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Sequencing Bone Marrow DNA, Neonates, Greening Interventions, Beckwith-Wiedemann Spectrum

Published on December 10, 2021 in Cornerstone Blog · Last updated 6 months ago
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In the News

mccannn [at] chop.edu (By Nancy McCann)

With this, our final research roundup of the year, we won't disappoint, as there are plenty of studies and published papers from our busy researchers to report on. Learn about the benefits of sequencing bone marrow DNA after CAR T-cell therapy and antibiotic resistance in neonates. And find out about a study on greening interventions for child maltreatment, as well as predictors of tumors in children across the Beckwith-Wiedemann Spectrum.

Stephan Grupp, MD, PhD

Stephan Grupp, MD, PhD

Sequencing Bone Marrow DNA After CAR T-cell Therapy Accurately Predicts Leukemia Relapse

A new study conducted by Children's Hospital of Philadelphia researchers shows next-generation DNA sequencing can predict which patients with acute lymphoblastic leukemia (ALL) treated with chimeric antigen receptor (CAR) T-cell therapy will relapse. The international, multi-institution study found that using sequencing to detect biomarkers associated with residual disease was more accurate than other methods currently used to predict relapse. Blood Cancer Discovery, a journal of the American Association for Cancer Research, published the findings.

Pioneered at CHOP and the University of Pennsylvania, tisagenlecleucel is a CAR T-cell treatment that engineers a patients' own T cells to attack ALL. Approximately 82 percent to 97 percent of ALL patients treated with the therapy experience complete remissions, although about half of those patients eventually relapse and require additional treatment, such as bone marrow transplant. Accurately predicting which patients will relapse would allow researchers to treat those patients earlier — before the cancer returns. Prior to this study, there were no reliable markers to predict relapse.

The researchers used highly sensitive next-generation DNA sequencing (NGS-MRD) to scan blood and bone marrow samples for residual disease after CAR T-cell infusion. By using NGS-MRD to detect cancer cells between three and 12 months after treatment, the research team found that this method accurately predicted all patients who eventually relapsed.

"This study shows that next-generation sequencing is the most sensitive tool to predict relapse, so that we can not only seek other treatments to prevent the disease from returning in at-risk patients, but also — and just as importantly — spare those who are benefitting from initial treatment from unnecessary interventions, including bone marrow transplant," said senior author Stephan Grupp, MD, PhD, director of Translational Research in the Center for Childhood Cancer Research, director of the Cancer Immunotherapy Frontier Program, chief of the Cellular Therapy and Transplant Section, and medical director of the Cell and Gene Therapy Laboratory.

Learn more at CHOP News or this press release from the American Association for Cancer Research.

Yuan He, MD, MPH

Yuan He, MD, MPH

Can Greening Interventions Reduce Child Maltreatment?

Reductions in violent crime, feelings of depression and stress, and improvements in social cohesion have been demonstrated in research as clear benefits to the neighborhoods in which greening — the planting of grass, trees, and vegetation to create parks or community gardens — interventions occur. Our own Yuan He, MD, MPH, an affiliate trainee at PolicyLab, attending physician in the Division of General Pediatrics at CHOP's Karabots Pediatric Care Center, and a research fellow in the National Clinician Scholars Program at the University of Pennsylvania, will be studying another possible benefit of greening intervention: reduction of child maltreatment.

This study is the first to explore the association between greening and child maltreatment and is supported by CHOP's Clinical Futures, a Research Institute Center of Emphasis, and PolicyLab's Pilot Grant Awards program. It looks to evaluate the effect of greening interventions on the neighborhood risk of child maltreatment in Philadelphia, possibly identifying mechanisms to address child maltreatment risk through place-based interventions.

"As providers who care for children, we can advocate for investment in neighborhoods to better care for the children and families that live in them," Dr. He wrote in a recent Center for Injury Research and Prevention (CIRP) blog post. "Interventions that address the built environment, such as tree-planting and other greening, can not only treat whole communities, but also represent an opportunity to center racial equity by investing in historically excluded and marginalized neighborhoods."

To learn more, go to Research In Action, the CIRP's official blog.

Jennifer Kalish, MD, PhD

Jennifer Kalish, MD, PhD

Researchers Explore Predictors of Tumor Risk in Children Across Beckwith-Wiedemann Spectrum

Cancer development is a common concern among parents and physicians caring for patients with Beckwith-Wiedemann Syndrome (BWS)/Beckwith-Wiedemann Spectrum (BWSp), as it is the most common epigenetic childhood cancer predisposition disorder. To manage personal cancer risk in this population, tumor screening programs have been developed with the goal of detecting tumor growth early to reduce treatment burden and improve patient outcomes.

In a recent study, CHOP researchers set out to explore tumor development rates and characteristics associated with the history of tumor development among patients representing the full BWSp population. They worked with the dataset from CHOP's Beckwith-Wiedemann Syndrome Registry and selected patients with a confirmed molecular diagnosis of BWSp, determined by a positive test result in blood and/or tissue samples.

The researchers demonstrated that tumor risk across BWSp differs from classic BWS and that certain phenotypic features are associated with specific epigenetic causes. For instance, nephromegaly (enlarged kidney/s) and/or hyperinsulinism appear associated with cancer in some patients.

The research team also discovered that prenatal and perinatal factors, which are not currently part of the BWSp classification, may factor into tumor risk. And interestingly, blood testing results are not necessarily synonymous with tissue testing results, suggesting that a "universal risk profile" cannot be established based on the blood testing results. They concluded that the current understanding from BWS of (epi)genetics and phenotype correlations with tumors is not represented in the BWSp.

"The way we classically thought we understood BWS is not what we're actually seeing in this broader patient population," said senior author Jennifer Kalish, MD, PhD, director of the Beckwith-Wiedemann Syndrome Program of Excellence, "and therefore further work is needed to determine how to quantify tumor risk in patients in the broader Beckwith-Wiedemann Spectrum, and we need to revise the current clinical characterization."

Dustin Flannery, DO, MSCE

Dustin Flannery, DO, MSCE

Multidrug-resistant Gram-negative Infections in Neonates

Antibiotic resistance is a serious public health problem, even for the littlest of patients. Certain multidrug-resistant gram-negative (MDR-GN) infections are increasing in the neonatal population and are associated with increased risk of morbidity and mortality.

Researchers from the Clinical Futures published a review article in Pediatric Research titled "Neonatal multidrug-resistant gram-negative infection: epidemiology, mechanisms of resistance, and management," addressing this issue in the neonatal population.

Reviewing the epidemiology of MDR-GN infections in neonates in the United States and internationally, the researchers focused on extended-spectrum β-lactamase (ESBL)-producing Enterobacterales and carbapenem-resistant Enterobacterales (CRE). With published single-center studies, neonatal collaborative reports, and national surveillance data, they discussed risk factors for and mechanisms of gram-negative resistance. The team reviewed current recommendations for empiric antibiotic therapy for suspected infections, as well as definitive treatment options for key MDR organisms. They also discussed best practices for prevention, current knowledge gaps, and areas for future research, including collaborations geared toward surveillance and prevention of MDR-GN infections in neonates.

"High rates of colonization and infection from resistant gram-negative organisms in low- and middle-income countries and reports of outbreaks in higher-income countries should serve as warning signs and prompt calls to action," said first author Dustin Flannery, DO, MSCE, attending neonatologist at CHOP Newborn Care at Pennsylvania Hospital and assistant professor of pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

ICYMI

Catch up on our headlines from our November 26 In the News:

  • CDC Podcast Features New Research From Planet Lab
  • Food Allergy Experts to Launch New Clinical Trial for Eosinophilic Esophagitis
  • NORD Names CHOP and Penn a Rare Disease Center of Excellence
  • Hypothalamus Model Helps Implicate Genes Associated with Sleep, Stress, and More

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