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Children's National News - Spring 2009

Children’s National Researchers Develop Anti-Tumor Vaccine

Children’s National Medical Center, in collaboration with investigators from the University of Iowa, developed a novel anti-tumor vaccine for neuroblastoma and melanoma. The vaccine is showing significant impact on tumor growth in mice, according to new research published in the October edition of the research journal Cancer Immunology, Immunotherapy. The vaccine uses the tumor’s own protein to induce an immune system response, allowing for a personalized approach to treatment.

The vaccine and delivery system, developed in the laboratory of Children’s National Chief of General and Thoracic Surgery Anthony Sandler, MD, involves the creation of synthetic microparticles known as “immune stimulatory antigen loaded particles” (ISAPs), that consist of tumor antigens (proteins) from the specific tumor to be targeted, as well as immune stimulatory agents. The ISAPs are detected and engulfed by specialized immune cells and sensed to be immune-stimulating “foreign bodies.”

The study shows that ISAPs are effective at blocking the growth of tumors in mice by inducing activation of immune cells that then stimulate the immune system to specifically target the tumor whose antigens match those that are loaded in the particles – known as tumor specific immunity.

The research team also discovered; however, that the impact of ISAPs on tumor growth was partially mitigated by an increased presence of regulatory t-cells (T-reg) when ISAPs are introduced into the body. The researchers believe that T-regs play a key role in how the vaccine impacts tumor growth by suppressing the development of the specific immune cells needed to combat the tumor. By adding a T-reg suppressor, such as cyclosphosphamide, or anti-CD25 antibody, the scientists were able to have a greater impact on preventing tumor growth using the ISAP approach.

“For tumors like neuroblastoma, reduction to minimal residual disease with standard therapies like chemotherapy and/or surgical resection and subsequent treatment with this vaccine could quite possibly cure the patient of the disease in the not too distant future,” said Dr. Sandler, lead author of the study. “Creation of ISAPs allows us to target our treatments to the specific tumor of interest, a capability that will more effectively combat a wide range of these tumors in a personalized fashion.”

The study was funded by the National Institutes of Health and the American Cancer Society.

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Diagnosis and Treatment of Chiari Type 1 Malformations at Children’s National

The Division of Neurosurgery at Children’s National Medical Center evaluates hundreds of patients with Chiari malformations each year. As a leading destination in the United States for the treatment of children with this congenital defect, Children’s team has experience in determining the optimal course of treatment given each child’s unique condition.

Figure 1
Figure 1
A Chiari malformation is an anomaly involving the craniocervical junction, the area between the base of the skull and upper cervical spine. It occurs when a significant portion of the cerebellum lies below the foramen magnum at the base of the skull (Figure 1). The condition is rare, affecting slightly less than 1 in 1,000 people, but this number appears to be increasing with a greater number of individuals having incidental Chiari malformations.

Diagnosis of Chiari I Malformations
Magnetic resonance imaging (MRI) of the brain and spine is needed to diagnose a Chiari Type 1 malformation. The radiologist and neurosurgeon identify abnormalities at the craniocervical junction and evaluate for the presence of a syringomyelia, an abnormal fluid collection within the spinal cord.

The table shows the frequency of symptoms among 110 patients who were surgically treated at Children’s National since 1997.

Frequency of Symptoms of Chiari 1 Malformation

A majority of patients with Chiari 1 malformations were found incidentally while being evaluated for the following:
  • Developmental delay
  • Attention deficit disorder
  • Autism
  • Seizures
  • Syncope
  • Endocrine dysfunction
  • Syndromic work-up
  • Trauma

Figure 2
Figure 2
Patients with radiographic findings of a Chiari 1 malformation should have a complete evaluation by a pediatric neurosurgeon who will base his/her recommendation on the patient’s symptoms and MRI findings. Patients presenting with intractable pain, neurological deficits, or those who demonstrate a syrinx (Figure 2) in the spinal cord, generally benefit from surgical treatment.

Recommended surgery includes simple bony decompression with utilization of intraoperative ultrasound to assess the degree of decompression and tonsillar relaxation after adequate bony removal at the posterior shelf of the occiput, as well as the ring of C1.

Figure 3A Figure 3B
Figure 3A Figure 3B
Patients with more severe restriction of cerebral spinal fluid flow at the foramen magnum or those who fail to demonstrate any improvement with real-time ultrasound, are considered better candidates for a more involved open dural exploration complete with lysis of intradural adhesions and duraplasty. It may even be necessary to place an intraventricular stent in the fourth ventricle (Figure 3A and 3B).

Outcome and Follow-Up
Of the 110 Chiari 1 malformation surgeries performed at Children’s National in the last decade, 94 percent of patients reported improvement in signs/symptoms after surgery, whereas 5.5 percent demonstrated no change in signs or symptoms. A 2.7 percent infection rate was reported, including superficial wound infection and bacterial meningitis. A 5 percent cerebral spinal fluid leak occurred among surgical patients and 8 percent required cerebral spinal fluid diversion. In addition, 18 percent of patients developed a pseudomeningocele post-operatively.

A pseudomeningocele is a collection of spinal fluid underneath the surgical site that often dissipates over time. However, a persistent pseudomeningocele may be an indication for the need for cerebral spinal fluid diversion.

Incidental Chiari Malformations
Physicians are increasingly finding patients with incidental Chiari malformations, which poses significant challenges for the treating clinician. While a majority of individuals remain asymptomatic and fail to require any additional therapeutic intervention, a small subset of patients may eventually need surgical decompression (up to 13 percent of patients). It is critical to follow these individuals closely to observe any evidence of intractable pain, neurological compromise, or the development of an intraspinal syrinx. This often necessitates clinical visits twice a year and annual MRI scans. Unfortunately, at this time physicians are not able to prospectively determine which individuals will require surgical intervention. Nevertheless, close clinical observation should prevent any long-term deterioration and offer the best possible therapeutic choices.

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Children’s National Researchers Discover Breakthrough in Duchenne Muscular Dystrophy Study

Genetic researchers at Children’s National Medical Center and the National Center of Neurology and Psychiatry in Tokyo published the results of the first successful application of “multiple exon-skipping” to curb the devastating effects of Duchenne muscular dystrophy in an animal larger than a mouse.

Multiple exon-skipping employs multiple DNA-like molecules as a “DNA band-aids” to skip over the parts of the mutated gene that block the effective creation of proteins. The study, conducted in Japan and the United States, was published in the peer-reviewed journal of the American Neurological Association, the Annals of Neurology.

“This study delivers the proof-of-concept that systemic anti-sense therapy can be done in a large organism, in Duchenne muscular dystrophy or any disease”, says Eric Hoffman, PhD, a senior author of the study and director of the Center for Genetic Medicine at Children’s National Medical Center.

The study dogs had a type of naturally occurring canine X-linked muscular dystrophy, which is genetically homologous to the Duchenne muscular dystrophy that strikes 1 of every 3,500 boys born in the United States and worldwide each year. Duchenne muscular dystrophy causes an inability of the body’s cells to effectively create dystrophin—which builds muscle tissue. Because the gene’s mutation could affect any of its 79 exons and sometimes more than one single exon at a time, scientists employed a “cocktail” of antisense called morpholinos to extend the range of this application. By skipping more than a single exon, this so-called DNA band-aid becomes applicable to between 80 and 90 percent of Duchenne muscular dystrophy patients, including the mutation found in dogs.

“This trial makes the much-talked about promise of exon-skipping as a systemic treatment for Duchenne muscular dystrophy in humans a real possibility in the near term,” said Toshifumi Yokota, PhD, lead author of the study. “Of course this success has also introduced even more avenues for investigation, but these findings finally overcome a significant hurdle to our progress—we’ve solved the riddle of an effective system-wide delivery to muscle tissue, and seen promising results.”

Work remains before this treatment can move into clinical trials in the United States—successful systemic treatment with morpholinos requires large doses of the antisense molecules—and the technology is costly and difficult to obtain. However, these early successes do show much promise for the oft-discussed exon-skipping method as an effective treatment for Duchenne muscular dystrophy and some other genetic disorders.

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Free Book Available

The Short Child - book offer
Children’s National is excited to offer physicians a free book, The Short Child: A Parents’ Guide to the Causes, Consequences, and Treatment of Growth Problems, written by Paul Kaplowitz, MD, chief of Endocrinology. This book will make a great addition to your medical library. Request your free copy today by e-mailing your name and mailing address to A limited number of books are available.

For additional information on short stature visit, The Short Child: Referral Guidelines.

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