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Original Research |
1 Division of Diagnostic and Interventional Radiology, Department of Oncology,
Transplants, and Advanced Technologies in Medicine, University of Pisa, Via
Roma 67, Pisa 56127, Italy.
2 Department of Radiology, S. Croce e Carle Hospital, Via Coppino 26, Cuneo
12100, Italy.
3 Department of Radiology, Santissimi Filippo e Nicola Hospital, Località
Tre Conche, Avezzano 67051, Italy.
4 Department of Radiology, Cardarelli Hospital, Via A. Cardarelli no. 9, Napoli
80131, Italy.
Received July 23, 2004; accepted after revision October 19, 2004.
Address correspondence to C. Vignali
(cvignali{at}med.unipi.it).
OBJECTIVE. Our objective is to describe the results of a multicenter prospective trial on the safety and efficacy of transjugular intrahepatic portosystemic shunts (TIPS) using the Viatorr stent-graft.
SUBJECTS AND METHODS. From 2001 to 2003, 114 patients (75 men and 39 women; mean age, 59.3 years) with portal hypertension underwent TIPS with the Viatorr stent-graft. Indications for treatment were variceal bleeding (n = 49, 43.0%), refractory ascites (n = 52, 45.6%), hypertensive gastropathy (n = 10, 8.8%), Budd-Chiari syndrome (n =1, 0.9%), and hepatorenal syndrome (n = 2, 1.7%). Eight patients (7.0%) had Child-Pugh class A cirrhosis; 60 (52.6%), Child-Pugh class B; and 46 (40.4%), Child-Pugh class C. Patients were monitored by color Doppler sonography and phlebography.
RESULTS. The procedure was successful in 113 (99.1%) of 114 patients; in one patient, creation of the track was not feasible. The mean portosystemic pressure gradient decreased from 21.8 to 8.7 mm Hg. Three minor immediate complications (2.6%) occurred (two cases of self-limiting hemoperitoneum and one extrahepatic portal puncture requiring covered stenting). At a mean follow-up of 11.9 months, the overall mortality rate was 31.0% (35/113), with a 30-day mortality rate of 8.8% (10/113). Mortality was significantly higher in patients in Child-Pugh class C with refractory ascites and with postprocedural encephalopathy. Cumulative primary patency rates were 91.9%, 79.9%, and 75.9% at 6, 12, and 24 months' follow-up, respectively. Restenosis occurred in 15 patients (13.3%) within the stent (n = 8, 53.3%) or at the ends of the portal (n = 1, 6.7%) or hepatic (n = 6, 40%) veins and was solved by percutaneous transluminal angioplasty (n = 11), stenting (n = 3), or parallel TIPS (n = 1). The secondary patency rate was 98.2%. Postprocedural encephalopathy occurred in 27 patients (23.9%).
CONCLUSION. The Viatorr stent-graft is safe and effective in TIPS creation, with high primary patency rates. Covering the entire track up to the inferior vena cava can increase patency.
In the last decade, the effectiveness of transjugular intrahepatic portosystemic shunts (TIPS) in managing complications of portal hypertension has been shown by several clinical studies [1–4].
Initial trials focused on the use of bare metal stents, whose major drawback was the high rate of shunt obstruction [5–7], requiring close, invasive, and costly surveillance and frequent revisions. In several randomized trials comparing TIPS with other treatment options, a significant reduction of rebleeding rates [2, 8, 9] and improvement of ascites [10] were shown; however, no survival benefits seemed to be associated with TIPS [11, 12]. Therefore, TIPS has been indicated in patients awaiting liver transplantation [13] or as a rescue procedure when other treatments have failed [12].
In the past few years, covered stent-grafts have been introduced as a valid alternative to bare stents in TIPS, and animal studies [14, 15] and initial clinical trials have shown high primary patency rates and significant survival benefits [16, 17].
The graft material should be biocompatible, nonthrombogenic, and impermeable to bile and should provide a substrate for the endothelial lining [16]. Initial experiences were with custom-made devices. However, in recent years, a new covered stent (Viatorr GORE-TEX vascular graft, W. L. Gore and Associates) has become commercially available in Europe; initial larger clinical trials have been published, reporting high technical success rates and a low incidence of restenosis at midterm follow-up [18–21].
The Viatorr stent-graft is a covered stent specifically designed for TIPS [17]. It is an expanded polytetrafluoroethylene (ePTFE)-covered nitinol stent-graft consisting of two parts: a distal 2-cm-long uncovered portion that lies in the portal vein and an inner covered portion (4–8 cm long) for the track and the hepatic side of the TIPS. The ePTFE is a trilaminar structure with slight porosity and impermeable to liquid bile, and the metal skeleton of the stent-graft consists of a 0.2-mm nitinol wire with a zigzag configuration. The stent-graft is available in 8-, 10-, and 12-mm diameters.
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Subjects and Methods
This prospective multicenter study was performed at four Italian hospitals. The study protocol was approved by the institutional ethics committees of all centers involved. Informed consent was obtained from all patients.
Patients
From February 2001 to December 2003, 114 consecutive patients (75 men and
39 women; age range, 18–83 years; mean, 59.3 ± 12.1 [SD] years)
experiencing complications from portal hypertension were enrolled.
Primary indications for TIPS included variceal bleeding (n = 49, 43%), refractory ascites (n = 52, 45.6%), hypertensive gastropathy (n = 10, 8.8%), Budd-Chiari syndrome (n = 1, 0.9%), and hepatorenal syndrome (n = 2, 1.7%), all of which were refractory to or intolerant of conventional endoscopic or medical therapies. In patients in whom refractory ascites was the indication for TIPS, examination of ascitic fluid revealed no evidence of spontaneous bacterial peritonitis or other infection. No patient had signs of systemic infection.
The causes of hepatic disease were hepatitis (n = 58), alcohol abuse (n = 36), both hepatitis and alcohol abuse (n = 14), Budd-Chiari syndrome (n = 2), a cryptogenic cause (n = 1), metastasis (n = 1), and portal vein thrombosis (n = 2) (Fig. 1A, 1B, 1C, 1D, 1E). Seven patients had undergone previous orthotopic liver transplantation.
Eight patients had Child-Pugh class A cirrhosis; 60, Child-Pugh class B; and 46, Child-Pugh class C.
Preprocedural Workup
Before the TIPS procedure, all patients underwent complete clinical and
laboratory assessments. Sonography and color-coded duplex sonography followed
by contrast-enhanced MDCT were performed on all patients to visualize the
liver parenchyma and exclude focal liver lesions, to assess the presence and
extent of complications of portal hypertension, to assess the vascular
anatomy, and to select the most proper hepatic vein for the procedure.
Inclusion and Exclusion Criteria
All incoming patients who had portal hypertension complications refractory
to or intolerant of medical or endoscopic therapies and who had adequate
vascular access at the level of the hepatic veins were considered for
inclusion in the study. Exclusion criteria were chronic severe encephalopathy,
severe right cardiac failure, and multifocal hepatocellular carcinoma.
TIPS Procedure, Stent-Graft Implantation, and Portosystemic Pressure Gradient (PPG) Measurement
The Viatorr stent-graft and TIPS procedure have been described elsewhere
[17]. The procedure was
performed in the angiographic suite while the patients were deeply sedated.
The present series included only elective TIPS creation.
The right jugular vein was punctured under sonographic guidance. A standard 10-French, 40-cm-long Rösch-Uchida TIPS set (Cook Europe) was used for TIPS creation. In most patients, the right hepatic vein and the right portal branch were used to create the track, under sonographic and fluoroscopic guidance. After dilatation of the track with high-pressure balloon catheters, a venogram was obtained with a calibrating catheter to assess the track length, select the proper stent-graft, and facilitate precise deployment. All stents were 10 mm in diameter; they varied in length.
Once the stent-graft had been deployed, the stent was dilated with high-pressure balloons of sizes equivalent to the nominal diameters of the grafts. Shunt venography was performed to monitor shunt patency and diameter and the persistence of varices. When required, variceal coil embolization was performed at the end of the procedure. When venography showed incomplete track coverage, an adjunctive covered stent was deployed.
The PPG was recorded before the procedure, after track creation, and at TIPS completion.
Follow-Up
After the procedure, all patients underwent strict clinical follow-up.
Stent patency was monitored by color-coded duplex sonography at discharge; at
1, 3, 6, and 12 months after TIPS; and annually thereafter and by portography
at 6 months' follow-up or in cases of suspected shunt malfunction.
Portography was performed either by a right jugular or by a common femoral venous access. PPG was always recorded. In some instances, MDCT was also required for a better depiction of the liver and vascular anatomy and of the stent-graft position and patency. In cases of complications, further percutaneous treatments were required.
Medication Protocol
All patients received broad-spectrum antibiotic medication as perioperative
prophylaxis, starting 2 days before the procedure and continuing for 1 week.
No anticoagulation protocol was followed in this series, either during the
procedure or postprocedurally.
Definition of Success
Immediate technical success was defined as creation of the TIPS, with an
associated 50% reduction in the preprocedural PPG or a PPG of less than 12 mm
Hg [22].
In-stent stenosis was defined as a 50% reduction in the stent-graft lumen or by a PPG increase of more than 12 mm Hg. In-graft and above-the-graft stenoses were recorded separately.
Primary and secondary patency rates and survival rates were calculated on follow-up. Immediate and long-term TIPS-related complications, such as encephalopathy and recurrence of bleeding or ascites, were recorded.
Statistical Analysis
Descriptive statistics (proportions, means, SDs, and medians) were
calculated for patient characteristics and numeric continuous data. The
chi-square, Pearson, and Fisher exact tests were used for categoric data,
whereas continuous data were analyzed by bivariate fit, one-way analysis of
variance, and Student's t test. Cumulative patency and survival rates
were calculated with the Kaplan-Meier method, and groups were compared using
the log-rank test (chi-square) or the Wilcoxon rank sum test. Stepwise
multiple logistic regression analyses were performed to assess factors
influencing shunt malfunction and mortality.
A p value of less than 0.05 was considered statistically significant. Statistical analysis was performed using a statistical software program (JMP; SAS Institute Inc.).
Results
Procedural Results
Shunt insertion was successful in 113 (99.1%) of 114 patients. In one
patient, the track could not be created because the vessels were severely
tortuous and hypotrophic.
Mean stent-graft length was 8 ± 1 mm; the following lengths were used: 4 mm in two patients, 6 mm in nine patients, 7 mm in 17 patients, 8 mm in 38 patients, 9 mm in 40 patients, and 10 mm in seven patients.
In 108 (95.6%) of 113 patients, the stent-graft was placed accurately with no evidence of immediate complications. In the remaining five patients, covering the entire track required the use of an adjunctive covered stent, represented by a Viatorr stent-graft in three patients and by a Jostent (Abbott Vascular Devices) in two patients. The Jostent was used to cover a remaining track length of 2–3 mm because this size is not available with the Viatorr stent-graft.
The adjunctive stent was required in two patients to cover a long track and in the remaining patients because of misjudgment of the track length, despite the use of a calibrated catheter.
At completion of the procedure, variceal coil embolization was considered necessary and was successfully performed on 11 patients.
Mean preprocedural PPG was 21.8 ± 5.6 mm Hg (range, 13–34 mm Hg). After the procedure, mean PPG was 8.7 ± 3.7 (range, 2–17 mm Hg), with a mean reduction of 60.3% ± 12.5% (range, 36–88%).
TIPS-Related Complications
Three minor immediate complications occurred: Two cases of self-limiting
hemoperitoneum and one extrahepatic portal puncture, sealed with an adjunctive
stent-graft.
One patient, who had Child-Pugh class C hepatitis C virus cirrhosis, ascites, hypertensive gastropathy, and hepatocellular carcinoma, experienced severe hematemesis and melena 10 hr after TIPS; the patient underwent portography, which showed no evidence of stent-graft occlusion or other complications, despite the finding of high PPG (16 mm Hg). Multiple angioplasties were performed within the stent and at the portal and hepatic veins margins; final PPG was 4 mm Hg. However, the patient died from multiorgan failure 2 days later.
No contrast medium–related complications occurred. No puncture-related major complications or infectious complications were observed.
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According to the Kaplan-Meier analysis, cumulative primary patency rates were 91.9%, 79.9%, and 75.9% at follow-up intervals of 6, 12, and 24 months, respectively (Fig. 2).
TIPS restenosis occurred in 15 (13.3%) of 113 patients either within the stent (n =8, 53.3%) or at the extremity of the portal (n =1, 6.7%) (Fig. 1A, 1B, 1C, 1D, 1E) or hepatic vein (n =6, 40%). The mean grade of stenosis was 72% ± 19.2% (range, 30–100%). Six patients were asymptomatic, five (4.4%) showed persistent or recurrent ascites, and the remaining four (3.5%) underwent further evaluation because of recurrent variceal bleeding (Table 1). Among patients with clinical recurrence, postprocedural PPG was greater than 12 mm Hg in only one patient, with variceal recurrent bleeding.
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Portography performed on these patients showed suboptimal coverage of the track at the hepatic vein extremity in all cases of hepatic vein restenosis and in seven of eight cases of in-stent restenosis. In one patient (patient 13, Table 2), with less than 30% early restenosis, we observed incomplete dilatation of the stent-graft with kinking in the midportion of the stent.
Patients were treated by percutaneous transluminal angioplasty (n = 11) or by a noncovered stent (n = 3; two Jostent and one Memotherm stent [Bard Peripheral Vascular]) (Table 1). One patient (patient 15, Table 2) required repeated percutaneous transluminal angioplasty within 1 month, resulting in technical and clinical success.
In one patient with persistent ascites (patient 13, Table 2), duplex sonography and MDCT showed graft displacement and complete thrombosis; stent-graft catheterization was not feasible by either femoral or jugular access, and creation of a new shunt was required (Fig. 3A, 3B, 3C, 3D).
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Shunt malfunction was significantly more frequent in male patients than in female patients (p = 0.05), younger patients (p = 0.03), or patients in whom shorter stents had been used (p = 0.002). In fact, mean stent length in the group of patients with shunt dysfunction was 7.2 mm, compared with 8.2 mm in patients without complications.
On the stepwise multiple regression analysis, stent length and the age and sex of the patient were independent risk factors for shunt malfunction. In particular, stent length represented the most important risk factor (p < 0.006; odds ratio, 49.5; 95% confidence interval, 0.2–1.1).
Ten patients underwent liver transplantation 1–18 months after TIPS (mean, 7 ± 6 months); in all these patients, inspection of the stent-graft did not reveal in-stent obstruction or restenosis.
Mortality and Other Complications
The 30-day mortality rate was 8.8% (10/113). Causes of early mortality were
acute hepatic failure (n = 5) and disseminated intravascular
coagulation (n =5), with no clear cases of procedure-related deaths.
The overall mortality rate was 31.0% (35/113).
Cumulative survival rates were 77.8%, 68.6%, and 59.3% at 6, 12, and 24 months, respectively (Fig. 4).
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The postprocedural PPG ranged from 2 to 8 mm Hg in 10 of 27 patients, whereas in the remaining patients it was higher than 8 mm Hg and in five patients it was higher than 12 mm Hg. No statistically significant difference in the immediate postprocedural PPG was observed between patients with and patients without postprocedural encephalopathy.
Discussion
The role of TIPS in the treatment of complications related to portal hypertension has been widely assessed [1–4]. The most frequently reported complication after TIPS is in-stent restenosis, occurring in up to 50% of patients at 12-months' follow-up [5–7].
Three models of shunt stenosis or occlusion have been reported [16]. Early stenosis may be caused by bile duct transection and biliary fistulas [5, 23], whereas later occlusions are caused by an inflammatory healing response to the stent and proliferation of fibroconnective tissue [24]. Finally, intimal hyperplasia can develop in the hepatic veins above the stent, contributing to shunt dysfunction [6, 25].
Ideally, stent-grafts should address all three types of stenosis, and the graft material should provide specific features to reduce bile leakage and fibroblast proliferation and to favor endothelial lining [17]. Several graft materials have been proposed. Nishimine et al. [14] and Haskal et al. [15] reported the benefits of lining the stents with ePTFE in porcine models, with an increased patency from 8% to 50% at 1 month's follow-up [14] and no bile staining in TIPS stent-grafts [15]. Other materials showed less promising results [26–29].
The Viatorr stent-graft uses an ePTFE lining that is biocompatible, microporous, nonthrombogenic, and relatively impermeable to bile and tissue and provides a substrate for endothelial lining [16, 17]. Initial studies reported high patency rates with this new, commercially available device [18–21].
Ideally, the increased patency would allow reduction of invasive follow-up and therefore reduce costs. Moreover, the longer durability of the stent-graft seems to improve survival [18].
In the present series, incomplete track coverage represented the main cause of shunt dysfunction [25], having been observed in all six cases of hepatic vein stenosis above the graft and in seven of the eight cases (7%) of in-graft restenosis. Portography performed on these seven patients revealed, at the level of the hepatic vein, the presence of incomplete track coverage that might cause displacement and kinking of the stent-graft, inducing thrombosis. This finding is in accordance with recently published data supporting the need for optimal and precise placement of the stent-graft up to the inferior vena cava with complete track coverage [16, 17, 30]. No complications related to complete coverage of the hepatic veins, such as partial Budd-Chiari syndrome or hepatic infarction, were observed in our series, although some cases have been reported in the literature [31]. Of a series of 20 patients, Otal et al. [31] reported two cases of partial Budd-Chiari syndrome with no clinical effects. It seems that hepatic venous occlusion is unlikely to be clinically significant because of the development of venous collateral circulation [32]. Puncturing the hepatic vein as close as possible to the inferior vena cava could reduce the risk of hepatic vein occlusion [31] and the incidence of hepatic vein stenosis and stent displacement [17].
In addition, in our series a statistically significant relationship was observed between the incidence of shunt dysfunction and the use of short stents. However, it is also extremely important not to use excessively long stents, particularly in patients suitable for liver transplantation, because coverage of the portal vein close to the hilum or coverage of the inferior vena cava might interfere with vascular clamping during transplantation [33].
Shunt dysfunction can be managed safely by percutaneous procedures, such as balloon angioplasty and adjunctive stenting [20, 21, 25], with high technical success rates. In our series, only one patient could not be re-treated by angioplasty or stenting, and a parallel TIPS was required. Up to 100% secondary patency rates have been reported, with low periprocedural complications [16, 17, 19, 21].
In the present study, clinical recurrence on follow-up was low, with only four cases (3.5%) of variceal recurrent bleeding and 5 cases (4.4%) of persistent ascites, all of which were associated with shunt dysfunction. These results compare favorably with previous studies, which reported 3–9% clinical relapse [19–21, 25].
In the prospective setting of the present study, close surveillance by duplex sonography and venography was required. However, sonography and duplex sonography are highly accurate and, particularly when associated with proper clinical and laboratory evaluation, might be sufficient to evaluate stent-graft patency and the presence of complications [34]. CT might represent a valuable diagnostic tool as well, particularly to visualize stent-graft displacement, although the use of iodinated contrast medium and irradiation and the higher costs may limit its role to specific cases. Venography still represents the only imaging technique able to measure PPG, yet it is highly invasive, costly, and resource demanding. The increased primary patency and reduced shunt dysfunction associated with the use of covered stents might eventually reduce the need for invasive imaging and favor noninvasive surveillance, with obvious benefits to patient management and costs.
No anticoagulation medication was used in our series. In fact, we could find no reported data supporting benefits from oral anticoagulation or antiplatelet medication alone on TIPS patency rates [35, 36]. The high cumulative primary patency rate (75.9% at 2 years) reported in our series might be a further confirmation that no anticoagulation protocol is needed, particularly in patients with liver dysfunction and a low platelet count, in whom the risks of anticoagulation seem to be higher than the supposed risks of graft stenosis.
Our data confirm the safety of TIPS and its high immediate technical success rate [21]. No major immediate complications were observed in our study, and the only case of severe melena, although of unclear cause, was not related to the procedure or to stent-graft dysfunction.
However, important complications have been reported during and immediately after TIPS, such as severe hemorrhage and graft infections in cases of bacteremia [37]. We believe that accurate patient selection is desirable whenever possible, to reduce the incidence of complications. Accurate procedural planning is possible using duplex sonography and MDCT with adequate postprocessing, to allow precise definition of the vascular and liver anatomy.
High immediate technical success rates can be achieved after adequate training of the operators. Puncture of the portal vein requires specific skills and knowledge of the anatomy and of the technique; when possible, sonographic guidance should be used to avoid puncture of important liver structures and multiple punctures of the extrahepatic track of the portal vein. Moreover, a calibrated catheter always should be used to evaluate track length: The length of the external curvature of the track (which is usually the longest one) represents the minimum stent-graft length required. A stent-graft length of 8 cm is usually recommended, with shorter devices deployed when the track is created between the left hepatic and left portal veins.
The early and overall mortality rates in our series are in accordance with published data, and the cumulative survival rate at 2 years' follow-up—59.3%—is lower than in other reports [18, 21]. However, in our series a higher rate (36%) of Child-Pugh class C patients was treated than in previous studies. Rossi et al. [21] reported an 82.7% survival rate at 1 year's follow-up, with only 18% of patients in Child-Pugh class C, whereas Angermayr et al. [18], 29% of whose patients were in Child-Pugh class C, reported a cumulative survival rate of 76% at 2 years' follow-up. In fact, Child-Pugh class represents an important predictor of survival [18]. As expected, most deaths in our series occurred in patients with severe cirrhosis (Child-Pugh class C) [38]. Recent reports have also focused on the usefulness of the MELD (model for end-stage liver disease) score to predict survival in patients after TIPS [39]. Moreover, as already pointed out in previous reports, survival was lower in patients who underwent TIPS for the treatment of refractory ascites than in patients whose indication for TIPS was variceal bleeding [18, 39]. In fact, ascites is known to be a poor prognostic factor in patients with cirrhosis, and its clinical management appears to be problematic. In a recent study, Ferral et al. reported a poor survival rate in patients with a MELD score of less than 17 and refractory ascites and suggested that TIPS creation should be avoided in the treatment of refractory ascites in patients with advanced liver failure [39].
In our series, another independent risk factor for survival was postprocedural encephalopathy, which has been reported to be a major drawback of TIPS, with reported incidences of 25–52% using bare stents [4] and 31–44% using the Viatorr stent-graft [20, 21]. No significant difference in the incidence of encephalopathy was found between bare and covered stents [19, 20]. In our series, encephalopathy occurred in 23.9% of patients, although it was severe in only five patients; all cases could be controlled by medical therapy. However, strictured stents have been proposed to reduce TIPS diameter and thus encephalopathy [40]. In our series, patients were treated exclusively by 10-mm-diameter stent-grafts, in an attempt to reduce the incidence of encephalopathy yet maintain acceptable patency.
The goal of TIPS is to reduce PPG to less than 12 mm Hg, thus reducing the risk of recurrent bleeding but increasing the incidence of encephalopathy. However, our series could not show a relationship between clinical relapse and high postprocedural PPG or between encephalopathy and low PPG, with five cases of encephalopathy occurring in patients with a PPG of more than 12 mm Hg.
To reduce the incidence of shunt-induced hepatic encephalopathy and liver failure, Rossle et al. [22] proposed that the goal of TIPS be to reduce PPG by 25–50%, rather than to reduce it to the widely used threshold value of 12 mm Hg. In defining our immediate technical success rate, we were agreeing with this finding.
The main limitations of our study were the relatively short follow-up period and the high number of patients lost during it. In fact, 12 patients (10.6%) did not comply with the required continuous follow-up and were lost to follow-up a few months after treatment.
Randomized prospective trials comparing covered and bare stents in TIPS are now needed to weigh the benefits of stent-grafts, in terms of patency and long-term survival, against their higher costs. These trials are under way. Were the benefits of covered stents to be confirmed, further studies comparing TIPS and medical and surgical therapies would be needed to establish the proper management protocol for patients with portal hypertension and its complications.
To our knowledge, this is the largest published series on the use of the Viatorr stent-graft for TIPS creation. This off-the-shelf, commercially available TIPS stent-graft is easy to handle and safe in selected patients. When adequately placed, the stent-graft does not interfere with eventual liver transplantation. In a follow-up of up to 38 months, the high primary patency rate was confirmed. In most patients, restenosis can be treated safely and effectively by further percutaneous procedures. Bridging the complete track to the inferior vena cava could result in higher patency rates, reducing the need for reinterventions and therefore making TIPS a more economic treatment for portal venous hypertension and its associated complications, despite the higher cost of the graft [16, 17].
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