Bladder Neck Surgery is not Routinely Needed to Achieve Urinary Continence in Patients with Primary Epispadias.

BACKGROUND: This study aims at investigating the continence outcome in primary epispadias patients treated at a tertiary center. The authors hypothesized that additional continence procedures following primary epispadias repair is not routinely needed. METHODS: Patients treated for primary epispadias at the authors' institution between 2007 and 2019 and toilet trained, were identified from a prospective maintained database. Males underwent chordee correction, urethroplasty and glanuloplasty. Females underwent genitoplasty with reduction urethroplasty. If continence was not achieved by 4-5 years of age, pelvic floor muscle (PFM) biofeedback therapy was performed. Other continent procedures were discussed with family/patient if still incontinent. PRIMARY OUTCOME: urinary continence. SECONDARY OUTCOMES: PFM biofeedback therapy, continence surgery, hydronephrosis. Type of epispadias, age at repair and follow-up presented as median was also reported. RESULTS: Thirty-three patients (29 males) were included. Twelve had penopubic epispadias, 13 glanular/penile, 4 duplicated urethra, 4 females. Median age at repair: 2 years (IQR 1-3), at follow-up: 8 years (IQR 6-10). Daytime continence: 100 % in penile/glanular; 33 % in penopubic and 75 % in duplicated urethra. Nighttime continence: respectively 92 %, 50 % and 100 %. 24 % of males were intermittently incontinent. All patients except one voided urethrally. One patient underwent bladder neck closure, ileocystoplasty and Mitrofanoff. One girl achieved daytime continence, 2 were intermittently incontinent, one continuously incontinent. All were enuretic. 38 % of boys and 100 % of girls had biofeedback therapy. None had hydronephrosis/renal impairment. CONCLUSIONS: Most children with primary epispadias can achieve social urinary continence spontaneously or with the support of PFM biofeedback therapy. Other continence procedures should be reserved for patients who do not attain satisfactory continence. LEVEL OF EVIDENCE: Treatment study - level IV.

Urethral Plate Grafting for Deficient Urethral Plate in Exstrophy: An Alternative Method to Augment Urethral Plate.

INTRODUCTION: Short urethral plate remains a challenge in exstrophy management. We report our experience with urethral plate grafting in cases of exstrophy with deficient urethral plate. METHODS: Among the exstrophy patients treated at the authors' institutions (2018-2022), those with a short urethral plate were prospectively included. A short urethral plate was defined as a distance between the verumontanum and the base of the glans of less than 10 mm. Urethral plate grafting was performed electively before the exstrophy closure. The urethral plate was divided just distal to verumontanum, and a thin inner preputial or para-exstrophy skin graft was harvested and deployed to cover the defect. Exstrophy closure was subsequently performed. The following parameters were recorded: age at grafting, type of graft and age at exstrophy closure. Reported outcomes include success of closure, complications, and follow up. RESULTS: Six male patients were included in the study: 3 classic bladder exstrophy (CBE) and 3 cloacal exstrophy (CE). Median age at grafting was 9 (3-18) months. Inner preputial grafts were utilized in the 3 CBE patients, and para-exstrophy skin grafts were used for the 3 CE patients. There was no graft loss, and longer and wide urethral plate was seen in all cases. Median time to bladder exstrophy closure was 3 (3-13) months after grafting. CONCLUSION: Pre-closure urethral plate grafting represents a safe and effective option for exstrophy patients with a short or inadequate urethral plate.

Clustering of Tadalafil API Samples According to their Manufacturer in the Context of API Falsification Detection.

This paper reports the results of the active pharmaceutical ingredient (API) fingerprint study, organised by the General European Official Medicines Control Laboratory Network (GEON), on tadalafil. A classical market surveillance study, evaluating compliance to the European Pharmacopoeia, was combined with a fingerprint study, the latter to obtain characteristic data for the different manufacturers, allowing the network laboratories to conduct authenticity tests for future samples, as well as to detect substandard and falsified samples. In total, 46 tadalafil API samples from 13 different manufacturers were collected. For all samples fingerprint data was collected through analysis of impurities and residual solvents, mass spectrometric screening, X-ray powder diffraction and proton nuclear magnetic resonance (1H-NMR). Chemometric analysis revealed that all manufacturers could be characterised based on the impurity, residual solvent and 1H-NMR data. Future suspicious samples in the network will therefore be analysed with these techniques in order to attribute the sample to one of the manufacturers. If the sample cannot be attributed, a more profound investigation will be necessary to reveal the origin of the sample. In cases where the suspect sample is claimed to be from one of the manufacturers included in this study, analysis can be limited to the test distinguishing that manufacturer.

The data project: a shared approach between stakeholders of the healthcare system in definition of a therapeutic algorithm for inflammatory arthritis.

Rheumatic musculoskeletal diseases or RMD [rheumatoid arthritis (RA) and spondyloarthritis (SpA)] are systemic inflammatory diseases for which there are no biomarkers capable of predicting treatments with a higher likelihood of response in naive patients. In addition, the expiration of the anti-TNF blocking drugs' patents has resulted in the availability of anti-TNF biosimilar drugs with the same efficacy and safety than originators but at significantly reduced prices. To guarantee a personalized therapeutic approach to RMD treatment, a board of rheumatologists and stakeholders from the Campania region, Italy, developed a clinically applicable arthritis therapeutic algorithm to guide rheumatologists (DATA project). The general methodology relied on a Delphi technique forecast to produce a set of statements that summarized the experts' consensus. Selected clinical scenarios were discussed in light of the available evidence, and there were two rounds of voting on the therapeutic approaches. Separate discussions were held regarding rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The decision-making factors for each disease were clinical presentation, demographics, and comorbidities. In this paper, we describe a virtuous process between rheumatologists and healthcare system stakeholders that resulted in the development of a shared therapeutic algorithm for RMD patients naive to bDMARDs.

A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy.

Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.

Narrowing the chromosome 22q11.2 locus duplicated in bladder exstrophy-epispadias complex.

INTRODUCTION: Bladder exstrophy-epispadias complex (BEEC) comprises a spectrum of anterior midline congenital malformations, involving the lower urinary tract. BEEC is usually sporadic, but families with more than one affected member have been reported, and a twin concordance study supported a genetic contribution to pathogenesis. Moreover, diverse chromosomal aberrations have been reported in a small subset of individuals with BEEC. The commonest are 22q11.2 microduplications, identified in approximately 3% of BEEC index cases. OBJECTIVES: We aimed to refine the chromosome 22q11.2 locus, and to determine whether the encompassed genes are expressed in normal developing and mature human urinary bladders. RESULTS: Using DNA from an individual with CBE, the 22q11.2 duplicated locus was refined by identification of a maternally inherited 314 kb duplication (chr22:21,147,293-21,461,017), as depicted in this image. Moreover, the eight protein coding genes within the locus were found to be expressed during normal developing and mature bladders. To determine whether duplications in any of these individual genes were associated with CBE, we undertook copy number analyses in 115 individuals with CBE without duplications of the whole locus. No duplications of individual genes were found. DISCUSSION: The current study has refined the 22q11.2 locus associated with BEEC and has shown that the eight protein coding genes are expressed in human bladders both during antenatal development and postnatally. Nevertheless, the precise biological explanation as to why duplication of the phenocritical region of 22q11 confers increased susceptibility to BEEC remains to be determined. The fact that individuals with CBE without duplications of the whole locus also lacked duplication of any of the individual genes suggests that in individuals with BEEC and duplication of the 22q11.2 locus altered dosage of more than one gene may be important in BEEC etiology. CONCLUSIONS: The study has refined the 22q11.2 locus associated with BEEC and has shown that the eight protein coding genes within this locus are expressed in human bladders.

Barrier-Forming Potential of Epithelial Cells from the Exstrophic Bladder.

Bladder exstrophy (BEX) is a rare developmental abnormality resulting in an open, exposed bladder plate. Although normal bladder urothelium is a mitotically quiescent barrier epithelium, histologic studies of BEX epithelia report squamous and proliferative changes that can persist beyond surgical closure. The current study examined whether patient-derived BEX epithelial cells in vitro were capable of generating a barrier-forming epithelium under permissive conditions. Epithelial cells isolated from 11 BEX samples, classified histologically as transitional (n = 6) or squamous (n = 5), were propagated in vitro. In conditions conducive to differentiated tight barrier formation by normal human urothelial cell cultures, 8 of 11 BEX lines developed transepithelial electrical resistances of more than 1000 Ω.cm2, with 3 squamous lines failing to generate tight barriers. An inverse relationship was found between expression of squamous KRT14 transcript and barrier development. Transcriptional drivers of urothelial differentiation PPARG, GATA3, and FOXA1 showed reduced expression in squamous BEX cultures. These findings implicate developmental interruption of urothelial transcriptional programming in the spectrum of transitional to squamous epithelial phenotypes found in BEX. Assessment of BEX epithelial phenotype may inform management and treatment strategies, for which distinction between reversible versus intractably squamous epithelium could identify patients at risk of medical complications or those who are most appropriate for reconstructive tissue engineering strategies.

GEONs API fingerprint project: Selection of analytical techniques for clustering of sildenafil citrate API samples.

Through its Active Pharmaceutical Ingredient Working Group (API-WG) the General European Official Medicines Control Laboratory (OMCL) Network (GEON), co-ordinated by the European Directorate for the Quality of Medicines & HealthCare (EDQM), regularly organises market surveillance studies for specific APIs for conformity to their monograph in the European Pharmacopoeia. During the past years some studies were combined with a fingerprint study of the APIs. The idea is to obtain a fingerprint for each manufacturer of the API under investigation, allowing the OMCL network to identify future samples as well as to detect substandard and falsified APIs. This paper reports the results of the latest fingerprint study, organised on sildenafil citrate API samples. Seventy-nine samples from 14 different manufacturers were collected throughout the Network. Fingerprint data was collected through Mid-Infrared spectroscopy, Raman spectroscopy, liquid chromatography for related substances, gas chromatography for residual solvents, X-ray diffraction and Nuclear Magnetic Resonance (NMR) spectroscopy. Chemometrics applied to the collected data showed that all manufacturers could be discriminated based on the data of only three of these tests, i.e. gas chromatography for residual solvents, X-ray diffraction and proton NMR. Suspicious API samples for sildenafil citrate will therefore be analysed in the future with the selected techniques in order to link the sample to a manufacturer or demonstrate the absence of such link. If the sample cannot be attributed to one of the manufacturers, further analysis and research on provenance and identity will be required. Of course, if the suspected sample claims to originate from one of the manufacturers included in the study, analysis can be limited to the test distinguishing this manufacturer.

The Genomic Architecture of Bladder Exstrophy Epispadias Complex.

The bladder exstrophy-epispadias complex (BEEC) is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine. The vast majority of BEEC cases are classified as non-syndromic and the etiology of this malformation is still unknown. This review presents the current knowledge on this multifactorial disorder, including phenotypic and anatomical characterization, epidemiology, proposed developmental mechanisms, existing animal models, and implicated genetic and environmental components.

Prognostic Role of Bacterial and Fungal Infections in Patients With Liver Cirrhosis With and Without Acute-on-Chronic Liver Failure: A Prospective 2-Center Study.

BACKGROUND: Bacterial and fungal infections (BFIs) are frequent in patients with cirrhosis and often trigger acute-on-chronic liver failure (ACLF). This prospective observational study aims to describe the interactions between BFI and ACLF in terms of mortality and related risk factors. METHODS: We performed a 2-center prospective observational study enrolling hospitalized patients with cirrhosis admitted for acute decompensation. Data were recorded at admission and during hospitalization. Survival was recorded up to 1 year. RESULTS: Among the 516 patients enrolled, 108 (21%) were infected at admission, while an additional 61 patients (12%) developed an infection during hospital stay. In the absence of ACLF, the 1-year mortality rate of patients with BFI did not differ from that of patients without BFI (33% vs 31%; P = .553). In contrast, those with ACLF triggered or complicated by BFI had a significantly higher mortality rate than those who remained free from BFI (75% vs 54%; P = .011). Competing risk analysis showed that the negative impact of ACLF-related BFI on long-term prognosis was independent from Model for End-stage Liver Disease (MELD) incorporating serum sodium concentration score, comorbidity, and basal C-reactive protein level. Finally, multivariable logistic regression showed that higher MELD score (P < .001), QuickSOFA score ≥2 points (P = .007), and secondary bloodstream (P = .022) and multidrug-resistant pathogen isolation (P = .030) were independently associated with ACLF in patients with BFI. CONCLUSIONS: This large prospective study indicated that the adverse impact of BFI on long-term survival in decompensated cirrhosis is not universal but is limited to those patients who also develop ACLF. Both disease severity and microbiological factors predispose infected decompensated patients to ACLF.

SLC20A1 Is Involved in Urinary Tract and Urorectal Development.

Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.

Oral Vaccination with Hepatitis E Virus Capsid Protein and Immunobiotic Bacterium-Like Particles Induce Intestinal and Systemic Immunity in Mice.

The hepatitis E virus (HEV) genotype 3 (GT3) is an emergent pathogen in industrialized countries. It is transmitted zoonotically and may lead to chronic hepatitis in immunocompromised individuals. We evaluated if the major antigen of HEV, the capsid protein, can be used in combination with immunobiotic bacterium-like particles (IBLP) for oral vaccination in a mouse model. We have cloned and expressed the RGS-His5-tagged HEV GT3 capsid protein (ORF2) in E. coli and purified it by NiNTA. IBLP were obtained from two immunobiotic Lactobacillus rhamnosus strains acid- and heat-treated. ORF2 and the IBLP were orally administered to Balb/c mice. After three oral immunizations (14-day intervals), blood, intestinal fluid, Peyer´s patches, and spleen samples were drawn. IgA- and IgG-specific antibodies were determined by ELISA. Mononuclear cell populations from Peyer's patches and spleen were analyzed by flow cytometry, and the cytokine profiles were determined by ELISA to study cellular immunity. Orally administered recombinant ORF2 and IBLP from two L. rhamnosus strains (CRL1505 and IBL027) induced both antigen-specific humoral and cellular immune responses in mice. IBLP027 was more effective in inducing specific secretory IgA in the gut. IFN-γ, TNF-α, and IL-4 were produced by Peyer's plaques lymphocytes stimulated with ORF2 ex vivo suggesting a mixed Th1/Th2-type adaptive immune response in immunized mice. Oral vaccines are not invasive, do not need to be administered by specialized personal, and elicit both systemic and local immune responses at the port of entry. Here, we present an experimental oral vaccine for HEV GT3, which could be further developed for human and/or veterinary use.

Novel approach to vaginal calculus in a girl with urogenital sinus anomaly.

Isolated urogenital sinus can cause distended bladder and/or vagina and may present with an abdominal mass and sepsis during infancy. Older children may present with recurrent urinary tract infections and hematocolpos. We describe a 3-year-old girl with recurrent urinary tract infections thought to be secondary to vesicoureteric reflux. On further investigation, an isolated urogenital sinus anomaly with a calculus inside one of the hemivaginae was noted. She was managed expectantly with a plan to intervene at puberty. At puberty, during removal of the stone, the hemivaginal introitus was found to be stenotic. Gradually increasing sizes of Amplatz type graduated renal dilators were introduced from the introitus of the urogenital sinus into the hemivaginal stone until a size 22F Amplatz sheath could be passed easily. Size 10F cystoscope was passed through this channel, and the stone was fragmented using electrohydraulic lithotripsy. At a later date, she underwent staged anterior sagittal transvulval mobilization of the urogenital sinus.

Brentuximab vedotin followed by bendamustine supercharge for refractory or relapsed Hodgkin lymphoma.

We evaluated the impact on progression-free survival (PFS) of achieving a deep metabolic response at 2-deoxy-2[18F] fluoro-d-glucose positron emission tomography (FDG-PET) in patients with refractory or relapsed (R/R) classic Hodgkin lymphoma (cHL) following a new salvage regimen named Bv+Bs (brentuximab vedotin + bendamustine supercharge), from 2013 to 2017. In this real-life study, 20 consecutive patients (aged <60 years) with R/R cHL after failure of ≥1 salvage treatments received Bv+Bs regimen consisting of 3-days outpatient IV infusions of 1.8 mg/kg of Bv on day 1 of each 3-week cycle combined in sequence to bendamustine on days 2 and 3 of the treatment cycle at a fixed dose of 120 mg/m2 per day, for a total of 4 courses. A robust primary prophylaxis approach, including premedication, antimicrobials, stimulating factors, and cytomegalovirus monitoring, was systematically performed. The 20 patients (all evaluable) underwent 4 courses of Bv+Bs with a median dose intensity of 100% for both Bv and Bs. Ten patients (50%) experienced grade ≥3 treatment-related adverse events, without requiring hospitalization. At post-Bv+Bs reevaluation, 80% of patients had deep metabolic responses with Deauville 5-point scale scores ≤2. Thereafter, 14 patients (70%) received autologous hematopoietic stem cell transplantation (HSCT; peripheral blood stem cells previously harvested in 12 cases), and 4 patients (10%) received allogeneic HSCT. At a median follow-up of 27 months from Bv+Bs regimen initiation, the 2-year PFS of the entire population was 93.7% (95% confidence interval, 62.7% to 99.6%). Our data suggest that Bv+Bs regimen-driven strategy may be a promising salvage option to improve long-term control of high-risk Hodgkin lymphoma.

Rare Variants in BNC2 Are Implicated in Autosomal-Dominant Congenital Lower Urinary-Tract Obstruction.

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853∗]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.

Distribution of Semen Parameters Among Adolescent Males Undergoing Fertility Preservation in a Multicenter International Cohort.

OBJECTIVE: To determine the distribution of semen parameters among adolescent and adult males presenting for fertility preservation. METHODS: A retrospective, cross-sectional cohort study of adolescent males age 11-19 who underwent semen analysis for fertility preservation at 3 centers in 2 countries with a comparison cohort of adult men presenting for fertility preservation. Prevalence of azoospermia and distribution of semen parameters was compared across groups. RESULTS: A total of 197 adolescents and 95 adults underwent semen analysis for fertility preservation. Azoospermia was present in 17 (8.6%) adolescents and 3 (3.2%) adults. There was decline in the prevalence of azoospermia with increasing age. After exclusion of patients with azoospermia, the adolescent and adult cohorts were comprised of 180 and 92 patients, respectively. Median age at presentation among adolescents vs adults was 16.5years (interquartile range [IQR] 15.2-17.6) and 30.8years (IQR 22.7-43.8), respectively. Median semen volume was 1.0mL (IQR 0.5-2.0) vs 2.5mL (IQR 1.5-3.5), P <.001. Median sperm concentration was 30million/mL (IQR 10-57) vs 39million/mL (IQR 14-57), P = .2. Median sperm motility was 39% (IQR 20-55) vs 45% (IQR 35-55), P = .01. Median total motile sperm count was 11million (IQR 1.4-33) for adolescents vs 29million (IQR 13-69) for adults, P <.001. CONCLUSION: Young adolescent males had higher prevalence of azoospermia and lower semen parameters compared to adults. In conjunction with physical examination, Tanner stage, and specific clinical context, these data can help to inform patients and their families about potential for fertility preservation, even in very young adolescent patients.

22q11.2 duplications in a UK cohort with bladder exstrophy-epispadias complex.

The bladder exstrophy-epispadias complex (BEEC) comprises of a spectrum of anterior midline defects, all affecting the lower urinary tract, the external genitalia, and the bony pelvis. In extreme cases, the gastrointestinal tract is also affected. The pathogenesis of BEEC is unclear but chromosomal aberrations have been reported. In particular, duplications of 22q11.2 have been identified in eight unrelated individuals with BEEC. The current study aimed to identify chromosomal copy number variants in BEEC. Analyses was performed using the Affymetrix Genome-wide SNP6.0 assay in 92 unrelated patients cared for by two UK pediatric urology centers. Three individuals had a 22q11.2 duplication, a significantly higher number than that found in a control group of 12,500 individuals with developmental delay who had undergone microarray testing (p < .0001). Sequencing of CRKL, implicated in renal tract malformations in DiGeorge syndrome critical region at 22q11, in 89 individuals with BEEC lacking 22q11 duplications revealed no pathogenic variants. To date, 22q11.2 duplication is the genetic variant most commonly associated with BEEC. This is consistent with the hypothesis that altered expression of a single, yet to be defined, gene therein is critical to the pathogenesis of this potentially devastating congenital disorder.

Outcome of long benign esophageal strictures undergoing endoscopictherapy: a tertiary center experience.

COMPLEX BENIGN ESOPHAGEAL STRICTURES ARE DEFINED BY LENGTH (≥2 CM), SMALL DIAMETER, AND STRICTURE ANGULATION OR TORTUOSITY. THE LONG-TERM COURSE OF COMPLEX ESOPHAGEAL STRICTURES BASED ON LENGTH IS CURRENTLY UNCLEAR. WE SUSPECT THAT THE ESOPHAGEAL STRICTURE LENGTH MIGHT IMPACT THE EFFECTIVENESS OF ENDOSCOPIC DILATION THERAPY. WE PERFORMED A RETROSPECTIVE STUDY OF ALL BENIGN ESOPHAGEAL STRICTURES OF 2 CM OR LONGER TREATED AT A SINGLE CENTER BETWEEN JULY 1, 2010, AND MAY 31, 2014. PRIMARY OUTCOMES WERE CHANGED IN DYSPHAGIA SCORE AT THE END OF FOLLOW-UP COMPARED TO FIRST DILATION AT OUR FACILITY AND THE NEED FOR GASTROSTOMY PLACEMENT OR ESOPHAGECTOMY DURING FOLLOW-UP. DATA WERE STRATIFIED INTO FOUR SUBGROUPS ACCORDING TO STRICTURE LENGTH 20­29, 30­49, 50­99, AND 100 MM OR LONGER. EIGHTY-SEVEN PATIENTS (MEAN AGE 66 YEARS, 54% WOMEN) WERE FOLLOWED OVER A MEDIAN OF 40 MONTHS. PATIENTS UNDERWENT A MEDIAN OF 6 DILATIONS, AVERAGING 0.3 DILATIONS PER MONTH. MEDIAN DYSPHAGIA SCORE REMAINED UNCHANGED AT 2; 37 (43%) PATIENTS REPORTED RESOLUTION OR IMPROVED DYSPHAGIA AND 50 (57%) PATIENTS REPORTED NO IMPROVEMENT OR WORSENED DYSPHAGIA. GASTROSTOMY PLACEMENT OR ESOPHAGECTOMY WAS NEEDED FOR 23 (26%) AND 3 (3%) PATIENTS, RESPECTIVELY. MEDIAN DEGREE OF DYSPHAGIA AT THE END OF FOLLOW-UP DID NOT DIFFER BETWEEN THE FOUR STRICTURE LENGTH SUBGROUPS, YET NO PATIENT HAD IMPROVEMENT IN THE 100 MM OR LONGER SUBGROUP. MORE THAN HALF OF PATIENTS WITH LONG BENIGN ESOPHAGEAL STRICTURES HAD UNCHANGED DYSPHAGIA OR DEVELOPED WORSE DYSPHAGIA DURING FOLLOW-UP. LONG-TERM OUTCOMES DID NOT DIFFER BETWEEN DIFFERENT STRICTURE LENGTHS: .

ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.