Balloon-occluded Retrograde Transvenous Obliteration Group Research Articles

Endoscopic N-butyl-2-cyanoacrylate and ethanolamine oleate injection is equivalent to balloon-occluded retrograde transvenous obliteration for preventing gastric variceal bleeding.

Endoscopic injection sclerotherapy (EIS) is effective for temporary hemostasis, but EIS and balloon-occluded retrograde transvenous obliteration (BRTO) have been reported as effective for secondary prophylaxis of gastric varices (GV) bleeding. This study retrospectively compared EIS and BRTO in patients with GV in terms of the efficacy for secondary prevention of GV bleeding and effects on liver function. From our database of patients with GV who underwent EIS or BRTO between February 2011 and April 2020, a total of 42 patients with GV were retrospectively enrolled. The primary endpoint was the bleeding rate from GV, which was compared between EIS and BRTO groups. Secondary endpoints were liver function after treatment and rebleeding rate from EV, compared between EIS and BRTO groups. Rebleeding rates from GV and EV and liver function after treatment were also compared between EIS-ethanolamine oleate (EO)/histoacryl (HA) and EIS-HA groups. Technical success was achieved for all EIS cases, but two cases were unsuccessful in the BRTO group and underwent additional EIS. No significant differences in bleeding rates or endoscopic findings for GV improvement were seen between EIS and BRTO groups. Liver function also showed no significant difference in the amount of change after treatment between groups. EIS therapy appears effective for GV in terms of preventing GV rebleeding and effects on liver function after treatment. EIS appears to represent an effective treatment for GV.

Efficacy and safety of EUS-guided coil embolization combined with endoscopic cyanoacrylate injection versus balloon-occluded retrograde transvenous obliteration for gastric varices with high-risk ectopic embolism: A multicenter and retrospective cohort study.

Gastric varices (GV) with spontaneous portosystemic shunt (SPSS) are associated with ectopic embolism in endoscopic cyanoacrylate. This study targeted to assess the efficacy and safety of EUS-guided coil embolization combined with endoscopic cyanoacrylate injection versus balloon-occluded retrograde transvenous obliteration (BRTO) for GV with high-risk ectopic embolism. We retrospectively analyzed six tertiary hospitals' 104 patients with GV at high-risk ectopic embolism (the narrowest diameter of SPSS was greater than or equal to 5 mm and the maximum diameter usually >8 mm) who underwent EUS-guided coil embolization combined with endoscopic cyanoacrylate injection or BRTO from January 2014 to December 2020. The outcomes included rebleeding, survival, and complications. The EUS group and BRTO group contained 59 and 45 patients, respectively. The technical success rate between the two groups was similar (96.6% vs. 95.6%, P = 1.000). During the follow-up, both groups' 5-day rebleeding rate and 6-week mortality rate were 0%. One-year all-cause rebleeding rate (20.0% vs. 18.9%, P = 0.900) and 1-year mortality rate (2.0% vs. 0%, P = 1.000) in the EUS group were similar to the BRTO group. One patient experienced ectopic embolism in the EUS group, while the BRTO group did not. Both groups had similar mean days (16.0 [interquartile range (IQR), 12.0-19.0] vs. 16.5 [IQR, 11.8-26.0], P = 0.165) and cost of hospitalization (¥ 45950.6 [IQR, 39330.2-55768.2] vs. ¥ 51205.8 [IQR, 31628.8-74251.5], P = 0.680). Multivariate analysis showed that the narrowest diameter of the shunt (odds ratio [OR] = 1.86; 95% confidence interval [CI]: 1.062-3.258; P = 0.03) and content of hemoglobin (OR = 0.941; 95% CI: 0.892-0.992; P = 0.025) were the prognostic factors for survival. The efficacy and safety of EUS-guided coil embolization combined with endoscopic cyanoacrylate injection for GV with high-risk ectopic embolism are comparable to BRTO.

Endoscopic Cyanoacrylate Injection Versus Balloon‐Occluded Retrograde Transvenous Obliteration for Prevention of Gastric Variceal Bleeding: A Randomized Controlled Trial

Background and Aims The optimal treatment for gastric varices (GVs) is a topic that remains open for study. This study compared the efficacy and safety of endoscopic cyanoacrylate injection and balloon‐occluded retrograde transvenous obliteration (BRTO) to prevent rebleeding in patients with cirrhosis and GVs after primary hemostasis. Approach and Results Patients with cirrhosis and history of bleeding from gastroesophageal varices type 2 or isolated gastric varices type 1 were randomized to cyanoacrylate injection (n = 32) or BRTO treatment (n = 32). Primary outcomes were gastric variceal rebleeding or all‐cause rebleeding. Patient characteristics were well balanced between two groups. Mean follow‐up time was 27.1 ± 12.0 months in a cyanoacrylate injection group and 27.6 ± 14.3 months in a BRTO group. Probability of gastric variceal rebleeding was higher in the cyanoacrylate injection group than in the BRTO group (P = 0.024). Probability of remaining free of all‐cause rebleeding at 1 and 2 years for cyanoacrylate injection versus BRTO was 77% versus 96.3% and 65.2% versus 92.6% (P = 0.004). Survival rates, frequency of complications, and worsening of esophageal varices were similar in both groups. BRTO resulted in fewer hospitalizations, inpatient stays, and lower medical costs. Conclusions BRTO is more effective than cyanoacrylate injection in preventing rebleeding from GVs, with similar frequencies of complications and mortalities.

Primary prophylaxis of gastric variceal bleeding: endoscopic obturation, radiologic intervention, or observation?

No single effective method has yet been established for the primary prophylaxis of bleeding from gastric varices (GV). We retrospectively analyzed liver cirrhosis patients with GV who had undergone either endoscopic variceal obturation (EVO) or balloon-occluded retrograde transvenous obliteration (BRTO) as prophylactic treatments, comparing them with those who were observed without any procedural intervention. The endpoints were GV bleeding rate and complete eradication rate. 72 patients in EVO, 41 patients in BRTO, and 97 patients in the clinical observation groups were enrolled. No difference was observed in baseline characteristics. As the primary endpoint, 14 (19.4%) patients in the EVO group and 3 (7.3%) in the BRTO group bled from GV after prophylactic treatment, and 34 (35.1%) patients bled in the observation group during the median follow-up of 35months (p = 0.001). Patients who received EVO or BRTO developed less bleeding from GV than those who received observation only, with no difference between EVO and BRTO (EVO vs. observation, p = 0.038; BRTO vs. observation, p = 0.001; EVO vs. BRTO, p = 0.089). As secondary endpoints, GV disappeared completely in 33 patients (45.8%) in the EVO group and 31 patients (75.6%) in the BRTO group (p = 0.003). By multivariate analysis, complete eradication of GV was the sole determinant for predicting GV bleeding. EVO and BRTO are effective and safe primary prophylactic treatments for preventing bleeding from GV. In particular, BRTO is better than EVO in complete eradication of GV.

Treatment outcomes after splenectomy with gastric devascularization or balloon-occluded retrograde transvenous obliteration for gastric varices: a propensity score-weighted analysis from a single institution.

BackgroundAlthough balloon-occluded retrograde transvenous obliteration (BRTO) is often selected to treat gastric varices caused by portal hypertension, data comparing BRTO and splenectomy with gastric devascularization (Sp + Dev) are limited.MethodsFrom January 2009 to February 2018, 100 patients with gastric varices caused by portal hypertension who underwent Sp + Dev (n = 45) or BRTO (n = 55) were included. Overall survival (OS) and the rebleeding rate were calculated using the inverse probability of a treatment weighting-adjusted log-rank test. Independent risk factors were identified by Cox regression analysis. Changes in liver function and adverse events after the procedures were analyzed.ResultsPatients in the Sp + Dev group tended to have lower platelet counts than those in the BRTO group, but liver function did not differ between these groups. The 5-year OS rates for the Sp + Dev and BRTO groups were 73.4 and 50.0% (p = 0.005), respectively. There were no significant differences in rebleeding rates between the two groups. Multivariate analysis showed that serum albumin level ≤3.6 g/dL, prothrombin time% activity (PT%) ≤80%, and serum creatinine level ≥0.84 mg/dL were poor prognostic factors. Although the Sp + Dev group had more short-term complications after procedures, Sp + Dev tended to be more effective in improving liver function than BRTO.ConclusionsSp + Dev showed better OS and improvement of liver function compared with BRTO for the treatment of gastric varices caused by portal hypertension.Electronic supplementary materialThe online version of this article (10.1007/s00535-020-01693-9) contains supplementary material, which is available to authorized users.

Balloon Retrograde Transvenous Obliteration Versus Endoscopic Cyanoacrylate in Bleeding Gastric Varices: Comparison of Rebleeding and Mortality with Extended Follow-up

PurposeTo assess short- and long-term mortality and rebleeding with endoscopic cyanoacrylate (EC) versus balloon-occluded retrograde transvenous obliteration (BRTO). Materials and MethodsA retrospective cohort comparison was conducted of 90 EC patients and 71 BRTO patients from 1997 through 2015 with portal hypertension who presented due to endoscopically confirmed bleeding cardiofundal gastric varices. Patients underwent either endoscopic intra-varix injection of 4-carbon-n-butyl-2-cyanoacrylate or sclerosis with sodium tetradecyl sulfate with balloon occlusion for primary variceal treatment. ResultsSeventy-one BRTO patients and 90 EC patients, of whom 89% had cirrhosis and 35% were women, were included, with a respective average Model for End-Stage Liver Disease (MELD) score of 13.4 and 14.4, respectively. Mortality at 6 weeks was 14.4% for EC patients and 13.1% for BRTO patients (Kaplan-Meier/Wilcoxon, P = .85). No long-term mortality difference was observed (Cox hazard ratio [HR] = 0.89, P = .64). Also, 5.1% of EC patients and 3.5% of BRTO patients (Kaplan-Meier/Wilcoxon, P = .62) rebled at 6 weeks, but at 1 year, 22.0% of EC patients and 3.5% of BRTO patients had rebled (Kaplan-Meier/Wilcoxon, P < .01). Lower rates of long-term rebleeding were found with BRTO (Cox HR = 0.25, P = .03). No difference was seen in the rate of new portal hypertensive complications (Cox HR = 1.21, P = .464). However, 16/71 patients who underwent BRTO had simultaneous transjugular intrahepatic portosystemic shunt. Age, sex, MELD score, and presence of cirrhosis were the primary predictors of mortality. One death in the EC group and 5 deaths in the BRTO group were deemed to be procedurally related (chi-square, P = .088). ConclusionsBRTO is associated with a lower rate of rebleeding but no change in mortality.

Endoscopic treatment or balloon-occluded retrograde transvenous obliteration is safe for patients with esophageal/gastric varices in Child-Pugh class C end-stage liver cirrhosis.

Background/AimsThere is a controversy about the availability of invasive treatment for esophageal/gastric varices in patients with Child-Pugh class C (CP-C) end-stage liver cirrhosis (LC). We have evaluated the validity of invasive treatment with CP-C end-stage LC patients.MethodsThe study enrolled 51 patients with CP-C end-stage LC who had undergone invasive treatment. The treatment modalities included endoscopic variceal ligation in 22 patients, endoscopic injection sclerotherapy in 17 patients, and balloon-occluded retrograde transvenous obliteration (BRTO) in 12 patients. We have investigated the overall survival (OS) rates and risk factors that contributed to death within one year after treatment.ResultsThe OS rate in all patients at one, three, and five years was 72.6%, 30.2%, and 15.1%, respectively. The OS rate in patients who received endoscopic treatment and the BRTO group at one, three, and five years was 67.6%, 28.2% and 14.1% and 90.0%, 36.0% and 18.0%, respectively. The average of Child-Pugh scores (CPS) from before treatment to one month after variceal treatment significantly improved from 10.53 to 10.02 (P=0.003). Three significant factors that contributed to death within one year after treatment included the presence of bleeding varices, high CPS (≥11), and high serum total bilirubin levels (≥4.0 mg/dL).ConclusionsThe study demonstrated that patients with a CPS of up to 10 and less than 4.0 mg/dL of serum total bilirubin levels may not have a negative impact on prognosis after invasive treatment for esophageal/gastric varices despite their CP-C end-stage LC.

The Incidence of Hepatocellular Carcinoma after Balloon-Occluded Retrograde Transvenous Obliteration

Balloon-occluded retrograde transvenous obliteration (BRTO) is a highly effective therapy for gastric varices with liver cirrhosis. We have investigated the incidence of hepatocellular carcinoma (HCC) after BRTO. We enrolled 71 patients with viral hepatitis in which HCC had not appeared with liver imaging findings at the time of BRTO. The overall survival rate after BRTO was 86.8%, 76.1%, and 50.5% at 1, 3, and 5 years. The occurrence rate of HCC after BRTO was 20.9%, 41.1%, and 60.7% at 1, 3, and 5 years, especially showing a higher occurrence of HCC at one year. Meanwhile, the occurrence rate of HCC after treatment which excluded BRTO for esophagogastric varices in patients was 6.3%, 19.2%, and 42.5% at 1, 3, and 5 years. The log-rank test revealed that the occurrence rate of HCC after treatment was significantly higher in the BRTO group compared with that in the non-BRTO group (P=0.0447). The recurrence rate of HCC after BRTO was 35.8% and 80.0% at 1 and 3 years. The present study demonstrated a high incidence of HCC after BRTO in liver cirrhosis patients with viral hepatitis infection. We have suggested the potential for BRTO to accelerate hepatocarcinogenesis.

Short-Term Rebleeding Rates for Isolated Gastric Varices Managed by Transjugular Intrahepatic Portosystemic Shunt versus Balloon-Occluded Retrograde Transvenous Obliteration

PurposeTo assess the short-term rebleeding rate associated with the use of a transjugular intrahepatic portosystemic shunt (TIPS) compared with balloon-occluded retrograde transvenous obliteration (BRTO) for management of gastric varices (GV). Materials and MethodsA single-center retrospective comparison of 50 patients with bleeding from GV treated with a TIPS or BRTO was performed. Of 50 patients, 27 (17 men and 10 women; median age, 55 y; range, 31–79 y) received a TIPS with covered stents, and 23 (12 men and 11 women; median age, 52 y; range, 23–83 y) underwent a BRTO procedure with a foam sclerosant. All study subjects had clinical and endoscopic evidence of isolated bleeding GV and were hemodynamically stable at the time of the procedure. Clinical and endoscopic follow-up was performed. Kaplan-Meier analysis was used to evaluate rebleeding rates from the GV. ResultsThe technical success rate was 100% in the TIPS group and 91% in the BRTO group (P = .21). Major complications occurred in 4% of the patients receiving TIPS and 9% of patients the undergoing BRTO (P = .344). Encephalopathy was reported in 4 of 27 (15%) patients in the TIPS group and in none of the patients in the BRTO group (0%; P = .12). At 12 months, the incidence of rebleeding from a GV source was 11% in the TIPS group and 0% in the BRTO group (P = .25). ConclusionsBRTO appears to be equivalent to TIPS in the short-term for management of bleeding GV. Further comparative studies are warranted to determine optimal management strategies in individual patients.

Efficacy of Balloon-occluded Retrograde Transvenous Obliteration, Percutaneous Transhepatic Obliteration and Combined Techniques for the Management of Gastric Fundal Varices and Hepatic Encephalopathy

Purpose: Currently, several types of therapeutic procedures, including surgical, endoscopic, and radiological interventions, are available for the treatment of gastric varices and hepatic encephalopathy. Although interventional embolitherapy has been applied for the treatment of gastric varices and hepatic encephalopathy, treatment indications and a recommended embolitherapeutic strategy have not yet been established. In this study, we evaluated the effect of three interventional treatments involving transvenous obliteration for the treatment of gastric varices and hepatic encephalopathy; the efficacy and adverse effects of these methods were compared. Methods: From 2003 to 2010, 25 patients with gastric fundal varices or hepatic encephalopathy underwent interventional radiologic embolitherapy in our hospital. Of the 25 patients, 15 were with GV, 10 were with hepatic encephalopathy. Four were treated with the balloon-occluded retrograde transvenous obliteration (BRTO) procedure, 13 were with the percutaneous transhepatic obliteration (PTO) procedure, and 8 were with the combined BRTO and PTO therapy “double balloon occluded embolization (DBOE)”. We examined the survival rate, recurrence rate of varices or encephalopathy, swelling of esophageal varices and complications in each group. Results: The BRTO, PTO, and DBOE were technically successful in 75% (3/4), 100% (13/13), and 100% (8/8) patients, respectively. Gastric varices disappeared or decreased in size, and hepatic encephalopathy was partially or completely improved in all patients. Recurrent gastric varices were found in 1 patient in the DBOE group. Recurrent encephalopathy was observed in 3 patients in the PTO group. Swelling esophageal varices were seen in 1 patient in the BRTO group, 2 patients in the PTO group and 2 patients in the DBOE group, but these varices could be treated with endoscopic injectional sclerotherapy. As a severe complication, there was 1 case of intraabdominal hemorrhage in the DBOE group and was stopped with coil embolization. Other mild complications were transient ascites, fever and abdominal pain. The 1- and 3-year survival rates were75% and 75% in the BRTO group, 76% and 55% in the PTO group, and 88% and 63% in the DBOE group, respectively. Conclusion: These three interventional treatments are safe and effective for patients with GV and hepatic encephalopathy.

Treatment of patients with gastric variceal hemorrhage: Endoscopic N‐butyl‐2‐cyanoacrylate injection versus balloon‐occluded retrograde transvenous obliteration

Our study aimed to evaluate the therapeutic results of endoscopic N-butyl-2-cyanoacrylate injection (EBC) and balloon-occluded retrograde transvenous obliteration (BRTO) in patients with gastric variceal hemorrhage (GVH) and/or high-risk gastric varices (GV). Twenty-seven patients with GVH and/or high-risk GV (>or= 5 mm in diameter, those with red spots, and a Child-Pugh grading of B or C liver cirrhosis) who were treated with either EBC or BRTO from April 2005 to December 2007 were included in our study. EBC or BRTO was initially used for the treatment of GVH in 14 and 13 patients, respectively. Technical success was achieved in all 14 patients (100%) initially treated with EBC, and 10 of 13 patients (76.9%) initially treated with BRTO. Significant rebleeding occurred in 10 patients (71.4%) of the EBC group, and two patients (15.4%) of BRTO group (P < 0.01). Five of six patients (83.3%) treated with rescue BRTO due to rebleeding after initial EBC achieved technical success, and all six patients who were treated with rescue BRTO had no rebleeding during the median follow up of 17 (range: 2-37) months. The cumulative survival rate of the EBC with the BRTO rescue group/BRTO group was significantly higher than the EBC group. The therapeutic efficacies of EBC and BRTO for the treatment of active GVH and/or high-risk GV appeared to be similar. However, EBC might be associated with a higher rebleeding rate than BRTO. BRTO could be an effective rescue treatment for patients with GVH after initial treatment of EBC.

Effect of Balloon-Occluded Retrograde Transvenous Obliteration on the Natural History of Coexisting Esophageal Varices

Balloon-occluded retrograde transvenous obliteration (BRTO) provides an effective mean of controlling gastric variceal (GV) bleeding; however, increased portal pressure after the obliteration of gastrorenal shunts may lead to a worsening and subsequent rupture of esophageal varices (EV). The aim of this study was to determine whether the natural history of coexisting EV is affected by BRTO. Two hundred thirty-seven patients with gastric varices and no history of EV or GV bleeding at the time of diagnosis were included. Clinical, laboratory, and endoscopic features were compared between 25 patients who underwent BRTO due to GV bleeding (BRTO group) and 198 patients who never experience GV bleeding (control group) during follow-up. The incidences of EV bleeding were evaluated and compared between these 2 groups. The BRTO and control groups were not significantly different with respect to baseline characteristics including age, sex, etiologies of cirrhosis, hepatic function, and the classification or extent of EV and GV. During follow-up (median 48 mo), the overall incidence of first EV bleeding in the patients with fundal varices was significantly higher in the BRTO group (P=0.04). The incidences of EV bleeding were not different at 1 or 3 years (10.1% vs. 12.9%, P=0.32 and 39.3% vs. 38.4%, P=0.57), but became significantly higher in the BRTO group at 5 (72.2% vs. 48.5%, P=0.02) and 7 years (90.7% vs. 50.6%, P<0.01). BRTO increased the bleeding rate of coexisting EV in the long term. Close monitoring and prophylaxis of EV bleeding may be warranted after BRTO.

Efficacy of balloon-occluded retrograde transvenous obliteration, percutaneous transhepatic obliteration and combined techniques for the management of gastric fundal varices

To evaluate the effect of three interventional treatments involving transvenous obliteration for the treatment of gastric varices, and to compare the efficacy and adverse effects of these methods. From 1995 to 2004, 93 patients with gastric fundal varices underwent interventional radiologic embolotherapy at our hospital. Of the 93 patients, 75 were treated with the balloon-occluded retrograde transvenous obliteration (BRTO) procedure; 8 were with the percutaneous transhepatic obliteration (PTO) procedure; and 10 were with the combined BRTO and PTO therapy. A follow-up evaluation examined the rates of survival, recurrence and rebleeding of the gastric varices, worsening of esophageal varices and complications in each group. The BRTO, PTO, and combined therapy were technically successful in 81% (75/93), 44% (8/18), and 100% (10/10) patients, respectively. Recurrence of gastric varices was found in 3 patients in the BRTO group and in 3 patients in the PTO group. Rebleeding was observed in 1 patient in the BRTO group and in 1 patient in the PTO group. The 1- and 3-year survival rates were 98% and 87% in the patients without hepatocellular carcinoma (HCC) in the BRTO group, 100% and 100% in the PTO group, and 90% and 75% in the combined therapy group, respectively. Combined BRTO and PTO therapy may rescue cases with uncontrollable gastric fundal varices that remained even after treatment with BRTO and/or PTO, though there were limitations of our study, including retrospective nature and discrepancy in sample size between the BRTO, PTO and combined therapy groups.

Prophylactic Balloon-Occluded Retrograde Transvenous Obliteration for Gastric Varices in Compensated Cirrhosis

Because gastric variceal bleeding is associated with a high mortality rate, its prophylaxis is expected to improve survival. We investigated the effectiveness of balloon-occluded retrograde transvenous obliteration (B-RTO) for the treatment of gastric fundal varices. A prospective nonrandomized study was conducted. Prophylactic B-RTO was performed in 17 patients (B-RTO group), whereas the remaining 17 patients received no specific treatment (control). The nonbleeding rate, cumulative survival rate, and prognostic values of the patients were assessed. The respective nonbleeding rates at 1, 3, and 5 years were 100%, 100%, and 83% in the B-RTO group and 81%, 59%, and 39% in the control. The respective cumulative survival rates at 1, 3, and 5 years were 94%, 85%, and 39% in the B-RTO group and 71%, 41%, and 22% in the control. Both the nonbleeding rate and the cumulative survival rate of the B-RTO group were significantly higher than those of the control (P = .01 and .04, respectively). B-RTO was determined by multivariate analysis to be a significant factor for low bleeding rate (relative risk, 0.06; 95% confidence interval [CI], 0.004-0.79), whereas B-RTO (0.11; 95% CI, 0.03-0.44) and Child-Pugh class A (0.10; 95% CI, 0.03-0.39) were the significant factors for a low mortality rate, and the presence of hepatocellular carcinoma (5.68; 95% CI, 1.49-21.7) was the significant factor for a high mortality rate. Prophylactic B-RTO is effective in preventing gastric variceal rupture and consequently improves patient survival.

Efficacy and safety of balloon-occluded endoscopic injection sclerotherapy as a prophylactic treatment for high-risk gastric fundal varices: A prospective, randomized, comparative clinical trial

Background: No single effective method has yet been established for the prophylactic treatment of gastric fundal varices at high risk for bleeding. A prospective, randomized trial was conducted to compare the efficacy and safety of a new technique, balloon-occluded endoscopic injection sclerotherapy (BO-EIS), to balloon-occluded retrograde transvenous obliteration (B-RTO) for treatment of high-risk gastric fundal varices. Methods: Twenty consecutive patients with gastric variceal diameters of over 5 mm by color Doppler EUS were randomized to undergo either BO-EIS or B-RTO. All patients underwent color Doppler EUS 2 weeks after treatment and EGD every 3 months for assessment of sclerosing effect. Results: The gastric varices in all patients except one in the B-RTO group were eradicated with either treatment. The volume of sclerosant used was significantly smaller in patients who underwent BO-EIS ( p < 0.05). The endoscopic grade of esophageal varices in 4 of 9 patients worsened after treatment with B-RTO ( p < 0.05). The method of randomization used resulted in an uneven distribution of women, although the difference between the groups was not statistically significant. When only men were compared, the results of the study were unchanged. Conclusions: BO-EIS is a safe and effective for treatment of high-risk gastric fundal varices. In contrast to B-RTO, it can be used even in patients without a gastrorenal shunt. (Gastrointest Endosc 2002;56:522-8.)