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Matt Oetgen talks about an x-ray

Nicotine-like anti-inflammatories may protect limbs, testicles from inflammatory damage after injury

Matt Oetgen talks about an x-ray

Dr. Matt Oetgen is teaming up with pediatric urologist Dan Casella for a POSNA-funded pre-clinical study of the anti-inflammatories varenicline and cytisine.

A new pre-clinical study will explore the use of anti-inflammatory medications to prevent the body’s inflammatory response from further damaging limbs after an injury restricts blood flow. Varenicline and cytisine, anti-inflammatories with similarities to nicotine, have shown early promise in similar pre-clinical laboratory studies of the testicles and will now be tested in arms and legs.

Matthew Oetgen, M.D., MBA, chief of Orthopaedic Surgery and Sports Medicine at Children’s National and Children’s pediatric urologist Daniel Casella, M.D., will jointly lead the new study entitled, “Modulation of the Injury Associated with Acute Compartment Syndrome,” which builds on Dr. Casella’s previous work with the two anti-inflammatory agents. Drs. Oetgen and Casella recently were awarded the Angela S.M. Kuo Memorial Award Research Grant to fund this research during the Pediatric Orthopaedic Society of North America’s (POSNA) Annual Meeting.

“We are honored that this important research was selected by POSNA for support,” says Dr. Oetgen. “An arm or leg injury can trigger the body’s natural inflammatory response, causing severe swelling that restricts blood flow. Even after blood flow is restored, the inflammatory response can lead to permanent muscle or nerve damage or even loss of limb. This grant will give us the opportunity to truly explore the application of anti-inflammatories after injury and see if this approach can modulate the immune response to protect the limbs.”

If successful in the laboratory, the team hopes to expand this work to human clinical trials.

The Angela S.M. Kuo Memorial Award Research Grant is given each year to an outstanding investigator aged 45 or younger based on criteria including the study’s potential significance, impact, originality/innovation, the investigator’s track record and study feasibility. The award totals $30,000.

While at POSNA’s 2019 Annual Meeting, Dr. Oetgen and Children’s pediatric orthopaedic surgery colleagues also participated in podium presentations and poster sessions, including:

  • “Achieving Consensus on the Treatment of Pediatric Femoral Shaft Fractures,” Matthew Oetgen, M.D., MBA
  • “A Prospective, Multi-centered Comparative Study of Non-operative and Operative Containment Treatments in Children Presenting with Late-stage Legg-Calve-Perthes Disease,” Benjamin Martin, M.D.

The Pediatric Orthopaedic Society of North America is an organization of 1,400 surgeons, physicians, and allied health members dedicated to advancing musculoskeletal care for children and adolescents. The annual meeting presents the latest research and expert clinical opinion in pediatric orthopaedics through presentations, posters, and symposia. It was held May 15-18, 2019, in Charlotte, North Carolina.

DNA Molecule

Decoding cellular signals linked to hypospadias

DNA Molecule

“By advancing our understanding of the genetic causes and the anatomic differences among patients, the real goal of this research is to generate knowledge that will allow us to take better care of children with hypospadias,” Daniel Casella, M.D. says.

Daniel Casella, M.D., a urologist at Children’s National, was honored with an AUA Mid-Atlantic Section William D. Steers, M.D. Award, which provides two years of dedicated research funding that he will use to better understand the genetic causes for hypospadias.

With over 7,000 new cases a year in the U.S., hypospadias is a common birth defect that occurs when the urethra, the tube that transports urine out of the body, does not form completely in males.

Dr. Casella has identified a unique subset of cells in the developing urethra that have stopped dividing but remain metabolically active and are thought to represent a novel signaling center. He likens them to doing the work of a construction foreman. “If you’re constructing a building, you need to make sure that everyone follows the blueprints.  We believe that these developmentally senescent cells are sending important signals that define how the urethra is formed,” he says.

His project also will help to standardize the characterization of hypospadias. Hypospadias is classically associated with a downward bend to the penis, a urethra that does not extend to the head of the penis and incomplete formation of the foreskin. Still, there is significant variability among patients’ anatomy and to date, no standardized method for documenting hypospadias anatomy.

“Some surgeons take measurements in the operating room, but without a standardized classification system, there is no definitive way to compare measurements among providers or standardize diagnoses from measurements that every surgeon makes,” he adds. “What one surgeon may call ‘distal’ may be called ‘midshaft’ by another.” (With distal hypospadias, the urethra opening is near the penis head; with midshaft hypospadias, the urethra opening occurs along the penis shaft.)

“By advancing our understanding of the genetic causes and the anatomic differences among patients, the real goal of this research is to generate knowledge that will allow us to take better care of children with hypospadias,” he says.

Parents worry about lingering social stigma, since some boys with hypospadias are unable to urinate while standing, and in older children the condition can be associated with difficulties having sex. Surgical correction of hypospadias traditionally is performed when children are between 6 months to 1 year old.

When reviewing treatment options with family, “discussing the surgery and postoperative care is straight forward. The hard part of our discussion is not having good answers to questions about long-term outcomes,” he says.

Dr. Casella’s study hopes to build the framework to enable that basic research to be done.

“Say we wanted to do a study to see how patients are doing 15-20 years after their surgery.  If we go to their charts now, often we can’t accurately describe their anatomy prior to surgery.  By establishing uniform measurement baselines, we can accurately track long-term outcomes since we’ll know what condition that child started with and where they ended up,” he says.

Dr. Casella’s research project will be conducted at Children’s National under the mentorship of Eric Vilain, M.D., Ph.D., an international expert in sex and genitalia development; Dolores J. Lamb, Ph.D., HCLD, an established leader in urology based at Weill Cornell Medicine; and Marius George Linguraru, DPhil, MA, MSc, an expert in image processing and artificial intelligence.

Rebecca Zee

Children’s urology fellow wins best basic science award

Rebecca Zee

Rebecca Zee, a Children’s urology fellow, was awarded the best basic science prize at the Societies for Pediatric Urology annual meeting for her abstract describing a novel treatment to prevent ischemia reperfusion injury following testicular torsion.

Occurring in 1 in 4,000 males, testicular torsion occurs when the testis twists along the spermatic cord, limiting blood supply to the testicle. Despite prompt surgical intervention and restoration of blood flow, up to 40 percent of patients experience testicular atrophy due to a secondary inflammatory response, or ischemia reperfusion injury. Cytisine, a nicotine analog that the Food and Drug Administration approved for smoking cessation, recently has been found to activate a novel anti-inflammatory cascade, limiting the post-reperfusion inflammatory response.

“Administration of cytisine was recently found to limit inflammation and preserve renal function following warm renal ischemia,” Zee says. “We hypothesized that cytisine would similarly prevent ischemia reperfusion injury and limit testicular atrophy following testicular torsion.”

Using an established experimental model, Zee and colleagues induced unilateral testicular torsion by anesthetizing the adult male experimental models and rotating their right testicles by 720 degrees for two hours. In the treatment arm, the preclinical models were given cytisine as a 1.5 mg/kg injection one hour before or one hour after creating the testicular torsion. Eighteen hours after blood flow was restored to the right testis, total leukocyte infiltration and inflammatory gene expression were evaluated. Thirty days later, the researchers measured testicular weight and evaluated pro-fibrotic genes.

“We found that the administration of cytisine significantly decreases long-term testicular atrophy and fibrosis following testicular torsion,” says Daniel Casella, M.D., a urologist at Children’s National Health System and the study’s senior author. “What is particularly exciting is that we found similar long-term outcomes in the group that was given cytisine one hour after the creation of testicular torsion. This scenario is much more clinically applicable, given that we would not be able to treat patients until they present with testicular pain,” Dr. Casella adds.

Additional research is needed to determine the optimal cytisine dosing and administration regimen, however the researchers are hopeful that they can transition their findings to a pilot clinical trial in the near future.

In addition to Zee and Dr. Casella, the multi-institutional team included Children’s co-authors Nazanin Omidi, Christopher Bayne, Michael Hsieh, M.D., and Evaristus Mbanefo, in addition to Elina Mukherjee and Sunder Sims-Lucas, Ph.D., from the University of Pittsburgh.

Financial support for this work was provided by the Joseph E. Robert Jr. Center for Surgical Care.

Veronica-Gomez-Lobo

Multidisciplinary care for children with urogenital differences

Veronica-Gomez-Lobo

Veronica Gomez-Lobo, M.D., brought together a multidisciplinary team to form the Positive Reevaluation of Urogenital Differences (PROUD) Clinic.

When a child is born with urogenital differences, the chromosomes, internal organs or external genitalia are considered to be atypical. While these differences were once thought to be rare, they are more common than people realize, with about 1 in 100 newborns affected.

The complexities of caring for children with urogenital differences, also known as differences of sex development (DSD), were not fully understood for many years. In the past, if a child was born with DSD, the family would see an endocrinologist for hormone therapy and a urologist for surgical options. Counseling was not part of the standard of care, so there was little support available to help families understand the tremendous psychosocial impacts of DSD.

In the last decade, fundamental changes have occurred in the way physicians care for children affected by DSD, with psychosocial health becoming a prominent focus. Veronica Gomez-Lobo, M.D., a Children’s National pediatric and adolescent gynecologist, was one of the physicians who embraced this focus and sought out a new care paradigm for her patients.

Creating the PROUD Clinic

Dr. Gomez-Lobo brought together a multidisciplinary team – including medical geneticist Eyby Leon Janampa, M.D., geneticist Eric Vilain, M.D., Ph.D., urologist Daniel Casella, M.D., endocrinologist Kim Shimy, M.D., psychiatrist David Call, M.D., and psychologist Elaine Goldberg, Ph.D. – to form the Positive Reevaluation of Urogenital Differences (PROUD) Clinic. It can be very challenging to bring together diverse specialists in a complex area like DSD, but her team possesses a similar philosophy – to care for the whole family by managing both the psychosocial and medical aspects of care in one location.

The team meets before each clinic to discuss the patients they will see that day. Patients vary significantly by the type of DSD and also by age – some patients are still in utero, while others may be newborns, children, adolescents or even occasionally adults.

Families see the entire team during their appointment, which can often last two to three hours to ensure that families receive the full support resources offered by the team.

“Even in difficult cases without a clear answer, we present the facts we know to the families, discussing all possibilities about psychosocial issues, gender identity, sexuality, function and fertility,” says Dr. Gomez-Lobo.

Long after the initial appointment, the PROUD Clinic continues to work closely with families and individual providers, following up as needed for medical diagnosis and care and providing continued psychosocial support with the entire team. Due to the efforts of the PROUD Clinic, patients and their families are now receiving compassionate care that looks at all facets of DSD, from childhood through adulthood.

Increasing DSD knowledge in the medical community

In order to give her patients the most thorough understanding of DSD and to expand the medical community’s knowledge, Dr. Gomez-Lobo’s program also participates in the Disorders of Sex Development Translational Research Network (DSD-TRN), which is led by Dr. Vilain. Supported by the National Institutes of Health (NIH), the DSD-TRN provides physicians across the country with the ability to perform research to advance knowledge regarding these conditions, as well as learn how to improve the care of these individuals and families. The DSD-TRN also provides a forum to seek advice about complex cases and to communicate how to transition patients from pediatric to adult medicine.

The relationship with the DSD-TRN helps the PROUD Clinic team further their goal of creating care for their patients that is current, individualized and compassionate.