- Bladder Exstrophy
- Johns Hopkins Research Focused on Early Stage Bladder Cancer Wins .2 Million Federal Grant
- Modern Management of the Exstrophy-Epispadias Complex
- 1. Introduction
- 2. Epidemiology
- 3. Etiopathogenesis
- 4.1. Urogenital Anomalies
- Special Voiding Improvement Program for the Exstrophy – Epispadias Patient
- Practice patterns in classic bladder exstrophy: A global perspective
To serve as a resource for information on current, ongoing and future research in the field of Bladder Exstrophy.
“The failed bladder closure in cloacal exstrophy: Management and outcomes.” Learn More>
“3D MRI-Guided Pelvic Floor Dissection in Bladder Exstrophy: A Single Arm Trial.” Learn More>
“Functional, histological and molecular characteristics of human exstrophy detrusor.” Learn More>
“Health-related quality of life among children, adolescents, and adults with bladder exstrophy-epispadias complex: a systematic review of the literature and recommendations for future research.” Learn More>
“22q11.2 duplications in a UK cohort with bladder exstrophy-epispadias complex.” Learn More>
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Bladder exstrophy is a rare, complex congenital birth defect that involves abnormalites of multiple body systems and organs including the lower abdominal wall, bladder, pelvis, genitalia, rectum and anus.
The condition is thought to occur due to abnormal development of the cloacal membrane during early fetal growth. This malformation results in protrusion of the bladder through the lower abdominal wall.
Incidence rates for bladder exstrophy have been reported to occur in approximately one of every 30,000 live births, with an estimated 2:1 male to female ratio. Current methods for gathering and reporting such figures vary however, so actual occurrence may differ from that previously reported.
Bladder exstrophy is a life altering condition requiring extensive surgical intervention, typically beginning shortly after birth when the child is just a few days old.
Surgeries can be numerous over the course of a lifetime depending on severity, co-existing conditions and/or complications.
Goals of surgical treatment include, but are not limited to: closure of the bladder and abdominal wall, realignment of the pelvis, preservation of kidney and sexual function, satisfactory appearance of external genitalia, and urinary continence.
It is important to note that a successful initial closure combined with overall growth and ultimate size of the bladder are key factors in determing continence; therefore, proper care and treatment by a surgeon specializing in exstrophy cannot be emphasized enough.
In addition to the physical aspects of bladder exstrophy, there are social and emotional issues that may arise due to the intimate nature and complexity of the condition. Steps should be taken to account for these needs as well.
Continued research is critical for the advancement of care for this condition. Research initiatives focusing on cutting edge treatment options and identification of causative factors including genetic and environmental sources are key towards meeting this goal.
Identification of Genetic Causes of Human Bladder Exstrophy Birth Defect
Boston Children's Hospital
The advent of genomic technologies enables a complete sequencing of patients’ genome, which is the key first step toward identification of the exstrophy-epispadias complex disease genes. Boston Children’s Hospital Exstrophy Genetics Initiative began in 2013.
This is a joint effort between faculty members at the Department of Urology, the Manton Center for Orphan Disease Research, Newborn Medicine, and the Department of Genetics.
At the same time, we have teamed up with pediatric urologists at Children’s Hospital of Philadelphia and Children’s Hospital of Wisconsin to form the Multi-Institutional Bladder Exstrophy Consortium, which has significantly broadened our patient base.
To date, we have accumulated a total of 12 patient samples (from both cheek swab and affected region) as well as control samples from unaffected normal parents (cheek swab). We will perform genome-wide sequencing of tissue samples from the affected region. Our overarching goal is to identify canonical disease gene(s) that may be responsible for the birth defect.
Characterization of Exstrophy Bladder Smooth Muscle Cells In Culture
The Johns Hopkins Hospital
Eventual continence in bladder exstrophy is determined in part by bladder capacity. At this time, it remains unexplained why some bladders grow better than others. Exstrophy bladder smooth muscle differs from normal bladder smooth muscle at a tissue level and at a molecular level in gene expression.
Preliminary studies from Johns Hopkins have suggested that exstrophy bladder smooth muscles cells may have increased levels of transforming growth factor-beta (TGF-beta), which regulates composition of the extracellular matrix, and impacts function and proliferation in multiple cell types.
Similarly, preliminary data have shown that alpha-actin, a muscle-specific protein responsible for muscle contraction, may also be expressed at different levels in bladder exstrophy compared to controls. This project will examine the RNA expression of TGF-b through RT-PCR.
Additionally, TGF-beta protein concentration and down-stream signaling proteins will be measured quantitatively through Western Blot and Elisa analysis. Other muscle-specific structural and dynamic proteins will be evaluated by Western Blot analysis. This study hopes to further identify why bladder exstrophy cells behave differently compared to controls.
Doing so may elevate understanding of the pathogenesis of bladder exstrophy, provide further insight into the prognosis and treatment of the disease, and perhaps will ultimately lead to improvements in tissue engineering.
Johns Hopkins Research Focused on Early Stage Bladder Cancer Wins $3.2 Million Federal Grant
Newswise — Researchers at the Johns Hopkins Kimmel Cancer Center, the Greenberg Bladder Cancer Institute, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the Brady Urological Institute, and the Center for Computational Genomics at Johns Hopkins have received a $3.2 million grant from the National Institutes of Health to study new treatment options for early-stage bladder cancer.
Early stage bladder cancer, formally known as non-muscle invasive bladder cancer, is identified in close to 50,000 patients each year, according to the National Cancer Institute, and typically is treated with a weakened form of bacillus Calmette-Guérin (BCG) bacteria instilled directly into the bladder.
BCG is similar to the bacterium that causes tuberculosis, and is used to immunize against TB. BCG bladder cancer therapy stimulates the immune system and can be temporarily successful in preventing the cancer from growing or returning.
But those undergoing this treatment have a high risk of cancer recurrence and frequently experience side effects such as increased frequency of and discomfort with urination.
The new grant will support efforts by Johns Hopkins physician-scientists to participate in a novel multidisciplinary clinical trial for this cancer, called ADAPT-BLADDER for its ability to accommodate changes during the trial that optimize and accelerate tests of promising treatments.
With initial plans to study anti-PD-L1-directed immunotherapy with the monoclonal antibody durvalumab in combination with BCG and radiation, the ADAPT-BLADDER (NCTO3317158) trial is the first systemic immunotherapy trial to involve all three modalities.
The Johns Hopkins study is also believed to be the only trial among non-muscle invasive bladder cancer trials combining BCG with a shortened, six-month course of systemic immunotherapy, according to Noah Hahn, M.D., associate professor of oncology and urology at the Johns Hopkins University School of Medicine, deputy director of the Greenberg Bladder Cancer Institute, and principal investigator of the study.
“We’re pleased and encouraged that NIH has chosen to support our work within the ADAPT-BLADDER trial,” says Hahn. “Studying the benefits of immunotherapy drugs in high-risk non-muscle invasive bladder cancer patients that have relapsed disease after standard BCG therapy is a natural next step. “
Overall, the NIH-funded ADAPT-BLADDER project is designed with several arms and phases, starting with the investigation of durvalumab combination treatments, but expandable to include other drugs and combinations at a future date without having to start a new trial.
Hahn said this adds a degree of flexibility to the trial, but also brings a wider array of cancer experts than is usually the case with clinical trials for this cancer.
“If this trial is successful, it could change the care of non-muscle invasive bladder cancer to a multidisciplinary treatment model,” Hahn says.
Other Johns Hopkins investigators collaborating on the planned research within the study are Luigi Marchionni, M.D., Ph.D.; Trinity Bivalacqua, M.D., Ph.D.; Woonyoung Choi, M.S., Ph.D.; Alexander Baras, M.D., Ph.D.; Kellie Smith, Ph.D.; Marianna Zahurak, M.S.; Drew Pardoll, M.D., PhD., David McConkey, Ph.D., and Gary Rosner, Sc.D.
Modern Management of the Exstrophy-Epispadias Complex
The exstrophy-epispadias complex is a rare spectrum of malformations affecting the genitourinary system, anterior abdominal wall, and pelvis. Historically, surgical outcomes were poor in patients with classic bladder exstrophy and cloacal exstrophy, the two more severe presentations.
However, modern techniques to repair epispadias, classic bladder exstrophy, and cloacal exstrophy have increased the success of achieving urinary continence, satisfactory cosmesis, and quality of life. Unfortunately, these procedures are not without their own complications.
This review provides readers with an overview of the management of the exstrophy-epispadias complex and potential surgical complications.
The exstrophy-epispadias complex (EEC) is a rare spectrum of defects affecting the genitourinary and gastrointestinal tracts, musculoskeletal system, pelvic floor musculature, and bony pelvis. The three most common presentations of EEC are epispadias, classic bladder exstrophy (CBE), and cloacal exstrophy (CE) (Figure 1).
Complete epispadias is the least severe form of EEC and presents with a dorsally open urethral meatus with mild pubic diastasis and a closed anterior abdominal wall and bladder.
CBE, the most common presentation of EEC, presents with a wide pubic diastasis and an abdominal wall defect exposing an open bladder and urethra with an epispadiac opening. CE, the most severe of the three presentations, is similar, but a portion of cecum or hindgut separates the two open hemibladders.
CE also presents with malformations of the gastrointestinal, musculoskeletal, and central nervous systems, also known as the OEIS (omphalocele, exstrophy, imperforate anus, and spinal abnormalities) complex.
Most patients with EEC undergo multiple reconstructive surgeries beginning with closure of the bony pelvis, bladder, and anterior abdominal wall, followed later by epispadias repair.
Oftentimes, children with CBE and CE must undergo pelvic osteotomy and lower extremity immobilization to ensure complete approximation and sufficient deepening of the pelvis for anatomic placement of the bladder.
While current techniques achieve reasonable success in preservation of renal function, continence, and cosmesis, there are also many recognized complications associated with reconstruction.
Complete epispadias is a rare congenital malformation. It occurs in one in every 117,000 male births, and only one of every 484,000 female births . CBE is the most common presentation of EEC, occurring in approximately one per 10,000 to 50,000 births  and affecting males approximately twice as often as females .
Risk factors include Caucasian race, young maternal age, and maternal multiparity . Furthermore, EEC is increased among children conceived with assisted-reproductive technologies such as in vitro fertilization . Arising in one in 200,000 births, CE is a more rare and severe presentation of EEC.
an institutional review board-approved database of 1202 EEC patients, only 112 patients had CE. Improved prenatal diagnosis increases the detection rate, allowing for elective termination of pregnancy. CE appears to be as much as twice as common among males as females.
No risk factors have been definitively associated with an increased risk of CE .
While the cause of EEC is not completely understood, it is theorized to result from a disorder of cloacal membrane development. During the fourth gestational week, the cloacal membrane may overdevelop, preventing mesenchymal migration between the ectoderm and endoderm.
It is thought that this malformation not only inhibits normal development of the lower abdominal musculature and pelvic bones, but also makes the cloacal membrane unstable and prone to early rupture.
The timing and location of rupture of the cloacal membrane dictate the patient’s presentation along the exstrophy-epispadias spectrum [7, 8]. Epispadias occurs if the rupture produces a division or nonunion at the distal end of the urinary tract.
CBE results if the rupture occurs after the urorectal septum divides the gastrointestinal from the genitourinary tracts while CE results if the rupture occurs before this separation .
There has also been a growing understanding of the molecular and genetic etiology of EEC. p63 is a member of the p53 tumor suppressor family that is highly expressed in stratified epithelium including the bladder and its overlying skin .
Its expression is decreased in CBE patients compared to controls, and p63 knockout mice have CBE- anomalies [11, 12].
These results led to the recent finding that insertion and deletion polymorphisms of ΔNp63 lead to the reduced p63 expression that may cause EEC .
4.1. Urogenital Anomalies
While the bladder is normal in epispadias, it is exposed anteriorly through the abdominal wall in both CBE and CE. In most cases the bladder and abdominal wall should be closed soon after birth. However, if the bladder template is too small (
Diagnosis can be made on careful repeated ultrasounds done before delivery, but usually the diagnosis is not made until the baby is born. The finding of the exposed bladder is typical.
Advances in surgery in the last 15 years have allowed reconstruction of the penis and bladder so that a more “normal” and functional lifestyle can be maintained by the patient and family.
Current state-of-the-art treatment for exstrophy involves reconstruction of the various aspects of the deformity (i.e. closing the bladder, repair of the penis, and prevention of urine leakage.
This usually involves separate operations at various times in the life of the child to obtain the best results.
- Initial Closure: This is usually done soon after the baby is born. At this first operation, the pelvic bones are reformed into their normal ring shape (by a Pediatric Orthopedic surgeon), the bladder, abdominal wall, and posterior urethra are closed and the belly button is reconstructed. This procedure takes between 4-6 hours. Following surgery, the baby is placed with the lower legs in traction to prevent separating the pelvic bones. Babies are observed carefully and may be in the Intensive Care Unit to be monitored for the first day or two. The baby usually stays in the hospital for 3-4 weeks of healing. Antibiotics are given following the operation to prevent infection. The tube in the bladder is removed four weeks following surgery. The size of the bladder gradually increases over time. In very special circumstances with an excellent bladder plate and good sized penis, bladder exstrophy closure and epispadias repair can be combined. However, this is only for very experienced exstrophy surgeons.
- Epispadias repair: This repair occurs around 6-12 months of age. Time of surgery and the extent of the surgery is dependent on the size of the bladder and the deformity of the penis. At this stage, the urethra on top of the flattened penis is closed and transferred to below the corporal bodies as in the normal penis.
- Continence Procedure: At this time the control of urine leakage is repaired and then further enlargement of the bladder is preformed if necessary. The timing of this procedure depends totally on the capacity of the bladder and the child's emotional and developmental status. The child must “want to be dry” and able to participate in a voiding program.
Special Voiding Improvement Program for the Exstrophy – Epispadias Patient
Children with bladder exstrophy face a combination of medical and emotional challenges as they work with their urology team. Developing a continence management program is an ongoing process that is often stressful for children and their families. The voiding improvement program provides hands-on one-on-one assistance to the child and family before and after bladder neck repair.
The clinic is staffed by a specially trained, multidisciplinary team including a pediatric urologist, pediatric nurse practitioner, pediatric behavioral psychologist, and pediatric clinical nurse.
The Voiding Improvement Team also assists the pediatric urologist in the evaluation of readiness for bladder neck reconstruction to help the child and family prepare for the post-surgical work that will allow for favorable continence outcome.
After bladder neck reconstruction surgery we work with children and families using both behavior modification and muscle retraining procedures to teach the child, family, and the child's bladder musculature to function at their maximum potential for long-term continence.
After bladder neck surgery, frequent daily phone consultations occur until the child is voiding well and tube free.
Visit usually last one hour and may include the following treatment components:
- bladder ultrasound
- urine culture
- medication management
- biofeedback for bladder muscle retraining
- establishment of a voiding urine
- assessment of barrier to adherence
- nutrition education
- behavior therapy
- relapse prevention recommendations
Progress is evaluated at each visit and communicated to the pediatric urologist.
Experience at the Johns Hopkins Hospital indicate that 72-75% of patients are free of urine leakage following reconstruction by the above-mentioned stages.
The deformity of the penis was corrected to the satisfaction of the patient and the family in most instances.
This, however, requires dedicated and intensive treatment and long-term follow up into adolescence and adulthood by the exstrophy team.
John P. Gearhart, Robert D. Jeffs: Exstrophy of the Bladder, Epispadias and other Bladder Anomalies in Campbell's Urology, Sixth Edition. Eds. Walsh PC, Retik AB, Stamey TA, Darracott Vaughan E, Jr., WB Saunders Co. Vol. 2 1772-1821.
John P. Gearhart: The bladder exstrophy-epispadias complex. In pediatric Urology. Es Gearhart JP, Rink RR, and Mouriquand P. Saunders, Philadelphia. Chapter 32, p 511-546.
Practice patterns in classic bladder exstrophy: A global perspective
While evaluation and management options for classic bladder exstrophy (CBE) patients are numerous and varied, little is known regarding the relative utilization of these different methods throughout the world. A large group of exstrophy surgeons practicing globally was surveyed, seeking to document their methods of care.
A list of international exstrophy surgeons' email addresses was compiled using professional contacts and referral networking. An online survey was sent to each email address. Surgeons who had not performed a CBE closure within the previous 5 years were excluded.
Survey questions queried the respondents' surgical practice type, years since training, and their preferred methods of preoperative evaluation, operative management, and postoperative management.
Survey invitations were sent out starting in December 2014 and responses were collected for approximately 6 months.
A total of 1152 valid email addresses were invited, resulting in 293 respondents (25%) from 39 countries and every American Urological Association (AUA) section. Seventy-six were excluded, leaving 217 respondents (Table). Respondents reported a median of 17 years since finishing their surgical training (IQR 8-25 years).
Practice types included pediatric urology (n = 209), general urology (n = 9), pediatric surgery (n = 59), and other practice makeup (n = 3).
On subgroup analyses, there were no significant regional practice differences, with the exception of complete primary repair of exstrophy (CPRE) and oral opioid prescribing being significantly higher in North America compared to other regions.
Findings indicate that there may be diversity in CBE practice patterns globally. While most responding surgeons from regions outside of North America indicated modern staged repair of exstrophy (MSRE) as their preferred closure technique, a relatively equal distribution of respondents from North America selected CPRE and MSRE.
A majority of North American surgeons chose performing osteotomies for both newborn and delayed closures, while an appreciable number of respondents from other regions selected never using osteotomies in their closures.
Limitations to this study include a low survey response rate, particularly from surgeons outside of the United States, which may have significantly impacted the ability to draw meaningful global comparisons.
Global variation among practices of surgeons performing CBE closures may exist.
The wide range of methods demonstrated by this survey suggests the need for more conclusive comparative studies to elucidate whether an optimal standard exists.
Local social factors, access to surgical expertise and transportation to referral centers, and finances play a role in what constitutes the best operative approach.
Journal of pediatric urology. 2020 Mar 06 [Epub ahead of print]
Mohammad H Zaman, Ezekiel E Young, Mahir Maruf, Christopher A Hesh, Kelly T Harris, Roni Manyevitch, Rachel Davis, Wayland J Wu, Saran A Hall, Heather DiCarlo, John Gearhart
Robert D. Jeffs Division of Pediatric Urology, James Buchanan Brady Urological Institutions, Johns Hopkins Hospital, Johns Hopkins Medical Institutions, Charlotte Bloomberg Children's Hospital, Baltimore, MD, USA., Department of Urology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA.
, Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA., Robert D. Jeffs Division of Pediatric Urology, James Buchanan Brady Urological Institutions, Johns Hopkins Hospital, Johns Hopkins Medical Institutions, Charlotte Bloomberg Children's Hospital, Baltimore, MD, USA. Electronic address: .