Efficacy Analysis of Suprapapillary versus Transpapillary Self-Expandable Metal Stents According to the Level of Obstruction in Malignant Extrahepatic Biliary Obstruction

Background/Aims@#The use of a self-expandable metal stent (SEMS) is recommended for unresectable malignant biliary obstruction (MBO). Stent-related adverse events might differ according to the position of the stent through the ampulla of Vater (AOV). We retrospectively evaluated SEMS patency and adverse events according to the position of the SEMS. @*Methods@#In total, 280 patients who underwent endoscopic SEMS placement due to malignant distal biliary obstruction were analyzed retrospectively. Suprapapillary and transpapillary SEMS insertions were performed on 51 patients and 229 patients, respectively. @*Results@#Between the suprapapillary group (SPG) and transpapillary group (TPG), the stent patency period was not significantly different (median [95% confidence interval]: 107 days [82.3 to 131.7] vs 120 days [99.3 to 140.7], p=0.559). There was also no significant difference in the rate of adverse events. In subgroup analysis, the stent patency for an MBO located within 2 cm from the AOV was found to be significantly shorter than that for an MBO located more than 2 cm from the AOV in the SPG (64 days [0 to 160.4] vs 127 days [82.0 to 171.9], p<0.001) and TPG (87 days [52.5 to 121.5] vs 130 [97.0 to 162.9], p<0.001). Patients with an MBO located within 2 cm from the AOV in both groups had a higher percentage of duodenal invasion (SPG: 40.0% vs 4.9%, p=0.002; TPG: 28.6% vs 2.9%, p<0.001) than patients with an MBO located more than 2 cm from the AOV. @*Conclusions@#The SPG and TPG showed similar results in terms of stent patency and rate of adverse events. However, patients with an MBO located within 2 cm from the AOV had a higher percentage of duodenal invasion with shorter stent patency than those with an MBO located more than 2 cm from the AOV, regardless of stent position.

Large Animal Models in Pancreas and Biliary Disease / 대한소화기학회지

Rodent models, which have played important roles in preclinical research of pancreas and biliary diseases, have some limitations to translating data from rodent models to human diseases. Large animal models have recently been developed to overcome these limitations and perform translational research of medical devices and drugs in pancreas and biliary diseases. Preclinical studies using large animal models are necessary before clinical application, especially for the research and development of equipment, instrumentation, and techniques in pancreato-biliary diseases. As long as the endoscope used in humans can enter an organ, there appears to be no limitation in terms of species or organ for endoscopic experiments of large animal models. Investigators have mainly used swine for pancreas and biliary endoscopic experiments. Until now, unique swine models that investigators have been established include the normal bile duct model, bile duct dilation model, bile duct dilation+direct peroral cholangioscopy model, benign biliary stricture model, hilar biliary obstruction model, and acute pancreatitis (post-ERCP pancreatitis) model. Many preclinical studies have been performed using these established endoscopy-based large animal models to develop novel medical devices. Furthermore, porcine pancreatic cancer models induced by a transgenic or orthotopic method are currently under development. These models appear to be available for general use in the future and will have multiple potential preclinical and clinical applications.

Safety Evaluation of Paclitaxel-Eluting Biliary Metal Stent with Sodium Caprate in Porcine Biliary Tract

BACKGROUND/AIMS: Metallic stents designed to relieve malignant biliary obstruction are susceptible to occlusive tumor ingrowth or overgrowth. In a previous report, we described metallic stents covered with paclitaxel-incorporated membrane (MSCPM-I, II) to prevent occlusion from tumor ingrowth via antitumor effect. This new generation paclitaxel-eluting biliary stent is further endowed with sodium caprate (MSCPM-III) for enhanced drug delivery. The purpose of this study is to examine the safety of its drug delivery system in the porcine biliary tract. METHODS: MSCPM-III (10% [wt/vol] paclitaxel) and covered metal stents (CMSs) were endoscopically inserted in porcine bile ducts in vivo. Histologic biliary changes, levels of paclitaxel released, and various serum analytes (albumin, alkaline phosphate, aspartate transaminase, alanine transaminase, total protein, total bilirubin, and direct bilirubin) were assessed. RESULTS: Based on the intensity of reactive inflammation and fibrosis, changes in porcine biliary epithelium secondary to implanted MSCPM-III were deemed acceptable (i.e., safe). Histologic features in the MSCPM-III and CMS groups did not differ significantly. In a related serum analysis, paclitaxel release from MSCPM-III stents was below the limit of detection for 28 days. Biochemical analyses were also similar for the two groups, and no evidence of hepatic or renal toxicity was found in animals receiving MSCPM-III stents. CONCLUSIONS: In a prototypic porcine trial, this newly devised metal biliary stent incorporating both paclitaxel and sodium caprate appears to be safe in the porcine bile duct.

A Novel High-Visibility Radiopaque Tantalum Marker for Biliary Self-Expandable Metal Stents

BACKGROUND/AIMS: Radiopaque metal markers are required to improve X-ray absorption by self-expandable metal stents (SEMSs) to enable precise stent placement. A new tantalum radiopaque marker was recently developed using an ultrasonic spray technique. The aim of the present study was to evaluate the safety and visibility of tantalum markers. METHODS: A total of three beagle dogs were used for a gastrointestinal tract absorption test. Five tantalum markers were placed in the stomach of each dog endoscopically. Excreted tantalum markers were collected, and their weights were compared to the original weights. In radiopacity tests, marker radiopacities on X-ray images were quantified using ImageJ software and compared with those of commercially available metal markers. Finally, the radiographic images of six patients who underwent biliary SEMS placement using tantalum marker Nitinol SEMSs (n=3) or gold marker Nitinol SEMSs (n=3) were compared with respect to marker brightness on fluoroscopic images. RESULTS: Absorption testing showed that the marker structures and weights were unaffected. Radiopacity tests showed that the mean brightness and total brightness scores were greater for tantalum markers (226.22 and 757, respectively) than for gold (A, 209 and 355, respectively; B, 204.96 and 394, respectively; C, 194.34 and 281, respectively) or platinum markers (D, 203.6 and 98, respectively). On fluoroscopic images, tantalum markers had higher brightness and total brightness scores (41.47 and 497.67, respectively) in human bile ducts than gold markers (28.37 and 227, respectively). CONCLUSIONS: Tantalum markers were found to be more visible than other commercially available markers in X-ray images and to be resistant to gastrointestinal absorption.

Development of an acute pancreatitis porcine model based on endoscopic retrograde infusion of contrast medium or sodium taurocholate

BACKGROUND/AIMS@#A reproducible, endoscope-based, large animal model, of acute pancreatitis was developed to meet the need for a suitable means of preclinically testing treatments. The aim of this study was to develop an endoscope-based animal model of acute pancreatitis.@*METHODS@#This experimental study was conducted on six mini-pigs. The pancreatitis model was induced by infusing contrast medium (CM) or sodium taurocholate (TCA) under high pressure (100 mmHg) into the main pancreatic duct by endoscopic retrograde pancreatography. Animals were randomly allocated to three groups: a CM group, a 10% TCA group, and a 20% TCA group. Pancreatic injuries were evaluated histologically, and serum amylase and lipase levels were measured.@*RESULTS@#Acute pancreatitis was observed in all animals during hematologic and histologic examinations. Serum amylase and lipase levels were significantly higher (> 10 times baseline), and pancreatic edema, vacuolization of acinar cells, and hemorrhagic necrosis were observed. Severity of pancreatitis tended to be greater in the TCA groups than in the CM group as assessed using histologic scores, and degrees of pancreatitis were found to be dose-dependently related to TCA concentration.@*CONCLUSIONS@#The two endoscopic procedures described are effective and safe for creating a swine model of acute pancreatitis. The authors hope the described endoscopic methods will assist in the development of a suitable treatment strategy.

Prospective Multicenter Study of the Challenges Inherent in Using Large Cell-Type Stents for Bilateral Stent-in-Stent Placement in Patients with Inoperable Malignant Hilar Biliary Obstruction

BACKGROUND/AIMS: Although endoscopic bilateral stent-in-stent placement is challenging, many recent studies have reported promising outcomes regarding technical success and endoscopic re-intervention. This study aimed to evaluate the technical accessibility of stent-in-stent placement using large cell-type stents in patients with inoperable malignant hilar biliary obstruction. METHODS: Forty-three patients with inoperable malignant hilar biliary obstruction from four academic centers were prospectively enrolled from March 2013 to June 2015. RESULTS: Bilateral stent-in-stent placement using two large cell-type stents was successfully performed in 88.4% of the patients (38/43). In four of the five cases with technical failure, the delivery sheath of the second stent became caught in the hook-cross-type vertex of the large cell of the first stent, and subsequent attempts to pass a guidewire and stent assembly through the mesh failed. Functional success was achieved in all cases of technical success. Stent occlusion occurred in 63.2% of the patients (24/38), with a median patient survival of 300 days. The median stent patency was 198 days. The stent patency rate was 82.9%, 63.1%, and 32.1% at 3, 6, and 12 months postoperatively, respectively. Endoscopic re-intervention was performed in 14 patients, whereas 10 underwent percutaneous drainage. CONCLUSIONS: Large cell-type stents for endoscopic bilateral stent-in-stent placement had acceptable functional success and stent patency when technically successful. However, the technical difficulty associated with the entanglement of the second stent delivery sheath in the hook-cross-type vertex of the first stent may preclude large cell-type stents from being considered as a dedicated standard tool for stent-in-stent placement.

Efficacy of a Multiplex Paclitaxel Emission Stent Using a Pluronic® Mixture Membrane versus a Covered Metal Stent in Malignant Biliary Obstruction: A Prospective Randomized Comparative Study

BACKGROUND/AIMS: A drug-eluting stent for unresectable malignant biliary obstruction was developed to increase stent patency by preventing tumor ingrowth. The safety and efficacy of a new generation of metallic stents covered with a paclitaxel-incorporated membrane using a Pluronic® mixture (MSCPM-II) were compared prospectively with those of covered metal stents (CMSs) in patients with malignant biliary obstructions. METHODS: This study was initially designed as a prospective randomized trial but was closed early because of a high incidence of early occlusion. Therefore, the data were analyzed using the intent-to-treat method. A total of 72 patients with unresectable distal malignant biliary obstructions were prospectively enrolled. RESULTS: The two groups did not differ significantly in basic characteristics and mean follow-up period (MSCPM-II 194 days vs CMS 277 days, p=0.063). Stent occlusion occurred in 14 patients (35%) who received MSCPM-II and in seven patients (21.9%) who received CMSs. Stent patency and survival time did not significantly differ between the two groups (p=0.355 and p=0.570). The complications were mild and resolved by conservative management in both groups. CONCLUSIONS: There were no significant differences in stent patency or patient survival in MSCPM-II and CMS patients with malignant biliary obstructions.

The Effect of Intragastric Administration of Botulinum Toxin Type A on Reducing Adiposity in a Rat Model of Obesity Using Micro-CT and Histological Examinations

BACKGROUND/AIMS: Botulinum toxin type A (BTX), a long-acting inhibitor of muscular contraction in both striated and smooth muscles, is responsible for gastric motility. The aim of this study was to investigate the effects of an endoscopic intragastric BTX injection on weight loss, body fat accumulation, and gastric emptying time. METHODS: The BTX group consisted of 15 obese rats in which 20 U of BTX were injected into the gastric antrum. The saline group consisted of 15 obese rats injected with 20 U of saline, and the control group included 10 obese rats that did not receive a surgical intervention. The gastric emptying time, biochemical parameters, and body fat volume were evaluated using micro-computed tomography (micro-CT) and histologic evaluations. RESULTS: The postoperative body weight of the BTX group was significantly lower than those of the other groups (p < 0.001) at 6 weeks after the operation. The gastric emptying time (156±54 minutes) was significantly delayed in the BTX group. The BTX group showed significantly lower lipid levels than the other groups. A reduction in body fat volume was observed in the BTX group using micro-CT and histological evaluations. CONCLUSIONS: BTX application to the gastric antrum represents a potentially effective treatment for obesity and may help improve the lipid profile by increasing the gastric emptying time.

A Double-Layered Covered Biliary Metal Stent for the Management of Unresectable Malignant Biliary Obstruction: A Multicenter Feasibility Study

BACKGROUND/AIMS: The covered self-expandable metal stent (CMS) was developed to prevent tumor ingrowth-induced stent occlusion during the treatment of malignant biliary obstruction. However, complications such as cholecystitis, pancreatitis, and stent migration can occur after the endoscopic insertion of CMSs. The aim of the present study was to assess the efficacy and safety of a double-layered CMS (DCMS) for the management of malignant bile duct obstruction. METHODS: DCMSs were endoscopically introduced into 59 patients with unresectable malignant extrahepatic biliary obstruction at four tertiary referral centers, and the patient medical records were retrospectively reviewed. RESULTS: Both the technical and functional success rates were 100%. Procedure-related complications including pancreatitis, cholangitis, stent migration, and liver abscess occurred in five patients (8.5%). The median follow-up period was 265 days (range, 31 to 752 days). Cumulative stent patency rates were 68.2% and 40.8% at 6 and 12 months, respectively. At the final follow-up, the rate of stent occlusion was 33.9% (20/59), and the median stent patency period was 276 days (range, 2 to 706 days). CONCLUSIONS: The clinical outcomes of DCMSs were comparable to the outcomes previously reported for CMSs with respect to stent patency period and complication rates.

Development of a Swine Benign Biliary Stricture Model Using Endoscopic Biliary Radiofrequency Ablation

The large animal model with benign biliary stricture (BBS) is essential to undergo experiment on developing new devices and endoscopic treatment. This study conducted to establish a clinically relevant porcine BBS model by means of endobiliary radiofrequency ablation (RFA). Endoscopic retrograde cholangiography (ERC) was performed on 12 swine. The animals were allocated to three groups (60, 80, and 100 W) according to the electrical power level of RFA electrode. Endobiliary RFA was applied to the common bile duct for 60 seconds using an RFA catheter that was endoscopically inserted. ERC was repeated two and four weeks, respectively, after the RFA to identify BBS. After the strictures were identified, histologic evaluations were performed. On the follow-up ERC two weeks after the procedure, a segmental bile duct stricture was observed in all animals. On microscopic examination, severe periductal fibrosis and luminal obliteration with transmural inflammation were demonstrated. Bile duct perforations occurred in two pigs (100 W, n = 1; 80 W, n = 1) but there were no major complications in the 60 W group. The application of endobiliary RFA with 60 W electrical power resulted in a safe and reproducible swine model of BBS.

Bile Flow Phantom Model and Animal Bile Duct Dilation Model for Evaluating Biliary Plastic Stents with Advanced Hydrophilic Coating

BACKGROUND/AIMS: The efforts to improve biliary plastic stents (PSs) for decreasing biofilm formation and overcome short patency time have been continued. The aim of this study is to evaluate the effect of advanced hydrophilic coating for patency and biodurability of PS. METHODS: Using an in vitro bile flow phantom model, we compared patency between prototype PS with hydrophilic coating (PS+HC) and prototype PS without hydrophilic coating (PS-HC). We performed an analysis of the degree of luminal narrowing by microscopic examination. Using an in vivo swine bile duct dilation model made by endoscopic papillary closure and stent insertion, we evaluated biodurability of hydrophilic coating. RESULTS: In the phantom model, PS+HC showed less biofilm formation and luminal narrowing than PS-HC at 8 weeks (p<0.05). A total of 31 stents were inserted into the dilated bile duct of seven swine models, and 24 stents were successfully retrieved 8 weeks later. There was no statistical difference of stent patency between the polyethylene PS+HC and the polyurethane PS+HC. The biodurability of hydrophilic coating was sustained up to 8 weeks, when assessing the coating layer by scanning electron microscopy examination. CONCLUSIONS: Advanced hydrophilic coating technology may extend the patency of PS compared to uncoated PS.

Efficacy of Magnesium Trihydrate of Ursodeoxycholic Acid and Chenodeoxycholic Acid for Gallstone Dissolution: A Prospective Multicenter Trial

BACKGROUND/AIMS: Cholecystectomy is necessary for the treatment of symptomatic or complicated gallbladder (GB) stones, but oral litholysis with bile acids is an attractive alternative therapeutic option for asymptomatic or mildly symptomatic patients. This study was conducted to evaluate the efficacy of magnesium trihydrate of ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on gallstone dissolution and to investigate improvements in gallstone-related symptoms. METHODS: A prospective, multicenter, phase 4 clinical study to determine the efficacy of orally administered magnesium trihydrate of UDCA and CDCA was performed from January 2011 to June 2013. The inclusion criteria were GB stone diameter or =50%, radiolucency on plain X-ray, and asymptomatic/mildly symptomatic patients. The patients were prescribed one capsule of magnesium trihydrate of UDCA and CDCA at breakfast and two capsules at bedtime for 6 months. The dissolution rate, response rate, and change in symptom score were evaluated. RESULTS: A total of 237 subjects were enrolled, and 195 subjects completed the treatment. The dissolution rate was 45.1% and the response rate was 47.2% (92/195) after 6 months of administration of magnesium trihydrate of UDCA and CDCA. Only the stone diameter was significantly associated with the response rate. Both the symptom score and the number of patients with symptoms significantly decreased regardless of stone dissolution. Adverse events necessitating discontinuation of the drug, surgery, or endoscopic management occurred in 2.5% (6/237) of patients. CONCLUSIONS: Magnesium trihydrate of UDCA and CDCA is a well-tolerated bile acid that showed similar efficacy for gallstone dissolution and improvement of gallstone-related symptoms as that shown in previous studies.

The Efficacy of Intraluminal Brachytherapy as Palliative Therapy of Hilar Cholangiocarcinoma / 대한췌담도학회지

BACKGROUND/AIMS: The aim of this study is to assess the therapeutic benefits of a combination of external beam radiation therapy (EBRT) and intraluminal brachytherapy (ILBT) in hilar cholangiocarcinoma as palliative therapy. METHODS: A total of 21 patients with hilar cholangiocarcinoma were included. Only 12 patients were treated with EBRT (group 1), and only nine patients were treated with EBRT and ILBT (group 2). The survival data and stent patency period were measured in both groups and the results were compared. RESULTS: No statistically significant difference in patient survival was observed between the two groups. The median survival period of group 1 was 353 days and that of group 2 was 224 days. Also, stent patency did not differ significantly between groups. The period for group 1 was 250 days, and that of group 2 was 133 days. In addition, there were no other factors influencing patient survival and stent patency period. However, patient survival tended to increase with increase in the amount of irradiation dose (Spearman's correlation coefficient=0.65, p=0.065). CONCLUSIONS: EBRT with ILBT did not have a benefit when compared with the treatment effect of EBRT alone as palliative therapy for hilar cholangiocarcinoma.

Percutaneous Papillary Large Balloon Dilation during Percutaneous Cholangioscopic Lithotripsy for the Treatment of Large Bile-Duct Stones: A Feasibility Study

When access to a major duodenal papilla or endoscopic retrograde cholangiopancreatography has failed, percutaneous transhepatic cholangioscopic lithotripsy (PTCS-L) may be useful for removing common bile duct (CBD) stones. However, the feasibility and usefulness of percutaneous transhepatic papillary large-balloon dilation (PPLBD) during PTCS-L for the removal of large CBD stones has not been established. We aimed to determine the safety and efficacy of PPLBD for the treatment of large CBD stones. Eleven patients with large CBD stones in whom the access to the major papilla or bile duct had failed were enrolled prospectively. Papillary dilation was performed using a large (12-20 mm) dilation balloon catheter via the percutaneous transhepatic route. Post-procedure adverse events and efficacy of the stone retrieval were measured. The initial success rate of PPLBD was 100%. No patient required a basket to remove a stone after PPLBD. Electrohydraulic lithotripsy was required in 2 (18.2%) patients. The median time to complete stone removal after PPLBD was 17.8 min and no adverse events occurred after PPLBD. Asymptomatic hyperamylasemia was not encountered in any patients. This study indicates that PPLBD is safe and effective for removal of large CBD stones.

Percutaneous Papillary Large Balloon Dilation during Percutaneous Cholangioscopic Lithotripsy for the Treatment of Large Bile-Duct Stones: A Feasibility Study

When access to a major duodenal papilla or endoscopic retrograde cholangiopancreatography has failed, percutaneous transhepatic cholangioscopic lithotripsy (PTCS-L) may be useful for removing common bile duct (CBD) stones. However, the feasibility and usefulness of percutaneous transhepatic papillary large-balloon dilation (PPLBD) during PTCS-L for the removal of large CBD stones has not been established. We aimed to determine the safety and efficacy of PPLBD for the treatment of large CBD stones. Eleven patients with large CBD stones in whom the access to the major papilla or bile duct had failed were enrolled prospectively. Papillary dilation was performed using a large (12-20 mm) dilation balloon catheter via the percutaneous transhepatic route. Post-procedure adverse events and efficacy of the stone retrieval were measured. The initial success rate of PPLBD was 100%. No patient required a basket to remove a stone after PPLBD. Electrohydraulic lithotripsy was required in 2 (18.2%) patients. The median time to complete stone removal after PPLBD was 17.8 min and no adverse events occurred after PPLBD. Asymptomatic hyperamylasemia was not encountered in any patients. This study indicates that PPLBD is safe and effective for removal of large CBD stones.

Recent Advances in Gastrointestinal Stent Development

Endoscopic stenting is increasingly being used in the management of gastrointestinal luminal obstruction, and has become the current treatment of choice for the palliation of blockage caused by malignant or benign growths. A variety of stents have been developed to enhance the efficacy of the procedure, and improvements are ongoing. In this article, we review the history of, and recent advances in, gastrointestinal stenting. We describe the rationale behind the design as well as the resulting outcome for each stent type.

Recent Advances in Gastrointestinal Stent Development

Endoscopic stenting is increasingly being used in the management of gastrointestinal luminal obstruction, and has become the current treatment of choice for the palliation of blockage caused by malignant or benign growths. A variety of stents have been developed to enhance the efficacy of the procedure, and improvements are ongoing. In this article, we review the history of, and recent advances in, gastrointestinal stenting. We describe the rationale behind the design as well as the resulting outcome for each stent type.

Clinical Features and Outcomes of Endoscopic Treatment for Stones in Stemware-Shaped Common Bile Ducts: A Multicenter Data Analysis

BACKGROUND/AIMS: Various anatomical features of the biliary tree affect ability to remove difficult common bile duct (CBD) stones. In this study, we evaluated the clinical characteristics and outcomes of the endoscopic treatment of stones in stemware-shaped CBDs. METHODS: Thirty-four patients with a stone and a stemware-shaped CBD who were treated at different tertiary referral centers from January 2008 to December 2012 were studied retrospectively. When stone removal failed, percutaneous or direct peroral cholangioscopic lithotripsy, endoscopic retrograde biliary drainage, or surgery was performed as a second-line procedure. RESULTS: The overall success rate of the first-line procedure was 41.2%. Five of the 34 patients (14.7%) experienced procedure-related complications. No procedure-related mortality occurred. Mechanical lithotripsy was required to completely remove stones in 13 patients (38.2%). Conversion to a second-line procedure was required in 20 patients (58.8%). Mechanical lithotripsy was needed in 75% and 66.7% of those with a stone size of or =1 cm, respectively. Stone recurrence occurred in two patients (9.1%) after 6 months and 27 months, respectively. CONCLUSIONS: The endoscopic treatment of stones in a stemware-shaped CBD is challenging. The careful assessment of difficult CBD stones is required before endoscopic procedures.

Delayed Flumazenil Injection after Endoscopic Sedation Increases Patient Satisfaction Compared with Immediate Flumazenil Injection

BACKGROUND/AIMS: Flumazenil was administered after the completion of endoscopy under sedation to reduce recovery time and increase patient safety. We evaluated patient satisfaction after endoscopy under sedation according to the timing of a postprocedural flumazenil injection. METHODS: In total, 200 subjects undergoing concurrent colonoscopy and upper endoscopy while sedated with midazolam and meperidine were enrolled in our investigation. We randomly administered 0.3 mg of flumazenil either immediately or 15 minutes after the endoscopic procedure. A postprocedural questionnaire and next day telephone interview were conducted to assess patient satisfaction. RESULTS: Flumazenil injection timing did not affect the time spent in the recovery room when comparing the two groups of patients. However, the subjects in the 15 minutes injection group were more satisfied with undergoing endoscopy under sedation than the patients in the immediate injection group according to the postprocedural survey (p=0.019). However, no difference in overall satisfaction, memory, or willingness to undergo a future endoscopy was observed between the two groups when the telephone survey was conducted on the following day. CONCLUSIONS: This study demonstrated that a delayed flumazenil injection after endoscopic sedation increased patient satisfaction without prolonging recovery time, even though the benefit of the delayed flumazenil injection did not persist into the following day.

Endoscopic Papillary Large Balloon Dilation: It Is about Time We Did for a Whopper

No abstract available.