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DOI: 10.1148/radiol.2443061330
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(Radiology 2007;244:890-897.)
© RSNA, 2007

Thoracic Imaging

Monitoring of Smoking-induced Emphysema with CT in a Lung Cancer Screening Setting: Detection of Real Increase in Extent of Emphysema1

Hester A. Gietema, MD, PhD, Arnold M. Schilham, PhD, Bram van Ginneken, PhD, Rob J. van Klaveren, MD, PhD, Jan Willem J. Lammers, MD, PhD, and Mathias Prokop, MD, PhD

1 From the Departments of Radiology (H.A.G., M.P.) and Pulmonology (J.W.J.L.) and Image Sciences Institute (A.M.S., B.v.G.), University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; and Department of Pulmonology, Erasmus Medical Center, Rotterdam, the Netherlands (R.J.v.K.). Received August 2, 2006; revision requested October 4; revision received October 31; accepted December 6; final version accepted January 26, 2007. Address correspondence to H.A.G. (e-mail: h.gietema{at}umcutrecht.nl).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Purpose:To retrospectively establish the minimum increase in emphysema score (ES) required for detection of real increased extent of emphysema with 95% confidence by using multi–detector row computed tomography (CT) in a lung cancer screening setting.

Materials and Methods: The study was a substudy of the NELSON project that was approved by the Dutch Ministry of Health and the ethics committee of each participating hospital, with patient informed consent. For this substudy, original approval and informed consent allowed use of data for future research. Among 1684 men screened with low-dose multi–detector row CT (30 mAs, 16 detector rows, 0.75-mm section thickness) between April 2004 and March 2005, only participants who underwent repeat multi–detector row CT with the same scanner after 3 months because of an indeterminate pulmonary nodule were included. Extent of emphysema was considered to remain stable in this short period. Extent of low-attenuation areas representing emphysema was computed for repeat and baseline scans as percentage of lung volume below three attenuation threshold values (–910 HU, –930 HU, –950 HU). Limits of agreement were determined with Bland-Altman approach; upper limits were used to deduce the minimum increase in ES required for detecting increased extent of emphysema with 95% probability. Factors influencing the limits of agreement were determined.

Results: In total, 157 men (mean age, 60 years) were included in the study. Limits of agreement for differences in total lung volume between repeat and baseline scans were –13.4% to +12.6% at –910 HU, –4.7% to +4.2% at –930 HU, and –1.3% to +1.1% at –950 HU. Differences in ES showed weak to moderate correlation with variation in level of inspiration (r = 0.20–0.49, P < .05). Scanner calibration could be excluded as a factor contributing to variation in ES.

Conclusion: Increase in ES required to detect increased extent of smoking-related emphysema with 95% probability varies between 1.1% of total lung volume at –950 HU and 12.6% at –910 HU for low-dose multi–detector row CT.

Clinical trial registration no. ISRCTN63545820 [controlled-trials.com] ; http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=nelson

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
To our knowledge, the most frequently used computer-based method to detect emphysema on computed tomographic (CT) scans involves highlighting and quantifying low-attenuation areas (1–3), and it was first described by Müller et al (4). Disappearance of lung tissue produces a relative increase of air within a voxel, which results in decreased attenuation within the voxel. The percentage volume of the highlighted voxels can be calculated relative to total volume, and the result is a voxel index or emphysema score (ES) in the range of 0%–100%.

Presently there are many ongoing lung cancer screening trials (5–8). Since lung cancer and emphysema share smoking as the main risk factor, CT performed in these trials may provide suitable data for studying the prevalence and natural course of smoking-related emphysema in relatively healthy participants (9). These data could be used to select groups of smokers in whom more aggressive risk-modifying treatment is necessary to prevent development of severe lung destruction and airflow limitation. To develop an automated method for screening and monitoring, more information is needed about issues such as interscan variation and the factors influencing the ESs (eg, level of inspiration or scanner calibration). Before an automated method can be used for screening and monitoring purposes, more information about an issue such as interscan variation and the effect of the factors that have been shown to influence ESs, such as level of inspiration (10) and scanner calibration (11), is required. Data about the interscan variation are useful to distinguish real progression of the extent of emphysema from measurement variation.

Thus, the aim of our study was to retrospectively establish the minimum increase in ES required for detection of a real increase in the extent of emphysema with 95% confidence by using multi–detector row CT in a lung cancer screening setting.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Participants
The Nederlands Leuvens long screeningsonderzoek, or NELSON, project is a population-based randomized Dutch-Belgian multicenter lung cancer screening trial for the study of 16 000 current and former heavy smokers. The trial was approved by the Dutch Ministry of Health and by the ethics committee of each participating hospital (12). Informed consent was obtained. For our retrospective substudy, the original approval and informed consent allowed use of data for future research. Selection of participants for the NELSON project was performed by sending a questionnaire about smoking history and other health-related issues to citizens between 50 and 75 years of age who lived in the areas around the participating centers. Among the respondents, subjects meeting the inclusion criterion of smoking a minimum of 16 cigarettes per day for 25 years or 11 cigarettes per day for 30 years were asked to participate in the trial. Because men had a better chance to meet this inclusion criterion of having smoked this minimum number of cigarettes during their lives, recruitment began with men.

After being informed about, among other factors, the radiation dose to which the participants would be exposed, those who gave written informed consent were equally randomized to either the screening arm or the control arm. Participants in the screening arm underwent baseline CT to assess the prevalence of lung cancer in this population and will undergo two further CT examinations in years 2 and 4 to establish the 1- and 3-year incidence of lung cancer in this population. Participants with a moderate or poor self-reported health status who were unable to climb two flights of stairs were excluded from participation.

Between April 2004 and March 2005, 1684 male participants received baseline screening in our center. From these participants, we included all participants who, according to the trial protocol, underwent short-term repeat chest CT after 3 months because of an indeterminate nodule (tumor volume, 50–500 mm3) found on the baseline scan. Extent of emphysematous lung destruction was considered to remain stable in this short period. To test this assumption, results of pulmonary function tests, performed in a subgroup of the investigated population on the same days as baseline and repeat CT was performed, were compared. No medical intervention was applied. Since CT scanning was performed with various 16–detector row scanners, we selected only participants who underwent scanning twice with the same scanner.

CT Scanning
Scanning was performed by using 16–detector row CT (Mx8000 IDT or Brilliance 16P; Philips Medical Systems, Cleveland, Ohio). All scans were obtained in about 12 seconds in the helical mode with 16 detector rows, 0.75-mm section thickness, and 15-mm table feed per rotation (pitch of 1.3) in a caudocranial scan direction to minimize breathing artifacts. Participants were asked to take a deep breath and to hold their breath. No spirometric gating was applied because spirometric gating is not standard in a lung cancer screening setting and would therefore make the results less applicable in a standard lung cancer screening setting. No intravenous contrast material was injected. Exposure settings were 30 mAs at 120 kVp for patients weighing 80 kg or less and 30 mAs at 140 kVp for those weighing more than 80 kg without dose modulation. All participants received the same radiation dose during both CT examinations. Transverse images of 1.0-mm thickness were reconstructed at a 0.7-mm increment by using the smallest field of view that included the outer rib margins at the widest dimension of the thorax. All scans were reconstructed with a 512 x 512 matrix and a moderately soft B kernel.

Emphysema Quantification
Data were transferred from the CT scanner to a digital workstation. The extent of low-attenuation areas was fully automated for quantification with software that was developed in-house. Total lung volume was calculated by using the following steps: First, segmentation of the trachea and both lungs was performed by using a region-growing program starting in the trachea, which included all connected areas with attenuation less than –500 HU. In a second step, the trachea and main bronchi were excluded from the lungs. The algorithm is similar to the one described by Hu et al (13). After segmenting the lung, the data were subjected to a median noise-reducing filter (14).

The extent of low-attenuation areas was determined by computing lung volume with CT attenuation less than a certain attenuation threshold value as percentage of total lung volume. We studied the three attenuation threshold values often mentioned in the literature: –910 HU, –930 HU, and –950 HU (4,15–17).

Influence of Level of Inspiration
CT numbers of voxels that represent the lungs are decreased when a participant reaches a higher level of inspiration as a result of an increase in the relative amount of air per voxel, as described by Kalender et al (18). So, the extent of low-attenuation areas increases not only when the extent of emphysema increases but also when a participant reaches a deeper level of inspiration during repeat scanning than during baseline scanning. For this reason, the correlation between natural variation in the level of inspiration of baseline and repeat scans of each participant and changes in ESs was evaluated. Total lung volume as calculated from each scan was used as the surrogate for level of inspiration.

Quality Control
Because the method of highlighting and quantifying low-attenuation areas starts from a fixed threshold, the method is sensitive to CT number shifts due to, for example, x-ray tube aging. We performed weekly air calibrations and obtained the screening scans within 24 hours after calibration. In addition, we performed scanning of a quality control phantom before and after each data acquisition session. This phantom consisted of a foam body (mimicking emphysematous areas) of 320 mm in diameter that included two cylinders, each 80 mm in diameter (Fig 1). One cylinder contained air; the other cylinder was filled with plastic. The phantom was scanned at 120 kVp with otherwise identical parameters as applied to the participants.


Figure 1
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  		Figure 1: CT scan of phantom used to monitor CT numbers during the study. The phantom consisted of a foam body, 320 mm in diameter, and two free spaces of 80 mm in diameter each. One of the free spaces was filled with plastic, whereas the other contained only air.

 
Average CT numbers for each structure were measured in a circular region of interest of 100 mm2 manually drawn by one observer (H.A.G., with 3 years of experience in radiology) in the center of both cylinders and in the periphery of the foam body, 2 cm from the outside border. We obtained five scans of the phantom in one session at the start of the study and again after 3 months to assess the variation in CT numbers within one session. Changes in average CT numbers within the region of interest during the period of data collection were determined.

Statistical Analysis
All statistical calculations were performed by using statistical software (SPSS, release 13.0; SPSS, Chicago, Ill). We calculated means, standard deviations, and 95% confidence intervals for normal-distributed differences in ES and medians and interquartile ranges for nonnormal-distributed ES. Changes in ESs were given as percentages of total lung volume.

Forced expiratory volume in 1 second (FEV1) tests performed on the day of baseline scanning (FEV1A) and on the day of repeat scanning (FEV1B) were compared after logistic transformation as follows:

Formula
The results of ln(FEV1A) and ln(FEV1B) were compared by using the t test for paired samples.

Differences in ESs ({Delta}ES) were calculated by subtracting the ES measured on the baseline scan (ES1) from the ES measured on the repeat scan (ES2). These differences were plotted against the mean of both ESs, by using the approach described by Bland and Altman (19), as follows:

Formula
Limits of agreement were given as 95% confidence intervals. For monitoring purposes, an increase in ES above these upper limits of agreement can, with 95% confidence, be attributed to a real increase in the extent of emphysema.

To assess the repeatability of the quantification of the extent of low-attenuation areas, we calculated coefficients of variation as the ratio of the within-subject standard deviation to the mean of both measurements. To determine whether these coefficients of variation were related to the extent of emphysema, represented by the mean of the two measurements, we calculated the Spearman correlation coefficient for each attenuation threshold value.

Correlation coefficients between the difference in total lung volumes and the difference in ESs for each pair of scans were best after logarithmic transformation of lung volumes, as described by Shaker et al (10). We determined the corresponding Pearson correlation coefficients for each attenuation threshold value to assess whether a correction factor for the level of inspiration could be calculated. Differences with a P value of less than .05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Emphysema Scores
Between April 2004 and March 2005, 249 consecutive male participants underwent baseline and 3-month follow-up CT. The group of participants in whom both scans were obtained with the same scanner included 157 participants (mean age, 60 years; range, 52–77 years). These participants were further evaluated (Fig 2).


Figure 2A
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  		Figure 2a: Coronal (a) baseline and (b) repeat scans in a 56-year-old man show areas with attenuation below –910 HU. The computer program divides the lungs into three equal volumes shown in red, yellow, and green and provides the total low-attenuation volume. Total lung volume was 5965 mL on the baseline scan and 6350 mL on the repeat scan.

 

Figure 2B
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  		Figure 2b: Coronal (a) baseline and (b) repeat scans in a 56-year-old man show areas with attenuation below –910 HU. The computer program divides the lungs into three equal volumes shown in red, yellow, and green and provides the total low-attenuation volume. Total lung volume was 5965 mL on the baseline scan and 6350 mL on the repeat scan.

 
Sixty subjects underwent pulmonary function testing on the day of baseline scanning and again on the day of repeat scanning. The FEV1 did not change significantly in the 3-month interval (P = .311). The 95% confidence interval of the ratio of the FEV1 during both tests ranged from 0.99 to 1.03, and this value indicated that the variation in FEV1 was only 4% in this 3-month interval.

ESs ranged from 0% for volume with an attenuation below –950 HU to 56.5% for volume with an attenuation below –910 HU for baseline scans (Table). Median ESs ranged from 0.08% for volume with an attenuation below –950 HU for repeat scans to 11.8% for volume with an attenuation below –910 HU for baseline scans (Table). Coefficients of variation ranged from 0% to 141% and decreased with increasing extent of emphysema (Table). Mean difference in ESs ranged from –0.1% for volume with an attenuation below –950 HU to –0.41% for volume with an attenuation below –910 HU for baseline scans (Fig 3).


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  		ESs for the Study Population

 

Figure 3A
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  		Figure 3a: Bland-Altman plots for ESs at (a) –910 HU, (b) –930 HU, and (c) –950 HU. The x-axes show the means of ESs on the baseline and repeat scans; the y-axes show ESs on the baseline scan subtracted from ESs on the repeat scan, expressed as percentage of total lung volume. The mean differences are shown with a solid line; the limits of agreement are shown with dashed lines. An increase in ES above the upper limit of agreement or a decrease below the lower limit of agreement has a 95% likelihood to be a real progression or regression of emphysema.

 

Figure 3B
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  		Figure 3b: Bland-Altman plots for ESs at (a) –910 HU, (b) –930 HU, and (c) –950 HU. The x-axes show the means of ESs on the baseline and repeat scans; the y-axes show ESs on the baseline scan subtracted from ESs on the repeat scan, expressed as percentage of total lung volume. The mean differences are shown with a solid line; the limits of agreement are shown with dashed lines. An increase in ES above the upper limit of agreement or a decrease below the lower limit of agreement has a 95% likelihood to be a real progression or regression of emphysema.

 

Figure 3C
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  		Figure 3c: Bland-Altman plots for ESs at (a) –910 HU, (b) –930 HU, and (c) –950 HU. The x-axes show the means of ESs on the baseline and repeat scans; the y-axes show ESs on the baseline scan subtracted from ESs on the repeat scan, expressed as percentage of total lung volume. The mean differences are shown with a solid line; the limits of agreement are shown with dashed lines. An increase in ES above the upper limit of agreement or a decrease below the lower limit of agreement has a 95% likelihood to be a real progression or regression of emphysema.

 
Level of Inspiration
Mean total lung volume was 6935 mL ± 1267 (standard deviation) for the baseline scans and 6945 mL ± 1322 for the repeat scans. Although many participants were not able to achieve the same inspirational volume during repeat scanning that they achieved at baseline scanning, the level of inspiration was not statistically different for both baseline and repeat scans on a cohort level (P = .8, Fig 4). After logarithmic transformation, we could demonstrate a significant (P < .001 for –910 HU and –930 HU, P < .01 for –950 HU) but weak to moderate correlation between changes in level of inspiration (lung volume) and ESs for all threshold attenuation values (r = 0.49 for –910 HU, r = 0.33 for –930 HU, and r = 0.20 for –950 HU) (Fig 5).


Figure 4
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  		Figure 4: Correlation between lung volumes on the baseline scans and lung volumes on repeat scans. Equal volumes are demonstrated by the solid line. No systematic difference between lung volume on baseline scan and that on repeat scan could be demonstrated.

 

Figure 5A
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  		Figure 5a: Correlation between the difference between inspiration level on repeat scans (volume 2) after logarithmic transformation and inspiration level on baseline scans (volume 1) after logarithmic transformation and difference in ESs between repeat scans and baseline scans at (a) –910 HU, (b) –930 HU, and (c) –950 HU. Significant but low to moderate correlations could be demonstrated.

 

Figure 5B
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  		Figure 5b: Correlation between the difference between inspiration level on repeat scans (volume 2) after logarithmic transformation and inspiration level on baseline scans (volume 1) after logarithmic transformation and difference in ESs between repeat scans and baseline scans at (a) –910 HU, (b) –930 HU, and (c) –950 HU. Significant but low to moderate correlations could be demonstrated.

 

Figure 5C
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  		Figure 5c: Correlation between the difference between inspiration level on repeat scans (volume 2) after logarithmic transformation and inspiration level on baseline scans (volume 1) after logarithmic transformation and difference in ESs between repeat scans and baseline scans at (a) –910 HU, (b) –930 HU, and (c) –950 HU. Significant but low to moderate correlations could be demonstrated.

 
Quality Control
The mean CT number for foam was –967.9 HU ± 2.0 for the five scans obtained in succession at the beginning of our study and –969.2 HU ± 2.2 for the five scans obtained in succession after 3 months, whereas the mean CT number was 968 HU ± 2.7 from April 2004 to March 2005. Variation in measured CT numbers was independent of the time of the day. The standard deviation of 2.7 HU is within the range of tolerance reported by the vendor (0–4 HU).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Our results provide information about interscan variation for the quantification of low-attenuation areas, representing emphysema, in a cohort of current and former heavy smokers who are participating in a lung cancer screening trial. This screening trial aims to detect lung cancer in a curable stage, so participants have to be able to undergo surgery. For this reason, participants with severe airflow limitation were excluded from participation; such exclusion resulted in a population with a relatively low extent of emphysema that was part of this investigation. Although in the early 1990s the quantification of low-attenuation areas had to be performed section by section and took hours to perform per CT scan (20), nowadays it takes less than 5 minutes for a complete CT examination and quantification can be applied for large groups of patients.

Gierada et al (20) and Shaker et al (21) demonstrated that determination of the extent of emphysema is highly repeatable on a cohort level in patients with large areas of destruction in tissue, but they did not report the limits of agreement, whereas knowledge about the interscan variability is mandatory to distinguish between a real increase in extent of emphysema and measurement variability in a monitored setting. With data reported in our study, an increase in ES of more than the corresponding upper limit of agreement can, with 95% likelihood, be considered as a real increase in extent of emphysema.

Since Müller et al (4) introduced the quantification of the extent of emphysema to highlight low-attenuation areas on CT images, this method has been used for several scanning techniques. Müller et al validated the technique with macroscopic histologic analysis results for a single contrast-enhanced 10-mm section and found that –910 HU was the best threshold value to detect the extent of macroscopic emphysema. Gevenois et al (16,22) determined the optimum attenuation threshold value for thin-section CT and recommended –950 HU for both microscopically and macroscopically detected emphysema. The difference in optimum attenuation threshold values was subjected to variation in section thickness, and this effect was also investigated by Kemerink et al (23).

Park et al (24) reported a high correlation between emphysema quantification on two-dimensional and three-dimensional data sets, making the technique also applicable to volumetric data. Recently Madani et al (25) compared the extent of both microscopically and macroscopically detected emphysema with the quantification of the extent of low-attenuation areas with multi–detector row CT and reported –960 HU to –970 HU as the optimum attenuation threshold value for multi–detector row CT. However, they applied a smaller radiation dose than did Gevenois et al (16,22) (140 kVp and 80 mAs vs 137 kVp and 255 mAs), and Mishima et al (26) already showed the effect of applied radiation dose on the extent of low-attenuation areas.

Finally, Parr et al (17) investigated several attenuation threshold values for monitoring purposes and recommended –930 HU as the optimum attenuation threshold value to monitor the progression or regression in the extent of emphysema. To our knowledge, there is no consensus about the optimum scanning technique for the quantification of the extent of emphysema by calculating the extent of low-attenuation areas and no consensus on the optimum attenuation threshold value (3). Therefore, we investigated the limits of agreement of the extent of low-attenuation areas on repeat scans for three attenuation threshold values often used in the literature so far. Our results do not provide any information about the accuracy of ESs for detection of lung destruction because we examined healthy participants and did not have any histologic specimens available.

The effect of level of inspiration on lung attenuation is well described (18,27,28). Shaker et al (10) reported a large variability of correlation coefficients between the ES and the total lung volume for the lower range of ESs, whereas for more severe emphysema a more stable correlation could be reported. We demonstrated a low to moderate but significant correlation between natural variation in level of inspiration and changes in ESs and also a large variation in this effect. Spirometric control could have narrowed the limits of agreement but would also have limited our results to spirometric controlled CT scanning. Because spirometric controlled scanning is not available in many hospitals, we performed CT in end-inspiratory volume, as is usual in clinical routine.

In our study, a low-dose protocol was applied because radiation dose has an intrinsic risk of inducing a neoplasm. For a structure of interest with high contrast to its surroundings, such as a pulmonary nodule in lung parenchyma, the detection and segmentation of this lesion are not affected by an accompanying increase in image noise (29,30). But for emphysema, especially for that with low extent of lung destruction, there is a low contrast between the areas with destruction and the normal lung parenchyma. In that situation the increased image noise leads to an increase in ESs, which can be reduced, but not excluded, with the application of a noise reduction filter (31).

Quality control showed that regular scanner calibration for air resulted in stable CT numbers. The small variations in CT numbers were within the range of tolerance of our scanner but still may contribute to variations in ESs.

Although our results can provide useful information for monitoring high-risk participants in a screening setting, the study also has an important limitation. Our study was performed in a lung cancer screening setting, and the results are therefore useful in a low-dose setting but not necessarily applicable to a clinical setting with a standard radiation dose. However, to our knowledge, emphysema quantification in large cohorts is mainly performed with low-dose scans for study purposes (9,21,32).

In conclusion, although ESs in a lung cancer screening setting are highly reproducible on a cohort level, individual variation can be substantial. An increase in the ES of at least 1.1% for –950 HU to 12.6% for –910 HU is required for detection of an increase in the extent of emphysema, with 95% confidence, when monitoring patients who have smoking-induced emphysema with low-dose CT in a lung cancer screening setting.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE
 References
 


   IMPLICATIONS FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
References
 


   FOOTNOTES
 

Abbreviations: ES = emphysema score • FEV1= forced expiratory volume in 1 second

Clinical trial registration no. ISRCTN63545820 [controlled-trials.com] ; http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=nelson

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, H.A.G., M.P.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, all authors; experimental studies, H.A.G., B.v.G., M.P.; statistical analysis, H.A.G., A.M.S., M.P.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 

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