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Vote for STAT Madness

It’s a three-peat! Children’s National again competes in STAT Madness

Vote for STAT Madness

Children’s National Hospital collects patients’ blood, extracts T-cells and replicates them in the presence of specific proteins found on cancer cells which, in essence, teaches the T-cells to target specific tumor markers. Training the T-cells, growing them to sufficient quantities and ensuring they are safe for administration takes weeks. But when patients return to the outpatient clinic, their T-cell infusion lasts just a few minutes.

For the third consecutive year, Children’s National was selected to compete in STAT Madness, an annual bracket-style competition that chooses the year’s most impactful biomedical innovation by popular vote. Children’s entry, “Immunotherapy of relapsed and refractory solid tumors with ex vivo expanded multi-tumor associated antigen specific cytotoxic T lymphocytes,” uses the body’s own immune system to attack and eliminate cancer cells in pediatric and adult patients with solid tumor malignancies.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

An estimated 11,000 new cases of pediatric cancer were diagnosed in children 14 and younger in the U.S. in 2019. And, when it comes to disease, cancer remains the leading cause of death among children, according to the National Institutes of Health. An enterprising research team led by Children’s National faculty leveraged T-cells – essential players in the body’s immune system – to treat pediatric and adult patients with relapsed or refractory solid tumors who had exhausted all other therapeutic options.

“We’re using the patient’s own immune system to fight their cancer, rather than more traditional chemotherapy drugs,” says Catherine M. Bollard, M.D., director of the Center for Cancer & Immunology Research at Children’s National and co-senior author of the study. “It’s more targeted and less toxic to the patient. These T-cells home in on any cancer cells that might be in the body, allowing healthy cells to continue to grow,” Dr. Bollard adds.

That means patients treated in the Phase I, first-in-human trial didn’t lose their hair and weren’t hospitalized for the treatment. After a quick clinical visit for their treatment, they returned to normal activities, like school, with good energy levels.

“With our specially trained T-cell therapy, many patients who previously had rapidly progressing disease experienced prolonged disease stabilization,” says Holly J. Meany, M.D., a Children’s National oncologist and the study’s co-senior author. “Patients treated at the highest dose level showed the best clinical outcomes, with a six-month, progression-free survival of 73% after tumor-associated antigen cytotoxic T-cell (TAA-T) infusion, compared with 38% with their immediate prior therapy.”

The multi-institutional team published their findings from the study online July 29, 2019, in the Journal of Clinical Oncology.

“Our research team and our parents are delighted that some patients treated in our study continue to do well following T-cell therapy without additional treatment. In some cases, two years after treatment, patients do not appear to have active disease and are maintaining an excellent quality of life,” says Amy B. Hont, M.D., the study’s lead author. “One of these was a patient whose parents were told his only other option was palliative care. Our innovation gives these families new hope,” Dr. Hont adds.

The 2020 STAT Madness #Core64 bracket opened March 2, and the champion will be announced April 6.

In addition to Drs. Hont, Meany and Bollard, Children’s National co-authors include C. Russell Cruz, M.D., Ph.D., Robert Ulrey, MS, Barbara O’Brien, BS, Maja Stanojevic, M.D., Anushree Datar, MS, Shuroug Albihani, MS, Devin Saunders, BA, Ryo Hanajiri, M.D., Ph.D., Karuna Panchapakesan, MS, Payal Banerjee, MS, Maria Fernanda Fortiz, BS, Fahmida Hoq, MBBS, MS, Haili Lang, M.D., Yunfei Wang, DrPH, Patrick J. Hanley, Ph.D., and Jeffrey S. Dome, M.D., Ph.D.; and Sam Darko, MS, National Institute of Allergy and Infectious Diseases.

Financial support for the research described in this post was provided by the Children’s National Hospital Heroes Gala, Alex’s Army Foundation, the Children’s National Board of Visitors and Hyundai Hope on Wheels Young Investigator Grant to Support Pediatric Cancer Research, the Children’s National Research Institute Bioinformatics Unit, the Clinical and Translational Science Institute and the National Institutes of Health under award No. UL1-TR001876.

Schistosoma

Parasitic eggs trigger upregulation in genes associated with inflammation

Schistosoma

Of the 200 million people around the globe infected with Schistosomiasis, about 100 million of them were sickened by the parasite Schistosoma haematobium.

Of the 200 million people around the globe infected with Schistosomiasis, about 100 million of them were sickened by the parasite Schistosoma haematobium. As the body reacts to millions of eggs laid by the blood flukes, people can develop fever, cough and abdominal pain, according to the Centers for Disease Control and Prevention. Schistosomiasis triggered by S. haematobium can also include hematuria, bladder calcification and bladder cancer.

Despite the prevalence of this disease, there are few experimental models specifically designed to study it, and some tried-and-true preclinical models don’t display the full array of symptoms seen in humans. It’s also unclear how S. haematobium eggs deposited in the host bladder modulate local tissue gene expression.

To better understand the interplay between the parasite and its human host, a team led by Children’s National Hospital injected 6,000 S. haematobium eggs into the bladder wall of seven-week-old experimental models.

After four days, they isolated RNA for analysis, comparing differences in gene expression in various treatment groups, including those that had received the egg injection and experimental models whose bladders were not exposed to surgical intervention.

Using the Database for Annotation, Visualization and Integrated Discovery (DAVID) – a tool that helps researchers understand the biological meaning of a long list of genes – the team identified commonalities with other pathways, including malaria, rheumatoid arthritis and the p53 signaling pathway, the team recently presented during the American Society of Tropical Medicine and Hygiene 2019 annual meeting. Some 325 genes were differentially expressed, including 34 genes in common with previous microarray data.

“Of particular importance, we found upregulation in genes associated with inflammation and fibrosis. We also now know that the body may send it strongest response on the first day it encounters a bolus of eggs,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National, and the research project’s senior author. “Next, we need to repeat these experiments and further narrow the list of candidate genes to key genes associated with immunomodulation and bladder cancer.”

In addition to Dr. Hsieh, presentation co-authors include Lead Author Kenji Ishida, Children’s National; Evaristus Mbanefo and Nirad Banskota, National Institutes of Health; James Cody, Vigene Biosciences; Loc Le, Texas Tech University; and Neil Young, University of Melbourne.

Financial support for research described in this post was provided by the National Institutes of Health under award No. R01-DK113504.

clatharin cage viewed by electron microscopy

IPSE infiltrates nuclei through clathrin-mediated endocytosis

clatharin cage viewed by electron microscopy

IPSE, one of the important proteins excreted by the parasite Schistosoma mansoni, infiltrates human cellular nuclei through clathrin-coated vesicles, like this one.

IPSE, one of the important proteins excreted by the parasite Schistosoma mansoni infiltrates human cellular nuclei through clathrin-mediated endocytosis (a process by which cells absorb metabolites, hormones and proteins), a research team led by Children’s National Hospital reported during the American Society of Tropical Medicine and Hygiene 2019 annual meeting.

Because the public health toll from the disease this parasite causes, Schistosomiasis, is second only to malaria in global impact, research teams have been studying its inner workings to help create the next generation of therapies.

In susceptible host cells – like urothelial cells, which line the urinary tract – IPSE modulates gene expression, increasing cell proliferation and angiogenesis (formation of new blood vessels). On a positive note, neurons appear better able to fend off its nucleus-infiltrating ways.

“We know that IPSE contributes to the severity of symptoms in Schistosomiasis, which leads some patients to develop bladder cancer, which develops from the urothelial lining of the bladder. Our team’s carefully designed experiments reveal IPSE’s function in the urothelium and point to the potential of IPSE playing a therapeutic role outside of the bladder,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National and the research project’s senior author.

In addition to Dr. Hsieh, research co-authors include Evaristus Mbanefo, Ph.D.; Kenji Ishida, Ph.D.; Austin Hester, M.D.; Catherine Forster, M.D.; Rebecca Zee, M.D., Ph.D.; and Christina Ho, M.D., all of Children’s National; Franco Falcone, Ph.D., University of Nottingham; and Theodore Jardetzky, Ph.D., and Luke Pennington, M.D., Ph.D., candidate, both of Stanford University.

Financial support for research described in this post was provided by the National Institutes of Health under award No. R01-DK113504.

pastel colored DNA strands

Germline microsatellite genotypes differentiate children with medulloblastoma

pastel colored DNA strands

A new study suggests that medulloblastoma-specific germline microsatellite variations mark those at-risk for medulloblastoma development.

Brian Rood, M.D., oncologist and medical director at the Brain Tumor Institute, and Harold “Skip” Garner, Ph.D., associate vice provost for research development at Edward Via College of Osteopathic Medicine, published a report in the Society for Neuro-Oncology’s Neuro-Oncology Journal about using a novel approach to identify specific markers in germline (non-tumor) DNA called microsatellites that can differentiate children who have the brain tumor medulloblastoma (MB) from those who don’t.

“Ultimately, the best way to save children from brain tumors and prevent them from bearing long-term side effects from treatment is to prevent those tumors from occurring in the first place,” says Dr. Rood. “New advancements hold the potential to finally realize the dream of cancer prevention, but we must first identify those children at-risk.”

While analyzing germline sequencing data from a training set of 120 MB subjects and 425 controls, the doctors identified 139 individual microsatellites whose genotypes differ significantly between the groups. Using a genetic algorithm, they were able to construct a subset of 43 microsatellites that distinguish MB subjects from controls with a sensitivity and specificity of 92% and 88% respectively.

“We made discoveries in an untapped part of the human genome, enabled by unique bioinformatics data mining approaches combined with clinical insight,” said Dr. Garner. “Our findings establish new genomic directions that can lead to high accuracy diagnostics for predicting susceptibility to medulloblastoma.”

What the doctors discovered and demonstrated in the study was that MB-specific germline microsatellite variations mark those at risk for MB development and suggest that other mechanisms of cancer predisposition beyond heritable mutations exist for MB.

“This work is the first to demonstrate the ability of specific DNA sequences to differentiate children with cancer from their healthy counterparts,” added Dr. Rood.

Contributing Authors to this research study included:  Brian R. Rood, M.D., Harold R. Garner, Ph.D., Samuel Rivero-Hinojosa, Ph.D., and Nicholas Kinney, Ph.D.

proton center

Johns Hopkins Proton Therapy Center opens in collaboration with Children’s National

proton center

The Center at Sibley offers state-of-the-art, pencil beam proton therapy equipment, as well as next-generation imaging technologies such as dual energy CT-guided treatment that reduces the range of error, and the latest innovation in biomatrix magnetic resonance imaging designed to target moving tumors in organs like the lung and liver.

Pediatric cancer patients in the Greater Washington region now have access to one of the most advanced, lifesaving proton therapy technologies offered in the U.S. The Johns Hopkins Proton Therapy Center opened Oct.28, 2019, at Sibley Memorial Hospital in collaboration with Children’s National Hospital.

The proton collaboration with Children’s National expands an existing collaboration between Children’s National and Johns Hopkins Medicine that established the pediatric radiation oncology program at Sibley, which treats a wide range of children’s cancer. Now, Sibley will offer the only proton center in the Washington D.C. region with a dedicated pediatric team, staff who are trained in pediatrics instead of adult providers who also treat children.

“This collaboration allows us to bring the latest technology to the region and offer the most advanced cancer treatment to help children live better lives,” says Kurt Newman, M.D., president and CEO at Children’s National. “As one of the Top 10 children’s hospitals in the nation, our goal is to ensure that patients and families are receiving the best care possible.”

The Center at Sibley offers state-of-the-art, pencil beam proton therapy equipment, as well as next-generation imaging technologies such as dual energy CT-guided treatment that reduces the range of error, and the latest innovation in biomatrix magnetic resonance imaging designed to target moving tumors in organs like the lung and liver. A large mechanical arm called a gantry can move the beam 360 degrees around the patient, treating the tumor from several angles as it destroys tumor cells layer by layer.

“Proton therapy is an advanced technology that allows radiation to be delivered precisely to cancer tissue,” says Jeffrey Dome, M.D., Ph.D., vice president for Cancer and Blood Disorders at Children’s National. “This provides a significant advantage compared with conventional radiation therapy, especially in children, where sparing the healthy tissue that surrounds the tumor may be critical for normal growth and development. Proton therapy shows great promise to reduce long-term side effects of radiation treatment.”

The Center at Sibley will have a fully integrated research room, which will allow clinical, basic science and medical physics faculty to advance clinical trial research, translational research and technology development research in proton therapy. Leading experts and oncologists will study proton outcomes for sarcoma, gynecological tumors, pancreatic and liver tumors, lymph node cancers and tumors located near the heart and major blood vessels, such as lung or breast cancers. In addition, the researchers will examine how the proton energy that kills cancer cells interacts with non-cancerous cells and tissue surrounding the tumors.

The JJohns Hopkins Proton Therapy Center opens in phases. The first treatment room opened October 2019. The second room is scheduled to open in spring 2020, and the third room and fixed beam research room are scheduled to open in fall 2020.

tube labeled "CRISPR"

$2M from NIH to extract meaningful data from CRISPR screens

tube labeled "CRISPR"

Protein-coding genes comprise a mere 1% of DNA. While the other 99% of DNA was once derided as “junk,” it has become increasingly apparent that some non-coding genes enable essential cellular functions.

Wei Li, Ph.D., a principal investigator in the Center for Genetic Medicine Research at Children’s National in Washington, D.C., proposes to develop statistical and computational methods that sidestep existing hurdles that currently complicate genome-wide CRISPR/Cas9 screening. The National Institutes of Health has granted him $2.23 million in funding over five years to facilitate the systematic study of genes, non-coding elements and genetic interactions in various biological systems and disease types.

Right now, a large volume of screening data resides in the public domain, however it is difficult to compare data that is stored in one library with data stored at a different library. Over the course of the five-year project, Li aims to:

  • Improve functional gene identification from CRISPR screens.
  • Develop new analyses algorithms for screens targeting non-coding elements.
  • Study genetic interactions from CRISPR screens targeting gene pairs.

Ultimately, Li’s work will examine a range of disease types. Take cancer.

“There is abundant information already available in the public domain, like the Project Achilles  from the Broad Institute. However, no one is looking to see what is going in inside these tumors,” Li says. “Cancer is a disease of uncontrolled cell growth that makes tumors grow faster.”

Li and colleagues are going to ask which genes control this process by looking at genes that hit the brakes on cell growth as well as genes that pump the gas.

“You knock out one gene and then look: Does the cell grow faster or does it grow more slowly? If the cell grows more slowly, you know you are knocking out a gene that has the potential to stop tumor growth. If cells are growing faster, you know that you’re hitting genes that suppress cancer cell growth.”

In a nutshell, CRISPR (clustered regularly interspaced short palindromic repeats) screens knock out different genes and monitor changes in corresponding cell populations. When CRISPR first became popular, Li decided he wanted to do something with the technology. So, as a Postdoc at Harvard, he developed comprehensive computational algorithms for functional screens using CRISPR/Cas9.

To reach as many people as possible, he offered that MAGeCK/MAGeCK-VISPR software free to as many researchers as possible, providing source code and offering internet tutorials.

“So far, I think there are quite a lot of people using this. There have been more than 40,000 software downloads,” he adds. “It’s really exciting and revolutionary technology and, eventually, we hope the outcomes also will be exciting. We hope to find something really helpful for cancer patients.”

Research reported in this publication was supported by the National Human Genome Research Institute of the National Institutes of Health under award number R01HG010753.

Test tube with DNA

“Liquid biopsies” could track diffuse midline gliomas

Test tube with DNA

A multi-institutional team led by researchers at Children’s National in Washington, D.C., developed and tested “liquid biopsy,” a measure of circulating tumor DNA in patients’ cerebrospinal fluid and blood plasma. They show that quantifying the amount of circulating tumor DNA possessing key mutations characteristic of diffuse midline gliomas could reliably predict the tumors’ response to radiotherapy.

Diffuse midline gliomas are rare, diagnosed in fewer than 800 Americans every year, the majority of whom are children. These cancers arise in the cellular “glue” that holds the brain and spinal cord’s neurons together, grow swiftly and have no cure. About half of patients with these cancers, including diffuse intrinsic pontine glioma, die within one year of diagnosis.

Clinical trials are increasingly investigating new treatments that could offer hope for patients and their families. Yet, thus far, there have been few ways to track the progression of these conditions, offering little insight on whether a treatment is hitting its intended goal.

To solve this problem, a multi-institutional team led by researchers at Children’s National in Washington, D.C., developed and tested “liquid biopsy,” a measure of circulating tumor DNA in patients’ cerebrospinal fluid and blood plasma. They show that quantifying the amount of circulating tumor DNA possessing key mutations characteristic of these cancers could reliably predict the tumors’ response to radiotherapy. The scientists published their results online Oct. 15, 2018, in Clinical Cancer Research.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The team at Children’s National searches for the histone 3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M,” says Lindsay B. Kilburn, M.D., a neurooncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers children to not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients who had undergone a tumor biopsy.”

With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously, Nazarian adds.

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D., and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital;  John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Mathew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

Oncology at Children’s National

Oncology at Children's National
ID-KD vaccine induced T-cell cytotoxicity

Fighting lethal cancer with a one-two punch

The immune system is the ultimate yin and yang, explains Anthony D. Sandler, M.D., senior vice president and surgeon-in-chief of the Joseph E. Robert Jr. Center for Surgical Care at Children’s National in Washington, D.C. With an ineffective immune system, infections such as the flu or diarrheal illness can run unchecked, causing devastating destruction. But on the other hand, excess immune activity leads to autoimmune diseases, such as lupus or multiple sclerosis. Thus, the immune system has “checks and balances” to stay controlled.

Cancer takes advantage of “the checks and balances,” harnessing the natural brakes that the immune system puts in place to avoid overactivity. As the cancer advances, molecular signals from tumor cells themselves turn on these natural checkpoints, allowing cancers to evade immune attack.

Several years ago, a breakthrough in pharmaceutical science led to a new class of drugs called checkpoint inhibitors. These medicines take those proverbial brakes off the immune system, allowing it to vigorously attack malignancies. However, Dr. Sandler says, these drugs have not worked uniformly and in some cancers, they barely work at all against the cancer.

One of these non-responders is high risk neuroblastoma, a common solid tumor found outside the skull in children. About 800 U.S. children are diagnosed with this cancer every year. And kids who have the high-risk form of neuroblastoma have poor prognoses, regardless of which treatments doctors use.

However, new research could lead to promising ways to fight high-risk neuroblastoma by enabling the immune system to recognize these tumors and spark an immune response. Dr. Sandler and colleagues recently reported on these results in the Jan. 29, 2018, PLOS Medicine using an experimental model of the disease.

The researchers created this model by injecting the preclinical models with cancer cells from an experimental version of neuroblastoma. The researchers then waited several days for the tumors to grow. Samples of these tumors showed that they expressed a protein on their cell surfaces known as PD-L1, a protein that is also expressed in many other types of human cancers to evade immune system detection.

To thwart this protective feature, the researchers made a cancer vaccine by removing cells from the experimental model’s tumors and selectively turning off a gene known as Id2. Then, they irradiated them, a treatment that made these cells visible to the immune system but blocked the cells from dividing to avoid new tumors from developing.

They delivered these cells back to the experimental models, along with two different checkpoint inhibitor drugs – antibodies for proteins known as CLTA-4 and PD-L1 – over the course of three treatments, delivered every three days. Although most checkpoint inhibitors are administered over months to years, this treatment was short-term for the experimental models, Dr. Sandler explains. The preclinical models were completely finished with cancer treatment after just three doses.

Over the next few weeks, the researchers witnessed an astounding turnaround: While experimental models that hadn’t received any treatment uniformly died within 20 days, those that received the combined vaccine and checkpoint inhibitors were all cured of their disease. Furthermore, when the researchers challenged these preclinical models with new cancer cells six months later, no new tumors developed. In essence, Dr. Sandler says, the preclinical models had become immune to neuroblastoma.

Further studies on human patient tumors suggest that this could prove to be a promising treatment for children with high-risk neuroblastoma. The patient samples examined show that while tumors with a low risk profile are typically infiltrated with numerous immune cells, tumors that are high-risk are generally barren of immune cells. That means they’re unlikely to respond to checkpoint inhibiting drugs alone, which require a significant immune presence in the tumor microenvironment. However, Dr. Sandler says, activating an immune response with a custom-made vaccine from tumor cells could spur the immune response necessary to make these stubborn cancers respond to checkpoint inhibitors.

Dr. Sandler cautions that the exact vaccine treatment used in the study won’t be feasible for people. The protocol to make the tumor cells immunogenic is cumbersome and may not be applicable to gene targeting in human patients. However, he and his team are currently working on developing more feasible methods for crafting cancer vaccines for kids. They also have discovered a new immune checkpoint molecule that could make this approach even more effective.

“By letting immune cells do all the work we may eventually be able to provide hope for patients where there was little before,” Dr. Sandler says.

In addition to Dr. Sandler, study co-authors include Priya Srinivasan, Xiaofang Wu, Mousumi Basu and Christopher Rossi, all of the Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI), at Children’s National in Washington, D.C.

Financial support for research described in this post was provided by the EVAN Foundation, the Catherine Blair foundation, the Michael Sandler Research Fund and SZI.

ID-KD vaccine induced T-cell cytotoxicity

Mechanism of Id2kd Neuro2a vaccination combined with α-CTLA-4 and α-PD-L1 immunotherapy in a neuroblastoma model. During a vaccine priming phase, CTLA-4 blockade enhances activation and proliferation of T-cells that express programmed cell death 1 (PD1) and migrate to the tumor. Programmed cell death-ligand 1 (PD-L1) is up-regulated on the tumor cells, inducing adaptive resistance. Blocking PD-L1 allows for enhanced cytotoxic effector function of the CD8+ tumor-infiltrating lymphocytes. Artist: Olivia Abbate

Children’s National ranked No. 6 overall and No. 1 for newborn care by U.S. News

Children’s National in Washington, D.C., is the nation’s No. 6 children’s hospital and, for the third year in a row, its neonatology program is No.1 among all children’s hospitals providing newborn intensive care, according to the U.S. News Best Children’s Hospitals annual rankings for 2019-20.

This is also the third year in a row that Children’s National has been in the top 10 of these national rankings. It is the ninth straight year it has ranked in all 10 specialty services, with five specialty service areas ranked among the top 10.

“I’m proud that our rankings continue to cement our standing as among the best children’s hospitals in the nation,” says Kurt Newman, M.D., President and CEO for Children’s National. “In addition to these service lines, today’s recognition honors countless specialists and support staff who provide unparalleled, multidisciplinary patient care. Quality care is a function of every team member performing their role well, so I credit every member of the Children’s National team for this continued high performance.”

The annual rankings recognize the nation’s top 50 pediatric facilities based on a scoring system developed by U.S. News. The top 10 scorers are awarded a distinction called the Honor Roll.

“The top 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver outstanding care across a range of specialties and deserve to be nationally recognized,” says Ben Harder, chief of health analysis at U.S. News. “According to our analysis, these Honor Roll hospitals provide state-of-the-art medical expertise to children with rare or complex conditions. Their rankings reflect U.S. News’ assessment of their commitment to providing high-quality, compassionate care to young patients and their families day in and day out.”

The bulk of the score for each specialty is based on quality and outcomes data. The process also includes a survey of relevant specialists across the country, who are asked to list hospitals they believe provide the best care for patients with challenging conditions.

Below are links to the five specialty services that U.S. News ranked in the top 10 nationally:

The other five specialties ranked among the top 50 were cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastro-intestinal surgery, orthopedics, and urology.

germ cells in testicular tissues

Experimental fertility preservation provides hope for young men

germ cells in testicular tissues

Confirming the presence of germ cells in testicular tissues obtained from patients. Undifferentiated embryonic cell transcription factor 1 (UTF1) is an established marker of undifferentiated spermatogonia as well as the pan-germ cell marker DEAD-box helicase 4 (DDX4). UTF1 (green) and/or DDX4 (red) immunostaining was confirmed in 132 out of 137 patient tissues available for research, including patients who had received previous non-alkylating (B, E, H, K) or alkylating (C, F, I, L) chemotherapy treatment. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Testicular tissue samples obtained from 189 males who were facing procedures that could imperil fertility were cryopreserved at one university, proving the feasibility of centralized processing and freezing of testicular tissue obtained from academic medical centers, including Children’s National, scattered around the world.

“It’s not surprising that the University of Pittsburgh would record the highest number of samples over the eight-year period (51 patients), given its role as the central processing facility for our recruiting network of academic medical centers,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National. “Children’s National recruited the third-highest number of patients, which really speaks to the level of collaboration I have with Jeff Dome’s team and their commitment to thinking about the whole patient and longer-term issues like fertility.”

An estimated 2,000 U.S. boys and young men each year receive treatments or have cancers or blood disorders that place them at risk for infertility. While older youths who have undergone puberty can bank their sperm prior to undergoing sterilizing doses of chemotherapy or radiation, there have been scant fertility preservation options for younger boys. However, some older adolescents and young men are too sick or stressed to bank sperm. For patients with no sperm to bank or who are too sick or stressed to bank sperm, the experimental procedure of freezing testicular tissue in anticipation that future cell- or tissue-based therapies can generate sperm is the only option.

Recent research in experimental models indicates that such testicular tissue biopsies contain stem cells, blank slate cells, hinting at the potential of generating sperm from biopsied tissue.

“This study demonstrates that undifferentiated stem and progenitor spermatogonia may be recovered from the testicular tissues of patients who are in the early stages of their treatment and have not yet received an ablative dose of therapy. The function of these spermatogonia was not tested,” writes lead author Hanna Valli-Pulaski, Ph.D., research assistant professor at the University of Pittsburgh, and colleagues in a study published online May 21, 2019, in Human Reproduction.

Right now, hematologists and oncologists discuss future treatment options with patients and families, as well as possible long-term side effects, including infertility. At Children’s National, they also mention the ongoing fertility preservation study and encourage families to speak with Dr. Hsieh. He meets with families, explains the study goals – which include determining better ways to freeze and thaw tissue and separating malignant cells from normal cells – what’s known about experimental fertility preservation and what remains unknown. Roughly half of patients decide to enroll.

“This study is unique in that there is definitely a potential direct patient benefit,” Dr. Hsieh adds. “One of the reasons the study is compelling is that it presents a message of hope to the families. It’s a message of survivorship: We’re optimistic we can help your child get through this and think about long-term issues, like having their own families.”

In this phase of the study, testicular tissue was collected from centers in the U.S. and Israel from January 2011 to November 2018 and cryopreserved. Patients designated 25% of the tissue sample to be used for the research study; 75 percent remains stored in liquid nitrogen at temperatures close to absolute zero for the patient’s future use. The fertility preservation patients ranged from 5 months old to 34 years old, with an average age of 7.9 years.

Thirty-nine percent of patients had started medical treatment prior requesting fertility preservation. Sixteen percent received non-alkylating chemotherapy while 23% received alkylating chemotherapy, which directly damages the DNA of cancer cells.

The research team found that the number of undifferentiated spermatogonia per seminiferous tubule increase steadily with age until about age 11, then rise sharply.

“We recommend that all patients be counseled and referred for fertility preservation before beginning medical treatments known to cause infertility. Because the decision to participate may be delayed, it is encouraging that we were able to recover undifferentiated spermatogonia from the testes of patients already in the early stages of chemotherapy treatments,” Dr. Hsieh says.

In addition to Dr. Hsieh, study co-authors include lead author, H. Valli-Pulaski, K.A. Peters, K. Gassei, S.R. Steimer, M. Sukhwani, B.P. Hermann, L. Dwomor, S. David, A.P. Fayomi, S.K. Munyoki, T. Chu, R. Chaudhry, G.M. Cannon, P.J. Fox, T.M. Jaffe, J.S. Sanfilippo, M.N. Menke and senior author, K.E. Orwig, all of University of Pittsburgh; E. Lunenfeld, M. Abofoul-Azab and M. Huleihel, Ben-Gurion University of the Negev; L.S. Sender, J. Messina and L.M. Klimpel, CHOC Children’s Hospital;  Y. Gosiengfiao, and E.E. Rowell, Ann & Robert H. Lurie Children’s Hospital of Chicago; C.F. Granberg, Mayo Clinic; P.P. Reddy, Cincinnati Children’s Hospital Medical Center; and J.I. Sandlow, Medical College of Wisconsin.

Financial support for the research covered in this post was provided by Eunice Kennedy Shriver National Institute for Child Health and Human Development under awards HD061289 and HD092084; Scaife Foundation; Richard King Mellon Foundation; University of Pittsburgh Medical Center; United States-Israel Binational Science Foundation and Kahn Foundation.

Stat Madness 2019

Vote for Children’s National in STAT Madness

Stat Madness 2019

Children’s National Health System has been selected to compete in STAT Madness for the second consecutive year. Our entry for the bracket-style competition is “Sensitive liquid biopsy platform to detect tumor-released mutated DNA using patient blood and CSF,” a new technique that will allow kids to get better treatment for an aggressive type of pediatric brain tumor.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

“Children’s National researchers collaboratively work across divisions and departments to ensure that innovations discovered in our laboratories reach clinicians in order to improve patient care,” says Mark Batshaw, M.D., Children’s Executive Vice President, Chief Academic Officer and Physician-in-Chief. “It’s gratifying that Children’s multidisciplinary approach to improving the lives of children with brain tumors has been included in this year’s STAT Madness competition.”

Pediatric brain cancers are the leading cause of cancer-related death in children younger than 14. Children with tumors in their midline brain structures have the worst outcomes, and kids diagnosed with diffuse midline gliomas, including diffuse intrinsic pontine glioma, have a median survival of just 12 months.

“We heard from our clinician colleagues that many kids were coming in and their magnetic resonance imaging (MRI) suggested a particular type of tumor. But it was always problematic to identify the tumor’s molecular subtype,” says Javad Nazarian, Ph.D., MSC, a principal investigator in Children’s Center for Genetic Medicine Research. “Our colleagues wanted a more accurate measure than MRI to find the molecular subtype. That raised the question of whether we could actually look at their blood to determine the tumor subtype.”

Children’s liquid biopsy, which remains at the research phase, starts with a simple blood draw using the same type of needle as is used when people donate blood. When patients with brain tumors provide blood for other laboratory testing, a portion of it is used for the DNA detective work. Just as a criminal leaves behind fingerprints, tumors shed telltale clues in the blood. The Children’s team searches for the histone 3.3K27M (H3K27M), a mutation associated with worse clinical outcomes.

“With liquid biopsy, we were able to detect a few copies of tumor DNA that were hiding behind a million copies of healthy DNA,” Nazarian says. “The blood draw and liquid biopsy complement the MRI. The MRI gives the brain tumor’s ZIP code. Liquid biopsy gives you the demographics within that ZIP code.”

Working with collaborators around the nation, Children’s National continues to refine the technology to improve its accuracy. The multi-institutional team published findings online Oct. 15, 2018, in Clinical Cancer Research.

Even though this research technique is in its infancy, the rapid, cheap and sensitive technology already is being used by people around the globe.

“People around the world are sending blood to us, looking for this particular mutation, H3K27M, ” says Lindsay B. Kilburn, M.D., a Children’s neurooncologist, principal investigator at Children’s National for the Pacific Pediatric Neuro-Oncology Consortium, and study co-author. “In many countries or centers, children do not have access to teams experienced in taking a biopsy of tumors in the brainstem, they can perform a simple blood draw and have that blood processed and analyzed by us. In only a few days, we can provide important molecular information on the tumor subtype previously only available to patients that had undergone a tumor biopsy.”

“With that DNA finding, physicians can make more educated therapeutic decisions, including prescribing medications that could not have been given previously,” Nazarian adds.

The STAT Madness round of 64 brackets opened March 4, 2019, and the championship round voting concludes April 5 at 5 p.m. (EST).

In addition to Nazarian and Dr. Kilburn, study co-authors include Eshini Panditharatna, Madhuri Kambhampati, Heather Gordish-Dressman, Ph.D., Suresh N. Magge, M.D., John S. Myseros, M.D., Eugene I. Hwang, M.D. and Roger J. Packer, M.D., all of Children’s National; Mariam S. Aboian, Nalin Gupta, Soonmee Cha, Michael Prados and Co-Senior Author Sabine Mueller, all of University of California, San Francisco; Cassie Kline, UCSF Benioff Children’s Hospital; John R. Crawford, UC San Diego; Katherine E. Warren, National Cancer Institute; Winnie S. Liang and Michael E. Berens, Translational Genomics Research Institute; and Adam C. Resnick, Children’s Hospital of Philadelphia.

Financial support for the research described in the report was provided by the V Foundation for Cancer Research, Goldwin Foundation, Pediatric Brain Tumor Foundation, Smashing Walnuts Foundation, The Gabriella Miller Kids First Data Resource Center, Zickler Family Foundation, Clinical and Translational Science Institute at Children’s National under award 5UL1TR001876-03, Piedmont Community Foundation, Musella Foundation for Brain Tumor Research, Matthew Larson Foundation, The Lilabean Foundation for Pediatric Brain Cancer Research, The Childhood Brain Tumor Foundation, the National Institutes of Health and American Society of Neuroradiology.

Karun-Sharma-and-kids-MR-HIFU

Clinical Trial Spotlight: Treating tumors with ThermoDox® and MR-HIFU

Karun Sharma, M.D., is working with AeRang Kim, M.D., Ph.D., to evaluate the use of ThermoDox®, a heat-activated chemotherapy drug, in combination with noninvasive magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) to treat refractory or relapsed solid tumors in children and young adults.

A Phase I Study of Lyso-thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox®) and Magnetic Resonance-Guided High Intensity Focused Ultrasound for Relapsed or Refractory Solid Tumors in Children, Adolescents, and Young Adults.

This study is looking to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lyso-thermosensitive liposomal doxorubicin (LTLD), a heat-activated formulation of liposomal doxorubicin with unique property of heat-activated release of doxorubicin, administered in combination with magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) in children with relapsed/refractory solid tumors.

MR-HIFU is an innovative device that provides precise and controlled delivery of heat inside a tumor using an external applicator. Unlike other heating systems used in local therapy, MR-HIFU is entirely non-invasive and does not use any radiation. Integration of MR imaging allows for real-time temperature monitoring for accurate and precise targeting of tumors. LTLD is a novel formulation of doxorubicin with the unique property of heat-activated release. This selective drug delivery mechanism allows for local and rapid release of doxorubicin in high concentrations in tumors when heated. This novel combination may potentiate known effective therapy to improve local control and drug delivery without increasing toxicity.

Children’s National Health System and Celsion Corp, a leading oncology drug-development company, were the first to launch a clinical study in the U.S. that evaluates the use of ThermoDox® with MR-HIFU. Learn more about the clinical trial.

For more information about this trial or other trials available at Children’s National, contact:

Melissa Salerno
Clinical Research Program Manager
202-476-2142
msalerno@childrensnational.org

View more open phase 1 and phase 2 cancer clinical trials at Children’s National.

The Children’s National Center for Cancer and Blood Disorders is committed to providing the best care for pediatric patients. Our experts play an active role in innovative clinical trials to advance pediatric cancer care. We offer access to novel trials and therapies, some of which are only available here at Children’s National. With research interests covering nearly aspect of pediatric cancer care, our work is making great advancements in childhood cancer.

PICU room

How to help bereaved families

PICU room

To help clinicians provide better care to families after children die, Tessie W. October, M.D., MPH, and colleagues recently published an article on this topic in a special supplement to Pediatric Critical Care Medicine on death and dying.

Death and dying are always difficult topics to discuss at hospitals. They’re especially hard conversations when they occur within pediatric intensive care units (PICUs), says Tessie W. October, M.D., MPH, a critical care specialist at Children’s National.

“It’s almost easier to pretend that children don’t die in the ICU. But they do,” Dr. October says.

Tragically, some children do die in ICUs. However, even when pediatric patients die, Dr. October adds, the pediatric care team’s relationship with the bereaved family continues. Knowing how to help vulnerable families during these trying times and ensuring they have needed resources can be critical to lessening the health and social consequences of grief. To help clinicians provide better care to families after children die, Dr. October and colleagues recently published an article on this topic in a special supplement to Pediatric Critical Care Medicine on death and dying.

The multi-institutional research team performed a narrative literature review for this budding field. They pored through more than 75 papers to better understand the health outcomes of parents whose child died within a PICU and the different ways that hospitals help families cope with these tragedies.

The researchers found a range of detrimental health outcomes, from a significantly increased risk of parental death in the aftermath of a child’s death to higher rates of myocardial infarction, cancer and multiple sclerosis. Bereaved parents used more health care resources themselves, took more sick days and had more sleep problems than parents who weren’t bereaved.

Likewise, parents whose child died were at a high risk of experiencing mental health conditions including complicated grief, anxiety, depression and posttraumatic stress disorder. Divorce was eight times higher among bereaved parents compared with the general population, and financial crises were common after voluntary or involuntary unemployment.

Knowing which risks parents could face can help the care team respond better if a child dies, Dr. October explains. Their review highlighted simple ways to support families in the immediate aftermath of a child’s death and beyond, such as:

  • Giving parents the opportunity to spend time alone with the child’s body
  • Allowing friends, family and others to visit at the parents’ discretion and
  • Providing easy access to professional support, such as chaplains, social workers and grief coordinators.

Even simple acts such as closing doors and blinds to provide privacy can be helpful, Dr. October says.

An ongoing relationship with health care providers is also important for helping parents grieve, she adds. Children’s National is among hospitals across the country to set up meetings for parents and other family members within weeks of a child’s death. This gives parents a chance to ask questions about what happened in the confusing blur of the PICU and to gather resources for themselves and surviving siblings. Children’s National also provides ongoing support through periodic calls, sending sympathy cards, attending funeral services and in a special annual memorial during which surviving family members release butterflies.

“Our role doesn’t end when a child dies,” Dr. October says. “To help parents through bereavement, we need to maintain that strong connection.”

Another way to help bereaved families is to make sure they have adequate information, she adds, particularly about the confusing subject of brain death. In a different study recently published in Chest Journal, Dr. October and Children’s colleagues sought to understand which information the public typically accesses about this topic.

The team searched Google and YouTube using “brain dead” and “brain death” as search terms. They evaluated the top 10 results on both sites, assessing the accuracy of information using 2010 guidelines released by the American Academy of Neurology. They also assessed the reading level of websites and evaluated comments about the YouTube videos for content accuracy and tone.

They found that there was inaccurate information on four of the 10 websites, six of the 10 videos and within 80 percent of the YouTube comments. Most of these inaccuracies dealt with using terms like brain death, coma and persistent vegetative state interchangeably. “These conditions are very different and affect how we treat patients,” Dr. October says.

The average reading level of the websites was 12th grade, far too sophisticated for much of the public to comprehend, she adds. And the majority of comments on the YouTube videos were negative, often disparaging clinicians and deriding organ donation.

“It’s really important for providers to recognize that this is an emotionally laden topic, and a lot of times, families come to us with information that’s not always true,” she says. “That’s why it’s especially important for the field to respond with empathy and care.”

In addition to Dr. October, co-authors of the Pediatric Critical Care Medicine study include Karen Dryden-Palmer, R.N., MSN, Ph.D., The Hospital for Sick Children; Beverley Copnell, Ph.D., BAppSc, R.N., Monash University; and Senior Author Kathleen L. Meert, M.D., FCCM, Children’s Hospital of Michigan. Dr. October’s co-authors for the Chest Journal article include Lead Author, Amy H. Jones, M.D., and co-author Zoelle B. Dizon, BA, both of Children’s National.

Maureen E Lyon

Maureen E. Lyon, Ph.D., ABPP, lauded for outstanding excellence in patient-centered advance care planning

Maureen E Lyon

Maureen E. Lyon, Ph.D., a principal investigator at Children’s Center for Translational Science, will be honored with a “Recognition Award for Excellence and Innovation in Research” by Respecting Choices for outstanding excellence in patient-centered advance care planning and shared decision-making.

Respecting Choices will present the award on Oct. 26, 2018, during its “National Share the Experience Conference” in Bloomington, Minnesota.

Lyon’s expertise is in advance care planning and shared decision-making for children and adolescents with life-threatening illnesses and their families, a field that has transformed in recent decades in order to pave better paths forward for difficult but necessary conversations.

“It came from my clinical experience,” Lyon says. “In the early days of the human immunodeficiency virus (HIV) epidemic in the U.S., everything, absolutely everything, was done to keep the kids alive in the hopes that some new drug would come around the corner, and we could bring them back from the brink. I remember one of the young boys saying to his case manager that he didn’t want all of these interventions. But he hadn’t told his family.”

That young man’s eye-opening comments – and learning that Children’s National Health System had a policy that teenagers were to be included in conversations about their own advance care planning – inspired Lyon to conduct a series of surveys involving adolescents, families and clinicians.

“I remember sitting down with friends and saying ‘There must be a better way to do this. Everyone is afraid to broach the subject,’ ” Lyon recalls. So, she conducted surveys of all healthy kids coming through Children’s adolescent clinic and kids diagnosed with HIV, cancer and sickle cell disease.

“It turned out the kids did want to talk about it. That was the first thing. Families told us they wanted help breaking the ice. Physicians felt it wasn’t their role – many doctors felt their role was to save people – or, they didn’t have the training,” she says.

Through a series of focus groups with youths living with HIV, families and community members, Lyon adapted the adult-centric Respecting Choices model to create a three-session intervention to better meet the advance care planning needs of youths and adolescents living with HIV.

Lyon’s recent work includes a single-blinded, randomized study published Oct. 19, 2018, in Pediatrics that finds the more families understand the end-of-life treatment preferences expressed by adolescents living with HIV, the less likely these youth are to suffer HIV-related symptoms, compared with youths whose families do not understand their end-of-life care goals.

She also has adapted the Respecting Choices intervention to facilitate its use with children diagnosed with cancer. More recently, she has adapted the model for use by parents of children with rare diseases who cannot communicate on their own.

“For the other life-threatening health conditions, we worked to support adolescents in expressing their advance care planning choices in their own voices. With rare diseases, we’re shifting gears,” she adds.

Published research indicates a sizable proportion of pediatric patients who die in hospitals now have confirmed or suspected rare diseases, she says. During a pilot involving seven families, many parents multitasked during the conversations, taking pauses to attend to various alarms as they sounded, to complete regular feedings and to contend with their child’s petit mal seizures.

“The level of burden of taking care of these children with terminal illnesses was pretty overwhelming,” she says. “Still, families were not too burdened to participate in advance care planning, but first wanted to identify their priority palliative care needs and to develop a support plan to meet those needs. We also had more fathers involved.”

Tessie October

Effectively expressing empathy to improve ICU care

Tessie October

“Families who feel we’re really listening and care about what they have to say are more likely to feel comfortable as they put their child’s life in our hands a second, third or fourth time,” says Tessie W. October, M.D., M.P.H.

In nearly every intensive care unit (ICU) at every pediatric hospital across the country, physicians hold numerous care conferences with patients’ family members daily. Due to the challenging nature of many these conversations – covering anything from unexpected changes to care plans for critically ill children to whether it’s time to consider withdrawing life support – these talks tend to be highly emotional.

That’s why physician empathy is especially important, says Tessie W. October, M.D., M.P.H., critical care specialist at Children’s National Health System.

Several studies have shown that when families believe that physicians hear, understand or share patients’ or their family’s emotions, patients can achieve better outcomes, Dr. October explains. When families feel like their physicians are truly empathetic, she adds, they’re more likely to share information that’s crucial to providing the best care.

“For the most part, our families do not make one-time visits. They return multiple times because their children are chronically ill,” Dr. October says. “Families who feel we’re really listening and care about what they have to say are more likely to feel comfortable as they put their child’s life in our hands a second, third or fourth time. They’re also less likely to regret decisions made in the hospital, which makes them less likely to experience long-term psychosocial outcomes like depression and anxiety.”

What’s the best way for physicians to show empathy? Dr. October and a multi-institutional research team set out to answer this question in a study published online in JAMA Network Open on July 6, 2018.

With families’ consent, the researchers recorded 68 care conferences that took place at Children’s pediatric ICU (PICU) between Jan. 3, 2013, to Jan. 5, 2017. These conversations were led by 30 physicians specializing in critical care, hematology/oncology and other areas and included 179 family members, including parents.

During these conferences, the most common decision discussed was tracheostomy placement – a surgical procedure that makes an opening in the neck to support breathing – followed by the family’s goals, other surgical procedures or medical treatment. Twenty-two percent of patients whose care was discussed during these conferences died during their hospitalization, highlighting the gravity of many of these talks.

Dr. October and colleagues analyzed each conversation, counting how often the physicians noticed opportunities for empathy and how they made empathetic statements. The researchers were particularly interested in whether empathetic statements were “buried,” which means they were:

  • Followed immediately by medical jargon
  • Followed by a statement beginning with the word “but” that included more factual information or
  • Followed by a second physician interrupting with more medical data.

That compares with “unburied” empathy, which was followed only by a pause that provided the family an opportunity to respond. The research team examined what happened after each type of empathetic comment.

The researchers found that physicians recognized families’ emotional cues 74 percent of the time and made 364 empathetic statements. About 39 percent of these statements were buried. In most of these instances, says Dr. October, the study’s lead author, the buried empathy either stopped the conversation or led to family members responding with a lack of emotion themselves.

After the nearly 62 percent of empathetic statements that were unburied, families tended to answer in ways that revealed their hopes and dreams for the patient, expressed gratitude, agreed with care advice or expressed mourning—information that deepened the conversation and often offered critical information for making shared decisions about a patient’s care.

Physicians missed about 26 percent of opportunities for empathy. This and striving to make more unburied empathetic statements are areas ripe for improvement, Dr. October says.

That’s why she and colleagues are leading efforts to help physicians learn to communicate better at Children’s National. To express empathy more effectively, Dr. October recommends:

  • Slow down and be in the moment. Pay close attention to what patients are saying so you don’t miss their emotional cues and opportunities for empathy.
  • Remember the “NURSE” mnemonic. Empathetic statements should Name the emotion, show Understanding, show Respect, give Support or Explore emotions.
  • Avoid using the word “but” as a transition. When you follow an empathetic statement with “but,” Dr. October says, it cancels out what you said earlier.
  • Don’t be afraid to invite strong emotions. Although it seems counterintuitive, Dr. October says helping patients express strong feelings can help process emotions that are important for decision-making.

In addition to Dr. October, study co-authors include Zoelle B. Dizon, BA, Children’s National; Robert M. Arnold, M.D., University of Pittsburgh Medical Center; and Senior Author, Abby R. Rosenberg, M.D., MS, University of Washington School of Medicine.

Research covered in this story was supported by the National Institutes of Health under grants 5K12HD047349-08 and 1K23HD080902 and the National Center for Advancing Translational Sciences under Clinical and Translational Science Institute at Children’s National Health System grant number UL1TR0001876.

Bladder cancer’s unique bacterial “fingerprint”

Michael H. Hsieh, M.D., Ph.D.

Michael H. Hsieh, M.D., Ph.D.

Decades ago, researchers thought that the native bacteria scattered throughout the human body—such as in the gut, the oral cavity and the skin—served little useful purpose. This microbiota, whose numbers at least match those of the cells in the body they live on and in, were considered mostly harmless hitchhikers.

More recently, research has revealed that these natural flora play key roles in maintaining and promoting health. In addition, studies have shown that understanding what a “typical” microbiome looks like and how it might change over time can provide an early warning system for some health conditions, including cancer.

Now, a small, multi-institutional study conducted in experimental models suggests that as bladder cancer progresses, it appears to be associated with a unique bacterial fingerprint within the bladder—a place thought to be bacteria-free except in the case of infection until just a few years ago. The finding opens the possibility of a new way to spot the disease earlier.

Bladder cancer is the fourth-most common malignancy among U.S. men but, despite its prevalence, mortality rates have remained stubbornly high. Patients often are diagnosed late, after bladder cancer has advanced. And, it remains difficult to discern which patients with non-invasive bladder cancer will go on to develop muscle-invasive disease.

Already, researchers know that patients with grade 4 oral squamous cell carcinoma, women with increasingly severe grades of cervical cancer and patients with cirrhosis who develop liver cancer have altered oral, vaginal and gut microbiomes, respectively.

New technological advances have led to identification of a diverse community of bacteria within the bladder, the urinary microbiome. Leveraging these tools, a research team that includes Children’s National Health System investigators studied whether an experimental model’s urinary bacterial community changed as bladder cancer progressed, evolving from a microbiome into a urinary “oncobiome.”

To test the hypothesis, the research team led by Michael H. Hsieh, M.D., Ph.D., a Children’s urologist, exposed an experimental model of bladder cancer to a bladder-specific cancer-causing agent, n-butyl-n-(4-hydroxybutyl) nitrosamine (BBN). Bladder cancers induced by BBN closely resemble human cancers in tissue structure at the microscopic level and by gene expression analyses. Ten of the preclinical models received a .05 percent concentration of BBN in their drinking water over five months and were housed together. Ten other experimental models received regular tap water and shared a separate, adjacent cage.

Researchers collected urine samples ranging from 10 to 100 microliters at the beginning of the longitudinal study, one week after it began, then once monthly. They isolated microbial DNA from the urine and quantified it to determine how much DNA was microbial. All of the bladders from experimental models exposed to BBN and two bladders from the control group were analyzed by a pathologist trained in bladder biology.

According to the study published online July 5, 2018, by the biology preprint server Biorxiv, they found a range of pathologies:

  • Five of the experimental models that received BBN did not develop cancer but had histology consistent with inflammation. Three had precancer on histology: urothelial dysplasia, hyperplasia or carcinoma in situ. Two developed cancer: invasive urothelial carcinomas, one of which had features of a squamous cell carcinoma.
  • The experimental model that developed invasive carcinoma had markedly different urinary bacteria at baseline, with Rubellimicrobium, a gram negative organism found in soil that has not been associated with disease previously, Escherichia and Kaistobacter, also found in soil, as the most prominent bacteria. By contrast, in the other experimental models the most common urinary bacteria were Escherichia, Prevotella, Veillonella, Streptococcus, Staphyloccoccus and Neisseria.
  • By month four, the majority of experimental models exposed to BBN had significantly higher proportion of Gardnerella and Bifidobacterium compared with their control group counterparts.

“Closely analyzing the urinary bacterial community among experimental models exposed to BBN, we saw distinct differences in microbial profiles by month four that were not present in earlier months,” Dr. Hsieh says. “While Gardnerella is associated with the development of cancer, Bifidobacterium has been shown to exert antitumor immunity, and its increasing abundance points to the need for additional research to understand its precise role in oncogenesis.”

Dr. Hsieh adds that although the study is small, its findings are of significance to children who are prone to developing urinary tract infections (UTIs), including children with spina bifida, due to the association between UTIs and bladder cancer. “This work is important because it not only suggests that the urinary microbiome could be used to diagnose bladder cancer, but that it could also perhaps predict cancer outcomes. If the urinary microbiome contributes to bladder carcinogenesis, it may be possible to favorably change the microbiome through antibiotics and/or probiotics in order to treat bladder cancer.”

In addition to Dr. Hsieh, co-authors include Catherine S. Forster, M.D., M.S., and Crystal Stroud, of Children’s National; James J. Cody, Nirad Banskota, Yi-Ju Hsieh and Olivia Lamanna, of the Biomedical Research Institute; Dannah Farah and Ljubica Caldovic, of The George Washington University; and Olfat Hammam, of Theodor Bilharz Research Institute.

Research reported in this news release was supported by the National Institutes of Health under award number R01 DK113504 and the Margaret A. Stirewalt Endowment.

Yuan Zhu

The brain tumor field moves forward with new findings and a research grant

Yuan Zhu

Yuan Zhu, Ph.D., and other experts completed new research findings evaluating the effects of manipulating the growth-promoting signaling pathways in brain tumors associated with adults and children.

This month, experts at Children’s National Health System made great strides in brain tumor research, specifically in gliomas, glioblastomas and medulloblastomas. Led by Yuan Zhu, Ph.D., the scientific director and Gilbert Endowed Professor of the Gilbert Family Neurofibromatosis Institute and Center for Cancer and Immunology Research at Children’s National, the team completed new research findings evaluating the effects of manipulating the growth-promoting signaling pathways in brain tumors associated with adults and children. Dr. Zhu’s research was recently published in Cell Reports and he was also awarded a U.S. Department of Defense (DoD) grant to gain a better understanding of how low-grade gliomas form. Together, this work moves the needle on developing more effective treatments for these debilitating and life-threatening tumors.

The study

In his recently published paper, Dr. Zhu and his colleagues, including Drs. Seckin Akgul and Yinghua Li, studied glioblastomas, the most common brain tumor in adults, and medulloblastomas, the most common brain tumor found in children, in genetically engineered experimental models. Dr. Zhu found that when they removed the p53 gene (the most commonly mutated tumor suppressor gene in human cancers) in the experimental model’s brain, most developed malignant gliomas and glioblastomas, while Sonic Hedgehog (SHH)-subtype (SHH) medulloblastomas were also observed. They further suppressed the Rictor/mTorc2 molecular pathway that is known in the regulation of tumor growth. This action greatly reduced the incidence of malignant gliomas and extended the survival of the models, validating the concept that Rictor/mTorc2 could be a viable drug target for this lethal brain cancer in adults.

The study also found that the same Rictor/mTorc2 molecular pathway serves the opposite function in SHH medulloblastoma formation, acting as a tumor suppressor. Findings suggest that if the same drug treatment is used for treating SHH medulloblastoma in children, it could potentially have an adverse effect and promote growth of the tumors.

Ultimately, the study demonstrates that Rictor/mTORC2 has opposing functions in glioblastomas in adults and SHH medulloblastomas in children. While drug therapies targeting Rictor/mTORC2 may be successful in adults, the findings reveal the risks of treating children with pediatric brain tumors when using the same therapies.

The grant

Continuing the study of brain tumors, Dr. Zhu recently received a $575,000 grant from DoD to research benign gliomas, with the hope of gaining a greater understanding of how the tumors form. Low-grade gliomas, or benign brain tumors, are the most common brain tumors in children. While not lethal like their high-grade counterpart, these tumors can lead to significant neurological defects, permanently impacting a child’s quality of life. Most commonly, the tumor can impair vision, often leading to blindness.

Since the tumors only occur in children under the age of eight, Dr. Zhu believes they are linked to neural stem or progenitor cells that exist in the optic nerve only during development, or when children are under eight-years-old. To test if his hypothesis is correct, Dr. Zhu will develop a preclinical model that mimics human brain tumors to study the development of the optic nerve. If his theory proves correct, Dr. Zhu’s long-term goal is to develop a strategy that prevents the tumor formation from ever occurring, ultimately preventing vision loss in children. The grant begins in July and will run for three years.

 

Brian Rood

Improving the understanding of medulloblastoma

Brian Rood

Brian Rood, M.D., employed quantitative proteomics to tumor samples that led to novel therapeutic targets for Medulloblastoma and other tumors.

In a recently published study, Brian Rood, M.D., a neuro-oncologist at Children’s National Health System, employed quantitative proteomics to tumor samples, a technique that could lead to novel therapeutic targets for medulloblastoma and other tumors in the future.

Currently, many experts use genomic characterization to understand the genetic makeup of cancer cells, which has deepened the field’s collective knowledge of tumor biology. However, it has remained challenging to infer specific information about how the tumors will respond and consequently develop more effective therapies. Medulloblastoma is the most common pediatric, malignant brain tumor. Through Dr. Rood’s research using proteomic analysis, he was able to identify and measure the protein makeup of medulloblastoma, which led to a potential pathway for clinical intervention to treat this life-threatening cancer. The findings were published online June 7, 2018, in Acta Neuropathologica Communications.

“The goal of this research was to find out how these tumor cells function at the protein level, which may ultimately help the field identify drug therapies to stop them,” says Dr. Rood. “The genes of a cancer cell are like a blueprint for a building, but the blueprints aren’t always followed in a cancer cell: Not every active gene will produce its corresponding protein. Proteins do the work of the cell, and understanding them will provide a better overall understanding of a cancer cell’s biology.”

Dr. Rood compared proteomic and genomic data to confirm that genetics do not accurately predict the quantity of proteins. By directly quantitating the proteins and comparing them between different subgroups of the disease, they were able to identify protein-based pathways driving tumor biology. With this information, Dr. Rood was able to demonstrate that medulloblastoma depends on a crucial pathway, the eukaryotic initiation factor 4F protein synthesis pathway, resulting in the identification of a potential target for new treatments in medulloblastoma.

Ultimately, Dr. Rood found that proteomic analysis complements genomic characterization and the two can be used together to create a more complete understanding of tumor biology. Going forward, he hopes proteomic analysis will become common practice for studying all tumors, allowing tumors to be categorized and grouped together by protein makeup to help the field identify more effective therapies for all tumors.

Making the grade: Children’s National is nation’s Top 5 children’s hospital

Children’s National rose in rankings to become the nation’s Top 5 children’s hospital according to the 2018-19 Best Children’s Hospitals Honor Roll released June 26, 2018, by U.S. News & World Report. Additionally, for the second straight year, Children’s Neonatology division led by Billie Lou Short, M.D., ranked No. 1 among 50 neonatal intensive care units ranked across the nation.

Children’s National also ranked in the Top 10 in six additional services:

For the eighth year running, Children’s National ranked in all 10 specialty services, which underscores its unwavering commitment to excellence, continuous quality improvement and unmatched pediatric expertise throughout the organization.

“It’s a distinct honor for Children’s physicians, nurses and employees to be recognized as the nation’s Top 5 pediatric hospital. Children’s National provides the nation’s best care for kids and our dedicated physicians, neonatologists, surgeons, neuroscientists and other specialists, nurses and other clinical support teams are the reason why,” says Kurt Newman, M.D., Children’s President and CEO. “All of the Children’s staff is committed to ensuring that our kids and families enjoy the very best health outcomes today and for the rest of their lives.”

The excellence of Children’s care is made possible by our research insights and clinical innovations. In addition to being named to the U.S. News Honor Roll, a distinction awarded to just 10 children’s centers around the nation, Children’s National is a two-time Magnet® designated hospital for excellence in nursing and is a Leapfrog Group Top Hospital. Children’s ranks seventh among pediatric hospitals in funding from the National Institutes of Health, with a combined $40 million in direct and indirect funding, and transfers the latest research insights from the bench to patients’ bedsides.

“The 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver exceptional care across a range of specialties and deserve to be highlighted,” says Ben Harder, chief of health analysis at U.S. News. “Day after day, these hospitals provide state-of-the-art medical expertise to children with complex conditions. Their U.S. News’ rankings reflect their commitment to providing high-quality care.”

The 12th annual rankings recognize the top 50 pediatric facilities across the U.S. in 10 pediatric specialties: cancer, cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastrointestinal surgery, neonatology, nephrology, neurology and neurosurgery, orthopedics, pulmonology and urology. Hospitals received points for being ranked in a specialty, and higher-ranking hospitals receive more points. The Best Children’s Hospitals Honor Roll recognizes the 10 hospitals that received the most points overall.

This year’s rankings will be published in the U.S. News & World Report’s “Best Hospitals 2019” guidebook, available for purchase in late September.