Good-Guy Bacteria May Help Cancer Immunotherapies Do Their Job

Individuals with certain types of bacteria in their gut may be more likely to respond well to cancer immunotherapy, researchers at the Harold C. Simmons Comprehensive Cancer Center found in a study of patients with metastatic melanoma.

The incidence of melanoma has been increasing over the past 40 years. Immunotherapies have dramatically improved the outlook for patients with metastatic melanoma in the past half-dozen years, but still only about half of these patients go into remission.

UT Southwestern cancer researchers analyzed the gut bacteria of 39 melanoma patients who were treated with immunotherapies and found a strong association between a good response and the presence of particular bacteria.

“Our research suggests there were certain good-guy bacteria that are needed to optimize the effectiveness of checkpoint inhibitors. These bacteria somehow prime your immune system so that it’s better able to attack cancer cells and kill them,” said senior author Dr. Andrew Koh, Associate Professor of Pediatrics and Microbiology with the Simmons Cancer Center.

Rick Spurr, former CEO of Zix, a company that provides email encryption services for banks and health care facilities, volunteered for the study that helped identify the link. The grandfather of six was diagnosed with metastatic melanoma, which was discovered on his lungs while he was fighting off a bout of pneumonia.

Mr. Spurr was treated with an every-other-week infusion of nivolumab, an immunotherapy drug that acts by lifting a brake on the immune system, allowing the body’s natural defenses to go into overdrive.

“I felt virtually no side effects from the treatment,” he said. “I started the treatment in the summer and I was skiing in November.”

Researchers found he had the beneficial gut bacteria and suspect this microbiome contributed to the outcome. As a group, patients who responded well to the immunotherapy had three specific bacteria:

  • Bacteroides thetaiotaomicron
  • Faecalibacterium prausnitzii
  • Holdemania filiformis

All three are common normal flora in the human intestinal tract.

After identifying the link, researchers looked for a potential reason for the association between the helper bacteria and immunotherapy effectiveness. “Is it something the bacteria are making? We examined metabolites in these subjects and found the strongest correlation between anacardic acid, present in cashews and mangoes, and the beneficial bacteria,” Dr. Koh said.

Researchers plan to follow up on the current research, which appears in the journal Neoplasia, with larger clinical studies.

“While these preliminary observations do not establish a firm causal connection between gut microbes and immunotherapy efficacy, they may lead eventually to a probiotic cocktail that could be given along with immunotherapy to enhance the chance of response,” said Dr. Koh, Director of Pediatric Hematopoietic Stem Cell Transplantation at UT Southwestern.

The research was supported by the Roberta I. and Norman L. Pollock Fund, the Melanoma Research Fund, the T. Boone Pickens Cancer Research Fund, the Cancer Prevention and Research Institute of Texas, and the National Institutes of Health.

The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 49 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Cancer Center includes 13 major cancer care programs. In addition, the Center’s education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 100,000 hospitalized patients, 600,000 emergency room cases, and oversee approximately 2.2 million outpatient visits a year.

Childhood obesity major link to hip diseases

New research from the University of Liverpool, published in the Archives of Disease in Childhood journal, shows a strong link between childhood obesity and hip diseases in childhood.

Significant hip deformities affect around 1 in 500 children. Slipped Capital Femoral Epiphysis (SCFE) is the most common hip disease of adolescence. The condition always requires surgery, can cause significant pain, and often leads to a hip replacement in adolescence or early adulthood.

Children with a SCFE experience a decrease in their range of motion, and are often unable to complete hip flexion or fully rotate the hip inward. Unfortunately many cases of SCFE are misdiagnosed or overlooked, because the first symptom is knee pain, referred from the hip. The knee is often investigated and found to be normal. Early recognition of SCFE is important as the deformity may worsen if the slip remains untreated.

Factors explored

In an effort to identify children at higher risk of this condition researchers from the University’s Institute of Translational Medicine, led by National Institute of Health Research (NIHR) Clinician Scientist and Senior Lecturer in Orthopaedic Surgery Daniel Perry, examined hospital and community based records to explore factors associated with SCFE, and explanations for diagnostic delays.

All of the records examined were of individuals under 16-years-of-age with a diagnosis of SCFE and whose electronic medical record was held by one of 650 primary care practices in the UK between 1990 and 2013.

Using the height and weight of children recorded in the notes at some point before the disease was diagnosed the researchers were able to identify that obese children appear at highest risk of this condition.

The study was funded by the Academy of Medical Sciences.

Best evidence

Daniel Perry, who is also an Honorary Consultant Orthopaedic Surgeon at Alder Hey Children’s Hospital, said: “This is the best evidence available linking this disease to childhood obesity – which makes this condition to be one of the only obesity-related disease that can cause life-long morbidity starting in childhood.

“A significant proportion of patients with SCFE are initially misdiagnosed and those presenting with knee pain are particularly at risk.

“Ultimately this study helps us to better understand one of the main diseases affecting the hip in childhood. Whilst we confirm a strong association with obesity, we are still unable to say that obesity causes this disease.”

One gene closer to regenerative therapy for muscular disorders

A detour on the road to regenerative medicine for people with muscular disorders is figuring out how to coax muscle stem cells to fuse together and form functioning skeletal muscle tissues. A study published June 1 by Nature Communications reports scientists identify a new gene essential to this process, shedding new light on possible new therapeutic strategies.

Led by researchers at the Cincinnati Children’s Hospital Medical Center Heart Institute, the study demonstrates the gene Gm7325 and its protein – which the scientists named “myomerger” – prompt muscle stem cells to fuse and develop skeletal muscles the body needs to move and survive. They also show that myomerger works with another gene, Tmem8c, and its associated protein “myomaker” to fuse cells that normally would not.

In laboratory tests on embryonic mice engineered to not express myomerger in skeletal muscle, the animals did not develop enough muscle fiber to live.

“These findings stimulate new avenues for cell therapy approaches for regenerative medicine,” said Douglas Millay, PhD, study senior investigator and a scientist in the Division of Molecular Cardiovascular Biology at Cincinnati Children’s. “This includes the potential for cells expressing myomaker and myomerger to be loaded with therapeutic material and then fused to diseased tissue. An example would be muscular dystrophy, which is a devastating genetic muscle disease. The fusion technology possibly could be harnessed to provide muscle cells with a normal copy of the missing gene.”

Bio-Pioneering in Reverse

One of the molecular mysteries hindering development of regenerative therapy for muscles is uncovering the precise genetic and molecular processes that cause skeletal muscle stem cells (called myoblasts) to fuse and form the striated muscle fibers that allow movement. Millay and his colleagues are identifying, deconstructing and analyzing these processes to search for new therapeutic clues.

Genetic degenerative disorders of the muscle number in the dozens, but are rare in the overall population, according to the National Institutes of Health. The major categories of these devastating wasting diseases include: muscular dystrophy, congenital myopathy and metabolic myopathy. Muscular dystrophies are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. The most common form is Duchenne MD.

Molecular Sleuthing

A previous study authored by Millay in 2014 identified myomaker and its gene through bioinformatic analysis. Myomaker is also required for myoblast stem cells to fuse. However, it was clear from that work that myomaker did not work alone and needed a partner to drive the fusion process. The current study indicates that myomerger is the missing link for fusion, and that both genes are absolutely required for fusion to occur, according to the researchers.

To find additional genes that regulate fusion, Millay’s team screened for those activated by expression of a protein called MyoD, which is the primary initiator of the all the genes that make muscle. The team focused on the top 100 genes induced by MyoD (including GM7325/myomerger) and designed a screen to test the factors that could function within and across cell membranes. They also looked for genes not previously studied for having a role in fusing muscle stem cells. These analyses eventually pointed to a previously uncharacterized gene listed in the database – Gm7325.

Researchers then tested cell cultures and mouse models by using a gene editing process called CRISPR-Cas9 to demonstrate how the presence or absence of myomaker and myomerger – both individually and in unison – affect cell fusion and muscle formation. These tests indicate that myomerger-deficient muscle cells called myocytes differentiate and form the contractile unit of muscle (sarcomeres), but they do not join together to form fully functioning muscle tissue.

Looking Ahead

The researchers are building on their current findings, which they say establishes a system for reconstituting cell fusion in mammalian cells, a feat not yet achieved by biomedical science.

For example, beyond the cell fusion effects of myomaker and myomerger, it isn’t known how myomaker or myomerger induce cell membrane fusion. Knowing these details would be crucial to developing potential therapeutic strategies in the future, according to Millay. This study identifies myomerger as a fundmentally required protein for muscle development using cell culture and laboratory mouse models.

The authors emphasize that extensive additional research will be required to determine if these results can be translated to a clinical setting.

Engineering Researcher at MSU Helps Design Artificial Lung Device

Children with chronic lung diseases often must wait months or even years for a transplant, while large, immobile hospital equipment that could help them breathe easier actually may worsen their condition by overtaxing already damaged lungs.

Additionally, the required bed confinement can bring about a decline in these young patients’ overall physical and mental states.

At Mississippi State, Greg Burgreen is part of a team at the university’s Center for Advanced Vehicular Systems helping address these critical issues. With a grant from the National Institutes of Health, the associate research professor is working with colleagues at the University of Pittsburgh to develop a more portable breathing device.

Regularly referred to by its acronym, CAVS is a member research center of the university’s High Performance Computing Collaboratory (HPC2) and has developed a global reputation for interdisciplinary education and research to expand and enhance the design, technology, production and infrastructure necessary for sustainable mobility. At HPC2, Burgreen also has access to one of the world’s most advanced supercomputers.

In the project with Pittsburgh, the CAVS team is using computational prototyping to develop digital models of a device called thePediatric Paracorporeal Assist Lung. When fully developed, P-PAL, as it’s known, will be about the size of an average adult fist.

Like larger devices for oxygenating blood cells while removing carbon dioxide, P-PAL will involve tubes connected to the body via either the femoral artery or jugular vein. Though invasive, it will enable patients to be mobile during treatment and enjoy a better quality of life while awaiting lung transplants.

A doctoral graduate in mechanical engineering from Old Dominion University, Burgreen came to CAVS shortly after it opened. Previously, he spent nearly a decade with a Pittsburgh medical research team involved in a national research effort to develop an artificial heart small enough for use in infants and children.

Historically, biomedical devices have been designed and tested using physical models that have been both expensive and time-consuming to create. The rise of computer-based prototyping has made possible significantly faster and cheaper ways to develop a device and simulate operation.

Even with progress made possible by advanced computer-based technologies, Burgreen said the P-PAL project still faces major challenges. “One of the hardest things in this type of research is trying to mimic the sophistication and efficiency of human physiology without causing mechanical damage to blood,” Burgreen said.

Though clinical use by patients remains years away, Burgreen said all involved on the project in Mississippi and Pennsylvania believe P-PAL can be a major therapeutic improvement, if not a full treatment, for children with lung diseases.

“Mississippi State University is helping to improve and prolong the lives of children suffering from lung diseases,” he said.

Scientists Find Possible Achilles Heel of Treatment Resistant Cancers

Scientists identify two signaling proteins in cancer cells that make them resistant to chemotherapy, and show that blocking the proteins along with chemotherapy eliminate human leukemia in mouse models.

Reporting results March 20 in Nature Medicine, researchers at Cincinnati Children’s Hospital Medical Center suggest that blocking the signaling proteins c-Fos and Dusp1 as part of combination therapy might cure several types of kinase-driven, treatment-resistant leukemia and solid tumor cancers.

These include acute myeloid leukemia (AML) fueled by the gene FLT3, lung cancers fueled by genes EGFR and PDGFR, HER2-driven breast cancers, and BCR-ABL-fueled chronic myeloid leukemia (CML), according to Mohammad Azam, PhD, lead investigator and a member of the Division of Experimental Hematology and Cancer Biology.

“We think that within the next five years our data will change the way people think about cancer development and targeted therapy,” Azam says. “This study identifies a potential Achilles heel of kinase-driven cancers and what we propose is intended to be curative, not just treatment.”

The weak spot is a common point of passage in cells (a signaling node) that appears to be required to generate cancer cells in both leukemia and solid tumors. The node is formed by the signaling proteins c-Fos and Dusp1, according to study authors. The researchers identified c-Fos and Dusp1 by conducting global gene expression analysis of mouse leukemia cells and human chronic myeloid leukemia (CML) cells donated by patients.

CML is a blood cancer driven by an enzyme called tyrosine kinase, which is formed by the fusion gene BCR-ABL. This fusion gene is the product of translocated chromosomes involving genes BCR (chromosome 22) and ABL (chromosome 9). Analysis of human CML cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive chemotherapy resistant cells.

Cancer sleeper cells

Cancer cells often become addicted to the mutated gene that causes them, such as BCR-ABL in kinase-driven chronic myeloid leukemia. Most chemotherapies work by blocking molecular pathways affected by the gene to shut down the disease process. In the case of CML, a chemotherapy called imatinib is used to block tyrosine kinase, which initially stops the disease. Unfortunately the therapeutic benefit is temporary and the leukemia comes back.

Azam and colleagues show in their CML models that signaling from tyrosine kinase – and growth factor proteins that support cell expansion (like interleukins IL3, IL6, etc.) – converge to dramatically elevate c-Fos and Dusp1 levels in the cancer cells.

Working together these molecules maintain the survival of cancer stem cells and minimal residual disease. The dormant cells wait around under the radar screen to rekindle the disease by acquiring additional genetic mutations after initially effective chemotherapy.

Azam says Dusp1 and c-Fos support the survival of cancer stem cells by increasing the toxic threshold needed to kill them. This means conventional imatinib chemotherapy will not eliminate the residual disease stem cells. Doctors can’t just increase the dose of chemotherapy because it doesn’t target the Dusp1 and c-Fos proteins that regulate toxic threshold.

Targeting c-Fos and Dusp1

After identifying c-Fos and Dusp1, the authors tested different treatment combinations on mouse models of CML, human CML cells, and mice transplanted with human leukemia cells. They also tested treatments on B-cell acute lymphoblastic leukemia (B-ALL).

The treatment combinations included: 1) solo therapy with just the tyrosine kinase inhibitor, imatinib; 2) solo treatment with just inhibitors of c-Fos and Dusp1; 3) treatment with all three combined – imatinib along with molecular inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression but the leukemia relapsed with the continued presence of residual disease cells. Treatment with c-Fos and Dusp1 inhibitors alone significantly slowed CML progression and prolonged survival in a majority of mice but wasn’t curative. Treatment for one month with c-Fos/Dusp1 inhibitors and imatinib cured 90 percent of mice with CML, with no signs of residual disease cells.

Azam and his colleagues also point to an interesting finding involving solo treatment with just the deletion of c-Fos and Dusp1. This eliminated expression of the signaling proteins and was sufficient to block B-ALL development, eradicating the disease in mouse models.

Next steps

The authors stress that because the study was conducted in laboratory mouse models, additional research is needed before the therapeutic strategy can be tested in clinical trials.
They are following up the current study by testing c-Fos and Dusp1as treatment targets for different kinase-fueled cancers, including certain types of lung cancer, breast cancers and acute forms of leukemia.

Predicting Autism: Researchers Find Autism Biomarkers in Infancy

By using magnetic resonance imaging (MRI) to study the brains of infants who have older siblings with autism, scientists were able to correctly identify 80 percent of the babies who would be subsequently diagnosed with autism at 2 years of age.

Researchers from the University of Washington were part of a North American effort led by the University of North Carolina to use MRI to measure the brains of “low-risk” infants, with no family history of autism, and “high-risk” infants who had at least one autistic older sibling. A computer algorithm was then used to predict autism before clinically diagnosable behaviors set in. The study was published Feb. 16 in the journal Nature.

This is the first study to show that it is possible to use brain biomarkers to identify which infants in a high-risk pool — that is, those having an older sibling with autism — will be diagnosed with autism spectrum disorder, or ASD, at 24 months of age.

“Typically, the earliest we can reliably diagnose autism in a child is age 2, when there are consistent behavioral symptoms, and due to health access disparities the average age of diagnosis in the U.S. is actually age 4,” said co-author and UW professor of speech and hearing sciences Annette Estes, who is also director of the UW Autism Center and a research affiliate at the UW Center on Human Development and Disability, or CHDD. “But in our study, brain imaging biomarkers at 6 and 12 months were able to identify babies who would be later diagnosed with ASD.”

The predictive power of the team’s findings may inform the development of a diagnostic tool for ASD that could be used in the first year of life, before behavioral symptoms have emerged.

“We don’t have such a tool yet,” said Estes. “But if we did, parents of high-risk infants wouldn’t need to wait for a diagnosis of ASD at 2, 3 or even 4 years and researchers could start developing interventions to prevent these children from falling behind in social and communication skills.”

People with ASD — which includes 3 million people in the United States — have characteristic social communication deficits and demonstrate a range of ritualistic, repetitive and stereotyped behaviors. In the United States, it is estimated that up to one out of 68 babies develops autism. But for infants with an autistic older sibling, the risk may be as high as one out of every five births.

This research project included hundreds of children from across the country and was led by researchers at four clinical sites across the United States: the University of North Carolina-Chapel Hill, UW, Washington University in St. Louis and The Children’s Hospital of Philadelphia. Other key collaborators are at the Montreal Neurological Institute, the University of Alberta and New York University.

“We have wonderful, dedicated families involved in this study,” said Stephen Dager, a UW professor of radiology and associate director of the CHDD, who led the study at the UW. “They have been willing to travel long distances to our research site and then stay up until late at night so we can collect brain imaging data on their sleeping children. The families also return for follow-up visits so we can measure how their child’s brain grows over time. We could not have made these discoveries without their wholehearted participation.”

Researchers obtained MRI scans of children while they were sleeping at 6, 12 and 24 months of age. The study also assessed behavior and intellectual ability at each visit, using criteria developed by Estes and her team. They found that the babies who developed autism experienced a hyper-expansion of brain surface area from 6 to 12 months, as compared to babies who had an older sibling with autism but did not themselves show evidence of autism at 24 months of age. Increased surface area growth rate in the first year of life was linked to increased growth rate of brain volume in the second year of life. Brain overgrowth was tied to the emergence of autistic social deficits in the second year.

The researchers input these data — MRI calculations of brain volume, surface area, and cortical thickness at 6 and 12 months of age, as well as sex of the infants — into a computer program, asking it to classify babies most likely to meet ASD criteria at 24 months of age. The program developed the best algorithm to accomplish this, and the researchers applied the algorithm to a separate set of study participants.

Researchers found that, among infants with an older ASD sibling, the brain differences at 6 and 12 months of age successfully identified 80 percent of those infants who would be clinically diagnosed with autism at 24 months of age.
If these findings could form the basis for a “pre-symptomatic” diagnosis of ASD, health care professionals could intervene even earlier.

“By the time ASD is diagnosed at 2 to 4 years, often children have already fallen behind their peers in terms of social skills, communication and language,” said Estes, who directs behavioral evaluations for the network. “Once you’ve missed those developmental milestones, catching up is a struggle for many and nearly impossible for some.”

Research could then begin to examine interventions on children during a period before the syndrome is present and when the brain is most malleable. Such interventions may have a greater chance of improving outcomes than treatments started after diagnosis.

“Our hope is that early intervention — before age 2 — can change the clinical course of those children whose brain development has gone awry and help them acquire skills that they would otherwise struggle to achieve,” said Dager.

The research team has gathered additional behavioral and brain imaging data on these infants and children — such as changes in blood flow in the brain and the movement of water along white matter networks — to understand how brain connectivity and neural activity may differ between high-risk children who do and don’t develop autism. In a separate study published Jan. 6 in Cerebral Cortex, the researchers identified specific brain regions that may be important for acquiring an early social behavior called joint attention, which is orienting attention toward an object after another person points to it.

“These longitudinal imaging studies, which follow the same infants as they grow older, are really starting to hone in on critical brain developmental processes that can distinguish children who go on to develop ASD and those who do not,” said Dager. “We hope these ongoing efforts will lead to additional biomarkers, which could provide the basis for early, pre-symptomatic diagnosis and serve also to guide individualized interventions to help these kids from falling behind their peers.”

Protein Network Linked To Cancer Is Critical To Male Fertility

Researchers studying reproductive science identified a network of proteins often linked to cancer as also important to male fertility and the birth of healthy offspring, according to a study in the Oct. 18 online issue of Cell Reports.

The study by Satoshi Namewaka, PhD, and colleagues at Cincinnati Children’s Hospital Medical Center focuses on the precise epigenetic regulation of the sex chromosomes, which is important to germline cells that make male sperm.

Epigenetics involves changes in organisms caused by modifications to gene expression, rather than alterations in the genetic code. Scientists increasingly study the epigenetics of reproduction to learn how environmental exposures or lifestyle may affect fertility or inherited traits in offspring.

The current study looks at the Fanconi anemia (FA) pathway, a network of 21 proteins that normally work to repair DNA damage in the body’s cells. Mutations in the FA pathway can lead to severe anemia, genetic instability and different cancers. But the current study also uncovers roles in ensuring healthy human reproduction.

“Our data show the FA pathway regulates epigenetic programming in the germline and has an impact on reproduction,” says Namewaka, lead author in the Division of Reproductive Sciences at Cincinnati Children’s. “Understanding the exact role of FA proteins in this regulation may also be important for understanding the substantial fertility defects associated with FA and the role of FA proteins in DNA repair.”

The study is part of a much larger body of reproductive science exploring the causes of infertility, premature birth, birth defects and miscarriage – all still major health problems in the world.

Namekawa’s team reports that during meiosis – a critical biological stage for the production of genetically healthy sperm – FA proteins accumulate on the male sex chromosomes. Certain FA proteins work with an enzyme called RNF8 to regulate histones, which form the spool that DNA wraps around inside a cell’s nucleus.

The researchers tested the FA-DDR (DNA damage response) network’s regulation of this process by studying meiosis in eight different mouse models. The mice were deficient for DDR proteins, including several Fanconi anemia proteins. This allowed the research team to unravel how FA-DDR proteins function in a pathway to regulate the male sex chromosomes, a key finding in reproductive science since disrupted sex chromosome regulation results in male infertility.

Data indicate that genetically modified mice lacking FA-DDR proteins are infertile and have substantial defects in the regulation of the male sex chromosomes during meiosis.

Scientists continue their research by digging deeper into how and when FA proteins and other DNA damage response proteins interact during meiosis, and how this affects sperm production and fertility in laboratory mouse models.

In Child Heart Patients, a Novel Approach Improves Symptoms of Hazardous Lymph Blockage

Pediatric researchers have devised an innovative, safe and minimally invasive procedure that helps relieve rare but potentially life-threatening airway blockages occurring in children who had surgery for congenital heart defects.

The physician-researchers developed new imaging tools and used minimally invasive catheterization techniques to treat plastic bronchitis, a condition in which abnormal circulation causes lymphatic fluid to dry into solid casts that clog a child’s airways.

The authors reported their retrospective study of 18 children with plastic bronchitis at The Children’s Hospital of Philadelphia (CHOP), online ahead of print on Feb. 10, 2016 in Circulation, the journal of the American Heart Association.

The study, which describes the pathophysiological mechanism of plastic bronchitis and a treatment approach, arose from collaboration between Maxim Itkin, M.D., an associate professor of Radiology in the Perelman School of Medicine at the University of Pennsylvania, and Yoav Dori, M.D., a pediatric cardiologist in the Cardiac Center at The Children’s Hospital of Philadelphia. They co-lead a specialized team dedicated to the care of lymphatic disorders as part of the Center for Lymphatic Imaging and Interventions at The Children’s Hospital of Philadelphia and the Hospital of the University of Pennsylvania.

“This is a new treatment option for children with plastic bronchitis, and has the potential to offer long-term improvement of this condition,” said Dori. “This procedure may even provide cure and avoid the need for a heart transplant.”

The current study builds on the team’s 2014 article in Pediatrics, the first case report of the successful use of their technique in a patient with plastic bronchitis. “We have expanded on that study to report short-term outcomes in a larger group, and to share insights into the development of plastic bronchitis, which has been poorly understood,” said Itkin. In addition to heart patients, children and adults with idiopathic plastic bronchitis, in which the cause is unknown, have also been treated successfully using these techniques.

Itkin and Dori discovered that the primary cause of plastic bronchitis is a lymphatic flow disorder, due to abnormal lymphatic flow into lung tissue. Because physical examinations and conventional imaging may not provide specific findings, lymphatic flow disorders often go undiagnosed.

Over the past several years, Itkin and Dori developed a customized form of magnetic resonance imaging (MRI), called dynamic contrast enhanced MR lymphangiogram, to visualize the anatomy and flow pattern of a patient’s lymphatic system. This technique allows clinicians to locate the site at which lymph leaks into the airways.

Plastic bronchitis may occur in children as a rare complication of early-childhood heart surgeries used for single-ventricle disease, in which one of the heart’s pumping chambers is severely underdeveloped. Approximately 5 percent of children surviving this surgery experience plastic bronchitis because the surgery alters venous and lymphatic pressure. The authors argue that this altered pressure may interact with pre-existing anatomical differences in the patients’ lymphatic vessels.

The abnormal circulation causes lymph to ooze backward into a child’s airways, drying into a caulk-like cast formation that takes the shape of the airways. The first sign of plastic bronchitis may be when a child coughs out the cast. However, if unable to cough it up, a child may suffer fatal asphyxiation.

After identifying the leakage site in a lymphatic vessel, the lymphatic team intervenes, using a technique called lymphatic embolization. Through small catheters, the team blocks the abnormal flow with a variety of tools: coils, iodized oil, and covered stents, based on an individual patient’s needs.

In the current report, the team was able to perform lymphatic embolization in 17 of their 18 patients, ranging from age two to age 15 (median age 8.6 years). Fifteen of those 17 patients had significantly improvements in cast formation, in some cases being cast-free longer than two years. Patients had transient side effects of abdominal pain and hypotension (low blood pressure), but the authors reported the procedure appeared safe in their patient group.

Drug Candidate Halts Crippling Excess Bone Growth in Animal Model of a Rare Bone Disease

New research in laboratory animals suggests that the drug palovarotene may prevent multiple skeletal problems caused by a rare but extremely disabling genetic bone disease, and may even be a candidate for use in newborn babies with the condition. Scientists at The Children’s Hospital of Philadelphia, who previously repurposed the drug to prevent excess bone formation in animal models of fibrodysplasia ossificans progressiva (FOP), have extended that research in animals carrying the exact human disease-causing mutation.

In humans with FOP, an activating mutation in the ACVR1 gene triggers extraskeletal cartilage and bone formation and accumulation starting in early childhood. The extraskeletal bone occurs in muscles and other tissues where it does not belong. This pathological process, collectively called heterotopic ossification (HO), causes progressive loss of skeletal motion and hampers breathing and swallowing.

Currently untreatable and painful, FOP often causes death early in adulthood.

“This work represents a big step toward therapy,” said co-study leader, Maurizio Pacifici, Ph.D., a developmental biologist and director of Orthopedic Research in the Division of Orthopedic Surgery at The Children’s Hospital of Philadelphia (CHOP). “The mice used in this study were engineered to carry the human mutation that causes FOP, and the drug showed powerful and comprehensive benefits for skeletal growth and function in addition to inhibiting HO. If these results translate to humans, we may be able to treat children with FOP early in life, before the disease progresses.”

The research appeared online March 12 in the Journal of Bone and Mineral Research.

“This is the first study to show in the mouse model of FOP that the drug palovarotene inhibits and abates multiple musculoskeletal problems associated with FOP,” said co-study leader Eileen M. Shore, Ph.D., a professor in Genetics and Orthopaedics at the Center for Research in FOP and Related Disorders in the Perelman School of Medicine at the University of Pennsylvania. Another co-author from Penn Medicine, Frederick S. Kaplan, M.D., is a world expert in FOP.

Masahiro Iwamoto, D.D.S., Ph.D., also of CHOP, and a co-study leader with Pacifici and Shore, said, “This study has generated an unexpected and exciting finding, in that palovarotene appears to be better tolerated by mutant mice than control mice. If this finding translates to patients, the drug could be even safer for children with FOP than we previously realized.”

Palovarotene was originally tested in adults with emphysema. Although the drug was not then developed beyond phase 2 trials for that indication, it showed few side effects. As a retinoic acid receptor (RAR) agonist, palovarotene is a class of drug that selectively targets a regulatory pathway involved in cartilage formation. The extra bone that occurs in FOP appears first as cartilage before becoming fully mature bone cells. Iwamoto and Pacifici showed in 2011 that palovarotene inhibited HO in mouse models of genetic HO and injury-induced HO. The Department of Defense supported this research, given that injury-induced HO is prevalent in severely wounded soldiers.

The current study extended that research by using palovarotene in a novel mouse model carrying the human mutation, ACVR1 R206H, that causes most cases of FOP. The drug had potent effects—it prevented HO, and also preserved limb motion and normal bone growth in young mutant mice. The benefits for growth were a welcome surprise, said Pacifici, because palovarotene and similar retinoid agonists can impair skeletal growth—a side effect seen in control mice.

When the scientists gave palovarotene to nursing female mice, they passed along the drug’s benefit to their offspring with the mutation. If the drug’s benefits translate to humans, said Iwamoto, it could mean that newborn babies diagnosed with FOP could benefit from early treatment. “This is especially important, because once the extraskeletal bone forms in patients, it is permanent.”

A major complication of FOP it that surgeons cannot remove the excess bone tissue, because tissue damage and injury from surgery trigger even more bone formation and growth. In this study, palovarotene not only inhibited spontaneous HO, but also prevented HO when mice were experimentally injured. This is another indicator of the drug’s potential benefits for humans—possibly allowing the safe removal of previously formed HO in FOP patients and preventing HO in the general population experiencing trauma or surgery.