measure eNO. We report a new, simple and cost-effective way of checking whether this machine is accurately calibrated to zero. When using the HypAir FeNO, ...
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
measure eNO. We report a new, simple and cost-effective way of checking whether this machine is accurately calibrated to zero. When using the HypAir FeNO, participants inhale nitric oxide (NO) free air by drawing air through an NO scrubber, thereby excluding the influence of ambient NO. Participants then expel this air back into the machine. A sample of the expired air is collected within the unit and analyzed by a fuel cell to determine the concentration of NO in parts per billion (ppb). As with all measurements, calibration of the measurement of eNO should be regularly undertaken to ensure accuracy. Although the manufacturer recommends that the HypAir FeNO is calibrated every 6 months with a 100 ppb NO gas, there are no instructions concerning regular zero calibration checking. The current ATS/ERS calibration recommendations are limited to ozone-/NO2-chemoluminescence–based analyzers (1). To determine whether our machine is correctly calibrated to zero, NO-free gas is required. Sourcing NO-free gas is difficult because routinely available ultra-high purity commercial gases still contain small impurities that may include NO. We have developed a simple and cost-effective way around this problem. A 3-liter syringe is used to simulate a person ‘‘inhaling’’ NOfree air through the HypAir FeNO using the unit’s NO scrubber. The breath is then ‘‘exhaled’’ at the appropriate rate, and the NO content is measured. Using this technique, we find the first ‘‘breath’’ by the 3-liter syringe is not usually NO-free, but contains 1 to 5 ppb NO. This is likely to represent residual NO in dead space within the FeNO unit and/or the 3-liter syringe. After 2 to 3 ‘‘breaths’’ by the 3-liter syringe we are able to reach zero ppb. We are now reassured that our fuel cell analyzer is accurately recording zero. This technique also provides a check for the functioning of the NO scrubber. We have incorporated this procedure as part of our study’s routine quality control. Calibration, using 100 ppb NO, must still be performed every 6 months. Author Disclosure: C.J.L. received industry-sponsored grants from the Myer Corporation ($10,001–$50,000); she received Ph.D. funding from NHMRC ($10,001–$50,000). R.U.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.C.D. has received sponsored grants from NHMRC, Asthma Foundations of Australia, Ilhan Food Allergy Foundation, Glaxo-Smith-Kline and the Sypkes Trust (all over $100,000). A.J.L. has received industry-sponsored grants from Dairy Australia ($50,001–$100,00), CRC for Asthma & Airways and Financial Markets Foundation for Children (both $10,001–$50,000), and has received sponsored grants from NHMRC (over $100,000), Asthma Foundation of Victoria, Australasian College of Dermatology and Monash University (all $10,001–$50,000). P.S.T. has received consultancy fees from Glaxo-Smith-Kline ($1001–$5000). M.J.A. has received advisory board fees from Glaxo-Smith-Kline (up to $1000); he has received lecture fees from Boehringer Ingelheim (up to $1000); he has received industry-sponsored Reckitts Benckiser ($10,001–$50,000).
CAROLINE J. LODGE, M.B., B.S. RIDA U. KHALAFZAI, M.B., B.S., M.P.H. and SHYAMALI C. DHARMAGE, M.B.B.S., M.SC., M.D., PH.D. Center for Molecular, Environmental, Genetic, and Analytic Epidemiology University of Melbourne Melbourne, Australia ADRIAN J. LOWE, B.B.SC., M.P.H., PH.D. Murdoch Children’s Research institute Royal Children’s Hospital Melbourne, Australia
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PAUL S. THOMAS, B.SC., M.B., B.S., M.D., F.R.C.P., F.R.A.C.P. Department of Respiratory Medicine Prince of Wales Clinical School University of New South Wales Sydney, Australia MICHAEL J. ABRAMSON, M.B., B.S., B.MED.SC., PH.D., F.R.A.C.P., F.A.F.P.H.M. Department of Epidemiology and Preventive Medicine Monash University Melbourne, Australia
Reference 1. ATS/ERS. ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. Am J Respir Crit Care Med 2005;171:912–930.
Does Lung Cancer Screening with Low-Dose CT Remain Promising Despite Disappointing DANTE Results? To the Editor:
Preliminary results from DANTE (1), a randomized low-dose computed tomography (LDCT) screening trial, indicate equal numbers of advanced lung cancers and lung cancer deaths in the screened and control arms, suggesting that screening fails to reduce lung cancer mortality. The authors are to be congratulated for starting the first randomized trial on LDCT screening, since uncontrolled studies cannot show whether screening reduces lung cancer mortality. However, it is important to consider several aspects of the study before concluding that the effect of screening on mortality ‘‘might be far smaller than anticipated’’ (1). First, follow-up is short (median 34 mo; only 6.5% over 5 yr), as the authors acknowledge. Any mortality reduction is unlikely to be evident before 6 years (2). Second, stage at diagnosis and resectability are lower in the DANTE screening arm than other studies: 55% stage 1 compared with 74% and 85% in two nonrandomized studies (3, 4), with overall resectability of 65% versus 89% and 85% (3, 4). Furthermore, a high number of DANTE study cancers were detected due to symptoms (interval cases) or other causes (13/60; 22%), compared with 3/177 (1.7%) in Cosmos (3). Lung cancer–specific mortality was also high: with 20/60 (33%) deaths in the DANTE screening arm, against 15% in Cosmos (unpublished data) and I-Elcap study (4). There are several possible reasons for this difference in screening performance. Low CT resolution could be one, since single-slice CT is already outmoded for CT screening. Another may be different diagnostic protocols and more restrictive criteria for surgical resection. As a matter of fact, the strict diagnostic algorithm of Cosmos and Elcap, probably reducing the individual subjectivity in evaluating the CT scans, allowed a low rate of interval and advanced tumors. We suggest the importance of assessing the causes of these differences in performance, particularly the high number of DANTE interval cases, so that the lessons can be learnt for the future. We look forward to the long-term follow-up results of the DANTE trial and hope they are not as disappointing as the preliminary findings. Author Disclosure: None of the authors has a financial relationship with a commerical entity that has an interest in the subject of this manuscript.
Correspondence
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GIULIA VERONESI, M.D. PATRICK MAISONNEUVE, ENG. D. T. M. DE PAS, M.D. MASSIMO BELLOMI, PH.D. European Institute of Oncology Milano, Italy
References 1. Infante M, Cavuto S, Lutman FR, Brambilla G, Chiesa G, Ceresoli G, Passera E, Angeli E, Chiarenza M, Aranzulla G, et al.; DANTE Study Group. A randomized study of lung cancer screening with spiral computed tomography: three-year results from the DANTE trial. Am J Respir Crit Care Med 2009;180:445–453. 2. McMahon PM, Kong CY, Johnson BE, Weinstein MC, Weeks JC, Kuntz KM, Shephard JA, Swensen SJ, Gazelle GS. Estimating long-term effectiveness of lung cancer screening in the Mayo CT screening study. Radiology 2008;248:278–287. 3. Veronesi G, Bellomi M, Mulshine JL, Pelosi G, Scanagatta P, Paganelli G, Maisonneuve P, Preda L, Leo F, Bertolotti R, et al. Lung cancer screening with lowdose computed tomography: a non-invasive diagnostic protocol for baseline nodules. Lung Cancer 2008;61:340– 349. 4. The International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:1763–1771.
From the Authors:
In our article (1), we have summarized the mid-term results of the randomized DANTE trial, comparing annual screening for lung cancer with spiral computed tomography (CT) versus annual clinical review. Over 99% of the subjects were 60 years or older, as compared with only 29% in the Milan study (2) and 56% in the I-ELCAP (3). The number of stage I cases was significantly higher in the screening arm than in the control arm (33 versus 12, P 5 0.004). Low screening performance is in our opinion an unlikely explanation for the relatively low proportion of stage I disease, the relatively high proportion of interval cancers, and diseasespecific mortality in our trial. In fact, 16/1,276 (1.25%) of screened subjects were diagnosed with stage I lung cancer at baseline, and 33/1,276 (2.6%) after 3 years, a relatively high stage I detection rate. Stage I proportion in the low-dose CT arm of the DANTE trial is, moreover, in line with that reported by several other authors (4–7). Lung cancer–specific mortality in the screening arm was 1/33 patients with stage I disease and 19/20 patients with higher stage disease. Only 2/13 (15%) patients with interval lung cancers had stage I disease. Their median age was 72 (range 63–78) versus 67 (60–76) in screening-detected cases. The lower proportion of stage I disease, higher number of interval cancers, and higher disease-specific mortality may be therefore due to the more advanced age of our study population, to the longer observation period compared with the Milan study and I-ELCAP, and possibly to overdiagnosis, rather than to low screening performance.
In our report, the rate of any surgery (including videoassisted thoracoscopic surgery [VATS] biopsies) for benign lesions was 22.6%, 13% considering major surgery only (i.e., thoracotomy or major VATS resection), comparable with that reported by the Mayo Clinic (8). A diagnostic algorithm that includes PET scan does reduce individual subjectivity and useless invasive procedures (as occurred in our study). However, it is at least premature to infer that it will reduce the rate of interval and advanced tumors in a comparable study population. As correctly remarked, follow-up was still short (median 34 months); therefore, we did not state that lung cancer screening is ineffective, but only suggested that its efficacy may be less than expected. We thank Dr. Veronesi and colleagues for their kind comments and for helping us clarify the subject further for the readership of the Journal. Author Disclosure: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
MAURIZIO INFANTE, M.D. SILVIO CAVUTO, D.SC. On behalf of all co-authors IRCCS Istituto Clinico Humanitas Milan, Italy References 1. Infante M, Cavuto S, Lutman FR, Brambilla G, Chiesa G, Ceresoli G, Passera E, Angeli E, Chiarenza M, Aranzulla G, et al.; DANTE Study Group. A randomized study of lung cancer screening with spiral computed tomography: three-year results from the DANTE trial. Am J Respir Crit Care Med 2009;180:445–453. 2. Veronesi G, Bellomi M, Mulshine JL, Pelosi G, Scanagatta P, Paganelli G, Maisonneuve P, Preda L, Leo F, Bertolotti R, et al. Lung cancer screening with low-dose computed tomography: a non-invasive diagnostic protocol for baseline lung nodules. Lung Cancer 2008;61: 340–349. 3. The International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:1763–1771. 4. Wilson DO, Weissfeld JL, Fuhrman CR, Fisher SN, Balogh P, Landreneau RJ, Luketich JD, Siegfried JM. The Pittsburgh Lung Screening Study (PLuSS): outcomes within 3 years of a first computed tomography scan. Am J Respir Crit Care Med 2008;178: 956–961. 5. Menezes RJ, Roberts HC, Paul NS, McGregor M, Chung TB, Patsios D, Weisbrod G, Herman S, Pereira A, McGregor A, et al. Lung cancer screening using low-dose computed tomography in at-risk individuals: the Toronto experience. Lung Cancer 2010;67:177–183. 6. Swensen SJ, Jett JR, Hartman TE, Midthun DE, Mandrekar SJ, Hillman SL, Sykes AM, Aughenbaugh GL, Bungum AO, Allen KL. CT screening for lung cancer: five-year lung prospective experience. Radiology 2005;235:259–265. 7. Gohagan JK, Marcus PM, Fagerstrom RM, Pinsky PF, Kramer BS, Prorok PC, Ascher S, Bailey W, Brewer B, Church T, et al. The lung screening study research group. Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer. Lung Cancer 2005;47:9–15. 8. Crestanello JA, Allen MS, Jett JR, Cassivi SD, Nichols FC III, Swensen SJ, Deschamps C, Pairolero PC. Thoracic surgical operations in patients enrolled in a computed tomographic screening trial. J Thorac Cardiovasc Surg 2004;128:254–259.
