Evaristus Mbanefo, Ph.D., M.S., M.Sc., a postdoctoral researcher at Children’s National Health System, was awarded the 2017 Urology Care Foundation Research Scholar Award in recognition of his potential for a successful career in urology research. Mbanefo’s project, “Therapeutic Exploitation of Interleukin-4-Inducing Principle from Schistosoma Mansoni Eggs: A Urogenital Parasite-Derived Host Immunomodulatory Protein for Hemorrhagic Cystitis and Bladder Hypersensitivity,” was among 70 applications for the highly competitive annual award. He works in the lab run by Michael H. Hsieh, M.D., Ph.D., Director of the Clinic for Adolescent and Adult Pediatric Onset Urology (CAPITUL) at Children’s National.
Daniel Casella, M.D,, wants to design a bracelet that uses ultrasound waves to stimulate the posterior tibial nerve in pediatric patients with overactive and underactive bladders. “Realistically and optimistically, we might be five years away from that,” says Dr. Casella, a pediatric urologist at Children’s National Health System who has been studying the ability of ultrasound mediated neuromodulation of the posterior tibial nerve to affect bladder function. For this work, he was named a research finalist at the Pediatric Urology Fall Congress in September.
Up to 40 percent of patients seen in a pediatric urology clinic have an element of voiding dysfunction. The majority of these patients can be managed with behavior modification and conservative measures; however there is a subset of these patients who will require more aggressive therapy. With the possibilities that this research holds, he suggests ultrasound mediated tibial nerve stimulation as potentially an ideal outpatient treatment of overactive bladder and dysfunctional elimination.
What we know
The S3 sacral nerve root contains neurons that play an important role in regulating bladder function. Stimulation of the S3 nerve root with a surgically placed neurostimulator is an effective treatment for overactive or underactive bladders in adults and more recently pediatric patients. The problem: Placement of the S3 nerve stimulator is an invasive surgical procedure that requires revision or additional procedures in up to 50 percent of pediatric patients.
Another treatment: Stimulation of the posterior tibial nerve (a peripheral extension of the S3 nerve root), with an electrical current is also an effective treatment of both overactive and underactive bladders. The problem: For a durable response, the posterior tibial nerve must be stimulated with an electrical current that produces a moderate level of discomfort for 30 minutes. These treatment sessions must then be repeated weekly for approximately 12 weeks, making it very difficult to offer this therapy to pediatric patients.
New hope for patients with bladder dysfunction
Using targeted ultrasound to stimulate nerves is an area of active research within the radiology and neuroscience community. To date, studies in humans are limited, however there have been promising results when transcranial ultrasound was used to stimulate the deep brain motor centers, potentially offering a novel treatment for movement disorders such as Parkinson’s.
Dr. Casella started this research during his pediatric fellowship at Vanderbilt with the support of a $25,000 grant from the Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction.
Dr. Casella says: “Using an established model of bladder overactivity in rats, we demonstrated that 2-3 minutes of ultrasound stimulation of the posterior tibial nerve can suppress bladder contractions for an average of 10 minutes.”
Dr. Casella plans to refine his techniques in animal models and work toward designing an ultrasound probe that can be used in humans. He is hopeful that his protocol will be ready for application in a clinical trial in the next one to two years. “Ultimately our goal is to design something that can be used at home,” Dr. Casella says. Ultrasound devices can be more compact if imaging isn’t the primary use. Ideally we would like to have the ultrasound transducer in the form of an ankle bracelet attached to a generator similar in size to a smartphone.
Parasites have developed ingenious strategies to change their host’s biology. A research team led by Michael H. Hsieh, M.D., Ph.D., Director of the Clinic for Adolescent and Adult PedIatric OnseT UroLogy (CAPITUL) at Children’s National, turned the tables on the pesky parasites by using their proteins to provide therapeutic benefits. The team’s paper, “Therapeutic Exploitation of IPSE, a Urogenital Parasite-Derived Host Modulatory Protein, for Chemotherapy-Induced Hemorrhagic Cystitis and Bladder Hypersensitivity,” won the “Best Basic Science” award–a coveted national honor–during the Pediatric Urology Fall Congress in September. “Our work represents the first time that a uropathogen-derived host modulatory molecule has been therapeutically exploited in bladder disease models,” Dr. Hsieh and co-authors write.
Children diagnosed with cancer face fear and uncertainty, a series of medical appointments, and multiple diagnostic tests and treatments. On top of these challenges, says Children’s National Health System urologist Michael Hsieh, M.D., Ph.D., many patients contend with additional issues: Treatment side effects, discomforts, and dangers that nearly eclipse that of the cancer itself. One of the most common side effects is hemorrhagic cystitis (HC), a problem marked by extreme inflammation in the bladder that can lead to tremendous pain and bleeding.
HC often results from administering two common chemotherapy drugs, cyclophosphamide and ifosfamide, used to treat a wide variety of pediatric cancers, including leukemias and cancers of the eye and nerves. In the United States alone, nearly 400,000 patients of all ages receive these drugs annually. Of these, up to 40 percent develop some form of HC, from symptomatic disease characterized by pain and bloody urine to cellular changes to the bladder detected by microscopic analysis.
“Having to deal with therapy complications makes the cancer ordeal so much worse for our patients,” says Dr. Hsieh, Director of the Clinic for Adolescent and Adult Pediatric Onset Urology at Children’s National. “Being able to eliminate this extremely detrimental side effect once and for all could have an enormous impact on patients at our hospital and around the world.”
Preventing complications with mesna
The severity of side effects from cyclophosphamide and ifosfamide can vary from mild and fleeting to bladder bleeding so extensive that patients require multiple transfusions and surgery to remove blood clots that can obstruct urinary release, says Dr. Hsieh, who frequently treats patients with this condition. But HC isn’t inevitable, he adds. A drug called mesna has the potential to prevent this complication when prescribed before a patient receives chemotherapy.
The problem is for a fraction of patients, mesna simply doesn’t work. For others, mesna can cause its own serious side effects, such as life-threatening malfunctions of the heart’s electrical system or allergic reactions.
“These kids are often already very sick from their cancers and treatments, and then you compound it with these complications,” says Dr. Hsieh. “There’s a desperate need for alternatives to mesna.”
Looking at alternative treatments
In a new review of the scientific literature, published August 24 by Urology, senior author Dr. Hsieh and a colleague detail all the substitutes for this drug that researchers have examined over several years.
One of these is hyperhydration, or delivering extra fluid intravenously to help flush the bladder and keep dangerous chemotherapy drug metabolites from accumulating and causing damage. Hyperhydration, however, isn’t an option for some patients with kidney, lung, or liver problems, who can’t tolerate excess fluid.
Researchers also have invested heavily in antioxidants as alternative treatments. Because much of the damage caused by these chemotherapy agents is thought to result from a cascade of oxidizing free radicals that cyclophosphamide and ifosfamide launch in the bladder, antioxidants might prevent injury by halting the free radical attack. Antioxidants that researchers have explored for this purpose include cytokines, or immune-signaling molecules, known as interleukin-1 and tumor necrosis factor, and a compound called reduced glutathione. Other studies have tested plant-based antioxidants, including a component of red wine known as resveratrol; a compound called diallyl disulfide isolated from garlic oil; and extracts from Uncaria tomentosa, a woody vine commonly known as “cat’s claw” that grows in the jungles of Central and South America.
Researchers also have tested options that focus on reducing the intense inflammation that cyclophosphamide and ifosfamide cause in the bladder, including the corticoid steroid drug dexamethasone as well as another cytokine known as interleukin-4.
However, Dr. Hsieh says, studies have shown that each of these treatments is inferior to mesna. To truly combat HC, researchers not only need to find new drugs and methods that outperform mesna but also new ways to reverse HC after other measures fail—problems he’s working to solve in his own lab.
One of the most common causes of premature death is cancer. But today, survival rates for many childhood cancers have surpassed 90 percent and the emphasis of care has shifted from survival to quality of life after survival. That’s according to Michael Hsieh, M.D., Ph.D., who is leading the program at Children’s National Health System and getting much support from oncology and neonatology.
“One of the important aspects of quality of life is fertility,” Dr. Hsieh says. “For those adult survivors of childhood cancer who want to have children, I think it’s imperative that we do whatever we can to help them.”
The program at Children’s National, part of a multi-institutional consortium based at the University of Pittsburgh, had one of the highest recruitment of all the satellite sites for this study, which offers cryopreservation of boys’ testicular tissue. From Dr. Hsieh’s program, tissue from 11 patients has been harvested in a year and a half.
Radiation and chemotherapy are toxic to the gonads, which have testicular and ovarian function. “The idea is that if we can freeze the testicular tissue until the technology catches up in such that we can restore fertility down the road, that’s a wonderful thing. Most of these children are in grade school and not interested in having children until at least 15-20 years.”
Getting the tissue samples
For the first time, parents of young cancer patients are having this discussion, and Hsieh says they are extremely appreciative, even if they decline to participate in the study.
Young men can provide a sperm sample, which can easily be frozen. For boys who haven’t gone through puberty or boys who are not able to give a sample because they are too sick or unwilling to do so, a biopsy can collect a tissue sample, which can then be frozen.
Storing samples at a cost
Hsieh says his work also is focused on improving funding for storage of tissues. The out-of-pocket costs to store samples are several hundred dollars a year, and it can be cost-prohibitive for some patients and families.
Hsieh has applied for financial assistance from Children’s National internal funding opportunities for the program to help even the playing field.
“I don’t think it’s fair that a child who is born into a poor family is unable to participate in fertility preservation whereas a child who happens to be born more affluent is able to,” Hsieh says.
A hot topic at national urology meetings is how to transition patients with pediatric-onset urologic conditions as they grow into adults. Michael Hsieh, MD, PhD, is leading the way in the U.S. by serving as a bridge for patients at the first dedicated transitional urology program in the mid-Atlantic region. The Clinic for Adolescent and Adult PedIatric OnseT UroLogy (CAPITUL) is a joint venture between Children’s National and George Washington University Hospital that started two years ago.
What’s most unique about the clinic is that Dr. Hsieh has a foot in both the pediatric world of urology and one in the adult world, with clinical privileges at both institutions. He sees the full span of pediatric urology patients, including expectant moms with fetuses that have suspected urologic anomalies to adults who may have congenital conditions that require follow-up. However, he sees more teenagers and young adults than his urology colleagues both at hospitals.
The clinic’s patients have included a 19-year-old man with multiple urethrocutaneous fistulas after failed hypospadias repairs, a 25-year-old woman with cloacal exstrophy and continent urinary diversion with a urinary tract infection and stones, and a 25-year-old man with spina bifida with incontinence urethral erosion from an indwelling catheter.
A number of significant urological conditions until recently led to premature death because of medical complications, Dr. Hsieh says. Today, 90 percent of spina bifida patients live past the age of 30. “There’s a synchronized wave of patients who are all now young adults with spina bifida, and they are facing issues of reproduction and sexuality,” Dr. Hsieh says. “These are issues that pediatric urologists generally speaking are not comfortable in managing. It makes sense: It’s been many, many years since they did that type of urology.”
The program is specifically following this transitional group on conditions that are long term and that may affect fertility, such as cancer and varicoceles.
One in five teenage boys have varicoceles, or varicose veins on the scrotum. “The relationship between having varicocele as a teenager and infertility as an adult is not clear, so we felt it important to include this diagnosis in the transitional program so we can follow these patients long term and monitor their testicular growth,” Dr. Hsieh says.
Proof that the program’s working
Dr. Hsieh tracks the messages from colleagues referring patients from one institution to the other. “Unfortunately, some patients and families—for a range of issues—fall through the cracks, so it is really important to have that direct link. If we didn’t have the program set up as it is, there would be fewer successful transitions between institutions,” he says.
Another way Dr. Hsieh knows the program is working is because of the uptick in adolescent and young adult patients in his practices at Children’s and at GW.
Dr. Hsieh says the optimal time to begin transition is at age 12, when the team makes the patient and family aware of the transition policy. From ages 14-16, it’s time to initiate the health care transition plan and begin discussing the adult model of care. By age 18, Dr. Hsieh recommends the transition to adult care, and by ages 23-26, patients are integrated into adult care.
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