Jan 12 2015

Researchers Lay Groundwork for Novel Therapy for Huntington’s Disease

Huntington’s Disease

The mutant HTT protein (mHTT) damages a brain region called the striatum, resulting in involuntary movements and severe cognitive and emotional disturbances.

New findings by researchers in the Center for Cellular and Molecular Therapeutics (CCMT) at The Children’s Hospital of Philadelphia suggest that an intricate pathway crucial to the development of Huntington’s disease (HD) rests on a “biological teeter-totter” that when carefully balanced could help to control this devastating neurodegenerative disorder.

HD affects about 30,000 Americans and is an incurable, inherited disease entailing progressive loss of brain cells and motor function, usually beginning in midlife. A defective gene produces repeated copies of a protein called huntingtin, or HTT. The mutant HTT protein (mHTT) damages a brain region called the striatum, resulting in involuntary movements and severe cognitive and emotional disturbances. A key signaling protein called mTORC1 that regulates cell growth and metabolism plays a major role in HD.

In their experiments, study leader Beverly L. Davidson, PhD, director of the CCMT, and co-investigators adjusted levels of mTORC1 in mice bred to model features of HD. They injected bioengineered viruses as a gene therapy tool to carry DNA that directed the production of regulatory proteins called Rheb and Rhes that act along the mTORC1 pathway. After the researchers restored mTORC1 activity to more normal levels, brain areas that had begun to atrophy recovered volume and permitted better motor function.

“It was particularly exciting to see plasticity in the neurons impaired by mHTT,” said Dr. Davidson, who also is on the faculty of the Perelman School of Medicine at the University of Pennsylvania. “This shows that brain cells are capable of responding even after disease onset and hints at the potential for reversing Huntington’s disease.”

She added that restoring proper balance to these delicate biological processes may offer even broader benefits in treating other neurological diseases, such as amyotrophic lateral sclerosis (ALS), fragile X mental retardation, and autism. Fragile X mental retardation and autism both feature overactive mTORC1 activity, while mTORC1 is reduced in ALS and HD.

“This pathway is poised on a biological teeter-totter, and our work highlights that it’s essential to control its activity to find the appropriate balance for each disease,” Dr. Davidson said.

In the future, the research team will focus on increasing their understanding of how they can carefully manipulate the dysregulated pathway to treat HD, with the goal of finding a potential drug therapy. Much work remains, as researchers must identify drug candidates that appropriately activate the mTORC1 pathway. Although gene therapy vectors were used for this research, Dr. Davidson envisions developing a small molecule that can appropriately modulate this pathway. Such a treatment might be combined with a gene therapy approach, also being pursued by her team and other groups, delivered directly to the brain to curtail mHTT expression.

The study team published its results online Dec. 31 in the journal Neuron. They performed a substantial part of this research in Dr. Davidson’s laboratory at the University of Iowa, before she and many of her colleagues moved to CHOP in 2014. John H. Lee, the paper’s first author, remains at the University of Iowa, where he is completing his MD/PhD training. For more information about their research, a press release is available.

The National Institutes of Health and the Roy J. Carver Trust supported this study.

Permanent link to this article: http://www.research.chop.edu/blog/researchers-lay-groundwork-novel-therapy-huntingtons-disease/

Jan 09 2015

Research Improves Training, Assessment of Teen Driving Skills

teen drivingA recent article in the Wall Street Journal on “one of the most dreaded rites of child-rearing — teaching a teenager to drive” — notes recent research on teen driving and training can help teens learn to be better drivers and so avoid accidents. The article touches on studies by Center for Injury Research and Prevention (CIRP) staff: one that examined a web-based intervention, and a more recent investigation of teen driving error frequency.

Though many parents do a good job of teaching the basics of driving — “steering, parking, and controlling the car” — the Wall Street Journal article notes that parents “are not so good, however, at teaching the skills young drivers need to actually avoid accidents, according to new research. Now, there are new techniques and even guides that have grown out of new scientific research into the parent-child dynamic in the car.”

Two studies cited by the Wall Street Journal article were led by CIRP experts. In August, JAMA Pediatrics published a study authored by Jessica Mirman, PhD, that examined the effectiveness of the web-based Teen Driving Plan (TDP) tool in improving teen driving performance as measured by the Teen On-road Driving Assessment (tODA).

Along with the Center for Injury Research and Prevention’s Allison E. Curry, PhD, MPH, and Flaura K. Winston, MD, PhD, among others, Dr. Mirman measured the TDP’s effectiveness in increasing the quantity of practice and teens’ driving performance in 217 teen-parent dyads. The dyads were randomized to receive either the TDP or standard Pennsylvania driver manuals.

She found that the “dyads reported more practice in 5 of the 6 environments and at night and in bad weather compared with control dyads.” In addition, fewer teenagers who used the TDP had their tODA’s terminated for safety reasons than did the control group, who received PA manuals. The study’s “evidence suggest that the TDP improves supervised practice and the driving performance of prelicensed teenaged drivers,” the study author’s notes.

Indeed, as the Wall Street Journal article notes, one parent who participated in Dr. Mirman’s study says the TDP helped improved her driving lessons. “Having a game plan to work with, and to be accountable for, was better,” said Monica Pica.

The second study, led by Dennis Durbin, MD, MSCE, director of CHOP Research’s Office of Clinical and Translational Research, follows Dr. Mirman’s work by investigating driving errors made by teens during their learner’s permit period. This study, published in Accident Analysis & Prevention, used the tODA at 12 and 24 weeks of study to examine driving errors in teen and adult drivers.

Dr. Durbin and colleagues found that 55 percent of novice teen drivers committed “critical errors” at the 12-week tODA and 54 percent committed errors on the 24-week tODA. Only one experienced adult driver committed a critical error at 12 weeks and one at 24 weeks.

“In comparison to a group of experienced adult drivers, a substantially higher proportion of learner teens committed safety-relevant critical driving errors at both time points of assessment,” the authors note. The finding, they write, “suggest further research is needed to better understand how teens might effectively learn skills necessary for safe independent driving while they are still under supervised conditions.”

To read more, see the Wall Street Journal article, “Better Ways to Teach Teens to Drive.” And to learn more about the research being conducted at the Center for Injury Research and Prevention, see the CIRP website.

Permanent link to this article: http://www.research.chop.edu/blog/research-improves-training-assessment-teen-driving-skills/

Jan 07 2015

CHOP Expert Elected to Scoliosis Research Society Presidency

Scoliosis Research SocietyThe Children’s Hospital of Philadelphia’s John P. Dormans, MD, FACS, was recently elected to the presidency of the Scoliosis Research Society’s board of directors. The former chief of Children’s Hospital’s Division of Orthopedics and a professor of Orthopedic Surgery at the Perelman School of Medicine, Dr. Dormans is an internationally recognized orthopedic surgeon and spine disorder researcher.

A condition in which the spine is curved sideways, scoliosis is most often seen in late childhood and adolescence, and is more common in girls than boys. There are several different types of scoliosis, including congenital, neuromuscular (when it is associated with cerebral palsy or another condition), and idiopathic scoliosis, or that of largely unknown origin. Idiopathic scoliosis affects approximately 2 to 3 percent of the U.S. population, about 9 million Americans.

The Scoliosis Research Society is a premier organization of roughly 1200 leading spine surgeons and researchers from more than 50 countries. Since it was founded in 1966, according to the Society’s website the Scoliosis Research Society “has maintained a commitment to research and education in the field of spinal deformities.” Dr. Dormans’ fellow board members hail from the University of Minnesota, Johns Hopkins, and Louisville, Ky.’s Norton Leatherman Spine Center.

Scoliosis Research SocietyIn late 2014, Dr. Dormans published a series of papers on scoliosis and orthopedics, including one in the Journal of Children’s Orthopaedics on surgical management of fibrous dysplasia (a condition in which fibro-osseous tissue proliferates in bone) of the proximal femur, and a Journal of Pediatric Orthopaedics (JPO) study of scoliosis in children who have Aicardi syndrome. A rare disorder occurring mainly in females, Aicardi syndrome is characterized by brain and eye abnormalities, distinctive facial features, and recurrent seizures that can be difficult to treat.

In the JPO paper, Dr. Dormans — along with CHOP’s Emmouil Grigoriou, MD, who held a 2013-2014 Orthopedic Surgery Research Fellowship — described for the first time scoliosis in patients with Aicardi syndrome. By performing a review of records of Aicardi syndrome patients treated for scoliosis at Children’s Hospital, they found scoliosis represents “a clinically significant problem that is underdiagnosed and overshadowed by the other severe medical complications associated with the syndrome.”

“It certainly is an honor to serve as President of the Scoliosis Research Society,” Dr. Dormans said. “I look forward to working with my fellow members to advance scoliosis research and care.”

To learn more about scoliosis and other spine treatments at CHOP, see The Children’s Hospital of Philadelphia’s Spine Program.

Permanent link to this article: http://www.research.chop.edu/blog/chop-expert-elected-scoliosis-research-society-presidency/

Jan 05 2015

Researchers Study Factors That May Complicate Concussion Recovery


A subset of patients may experience a more complicated recovery that can last for months.

Recognition and diagnosis of concussions have exploded over the past decade, mainly due to increased media attention on how professional sports teams deal with these serious injuries. Nearly 173,000 children and adolescents are seen in emergency departments annually for sports- and recreation-related traumatic brain injuries (TBI), including concussions, according to the Centers for Disease Control and Prevention.

“Concussions have become a hot button issue across the country,” said Daniel J. Corwin, MD, of the Division of Emergency Medicine at CHOP. “We have become much more aware and adept at concussion diagnosis and management.”

As the number of children treated for concussions continues to increase, the evidence-based program Minds Matter developed by concussion experts at The Children’s Hospital of Philadelphia has expanded to clinicians in the emergency room and primary care practices. A concussion is a mild TBI caused by a blow or jolt to the head or body that causes the brain to shake. The injury disrupts how well the brain’s cells function and work together, and it can cause multiple symptoms, including headaches and dizziness, sleep problems, confusion, and irritability. Some symptoms are obvious and immediate, while others are more subtle and may not show up for several days.

A subset of patients may experience a more complicated recovery that can last for months. In a retrospective study published in the December issue of the Journal of Pediatrics, Dr. Corwin and colleagues investigated a broad group of characteristics that may help clinicians to identify which patients are most at risk for prolonged recovery.

“We suspect that there is something about these children that may predispose them to having poorer outcomes from concussion and longer recovery times,” Dr. Corwin said. “It is possible that even if a child has mild symptoms, they may have a longer recovery time if they have one of the pre-existing conditions or the specific types of clinical presentations that we studied.”

The study team hypothesized that patients with pre-existing mood disturbances or learning disabilities, dizziness as an initial symptom, abnormal findings upon vestibular examination, a history of prior concussion, and younger age would be associated with a more complicated recovery from concussions. They analyzed data collected via an electronic medical record query from patients aged 5 to 18 with concussion who were referred to CHOP’s sports medicine clinic.

The investigators examined several recovery outcomes, including how long on average it took for patients to be symptom-free (64 days), how long until they were fully cleared to return to learning without any academic accommodations (35 days), and how long until they were fully cleared for all activities, including sports (76 days). Overall, the study reported recovery times that were longer than the healing times estimated in previous studies among the general pediatric population (14 to 28 days).

Because it was a retrospective study, many of the differences that the researchers identified in association with specific patient characteristics did not reach statistical significance, but their findings could spark more in-depth studies of these predisposing factors. For example, the investigators found that patients with a history of anxiety and depression had prolonged recovery time and worse school outcomes.

“They may have underlying abnormalities that make their brain a little more sensitive to a given impact,” Dr. Corwin suggested as a hypothesis for future exploration.

He also anticipates that the study’s findings will prompt more research into how assessment of vestibular deficits could be incorporated into concussion exams to help with prognosis, which already is the standard for care for CHOP’s sports medicine specialists but is not done universally. The vestibular system includes parts of the inner ear and brain that help control balance and eye movements.

One element of the assessment tests near-point convergence, which determines how difficult it is for patients to see an object clearly as it moves closer. In the current study, patients who demonstrated abnormal near-point convergence ended up having prolonged symptoms and poorer school outcomes.

“Usually, an object becomes blurry at about 6 cm,” Dr. Corwin said. “We found that for some patients, an object was blurry at 10 cm to 20 cm, which can make schoolwork quite difficult.”

The study team also considered concussion patients who had difficulty looking horizontally and vertically back and forth rapidly, as they do in a classroom when taking notes. Patients with initial oculomotor abnormalities on physical examination also had prolonged symptoms and poorer school performance.

“Perhaps if these vestibular deficits are present at the initial exam, they could be markers that a concussion injury may cause more severe dysfunction,” Dr. Corwin said, adding that this is an area where researchers could help to provide future data.

Other factors that the study team associated with patients who took longer for their symptoms to resolve included those who reported dizziness or loss of consciousness at the time of injury, at least two prior concussions, and younger age, especially those 12 and under.

Future research also is needed to see how clinicians’ recommendations for physical rest and early cognitive rest — which restricts patients’ exposure to activities that may stress the brain and worsen symptoms, such as sports, schoolwork, computers, texting, or video games — could affect patient outcomes in these high risk groups.

“It can often be challenging to have patients cognitively rest,” Dr. Corwin said. “As clinicians are counseling families and following up with these patients, they can be aware of which children are at increased risk for prolonged recovery and worse outcomes, and hopefully better prepare them and set expectations from the beginning that will encourage them to rest more effectively.”

Permanent link to this article: http://www.research.chop.edu/blog/researchers-study-factors-may-complicate-concussion-recovery/

Dec 30 2014

A Year of Distinction

distinctionWe are fortunate to celebrate another year of firsts at The Children’s Hospital of Philadelphia. In 2014, the Hospital was again tied for the top spot in U.S. News & World Report’s Honor Roll of the nation’s best children’s hospitals. In addition, the publication also ranked the Perelman School of Medicine’s Department of Pediatrics—CHOP’s academic partner—No. 1 in the nation for the second year in a row, marking the 11th consecutive year that the program has been ranked first or second.

Likewise, the researchers, graduate students, technicians, coordinators, and staff that comprise The Children’s Hospital of Philadelphia Research Institute were responsible for a number of firsts and breakthroughs: a groundbreaking extracorporeal life support system for preterm infants; a new method of treating neuroblastoma with nanocarriers; and the first multicenter trial of sleep apnea in children, to name a few.

All of these stories, and many more, are detailed in this year’s CHOP Research Annual Report. Weighing in at 43 articles spread among eight sections, this year’s report focuses on the theme of “distinction” and the stories contained within echo that theme and span the research spectrum, covering everything from genetics to community programs.

In the 2014 Annual Report, you’ll find articles on preventive antibiotics; the creation of the new Penn Medicine/CHOP Friedreich’s Ataxia Center of Excellence, which will seek to advance treatments for the rare neurodegenerative condition; work to raise awareness of palliative care; and several articles on technologies that may change the face of healthcare.

The report also includes the vital statistics that show, briefly, how actively engaged Research Institute investigators are every day: lists of patents; operating expenses, grants, and publications; and a sampling of who’s who in the sprawling, thriving institution that is The Children’s Hospital of Philadelphia Research Institute.

I encourage you to peruse the 2014 CHOP Research Annual Report and continuing letting us know your stories so we can share them. This report is a testament to the diligence of everyone who is part of the growing Research Institute, whose work every day helps to ultimately improve the health of children. And that is our greatest distinction.

Philip R. Johnson, MD
Director, The Children’s Hospital of Philadelphia Research Institute
Chief Scientific Officer and Executive Vice President

Permanent link to this article: http://www.research.chop.edu/blog/year-distinction/

Dec 29 2014

Researchers Explore Parents’ Sense of Duty When Child Seriously Ill

parentsParents of children with serious illnesses often have mixed emotions fluctuating from happiness, pride, and joy to concern, fear, and anger. Add in the stress of running back and forth from the hospital, potentially trying to attend work, and taking care of other children in the family. During such tumult, how do parents concentrate on making difficult medical decisions on behalf of their children?

For more than a decade, Chris Feudtner, MD, PhD, MPH, pediatrician, epidemiologist, and ethicist at The Children’s Hospital of Philadelphia and professor of pediatrics, medical ethics, and health policy at the University of Pennsylvania, has researched how parents of seriously ill children make healthcare choices. He realized that in parallel to thinking about what is the best thing to do medically for their child, parents also place great importance on certain core duties that they believe they must fulfill in order to be a good parent for their child.

“We focus so much on the disease problems that the patient has, but we have largely neglected the inner work that the decision-maker is doing, which ultimately may be the most decisive element,” Dr. Feudtner said. “At the end of the day, parents have to feel that they did the right thing.”

In a study supported by a National Institutes of Health grant that was published early online in JAMA Pediatrics, Dr. Feudtner and colleagues reported on an experiment they conducted that used an innovative discrete-choice method to help them better understand how 12 good-parent beliefs potentially influence medical decisions. The discrete-choice technique often is used by marketing researchers who want to determine the product characteristics that are most important to customers.

Two hundred parents of seriously ill children participated in the study. From groups of four choices, the parents picked one attribute that was most important to them and one attribute that was the least important. Using software to analyze the responses, the researchers identified four sets of duties that the parents embraced:

  1. making sure my child feels loved (68 parents)
  2. focusing on my child’s health (56 parents)
  3. making informed medical care decisions and advocating for my child (55 parents)
  4. focusing on my child’s spiritual well-being (21 parents).

However, the results also revealed that parents’ views of specific attributes were diverse, which demonstrates a key point that the researchers emphasized in the JAMA Pediatrics article: “There is no single right way to be a good parent to a child with a serious illness.” They suggested that clinicians use the study’s findings to tailor their conversations with parents and provide more effective decision support by framing medical choices in ways that are most pertinent to parents’ individual aspirations.

“In supporting parents as they grapple with how to make medical decisions for their child, clinicians need to talk about the medical care that the child might receive, including the pros and cons of any particular course of action,” Dr. Feudtner said. “But they also need to talk about how the parents are feeling about themselves in trying to make these decisions.”

The study’s authors offer some practical guidance for clinicians on how to deepen these conversations with parents during clinical encounters. For example, asking, “What do you feel you need to do to be a good parent to your child?” puts the issue squarely on the table and shows parents that the clinician wants to help them in their quest to be the best parents that they can be during a difficult situation.

“We think that more frank, compassionate discussions will help families with issues that range from post-traumatic stress, to bereavement if the child does not survive, to recovery of the family if the child does improve and goes home, so that they are able to carry on in a healthier manner,” Dr. Feudtner said.

Future research projects that Dr. Feudtner is involved in will focus on how to help parents handle the stress and strain of having a child with a serious illness. He currently is seeking funding to support pilot testing of a coping kit that offers seven interventions for parents to choose from depending on their personal circumstances.

Permanent link to this article: http://www.research.chop.edu/blog/researchers-explore-parents-sense-duty-child-seriously-ill/

Dec 23 2014

Pediatric Leukemia Expert Named CCCR Director

Hunger,Stephen_blogStephen P. Hunger, MD, a nationally prominent specialist in children’s cancer, has been named the new director of the Center for Childhood Cancer Research (CCCR) and chief of the Division of Oncology. Dr. Hunger, who started Nov. 1, joins a premier, comprehensive program, staffed by internationally recognized experts in pediatric cancer who rely on the most current advances in research and treatment. In U.S. News & World Report’s most recent rankings of pediatric care specialties, CHOP’s cancer care ranked second in the nation.

“We are delighted to welcome this internationally renowned pediatric oncologist to CHOP to lead our pediatric cancer program, advancing the treatment of children, adolescents, and young adults with cancer and overseeing pediatric oncology research,” said CHOP’s Physician-in Chief and Chair of the Department of Pediatrics, Joseph St. Geme, MD. “Dr. Hunger has an impressive background as a clinician, investigator, teacher, and leader in pediatric oncology and will undoubtedly have a major impact at CHOP.”

Dr. Hunger comes to CHOP from Children’s Hospital Colorado, where he was most recently director of the Center for Cancer and Blood Disorders and holder of the Ergen Family Chair in Pediatric Cancer. He also was a professor of Pediatrics at the University of Colorado School of Medicine and the chief of the Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation.

He has a particular research interest in acute lymphoblastic leukemia (ALL), the most common childhood cancer. Recent papers include a Journal of Clinical Oncology pharmacokinetic study in acute lymphoblastic leukemia patients, an Annals of the New York Academy of Sciences paper on the development of asparaginase as an ALL treatment, and a Frontiers in Oncology review of current concepts in Philadelphia chromosome-positive ALL.

A leading member of the Children’s Oncology Group (COG), the national cooperative organization of pediatric cancer centers, Dr. Hunger has sat on numerous COG study committees, and has served as chair of the organization’s acute lymphoblastic leukemia Committee since 2008. He also has served on NIH study sections and committees of the National Cancer Institute, the American Society of Hematology, the American Society of Clinical Oncology, and numerous other foundations and groups.

Dr. Hunger has received research grants from the National Institutes of Health, the St. Baldrick’s Foundation, and the Leukemia and Lymphoma Society, among others. He has published scores of scientific articles, reviews and book chapters, and has made invited presentations throughout the world on pediatric oncology.

“I am tremendously excited by this opportunity to join one of the premier pediatric cancer programs in the world and to help CHOP develop more and better therapies toward our eventual goal of curing all pediatric cancers,” said Dr. Hunger.

To learn more about cancer care and research at The Children’s Hospital of Philadelphia, see the Center for Childhood Cancer Research site and the Cancer Center website.

Permanent link to this article: http://www.research.chop.edu/blog/pediatric-leukemia-expert-named-cccr-director/

Dec 22 2014

Alarming Problem of Noisy Patient Monitors Triggers NHLBI-Funded Study

patient monitors

Alarm fatigue is when caregivers become desensitized because too many previous alarms were insignificant, putting them at risk for missing an important alarm.

If you ever have visited a hospitalized patient, you probably heard a symphony of blips, chirps, and buzzes emanating from a variety of monitors. In fact, hundreds of alarms signal for every critically ill patient each day, but research shows that 85 percent to 99 percent of alarms do not require clinical intervention. For clinicians and nurses who must distinguish these simultaneous alarms— usually while performing other high-risk tasks —the symphony often becomes white noise.

Hospital administrators, prominent healthcare organizations, and researchers have begun to sit up and listen: The barrage of unnecessary alarms could threaten the safety of the 60,000 Americans who are treated in intensive care units each day.

The ECRI Institute, an independent nonprofit that researches the best approaches to improving patient care, named clinical alarms the No. 1 health technology hazard for 2014. In addition, the Joint Commission announced alarm management as a 2014 National Patient Safety Goal. This followed an April 2013 Sentinel Event Alert in which the Joint Commission reported 80 alarm-related deaths from 2009 to 2012 and blamed alarm fatigue as the “most common contributing factor.”

Alarm fatigue is when caregivers become desensitized because too many previous alarms were insignificant, putting them at risk for missing an important alarm. While alarm fatigue is not a new problem, the number of patients connected to alarm-based physiologic monitors has increased as medical technology has advanced, multiplying the sounds that these devices generate.

Recognizing that alarm management has become a high-priority patient safety issue, Christopher Bonafide, MD, MSCE, an attending physician at The Children’s Hospital of Philadelphia wants to lead the way in alarm fatigue research nationally, with the support of a five-year career development award he recently received from the National Heart, Lung, and Blood Institute.

“No one has actually quantified alarm fatigue in the hospital before,” Dr. Bonafide said. “We want to evaluate the relationship between the number of false alarms that nurses are exposed to and their response time to critical alarms. In doing this, we hope to learn more about the science behind alarm fatigue and discover new ways to combat it.”

Dr. Bonafide has created a video research lab that uses small GoPro cameras temporarily mounted in patients’ rooms, with families’ and nurses’ permission. Every time an alarm goes off, the research team can see exactly what happens next from multiple camera angles. They synchronize the video with monitor data to allow for objective review by experts to determine the validity of alarms and measure response time.

Dr. Bonafide hypothesizes that, “Experiencing lots of false alarms leads to alarm fatigue, and this can delay responses to alarms that might represent true signs of impending cardiac or respiratory arrest. Alarms also interrupt high-risk tasks, and that can lead to dangerous medical errors. We need to do everything we can to ensure that alarms help patients, not harm them.”

Dr. Bonafide plans to use the findings of his video analysis to support future research to evaluate interventions aimed at making alarm management safer.

Permanent link to this article: http://www.research.chop.edu/blog/alarming-problem-noisy-patient-monitors-triggers-nhlbi-funded-study/

Dec 19 2014

Benefits Persist in T Cell Therapy for Children with Relapsed Leukemia

leukemiaAcute lymphoblastic leukemia (ALL) is the most common childhood cancer and the most common childhood leukemia. Some patients with ALL have a highly aggressive form of the disease, one that causes either the cancer to recur or is resistant from the start to standard treatment.

An innovative cell therapy for this stubborn form of ALL continues to show highly promising results in children treated in a pilot clinical trial. Study leader Stephan A. Grupp, MD, PhD, a pediatric oncologist at The Children’s Hospital of Philadelphia and a professor of Pediatrics at the Perelman School of Medicine of the University of Pennsylvania, described outcomes and follow-up results of this study for pediatric patients with ALL in a press program on Dec. 6 at the annual meeting of the American Society of Hematology (ASH) in San Francisco.

Dr. Grupp, first author Shannon Maude, MD, PhD, a pediatric oncologist at CHOP and assistant professor of Pediatrics at UPenn, and colleagues reported that of the 39 children treated, 36 (92 percent) had complete responses one month after treatment. Of those 36 patients, 25 (69 percent) remained in remission at a median follow-up of 6 months after treatment. There were 10 relapses among the 36 patients with complete responses; 5 of the relapsed patients died.

The treatment is a personalized cell therapy program that reprograms a patient’s immune system and offers the potential of long-term success. At the heart of the therapy are bioengineered “hunter” T cells called CTL019 cells.

A relatively new approach in cancer treatment, this type of immunotherapy modifies T cells, the workhorses of the body’s immune system, to attack B cells, other immune cells that become cancerous in specific leukemias such as ALL. The CTL019 cells function as cancer hunters, killing the leukemia cells that normally evade regular T cell surveillance.

Researchers first extract a patient’s own T cells. They then use bioengineering techniques to reprogram each patient’s T cells into chimeric antigen receptor cells—the CTL019 cells—custom-designed to bind to a protein called CD19 that exists only on the surface of B cells. After being returned to the patient’s body, the CTL019 cells proliferate and then eliminate B cells. Moreover, they persist in the circulation, helping to guard against the cancer’s recurrence.

As the CTL019 cells potently attack leukemia cells, they also stimulate an unwanted, toxic immune response called cytokine release syndrome in patients. The care team successfully counteracted these side effects with an immunomodulating drug that had never been used for that purpose before, an approach which now has been adopted widely by cell therapy groups. In addition, because the CTL019 therapy eliminates healthy B cells along with cancerous B cells, patients must receive infusions of immunoglobin to perform the immune function provided by normal B cells.

“As we continue to follow children in this study, we see exciting results for patients who have exhausted their other treatment options,” said Dr. Grupp, who is an ongoing collaborator with colleagues at Penn Medicine, led by Carl H. June, M.D., who offer this personalized cell therapy as a treatment for adult patients with other types of cancer.

The first child to undergo this therapy, 9-year-old Emily Whitehead, remains cancer-free since her T cell treatment in April 2012, and continues to enjoy normal childhood activities like going to school and playing with her dog, Lucy. Emily has appeared prominently in news stories since her doctors announced dramatic findings during the December 2012 ASH meeting.

“Our results show that these engineered ‘hunter’ cells greatly expand in patients, producing very high complete response rates that then persist in patients, potentially allowing for long-term disease control,” said Dr. Grupp. “Our next step is to conduct a Phase II, multi-site trial to assess safety and efficacy in multiple centers, which is now underway.”

This past July, the U.S. Food and Drug Administration designated the CTL019 approach as a Breakthrough Therapy, helping to expedite its progress into broader clinical trials.

In August 2012, Novartis acquired exclusive rights from Penn to CTL019. Several authors from Novartis are co-authors of the abstracts presented by Dr. Grupp and others at the ASH meeting.

Permanent link to this article: http://www.research.chop.edu/blog/benefits-persist-t-cell-therapy-children-relapsed-leukemia/

Dec 17 2014

Affordable Care Act Results in Patchwork of Coverage for Children

Affordable Care ActAn article published recently in Health Affairs is the first to investigate the Affordable Care Act’s (ACA) Essential Health Benefit (EHB) as it relates to children. The study — which was led by George Washington University’s Sara Rosenbaum, JD, and included contributions from CHOP PolicyLab experts Kathleen Noonan, JD, and David Rubin, MD, MSCE — found the EHB has resulted in a state-by-state patchwork of coverage for children and adolescents that has significant exclusions, particularly for children with developmental disabilities and other special needs.

Previous studies have compared the EHB standard more broadly to the Children’s Health Insurance Program (CHIP), but this analysis presents the detailed evidence regarding the types of exclusionary practices that limit the effectiveness of coverage for children insured through health plans sold in the individual and small group markets. CHIP “provides low-cost health coverage to children in families that earn too much money to qualify for Medicaid,” according to Healthcare.gov. As of 2013, there were roughly eight million children enrolled in CHIP nationwide, with more than 200,000 in New Jersey and 250,000 in Pennsylvania.

“The Affordable Care Act offers great promise for kids, but we are concerned that its intended benefits are not fully realized for children,” said the study’s lead author, Aimee M. Grace, MD, MPH, a pediatrician and fellow at Children’s National Health System. “We sought to understand which pediatric services are covered, and which ones are excluded, by health insurance plans in the health insurance Marketplaces.”

“Pediatric services” is one of ten benefit classes required by the Affordable Care Act that must be covered in all health insurance plans sold in the individual and small-group health insurance Marketplaces.  However, other than oral health and vision care, neither the ACA nor the regulations for implementing it define “pediatric services”.

And while the Affordable Care Act gave the U.S. Department of Health and Human Services (HHS) Secretary the ability to define a pediatric benefit standard at the national level, HHS chose instead a state-by-state benchmark plan approach akin to CHIP, which affords greater discretion to both states and payers.

In the Health Affairs study, the researchers found that the state-by-state approach has led to great variation in coverage. For example, 25 states specifically cover treatments for congenital defects, and 24 specifically include coverage for both autism spectrum disorder (at least in part) and hearing aids. There is also great variation among states regarding exclusion of certain pediatric services. For example, 13 states specifically exclude services for children with learning disabilities, and 10 states exclude speech therapy for developmental delays, stuttering, or both.

Stitching the Patchwork

“This benefit patchwork means significant state-to-state variation in what will be covered for children with special needs,” said Rosenbaum.

The analysis suggests four potential steps:

  1. Pediatric treatment limits and exclusions, particularly exclusions based on mental retardation, mental disability, or other developmental conditions, should be barred.
  2. The concept of “medical necessity” should be incorporated into the defined pediatric benefit. Medical necessity should include not only the clinical utility and appropriateness of a covered service, but also whether the service is appropriate in the pediatric developmental health context.
  3. The essential health benefits standard for pediatric services should be revised to address covered services, particularly for children with special needs, and actuarial value (the percentage that the average person can expect the plan to cover).
  4. The use of CHIP plans as a benchmark plan for pediatric services should be permitted.

HHS made a commitment to review its “benchmark plan” approach for the 2016 plan year. At this time, HHS could define a pediatric benefit standard at the national level. Establishing a benefit standard has important implications for the eight million children who currently receive their health insurance coverage through CHIP, whose funding has not been extended beyond 2015.

If this funding were not extended, many of these children would enter the Marketplaces for their insurance coverage. For these children, as well as the children already covered by plans in the Marketplaces, the appropriateness of the essential health benefits standard for children is one of the most important issues in child health policy today.

“With Congressional debate expected about whether to extend funding for CHIP beyond fiscal year 2015, how well the pediatric services element of the essential health benefits standard addresses the needs of children will be an important factor to consider,” said PolicyLab’s Noonan.

To read more, see the study abstract.

Permanent link to this article: http://www.research.chop.edu/blog/affordable-care-act-results-patchwork-coverage-children/

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