clinicaltrials.gov Identifier: NCT00432640
1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer
statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108.
2. Vilmann P, Clementsen PF, Colella S, et al. Combined endobronchial and
oesophageal endosonography for the diagnosis and staging of lung cancer. Eur
Respir J. 2015;46(1):40-60.
Figure. Survival Among Patients With Lung Cancer in the Endosonographic vs Surgical Staging Strategies
1.0
0.8
0.6
0.4
0.2
0
0
118
121
100
1
0
Cumulative Survival
Months After Randomization
No. at risk
Surgical staging
Endosonographic staging
60
40
41
80
23
22
40
52
52
20
77
76
Surgical staging
Endosonographic staging
Adjusted for mediastinal nodal
metastases status (N0/N1
vs N2/N3) (adjusted hazard ratio,
0.98 [95% CI, 0.73-1.32]).
The median duration of follow-up
was 33 months (interquartile range
[IQR], 13-76) for surgical staging
and 31 months (IQR, 13-75) for
endosonographic staging.
Letters
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Copyright 2016 American Medical Association. All rights reserved.
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3. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell
lung cancer. Chest. 2013;143(5 suppl):e211S-250S.
4. Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs
endosonography for mediastinal nodal staging of lung cancer. JAMA. 2010;304
(20):2245-2252.
5. Navani N, Nankivell M, Lawrence DR, et al. Lung cancer diagnosis
and staging with endobronchial ultrasound-guided transbronchial needle
aspiration compared with conventional approaches. Lancet Respir Med. 2015;3
(4):282-289.
COMMENT & RESPONSE
Sodium Excretion, Cardiovascular Disease,
and Chronic Kidney Disease
To the Editor In the study by Mills and colleagues,
1
high uri-
nary sodium excretion was associated with increased car-
diovascular disease (CVD) risk in patients with chronic kid-
ney disease (CKD). Patients were divided into 4 groups
based on quartiles of calibrated urinary sodium excretion
(<2894 mg/24 hours; 2894-3649 mg/24 hours; 3650-4547
mg/24 hours; and ≥4548 mg/24 hours) and were followed
up for a median of 6.8 years. The cumulative incidence of
CVD for each group from lowest to highest urinary sodium
excretion was 18.4%, 16.5%, 20.6%, and 29.8%, respec-
tively. After multivariable adjustment, no significant asso-
ciation was found between urinary potassium excretion and
CVD events.
The authors did not mention whether there was an
interaction between sodium and potassium excretion for
the composite outcome measure.
2
A urinary sodium to
potassium excretion ratio might yield a different association
with CVD risk.
3
Also, they did not evaluate CVD mortality risk in their
study. In a study of patients with established CVD or diabe-
tes mellitus, O’Donnell and colleagues
2
found an increased
risk of CVD with urinary sodium excretion of more than
7000 mg/24 hours and, surprisingly, an increased risk of
cardiovascular mortality at urinary sodium excretion of less
than 3000 mg/24 hours. Additionally, higher urinary potas-
sium excretion rates were associated with a decreased risk
of stroke. Although Mills and colleagues did not evaluate
cardiovascular mortality and their study population was dif-
ferent from the patients in the study by O’Donnell and col-
leagues, the results of increasing CVD risk with higher
sodium excretion are similar. Further studies are needed
before using these findings in the management of such
patients.
Mehmet Hursitoglu, MD
Author Affiliation: Department of Internal Medicine, Bakirkoy Dr Sadi Konuk
Training and Research Hospital, Istanbul, Turkey.
Corresponding Author: Mehmet Hursitoglu, MD, Department of Internal
Medicine, Bakirkoy Dr Sadi Konuk Training and Research Hospital, Bakirkoy,
Istanbul 34100, Turkey (hursitoglum@yahoo.com).
Conflict of Interest Disclosures: The author has completed and submitted the
ICMJE Form for Disclosure of Potential Conflicts of Interest and none were
reported.
1. Mills KT, Chen J, Yang W, et al; Chronic Renal Insufficiency Cohort (CRIC)
Study Investigators. Sodium excretion and the risk of cardiovascular disease in
patients with chronic kidney disease. JAMA. 2016;315(20):2200-2210.
2. O’Donnell MJ, Yusuf S, Mente A, et al. Urinary sodium and potassium
excretion and risk of cardiovascular events. JAMA. 2011;306(20):2229-2238.
3. Hedayati SS, Minhajuddin AT, Ijaz A, et al. Association of urinary
sodium/potassium ratio with blood pressure: sex and racial differences. Clin J
Am Soc Nephrol. 2012;7(2):315-322.
To the Editor Mills and colleagues
1
found that among patients
with CKD, higher urinary sodium excretion was associated with
increased risk of CVD. Analyses were adjusted for important
covariates for CVD. In all the models, a significantly in-
creased risk of CVD was documented in patients with the high-
est quartile of sodium excretion.
One of the variables that was not included in the statisti-
cal analysis was urinary protein excretion. In Table 1 in the
article, where the characteristics of patients were described,
urinary protein excretion was correlated with urinary sodium
excretion. This correlation has been described previously by
the same group in the same cohort of patients.
2
It is widely accepted that urinary albumin excretion is an
independent predictor of cardiovascular morbidity and mor-
tality in patients with CKD and in the general population.
3,4
Therefore, considering the interaction between urinary
sodium excretion and proteinuria, urinary protein excretion
should be included in the statistical analysis.
Jaume Almirall, MD
Author Affiliation: Department of Nephrology, Parc Tauli Sabadell, Hospital
Universitari, Barcelona, Spain.
Corresponding Author: Jaume Almirall, MD, Nephrology Department ,
Parc Tauli Sabadell, Hospital Universitari, Sabadell, Barcelona 08208, Spain
(jalmirall@tauli.cat).
Conflict of Interest Disclosures: The author has completed and submitted the
ICMJE Form for Disclosure of Potential Conflicts of Interest and none were
reported.
1. Mills KT, Chen J, Yang W, et al; Chronic Renal Insufficiency Cohort (CRIC)
Study Investigators. Sodium excretion and the risk of cardiovascular disease in
patients with chronic kidney disease. JAMA. 2016;315(20):2200-2210.
2. Weir MR, Townsend RR, Fink JC, et al. Urinary sodium is a potent correlate of
proteinuria: lessons from the chronic renal insufficiency cohort study. Am J
Nephrol. 2012;36(5):397-404.
3. Hemmelgarn BR, Manns BJ, Lloyd A, et al; Alberta Kidney Disease Network.
Relation between kidney function, proteinuria, and adverse outcomes. JAMA.
2010;303(5):423-429.
4. Hillege HL, Fidler V, Diercks GF, et al; Prevention of Renal and Vascular End
Stage Disease (PREVEND) Study Group. Urinary albumin excretion predicts
cardiovascular and noncardiovascular mortality in general population. Circulation.
2002;106(14):1777-1782.
In Reply In response to Dr Hursitoglu, we found that the uri-
nary sodium to potassium excretion ratio was not signifi-
cantly associated with CVD in our study (P for trend = .11).
This is likely due to the lack of an inverse association
between urinary potassium and CVD among patients with
CKD. We additionally adjusted for urinary potassium excre-
tion in a multivariable model and the results were not sig-
nificantly changed (Table).
We have previously reported that urinary sodium excre-
tion was positively and significantly associated with all-
cause mortality in patients with CKD.
1
However, cause-
specific mortality data are not yet available in our study.
Letters
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Copyright 2016 American Medical Association. All rights reserved.
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Citations
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Journal ArticleDOI
TL;DR: It is hypothesized that omitting mediastinoscopy after negative endosonography in mediastinal staging of NSCLC does not result in an unacceptable percentage of unforeseen N2 disease at surgical resection, and may be associated with lower morbidity and comparable survival.
Abstract: In case of suspicious lymph nodes on computed tomography (CT) or fluorodeoxyglucose positron emission tomography (FDG-PET), advanced tumour size or central tumour location in patients with suspected non-small cell lung cancer (NSCLC), Dutch and European guidelines recommend mediastinal staging by endosonography (endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS)) with sampling of mediastinal lymph nodes. If biopsy results from endosonography turn out negative, additional surgical staging of the mediastinum by mediastinoscopy is advised to prevent unnecessary lung resection due to false negative endosonography findings. We hypothesize that omitting mediastinoscopy after negative endosonography in mediastinal staging of NSCLC does not result in an unacceptable percentage of unforeseen N2 disease at surgical resection. In addition, omitting mediastinoscopy comprises no extra waiting time until definite surgery, omits one extra general anaesthesia and hospital admission, and may be associated with lower morbidity and comparable survival. Therefore, this strategy may reduce health care costs and increase quality of life. The aim of this study is to compare the cost-effectiveness and cost-utility of mediastinal staging strategies including and excluding mediastinoscopy. This study is a multicenter parallel randomized non-inferiority trial comparing two diagnostic strategies (with or without mediastinoscopy) for mediastinal staging in 360 patients with suspected resectable NSCLC. Patients are eligible for inclusion when they underwent systematic endosonography to evaluate mediastinal lymph nodes including tissue sampling with negative endosonography results. Patients will not be eligible for inclusion when PET/CT demonstrates ‘bulky N2-N3’ disease or the combination of a highly suspicious as well as irresectable mediastinal lymph node. Primary outcome measure for non-inferiority is the proportion of patients with unforeseen N2 disease at surgery. Secondary outcome measures are hospitalization, morbidity, overall 2-year survival, quality of life, cost-effectiveness and cost-utility. Patients will be followed up 2 years after start of treatment. Results of the MEDIASTrial will have immediate impact on national and international guidelines, which are accessible to public, possibly reducing mediastinoscopy as a commonly performed invasive procedure for NSCLC staging and diminishing variation in clinical practice. The trial is registered at the Netherlands Trial Register on July 6th, 2017 ( NTR 6528 ).

30 citations


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TL;DR: EBUS-TBNA is more cost-effective than Med and it is currently recommended as the test of first choice for invasive mediastinal LN staging in lung cancer.
Abstract: This review provides an update on the current role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and mediastinoscopy (Med) in assessment of patients with non-small cell lung cancer (NSCLC). Invasive mediastinal lymph node (LN) staging is the major application for both of these techniques. Up until recently, Med was the gold standard for invasive mediastinal LN staging in NSCLC. However, EBUS-TBNA has shown to be equivalent, and in some studies better than Med for invasive staging of lung cancer. EBUS-TBNA offers access to N1 LNs and development of the thin convex probe EBUS (TCP-EBUS) will expand EBUS-TBNA access from the paratracheal region and central airways to more distal parabronchial regions allowing for more extensive N1 LN assessment and sampling more distal lung tumors. EBUS-TBNA is more cost-effective than Med and it is currently recommended as the test of first choice for invasive mediastinal LN staging in lung cancer. Confirmatory Med should be performed selectively in patients with high pretest probability of metastatic disease. Addition of esophageal ultrasound fine needle aspiration (EUS-FNA) may increase diagnostic yield of EBUS-TBNA mediastinal staging. Both Med and EBUS-TBNA can be used in primary lung cancer diagnosis, restaging of the mediastinum following neoadjuvant therapy and in diagnosis of lung cancer recurrence. In the future, a combination of EBUS-TBNA with or without EUS-FNA and Med is most likely going to provide the most optimal invasive assessment of the mediastinum in patients with lung cancer. The decision on test choice and sequence should be made on a case-by-case basis and factoring in local resources and expertise.

25 citations


Journal ArticleDOI
TL;DR: The latest findings regarding the benefits of EBUS are outlined in this review, which is the first to emphasise the impact of the procedure, both on timing and costs of lung cancer staging, as well as on survival.
Abstract: The use of endobronchial ultrasound trans-bronchial needle aspiration (EBUS-TBNA) as the initial diagnostic and staging procedure in patients with suspected, non-metastatic lung cancer has gained substantial support, and is now recommended by numerous guidelines. Whereas considerable attention has been pointed to the reductions in costs achieved by EBUS-TBNA, that has not been the case for some of its more significant benefits, namely the reduction of the diagnostic work-up time and its ability to accurately assess and restage lymph nodes, which were previously stated incorrectly by CT or PET scan. Both these benefits translate into improved outcomes for patients, as delays are reduced, futile surgeries are prevented and curable operations can be performed on patients previously excluded by CT or PET scan. Indeed, the use of EBUS as the initial diagnostic and staging procedure has been proven to significantly increase survival, compared with conventional diagnostic and staging procedures, in a pragmatic, randomised controlled trial (Navani N. et al, 2015). The instalment of EBUS will have the greatest effect on overwhelmed, suboptimally functioning national healthcare systems, by decreasing the number of required diagnostic and staging procedures, therefore reducing both treatment delays and costs. The improved selection of surgical candidates by EBUS will result in improved patient outcomes. The latest findings regarding the benefits of EBUS are outlined in this review, which, to the best of our knowledge, is the first to emphasise the impact of the procedure, both on timing and costs of lung cancer staging, as well as on survival.

15 citations


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TL;DR: The rate of unforeseen N2 disease after negative endosonography findings was similar in patients undergoing immediate lung tumor resection to those undergoing confirmatory mediastinoscopy first, at the cost of 6.0% rate of complications by mediastinescopy.
Abstract: Introduction Confirmatory mediastinoscopy after negative endosonography findings is advised by the guidelines on patients with resectable NSCLC and suspected intrathoracic nodes on fludeoxyglucose F 18 positron emission tomography–computed tomography. Its role however is under debate owing to its limited nodal metastasis detection rate, morbidity, associated treatment delay, and unknown impact on survival. Methods Systematic review and meta-analysis of studies on invasive mediastinal staging in patients with (suspected) NSCLC. The Medline, Embase, and Cochrane databases were searched until September 19, 2018, without year or language restrictions. The Quality Assessment Tool for Diagnostic Accuracy Studies, version 2, was used to evaluate the risk of bias and applicability of the included studies. Rates of unforeseen N2 disease were assessed for endobronchial ultrasound and/or endoscopic ultrasound staging strategies with or without confirmatory mediastinoscopy. Additionally, the complication rates of cervical video mediastinoscopy for mediastinal staging of NSCLC were investigated. Results A total of 5073 articles were found, of which 42 studies or subgroups (covering a total of 3248 patients undergoing the surgical reference standard of treatment) were considered in the analysis. Random effects meta-analysis of endosonography with or without confirmatory mediastinoscopy showed rates of unforeseen N2 disease of 9.6% (95% confidence interval [CI]: 7.8%–11.7%, I2 = 30%) versus 9.9% (95% CI: 6.3%–15.2%, I2 = 73%), respectively. Random effects meta-analysis of mediastinoscopy (eight studies [1245 patients in total]) showed a complication rate of 6.0% (95% CI: 4.8%–7.5%), with laryngeal recurrent nerve palsy accounting for 2.8% (95% CI: 2.0%–4.0%). Conclusion The rate of unforeseen N2 disease after negative endosonography findings was similar in patients undergoing immediate lung tumor resection to those undergoing confirmatory mediastinoscopy first, at the cost of 6.0% rate of complications by mediastinoscopy.

13 citations


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TL;DR: Transvascular endosonographic-guided biopsy is an important adjunct to conventional endoscopic techniques and allows the thoracic endoscopist to obtain biopsy specimens from intrathoracic lesions that are not accessible without vascular puncture.
Abstract: Background Endoscopic ultrasound–guided biopsy techniques, including endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound–guided fine-needle aspiration (EUS-FNA), are currently the standard of care for the assessment of mediastinal lymphadenopathy. Traditionally, passing the needle through and through vascular structures has been avoided owing to the risk of bleeding. In this study, we evaluated the safety and diagnostic accuracy of transvascular endosonographic-guided biopsies of mediastinal, hilar and lung lesions. Our hypothesis is that the approach is safe and adds to the endoscopic armamentarium, avoiding the need for surgical biopsy in specifically selected cases. Methods One hundred patients who underwent transvascular EBUS- or EUS-guided biopsy between 2012 and 2018 were identified from a prospective interventional endoscopy database. Results Biopsy was performed under EUS guidance in 65 patients and under EBUS guidance in 35 patients. The most frequent targets were the mediastinum (60 patients), lung (21 patients), and hilar lymph nodes (16 patients). The aorta was the vessel most commonly traversed (n = 57), followed by the pulmonary artery (n = 33). A median of 2 passes were performed per target (range, 1-5). The samples were adequate to make a diagnosis in 80 patients, and the endoscopic diagnosis was a malignancy in 62 patients. The overall sensitivity was 71.5%, and the accuracy was 74.5%. There were no observed intraoperative or immediate postoperative complications. A delayed complication, aortic pseudoaneurysm, was observed in 1 patient. Follow-up was completed in 84 patients, with a median duration of 12.3 ± 18 months. Conclusions Transvascular endosonographic-guided biopsy is an important adjunct to conventional endoscopic techniques and allows the thoracic endoscopist to obtain biopsy specimens from intrathoracic lesions that are not accessible without vascular puncture.

12 citations


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Journal ArticleDOI
TL;DR: A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests.
Abstract: Cancer constitutes an enormous burden on society in more and less economically developed countries alike. The occurrence of cancer is increasing because of the growth and aging of the population, as well as an increasing prevalence of established risk factors such as smoking, overweight, physical inactivity, and changing reproductive patterns associated with urbanization and economic development. Based on GLOBOCAN estimates, about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. Over the years, the burden has shifted to less developed countries, which currently account for about 57% of cases and 65% of cancer deaths worldwide. Lung cancer is the leading cause of cancer death among males in both more and less developed countries, and has surpassed breast cancer as the leading cause of cancer death among females in more developed countries; breast cancer remains the leading cause of cancer death among females in less developed countries. Other leading causes of cancer death in more developed countries include colorectal cancer among males and females and prostate cancer among males. In less developed countries, liver and stomach cancer among males and cervical cancer among females are also leading causes of cancer death. Although incidence rates for all cancers combined are nearly twice as high in more developed than in less developed countries in both males and females, mortality rates are only 8% to 15% higher in more developed countries. This disparity reflects regional differences in the mix of cancers, which is affected by risk factors and detection practices, and/or the availability of treatment. Risk factors associated with the leading causes of cancer death include tobacco use (lung, colorectal, stomach, and liver cancer), overweight/obesity and physical inactivity (breast and colorectal cancer), and infection (liver, stomach, and cervical cancer). A substantial portion of cancer cases and deaths could be prevented by broadly applying effective prevention measures, such as tobacco control, vaccination, and the use of early detection tests.

21,062 citations


Journal ArticleDOI
TL;DR: Urinary albumin excretion is a predictor of all-cause mortality in the general population and the excess risk was more attributable to death from CV causes, independent of the effects of other CV risk factors.
Abstract: Background— For the general population, the clinical relevance of an increased urinary albumin excretion rate is still debated. Therefore, we examined the relationship between urinary albumin excretion and all-cause mortality and mortality caused by cardiovascular (CV) disease and non-CV disease in the general population. Methods and Results— In the period 1997 to 1998, all inhabitants of the city of Groningen, the Netherlands, aged between 28 and 75 years (n=85 421) were sent a postal questionnaire collecting information about risk factors for CV disease and CV morbidity and a vial to collect an early morning urine sample for measurement of urinary albumin concentration (UAC). The vital status of the cohort was subsequently obtained from the municipal register, and the cause of death was obtained from the Central Bureau of Statistics. Of these 85 421 subjects, 40 856 (47.8%) responded, and 40 548 could be included in the analysis. During a median follow-up period of 961 days (maximum 1139 days), 516 deat...

1,470 citations


Journal ArticleDOI
01 May 2013-Chest
TL;DR: It is demonstrated that PET scanning is more accurate than CT scanning, but tissue biopsy is still required to confirm PET scan findings, and evidence suggests that more complete staging improves patient outcomes.
Abstract: Background Correctly staging lung cancer is important because the treatment options and prognosis differ significantly by stage. Several noninvasive imaging studies and invasive tests are available. Understanding the accuracy, advantages, and disadvantages of the available methods for staging non-small cell lung cancer is critical to decision-making. Methods Test accuracies for the available staging studies were updated from the second iteration of the American College of Chest Physicians Lung Cancer Guidelines. Systematic searches of the MEDLINE database were performed up to June 2012 with the inclusion of selected meta-analyses, practice guidelines, and reviews. Study designs and results are summarized in evidence tables. Results The sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis were approximately 55% and 81%, respectively, confirming that CT scanning has limited ability either to rule in or exclude mediastinal metastasis. For PET scanning, estimates of sensitivity and specificity for identifying mediastinal metastasis were approximately 77% and 86%, respectively. These findings demonstrate that PET scanning is more accurate than CT scanning, but tissue biopsy is still required to confirm PET scan findings. The needle techniques endobronchial ultrasound-needle aspiration, endoscopic ultrasound-needle aspiration, and combined endobronchial ultrasound/endoscopic ultrasound-needle aspiration have sensitivities of approximately 89%, 89%, and 91%, respectively. In direct comparison with surgical staging, needle techniques have emerged as the best first diagnostic tools to obtain tissue. Based on randomized controlled trials, PET or PET-CT scanning is recommended for staging and to detect unsuspected metastatic disease and avoid noncurative resections. Conclusions Since the last iteration of the staging guidelines, PET scanning has assumed a more prominent role both in its use prior to surgery and when evaluating for metastatic disease. Minimally invasive needle techniques to stage the mediastinum have become increasingly accepted and are the tests of first choice to confirm mediastinal disease in accessible lymph node stations. If negative, these needle techniques should be followed by surgical biopsy. All abnormal scans should be confirmed by tissue biopsy (by whatever method is available) to ensure accurate staging. Evidence suggests that more complete staging improves patient outcomes.

945 citations


Journal ArticleDOI
03 Feb 2010-JAMA
TL;DR: The risks of mortality, myocardial infarction, and progression to kidney failure associated with a given level of eGFR are independently increased in patients with higher levels of proteinuria.
Abstract: Context The current staging system for chronic kidney disease is based primarily on estimated glomerular filtration rate (eGFR) with lower eGFR associated with higher risk of adverse outcomes. Although proteinuria is also associated with adverse out- comes, it is not used to refine risk estimates of adverse events in this current system. Objective To determine the association between reduced GFR, proteinuria, and ad- verse clinical outcomes. Design, Setting, and Participants Community-based cohort study with partici- pants identified from a province-wide laboratory registry that includes eGFR and pro- teinuria measurements from Alberta, Canada, between 2002 and 2007. There were 920985 adults who had at least 1 outpatient serum creatinine measurement and who did not require renal replacement treatment at baseline. Proteinuria was assessed by urine dipstick or albumin-creatinine ratio (ACR). Main Outcome Measures All-cause mortality, myocardial infarction, and progres- sion to kidney failure. Results The majority of individuals (89.1%) had an eGFR of 60 mL/min/1.73 m 2 or greater. Over median follow-up of 35 months (range, 0-59 months), 27959 participants (3.0%)died.Thefullyadjustedrateofall-causemortalitywashigherinstudyparticipants with lower eGFRs or heavier proteinuria. Adjusted mortality rates were more than 2-fold higher among individuals with heavy proteinuria measured by urine dipstick and eGFR of 60mL/min/1.73m 2 orgreater,ascomparedwiththosewitheGFRof45to59.9mL/min/ 1.73 m 2 and normal protein excretion (rate, 7.2 (95% CI, 6.6-7.8) vs 2.9 (95% CI, 2.7- 3.0)per1000person-years,respectively;rateratio,2.5(95%CI,2.3-2.7)).Similarresults were observed when proteinuria was measured by ACR (15.9 (95% CI, 14.0-18.1) and 7.0 (95% CI, 6.4-7.6) per 1000 person-years for heavy and absent proteinuria, respec- tively;rateratio,2.3(95%CI,2.0-2.6))andfortheoutcomesofhospitalizationwithacute myocardial infarction, end-stage renal disease, and doubling of serum creatinine level. Conclusion The risks of mortality, myocardial infarction, and progression to kidney failure associated with a given level of eGFR are independently increased in patients with higher levels of proteinuria.

879 citations


Journal ArticleDOI
Martin O'Donnell1, Salim Yusuf, Andrew Mente, Peggy Gao  +8 moreInstitutions (1)
23 Nov 2011-JAMA
TL;DR: The precise relationship between sodium and potassium intake and cardiovascular (CV) risk remains uncertain, especially in patients with CV disease or diabetes mellitus, and Cox proportional hazards multivariable models were used to determine the association.
Abstract: [HR], 1.53; 95% CI, 1.26-1.86; and 11.2% for 8 g/day; HR, 1.66; 95% CI, 1.312.10), MI (6.8%; HR, 1.48; 95% CI, 1.11-1.98 for 8 g/day), stroke (6.6%; HR, 1.48; 95% CI, 1.09-2.01 for 8 g/day), and hospitalization for CHF (6.5%; HR, 1.51; 1.122.05 for 8 g/day). Lower sodium excretion was associated with an increased risk of CV death (8.6%; HR, 1.19; 95% CI, 1.02-1.39 for 2-2.99 g/day; 10.6%; HR, 1.37; 95% CI, 1.09-1.73 for 2 g/day), and hospitalization for CHF (5.2%; HR, 1.23; 95% CI, 1.01-1.49 for 2-2.99 g/day) on multivariable analysis. Compared with an estimated potassium excretion of less than 1.5 g per day (n=2194; 6.2% with stroke), higher potassium excretion was associated with a reduced risk of stroke (4.7% [HR, 0.77; 95% CI, 0.63-0.94] for 1.5-1.99 g/day; 4.3% [HR, 0.73; 95% CI, 0.59-0.90] for 2-2.49 g/day; 3.9% [HR, 0.71; 95% CI, 0.56-0.91] for 2.5-3 g/day; and 3.5% [HR, 0.68; 95% CI, 0.49-0.92] for 3 g/day) on multivariable analysis. Conclusions The association between estimated sodium excretion and CV events was J-shaped. Compared with baseline sodium excretion of 4 to 5.99 g per day, sodium excretion of greater than 7 g per day was associated with an increased risk of all CV events, and a sodium excretion of less than 3 g per day was associated with increased risk of CV mortality and hospitalization for CHF. Higher estimated potassium excretion was associated with a reduced risk of stroke.

493 citations