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Children's National Red Badge Project

The Red Badge Project: expediting ED care

Children's National Red Badge Project

A red badge allows newly diagnosed cancer patients and BMT patients to bypass security and triage so they can receive lifesaving antibiotics within an hour of fighting fever.

Chemotherapy and bone marrow transplant procedures leave cancer patients with compromised immune systems, leading many to develop life-threatening infections or other complications. In particular, neutropenia, or abnormally low levels of white blood cells that are critical to fighting off infections, is prevalent among this population. Fever with neutropenia can be fatal.

As part of the Children’s National Health System commitment to deliver better outcomes and safer care through innovative approaches, the Hematology/Oncology/Bone Marrow Transplant (BMT) Family Advisory team developed a protocol to rapidly identify BMT and cancer patients with suspected neutropenia to receive antibiotics within 60 minutes of arriving at the Emergency Department (ED). The Red Badge Project was born with the following goals:

• Decrease the median triage-to-antibiotic time in cancer patients with fever and suspected neutropenia or bone marrow transplant patients to 30 minutes
• Increase the proportion of patients receiving antibiotics within one hour to 90 percent

As part of the protocol, newly diagnosed cancer and bone marrow transplant patients receive a Red Badge and education regarding how to use it. If they run a fever and need medical attention, the patient and family present the Red Badge upon arrival at the ED in order to bypass the welcome desk and ED triage. This action accelerates the process, keeps the child from waiting in an area where there are other sick children and ensures the patient receives lifesaving antibiotics as fast as possible.

Work done before the patient walks through the ED doors contributes to the success of this program. When a patient runs a fever, the family is instructed to call the Hematology Oncology Fellow on-call. If it is determined that the patient needs to come to the ED, the Fellow then: 1) receives the patient’s estimated arrival time so that staff can clean and prep a room 2) reminds them to apply their topical analgesia to numb the port site where the antibiotic will be administered 3) reminds them to bring their Red Badge.

From there, swift action is taken. By the time the patient arrives, he or she has already been registered and the appropriate medications have been ordered. The patient bypasses security and triage using their Red Badge as a visual cue and is then directed to a prepped room complete with medications ready for administration.

To date, the median time from triage to administration of antibiotics has decreased nearly 50 percent while the proportion of patients who received antibiotics within 60 minutes of triage improved to 90 percent.

Leveraging that success, the next step is to develop education for non-English speaking families in order to extend the reach of this lifesaving practice.

Cancer update: tumor targeting, neurofibromatosis type 1 symptoms

June 6, 2016Targeting tumors more precisely, with fewer lasting side effects for kids
Pediatric patients with cancer are often treated with a cocktail of therapies to attack the disease through a variety of mechanisms. While this approach has been instrumental in saving children’s lives, the life-saving therapies can be accompanied by acute side effects, and the treatments may have lingering impacts as cancer survivors enter adulthood. Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) holds the promise of surgically removing large tumors without exacting the same array of harsh side effects. Ultrasound relies on high-frequency sound waves to make diagnostic images, and those same sound waves can be used therapeutically to destroy tumors. Layering on MR imaging gives clinicians the ability to precisely guide the ultrasound therapy in real time. A study led by Children’s National Health System researchers and clinicians is using MR-HIFU for the first time in children to examine its safety and feasibility.

May 11, 2016 – Quantitative MRI criteria for optic pathway enlargement in neurofibromatosis type 1
Symptoms of neurofibromatosis type 1 (NF1) vary widely, but the condition is characterized by changes in skin pigmentation and growth of tumors along nerves. The research team sought to determine quantitative size thresholds for enlargement of the optic nerve, chiasm, and tract in children aged 0.5 to 18.6 years with NF1. The study, published in Neurology, found that quantitative reference values for anterior visual pathway enlargement will enhance development of objective diagnostic criteria for optic pathway gliomas secondary to NF1.

Training t-cells, essential players in the immune system, to fight a trio of viruses

Children's is the only U.S. pediatric hospital that manufactures specialized T-cells from native cord blood

What’s Known
Following treatment, patients with leukemia, lymphoma, and other cancers may receive a transplant in order to restore their body’s natural ability to fight infection and, sometimes, such transplants are a component of leukemia treatment. (Leukemia is the second most common blood cancer, after lymphoma, and its incidence rate has increased by 0.2 percent annually from 2002 to 2011.) A stem cell or cord blood transplant restores the body’s ability to produce infection-fighting white blood cells. After such transplants, however, patients can face heightened risk of developing a life-threatening infection with such viruses as adenovirus, cytomegalovirus, or Epstein-Barr virus.

What’s New
A head-to-head comparison of two strategies to thwart such viral infections shows that both approaches leverage the power of multivirus-specific, donor-derived T-cells (mCTL), which are highly skilled at recognizing foreign invaders. The research team, made up of nine scientists and clinicians affiliated with Children’s National Health System, grew personalized T-cells from peripheral blood (PB) of adult donors who were seropositive for CMV and also coaxed T-cells to grow from naïve cord blood (CB). PB-derived cells have long memories of past battles; naïve CB-derived cells need additional training to acquire such skills. From 35 to 384 days after their stem cell or cord blood transplant, 13 patients were infused with PB mCTL and 12 patients were infused with CB mCTL. Within four weeks, patients experienced up to a 160-fold increase in virus-specific T-cells, which coincided with their response to therapy. Overall response rate was 81 percent.

Questions for Future Research
Q: Could T-cells be personalized to attack other viruses that infect patients post-transplant, such as human parainfluenza virus and BK polyomavirus, providing the potential to target five viruses in a single infusion?
Q: Could the proteins that are used to train T-cells to attack certain viruses also be used to create a personalized approach to tumor suppression?

Source: “A Phase 1 Perspective: Multivirus-Specific T Cells From Both Cord Blood and Bone Marrow Transplant Donors.” Hanley, P., M. D. Keller, M. Martin Manso, C. Martinez, K. Leung, C.R. Cruz, C. Barese, S. McCormack, M. Luo, R.A. Krance, D. Jacobsohn, C. Rooney, H. Heslop, E.J. Shpall, and C. Bollard. Presented during the International Society for Cellular Therapy 2016 Annual Meeting, Singapore. May 26, 2016.

Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma

What’s Known
Needle biopsies help to guide diagnosis and targeted therapies for diffuse intrinsic pontine gliomas (DIPGs), which make up 10 percent to 15 percent of all pediatric brain tumors but carry a median survival of 9 to 12 months. This dismal survival rate compares with a 70 percent chance of children surviving other central nervous system tumors five years post diagnosis. In DIPG, tumors appear in the pons, an area of the brain that houses cranial nerve nuclei. Surgical options are limited. Spatial and temporal tumor heterogeneity is a major obstacle to accurate diagnosis and successful targeted therapy.

What’s New
The team sought to better define DIPG heterogeneity. They analyzed 134 specimens from nine patients and found that H3K27M mutations were ubiquitous in all 41 samples with oncogenic content, and always were associated with at least one partner driver mutation: TP53, PPM1D, ACVR1 or PIK3R1. These H3K27M mutations are the initial oncogenic event in DIPG, writes the research team led by Children’s National Health System. “Driver” mutations, such as H3K27M, are essential to begin and sustain tumor formation. This main driver partnership is maintained throughout the course of the disease, in all cells across the tumor, and as tumors spread throughout the brain. Because homogeneity for main driver mutations persists for the duration of illness, efforts to cure DIPG should be directed at the oncohistone partnership, the authors write. Based on early tumor spread, efforts to cure DIPG should aim for early systemic tumor control, rather focused exclusively on the pons.

Questions for Future Research
Q: If a larger sample size were analyzed, what would it reveal about the true heterogeneity/homogeneity status of DIPGs?
Q: “Accessory” driver mutations are not absolutely essential but do help to further promote and accelerate tumor growth. What is their precise role?

Source: Spatial and Temporal Homogeneity of Driver Mutations in Diffuse Intrinsic Pontine Glioma.” H. Nikbakht, E. Panditharatna, L.G. Mikael, R. Li, T. Gayden, M. Osmond, C.Y. Ho, M. Kambhampati, E.I. Hwang, D. Faury, A. Siu, S. Papillon-Cavanagh, D. Bechet, K.L. Ligon, B. Ellezam, W.J. Ingram, C. Stinson, A.S. Moore, K.E. Warren, J. Karamchandani, R.J. Packer, N. Jabado, J. Majewski, and J. Nazarian. Published by Nature Communications on April 6, 2016.

The role of NG2 proteoglycan in glioma

A large number of staffers contribute to the Children's National team effort to unravel the mysteries of DIPG. We photograph a few essential players in Dr. Nazarian's lab.

What’s Known
Neuron glia antigen-2 (NG2) is a protein expressed by many central nervous system cells during development and differentiation. NG2-expressing oligodendrocyte progenitor cells have been identified as the cells of origin in gliomas, tumors that arise from the brain’s gluey supportive tissue. What’s more, NG2 expression also has been associated with childhood diffuse intrinsic pontine glioma (DIPG) an aggressive tumor that accounts for 10 percent to 20 percent of pediatric central nervous system (CNS) tumors. Radiation can prolong survival by a few months, but children diagnosed with DIPG typically survive less than one year.

What’s New
Researchers are searching for appropriate targets and effective drugs that offer some chance of benefit. A team of Children’s National Health System researchers investigated whether NG2 – which plays a critical role in proliferation and development of new blood vessels and promotes tumor infiltration – could be a potential target for cancer treatment. Of the various options, antibody-mediated mechanisms of targeting NG2 are feasible, but the size of antibodies limits their ability to cross the blood-brain barrier. “Due to its role in maintaining a pluripotent pool of tumor cells, and its role in tumor migration and infiltration, NG2 provides multiple avenues for developing therapeutics,” the research team concludes. “Moreover, the large extracellular domain of NG2 provides an excellent antigen repertoire for immunotherapeutic interventions. As such, further research is warranted to define the role and expression regulation of NG2 in CNS cancers.”

Questions for Future Research

Q: Because healthy oligodendrocyte progenitor cells are important for the child’s developing brain, how could further characterization of NG2 isoforms help prevent drugs from damaging those beneficial cells?

Q: Could NG2-binding peptides cross the blood-brain barrier to deliver anti-cancer therapies precisely to tumor sites?

Source: The Role of NG2 Proteoglycan in Glioma.” S. Yadavilli, E.I. Hwang, R. J. Packer, and J. Nazarian. Published by Translational Oncology on February 2016.

Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape

Dr. Nazarian's lab

What’s Known
Fewer than 150 U.S. children per year are diagnosed with diffuse intrinsic pontine glioma (DIPG), one of the most lethal pediatric central nervous system cancers. Despite an increasing number of experimental therapies tested via clinical trials, more than 95 percent of these children die within two years of diagnosis. Molecular studies have yielded additional insight about DIPG, including that mutations in histone-encoding genes are associated with 70 percent of cases. Understanding mutations that drive tumors and the genomic landscape can help to guide development of targeted therapies.

What’s New: Frequently found genetic alterations prevalent in DIPGs

dipg-gene-mutations-and-biological-consequences

Source: Clinicopathology of Diffuse Intrinsic Pontine Glioma and Its Redefined Genomic and Epigenomic Landscape.” E. Panditharatna, K. Yaeger, L.B. Kilburn, R.J. Packer, and J. Nazarian. Published by Cancer Genetics on May 1, 2015.