Progressive Stricture Research Articles

Uropathogenic Dysbiosis Pattern is Associated With Urethral Fibrosis

Purpose: Cellular mechanisms of stricture progression after repeated transurethral interventions are unclear. We hypothesize that urethral injury and mechanical stretch cause tears on the urethral epithelial cell lining leading to leaking epithelium and urine extravasation. Urinary bacteria traverse the epithelial lining and may promote fibrogenesis through inflammation due to microbial activity. Our objective was to perform a case-control study of the urobiome from patients with urethral stricture disease or healthy controls using 16S rRNA and shotgun metagenomic sequencing profiling to elucidate the clinical relevance of the urobiome in urinary stricture progression. Materials and Methods: First catch urine samples from patients and healthy volunteers were collected and pelleted urine was used for DNA extraction, followed by high throughput 16S rRNA and shotgun metagenomic sequencing. Sequencing data were used to determine microbial taxa and functions associated with urethral stricture disease. Results: Sequencing results revealed that the lower urinary tract urobiome was significantly different between urethral stricture disease cases and healthy controls. In particular, taxonomic and metabolic profiles point toward anaerobic biofilm formation by antibiotic-resistant species of Klebsiella, which is a known uropathogen. Importantly, no patients in the study exhibited signs or symptoms of clinical infection. Conclusions: Our findings suggest a role for biofilm formation by uropathogens such as Klebsiella spp. in developing an inflammatory environment and consequent fibrosis progression. Future studies will elucidate specific mechanisms of Klebsiella-induced fibrosis. Our data suggest that targeting specific bacteria or biofilm formation may be beneficial for urethral stricture disease detection and prevention of progression.

Ostomy Management for Pediatric Perianal Crohn's Disease

IntroductionPediatric patients with perianal Crohn's Disease (CD) suffer recalcitrant fistulas, abscesses, and strictures. Fecal diversion is a palliative last resort, but the expected clinical course and long-term management of the ostomy for this population is unclear. We sought to identify factors predictive of ostomy takedown and establish management recommendations for fistulizing and stenosing disease. MethodsWe reviewed our institutional registry for patients aged 1–18 years with CD who received perianal surgery from 2011 to 2021. We analyzed medical therapy, examinations under anesthesia (EUA), fistula and stenosis response, and rates of fecal diversion and reversal. ResultsThere were 109 patients with fistulizing CD and 21 with stenosing CD. There were 8 diverted for fistula and 4 due to stricture [8/109 (7 %) vs 4/21 (19 %), p = 0.213]. Three patients with fistulizing disease had their ostomy reversed at an average of 1.46 years. Each demonstrated consistent CD control and with no additional perianal flares. The remainder have been diverted 3.15 ± 4.57 years with 2.1 ± 2.8 EUAs. Only one patient with stricture was durably reversed, but they still require serial anal dilation. Two were reversed but required re-diversion due to stricture progression. ConclusionReversal rates after fecal diversion for pediatric perianal CD remain disappointingly low and diversion does not obviate the possibility of future EUAs. While reversal was successful for medically responsive patients with fistulizing disease, those with stenosing disease remained dependent on anal dilations and were more likely to fail reversal. Fecal diversion does nothing to reverse an established stricture and such patients will likely need to decide between indefinite dilations or permanent ostomy. Level of evidenceIV. Type of studyRetrospective review.

A104 INVISIBLE COLONIC MALIGNANCY AND POSSIBLE IDIOSYNCRATIC DRUG-INDUCED LIVER INJURY FROM VEDOLIZUMAB IN A PATIENT WITH ULCERATIVE COLITIS, PRIMARY SCLEROSING CHOLANGITIS AND AUTOIMMUNE HEPATITIS OVERLAP SYNDROME

Abstract Background Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. Due to an increased risk of developing colorectal cancer, regular surveillance for dysplastic lesions via colonoscopy is recommended. Invisible dysplasia is the abnormal development of cells noted on pathology with no visible lesion seen during colonoscopy. Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease leading to progressive stricturing and fibrosis of the bile ducts. There is significant association between PSC and IBD, as up to 80% of patients with PSC having underlying IBD. Drug induced liver injury (DILI) is a common cause of acute liver failure in most Western countries. Most cases of DILI are self-limited, with resolution of laboratory and clinical findings after cessation of the offending agent. Purpose To describe a case of invisible colonic malignancy and possible idiosyncratic drug-induced liver injury from vedolizumab (VDZ) in a patient with ulcerative colitis (UC), PSC and autoimmune hepatitis (AIH) overlap syndrome. Method Patient consent was obtained. Information from electronic records was extracted, including admission notes and procedural reports. A literature review was performed using Pubmed. Result(s) A 32-year-old Caucasian female with UC on VDZ with PSC and AIH had multiple colonoscopies performed demonstrating multifocal low-grade dysplasia. However, she remained resistant to surgery. She presented to clinic with tea-coloured urine, fatigue, and scleral icterus. Investigations revealed conjugated hyperbilirubinemia with elevation in hepatocellular liver enzymes. Imaging was consistent with large duct PSC, and liver biopsy showed grade 2 chronic hepatitis raising the possibility of large bile duct obstruction. She underwent liver transplant assessment and VDZ was held. Her bilirubin and liver enzymes recovered. Given multiple colonoscopies showing multifocal dysplastic changes and the patient declining other biologics, she would ultimately undergo total proctocolectomy with end ileostomy. Pathology demonstrated mucinous adenocarcinoma with a signet ring component. Conclusion(s) Both mucinous adenocarcinoma and signet ring carcinoma are more aggressive malignancies associated with poor prognosis. Found more often in younger patients, they are often diagnosed in later stages with lymphovascular invasion. Here, there was no evidence of metastases in any of the 40 lymph nodes examined, which indicated more favourable prognosis. The mechanism by which VDZ potentially causes liver injury is unknown. Multiple therapies for PSC-AIH overlap and IBD were entertained as causative agents. However, significant improvement in clinical symptoms and serologic parameters following cessation of VDZ was temporally suggestive. This case simultaneously highlights the importance of both timely colectomy in IBD patients with high-risk features during surveillance and early recognition and cessation of potential causative medications which induce liver injury. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

PD31-04 LOWER URINARY TRACT MICROBIOTA DYSBIOSIS IS ASSOCIATED WITH URETHRAL FIBROSIS

You have accessJournal of UrologyCME1 May 2022PD31-04 LOWER URINARY TRACT MICROBIOTA DYSBIOSIS IS ASSOCIATED WITH URETHRAL FIBROSIS Michael Witthaus, Valmik Bhargava, Jill Buckley, and Mahadevan Rajasekaran Michael WitthausMichael Witthaus More articles by this author , Valmik BhargavaValmik Bhargava More articles by this author , Jill BuckleyJill Buckley More articles by this author , and Mahadevan RajasekaranMahadevan Rajasekaran More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002582.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cellular mechanisms of stricture progression after repeated transurethral interventions (TUI) are unclear. We hypothesize urethral injury and mechanical stretch can cause tears on the urethral epithelial cell lining leading to leaking epithelium and urine extravasation (Fig A). Urinary microbiota traverses the epithelial lining and fibrogenesis can be mediated by inflammation due to microbial metabolites. Our objective is to characterize the urinary microbiome of patients with urethral stricture disease (USD) using 16S rRNA taxonomic profiling to elucidate the clinical relevance of the urinary microbiome in USD progression. METHODS: First catch urine samples from USD patients and healthy volunteers were collected and frozen to −80°C. Prior to analysis, samples were thawed at 2-8°C and centrifuged at 4°C for 15 mins to form a pellet. The pellet was then used for bacterial genomic DNA extraction using the PowerMag Soil DNA Isolation Kit. PCR amplification of the V3 and V4 regions of the 16S rRNA gene was performed. Illumina sequencing adapters and unique dual-index barcodes were added by PCR. Samples were then pooled and sequenced with paired-end 150 base pair reads (PE150) on an Illumina MiSeq Instrument. Data was analyzed using Qiime, which was used to determine alpha and beta diversity metrics per sample and to determine which microbes were presented differentially between the two cohorts. RESULTS: Our results are summarized in Fig B-D. Visualizing the specific microbes using a relative abundance bar plot (Fig B), the microbiome of healthy urine was more diverse than patients with USD. A divergence between the two groups supported distinct microbiomes, and a significant difference between patients with USD and controls was observed with beta diversity analysis (Fig C, D). The findings were indicative of the overall composition of microbial communities in each patient population. CONCLUSIONS: Our findings suggest a potential role for urinary microbiota alterations in developing an inflammatory environment and consequent fibrosis progression in USD. Future studies will determine specific urinary microbes between the two cohorts and their relevance to USD. Further potential for targeting specific microbes using next-generation probiotics to correct the urinary microbiota dysbiosis may be beneficial in preventing stricture progression. Source of Funding: UCSD Academic Senate © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e542 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Witthaus More articles by this author Valmik Bhargava More articles by this author Jill Buckley More articles by this author Mahadevan Rajasekaran More articles by this author Expand All Advertisement PDF DownloadLoading ...

PD31-05 REPEATED TRANSURETHRAL INTERVENTIONS INCREASE ELASTIN DEGRADATION AND STRICTURE SEVERITY

You have accessJournal of UrologyCME1 May 2022PD31-05 REPEATED TRANSURETHRAL INTERVENTIONS INCREASE ELASTIN DEGRADATION AND STRICTURE SEVERITY Michael Witthaus, Jathin Bandari, Thomas Will Fuller, Valmik Bhargava, Jill Buckley, and Mahadevan Rajasekaran Michael WitthausMichael Witthaus More articles by this author , Jathin BandariJathin Bandari More articles by this author , Thomas Will FullerThomas Will Fuller More articles by this author , Valmik BhargavaValmik Bhargava More articles by this author , Jill BuckleyJill Buckley More articles by this author , and Mahadevan RajasekaranMahadevan Rajasekaran More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002582.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Repeated transurethral interventions can cause or exacerbate urethral stricture disease by increasing tissue damage. A clear understanding of molecular mechanisms involved in increased fibrogenesis would enable development of optimal strategies to minimize progression or prevent stricture recurrence. Recently elastin, an extracellular matrix protein has been implicated in heart, liver and kidney fibrosis. We hypothesize repeated transurethral mechanical stretch accelerates elastin degradation and increases stricture severity. METHODS: Electrocautery was used to induce strictures in middle aged rabbits (12 months; n=6; Fig A). Rabbits (n=3) that showed evidence of stricture development at 14 days post-injury were further subjected to urethral wall stretch using a Foley catheter (balloon inflated to 14 mm diameter for 10 minutes, once a week for 4 weeks; Fig B). Animals were then allowed to recover and subjected to retrograde urethrogram (RUG) to confirm stricture progression and sacrificed at 45 days post-injury. Urethral tissues were harvested and subjected to immunostaining (Verhoeff–Van Gieson; VVG) for elastin. Results were then validated in human urethral scar tissues (n=3) obtained from patients undergoing urethroplasty. RESULTS: RUG findings are summarized in the Fig C. The RUGs performed showed a significant increase in stricture severity after balloon dilation (Fig C -bottom panel). The methodology utilized in the animal model was confirmed fluoroscopically to be replicable. VVG showed strong labeling for elastin (Fig E-F; black stain; yellow arrows) in rabbit and human (Fig G) scar tissues relative to controls (Fig D). CONCLUSIONS: Our findings confirm that this approach is a viable model to study transurethral intervention induced fibrogenesis. It further supports our hypothesis that urethral wall stretch worsens stricture severity due to elastin degradation. This may be an initiating factor in tissue remodeling after injury. Targeting elastin using an elastase may be a potential pharmacological intervention to treat or prevent stricture recurrence after transurethral interventions. Source of Funding: UCSD Academic Senate © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e542 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Witthaus More articles by this author Jathin Bandari More articles by this author Thomas Will Fuller More articles by this author Valmik Bhargava More articles by this author Jill Buckley More articles by this author Mahadevan Rajasekaran More articles by this author Expand All Advertisement PDF DownloadLoading ...

Characterization of urethral fibrosis in a rabbit model: Potential roles of Wnt-β catenin pathway and epithelial to mesenchymal transition.

To elucidate the precise cellular and molecular mechanisms that underlie urethral fibrogenesis. Endoluminal electrocautery injury (using Karl Storz 10 Fr. Pediatric urethroscope) was employed in male rabbits (n = 6) to create mucosal injury. Retrograde urethrogram (RUG) and endoluminal ultrasound techniques were used to assess severity and changes in luminal cross-sectional area. Six control rabbits were subjected to sham injury, in which the electrocautery was inserted but not powered. Urethral tissues were harvested 30 days postinjury and subjected to RNA sequencing and quantitative polymerase chain reaction (qPCR) to determine changes in gene expression. Histological, immunostaining, and Western blot studies were used to determine changes in protein expression of known markers of fibrosis (eg, collagen, Integrinαv, GIV/Girdin, transforming growth factor-β (TGF-β), and pSMAD1,2,3). Trichrome staining confirmed increased connective tissue in urethral scar tissues. Immunostaining revealed a potential role for epithelial to mesenchymal cell transition (EMT) and positive labeling for all fibrotic markers (eg, collagen-1, Integrin αv, GIV/Girdin, transforming growth factor-β (TGF-β), and SMAD1,2,3). Western blot analysis confirmed increased protein levels of these fibrotic markers. Our RNA sequencing and qPCR studies, in conjunction with our protein data, suggest that urethral mucosal fibrogenesis may be mediated by novel fibrogenic signaling pathways involving Wnt-β catenin, TGF-β, GIV/Girdin, and EMT which lead to increased collagen deposition. Therapeutic strategies targeting these pathways may be beneficial in attenuating fibrogenesis and stricture progression.

Frumkomin trefjunargallgangabólga á Íslandi 1992-2012

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease affecting the intra- and/or extrahepatic biliary tree with inflammation and progressive stricture formation that can lead to cirrhosis, end stage liver failure and liver transplantation. Known risk factors include inflammatory bowel diseases (IBD), mainly ulcerative colitis (UC). Highest reported incidence in an adult population is 1.2-1.3/100.000 in Norway and Sweden, where 60-76% have IBD. The aim of this study was to investigate epidemiology of PSC in Iceland in the years 1992 to 2012 and the patients outcomes. A search for the diagnosis "cholangitis" (ICD-10, K83.0) was performed in the database for hospital records in Landspítali (The National University Hospital of Iceland, LSH) and Akureyri Hospital from 1992 to 2012. We also looked through all ERCP and MRCP imaging done in LSH in the same period along with a text search in both the hospital records and the pathology database for liver biopsies. Data on these patients was collected until the end of 2016. A total of 42 patient got the diagnosis PSC within the period. Median age at diagnosis was 34 years, 67% were male and 90% adults (≥18 years old). Mean incidence per year was 0.69/100.000. Overall 88% of patients had IBD, thereof 89% UC. Seven patients have been diagnosed with cancer, four with cancer in the bile ducts and one in the gallbladder. Within the study period a total of five patients died (12%), 51 months (median) from diagnosis and three from cholangiocarcinoma, 51 months (median) from diagnosis. Three patients (7%) underwent liver transplantation, one required a transplant two times. The incidence of PSC in Iceland turned out to be lower than in our neighbouring countries in Scandinavia. It is unclear if this is due to underdiagnosis or, more likely, that PSC is simply more uncommon in Iceland. Overall 7% underwent liver transplantation and 12% died within the study period, main cause of mortality being cholangiocarcinoma.

The protective and anti-inflammatory effect of methylene blue in corrosive esophageal burns: An experimental study.

In developing countries, esophageal burns are quite common. They are caused by the ingestion of corrosive substances that may lead to esophageal perforation in the short-term and stricture formation in the long-term. Prevention of stricture progression in the esophagus is the main aim of the treatment for corrosive esophageal burns. We aimed to investigate the protective and anti-inflammatory effects of methylene blue (MB) treatment on corrosive esophageal burns. Twenty-eight rats were used in the study and randomly divided into four equal groups; group 1 (Sham), group 2 (control), group 3 (topical treatment), and group 4 (topical plus systemic treatment). Except for group 1 (Sham group), all three groups received sodium hydroxide (NaOH) in order to generate esophageal burns. In addition, group 2 was given normal saline, group 3 topical MB, and group 4 topical and systemic MB. Hydroxyproline levels were found to be lower in each of the treatment groups as compared to the control group (p=0.005 for group 3 and p=0.009 for group 4). There were no differences in the tumor necrosis factor-α (TNF-α) levels between the groups. The stenosis index (SI) in the treatment groups was also lower than the control group (p=0.016 for group 3 and p=0.015 group 4). The histopathologic damage score (HDS) was prominently lower in group 4 as compared to the control group (p=0.05). MB is effective in treating tissue damage caused by corrosive esophageal burns and in preventing esophageal stenosis. Complication rates of corrosive esophageal burns may be decreased by using MB in the initial treatment stage.

Autologous granulation tissue tubes for replacement of urethral defects: An experimental study in male rabbits

Tubularized urethroplasty is commonly performed in clinical practice using genital skin flaps, bladder mucosa, and buccal mucosa. However, the long-term effects are not satisfying, and donor site morbidities remain a problem. Besides, those grafts are unavailable with malignant conditions of the urinary tract, a history of lichen sclerosis, or oral disease. An autologous granulation tissue tube of any required length and diameter can be produced by implanting foreign objects subcutaneously (Summary Fig.). The current study aimed to investigate to what extent of length this fully autologous tissue could be used for tubularized urethroplasty, satisfying urethral patency and tissue regeneration, in male rabbits. Twenty-seven New Zealand male rabbits were randomly divided into three groups. Silastic tubes were implanted subcutaneously in Group 1 and Group 2. By 2 weeks the granulation tissue encapsulating the tubes was harvested. In Group 1, pendulous urethral segments of 1cm were excised, and urethroplasty was performed with the granulation tissue tube in an end-to-end fashion. In Group 2, a pendulous urethral segment of 1.5cm was replaced with the tissue tube. In Group 3, a pendulous urethral defect of 1cm was repaired by re-anastomosis as control. Serial urethrograms were performed at 1, 2 and 6 months postoperatively. Meanwhile, the neo-urethra were harvested and analyzed grossly and histologically. The urethrograms showed that all animals in Group 1 maintained a wide urethral caliber. In contrast, animals in Group 2 and Group 3 developed progressive strictures. Histologically, an intact urothelium with one to two cell layers lined the graft by 1 month, which was surrounded by increasing organized smooth muscle in Group 1. By 6 months, the grafts were completely integrated into native urethra. Nevertheless, extensive fibrosis occurred in Group 2 and Group 3. The tissue successfully maintained patency and guided urethral regeneration across a distance of 1cm. As an epithelium-free graft, the tissue showed better results than acellular matrix for tubularized urethroplasty compared with previous studies. Nevertheless, several limitations existed: (1) the urethral defect was created in healthy urethra, which could not fully simulate the clinical situation; (2) as a small animal model, rabbit was less informative for clinical problems; (3) the tissue was inadequate for long segmental urethral replacement. Further study is needed before the procedure is used clinically. An autologous granulation tissue tube grown subcutaneously could be successfully used to repair urethral defects of 1cm in male rabbits.

Safety and efficacy of coaxial lumen-apposing metal stents in the management of refractory gastrointestinal luminal strictures: a multicenter study.

Background and aims Benign gastrointestinal (GI) strictures are often refractory to standard endoscopic interventions. Fully covered coaxial lumen-apposing metal stents (LAMS) have emerged as a novel therapy for these strictures. The aim of this study was to evaluate the safety and efficacy of LAMS for refractory GI strictures. Patients and methods A retrospective analysis was performed for patients who underwent LAMS placement for benign luminal strictures in three US centers between January 2014 and December 2016. The primary outcomes were technical success and initial clinical success of LAMS placement. Secondary outcomes were stent migration, rate of re-intervention, and adverse events. Results A total of 49 patients underwent 56 LAMS placement procedures. Previous treatment had failed in 39 patients (79.6 %), and anastomotic strictures were the indication in 77.6 % (38/49), with the most common site being gastrojejunal (34.7 % [17/49]). Technical success was achieved in all procedures and initial clinical success was achieved in 96.4 % of all procedures (54/56). Patient initial clinical success was 95.9 % (47/49). Stent migration occurred in 17.9 % of procedures, and was more likely to occur at sites in the lower GI tract ( P = 0.02). The mean stent dwell time was 100.6 days, and the mean follow-up was 169.8 days. Minor adverse events, not requiring hospitalization, occurred in 33.9 % of procedures, including subsequent stricture progression (10.7 %). In cases where LAMS were removed, mean follow-up time was 102.2 days. The re-intervention rate was 75 % at 300 days follow-up after stent removal. Of the LAMS placed at anastomotic strictures, 36.4 % required re-intervention, with approximately two-thirds of these re-interventions requiring placement of a new stent or surgery. Conclusion LAMS placement was successful for the management of refractory GI strictures, with good technical and initial clinical success rates. However, re-intervention rates after LAMS removal were high, and many strictures were not resolved by an extended period of stenting with these coaxial stents. LAMS placement offers additional therapeutic options and in selected cases might be considered a destination therapy for patients with recalcitrant benign strictures.

Secondary sclerosing cholangitis in critically ill patients: current perspectives.

Secondary sclerosing cholangitis (SSC) is a term used for a group of chronic cholestatic disease affecting the intra- and/or extrahepatic biliary tree with inflammation and progressive stricture formation, which can lead to biliary cirrhosis. A newly recognized form of SSC is secondary sclerosing cholangitis in critically ill patients (SSC-CIP). Pathogenesis is believed to involve ischemic injury of intrahepatic bile ducts associated with prolonged hypotension, vasopressors administration, and/or mechanical ventilation in patients treated in the intensive care unit (ICU). Patients diagnosed with SSC-CIP have no prior history of liver disease and no known pathologic process or injury responsible for bile duct obstruction prior to ICU treatment. Reasons leading to ICU treatment are many including multitrauma, burn injury, cardiac surgery, severe pneumonia, other infections, or bleeding after abdominal surgery. Patients have in common prolonged ICU admission. SSC-CIP is associated with rapid progression to liver cirrhosis and poor survival with limited treatment options except a liver transplantation. Transplant-free survival is around 17–40 months, which is lower than in other SSC patients. During the initial stages of the disease, the clinical symptoms and biochemical profile are not specific and easily missed. Biliary casts formation may be considered pathognomonic for SSC-CIP since most patients have them in early stages of the disease. Increased awareness and early detection of the disease and its complications is considered to be crucial to improve the poor prognosis.

Rectal Perforation Caused by Anal Stricture After Hemorrhoid Treatment

Inappropriate therapies for hemorrhoids can lead to various complications including anorectal stricture. We report a patient presenting with catastrophic rectal perforation due to severe anal stricture after inappropriate hemorrhoid treatment. A 67-years old man with perianal pain visited the emergency room. The hemorrhoids accompanied by constipation, had tortured him since his youth. Thus he had undergone injection sclerotherapy several times by an unlicensed therapist and hemorrhoidectomy twice at the clinics of private practitioners. His body temperature was as high as 38.5℃. The computed tomographic scan showed a focal perforation of posterior rectal wall. The emergency operation was performed. The fibrotic tissues of the anal canal were excised. And then a sigmoid loop colostomy was constructed. The patient was discharged four days following the operation. This report calls attention to the enormous risk of unlicensed injection sclerotherapy and overzealous hemorrhoidectomy resulting in scarring, progressive stricture, and eventual rectal perforation.

A novel device for ablation of abnormal esophageal mucosa (with video)

Current ablation devices for Barrett's esophagus are effective but have significant limitations. To evaluate a new ablation device. Laboratory and animal model evaluation of the CryoBalloon, a compliant balloon that is simultaneously inflated and cooled by liquid nitrous oxide delivered by using a small, disposable, handheld unit. Cryoablation of esophageal mucosa was performed in 11 swine. Multiple ablations were created in each animal at various ablation times. Animals were euthanized at 4 days (n = 6) or 28 days (n = 5), and histological assessments were performed. At 4 days, the percentage of esophageal mucosa successfully ablated was measured. At 28 days, the circumference of the esophagus at the center of the ablation zone was measured to assess for stricture formation. The CryoBalloon was simple to operate, and balloon contact with tissue was easily maintained. As the ablation time was increased from 6 to 12 seconds, the percentage of mucosa ablated increased from below 60% to above 90%. Maximal effect on the mucosa was reached at 12 seconds. Ablation of up to 14 seconds resulted in minimal luminal narrowing. As the ablation duration increased from 14 to 22 seconds, there was progressive stricture formation evident at 28 days. All of the animals tolerated the treatments without difficulty and, regardless of ablation duration, were able to continue oral intake and gain weight after the procedure. Ablation of normal porcine squamous mucosa may differ from that of human Barrett's esophagus. The CryoBalloon device enables circumferential mucosal ablation in a 1-step process by using a novel, through-the-scope balloon. The maximal effect on the mucosa is achieved with a 12-second application time. Because of its ease of use, this new device merits further study so that we can find its possible role in the treatment of Barrett's esophagus.

Eosinophilic esophagitis

Eosinophilic esophagitis (EE) is a chronic esophageal inflammatory disease mediated by oral antigens with the infiltration of eosinophilic granulocytes. EE can lead to various reflux-like symptoms including dysphagia, progressive strictures and bolus obstruction. EE mostly affects young male population and is associated with atopic disorders and sensitization to oral antigens. Environmental (antigens) and genetic factors (eotaxin-3) have been reported to play role in the pathogenesis of the disease. Symptoms and histological changes are reversible by the elimination of the allergens and the use of anti-inflammatory agents. Remission requires long-term treatment. Strictures with severe symptoms require mechanical balloon dilatation.

The thermo‐expandable metallic ureteric stent: an 11‐year follow‐up

To review our long-term use of the thermo-expandable metallic ureteric stent, (model 051, PNN Medical, Denmark) for ureteric obstruction, and review current reports on its use. Data were collected prospectively on all patients who had a Memokath 051 ureteric stent inserted between November 1996 and November 2007. The standard stent, and wide and dual expansion versions were used. The stricture characteristics were recorded in a standard way. All stents were inserted by one surgeon in the UK and internationally, following a standard protocol. In all, 74 stents were inserted into 55 patients in the study period (mean age 60 years, range 11-90). The indications for metallic stenting included primary stenting for malignancy, failed conventional open and endoscopic techniques, palliation, and where significant comorbidity limited repetitive stent changes. In 28 patients the obstruction was caused by malignancy, whereas in 27 it was caused by recurrent benign disease. The mean (range) hospital stay was 1.43 (0-7) days. Imaging after insertion showed normal or improved functional drainage in all but three patients, with immediate complications including urinary extravasation (one), poor thermo-expansion (one) and equipment failure (locking assembly) (one). Late complications included migration (13), encrustation (two) and fungal infections (three). In all, 14 patients needed reinsertion (mean of 7.1 months, range 1-14) after insertion for migration (eight), encrustation (two), stricture progression (three) and incorrect stent length (one). Overall, 29 patients have died with the stents in-situ. The mean (range) follow-up was 16 (4-98) months. The thermo-expandable metallic Memokath 051 ureteric stent offers effective and durable long-term relief from ureteric obstruction, and is a safe alternative to conventional JJ stenting. In addition there is an emerging role in palliation and the primary management of ureteric strictures.

Nonanastomotic biliary strictures after liver transplantation, part 2: Management, outcome, and risk factors for disease progression

Nonanastomotic biliary strictures (NAS) after orthotopic liver transplantation (OLT) are associated with high retransplant rates. The aim of the present study was to describe the treatment of and identify risk factors for radiological progression of bile duct abnormalities, recurrent cholangitis, biliary cirrhosis, and retransplantation in patients with NAS. We retrospectively studied 81 cases of NAS. Strictures were classified according to severity and location. Management of strictures was recorded. Possible prognostic factors for bacterial cholangitis, radiological progression of strictures, development of severe fibrosis/cirrhosis, graft survival, and patient survival were evaluated. Median follow-up after OLT was 7.9 years. NAS were most prevalent in the extrahepatic bile duct. Twenty-eight patients (35%) underwent some kind of interventional treatment, leading to a marked improvement in biochemistry. Progression of disease was noted in 68% of cases with radiological follow-up. Radiological progression was more prevalent in patients with early NAS and one or more episodes of bacterial cholangitis. Recurrent bacterial cholangitis (>3 episodes) was more prevalent in patients with a hepaticojejunostomy. Severe fibrosis or cirrhosis developed in 23 cases, especially in cases with biliary abnormalities in the periphery of the liver. Graft survival, but not patient survival, was influenced by the presence of NAS. Thirteen patients (16%) were retransplanted for NAS. In conclusion, especially patients with a hepaticojejunostomy, those with an early diagnosis of NAS, and those with NAS presenting at the level of the peripheral branches of the biliary tree, are at risk for progressive disease with severe outcome.

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease characterized by fibrosis leading to progressive stricturing of the biliary system. It was first described in 1874, but more than a century later, fewer than 100 cases had been reported. However, in the last 25 years the development of endoscopic and radiologic techniques allowed the diagnosis of PSC to be made without resort to surgery or postmortem examinations. This led to the realization that PSC was much more common than previously thought. Since 1980, more than 1500 articles on PSC have been published.

Esophageal squamous papillomatosis

Esophageal squamous papillomatosis is rare and has been associated with gastroesophageal reflux and recurrent respiratory papillomatosis. We report a case of extensive esophageal papillomatosis, no airway involvement and a slowly progressive clinical course with progressive strictures and ultimately fatal squamous cell carcinoma. In-situ hybridization performed on biopsy specimens was negative for high-risk human papilloma virus types. Due to the paucity of reported cases, little is conclusively known about the etiology, natural course and best clinical management of this disease. Human papilloma virus has been linked to some, but not all, cases, and the clinical course has been reported to vary from spontaneous regression to malignant transformation. Surveillance for malignancy by conventional endoscopic biopsies or computed tomography scan appears to have low sensitivity. This case illustrates the difficulties in clinical management and establishing a definite etiology in esophageal squamous papillomatosis.

Is Cellular Atypia Predictive of Cholangiocarcinoma in Patients with Primary Sclerosing Cholangitis? A Long Term Follow-Up Study

Background: Primary sclerosing cholangitis (PSC) is a cholestatic liver disorder that causes progressive strictures of the biliary system. Patients with PSC are at risk for development of cholangiocarcinoma. Endoscopic brushing and cytological examination of strictures is a standard practice to detect malignancy. Aim: To assess the prognostic value of cytological diagnosis in subsequent development of cholangiocarcinoma. Methods: Computerized data base of prospectively collected data of all endoscopic retrograde cholangiopancreatographies (ERCP) done in a tertiary care referral center was searched for ERCP diagnosis of PSC. Charts of those identified to have PSC were reviewed for initial cytological diagnosis and subsequent outcomes. Results: 49 patients were identified: 30 (61%) males and 19 (39%) females. 34 (69%) had an underlying inflammatory bowel disease. Mean age at diagnosis was 54. Repeat ERCP was performed at intervals of 6-12 months dependent on symptoms. 14 (28%) patients had main duct disease, 10 (20%) with small duct disease and 26 (52%) had both. Initial cytological diagnoses were benign columnar cells in 36 (74%), reactive cells in 7 (14%) and atypical cells in 6 (12%). On a median follow up of 48 months, 6 (12%) developed cholangiocarcinoma. Of those who developed cholangiocarcinoma, only 2 (33%) had atypical cells at the initial cytology and remained atypical until diagnosis of malignancy was made. 2 (33%) had benign and 2(33%) had reactive cells on initial cytology. In these patients when followed over a prolonged period, subsequent cytological diagnoses were not similar; and there was no definite trend identified. Conclusions: 1. The risk of developing cholangiocarcinoma in those with PSC is high. 2. Cellular atypia on cytology is not prognostic for development of cholangiocarcinoma. 3. Better tissue acquisition with use of tumor markers are probably required to better identify those at risk of development of malignancy. Background: Primary sclerosing cholangitis (PSC) is a cholestatic liver disorder that causes progressive strictures of the biliary system. Patients with PSC are at risk for development of cholangiocarcinoma. Endoscopic brushing and cytological examination of strictures is a standard practice to detect malignancy. Aim: To assess the prognostic value of cytological diagnosis in subsequent development of cholangiocarcinoma. Methods: Computerized data base of prospectively collected data of all endoscopic retrograde cholangiopancreatographies (ERCP) done in a tertiary care referral center was searched for ERCP diagnosis of PSC. Charts of those identified to have PSC were reviewed for initial cytological diagnosis and subsequent outcomes. Results: 49 patients were identified: 30 (61%) males and 19 (39%) females. 34 (69%) had an underlying inflammatory bowel disease. Mean age at diagnosis was 54. Repeat ERCP was performed at intervals of 6-12 months dependent on symptoms. 14 (28%) patients had main duct disease, 10 (20%) with small duct disease and 26 (52%) had both. Initial cytological diagnoses were benign columnar cells in 36 (74%), reactive cells in 7 (14%) and atypical cells in 6 (12%). On a median follow up of 48 months, 6 (12%) developed cholangiocarcinoma. Of those who developed cholangiocarcinoma, only 2 (33%) had atypical cells at the initial cytology and remained atypical until diagnosis of malignancy was made. 2 (33%) had benign and 2(33%) had reactive cells on initial cytology. In these patients when followed over a prolonged period, subsequent cytological diagnoses were not similar; and there was no definite trend identified. Conclusions: 1. The risk of developing cholangiocarcinoma in those with PSC is high. 2. Cellular atypia on cytology is not prognostic for development of cholangiocarcinoma. 3. Better tissue acquisition with use of tumor markers are probably required to better identify those at risk of development of malignancy.

Management of biliary and duodenal complications of chronic pancreatitis.

Biliary stricture and duodenal obstruction have been increasingly recognized as complications of chronic pancreatitis. The anatomical relationship of the distal common bile duct and the duodenum with the head of the pancreas is the main factor for their involvement in chronic pancreatitis. In hospitalized patients with pancreatitis, the incidence of biliary stricture and duodenal obstruction is reported to be about 6% and 1.2%, respectively. For patients requiring an operation for chronic pancreatitis the incidence increases to 35% for biliary stricture and 12% for duodenal obstruction. Fibrosis around the distal common bile duct can cause stenosis with obstruction of bile flow. Clinically, the presentation of these patients ranges from being asymptomatic with elevated alkaline phosphatase or bilirubin, or both, to being septic with cholangitis. Jaundice, cholangitis, hyperbilirubinemia, and persistent elevation of serum alkaline phosphatase occur more frequently in patients with pancreatitis with a biliary stricture. A twofold elevation of alkaline phosphatase is a marker of possible common duct stenosis in patients with chronic pancreatitis. The incidence of both biliary cirrhosis and cholangitis in these patients is about 10%. ERCP reveals a characteristic long, smoothly tapered stricture of the intrapancreatic common bile duct. In duodenal obstruction, the factors that convert self-limiting edema to chronic fibrosis and stricture formation are unknown, but ischemia superimposed on inflammation may be the major cause. These patients present with a prolonged history of nausea and vomiting. Barium studies typically show a long constricting lesion of the duodenum, and endoscopy reveals reactive inflammatory changes in a narrowed duodenum. Operation is indicated in patients with common bile duct strictures secondary to chronic pancreatitis when there is evidence of cholangitis, biliary cirrhosis, common duct stones, progression of stricture, elevation of alkaline phophatase and/or bilirubin for over a month, and an inability to rule out cancer. The operation of choice is either choledochoduodenostomy or choledochojejunostomy. A cholecystoenterostomy is less favored because of its higher failure rate (23%). Endoscopic stenting plays a role in patients who are unfit for surgery, but it is not recommended as definitive therapy. For duodenal obstruction, failure to resolve the obstruction with 1-2 weeks of conservative therapy is an indication for bypass. The operation of choice is a gastrojejunostomy. Not uncommonly, combined obstruction of the pancreatic duct, common bile duct, and duodenum will develop. Combined drainage procedures or resection are used to manage these problems.