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Reproducibility of contrast-enhanced transrectal ultrasound of the prostate
Ultrasound in Med. & Biol., Vol. 27, No. 5, pp. 595– 602, 2001 Copyright © 2001 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/01/$–see front matter
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● Original Contribution REPRODUCIBILITY OF CONTRAST-ENHANCED TRANSRECTAL ULTRASOUND OF THE PROSTATE J. P. MICHIEL SEDELAAR, TJERK E. B. GOOSSEN, HESSEL WIJKSTRA and JEAN J. M. C. H. DE LA ROSETTE Department of Urology, University Medical Center, St Radboud, Nijmegen, The Netherlands (Received 3 October 2000; in final form 22 January 2001)
Abstract—Transrectal three-dimensional (3-D) contrast-enhanced power Doppler ultrasound (US) is a novel technique for studying possible prostate malignancy. Before studies can be performed to investigate the clinical validity of the technique, reproducibility of the contrast US studies must be proven. Reproducibility of contrast US was studied in 10 patients with biopsy-proven prostate cancer. The studies performed included static investigations and dynamic investigations of the prostate vasculature. All studies were double performed. The assessment of reproducibility was done objectively using a computer program and, subjectively, by visual assessment. The results indicate high reproducibility of static contrast investigations, for both the objective and subjective assessment. The subjective assessment of the dynamic studies was also highly reproducible. The objective assessment of the dynamic contrast studies, however, was less reproducible, mainly due to motion artefact. We concluded that, especially static 3-D contrast-enhanced, power Doppler investigations of the prostate are highly reproducible. (E-mail: [email protected]) © 2001 World Federation for Ultrasound in Medicine & Biology. Key Words: Contrast-enhanced ultrasound, Prostate, 3-D ultrasound, Reproducibility studies.
localizing prostate cancer. Contrast improves the acoustic properties of the blood flow, making the combination of Doppler US and US contrast even more sensitive for detection of alterations in blood flow. Adding 3-D modalities to contrast Doppler US could provide a method to study the vascularity of the whole prostate in a single image, and could, thus, facilitate the assessment of possible abnormal vascularity. Currently, research programs are performed to study the use of transrectal (3-D) contrast-enhanced power Doppler ultrasonography in the detection of prostate cancer (Bogers et al. 1999; Unal et al. 2000; Halpern et al. 2000). These studies are performed to investigate if contrast-enhanced power Doppler ultrasonography has additional value over conventional transrectal ultrasonography in the detection and follow-up of different prostate pathologies, especially prostate cancer. Early findings indicate an additional value of transrectal contrast ultrasonography in the diagnosis of prostate cancer using the static and dynamic information provided (Bogers et al. 1999; Aarnink et al. 1999). Before contrast ultrasonography can be accepted as a reliable tool for the detection of prostate cancer, reproducibility of this method is of crucial importance. Results
INTRODUCTION Conventional grey-scale transrectal ultrasound (US) of the prostate has proven its usefulness in volume measurement (Roehrborn 1998; Bergdahl et al. 1999) and biopsy guidance (Levine et al. 1998), but has a limited sensitivity and specificity in detection, localization and staging of prostate cancer (Halpern and Strup 2000; Sedelaar et al. 1999). New US imaging modalities are being developed to increase the usefulness of transrectal US in the detection of prostate cancer. Some of these new modalities focus on imaging the vascularity of the prostate. It is a fact that the development of prostate cancer involves angiogenesis and the formation of arteriovenous shunts (Matsushima et al. 1999; Lee et al. 1999) that alter the hemodynamics and vascular anatomy. Visualization of these blood and vessel abnormalities using Doppler ultrasonography could provide a method of increasing the sensitivity and specificity of US in detecting and Address correspondence to: J. P. Michiel Sedelaar, M.D., Department of Urology, University Medical Center, St Radboud, Nijmegen, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: [email protected] 595
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of repetitive investigations performed following a strict protocol must be objectively and subjectively comparable, and must lead to unanimous conclusions regarding the diagnosis. The objective of the present study was to determine the reproducibility of transrectal 3-D contrast-enhanced power Doppler ultrasonography. MATERIALS AND METHODS Reproducibility of 3-D contrast-enhanced power Doppler ultrasonography was investigated in a group of patients with biopsy-proven prostate carcinoma and scheduled for transrectal ultrasonography of the prostate for staging. The study was performed using a strict protocol for US investigations, preparation and administration of the US contrast agent and image analysis. Image analysis was performed using specially designed computer software (Borland威 Delphi 3 Professional combined with Skyline Tools威 Imagelib 3.0). A total of 10 patients with biopsy-proven prostate cancer who were scheduled to undergo radical prostatectomy were included in the protocol after giving informed consent. We performed transrectal grey-scale US, 3-D transrectal US and power Doppler US studies using a Kretz威 Voluson 530D US scanner in combination with a S-VDW 5- to 8-MHz probe (Kretztechnik AG, Zipf, Austria). For the contrast investigations, we used IVadministered 7 mL (300 mg/mL) Levovist威 microbubble US contrast (Schering AG, Berlin, Germany). For all US investigations, we used the same settings of the US scanner. Before the start of the US contrast studies, an 18gauge IV cannula (Venflon威 2, Ohmeda AB, Helingborg, Sweden) was inserted in an antecubital vein in the right arm of the patient. All investigations were performed with the patient in the left lateral decubitus position. One physician performed the US studies and one person prepared and administered the US contrast to all patients. The US contrast agent was prepared according to the manufacturer’s protocol: the US contrast is prepared for use by mixing 7 mL of sterile water with 2.5 g of Levovist威 and firmly shaken during 10 s. A milky suspension of galactose microparticles and microbubbles is formed after resting the mixture for 2 min. After these 2 min, the suspension is ready for IV administration and will be stable for about 10 min. We performed the reproducibility study in two parts: a dynamic response and a static response. Both parts of the study were performed twice. The first part of the study concerned the dynamic response, to study the hemodynamics of the prostate blood vessels. We gave a fast-bolus infusion (4 s) of 7-mL microbubble US contrast (300 mg/mL) while hold-
Fig. 1. Time intensity curve. Example of the different dynamic parameters obtained from the plotted time-intensity curve. Arrival time (AT) ⫽ time at which enhancement is greater than 1.5* baseline, or greater than 10 when baseline ⫽ 0; Peak ⫽ maximum intensity; Peak time ⫽ time at maximum intensity; Full width half maximum (FWHM) ⫽ curve width at half maximum; Enhance time (ET) ⫽ peak time minus arrival time.
ing the transrectal US probe on a steady transverse crosssection through the prostate. After the effect of the first enhancement had disappeared, the exact same fast-bolus investigation was performed using a second infusion of US contrast, and holding the US probe on the same transverse cross-section of the prostate. The power Doppler enhancement images were recorded on video (S-VHS) and afterward digitized by computer. A computer program was designed to calculate, for both fastbolus investigations, the number of colored pixels during the first min of the enhancement in the right lobe and the left lobe of the prostate and plotted against the time. For both investigations, the right and left curves were normalized to the maximum. We choose to use standard hemodynamic parameters, which were both time-dependent and time-independent. The following hemodynamic parameters were obtained for the quantification of the contrast studies: the arrival time (AT ⫽ start of enhancement), peak (P ⫽ maximum enhancement), peak time (PT ⫽ time of maximum enhancement), full-width half maximum (FWHM ⫽ the width of the enhancement curve at the half of the maximum enhancement) and enhance time (ET ⫽ peak time minus arrival time). The hemodynamic parameters were mainly chosen to test reproducibility of the contrast US technique, but the clinical value is not yet proven. This is illustrated in Fig. 1. After the objective computer comparison between the two dynamic studies, two US experts performed a subjective random assessment of the US images by visual inspection of the recorded images and assessed the presence of asymmetrical enhancement in three grades: no asymmetry, slight asymmetry and clear asymmetry.
Reproducibility of contrast ultrasound ● J. P. M. SEDELAAR et al.
Table 1. Grading scale used for subjective assessment. Asymmetry grading Grade 0 No asymmetry Grade 1 Slight asymmetry Grade 2 Marked asymmetry Vessel distribution grading Grade 0 Visible flow in the capsular and periurethral zones Grade 1 Vascularity throughout the prostate distributed in a homogeneous fashion Grade 2 Focal increase in vascularity Grade 3 Intense focal increase in vascularity
The second part of the study concerned the static imaging of the blood vessel architecture. For this study, we administered a slow infusion (25 s) of 7-mL microbubble US contrast (300 mg/mL). This prolonged infusion resulted in a longer duration of the enhancement due to the more evenly distributed contrast agent. At 1 min after the beginning of the contrast infusion, a 3-D power Doppler scan of the whole prostate was made. This 3-D image was stored on the hard disc of the computer. Second, we performed an identical slow infusion investigation when the first enhancement had died out. Using the stored image, a 3-D model of the vascular anatomy of the prostate was created for both slow studies. Slices of the prostate (4 mm) were made using the 3-D images. The 4-mm slices were divided in 4 mm3 cubes and of these cubes the enhanced vessel density could be calculated by computer as the ratio between colored pixel and grey pixels. This quantification was performed for both the right and the left side of the prostate, as well as the whole prostate. The images were also subjectively judged by visual inspection. The images were scored by two US experts on asymmetry and vessel distribution, respectively, in three grades (no asymmetry, slight asymmetry and clear asymmetry) and in 4 grades (visible flow in capsular and periurethral zone, homogenous distribu-
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tion throughout the prostate, focal increase, intense increase). In Table 1 the three-point grading scale is represented. Standard statistical computer software was used for statistical analysis of the data. Statistical analysis of the data were performed using the student’s t-test and Pearson product. RESULTS No adverse events or complications were observed during or after the IV administration of the microbubble US contrast. Table 2 summarizes the clinical data of the patients. The first part of the study concerned the fast-bolus infusion to study the hemodynamics. The time-intensity curves for the two fast-bolus infusions were calculated and plotted. In Fig. 1, the time-intensity curve is plotted as an example to illustrate the different hemodynamic parameters that could be examined. The objective assessment of the parameters was performed using specially designed computer software. The results are given in Tables 3 and 4. In Table 3, the raw data and % difference between the first and second fast-bolus infusion is given. In Table 4, the statistical assessment of the % difference between the first and second fast-bolus infusions are calculated for all dynamic parameters mentioned. Tables 3 and 4 show that the arrival time (AT) and the peak time (PT) parameters were statistically significantly equal, indicating good reproducibility. All other dynamic parameters were statistically different. Patient 3 had the most marked difference regarding the dynamic parameters between the first and second fast-bolus infusion, caused by motion artefacts during the second fast-bolus contrast investigation. Power Doppler US is very sensitive to motion artefact. Motion artefacts can be suppressed by comfortable po-
Table 2. Clinical data of the patient group. Patient number
Age
DRE
PSA
Conv. TRUS
1 2 3 4 5 6 7 8 9 10
66 70 69 64 57 58 57 49 50 67
T2R B B T2L B T2L T2L B T2R T2L
12.9 6.4 12.0 14.4 20.4 6.4 3.5 4.2 10.5 1.4
T2 R⫹L T0 T0 T0 T2 R⫹L T2/3 L T0 T2 R T2 R⫹L T2L
Number of pos. biopsies R R R R R R R R R R
1 3 1 0 3 0 1 3 2 1
of of of of of of of of of of
3, 3, 3, 3, 3, 3, 3, 3, 3, 3,
L L L L L L L L L L
3 0 0 1 3 2 0 0 1 0
of of of of of of of of of of
3 3 3 3 3 3 3 3 3 3
(Gl (Gl (Gl (Gl (Gl (Gl (Gl (Gl (Gl (Gl
5) 6) 6) 6) 6) 6) 6) 6) 7) 5)
Clinical diagnosis cT2 cT1 cT1 cT2 cT2 cT3 cT2 cT2 cT2 cT2
All patients had biopsy proven prostate cancer and were seen as part of staging investigations. DRE ⫽ digital rectal examination; PSA (ng/mL) ⫽ serum prostate specific antigen; TRUS ⫽ transrectal ultrasonography; R ⫽ right side; L ⫽ left side of the prostate; Gl ⫽ Gleason sum score. All patients were scheduled for radical retropubic prostatectomy.
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Table 3. Objective assessment of fast-bolus infusion. Pt
AT 1
AT 2
%
PT 1
PT 2
%
ET 1
ET 2
%
MI 1
1 2 3 4 5 6 7 8 9 10
270 236 388 494 250 222 474 265 447 448
270 218 455 503 248 232 461 286 444 403
0 7.9 15.8 1.8 0.8 4.4 2.8 7.6 0.7 10.6
308 267 438 626 317 287 531 322 497 515
307 262 545 641 323 295 513 338 511 465
.3 1.9 21.8 2.4 1.9 2.7 3.4 4.8 2.8 10.2
38 31 50 132 67 65 57 57 50 67
37 44 129 138 75 63 52 52 67 62
2.7 34.6 88.3 4.4 11.3 3.1 9.2 9.2 29.0 7.8
161 78 117 313 1602 192 198 614 578 168
MI 2
%
227 34.0 178 78.1 545 129.3 601 63.0 2279 34.9 129 39.25 457 79.1 810 27.5 591 2.2 129 26.3
FWHM 1
FWHM 2
%
80 66 146 157 74 95 56 91 43 208
61 52 160 136 118 104 58 90 55 50
27.0 23.7 9.2 14.3 45.8 9.0 3.5 1.1 24.5 122.5
For all patients, every contrast investigation was performed twice (1 and 2). AT ⫽ arrival time; PT ⫽ peak time; ET ⫽ enhance time; MI ⫽ maximum intensity; FWHM ⫽ full width half maximum; % ⫽ difference between the first and second measurement.
jective assessment of the 3-D volume scans by counting the number of colored pixels and grey pixels, and calculating the ratio. The results are summarized in Table 6. The average % difference between the first and second slow-infusion for the left side, right side and total prostate, respectively, is 14.0%, 15.0% and 0.0%, respectively, indicating fair reproducibility. Figure 2 shows the images of the 3-D contrast-enhanced investigations in all 10 patients, for both the slow infusion studies. Figure 2 shows the close relationship and excellent reproducibility between the first and second contrast study in the patients 1, 2, 3, 5, 6, 9 and 10 with relatively good reproducibility in the patients 4, 7 and 8. The subjective assessment of the slow-infusion contrast study was performed by two US experts, and was performed using the 3-D reconstruction of the prostate (Fig. 2). The 3-D reconstruction was made using the downloaded US volume-scan, performed 1 min after the start of the slow-contrast infusion and using standard 3-D software of the ultrasound scanner. After reconstruction the 3D-image could be rotated on screen, to assess the total amount of blood vessels. The subjective assessment of the vascularity was based on the parameters of Table 1. The results are summarized in Table 7. The results indicate that the experts had good agreement between the first and second slow-infusion investigation (for both
sitioning of the patient, steady control over the US probe, and by informing the patient about the investigation. The subjective assessment was performed by visual observation of the recorded contrast-enhanced images. The results are given in Table 5. After visual assessment of possible hemodynamic asymmetry of the US images of the first fast infusion, the experts were in agreement about the side of greatest contrast enhancement in all patients, although the amount of enhancement was scored differently. After visual assessment of possible hemodynamic asymmetry of the US images of the second fast infusion, the experts had agreement about the asymmetrical distribution of contrast enhancement in 8 patients, but 2 were judged differently. By judging the hemodynamic asymmetry of the 8 agreed patients, the correct tumor side (or side with the largest tumor after histology) was assessed in 7 patients. It should be mentioned that, before assessing possible asymmetrical vasculature, the experts were aware that all patients had prostate cancer, but were blinded to the side of the prostate were the prostate biopsies were positive. However, knowing that asymmetry of vasculature can occur in these patients could be a bias in the visual assessment. The second part of the study concerned the slow infusion of US contrast to study the vascular anatomy. A specially designed computer program performed the ob-
Table 4. Statistical analysis fast-bolus infusion.
AT PT ET MI FWHM
Average
SD
Median
Min
Max
t-test
Pearson
p value
5.2 5.2 19.9 51.4 28.1
5.17 6.4 26.3 36.6 35.7
3.6 2.8 9.2 37.0 19.0
0 0.3 2.7 2.2 1.1
15.9 21.8 88.3 129.3 122.5
0.39 0.24 0.11 0.01 0.23
0.96 0.95 0.68 0.96 0.32
⬍0.01 ⬍0.01 0.09 0.4 0.5
Abbreviations same as in Table 3; Max ⫽ maximum; Min ⫽ minimum; are calculated from the %. The t-test and the Pearson product and p value are calculated from the numerical data. Only the arrival time and peak time are statistically significantly equal.
Reproducibility of contrast ultrasound ● J. P. M. SEDELAAR et al.
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Table 5. Subjective assessment of fast-bolus infusion. Expert 1
Expert 2
Infusion 1
Infusion 2
Infusion 1
Infusion 2
Pt. No.
A
R/L
A
R/L
A
R/L
A
R/L
1 2 3 4 5 6 7 8 9 10
2 1 1 1 1 2 1 0 1 1
L R L L L L R — R R
2 1 1 2 1 1 1 0 1 2
L R R L L L R — R R
1 1 2 1 1 1 1 0 1 2
L R L L L L R — R R
2 1 1 1 1 1 2 1 1 2
L R L L L L R R R R
A ⫽ asymmetry; R ⫽ right side; L ⫽ left side; 0 ⫽ no asymmetry; 1 ⫽ slight asymmetry; 2 ⫽ clear asymmetry.
experts 8 of 10), and also between the two experts (7 of 10). Although the experts agreed for more patients on the side of enhancement, the amount of enhancement was scored differently. For this subjective part of the study, the same arguments as mentioned before (Table 5) can be made. The experts were aware of the fact that all patients had prostate cancer, and visual assessment of asymmetrical vasculature could be biased by this fact. However, inspecting Table 7 indicates that both experts noticed differences in the same patients (patient 3 and 10), and agreed on most of the other patients. DISCUSSION Before new technologies can be introduced and accepted in the medical field, research programs must be performed to establish the value of these techniques. Research investigating the validity of a new technique by studying the sensitivity in detecting a certain pathologic state and the specificity to exclude this certain pathologic state, must be performed to indicate the additional value
of the new techniques over existing and established techniques. Reproducibility of the new technology is another well-discussed issue. Reproducibility is the degree to which repeated measurements of the same test fluctuate. In case of good reproducibility, the variation of repeated measurements of a diagnostic test must be small relative to the variation between a positive or negative test outcome. If a new technology shows good reproducibility and, thus, makes it a reliable test, validity studies can be performed to show clinical validity. By duplicating the contrast ultrasonography investigations of the prostate, following a strict protocol and literally repeating the investigation, the reproducibility of contrast ultrasonography was studied both subjectively by two ultrasound experts and objectively, using special designed computer software. The subjective assessment was concentrated on finding asymmetry in the enhanced images, both for the visual assessment of the video recording of the enhancement of the fast-infusion studies, and the visual assessment of the vasculature of the
Table 6. Objective assessment of slow-bolus infusion. Pt
% left (1)
% left (2)
Difference
% right (1)
% right (2)
Difference
% total (1)
% total (2)
Difference
1 2 3 4 5 6 7 8 9 10 Average
3.0 0.6 5.9 4.1 6.7 3.0 7.6 6.6 2.5 3.5 4.3
3.5 0.7 5.8 5.5 6.7 2.9 5.4 4.9 3.3 3.8 4.2
14.3 14.3 1.7 10.9 0 3.3 28.9 25.6 24.2 8.6 14.0
2.6 1.3 5.3 4.2 6.2 1.1 6.0 5.1 3.1 4.3 3.9
2.7 1.5 5.9 5.8 6.9 0.9 5.2 3.6 3.5 4.0 4.0
3.8 13.3 10.2 27.6 10.1 18.2 13.3 29.4 11.4 7.0 15.0
2.7 0.9 5.6 4.2 6.4 2.2 6.8 5.9 2.8 3.9 4.1
3.1 1.1 5.8 5.6 6.8 2.0 5.3 4.3 3.4 3.9 4.1
12.9 18.2 3.4 25.0 5.9 9.1 22.1 27.1 17.6 0.0 0.0
Computer calculation of the percentage of colored pixels compared to the number of grey pixels for both the left side and the right side and of the whole prostate. Difference is in % colored pixels between the first and second slow-infusion.
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Fig. 2. Examples of static contrast images. Static studies: 3-D CE-PDU reconstruction of all 10 patients, made using the 3-D modality of the Kretz Voluson 530D US scanner. The images on the left side are reconstructions made of the first slow-contrast infusion, the images on the right side are reconstructions made of the second slow-contrast infusion. These images were used for the subjective (visual) assessment of the reproducibility of the slow-contrast infusion.
3-D reconstruction made of the slow-infusion study. In visual assessment, detecting asymmetry in the vascularity of the prostate, indicating increased (micro) vessel density of one side of the prostate, could indicate a possible prostate cancer lesion (Borre et al. 1998; Bostwick and Iczkowski 1998). The visual assessment of the fast-infusion contrast studies showed good intraobserver variability. Also, the interobserver variability was good. Regarding the slow infusion contrast studies, the intraobserver variability between the first and second contrast studies was found to be 80% both for expert I and expert II. Comparing the histology with the agreement findings, all 7 patients had prostate cancer on the identified prostate side. These results indicate good reproducibility of the subjective assessment. The objective assessment of reproducibility, both for the fast- and slow-infusion study was performed
using specially designed computer software. The objective assessment of the hemodynamic parameters was hindered by some difficulties. The difficulties occurred due to motion artefacts (from the patient as well as the investigator), obscuring the contrast enhancement. Improving techniques, which could filter out motion artefacts, could improve the use of contrast ultrasonography to study the hemodynamics of the prostate in the detection of prostate cancer. Up till then, slow-infusion contrast ultrasonography of the prostate should concentrate on the vascular anatomy of the prostate, especially using 3-D reconstruction techniques. The motion artefacts did not influence the arrival time (AT) or peak time (PT), but was influencing the maximum-intensity (MI) and the full-width half-maximum (FWHM). Concerning the slow-infusion contrast study, a specially designed computer program calculated the number of colored pixels,
Reproducibility of contrast ultrasound ● J. P. M. SEDELAAR et al.
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Table 7. Subjective assessment of slow-bolus infusion. Expert I
Expert II
Study I
Study II
Study I
Study II
Pt
AG
VG
Side
AG
VG
Side
AG
VG
Side
AG
VG
Side
1 2 3 4 5 6 7 8 9 10
1 1 0 1 0 2 1 1 2 2
3 2 1 1 1 3 2 1 3 3
L R – L – L R R R R
2 1 1 1 0 2 1 1 1 0
3 2 2 2 1 3 2 1 2 1
L R R L – L R R R –
1 2 1 1 1 2 1 0 2 2
2 2 2 2 2 3 2 1 3 3
L R R L L L L – R R
2 2 2 1 1 2 1 1 2 1
3 2 3 2 2 3 2 2 3 2
L R R R L L L R R R
Two experts assessed the vascularity of the prostate, using the 3-D reconstructed US image, according to the parameters mentioned in Table 1. AG ⫽ asymmetry grading; VG ⫽ vessel distribution grading; Side ⫽ side of the asymmetry.
relative to the number of grey-scale pixels. This calculation was performed using the 3D reconstruction of the US image, made 1 min after the start of contrast infusion. In 80% of the patients, an agreement was found on the side of maximum enhancement (asymmetry parameter). Minimal difference in % colored pixels was found with regard to the first and second slow infusion. In summary, these results indicate very good reproducibility of the subjective assessment of the fast- and slow-infusion contrast studies, as well as for the objective assessment of the slow-infusion study, but with limited reproducibility of the objective assessment of the fast-infusion study. With regard to the reproducibility of contrast US, some issues must be taken into consideration. We performed the contrast US studies, both the slow- and fastinfusion investigations of each individual patient, on 1 day, directly after each other. By performing the studies successively, we wanted to eliminate possible exogene vasoactive factors that could influence the vascularity of the prostate by causing vasodilatation or vasoconstriction. In real practice, successive contrast investigations will not be performed the same day, but with an interval, mostly more than 1 day. By increasing the time in between investigations, it is more likely that vasoactive factors could influence the vascularity of the prostate and, thus, influence the outcome of the dynamic part of the contrast US investigation. These vasoactive factors, however, are not likely to influence the vascular anatomy of the prostate, making the assessment of the static enhancement even more reliable than the assessment of the dynamic enhancement. Combining our study results, indicating that static contrast investigations are accurately reproducible and the assumed relative immunity of static contrast studies for exogene (vasoactive) factors, make static contrast investigations an interesting tool for the detection of
prostate cancer. However, we should not dismiss dynamic contrast studies of the prostate. Although dynamic contrast investigations showed limited reproducibility, which makes them unreliable, dynamic information might still be of use in the assessment of a prostate tumor. Studies have proven that the histology of tumor blood vessels is different than healthy tissue blood vessels, resulting in disorganized blood vessel architecture and leaky blood vessels (Dvorak et al. 1988; Gerlowski and Jain 1986). Our results indicate that the arrival time (AT) and the peak time (PT) of the dynamic contrast studies are accurately reproducible. In the future, these two parameters could possibly be used to assess prostate tumor, or even the aggressiveness of a certain prostate tumor. In our present study, we have studied the reproducibility of the contrast dynamics of the prostate in 2-D, using only the one plane through the prostate. These 2-D dynamic studies could be seen as a precursor for the expected clinical applications of contrast US. It is expected that, in the near future, US scanners will have the possibility of imaging the perfusion of the prostate in real-time and in 3-D. The expected development of the US scanners will also influence the costs of the contrast US investigations. In the present setting, we used two contrast infusions to study the static and dynamic information of the prostate; in the future, we just need one infusion to get all the contrast information we need. CONCLUSION In the study presented, the reproducibility of 3-D contrast-enhanced power Doppler transrectal US of the prostate has been investigated, both by objective and subjective assessment of the fast infusion (hemodynamics) and the slow infusion (vascular anatomy). We con-
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cluded that, especially the slow infusion, is reproducible, both by objective and subjective assessment. For the fast infusion, some difficulties occurred caused by motion artefacts that mainly influenced the objective assessment. The subjective assessment of the hemodynamics was reproducible but, using the objective assessment, only the arrival time and the peak time proved reproducible. Further research will indicate the clinical validity of transrectal contrast US for the detection and follow-up of prostate cancer. Acknowledgements—This study was supported by an educational grant of the Kretz Co. (Austria) and of the Schering Co. (The Netherlands).
REFERENCES Aarnink RG, Beerlage HP, de la Rosette JJ, Debruyne FM, Wijkstra H. Contrast angiosonography: A technology to improve Doppler ultrasound examinations of the prostate. Eur Urol l999;35:9 –20. Bergdahl S, Aus G, Lodding P, Norlen L, Hugosson J. Transrectal ultrasound with separate measurement of the transition zone volume predicts the short-term outcome after transurethral resection of the prostate. Urology 1999;53:926 –930. Bogers JA, Sedelaar JPM, Beerlage HP, de la Rosette JJMCH, Debruyne FMJ, Wijkstra H, Aarnink RG. Contrast enhanced 3D power Doppler angiography of the human prostate: Correlation with biopsy outcome. Urology 1999;54:97–104. Bostwick DG, Iczkowski KA. Microvessel density in prostate cancer: Prognostic and therapeutic utility. Semin Urol Oncol 1998;16:118 – 123. Borre M, Offersen BV, Nerstrom B, Overgaard J. Microvessel density
Volume 27, Number 5, 2001 predicts survival in prostate cancer patients subjected to watchful waiting. Br J Cancer 1998;78:940 –944. Dvorak HF, Nagy JA, Dvorak JT, Dvorak AM. Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol 1988;133:95–109. Gerlowski LE, Jain RK. Microvascular permeability of normal and neoplastic tissues. Microvasc Res 1986;31:288 –305. Halpern EJ, Strup SE. Using gray-scale and color and power Doppler sonography to detect prostatic cancer. Am J Roentgenol 2000;174: 623– 627. Halpern EJ, Verkh L, Forsberg F, Gomella LG, Mattrey RF, Goldberg BB. Initial experience with contrast-enhanced sonography of the prostate. Am J Roentgenol 2000;174:1575–1580. Lee C, Sintich SM, Mathews EP, Shah AH, Kundu SD, Perry KT, Cho JS, Ilio KY, Cronauer MV, Janulis L, Sensibar JA. Transforming growth factor-beta in benign and malignant prostate. Prostate 1999; 39:285–290. Levine MA, Ittman M, Melamed J, Lepor H. Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 1998;159:471– 475. Matsushima H, Goto T, Hosaka Y, Kitamura T, Kawabe K. Correlation between proliferation, apoptosis, and angiogenesis in prostate carcinoma and their relation to androgen ablation. Cancer 1999;85: 1822–1827. Roehrborn CG. Accurate determination of prostate size via digital rectal examination and transrectal ultrasound. Urology 1998;51: 19 –22. Sedelaar JPM, de la Rosette JJMCH, Beerlage HP, Wijkstra H, Debruyne FMJ, Aarnink RG. Transrectal ultrasound imaging of the prostate: Review and perspectives of recent developments. Prostate Cancer Prostatic Dis 1999;2:241–252. Unal D, Sedelaar JPM, Aarnink RG, van Leenders GJLH, Wijkstra H, Debruyne FMJ, de la Rosette JJMCH. Three-dimensional contrastenhanced power Doppler ultrasound and conventional examnination methods: Value of diagnostic predictors of prostate cancer. Br J Urol Int 2000;86:58 – 64.
PII: S0301-5629(01)00346-5
● Original Contribution REPRODUCIBILITY OF CONTRAST-ENHANCED TRANSRECTAL ULTRASOUND OF THE PROSTATE J. P. MICHIEL SEDELAAR, TJERK E. B. GOOSSEN, HESSEL WIJKSTRA and JEAN J. M. C. H. DE LA ROSETTE Department of Urology, University Medical Center, St Radboud, Nijmegen, The Netherlands (Received 3 October 2000; in final form 22 January 2001)
Abstract—Transrectal three-dimensional (3-D) contrast-enhanced power Doppler ultrasound (US) is a novel technique for studying possible prostate malignancy. Before studies can be performed to investigate the clinical validity of the technique, reproducibility of the contrast US studies must be proven. Reproducibility of contrast US was studied in 10 patients with biopsy-proven prostate cancer. The studies performed included static investigations and dynamic investigations of the prostate vasculature. All studies were double performed. The assessment of reproducibility was done objectively using a computer program and, subjectively, by visual assessment. The results indicate high reproducibility of static contrast investigations, for both the objective and subjective assessment. The subjective assessment of the dynamic studies was also highly reproducible. The objective assessment of the dynamic contrast studies, however, was less reproducible, mainly due to motion artefact. We concluded that, especially static 3-D contrast-enhanced, power Doppler investigations of the prostate are highly reproducible. (E-mail: [email protected]) © 2001 World Federation for Ultrasound in Medicine & Biology. Key Words: Contrast-enhanced ultrasound, Prostate, 3-D ultrasound, Reproducibility studies.
localizing prostate cancer. Contrast improves the acoustic properties of the blood flow, making the combination of Doppler US and US contrast even more sensitive for detection of alterations in blood flow. Adding 3-D modalities to contrast Doppler US could provide a method to study the vascularity of the whole prostate in a single image, and could, thus, facilitate the assessment of possible abnormal vascularity. Currently, research programs are performed to study the use of transrectal (3-D) contrast-enhanced power Doppler ultrasonography in the detection of prostate cancer (Bogers et al. 1999; Unal et al. 2000; Halpern et al. 2000). These studies are performed to investigate if contrast-enhanced power Doppler ultrasonography has additional value over conventional transrectal ultrasonography in the detection and follow-up of different prostate pathologies, especially prostate cancer. Early findings indicate an additional value of transrectal contrast ultrasonography in the diagnosis of prostate cancer using the static and dynamic information provided (Bogers et al. 1999; Aarnink et al. 1999). Before contrast ultrasonography can be accepted as a reliable tool for the detection of prostate cancer, reproducibility of this method is of crucial importance. Results
INTRODUCTION Conventional grey-scale transrectal ultrasound (US) of the prostate has proven its usefulness in volume measurement (Roehrborn 1998; Bergdahl et al. 1999) and biopsy guidance (Levine et al. 1998), but has a limited sensitivity and specificity in detection, localization and staging of prostate cancer (Halpern and Strup 2000; Sedelaar et al. 1999). New US imaging modalities are being developed to increase the usefulness of transrectal US in the detection of prostate cancer. Some of these new modalities focus on imaging the vascularity of the prostate. It is a fact that the development of prostate cancer involves angiogenesis and the formation of arteriovenous shunts (Matsushima et al. 1999; Lee et al. 1999) that alter the hemodynamics and vascular anatomy. Visualization of these blood and vessel abnormalities using Doppler ultrasonography could provide a method of increasing the sensitivity and specificity of US in detecting and Address correspondence to: J. P. Michiel Sedelaar, M.D., Department of Urology, University Medical Center, St Radboud, Nijmegen, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: [email protected] 595
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of repetitive investigations performed following a strict protocol must be objectively and subjectively comparable, and must lead to unanimous conclusions regarding the diagnosis. The objective of the present study was to determine the reproducibility of transrectal 3-D contrast-enhanced power Doppler ultrasonography. MATERIALS AND METHODS Reproducibility of 3-D contrast-enhanced power Doppler ultrasonography was investigated in a group of patients with biopsy-proven prostate carcinoma and scheduled for transrectal ultrasonography of the prostate for staging. The study was performed using a strict protocol for US investigations, preparation and administration of the US contrast agent and image analysis. Image analysis was performed using specially designed computer software (Borland威 Delphi 3 Professional combined with Skyline Tools威 Imagelib 3.0). A total of 10 patients with biopsy-proven prostate cancer who were scheduled to undergo radical prostatectomy were included in the protocol after giving informed consent. We performed transrectal grey-scale US, 3-D transrectal US and power Doppler US studies using a Kretz威 Voluson 530D US scanner in combination with a S-VDW 5- to 8-MHz probe (Kretztechnik AG, Zipf, Austria). For the contrast investigations, we used IVadministered 7 mL (300 mg/mL) Levovist威 microbubble US contrast (Schering AG, Berlin, Germany). For all US investigations, we used the same settings of the US scanner. Before the start of the US contrast studies, an 18gauge IV cannula (Venflon威 2, Ohmeda AB, Helingborg, Sweden) was inserted in an antecubital vein in the right arm of the patient. All investigations were performed with the patient in the left lateral decubitus position. One physician performed the US studies and one person prepared and administered the US contrast to all patients. The US contrast agent was prepared according to the manufacturer’s protocol: the US contrast is prepared for use by mixing 7 mL of sterile water with 2.5 g of Levovist威 and firmly shaken during 10 s. A milky suspension of galactose microparticles and microbubbles is formed after resting the mixture for 2 min. After these 2 min, the suspension is ready for IV administration and will be stable for about 10 min. We performed the reproducibility study in two parts: a dynamic response and a static response. Both parts of the study were performed twice. The first part of the study concerned the dynamic response, to study the hemodynamics of the prostate blood vessels. We gave a fast-bolus infusion (4 s) of 7-mL microbubble US contrast (300 mg/mL) while hold-
Fig. 1. Time intensity curve. Example of the different dynamic parameters obtained from the plotted time-intensity curve. Arrival time (AT) ⫽ time at which enhancement is greater than 1.5* baseline, or greater than 10 when baseline ⫽ 0; Peak ⫽ maximum intensity; Peak time ⫽ time at maximum intensity; Full width half maximum (FWHM) ⫽ curve width at half maximum; Enhance time (ET) ⫽ peak time minus arrival time.
ing the transrectal US probe on a steady transverse crosssection through the prostate. After the effect of the first enhancement had disappeared, the exact same fast-bolus investigation was performed using a second infusion of US contrast, and holding the US probe on the same transverse cross-section of the prostate. The power Doppler enhancement images were recorded on video (S-VHS) and afterward digitized by computer. A computer program was designed to calculate, for both fastbolus investigations, the number of colored pixels during the first min of the enhancement in the right lobe and the left lobe of the prostate and plotted against the time. For both investigations, the right and left curves were normalized to the maximum. We choose to use standard hemodynamic parameters, which were both time-dependent and time-independent. The following hemodynamic parameters were obtained for the quantification of the contrast studies: the arrival time (AT ⫽ start of enhancement), peak (P ⫽ maximum enhancement), peak time (PT ⫽ time of maximum enhancement), full-width half maximum (FWHM ⫽ the width of the enhancement curve at the half of the maximum enhancement) and enhance time (ET ⫽ peak time minus arrival time). The hemodynamic parameters were mainly chosen to test reproducibility of the contrast US technique, but the clinical value is not yet proven. This is illustrated in Fig. 1. After the objective computer comparison between the two dynamic studies, two US experts performed a subjective random assessment of the US images by visual inspection of the recorded images and assessed the presence of asymmetrical enhancement in three grades: no asymmetry, slight asymmetry and clear asymmetry.
Reproducibility of contrast ultrasound ● J. P. M. SEDELAAR et al.
Table 1. Grading scale used for subjective assessment. Asymmetry grading Grade 0 No asymmetry Grade 1 Slight asymmetry Grade 2 Marked asymmetry Vessel distribution grading Grade 0 Visible flow in the capsular and periurethral zones Grade 1 Vascularity throughout the prostate distributed in a homogeneous fashion Grade 2 Focal increase in vascularity Grade 3 Intense focal increase in vascularity
The second part of the study concerned the static imaging of the blood vessel architecture. For this study, we administered a slow infusion (25 s) of 7-mL microbubble US contrast (300 mg/mL). This prolonged infusion resulted in a longer duration of the enhancement due to the more evenly distributed contrast agent. At 1 min after the beginning of the contrast infusion, a 3-D power Doppler scan of the whole prostate was made. This 3-D image was stored on the hard disc of the computer. Second, we performed an identical slow infusion investigation when the first enhancement had died out. Using the stored image, a 3-D model of the vascular anatomy of the prostate was created for both slow studies. Slices of the prostate (4 mm) were made using the 3-D images. The 4-mm slices were divided in 4 mm3 cubes and of these cubes the enhanced vessel density could be calculated by computer as the ratio between colored pixel and grey pixels. This quantification was performed for both the right and the left side of the prostate, as well as the whole prostate. The images were also subjectively judged by visual inspection. The images were scored by two US experts on asymmetry and vessel distribution, respectively, in three grades (no asymmetry, slight asymmetry and clear asymmetry) and in 4 grades (visible flow in capsular and periurethral zone, homogenous distribu-
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tion throughout the prostate, focal increase, intense increase). In Table 1 the three-point grading scale is represented. Standard statistical computer software was used for statistical analysis of the data. Statistical analysis of the data were performed using the student’s t-test and Pearson product. RESULTS No adverse events or complications were observed during or after the IV administration of the microbubble US contrast. Table 2 summarizes the clinical data of the patients. The first part of the study concerned the fast-bolus infusion to study the hemodynamics. The time-intensity curves for the two fast-bolus infusions were calculated and plotted. In Fig. 1, the time-intensity curve is plotted as an example to illustrate the different hemodynamic parameters that could be examined. The objective assessment of the parameters was performed using specially designed computer software. The results are given in Tables 3 and 4. In Table 3, the raw data and % difference between the first and second fast-bolus infusion is given. In Table 4, the statistical assessment of the % difference between the first and second fast-bolus infusions are calculated for all dynamic parameters mentioned. Tables 3 and 4 show that the arrival time (AT) and the peak time (PT) parameters were statistically significantly equal, indicating good reproducibility. All other dynamic parameters were statistically different. Patient 3 had the most marked difference regarding the dynamic parameters between the first and second fast-bolus infusion, caused by motion artefacts during the second fast-bolus contrast investigation. Power Doppler US is very sensitive to motion artefact. Motion artefacts can be suppressed by comfortable po-
Table 2. Clinical data of the patient group. Patient number
Age
DRE
PSA
Conv. TRUS
1 2 3 4 5 6 7 8 9 10
66 70 69 64 57 58 57 49 50 67
T2R B B T2L B T2L T2L B T2R T2L
12.9 6.4 12.0 14.4 20.4 6.4 3.5 4.2 10.5 1.4
T2 R⫹L T0 T0 T0 T2 R⫹L T2/3 L T0 T2 R T2 R⫹L T2L
Number of pos. biopsies R R R R R R R R R R
1 3 1 0 3 0 1 3 2 1
of of of of of of of of of of
3, 3, 3, 3, 3, 3, 3, 3, 3, 3,
L L L L L L L L L L
3 0 0 1 3 2 0 0 1 0
of of of of of of of of of of
3 3 3 3 3 3 3 3 3 3
(Gl (Gl (Gl (Gl (Gl (Gl (Gl (Gl (Gl (Gl
5) 6) 6) 6) 6) 6) 6) 6) 7) 5)
Clinical diagnosis cT2 cT1 cT1 cT2 cT2 cT3 cT2 cT2 cT2 cT2
All patients had biopsy proven prostate cancer and were seen as part of staging investigations. DRE ⫽ digital rectal examination; PSA (ng/mL) ⫽ serum prostate specific antigen; TRUS ⫽ transrectal ultrasonography; R ⫽ right side; L ⫽ left side of the prostate; Gl ⫽ Gleason sum score. All patients were scheduled for radical retropubic prostatectomy.
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Table 3. Objective assessment of fast-bolus infusion. Pt
AT 1
AT 2
%
PT 1
PT 2
%
ET 1
ET 2
%
MI 1
1 2 3 4 5 6 7 8 9 10
270 236 388 494 250 222 474 265 447 448
270 218 455 503 248 232 461 286 444 403
0 7.9 15.8 1.8 0.8 4.4 2.8 7.6 0.7 10.6
308 267 438 626 317 287 531 322 497 515
307 262 545 641 323 295 513 338 511 465
.3 1.9 21.8 2.4 1.9 2.7 3.4 4.8 2.8 10.2
38 31 50 132 67 65 57 57 50 67
37 44 129 138 75 63 52 52 67 62
2.7 34.6 88.3 4.4 11.3 3.1 9.2 9.2 29.0 7.8
161 78 117 313 1602 192 198 614 578 168
MI 2
%
227 34.0 178 78.1 545 129.3 601 63.0 2279 34.9 129 39.25 457 79.1 810 27.5 591 2.2 129 26.3
FWHM 1
FWHM 2
%
80 66 146 157 74 95 56 91 43 208
61 52 160 136 118 104 58 90 55 50
27.0 23.7 9.2 14.3 45.8 9.0 3.5 1.1 24.5 122.5
For all patients, every contrast investigation was performed twice (1 and 2). AT ⫽ arrival time; PT ⫽ peak time; ET ⫽ enhance time; MI ⫽ maximum intensity; FWHM ⫽ full width half maximum; % ⫽ difference between the first and second measurement.
jective assessment of the 3-D volume scans by counting the number of colored pixels and grey pixels, and calculating the ratio. The results are summarized in Table 6. The average % difference between the first and second slow-infusion for the left side, right side and total prostate, respectively, is 14.0%, 15.0% and 0.0%, respectively, indicating fair reproducibility. Figure 2 shows the images of the 3-D contrast-enhanced investigations in all 10 patients, for both the slow infusion studies. Figure 2 shows the close relationship and excellent reproducibility between the first and second contrast study in the patients 1, 2, 3, 5, 6, 9 and 10 with relatively good reproducibility in the patients 4, 7 and 8. The subjective assessment of the slow-infusion contrast study was performed by two US experts, and was performed using the 3-D reconstruction of the prostate (Fig. 2). The 3-D reconstruction was made using the downloaded US volume-scan, performed 1 min after the start of the slow-contrast infusion and using standard 3-D software of the ultrasound scanner. After reconstruction the 3D-image could be rotated on screen, to assess the total amount of blood vessels. The subjective assessment of the vascularity was based on the parameters of Table 1. The results are summarized in Table 7. The results indicate that the experts had good agreement between the first and second slow-infusion investigation (for both
sitioning of the patient, steady control over the US probe, and by informing the patient about the investigation. The subjective assessment was performed by visual observation of the recorded contrast-enhanced images. The results are given in Table 5. After visual assessment of possible hemodynamic asymmetry of the US images of the first fast infusion, the experts were in agreement about the side of greatest contrast enhancement in all patients, although the amount of enhancement was scored differently. After visual assessment of possible hemodynamic asymmetry of the US images of the second fast infusion, the experts had agreement about the asymmetrical distribution of contrast enhancement in 8 patients, but 2 were judged differently. By judging the hemodynamic asymmetry of the 8 agreed patients, the correct tumor side (or side with the largest tumor after histology) was assessed in 7 patients. It should be mentioned that, before assessing possible asymmetrical vasculature, the experts were aware that all patients had prostate cancer, but were blinded to the side of the prostate were the prostate biopsies were positive. However, knowing that asymmetry of vasculature can occur in these patients could be a bias in the visual assessment. The second part of the study concerned the slow infusion of US contrast to study the vascular anatomy. A specially designed computer program performed the ob-
Table 4. Statistical analysis fast-bolus infusion.
AT PT ET MI FWHM
Average
SD
Median
Min
Max
t-test
Pearson
p value
5.2 5.2 19.9 51.4 28.1
5.17 6.4 26.3 36.6 35.7
3.6 2.8 9.2 37.0 19.0
0 0.3 2.7 2.2 1.1
15.9 21.8 88.3 129.3 122.5
0.39 0.24 0.11 0.01 0.23
0.96 0.95 0.68 0.96 0.32
⬍0.01 ⬍0.01 0.09 0.4 0.5
Abbreviations same as in Table 3; Max ⫽ maximum; Min ⫽ minimum; are calculated from the %. The t-test and the Pearson product and p value are calculated from the numerical data. Only the arrival time and peak time are statistically significantly equal.
Reproducibility of contrast ultrasound ● J. P. M. SEDELAAR et al.
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Table 5. Subjective assessment of fast-bolus infusion. Expert 1
Expert 2
Infusion 1
Infusion 2
Infusion 1
Infusion 2
Pt. No.
A
R/L
A
R/L
A
R/L
A
R/L
1 2 3 4 5 6 7 8 9 10
2 1 1 1 1 2 1 0 1 1
L R L L L L R — R R
2 1 1 2 1 1 1 0 1 2
L R R L L L R — R R
1 1 2 1 1 1 1 0 1 2
L R L L L L R — R R
2 1 1 1 1 1 2 1 1 2
L R L L L L R R R R
A ⫽ asymmetry; R ⫽ right side; L ⫽ left side; 0 ⫽ no asymmetry; 1 ⫽ slight asymmetry; 2 ⫽ clear asymmetry.
experts 8 of 10), and also between the two experts (7 of 10). Although the experts agreed for more patients on the side of enhancement, the amount of enhancement was scored differently. For this subjective part of the study, the same arguments as mentioned before (Table 5) can be made. The experts were aware of the fact that all patients had prostate cancer, and visual assessment of asymmetrical vasculature could be biased by this fact. However, inspecting Table 7 indicates that both experts noticed differences in the same patients (patient 3 and 10), and agreed on most of the other patients. DISCUSSION Before new technologies can be introduced and accepted in the medical field, research programs must be performed to establish the value of these techniques. Research investigating the validity of a new technique by studying the sensitivity in detecting a certain pathologic state and the specificity to exclude this certain pathologic state, must be performed to indicate the additional value
of the new techniques over existing and established techniques. Reproducibility of the new technology is another well-discussed issue. Reproducibility is the degree to which repeated measurements of the same test fluctuate. In case of good reproducibility, the variation of repeated measurements of a diagnostic test must be small relative to the variation between a positive or negative test outcome. If a new technology shows good reproducibility and, thus, makes it a reliable test, validity studies can be performed to show clinical validity. By duplicating the contrast ultrasonography investigations of the prostate, following a strict protocol and literally repeating the investigation, the reproducibility of contrast ultrasonography was studied both subjectively by two ultrasound experts and objectively, using special designed computer software. The subjective assessment was concentrated on finding asymmetry in the enhanced images, both for the visual assessment of the video recording of the enhancement of the fast-infusion studies, and the visual assessment of the vasculature of the
Table 6. Objective assessment of slow-bolus infusion. Pt
% left (1)
% left (2)
Difference
% right (1)
% right (2)
Difference
% total (1)
% total (2)
Difference
1 2 3 4 5 6 7 8 9 10 Average
3.0 0.6 5.9 4.1 6.7 3.0 7.6 6.6 2.5 3.5 4.3
3.5 0.7 5.8 5.5 6.7 2.9 5.4 4.9 3.3 3.8 4.2
14.3 14.3 1.7 10.9 0 3.3 28.9 25.6 24.2 8.6 14.0
2.6 1.3 5.3 4.2 6.2 1.1 6.0 5.1 3.1 4.3 3.9
2.7 1.5 5.9 5.8 6.9 0.9 5.2 3.6 3.5 4.0 4.0
3.8 13.3 10.2 27.6 10.1 18.2 13.3 29.4 11.4 7.0 15.0
2.7 0.9 5.6 4.2 6.4 2.2 6.8 5.9 2.8 3.9 4.1
3.1 1.1 5.8 5.6 6.8 2.0 5.3 4.3 3.4 3.9 4.1
12.9 18.2 3.4 25.0 5.9 9.1 22.1 27.1 17.6 0.0 0.0
Computer calculation of the percentage of colored pixels compared to the number of grey pixels for both the left side and the right side and of the whole prostate. Difference is in % colored pixels between the first and second slow-infusion.
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Fig. 2. Examples of static contrast images. Static studies: 3-D CE-PDU reconstruction of all 10 patients, made using the 3-D modality of the Kretz Voluson 530D US scanner. The images on the left side are reconstructions made of the first slow-contrast infusion, the images on the right side are reconstructions made of the second slow-contrast infusion. These images were used for the subjective (visual) assessment of the reproducibility of the slow-contrast infusion.
3-D reconstruction made of the slow-infusion study. In visual assessment, detecting asymmetry in the vascularity of the prostate, indicating increased (micro) vessel density of one side of the prostate, could indicate a possible prostate cancer lesion (Borre et al. 1998; Bostwick and Iczkowski 1998). The visual assessment of the fast-infusion contrast studies showed good intraobserver variability. Also, the interobserver variability was good. Regarding the slow infusion contrast studies, the intraobserver variability between the first and second contrast studies was found to be 80% both for expert I and expert II. Comparing the histology with the agreement findings, all 7 patients had prostate cancer on the identified prostate side. These results indicate good reproducibility of the subjective assessment. The objective assessment of reproducibility, both for the fast- and slow-infusion study was performed
using specially designed computer software. The objective assessment of the hemodynamic parameters was hindered by some difficulties. The difficulties occurred due to motion artefacts (from the patient as well as the investigator), obscuring the contrast enhancement. Improving techniques, which could filter out motion artefacts, could improve the use of contrast ultrasonography to study the hemodynamics of the prostate in the detection of prostate cancer. Up till then, slow-infusion contrast ultrasonography of the prostate should concentrate on the vascular anatomy of the prostate, especially using 3-D reconstruction techniques. The motion artefacts did not influence the arrival time (AT) or peak time (PT), but was influencing the maximum-intensity (MI) and the full-width half-maximum (FWHM). Concerning the slow-infusion contrast study, a specially designed computer program calculated the number of colored pixels,
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Table 7. Subjective assessment of slow-bolus infusion. Expert I
Expert II
Study I
Study II
Study I
Study II
Pt
AG
VG
Side
AG
VG
Side
AG
VG
Side
AG
VG
Side
1 2 3 4 5 6 7 8 9 10
1 1 0 1 0 2 1 1 2 2
3 2 1 1 1 3 2 1 3 3
L R – L – L R R R R
2 1 1 1 0 2 1 1 1 0
3 2 2 2 1 3 2 1 2 1
L R R L – L R R R –
1 2 1 1 1 2 1 0 2 2
2 2 2 2 2 3 2 1 3 3
L R R L L L L – R R
2 2 2 1 1 2 1 1 2 1
3 2 3 2 2 3 2 2 3 2
L R R R L L L R R R
Two experts assessed the vascularity of the prostate, using the 3-D reconstructed US image, according to the parameters mentioned in Table 1. AG ⫽ asymmetry grading; VG ⫽ vessel distribution grading; Side ⫽ side of the asymmetry.
relative to the number of grey-scale pixels. This calculation was performed using the 3D reconstruction of the US image, made 1 min after the start of contrast infusion. In 80% of the patients, an agreement was found on the side of maximum enhancement (asymmetry parameter). Minimal difference in % colored pixels was found with regard to the first and second slow infusion. In summary, these results indicate very good reproducibility of the subjective assessment of the fast- and slow-infusion contrast studies, as well as for the objective assessment of the slow-infusion study, but with limited reproducibility of the objective assessment of the fast-infusion study. With regard to the reproducibility of contrast US, some issues must be taken into consideration. We performed the contrast US studies, both the slow- and fastinfusion investigations of each individual patient, on 1 day, directly after each other. By performing the studies successively, we wanted to eliminate possible exogene vasoactive factors that could influence the vascularity of the prostate by causing vasodilatation or vasoconstriction. In real practice, successive contrast investigations will not be performed the same day, but with an interval, mostly more than 1 day. By increasing the time in between investigations, it is more likely that vasoactive factors could influence the vascularity of the prostate and, thus, influence the outcome of the dynamic part of the contrast US investigation. These vasoactive factors, however, are not likely to influence the vascular anatomy of the prostate, making the assessment of the static enhancement even more reliable than the assessment of the dynamic enhancement. Combining our study results, indicating that static contrast investigations are accurately reproducible and the assumed relative immunity of static contrast studies for exogene (vasoactive) factors, make static contrast investigations an interesting tool for the detection of
prostate cancer. However, we should not dismiss dynamic contrast studies of the prostate. Although dynamic contrast investigations showed limited reproducibility, which makes them unreliable, dynamic information might still be of use in the assessment of a prostate tumor. Studies have proven that the histology of tumor blood vessels is different than healthy tissue blood vessels, resulting in disorganized blood vessel architecture and leaky blood vessels (Dvorak et al. 1988; Gerlowski and Jain 1986). Our results indicate that the arrival time (AT) and the peak time (PT) of the dynamic contrast studies are accurately reproducible. In the future, these two parameters could possibly be used to assess prostate tumor, or even the aggressiveness of a certain prostate tumor. In our present study, we have studied the reproducibility of the contrast dynamics of the prostate in 2-D, using only the one plane through the prostate. These 2-D dynamic studies could be seen as a precursor for the expected clinical applications of contrast US. It is expected that, in the near future, US scanners will have the possibility of imaging the perfusion of the prostate in real-time and in 3-D. The expected development of the US scanners will also influence the costs of the contrast US investigations. In the present setting, we used two contrast infusions to study the static and dynamic information of the prostate; in the future, we just need one infusion to get all the contrast information we need. CONCLUSION In the study presented, the reproducibility of 3-D contrast-enhanced power Doppler transrectal US of the prostate has been investigated, both by objective and subjective assessment of the fast infusion (hemodynamics) and the slow infusion (vascular anatomy). We con-
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cluded that, especially the slow infusion, is reproducible, both by objective and subjective assessment. For the fast infusion, some difficulties occurred caused by motion artefacts that mainly influenced the objective assessment. The subjective assessment of the hemodynamics was reproducible but, using the objective assessment, only the arrival time and the peak time proved reproducible. Further research will indicate the clinical validity of transrectal contrast US for the detection and follow-up of prostate cancer. Acknowledgements—This study was supported by an educational grant of the Kretz Co. (Austria) and of the Schering Co. (The Netherlands).
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