Sonographic Evaluation of Venous Obstruction in Liver Transplants

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1 Sonography of Venous Obstruction in Liver Transplants Hepatobiliary Imaging Original Research Wui K. Chong 1 Jason C. Beland 1,2 Susan M. Weeks 1,3 Chong WK, Beland JC, Weeks SM Keywords: Doppler sonography, hepatobiliary imaging, liver transplantation, venography, venous obstruction DOI: /AJR Received September 24, 2006; accepted after revision December 18, Department of Radiology, CB 7510, University of North Carolina Hospitals, 101 Manning Dr., Chapel Hill, NC Address correspondence to W. K. Chong. 2 Present address: Department of Radiology, Saint Joseph s Hospital, Atlanta, GA. 3 Present address: Interventional Services, Wake Radiology Diagnostic Imaging, Inc., Cary, NC. WEB This is a Web exclusive article. AJR 2007; 188:W515 W X/07/1886 W515 American Roentgen Ray Society Sonographic Evaluation of Venous Obstruction in Liver Transplants OBJECTIVE. The purpose of our study was to identify specific Doppler criteria for portal vein and outflow vein (hepatic veins and inferior vena cava) obstruction in liver transplants. MATERIALS AND METHODS. A retrospective review was performed of Doppler sonographic studies and angiograms in 94 liver transplant cases (72 whole liver, 22 lobar) with suspected vascular obstruction. The angiograms were classified as normal, occluded, or stenosed on the basis of appearance and elevated pressure gradient. Sonography was correlated with angiography. The following Doppler parameters were evaluated: for the portal vein, peak anastomotic velocity and anastomotic-to-preanastomotic velocity ratio; and for the outflow veins, venous pulsatility index. Receiver operating characteristic curves were constructed and optimum thresholds for stenosis were defined. RESULTS. There were 16 cases of portal vein obstruction (11 stenosis, five occlusion) and 35 cases of outflow vein obstruction (34 stenoses, one occlusion). Mean peak anastomotic velocity in normal portal veins was 58 cm/s, whereas mean peak anastomotic velocity in stenosed veins was 155 cm/s (p = ). Peak anastomotic velocity threshold of > 125 cm/s was 73% sensitive and 95% specific for stenosis. Mean anastomotic-to-preanastomotic velocity ratio in normal portal veins was 1.5, and mean anastomotic-to-preanastomotic velocity ratio in stenosed veins was 4.69 (p = 0.001). A 3:1 ratio was 73% sensitive and 100% specific for stenosis. Mean venous pulsatility index for normal outflow veins was 0.75, and mean venous pulsatility index in stenosed veins was A venous pulsatility index of < 0.45 was 95.7% specific for stenosis. The areas under the receiver operating characteristic curve were 0.83 for peak anastomotic velocity, 0.86 for anastomotic-to-preanastomotic velocity ratio, and 0.84 for venous pulsatility index, indicating good correlation. CONCLUSION. Peak anastomotic velocity, anastomotic-to-preanastomotic velocity ratio, and venous pulsatility index are useful parameters for diagnosing venous stenosis in liver transplants. ascular obstruction, defined as V reduction or cessation of flow, is a major complication of liver transplantation. Hepatic artery obstruction is the most common vascular complication [1, 2]; it can lead to loss of the transplant [3]. However, obstruction of the portal vein and outflow veins may also have deleterious consequences, including ascites, abdominal distention, liver enzyme elevation, and gastrointestinal bleeding [4, 5]. Doppler sonography is a quick, noninvasive method for assessing the transplant liver [6, 7]. Doppler criteria for hepatic artery stenosis and occlusion are well established [8], but sonographic criteria for venous obstruction are less clear. In this study, we sought to establish sonographic parameters for venous outflow (hepatic vein and inferior vena cava [IVC]) and portal vein obstruction in liver transplants. Materials and Methods At our institution, postoperative Doppler sonography to assess vascular patency is routinely performed on liver transplant patients. Sonography is performed on a daily basis during the immediate postoperative period, before discharge, and at outpatient follow-up at 1, 6, and 12 months. The study population was composed of liver transplant recipients who had confirmatory angiograms within 7 days of their Doppler sonography. This study was approved by the institutional review board. Patients The records of 456 patients who had liver transplants at our institution between 1996 and 2003 were reviewed. The patients ages ranged W515

2 Fig year-old male liver transplant recipient. Measurement of venous pulsatility index on triphasic waveform from the middle hepatic vein (MHV). Venous pulsatility index is difference between maximum (A) and minimum (B) frequency shift divided by A. With triphasic waveform (above), this is A + B / A. from 1 to 67 years (mean age, 41 years; SD, 18.2 years). Forty-four patients had partial or lobar liver transplants and 412 patients had whole-liver transplants. The records showed that 97 angiograms of the portal vein or hepatic vein/ivc were performed on these patients after transplantation. The angiograms were obtained because arterial or venous obstruction was suspected on clinical grounds or because Doppler sonography suggested the presence of arterial or venous obstruction. Three patients were excluded because their venogram was not preceded by a recent Doppler study (defined as 7 days). The remaining 94 patients made up the study population. There were 58 posttransplant hepatic venograms, 42 in whole-liver transplants and 16 in partial (lobar) transplants. There were 36 portal venograms, 30 in whole and six in partial (lobar) transplants. The portal venograms included direct and indirect portograms. The latter were delayed images after hepatic arterial injection. Indirect portograms that were suspicious for stenosis or thrombosis was confirmed by direct portography with pressure gradient measurements. Direct portograms were not performed if the indirect portograms were normal. Therefore, all indirect portograms in study patients were normal. All hepatic venograms included pressure gradient measurements. The angiograms were classified as normal, significantly stenosed, or completely occluded or thrombosed. Significant stenosis was defined as a morphologic stenosis that required stent placement and angioplasty (as was the case in all but three patients in the stenosed group; the exceptions were not stented because their stenoses were caused by extrinsic compression from hematoma or an edematous liver); or as a pressure gradient across the stenosis of 3 mm Hg or greater. The median pressure gradient was 8 mm Hg in the stenosed group. Angiography was used as the reference standard. All studies were performed on Sequoia (Acuson) sonography machines with a 4 7-MHz transducer. The studies were performed by registered diagnostic medical sonographers and supervised by radiologists with fellowship training in sonography. Doppler sonography was performed on the portal veins, IVC, and hepatic veins according to a standard protocol. Protocol The main, right, and left portal veins were imaged with color Doppler sonography. Angle-corrected velocities in the main portal vein proximal to, at, and distal to the anastomosis were measured. Turbulence and aliasing on color Doppler sonography were used to identify the area of peak velocity. Measurements were made in suspended inspiration. The portal vein anastomosis was identified by a change in caliber of the vein and the presence of surgical clips or sutures. Gain and filter settings were optimized for abdominal venous flow. Color Doppler images and Doppler spectra were obtained from the right, middle, and left hepatic veins and the IVC in whole-liver transplants. In partial transplants, spectra were obtained from the solitary hepatic vein and the IVC. Hepatic vein spectra were obtained 3 5 cm from the junction with the IVC. Fig. 2 Doppler sonogram of 52-year-old female liver transplant patient shows main portal vein (MPV) occlusion due to thrombus. Measurements The sonography studies for the normal and stenosed groups were compared. The sonography study performed closest in time to the angiogram was used for analysis. Maximum and minimum velocities were measured on representative waveforms from each vein. To quantify the phasicity of the hepatic venous waveform, the venous pulsatility index for the right, middle, and left hepatic veins and the IVC was retrospectively calculated. This was performed by downloading the hepatic vein and IVC spectra to a PC and measuring the venous pulsatility index using a commercially available software package (Carnoy, Plant Systematic). A single individual performed the analysis. The venous pulsatility index was defined as the difference between the maximum and minimum frequency shifts in the venous waveform in a cardiac cycle, divided by the maximum. A completely monophasic (flat) waveform has a venous pulsatility index of 0. A biphasic waveform has a venous pulsatility index between 0 and 1. A triphasic waveform has a venous pulsatility index of > 1 (Fig. 1). The mean venous pulsatility index, which was obtained from averaging the venous pulsatility indexes of each hepatic vein and the IVC, was used for analysis. In the portal vein, we measured the following parameters: portal vein peak anastomotic velocity and the ratio of the portal vein anastomotic velocity to the preanastomotic velocity, which we called the portal vein velocity ratio (anastomoticto-preanastomotic velocity ratio). W516

3 Sonography of Venous Obstruction in Liver Transplants Patients with complete occlusion had no flow on Doppler sonography and consequently were not included in this analysis. Statistical Analysis A Student s t test for the difference of means was performed first to confirm the validity of receiver operating characteristic (ROC) analysis. ROC curves were then constructed for peak anastomotic velocity, anastomotic-to-preanastomotic velocity ratio, and venous pulsatility index using Medicalc software (Mariakerke). Sensitivity, specificity, and likelihood ratios for anastomotic-to-preanastomotic velocity ratio and peak anastomotic velocity threshold values were calculated from the ROC. Likelihood ratios were used instead of predictive values because the sample size is relatively small and prevalence (which determines predictive values) will vary in different institutions. Because the venous pulsatility index numbers were means obtained by averaging the venous pulsatility index from each hepatic vein and the IVC, we took the additional step of calculating venous pulsatility index thresholds by performing the Student s t test for each of the averages against the software derived optimum at a 95% confidence level. Results Portal Vein Among the 36 portal venograms were 16 cases of portal vein obstruction (11 stenosis, five complete occlusion or thrombosis) (Fig. 2). The mean pressure gradient in the stenosed portal veins was 8.3 mm Hg. Four of the stenoses occurred in partial transplants, and the remainder occurred in wholeliver transplants. There were 20 normal portal venograms, two in partial transplants and the remainder in whole-liver transplants. All cases of complete occlusion (all due to thrombosis) were correctly identified by absence of flow on Doppler sonography. All cases of portal vein stenosis were caused by anastomotic strictures. The mean portal vein velocity at the anastomosis was 58 cm/s in patients with angiographically normal portal veins. The mean ratio of portal vein velocity at the anastomosis to the velocity before anastomosis was 1.5:1. The mean portal vein velocity at the anastomosis in patients with portal vein stenosis was 155 cm/s. The mean ratio of portal vein velocity at the anastomosis to the velocity preanastomosis was 4.69:1 (Fig. 3). For portal vein velocity ratio (anastomotic-to-preanastomotic velocity ratio), comparison of stenosed with normal veins showed p = using the Student s t test for difference of means, assuming unequal variances. This indicated that an ROC analysis was valid given the sample size. The ROC analysis is shown in Figure 4. The area under the ROC curve is 0.86 (SE, 0.078; 95% CI, ). The optimal threshold velocity ratio for anastomotic stenosis is approximately 3:1, which has a sensitivity of 73% and a specificity of 100% (Table 1). For peak portal vein anastomotic velocity, comparison of stenosed with normal veins showed p = using the Student s t test for difference of means, assuming unequal variances. This indicated that an ROC analysis was valid given the sample size. The ROC analysis is shown in Figure 5. The area under the ROC curve was 0.83 (SE, 0.084; 95% CI, ). The optimum peak anastomotic velocity threshold is > 87 cm/s, which has a sensitivity of 82% and specificity of 90% for stenosis. A threshold of 125 cm/s is 73% sensitive and 95% specific, whereas a threshold of > 200 cm/s is 100% specific but only 18% sensitive (Table 2). Outflow Veins (Hepatic Veins and IVC) Among the 58 hepatic venograms were 34 cases of outflow vein stenosis and one case of thrombotic occlusion. Eleven cases of stenosis occurred in partial-liver transplants and 23 in whole-liver transplants. In all except six cases, the stenosis was caused by an anastomotic stricture. Of the exceptions, three cases were due to extrinsic compression by hematoma or edematous liver, two cases due to torsion of the transplant, and one case had a partial thrombus. The mean pressure gradient in patients with outflow vein stenosis was 9.6 mm Hg. The mean pressure gradient in normal venograms was 2.4 mm Hg. There were 23 normal venograms, five in partial-liver transplants and 18 in whole-liver transplants. Only one patient with hepatic vein or IVC stenosis showed a triphasic waveform. The mean venous pulsatility index for patients with normal outflow veins was The mean venous pulsatility index for patients with stenosis was For venous pulsatility index, comparison of stenosed with normal veins showed p = using the Student s t test for the difference of means, assuming unequal variances. This indicated that an ROC analysis was valid given the sample size. The results of the ROC analysis are shown in Figure 6. The area under the curve was 0.84 (SE, 0.058; 95% CI, ), indicating a good correlation. The Student s t test for each of the averages at the 95% confidence level showed that a venous pulsatility index of < 0.66 had a sensitivity of 67.6% and specificity of 78.3% for outflow vein stenosis. Lowering the threshold to < 0.45 reduces sensitivity to 41% but increases specificity to 95% (Table 3). Discussion Venous obstruction in hepatic transplants is not rare. The incidence of portal vein obstruction in one series was 2.7% [9]. Surgical techniques that preserve the recipient s vena cava (such as the piggyback technique) have gained popularity in recent years. This technique is standard at our institution. The reported incidence of venous outflow obstruction with caval-preserving surgery ranges from 2% to 10% [10, 11]. Hepatic vein and IVC stenosis can lead to hepatic congestion and graft dysfunction [12]. If diagnosed early, venous obstruction is treatable with balloon angioplasty and stenting [13] (Figs. 3C, 3D, and 7). Doppler sonography is widely used as a first-line study to evaluate vascular patency in transplants. It is less invasive than angiography and does not use iodinated contrast media. However, there has been less research on sonographic criteria for venous obstruction than for arterial obstruction, particularly in whole-liver transplants. Most articles consist of case reports or series of fewer than 10 cases. To our knowledge, ours is the largest series to analyze sonographic parameters for venous stenosis in liver transplants. Doppler sonography accurately identified all cases of complete venous obstruction in our study. This is consistent with prior studies [14]. Portal Vein Stenosis The area under the ROC curve was 0.83 for peak anastomotic velocity and 0.86 for velocity ratio, indicating a good correlation between these parameters and portal vein stenosis. Accelerated portal vein anastomotic velocities have previously been shown to indicate stenosis in pediatric reduced-size transplants (average age, 2.5 years) [15]. We have found that this parameter applies to all transplants. Peak velocities of > 125 cm/s or an anastomotic-to-preanastomotic velocity ratio of 3:1 have a specificity of 95% or better for portal vein anastomotic stenosis (Tables 1 and 2). W517

4 Outflow Vein Stenosis Venous pulsatility in hepatic veins has usually been assessed by characterizing the waveform as monophasic, biphasic, or triphasic. Reduced pulsatility has been associated with parenchymal liver disease [16, 17] and Budd- Chiari syndrome [18]. Reduced pulsatility is A C Fig. 3 Doppler sonograms in 46-year-old male liver transplant patient with main portal vein (MPV) stenosis. V = velocity, PRE = preanastomosis, ANA = anastomosis. A, Angle-corrected MPV preanastomotic velocity is 31.8 cm/s. B, Velocity at MPV anastomosis is 153 cm/s. Anastomotic-to-preanastomotic velocity ratio is C, Corresponding angiogram shows anastomotic stenosis. D, Angiographic improvement after balloon dilatation. also associated with transplant hepatic vein stenosis [19]; in a small series of patients, monophasic waveforms were found to indicate stenosis [20]. However the mono/bi/tri classification is qualitative; in practice, venous phasicity is a continuum and there is no clear distinction between monophasic and biphasic waveforms. The venous pulsatility index, first described by Coulden et al. [21], is a means of quantifying venous pulsatility. It has not previously been used to evaluate liver transplants. Our ROC analysis showed a good correlation between venous pulsatility index and outflow vein stenosis: The lower the venous B D W518

5 Sonography of Venous Obstruction in Liver Transplants Fig. 4 Receiver operating characteristic curve for evaluation of portal vein stenosis with portal vein velocity ratio (PVVR). TABLE 1: Thresholds of Portal Vein Velocity Ratio for Portal Vein Stenosis Portal Vein Velocity Ratio Sensitivity (%) 95% CI Specificity (%) 95% CI + LR LR > > > NA 0.27 Note LR = likelihood ratio, NA = not applicable. Fig. 5 Receiver operating characteristic curve for evaluation of portal vein stenosis with peak portal vein velocity (PPVV). Sensitivity (%) Sensitivity (%) PVVR Specificity (%) PPVV Specificity (%) pulsatility index, the greater the chance of stenosis. Figure 7 illustrates how the venous pulsatility index can be more precise than the mono/bi/tri classification for evaluating stenosis. The Doppler waveform in a patient with outflow vein stenosis on angiography (pressure gradient, 7 mm Hg) shows a weak biphasic waveform and low venous pulsatility index. After angioplasty, angiographic improvement and disappearance of the pressure gradient were seen. The postangioplasty Doppler waveform is still biphasic, but it is clearly more pulsatile, as shown by an increase in the venous pulsatility index. We did not use peak anastomotic velocities in the outlet veins in our protocol because we could not reliably get a good Doppler angle at the caval anastomosis as a result of its course and depth. However, elevated anastomotic velocities were incidentally seen in a few patients with stenosis, and this may be another useful parameter of obstruction. Doppler findings should be interpreted with caution in the immediate postoperative period. We have observed transient elevation of portal vein velocities and ratios and reduced hepatic vein pulsatility during this time that resolve spontaneously after a few days. Veins are easily compressible, and these findings are likely due to temporary narrowing resulting from postoperative inflammation [22] or compression from fluid collections. Limitations The limitations of this study are its retrospective nature and the fact that the study population includes partial- and whole-liver transplants. A selection bias exists in the study population because angiograms were performed only on transplants that had clinical or Doppler evidence of vascular obstruction. However, we are confident that all patients with venous obstruction in our transplant population were included because it is extremely unlikely that significant venous obstruction would be present in the absence of clinical, biochemical, or sonographic abnormality. Even if selection bias were present, it should not affect the outcome of this study, which was designed to delineate the relationship between Doppler sonography and angiography. We used angiography and elevated pressure as the sole reference standards, and we did not address the clinical significance of these standards. Another possible complicating factor is that some patients with normal venograms had hepatic artery obstruction, which could W519

6 TABLE 2: Thresholds of Peak Portal Vein Velocity for Portal Vein Stenosis Peak Velocity (cm/s) Sensitivity (%) 95% CI Specificity (%) 95% CI + LR LR > > > > NA 0.82 Note LR = likelihood ratio, NA = not applicable. Fig. 6 Receiver operating characteristic curve for evaluation of hepatic vein/ivc stenosis with venous pulsatility index (VPI). Fig year-old male liver transplant patient with outflow vein stenosis. LHV = left hepatic vein, V = velocity. A, Doppler spectrum from LHV shows weak biphasic waveform (venous pulsatility index = 0.22). (Fig. 7 continues on next page) Sensitivity (%) VPI Specificity (%) A TABLE 3: Thresholds of Venous Pulsatility Index for Outflow Vein Stenosis Venous Pulsatility Index Sensitivity (%) Specificity (%) < < < < theoretically increase overall portal venous flow and therefore portal velocity as well. Nevertheless, the patients with portal vein stenosis still had significantly higher peak velocity than the normal group, even though the normal group contained cases of arterial obstruction. Arterial obstruction should not affect portal velocity ratio or venous pulsatility index. Another consideration is that hepatic vein pulsatility is altered by factors other than venous stenosis; for instance, venous pulsatility is accentuated in cardiac failure. Conclusion In conclusion, we found a strong correlation between peak portal vein velocities, velocity ratios, and portal vein stenosis and between venous pulsatility indexes and hepatic vein stenosis. Elevated portal vein anastomotic velocities and velocity ratios are good indicators of stenosis. Peak anastomotic velocity of > 125 cm/s or a ratio of 3:1 at the portal vein anastomosis are > 95% specific for portal venous obstruction. Use of the venous pulsatility index enables greater precision in measuring hepatic vein pulsatility: The lower the venous pulsatility index, the greater the possibility of stenosis. A venous pulsatility index of 0.66 is 67.6% sensitive and 78.3% specific for stenosis, whereas a venous pulsatility index < 0.45 is > 95% specific for stenosis. Routine use of these parameters may aid in the evaluation of portal vein and outflow vein obstruction in transplants. These findings on sonography should merit consideration of performing angiography if clinical abnormalities are present that can be attributed to venous obstruction. Acknowledgments We acknowledge the assistance of Zeynap Firat with data collection and M. Radu-Rosu with statistical analysis. W520

7 Sonography of Venous Obstruction in Liver Transplants Fig. 7 (continued) 52-year-old male liver transplant patient with outflow vein stenosis. LHV = left hepatic vein, V = velocity. B, Transjugular hepatic venogram shows anastomotic stenosis (arrow). Balloon dilatation was performed and stent was placed across stenosis. C, Posttreatment Doppler sonogram shows waveform that is still biphasic, but pulsatility is improved (venous pulsatility index = 0.45). References 1. Cavallari A, Vivarelli M, Bellusci R, Jovine E, Mazziotti A, Rossi C. Treatment of vascular complications following liver transplantation: multidisciplinary approach. Hepatogastroenterology 2001; 48: Langnas AN, Marujo W, Stratta RJ, Wood RP, Shaw BW Jr. Vascular complications after orthotopic liver transplantation. Am J Surg 1991; 161: Pinna AD, Smith CV, Furukawa H, Starzl TE, Fung JJ. Urgent revascularization of liver allografts after early hepatic artery thrombosis. Transplantation 1996; 62: Zanotelli ML, Vieira S, Alencastro R, et al. Management of vascular complications after pediatric liver transplantation. Transplant Proc 2004; 36: Totsuka E, Hakamada K, Narumi S, et al. Hepatic vein anastomotic stricture after living donor liver transplantation. Transplant Proc 2004; 36: Hellinger A, Roll C, Stracke A, Erhard J, Eigler FW. Impact of colour Doppler sonography on detection of thrombosis of the hepatic artery and the portal vein after liver transplantation. Langenbecks Arch Chir 1996; 381: Dalen K, Day DL, Ascher NL, et al. Imaging of vascular complications after hepatic transplantation. AJR 1988; 150: Dodd GD III, Memel DS, Zajko AB, Baron RL, B Santaguida LA. Hepatic artery stenosis and thrombosis in transplant recipients: Doppler diagnosis with resistive index and systolic acceleration time. Radiology 1994; 192: Settmacher U, Nussler NC, Glanemann M, et al. Venous complications after orthotopic liver transplantation. Clin Transplant 2000; 14: Cescon M, Grazi GL, Varotti G, et al. Venous outflow reconstructions with the piggyback technique in liver transplantation: a single-center experience of 431 cases. Transpl Int 2005; 18: Egawa H, Inomata Y, Uemoto S, et al. Hepatic vein reconstruction in 152 living-related donor liver transplantation patients. Surgery 1997; 121: Pfammatter T, Williams DM, Lane KL, Campbell DA Jr, Cho KJ. Suprahepatic caval anastomotic stenosis complicating orthotopic liver transplantation: treatment with percutaneous transluminal angioplasty, Wallstent placement, or both. AJR 1997; 168: Navarro F, Le Moine MC, Fabre JM, et al. Specific vascular complications of orthotopic liver transplantation with preservation of the retrohepatic vena cava: review of 1361 cases. Transplantation 1999; 68: Lomas DJ, Britton PD, Farman P, et al. Duplex Doppler ultrasound for the detection of vascular occlusion following liver transplantation in children. Clin Radiol 1992; 46: Lee J, Ben-Ami T, Yousefzadeh D, et al. Extrahepatic portal vein stenosis in recipients of living-donor allografts: Doppler sonography. AJR 1996; 167: von Herbay A, Frieling T, Haussinger D. Association between duplex Doppler sonographic flow pattern in right hepatic vein and various liver diseases. J Clin Ultrasound 2001; 29: Bolondi L, Li Bassi S, Gaiani S, et al. Liver cirrhosis: changes of Doppler waveform of hepatic veins. Radiology 1991; 178: Hosoki T, Kuroda C, Tokunaga K, Marukawa T, Masuike M, Kozuka T. Hepatic venous outflow obstruction: evaluation with pulsed duplex sonography. Radiology 1989; 170(3 Pt 1): Rossi AR, Pozniak MA, Zarvan NP. Upper inferior vena caval anastomotic stenosis in liver transplant recipients: Doppler US diagnosis. Radiology 1993; 187: Ko EY, Kim TK, Kim PN, et al. Hepatic vein stenosis after living donor liver transplantation: evaluation with Doppler US. Radiology 2003; 229: Coulden RA, Lomas DJ, Farman P, Britton PD. Doppler ultrasound of the hepatic veins: normal appearances. Clin Radiol 1992; 45: Stell D, Downey D, Marotta P, et al. Prospective evaluation of the role of quantitative Doppler ultrasound surveillance in liver transplantation. Liver Transpl 2004; 10: C W521