May 09 2015

Pathways in Cornelia de Lange Syndrome Open New Possibilities

Cornelia de Lange Syndrome

May 9 is CdLS Awareness Day!

Cornelia de Lange Syndrome (CdLS) is a relatively rare developmental diagnosis that involves a constellation of symptoms affecting almost every body system in children who have the most severe form of the diagnosis. Finding out its causes could be extremely important to understanding human development at all levels, which is why Ian Krantz, MD, medical director of the Center for Cornelia de Lange Syndrome and Related Diagnosis at The Children’s Hospital of Philadelphia, and his colleagues have dedicated the past two decades to research that is piecing together the basic biology of CdLS.

A unique aspect of the studies, which have been funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), is that it is a collaboration of scientists from across the country who started out by studying yeast and then small flies called Drosophilia, continued on to analyze zebrafish and mouse models, and then translated their findings to humans.

“This is a model of how you can go from a rare diagnosis, studying it clinically, and providing excellent care to the kids and the families, and then leveraging that population for discovery to find the genes and causes, and then to move on to the next level, which would be therapeutics, and hopefully give that back to the families,” Dr. Krantz said.

In recognition of Cornelia de Lange Syndrome Awareness Day May 9, let us take a look at the projects’ history and recent findings.

Finding the First Genetic Mutation That Causes CdLS

Most children with CdLS do not inherit the disease from their families. It results from a new change in their genetic makeup, which can be tricky to find. Using DNA sequencing technology, Dr. Krantz’s study team made an exciting discovery in 2004 when they identified the first gene, NIPBL, which causes CdLS when altered or mutated.

The gene, and the pathway it controls — called cohesin — had never been known to be mutated in any other human condition, but it is essential to cell division. Humans have 23 pairs of chromosomes that are packages of DNA, a long molecule that contains our unique genetic information. When new cells are forming, two daughter cells separate at a precise moment toward the very end of cell division and are released with duplicate copies of each chromosome.

The process that holds these duplicated chromosomes together until the end of cell division is known as sister chromatid cohesion and is regulated by cohesin, a protein complex. If it is disrupted, the chromosomes cannot go into the new cells in the right number or complement, and that is generally lethal to the cells.

Creating a ‘New Realm of Biology’

Dr. Krantz’s co-investigator, Dale Dorsett, PhD, of the department of Biochemistry and Molecular Biology at St. Louis University School of Medicine, revealed in his studies of Drosophilia that NIPBL and cohesin play another integral role in gene expression, a complicated process that involves elements in DNA called regulators that act as enhancers and repressors for target genes. Basically, these regulators communicate with a region of a gene called a promotor that tells the gene when to turn on or off, what cells to turn on or off in, and how much the gene should be turned on or off.

About 60 percent of the children with CdLS have an NIPBL mutation that the study team suggests interferes with cohesin’s role in the regulation of normal gene expression, resulting in diverse genes being turned on or off at inappropriate levels in different cells during development. For example, a child’s heart cells or brain cells may not form properly because the appropriate genes are not being told to turn on at certain levels at the right time. Since sister chromatid cohesion defects are not seen in CdLS, the investigators suggest that early dysregulation of appropriate gene expression during development is what causes the symptoms seen in children with CdLS, which include limb differences, developmental delays, autistic-like behaviors, small stature, cardiac problems, and gastrointestinal issues.

“So this is a whole new realm of biology that has been created, which is cohesin’s role in gene expression regulation and development,” Dr. Krantz said. “It has many, many roles, and it’s been one of the complexes now that is at the core of all cellular processes. It’s become a very important, very basic, fundamental biologic pathway.”

Advancing Understanding of Isolated Birth Defects

In order to further understand the basic molecular determinants of structural birth defects, the next step was to build a biological model using zebrafish and mice. Developmental biologists at the University of California Irvine, Arthur Lander, MD, PhD, and his wife, Anne Calof, PhD, had a child with CdLS who had died as a newborn. They wanted to help the researchers understand how the NIPBL gene functioned. They joined Dr. Krantz and Dr. Dorsett in successfully submitting the initial grant application to the NICHD in 2006 to leverage this information to find causes for the isolated birth defects that are seen in constellation in CdLS.

Since then, the team as achieved many discoveries, including identifying four more genes that cause CdLS when mutated all involved in the cohesin pathway. The NICHD grant was renewed in 2011, which is allowing the study team to figure out if cohesin is a master switch that regulates many genes’ expression. So far, they have found about 240 genes out of 20,000 in the human genome that are significantly up or down regulated consistently among children with CdLS. The next step is to determine if any fluctuations in those genes could disrupt downstream targets that potentially interfere with normal development.

“We could use our insight into this rare diagnosis to track down causes for much more common birth defects and intellectual disability,” Dr. Krantz said.

Translating Research Into Future Treatments

The study team is not only concentrating on identification of the causes of birth defects, but they also hope to uncover ways to treat them. Since we have two copies of all of our genes — one set inherited from our mother and one set inherited from our father — when one copy of the NIPBL gene is mutated, it results in CdLS, even though there is still another normally functioning copy. Since one mutated copy is sufficient to cause CdLS, the diagnosis follows an autosomal dominant pattern of inheritance.

The study team has shown that the normal copy of NIPBL tries to compensate for the deficient copy by increasing its level to make more normal acting NIPBL protein. If NIPBL expression levels fall below 50 percent, then the cells will likely die due to sister chromatid cohesion problems.

The study team suggests that if they can identify the regulatory mechanisms that allow the normal copy of NIPBL to somehow turn up its expression up from 50 percent to 60 or 70 percent, then perhaps they could test some drugs that could boost the gene’s expression to 80 to 90 percent and potentially help to correct some of the physiological differences seen in CdLS such as intellectual disability and slow growth.

“We’re hoping that the research will result in breakthroughs that we can then give back to the families and improve the outcomes of their children,” Dr. Krantz said.

Many families who have children with CdLS helped to establish an endowment for The Center for Cornelia de Lange Syndrome and Related Diagnoses, a “medical home” that provides multidisciplinary care for children with CdLS. Their goal is to fully fund the center with an endowment of $5 million, which will allow the Center to continue its remarkable progress in advancing novel diagnostic, management, and therapeutic tools through research.

Permanent link to this article: http://blog.research.chop.edu/pathways-in-cornelia-de-lange-syndrome-open-new-possibilities/

May 08 2015

Cookies for Kids’ Cancer Funds Support Rapid Discovery of New Therapies

Cookies for Kids' CancerWhat comes from a “Box of Hope?” Inside you will find three kinds of scrumptious cookies, but what you are truly unwrapping is the potential for pediatric cancer researchers to advance novel treatments to clinical trial as quickly as possible.

Cookies for Kids’ Cancer, a nonprofit foundation dedicated to pediatric cancer research, uses the proceeds from its cookie sales and other fundraising events to provide grants to support the work of scientists at five of the nation’s leading pediatric cancer centers. The Children’s Hospital of Philadelphia has received continuous funding since the Cookies for Kids’ Cancer foundation was established in 2008. Most recently, two CHOP teams received a total of $200,000 in grants to focus on pediatric neuroblastoma and acute myeloid leukemia (AML) research.

John Maris, MD, a CHOP pediatric oncologist and the Giulio D’Angio Chair in Neuroblastoma Research, met the Cookies for Kids’ Cancer founders, Gretchen and Larry Witt, when their son, Liam, was at CHOP to receive treatment for neuroblastoma. An aggressive cancer of the peripheral nervous system that usually appears as a solid tumor in the chest or abdomen, neuroblastoma accounts for 7 percent of all childhood cancers, but it causes 15 percent of all childhood cancer deaths.

“The family saw early on that for children who have relapsed or refractory types of cancers there was a huge gap in funding,” Dr. Maris said. “There were not enough effective treatments, and the key to changing that was research.”

In the first Cookies for Kids’ Cancer bake sale, Gretchen baked and sold 96,000 cookies with the help of 250 volunteers, raising more than $400,000 for research. Since 2008, the foundation has supported four dozen childhood cancer research grants that have led to nine new treatments being tested in clinical trials.

“The foundation is unique in that it will only fund research projects where there is a tangible deliverable to the clinic,” said Dr. Maris, who also serves on the foundation’s medical advisory board and gives advice on other institutions’ projects that have the highest potential to make an impact.

That is certainly the case for Dr. Maris’ research program, which is capitalizing on findings supported by a previous Cookies for Kids’ Cancer grant that helped investigators to identify a good therapeutic target called CDK6, which is a protein that is hyperactivated in certain neuroblastoma tumors. The current grant will extend this discovery.

Some cancer cells can figure out how to escape a single drug target. Lori Hart, PhD, a senior research scientist, is leading a program within Dr. Maris’ study team and focusing on a combination approach that aims to promote the killing of neuroblastoma cells with two new drugs in development. One inhibits CDK6, while the second inhibits MEK, a molecule that is part of a signaling pathway essential to regulating many cellular processes. Dr. Hart has shown therapeutic synergy when these two drugs are used together in neuroblastoma models.

“Cells that may be a little bit sensitive to one drug or a little bit sensitive to the other drug appear to be very, very sensitive to both,” Dr. Maris said. “There is exquisite cell death in our laboratory models.”

Based on these results, Dr. Maris has proposed a clinical trial to see if the novel combination therapy shows any benefit for children with neuroblastoma whose tumors have the genetic vulnerabilities that these drugs target. He expects that about 30 percent of children with relapsed neuroblastoma will fit the genetic qualifications required to enter the trial.

Chimeric Antigen Receptor Immunotherapy for Pediatric AML

The Cookies for Kids’ Cancer foundation also is supporting drug discovery research for AML, another pediatric cancer that urgently needs new drug options to prevent relapses and improve long-term cures. AML is the second most common blood cancer in children, affecting about 500 children in the U.S. each year. Despite treatment with the most intensive multi-agent chemotherapies available, approximately 30 to 40 percent of children with AML will relapse.

“We’re just so thankful for the support from Cookies for Kids’ Cancer,” said Richard Aplenc, MD, PhD, a CHOP pediatric oncologist and Hematologic Malignancies section chief. Dr. Aplenc and his co-investigator Sarah Tasian, MD, also a CHOP pediatric oncologist and physician-scientist, are leading the study that aims to increase therapeutic strategies for AML by rigorously testing new chimeric antigen receptor T cell (CART) approaches. “This funding will make a world of difference in our research.”

A team of investigators at CHOP and the University of Pennsylvania leads the CART field in pediatric leukemias and has demonstrated remarkable success using immunotherapy for acute lymphoblastic leukemia (ALL). B-ALL is a common form of leukemia in which B cells that are found in the immune system become cancerous. The study team demonstrated in a groundbreaking trial that they could genetically program immune system T cells taken from patients’ own blood. The bioengineered “hunter” T cells, called CTL019, multiplied when they were returned to the patients’ bodies and eliminated the malignant B cells. One of the first pediatric patients to receive the investigational treatment — formerly known as CART19 — achieved a complete response and remains cancer-free now three years later.

Progress in using CART for AML, however, has proven to be more problematic so far. Many of the protein targets that researchers have identified on AML cells also appear at lower levels in normal cells that are critical to bone marrow formation. In previous studies, Dr. Tasian and colleagues have shown that CART cells can be successfully engineered to attack the protein CD123 on AML cells in mouse models, but this toxicity is long-lasting and has side effects on healthy bystander cells.

In the Cookies for Kids’ Cancer study, Drs. Aplenc and Tasian will investigate various “suicide switch” modifications to CART123 technologies that will allow effective eradication of AML but then turn off the CART cells to minimize collateral damage to healthy tissues.

“We’re looking at ways either to eliminate the T cells after they’ve killed the leukemia, perhaps with a treatment with an antibody, or even incorporation of a gene into the T cell itself that we can then turn off with a chemical or medication,” Dr. Tasian said.

In addition to finding an effective CART123 termination approach, the AML team is studying other proteins expressed by AML cells with the goal of identifying potential candidates for new CAR-based immunotherapies. Their ability to gain a better understanding of leukemia biology and explore more CAR strategies is crucial, as it is unlikely that a single agent will achieve a cure for the broad spectrum of children with AML.

Drs. Aplenc and Tasian, who are also associate and assistant professors of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, respectively, ultimately hope to develop a spectrum of innovative immunotherapies that will translate swiftly to the clinic. Based upon the team’s initial preclinical findings, a phase 1 trial of immunotherapy for pediatric AML is already under development in conjunction with co-investigators at the University of Pennsylvania.

“There is a very big need for new therapies in AML because there is not a pipeline of medications that are coming through and are available for children,” Dr. Aplenc said. “This grant is fantastic for us because its resources helped us to get started rapidly on an exciting new project.”

Sounds like both study teams are going to work up an appetite over the course of the two-year grants. Cookies, anyone?

For more information on Cookies for Kids Cancer, visit http://www.cookiesforkidscancer.org/.

Permanent link to this article: http://blog.research.chop.edu/cookies-for-kids-cancer-funds-support-rapid-discovery-of-new-therapies/

May 07 2015

Study Team Uses Virtual Visits to Help Families Transition to Home

virtual visitsClinicians at The Children’s Hospital of Philadelphia care for patients with complex medical and surgical conditions, and many rely on sophisticated technology long after they return home. The initial transition from hospital to home can be a daunting time for parents, as they take charge of operating this equipment, such as responding to ventilator alarms or keeping gastrostomy tubes in place.

A pilot quality improvement project underway at CHOP aims to reduce the emotional and operational stress on these families by conducting virtual visits via video chat on mobile devices a few days after children are discharged. Lead investigator John Chuo, MD, MS, hopes that by describing and characterizing the kind of issues that parents are facing, the implementation team will be able to better understand how telemedicine could be of value to augment the standard of care and perhaps avoid urgent care or emergency room visits and readmissions.

“The providing staff at CHOP are excellent at educating parents before discharge, but it can be overwhelming for parents who overnight become the sole caretakers for their child,” said Dr. Chuo, who is an attending neonatologist and medical director of telemedicine at CHOP. “It is a vulnerable time, for the patient and their quality of care, so we want to use telemedicine to help them make the transition.”

The research project methodology centers on a quality improvement framework, which gives investigators the flexibility to problem-solve using “plan-do-study act” cycles based on the data learned during the remote check-ins. They already have engaged several CHOP teams such as the Chronic Lung Disease Program in the Division of Neonatology, the Division of Plastic and Reconstructive Surgery, General Surgery, Home Care, and Compass Care, which seeks to improve the health of the most medically complex patients.

Those teams each have dedicated clinicians to participate in the project. Together with the telemedicine team, they will follow specific “swimlane” workflows that include identifying families willing to take part in the study, setting up parents’ mobile phones or tablets, and making appointments for the video chats before discharge. When it is time for the appointment, the clinicians will use a hosted service to connect with the families by video call and interview the parents based on a checklist of questions that are pertinent to their child’s care.

These are typical questions that would be asked via a telephone call with one addition – now, the clinicians can ask “show me” questions that may uncover issues not discoverable before with voice only calls. The items will help to reinforce education and resolve parents’ questions, focusing specifically on use of equipment and supplies, certain medical and surgical screening, compliance with medications and appointments, and unanticipated events and complications.

For example, the clinician will ask, “Are you having any problems administering the medication?” and then follow up with, “Please show me how to draw up one of your medications.” Having parents demonstrate their technique using the syringe could help to avoid medication errors. Another example is asking parents to show the clinician the child’s feeding tube site. Most mobile devices’ cameras have high enough resolution, Dr. Chuo pointed out, that the clinician potentially could see the condition of the insertion site.

Afterward, the clinician will document the virtual patient encounter in a database and communicate information to other providers, as they normally would do. Over a 12-month period, the researchers will track call rates, home visit rate, emergency room referrals, readmission rates, patient and provider satisfaction, and the number of equipment and patient issues that were identified and resolved.

In the end, Dr. Chuo expects to identify clinical scenarios where the use of video calls would have greatest value and learn how to better implement telemedicine in those situations as a way to optimize care coordination and overcome geographic barriers to access. Some families do not have an easy means of seeing a specialist should something unexpected arise, and most go to the emergency room when problems escalate.

“We are dedicated to providing children access to the right care at the right time,” Dr. Chuo said. “From a healthcare community standpoint, better and quicker access can reduce healthcare costs. The use of telemedicine has avoided patient transports by ambulance, thereby from a quality improvement perspective, it reduces travel time, which is non-value added work.”

Dr. Chuo, who also is an assistant professor of Clinical Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, is appreciative that CHOP already has in place the clinical infrastructure and support for patient care to make this project possible. He gave kudos to CHOP’s Information Technology and Telemedicine groups for facilitating the study team’s easy access to a simple-to-use, reliable communications platform. Dr. Chuo also expressed special thanks to Verizon for their ongoing financial support of telemedicine research initiatives at CHOP.

Permanent link to this article: http://blog.research.chop.edu/study-team-uses-virtual-visits-to-help-families-transition-to-home/

May 06 2015

Gynecologist’s Studies Aim to Improve Adolescent Girls’ Health

adolescent girls' healthAdolescent gynecologist Aletha Y. Akers, MD, MPH, is a busy woman. Still relatively new to CHOP, Dr. Akers has already tackled her many responsibilities with aplomb: launching Children’s Hospital’s new adolescent gynecological consult service; seeing patients in the clinic; and leading two studies: a clinical trial, and an analysis of data from two large datasets of adolescent health in the U.S.

Dr. Akers’ clinical trial, funded by a grant from Bayer Healthcare is an investigation of the new Skyla intrauterine system (IUS, also known as an IUD), which was approved by the FDA in late 2013. Her second study is supported by an award from the NIH Dr. Akers received to study the role romantic and peer relationships play in the sexual behavior of obese and non-obese adolescent girls.

After spending eight years at the University of Pittsburgh Medical Center’s Magee-Womens Research Institute, Dr. Akers came to Children’s Hospital in August 2014. In addition to being a practicing gynecologist, Dr. Akers — who is also a faculty member at PolicyLab — conducts research focused on adolescent sexual behavior and reproductive health services. She is also director of the Division of Adolescent Medicine’s new Adolescent Gynecology Consultative Services, which she will be developing in conjunction with Hospital of the University of Pennsylvania (HUP) gynecologists.

Investigating Contraceptive Pain

Dr. Akers’ Skyla IUS trial is rooted in the fact that adolescents experience the highest rates of unintended pregnancy among women of all reproductive age groups, she said. Indeed, according to CDC data, the birth rate for teens aged 15 to 19 years old outpaces that of the general population, at 26.5 live births per 1,000 versus 12.4 births per 1,000.

Long-acting reversible contraceptives like IUDs are considered first-line options for pregnancy prevention in adolescents, and are very effective at treating menstrual disorders, but their uptake remains low among adolescents, Dr. Akers noted. Many adolescents cite the fear of pain during insertion of these devices as a major barrier to adoption.

While a number of studies have examined pain control options among adult women, few have been focused on adolescent women under age 21, who are unlikely to have ever had a pelvic exam or gynecologic procedure. To that end, Dr. Akers has been leading a study of pain associated with the latest intrauterine system (IUS) to hit the market, the Skyla. Manufactured by Bayer Healthcare, the Skyla IUS is the smallest IUS currently on the market. Skyla’s smaller size could mean its insertion is less painful than other, larger IUS devices.

With this trial Dr. Akers hopes to answer the question of how effective paracervical nerve blocks, in which pain medication is injected into sites around the cervix, are at reducing IUS pain in women aged 14 to 22 years. Subjects will be randomized to receive an anesthetic versus those who will receive a “sham” paracervical block, meaning they will be touched with the end of a Q-tip rather than injected.

Because adolescents often have less experience with gynecological procedures, they have less experience with discomfort in that part of the body, and can be more wary of vaginal examinations or procedures, Dr. Akers noted. And because Skyla doesn’t carry the same minimum uterus size restrictions as other IUS devices, it could be used in adolescents who need menstrual cycle control or help with family planning, she said.

Obesity and Sexual Behavior

Where her Skyla investigation is clinical, Dr. Akers’ second project, funded by the NICHD, is data-based. Over the course of the investigation, she will be examining the role social relationships play in the sexual behavior of obese and non-obese girls. By studying large datasets, Dr. Akers and her team hope to determine whether body mass index accounts for differences in how girls develop relationships, and whether that has an impact on their sexual practices.

“There is previous literature that shows that there is a relationship between obesity and reproductive health and relationship formation for women,” noted Dr. Akers.

Adolescent obesity is associated with higher rates of sexual risk-taking and drug use. For example, a 2014 Journal of Obesity study showed obese, sexually active adolescent girls were more likely to have multiple sex partners and engage in unprotected intercourse. And work by Dr. Akers, published in Pediatrics in 2009, showed girls who perceive themselves to be overweight may be less likely to negotiate condom use and more likely to initiate sex early. Moreover, the relationship between obesity and sexual behaviors varied significantly by race.

In their current investigation, the researchers will be making use of two datasets: the Pittsburgh Girls Study which completed 14 years of data collection in 2013 and the National Longitudinal Study of Adolescent Health, which started in 1994 and is currently collecting its fifth wave of data. Both are large datasets and compliment each other.

The overall point of the work, Dr. Akers said, is to ask, “if we look at how peer relationships develop for children, and if we look more at how romantic relationships develop … is there a relationship between the two, and can we identify some key factors that begin to help us to think about how we may want to structure prevention efforts, educational efforts for these girls?”

To learn more about Dr. Akers’ work and adolescent medicine at CHOP, see the April edition of Bench to Bedside.

Permanent link to this article: http://blog.research.chop.edu/gynecologists-studies-aim-to-improve-adolescent-girls-health/

May 05 2015

New Guideline Curbs Overuse of Antibiotics for Tonsillectomies

tonsillectomyAntimicrobial resistance is spreading around the world, hampering physicians’ capacity for treating bacterial infections swiftly and reliably. Partly to blame is clinical overuse of antibiotics, so researchers are examining ways that clinicians can change or improve their antibiotic stewardship practices.

For example, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) published a guideline in 2011 recommending that “clinicians should not routinely administer or prescribe perioperative antibiotics to children undergoing tonsillectomy.”

“This is a big deal because tonsillectomy is the second most common surgical procedure in kids — each year, more than 500,000 children undergo the procedure in the U.S.,” said Jeffrey S. Gerber, MD, PhD, MSCE, an attending physician in Infectious Diseases at The Children’s Hospital of Philadelphia. “Just at CHOP and our satellite ambulatory surgical centers, we perform about 3,000 tonsillectomies per year.”

Tonsillectomy is usually an outpatient procedure in which a surgeon removes a child’s tonsils. In many cases, the reason for a child having a tonsillectomy is a history of recurrent throat infections or obstructive sleep apnea.

Prior to the implementing the AAO-HNS guideline, patients undergoing tonsillectomy at CHOP received antibiotics in the operating room and then were sent home with a prescription for three to five days of outpatient oral antibiotics. Do some quick math, and that equals about 12,000 additional patient-days of antibiotic use. Reducing children’s exposure to antibiotics not only would help to combat antimicrobial resistance, but it also would avoid antibiotics’ adverse side effects, such as allergic reactions, and reduce drug costs.

Dr. Gerber and colleagues designed a study to see what happened at CHOP after this guideline was published. If clinicians followed the guideline, did this change in practice have any effect on patients’ health? In order to assess these trends, they conducted a time series analysis, which basically is a before-and-after study that takes into account trends over time. They used data from CHOP’s shared electronic health record and narrowed it down to 5,359 routine tonsillectomy cases performed from January 2009 through August 2012.

The results showed “a dramatic decrease in perioperative antibiotic use in concordance with the guideline’s recommendation,” wrote the study’s lead author, Edmund A. Milder, MD, of the Naval Medical Center in San Diego, in JAMA Otolaryngology-Head & Neck Surgery.

The findings suggest that CHOP’s group of 10 ear, nose, and throat surgeons quickly adapted their practices to meet the new guidelines, essentially stopping cold turkey from prescribing perioperative antibiotics for tonsillectomies. The researchers reported a 91 percent decrease in perioperative antibiotic use.

“That is pretty impressive,” Dr. Gerber said. “They perform operations at three different sites, and they were all doing things in a standardized, guideline-adherent way, which was terrific.”

The potential rub of the study, however, is that the researchers uncovered a small but statistically significant increase in the rate of post-tonsillectomy bleeding in the month following guideline publication. Other clinical complications were uncommon, and there was no increase in the rate of surgery office visits, emergency department visits, or hospital admissions.

The researchers found the increased rate of bleeding surprising, Dr. Gerber said, because there is not a plausible biological mechanism to explain to why antibiotics would prevent bleeding or, on the other hand, why it would be an unintentional consequence of the practice change to decrease antibiotic use. The study team plans to investigate this unexpected outcome further in a larger, multicenter study that is underway.

“We are looking at a database of 48 children’s hospitals across the country,” said Dr. Gerber, who also is associate director for Inpatient Research Activities for CHOP’s Center for Pediatric Clinical Effectiveness and director of CHOP’s Antimicrobial Stewardship Program. “We’ll see if other hospitals, in addition to CHOP, changed their practice according to the guideline, and if so, is there a relationship between antibiotic use and post-tonsillectomy bleeding?”

The study team’s goal is to have some preliminary data ready to present at ID Week, an international infectious disease meeting being held in San Diego this October.

Mark Rizzi, MD, a CHOP otorhinolaryngologist and assistant professor of Clinical Otorhinolaryngology in the department of Head and Neck Surgery at the Perelman School of Medicine of the University of Pennsylvania; Knashawn Morales ScD, assistant professor of Biostatistics and Epidemiology at UPenn; Rachael Ross, MPH, of CHOP’s division of Infectious Diseases and the Center for Pediatric Clinical Effectiveness; and Ebbing Lautenbach, MD, MPH, MSCE, chief of the division of Infectious Diseases and associate director of the Clinical Epidemiology Unit at the Center for Clinical Epidemiology and Biostatistics at UPenn, contributed to the JAMA Otolaryngology-Head & Neck Surgery article.

Permanent link to this article: http://blog.research.chop.edu/new-guideline-curbs-overuse-of-antibiotics-for-tonsillectomies/

May 04 2015

Precision Medicine Trial to Focus on Children With Advanced Cancers

cancer treatmentWhen a clear, curative pathway is not available for pediatric cancers that relapse, families often will turn to new, experimental treatments being studied by The Children’s Oncology Group with hopes of exploring other options to care for their children. A new research opportunity under development as part of its Project:EveryChild, called Project:EveryChild Pediatric MATCH (Molecular Analysis for Therapy Choice), aims to use the power of precision medicine to potentially provide investigational therapies for some children with advanced cancers.

The Children’s Oncology Group, a collaboration of more than 220 leading children’s hospitals, universities, and cancer centers from across the globe — including The Children’s Hospital of Philadelphia — is the world’s largest organization devoted exclusively to childhood and adolescent cancer research.

Each year, nearly 13,500 children and teens are diagnosed with numerous types of cancer. Within those types of cancer, there are multiple subsets of disease. Some are harder to treat than others. Scientists suspect that the tumors involved in those stubborn cases may have different genetic alterations that help them to resist standard therapy and begin to grow.

“Pediatric MATCH will try to match genomic changes in certain children’s cancers with drugs that are either approved for adult cancers or with drugs that are still under investigation and not yet approved,” said Peter Adamson, MD, chair of the Children’s Oncology Group and a pediatric oncologist at CHOP. “The other goal is to try to understand if there is a genomic basis for when our treatments fail and how the cancers may have changed from the time of original diagnosis.”

While Pediatric MATCH is still under development, Dr. Adamson expects that the study enrollment will include about 300 children each year with advanced cancers that have progressed on standard therapy. Although only some of these children will have cancers that can be matched to a new drug, a significant aspect of Pediatric MATCH is those children with matches will be assigned to a phase II research protocol based on the genetic abnormality that seems to be fueling their disease progression, not the type of cancer.

After the child undergoes a tumor biopsy at relapse, some of the tissue will be sent to a centralized center for specific tests that may include next-generation DNA sequencing. Once investigators identify the tumor’s genomic changes and characteristics, they will sort through a group of 20 to 25 selected targeted drugs to see if one has shown some efficacy against tumors with the same genetic alterations. Should a match be found, the child will then be able to receive that drug to see if it is of some potential benefit.

“What we know to date about the genomics of cancer at diagnosis and at relapse is that perhaps there are somewhere in the order of about 15 percent of cancers that may have a finding for which we may have a drug,” Dr. Adamson said.

In a unique arrangement, the Pediatric MATCH trial is a combined effort of the Children’s Oncology Group, the National Cancer Institute (NCI), and a range of pharmaceutical companies that already have committed to providing drugs to be tested in an adult NCI MATCH Trial slated to begin this year. Dr. Adamson anticipates that many of this similar counterpart trial’s pharmaceutical agreements will carry over to Pediatric MATCH. New drugs could be added to the trials over time.

“That is of great importance to this project because all childhood cancers are rare diseases, and there generally isn’t an economic model for pharmaceutical companies to study childhood cancers,” Dr. Adamson said.

While the Children’s Oncology Group has partnered successfully in the past with companies to provide two different experimental drugs in a single research trial, Pediatric MATCH will be a significant leap beyond that model. Dr. Adamson estimates up to 10 companies will be participating in Pediatric MATCH, and each will receive information that will advance knowledge, may benefit children, and also could help the companies to accelerate their drug development.

“We hope that we will be able to see signals of efficacy that these drugs are working that would then lead to potentially additional trials that become disease-specific for that drug,” Dr. Adamson said. “Well-defined genomic testing may one day provide a lead to having a portfolio of drugs that may be of benefit to the child.”

The Pediatric MATCH study team also will share tumor analysis results with the child’s cancer specialists to help them guide the family’s treatment choices. In addition, the tissue samples will be highly valuable to future researchers as they try to explain the basis of cancer treatment failure and relapse.

“If we find that a certain pathway is very important for a disease or subset of diseases, we can build upon that and perhaps bring new treatments into that disease area, not only for relapsed cancer, but potentially to move those treatments earlier into therapy for appropriate populations,” said Dr. Adamson, who also is a professor of pediatrics and pharmacology at the Perelman School of Medicine at the University of Pennsylvania.

Pediatric MATCH is a high priority for the Children’s Oncology Group, Dr. Adamson said, with five working groups focused on an aggressive timeline of launching the trial toward the beginning of 2016.

Permanent link to this article: http://blog.research.chop.edu/precision-medicine-trial-to-focus-on-children-with-advanced-cancers/

May 01 2015

New CHOP Research Center Will Address Pediatric Health Disparities

health disparitiesThough clinicians are tasked with doing their very best to extend the same level of care to all patients, the fact remains disparities exist in care and health outcomes, especially in pediatric patients. A new center at The Children’s Hospital of Philadelphia Research Institute will seek to support these most vulnerable patients by conducting research to better understand the root of disparities — be they racial, gender-based, or caused by geography.

The Center for Perinatal and Pediatric Health Disparities Research (CPHD) will work to “identify, describe, and understand disparities in care and care practices among perinatal and pediatric patients.”

The new Center will be led by Scott Lorch, MD, MSCE, the Harriet and Ronald Lassin Endowed Chair in Pediatric Neonatology. Dr. Lorch is also director of the Neonatal-Perinatal Medicine Fellowship Program in the Division of Neonatology and Deputy Director of the Center for Outcomes Research at CHOP, as well as an associate professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.

“Research in adult patients has shown that there are extensive disparities in the care received by minority patients, particularly Hispanic and African-American patients,” said Dr. Lorch. “CPHD, through multidisciplinary academic and clinical research, aims to understand how these same disparities apply to the perinatal population, where the mother-fetal interaction is of primary importance, and the pediatric population, where family/mother-child interaction is of primary importance.”

Dr. Lorch is an ideal choice to lead the new Center, because his work — focused on health disparities, the economics and geography of healthcare, and perinatal epidemiology — dovetails nicely with the Center’s mission. In addition to currently overseeing several federally funded investigations, Dr. Lorch has contributed to recent papers in the American Journal of Obstetrics and Gynecology, Pediatrics, JAMA Pediatrics, and The American Journal of Public Health.

Other faculty associated with the new Center include Nadia Dowshen, MD; Kristin Feemster, MD, MPH, MSHP; Chén Kenyon, MD, MSHP; and Saba Khan, MD. The Center’s Associate Director is Ashley E. Martin, MPH, while Molly Passarella, MS, will perform statistical programming for the CPHD.

And though it was only recently established, the CPHD has already announced its first round of pilot project funding for junior investigators associated with CHOP. Designed to support pediatric and perinatal health disparities projects, the CPHD Pilot Grant Program “aims to engage fellows and junior faculty in HD research and to assist established faculty in developing new lines of research in this area,” said Martin.

The CPHD has also partnered with a number of community organizations and other partners to advance its goals of identifying and addressing pediatric and perinatal disparities. They range from the governmental to those in higher education, such as the University of Pennsylvania’s Netter Center for Community Partnerships, and nonprofit organizations like Public Citizens for Children and Youth.

Indeed, one of Dr. Lorch’s current investigations, on obstetric (OB) unit closures in Philadelphia, involved working with obstetric department chairs, leaders of private obstetric groups, and others to understand the impact OB unit closures can have on patients and hospital.

All of the Center for Perinatal and Pediatric Health Disparities Research’s work seeks to better understand and confront disparities. Ultimately, Dr. Lorch said, with its work the Center hopes to inspire the next generation of pediatric medical researchers to conduct health disparities research, and to start a dialogue about pediatric and perinatal health disparities, with the ultimate goal of improving outcomes for patients.

To learn more about the Center for Perinatal and Pediatric Health Disparities Research, see the April issue of Bench to Bedside.

Permanent link to this article: http://blog.research.chop.edu/new-chop-research-center-will-address-pediatric-health-disparities/

Apr 30 2015

Researchers Developing Registry for Pediatric Pulmonary Hypertension

hypertensionWhile pulmonary hypertension (PH) is a relatively rare problem in pediatrics, the frequency of the diagnosis and PH-related hospitalizations are rising. PH complicates a number of different disease processes, including congenital heart disease, chronic lung disease of prematurity, and genetic disorders. In other cases, the cause of PH may be unknown.

“Without being melodramatic, pulmonary hypertension is a massive problem in the U.S.,” said Brian Hanna, MDCM, PhD, director of the pulmonary hypertension program at The Children’s Hospital of Philadelphia that follows more 650 children and adolescents with PH. “It consumes a huge amount of resources, not just hospital beds. We consult with virtually every service in the hospital — catheterizations, echocardiograms, laboratories, pharmacy, and others.”

Pulmonary hypertension occurs when the arteries of the lungs (the pulmonary arteries) have high blood pressure. Over time, the pulmonary arteries narrow, making the right side of the heart work harder. While researchers have come a long way in the past few decades in terms of understanding the disease, there is no cure or FDA-approved therapies for pediatric PH.

“We still have more questions than answers,” said Rachel Hopper, MD an attending cardiologist in pulmonary hypertension at the CHOP Cardiac Center  and assistant professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “Who gets pulmonary hypertension? Why do they get pulmonary hypertension? Why do some children with hypertension improve over time, while others will end up needing a lung transplant? We need to collaborate as practitioners to pool enough data to answer those questions.”

That is why Dr. Hanna and Dr. Hopper are excited that The National Heart, Lung, and Blood Institute recently awarded a grant to support the nine pediatric centers, including CHOP, that are members of the Pediatric Pulmonary Hypertension Network (PPHNet) in their efforts to build an informatics registry.

For research purposes, a registry provides a shared infrastructure and standardized data collection in a single resource so that investigators can evaluate specific outcomes for a group of patients who share the same condition. For example, the PPHNet registry could help researchers determine the response of children with PH to certain therapies. On its own, an individual pediatric PH center would not be able to gather this information for a large enough number of children with PH.

Traditionally, registries are expensive to run because they require diligent maintenance to ensure that the data is precisely collected and valid for research. A unique feature of the PPHNet project is that it aims to determine if it is possible to obtain the same type of data using computer software to crawl through electronic health records (EHRs). The researchers will compare the value of both methods and determine if the data generated produce the same results upon analysis during an observational study.

As they figure out the most efficient and accurate way to collect and store registry information about children with PH, the researchers also hope to gain important insights into the causes, clinical course, and diagnostic approaches to the diverse conditions associated with PH that will lead to better treatment.

Unfortunately, many of the current care practices for children with PH are based on findings from adult studies, Dr. Hanna pointed out. Clinicians do not know, for instance, if a 13-year-old who has PH on a genetic basis and starts medicines earlier than a 35-year-old with the exact same genetic mutation will have a longer, better life.

“The concept of pooling and precisely phenotyping children is going to make a huge difference,” said Dr. Hanna, who is also a clinical professor of pediatrics for the Perelman School of Medicine at the University of Pennsylvania. “A key thing is that we eventually will be able to make diagnoses and conduct research protocols all the same way. We’ll be able to advance the science faster and understand it better, so that we’ll be to answer questions about pediatric pulmonary hypertension.”

Permanent link to this article: http://blog.research.chop.edu/researchers-developing-registry-pediatric-pulmonary-hypertension/

Apr 28 2015

Antipsychotic Use May Increase Diabetes Risk in Some Children

diabetesResearchers from The Children’s Hospital of Philadelphia’s PolicyLab recently published the largest study to date documenting the significant risks to children’s health associated with prescription antipsychotics, a powerful a class of medications used to treat mental and behavioral health disorders.

The results, which were published in JAMA Pediatrics, suggest that initiating antipsychotics may elevate a child’s risk not only for significant weight gain, but also for Type II diabetes by nearly 50 percent. Moreover, among children who are also receiving antidepressants, the risk may double. Previous PolicyLab research showed that one in three youth receiving antidepressants in the Medicaid program were receiving an antipsychotic at the same time.

In a blog post about the study, Policylab co-Director David Rubin, MD, MSCE, notes, “These new findings should give us pause. With such vast numbers of children being exposed to these medications, the implications for potential long-lasting harm can be jarring.”  Dr. Rubin is also a professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Traditionally, antipsychotics have been narrowly prescribed to children with a diagnosis of schizophrenia or bipolar disorder, or to those with significant developmental delays who were displaying aggressive behaviors that were potentially injurious to themselves or others. However, in recent years, antipsychotics are increasingly being prescribed in the absence of strong supporting safety and efficacy data to treat healthier children and adolescents with disruptive behaviors, such as those who are diagnosed with attention-deficit/hyperactivity disorder.

The JAMA Pediatrics study, which used Medicaid data on more than 1.3 million youth ages 10 to 18 with a mental health diagnosis from the Centers for Medicare and Medicaid Services, must be interpreted in the context of emerging evidence that Medicaid-enrolled children are far more likely than privately insured children to be prescribed antipsychotic medications. Overall, over 25 percent of Medicaid-enrolled children receiving prescription medications for behavioral problems were prescribed antipsychotics by 2008, largely for less severe disorders.

Despite the number of children being exposed to antipsychotics, the researchers remain cautious about over-reacting to these findings.

“We need to incorporate these new revelations about the risk for diabetes into a more thoughtful consideration of the true risks and benefits of prescribing an antipsychotic to a child,” Dr. Rubin said. “Yes, we should try, by all means possible, to minimize the numbers of children and adolescents exposed to these powerful medications. But for some children in immediate crisis, we must also concede that the benefit of the antipsychotic for acute management may still outweigh the risk.”

The study’s authors recommend that clinicians and families who are making medication decisions periodically revisit the treatment strategy to address challenging behaviors. For example, when planning to prescribe antipsychotics to a child, professional organizations recommend beginning cautiously with the lowest dose possible, while strictly monitoring for early evidence of weight gain or abnormal lab tests that often predict later onset of diabetes.

Ultimately, say Dr. Rubin and his co-authors, the prescription of antipsychotics to children and adolescents is likely to continue, reflecting a growing demand to address very challenging behaviors in children.

“At the end of the day, the approach to the individual child who is in crisis is still a case-by-case decision between a family and the treating provider,” said Dr. Rubin. “We can only hope that those decisions are made in full recognition of our findings, and that for some children, alternatives to these powerful medications—such as counseling or other supportive services, will be considered first.”

For more information about the study, see the full press release. To learn more about PolicyLab’s portfolio of work on antipsychotic medications, visit http://www.research.chop.edu/PolicyLab.

Permanent link to this article: http://blog.research.chop.edu/antipsychotic-use-may-increase-diabetes-risk-in-some-children/

Apr 27 2015

Minimal Improvement in Infants’ Neurodevelopment After Cardiac Surgery

neurodevelopmentCardiac specialists have concentrated for many years on helping high-risk infants with complex congenital heart disease (CHD) to survive surgery. As advances in surgical and perioperative care have improved their success rates dramatically, researchers, clinicians, and families now are able to turn their attention to these children’s long-term outcomes.

The most common complication for children who undergo CHD surgery in infancy is neurodevelopmental disability. Previous research has shown that they have lower abilities with reasoning, learning, executive function, inattention and impulsive behavior, language skills, and social skills compared to the general pediatric population.

The International Cardiac Collaborative on Neurodevelopment (ICCON) Investigators looked at trends over a 14-year interval in neurodevelopmental outcomes for survivors of CHD surgery. Twenty-six institutions from six countries — the U.S., Canada, Austria, New Zealand, Japan, and Switzerland — submitted study participant data for the pooled analysis project. The study team evaluated 1,770 children born between 1996 and 2009 who underwent CHD surgery, which is the largest cohort reported to date.

The investigators assessed the study participants’ scores at age 14.5 months on the Bayley Scales Version 2, a standard series of measurements that examine multiple facets of child development. They reported that these scores were significantly lower than expected compared with the general population.

“We showed that over the last 15 years, despite all the improvements in care, we have really made very little progress in improving the long-term neurodevelopmental outcomes for these kids,” said J. William Gaynor, MD, first author of a Pediatrics article that reported the ICCON investigators’ results. “Once you’re past the excitement and stress of the operation, this is what parents really care about: Is my child going to need special education? Is my child going to have attention-deficit/hyperactivity disorder? Is she going to be able to have a job? Is he going to be able to have a family? That’s what we’re trying to answer.”

The ICCON investigators will continue their worldwide collaboration to study factors that may explain the lack of greater improvement in early neurodevelopmental outcomes over the study period. The study team already is gathering data to determine if there is any relationship between intraoperative management strategies and neurodevelopmental outcomes. Another possibility is that brain development in children with CHD is immature prior to birth.

“The data here is suggestive that if you’re going to make these kids better, we’ve got to make their brains better before they’re even born,” said Dr. Gaynor, who is an attending cardiothoracic surgeon at The Children’s Hospital of Philadelphia and associate professor of surgery at the University of Pennsylvania School of Medicine. “Our goal is that when you meet these kids, if you didn’t see the scar on their chests, you would not know that they had heart surgery because they’re completely like every other kid in every other way. We’re not there yet, but this is the type of research that we need to get us there.”

The pooled data analysis project was funded by a grant from the Mend-a-Heart Foundation.

Permanent link to this article: http://blog.research.chop.edu/minimal-improvement-in-infants-neurodevelopment-after-cardiac-surgery/

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