Bench to Bedside

September 2016

Going with the Flow: How Lymphatics is Emerging as Medicine’s Newest Specialty


At first blush, the newest emerging field in medicine might sound very old: Lymphatics. Medicine has put so little emphasis on lymph, a protein-filled fluid that flows through vessels throughout most of the body, that the term can sound as archaic as doctors treating the four humors by purging blood, phlegm, or black bile. But new discoveries at The Children’s Hospital of Philadelphia and University of Pennsylvania are showing that the lymphatic system plays an understudied role in many diseases, providing new ideas for minimally invasive treatments and offering insights into other fields from neonatology to immunology.

“We have opened a small door to enormous opportunities to discover new diseases and explanations for known diseases,” said Maxim Itkin, MD, an interventional radiologist at the Hospital of the University of Pennsylvania (HUP) and director of the CHOP/HUP  Center for Lymphatic Imaging and Interventions Program, who is also an associate professor of Radiology at the Perelman School of Medicine. “And we’re already working on that.”

A team at CHOP and Penn led by Dr. Itkin and Yoav Dori, MD, PhD, a pediatric cardiologist and director of Pediatric Lymphatic Imaging and Interventions and Lymphatic Research at CHOP, caught the world’s attention this year with the publication of their results treating 18 patients with the devastating condition plastic bronchitis, in which the lungs suffuse with fluid that hardens into rubbery casts. Fifteen of the 17 patients who underwent their new intervention procedure had a significant improvement in symptoms nearly a year later, they reported in the journal Circulation. Previously, the only intervention that offered some patients long-term relief from plastic bronchitis was a heart transplant.

Drs. Itkin and Dori were the first to confirm the role of the lymphatic system in the mechanism of this disease. And their success is likely just the first of many to emerge from the team’s lymphatics discoveries.

How the Lymphatics Revolution Began

It is only an accident of history that the lymphatic system was largely ignored in modern medicine until now. The main obstacle was a lack of effective clinical imaging.

“Imaging drives many fields,” Dr. Itkin said. “The more you can see, the better you can treat.”

And the drive for better imaging in lymphatics emerged from the first treatments for the lymphatic system. Twenty years ago, one of the fathers of interventional radiology, Constantin Cope, MD, conceptualized the idea of accessing the lymphatic system through the abdomen to treat traumatic cases of a condition involving leakage of lymph into the chest, called chylothorax. This idea initially sounded like science fiction to other experts in the field, but, slowly, the concept emerged as the main treatment approach.  As Dr. Cope neared retirement, Dr. Itkin came to Penn to learn these techniques. He ultimately continued the tradition and refined the eight-hour surgical procedure into a 40-minute one.

Existing lymphatic imaging techniques at the time involved injecting imaging dye through a patient’s foot, and they were both difficult and time-consuming, while producing low-resolution imaging of the flow of lymph through the body. The small size of the vessels and the system’s unpredictable anatomy made it too hard to see contrast in the lymphatic system.

In 2012, Dr. Itkin began to make progress on a new method, the intranodal lymphangiogram. In this method, he injected dye into the lymph node in a patient’s groin, making it possible to see the lymphatic anatomy almost immediately. This technically simple replacement of a traditional lymphangiogram technique made lymphatic interventions easier to perform and more widely accepted by other physicians. But this method still lacked the level of detail of cross sectional imaging methods such as magnetic resonance imaging (MRI) and computerized tomography.

Everything changed again when, after a recreational basketball game, Dr. Itkin got into conversation with Dr. Dori, who is also an assistant professor of Pediatrics at the Perelman School of Medicine. Until that day, the pair had never worked together, and Dr. Dori had never given much thought to the lymphatic system. But Dr. Itkin had given a lot of thought to pediatric cardiology, trying for some time to find collaborators at CHOP to explore the possible role of lymphatic flows in complications of congenital heart disease.

Together, Dr. Dori and Dr. Itkin conceptualized the idea of MRI lymphangiography.  This technique utilizes the same approach as the intranodal lymphangiogram but delivers a magnetic resonance contrast agent.

“Suddenly we discover the whole world of lymphatic abnormalities,” Dr. Itkin said. “Nobody had ever done that before. We can actually light up almost the whole lymphatic system and see abnormalities there.”

How the Lymphatic System Works, Goes Awry, and Gets Fixed

The lymphatic system is a set of vessels throughout the body that collects fluids from soft tissues and organs, especially the liver and intestine. It carries those fluids to the thoracic duct, the largest lymphatic vessel, the one that was sealed off in Dr. Cope’s pioneering intervention.  From the thoracic duct, the fluid is transported back into the veins.

The first time they tried their new imaging technique on a patient with plastic bronchitis, it was immediately clear to Drs. Itkin and Dori that some lymph from the thoracic duct was leaking into the lungs — and they have since found a similar flow pattern in patients with other conditions. Dr. Itkin hypothesizes that such lymphatic leaks into the lungs are a normal variant that some people are born with, and that typically does not cause major medical problems.

But it predisposes some people to plastic bronchitis. Although plastic bronchitis can occur at any age and without any specific triggering event, doctors see it most commonly in children who have undergone a Fontan operation for congenital heart disease. The researchers suggest that this occurs because, in children who have congenital heart failure on the right side, soft tissues are congested, and the amount of fluid that the lymphatic system would normally absorb and carry away exceeds the system’s capacity. Far too much excess lymph flow can then accumulate in the lungs in patients prone to these flow leakages.

The ability to image the lymphatic system revolutionized the potential for treatments in the way imaging innovations transformed treatments in many of the body’s other systems 50 years ago. The advent of MRIs, arteriography, CAT scans, and other imaging technologies suddenly made physical abnormalities visible to physicians. Many of those abnormalities could then be treated with easy-to-explain interventions — embolizing to close off passages that should not be open, inserting stents to open those that should not be closed.

Now Drs. Dori and Itkin are treating plastic bronchitis with a minimally invasive procedure that is similarly simple to explain: While imaging the abnormal flows in a patient, they selectively embolize lymphatic passageways to stop the fluid from leaking into the lungs.

“Predictability is almost 100 percent,” Dr. Itkin said. “It’s a simple plumbing problem.”

An Exciting Future for Lymphatics and a Search for ‘Lymphomaniacs’

To expand their impact beyond plastic bronchitis, Drs. Itkin and Dori are now seeking out so-called “lymphomaniacs” from other clinical specialties at CHOP who can identify conditions that could have an unknown involvement of the lymphatic system. They are collaborating with neonatology and pulmonary divisions at CHOP to image and understand newborns with swollen limbs and children with unexplained lung diseases for possible underlying lymphatic involvement.

Often, this imaging teaches them more about how lymphatic flows are involved. Sometimes they are even able to intervene.

Their efforts have been designated as a CHOP Frontier Program, which has given the team the opportunity to further refine their imaging techniques for different areas of the body, and to establish a comprehensive research program focused on lymphatics with a prospective clinical study and a basic science research lab.

The lymph itself is opening up new possibilities for study in immunology as well.

“We now have the first-time opportunity to sample the lymphatic system from live human beings and analyze it,” Dr. Itkin said. “We are working closely with the Penn Institute for Immunology, of which CHOP is a member, with multiple studies planned and already going on to understand the immune function of the lymphatic system better than ever before. This has enormous implications in areas such as HIV and cancer immune therapy.”

For now, this intensive study and treatment innovation in lymphatics is unique to CHOP and Penn, found nowhere else in the world.

“This is kind of a new organ system,” Dr. Dori said. “It’s extraordinarily rare in medicine to fall on something like this, an organ system that has been ignored because people couldn’t see it.”

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Pediatricians May Better Help Parents Quit Smoking With Decision Support Tool


A parent’s love for a child is a powerful motivator. But when it comes to quitting smoking, often even the strongest motivation, in itself, is not enough. Only about 5 percent of smokers successfully quit each year, although many more try. That is why researchers at The Children’s Hospital of Philadelphia are refining processes and tools to help pediatricians help parents stop smoking.

“The big picture is, we’re trying to protect children, and the best way to protect a child from secondhand smoke exposure really is to help the parent quit,” said Brian Jenssen, MD, a primary care pediatrician and researcher in CHOP’s PolicyLab, who led two pilot studies of a process making it easier for pediatric clinicians to support parental smoking cessation. Findings from these studies in a primary care outpatient setting and in an inpatient setting were published this year in Pediatrics and Applied Clinical Informatics, respectively.

The work builds on decades of research showing that parents who smoke are receptive to the idea that pediatricians should address their children’s health by asking about the children’s exposure to secondhand smoke and supporting parents’ efforts to quit. The idea behind this specific effort is that there is no single magic bullet that guarantees a person will quit smoking, but there are numerous small steps that can each incrementally add to the likelihood of success. Examples include being asked by a physician about quitting, using nicotine replacement therapy (such as the patch or gum), and participating in counseling services.

“Most physicians want to encourage and support parents who wish to quit smoking, but it doesn’t fit well into our current system,” said Dr. Jenssen, who is also a faculty member in the Department of Biomedical and Health Informatics at CHOP and Instructor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Jenssen designed processes and tools built into pediatricians’ workflow to make it easier to connect parents to the right resources. This entails, first, a prompt in the child’s electronic medical record to remind pediatricians to screen for parents’ tobacco use by asking in a way that prior studies have shown to work well: “One of the best things you can do for your health and for the health of your child is to quit. What can I do to help you quit?” Next, the CHOP team’s intervention simplifies the process for pediatricians to prescribe the parent a nicotine patch or gum, if they express interest in using these therapies. Parents also receive a warm handoff to an adult tobacco treatment group to help them receive ongoing support.

The two pilot studies tested feasibility, acceptability, and usability of this clinical decision support tool and process. During the three-month pilot study at one of CHOP’s urban outpatient primary care facilities, pediatric clinicians used the tool to screen for children’s secondhand smoke exposure at more than 75 percent of patient visits. More than half of the parents present at these visits who said that they did smoke, expressed interest in quitting and were offered treatment by the clinician.

In the three-month inpatient pilot study conducted in a single hospital unit at CHOP, first-year pediatric residents used the tool to screen parents of just over half of those patients admitted to the unit who were identified as exposed to secondhand smoke. In both pilot studies, physicians who were surveyed about the tool reported that they were satisfied with it and found it helpful.

In addition, the outpatient pilot study measured the clinical impact on parents. No parents took advantage of the referral many received to an in-person smoking cessation program at the University of Pennsylvania, but by other measures, the intervention did help parents. When surveyed a few weeks after the visit to the pediatrician’s office, a large majority of parents who had expressed interest in quitting smoking reported that they were satisfied or very satisfied with the clinical visit. More than 60 percent of those surveyed said they had received a prescription for nicotine replacement, and 25 percent said they had filled the prescription and were currently using the therapy.

The potential impact for pediatricians helping parents in this way is particularly profound in high-need, lower-income communities. At the CHOP facility in Philadelphia where the outpatient pilot study was conducted, most parents are medically underserved and do not see their own medical provider. Their child’s pediatrician is the only physician they routinely see. At the same time, smoking rates are believed to be much higher in underserved communities — as many as 40 percent of adults receiving Medicaid may smoke, compared to 16 to 17 percent in the U.S. population overall. In national samples, 40 percent of children have biologically confirmed evidence of secondhand smoke exposure, and exposure rates are even higher in lower socioeconomic strata and among racial and ethnic minorities.

“In all our efforts at CHOP focused on better approaches to asthma care, reducing hospitalizations, and doing better things with preventive care to keep kids out of the hospital, we have to tackle this, too, because smoking exacerbates virtually everything,” Dr. Jenssen said.

He credits his collaborator and co-author Tyra Bryant-Stephens, MD, medical director of CHOP’s Community Asthma Prevention Program, as a kindred spirit in working to improve outcomes for children at risk for asthma and its complications, especially by reducing tobacco exposure.

Encouraged by the success of the pilot studies, the CHOP team is beginning a longer study that will connect parents with a direct referral to counseling services from Pennsylvania’s PA Free Quitline. Quitline counselors will initiate contact with parents once they are referred electronically, and parents can remain in contact via either phone calls or text messages — an advantage over the in-person counseling services that did not fit well into parents’ busy lives.

“When you help a parent quit, it reduces the majority of their children’s smoke exposure and all its associated health risk, and it also decreases the risk of their children becoming smokers when they become adults,” Dr. Jenssen said.

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Discovering How a Neurological ‘Pit Crew’ Keeps the Brain on Track


Imagine taking neuroscientists to a NASCAR race. While most spectators keep their eyes on the speeding cars, you might catch a few scientists in the crowd instead watching the activities of the pit crews at work on the sidelines, helping drivers to refuel and repair their cars to keep racing at top form. Michael Robinson, PhD, would be one of them; metaphorically, research in his lab at The Children’s Hospital of Philadelphia has followed the actions of a neurological “pit crew” with research on the functions of astrocytes, the most abundant type of cell in the brain. His team is making early-stage foundational discoveries that could profoundly influence how scientists think about how the brain works, and eventually, how they treat brain injuries and neurological diseases.

“This work has changed a lot for us,” said Dr. Robinson, a professor of Pediatrics and Systems Pharmacology and Translational Therapeutics at CHOP and the Perelman School of Medicine at the University of Pennsylvania. “I’ve been here for 28 years. This whole story is something that people are really interested in. It is very gratifying to see people so excited.”

The excitement stems in large part from the fact that scientists are only recently awakening to the importance of astrocytes. Although neurons, like race-car drivers, usually get more attention for being the site of the action in brain functions, astrocytes play a vital supporting role in refueling and repair. Astrocytes respond to the energy demands of active neurons by relaying signals to blood vessels in the brain to send more oxygen-rich blood flow. Astrocytes also supply neurons with numerous vital chemicals and clear others to facilitate crisp signaling and prevent neuronal death. While it is widely recognized now that astrocytes have these essential “pit crew” functions in support of neurons, many unknowns remain about their specific activities and how they achieve them.

New insights and even more questions are emerging now thanks to the overturning of a misconception about astrocytes within the last decade. These bushy-shaped cells have multiple spiky protrusions (called processes) reaching out into the synapses between neurons. Until just a few years ago, scientists believed that mitochondria, the structures that are the primary source of energy within cells, were only located in the astrocytes’ cell body because the processes seemed too narrow to fit them.

“Now, I think most people agree that there are mitochondria throughout these processes in vivo and in vitro,” Dr. Robinson said. “Several different labs have now seen it. That essentially changes the equation.”

Finding out what mitochondria do in the spiky outer reaches of astrocytes became a key question. One obvious answer is that they help capture more of the energy from glucose in the form of ATP, which is the classic core function of mitochondria in all cells.

By investigating the movements of mitochondria within astrocytes, a team led by Joshua Jackson, PhD, then a postdoctoral fellow in Dr. Robinson’s lab, with Dr. Robinson and graduate student John O’Donnell, found another activity for these energizing organelles. Their results, published in the Journal of Neuroscience in 2014, implied that mitochondria support astrocytes’ ability to act like a cleanup crew to remove a hazard from the race track. Specifically, mitochondria appear to be recruited to positions within the astrocyte that are both near synapses and adjacent to transporter proteins that remove glutamate (the most common neurotransmitter in the brain); this removal is essential because glutamate is toxic to neurons with prolonged exposure.

Next, O’Donnell turned his attention to how mechanisms involving astrocytes are involved in the brain’s response after stroke. In the aftermath of a stroke, astrocytes undergo certain morphological changes — but, unlike a lot of neurons, they generally survive. This has made them a compelling potential target for future drug therapies. The team’s paper published this summer in the Journal of Neuroscience details the results of in vitro experiments to understand the activities of astrocytes and their mitochondria after a simulated stroke. O’Donnell, who defends his doctoral dissertation in Pharmacology in September and will next join the lab of D. Kacy Cullen, PhD, at Penn, was the paper’s first author.

One major finding was that mitochondria in the astrocytes’ spiky processes were broken down. This was a large effect, and one that was previously unknown, involving a cellular compartment that is vital for clearing glutamate from synapses. More surprisingly, they found that blocking uptake of glutamate into astrocytes prevented that loss of mitochondria. But the researchers still know too little to interpret these changes; they do not even know if the loss of mitochondria from astrocytes is good or bad for the brain’s recovery from stroke.

“It seems that during stroke, pathologic activation of glutamate transport is driving the loss of mitochondria,” Dr. Robinson said. “I have no idea what it means.”

In addition, the researchers learned more about how mitochondria are involved in calcium signaling within astrocytes, both under normal conditions and after the simulated stroke. Calcium signaling is a key mechanism by which astrocytes call for increased blood flow to the brain (a mechanism called neurovascular coupling). The team found that, under normal conditions, mitochondria are associated with two kinds of calcium signals, both of which are highly structured. A continuous cloud of calcium ions surrounds mitochondria, representing a low-level, constant hum of conversation in areas of the astrocyte process where mitochondria are located. And, intermittently, there is a so-called extramitochondrial spike, or an instantaneous calcium signal that extends between two mitochondria within the cell — a kind of quick text message between distant neighbors.

After a simulated stroke, O’Donnell and colleagues found that those two normally well-ordered calcium signaling patterns go haywire. The calcium clouds that once surrounded mitochondria shrink as many mitochondria break down, and the remaining mitochondria get smaller. Also, the extramitochondrial spikes are no longer contained between mitochondria, but propagate on and on. The exact impact of these altered signals is unclear, but the researchers feel confident that it has effects on neurovascular coupling.

Dr. Jackson, now a staff scientist at CHOP, is embarking on in vivo imaging to understand the mechanisms by which astrocytes control blood flow. And that is just the first of many questions that are unfolding to understand an area of basic science that is largely unknown territory.

“It’s great to have a strong mitochondrial research group at CHOP; it makes it easier for us to learn about the field and get feedback on our findings,” Dr. Robinson added. “The great thing about this job is that I’m always learning new fields. I just can’t believe that we’re sitting on this right now. The next steps are pretty obvious; it will be fun to see how it works.”

Because this research is still in early stages of basic science discovery, drug approaches for brain injury and neurological disease based on these findings are likely a long way away. Still, the potential for future therapies is something many investigators are attuned to as they learn more about astrocytes.

“Astrocytes are the most abundant cell type in the brain, so it may make sense to target these cells that are so well positioned, being completely integrated with synapses and the vasculature, and that aren’t that badly harmed during this injury,” O’Donnell said.

In other words, equipping the pit crew with the resources it needs might be a good way to help a race car driver get back on track after a crash.

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Scientists Identify Molecule Controlling Inflammatory Immune Response


When bacteria or viruses invade, the body’s ability to rapidly deploy white blood cells to attack the invader is a remarkable biological feat. But these rapid-attack cells, called myeloid cells, ideally work only as first responders to keep a pathogen contained. When responding to an infection, they are generally short-lived, followed by other specialized types of immune cells, for good reason.

“Because these cells are quite unspecific in their mechanism of action, they do kill and contain bacteria, but they also generate a lot of damage in the surrounding tissue,” said Jorge Henao-Mejia, MD, PhD, an assistant professor of Pathology and Laboratory Medicine at The Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania. “For that reason, these cells are involved not only in the immunopathology after infection, but also in every chronic human disease that has an inflammatory component, such as obesity, cancer, asthma, you name it.”

Keeping those short-lived but destructive cells under control is therefore a desirable approach for reducing the harm associated with those inflammatory processes. Thanks to Dr. Henao-Mejia and his collaborators, scientists are now a step closer to doing that.

They have identified how, at the molecular level, the body regulates the short lifespan of myeloid cells, specifically eosinophils, neutrophils, and monocytes. Published in Nature in August, the team’s findings from in vitro studies and a genetically modified mouse model have implications for finding future therapies that act on the equivalent molecular pathways in human disease, especially inflammatory disorders.

“Despite the fact that, for more than 70 or 80 years it has been known that these cells exist and live only a short time, the molecular mechanism of how the lifespan of these cells is actually regulated was pretty much unknown,” Dr. Henao-Mejia said. “So I think we found a pretty important clue of how this is working.”

The first steps toward this discovery began during Dr. Henao-Mejia’s postdoctoral fellowship at Yale University. He led the discovery there of a gene that codes for an RNA molecule they named Morrbid (MyelOid RNA Regulator of Bim-Induced Death). This molecule is a long non-coding RNA, a type of molecule that cells produce by transcribing DNA into RNA that is not then translated into the production of a protein. Such molecules are the products of about 70 percent of the human genome, and the majority of their functions are unknown. (That fact may come as a surprise to those who learned the “central dogma” of biology over the past several decades, that genes code for RNA which is used to produce proteins; only about 2 percent of the human genome codes for proteins in this way.) The team at Yale also genetically engineered a mouse model that lacked Morrbid.

When Dr. Henao-Mejia started his own lab at CHOP in 2014, he led continuing studies of this molecule with several of his students. The team found that eosinophils, neutrophils, and monocytes were the specific types of cells that highly expressed Morrbid, and they discovered how it is involved in the tightly and rapidly regulated death of these cells. Essentially, when the body releases immune signaling molecules that support myeloid cell survival, these signals induce Morrbid. Morrbid, in turn, blocks the expression of a nearby “death” gene called Bim. In the absence of Morrbid, Bim regulates the programmed death of the cell — and this is what happens when survival signals are absent from the periphery and Morrbid is no longer expressed. Because the two genes, Morrbid and Bim, are nearly adjacent to each other in the DNA sequence, Morrbid can control Bim and the cell’s death process extremely rapidly. That is exactly what the body would need to retain precise control over the lifespan of myeloid cells.

Next, taking a step toward translating this finding from mice to humans, Dr. Henao-Mejia and colleagues looked at cells from human patients with hypereosinophilic syndrome, a group of inflammatory disorders often involving overactive eosinophils. In these cells, the human version of the long non-coding RNA, MORRBID, was indeed overexpressed.

“What this provides is an entry point to try to regulate inflammatory conditions by simply targeting this RNA,” Dr. Henao-Mejia said.

Dr. Henao-Mejia sees several next steps as key to translating these findings into a possible human therapy. One step will be to identify whether Morrbid regulates cell death in other types of immune cells beyond those identified in the experiments to date. In addition, he needs to more definitively confirm what his current human-cell finding implies — that the human RNA MORRBID has the same function as the mouse RNA Morrbid used in the majority of his team’s experiments. If it does, he will move toward developing molecules that have potential use as therapies to inhibit this RNA, allowing the body to more rapidly shut down its destructive immune cells when they are harming more than helping.

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Study Confirms Increasing Endocrine Disorders in Aging Childhood Cancer Survivors


A notable glowing success in the world of pediatric oncology is that there are more candles lighting up birthday cakes of young cancer survivors. As the years add up, these milestones are also significant reminders that cancer survivors must remain vigilant throughout their lifetimes to protect their hard-won health.

An estimated 420,000 childhood cancer survivors are in the U.S., and their remarkable recoveries are mainly due to significant advances in cancer therapies. Yet these same life-saving treatments often lead to several late effects in survivors as they reach adolescent and adult years, said Sogol Mostoufi-Moab, MD, MSCE, an oncologist and endocrinologist at The Children’s Hospital of Philadelphia.

Dr. Mostoufi-Moab recently led a study that showed childhood cancer survivors are at increased risk for endocrine system disorders over time. The endocrine system, a group of glands that help control growth, metabolism, puberty, and stress responses, is especially sensitive to chemotherapy and radiation.

“Endocrine abnormalities constitute a significant burden of late effects in childhood cancer survivors,” Dr. Mostoufi-Moab said. “Childhood cancer survivors demonstrate common endocrine abnormalities, such as thyroid disorders or type 2 diabetes mellitus commonly seen in older adult life, but at a much younger age.”

The investigators analyzed 14,290 survivors who participated in the Childhood Cancer Survivor Study (CCSS). Survivors were diagnosed with various cancers before age 21 and treated between 1970 and 1986. Their median age of cancer diagnosis was 6 years, and median age at last follow-up was 32. The study participants completed multi-item surveys that included their age at the onset of endocrine conditions such as underactive or overactive thyroid, thyroid nodule, thyroid cancer, hypopituitarism, osteoporosis, obesity, diabetes mellitus, male gonadal dysfunction, and premature ovarian insufficiency.

The researchers also collected information about the study participants’ prior exposures to cancer therapy, including head and neck, pelvic, abdominal or total body radiation, and alkylating chemotherapy. They adapted the Children’s Oncology Group Long-Term Follow-Up Guidelines to classify endocrine outcomes according to these treatment exposures. The study team analyzed this data to determine the likelihood of developing a specific endocrine disorder depending on disease diagnosis and type of therapy.

“The magnitude and burden of endocrine abnormalities in childhood cancer survivors, particularly after high-risk cancer therapies, are striking,” the study authors wrote.

The results, which were published in the Journal of Clinical Oncology, showed that 44 percent of survivors demonstrated at least one endocrinopathy, 16.7 percent at least two, and 6.6 percent three or more. Survivors of Hodgkin lymphoma had the highest frequency of an endocrine abnormality (60 percent), followed by survivors of central nervous system tumors (54 percent), leukemia (45.6 percent), sarcoma (41.3 percent), non-Hodgkin lymphoma (39.7 percent), neuroblastoma (31.9 percent), Wilms tumor (28.5 percent), and bone cancer (27.8 percent).

For common endocrine disorders such as thyroid abnormalities, obesity, and diabetes mellitus, survivors were compared to 4,031 siblings with no history of cancer. The findings showed that overall, childhood cancer survivors had much higher prevalence of common types of endocrine problems as they aged compared to their siblings. Those survivors who had very high-risk treatments, such as neck radiation or radiation to the head area, demonstrated significantly higher frequency of these disorders.

An important take-home message from the study, Dr. Mostoufi-Moab pointed out, is that even survivors without exposure to “high-risk” therapies still demonstrated significant late effects in common endocrine abnormalities such as thyroid disorders, obesity, and diabetes mellitus compared to siblings.

“These results highlight that there is no such thing as a ‘low-risk’ cancer survivor,” Dr. Mostoufi-Moab said. “Any adult who is a survivor of a childhood cancer should be considered at risk for endocrine late effects. Our findings emphasize the need for lifelong risk-based endocrine screening in the growing population of childhood cancer survivors.”

Childhood cancer survivors should also take an active role participating in their healthcare, particularly as they enter adulthood, she added. Primary care physicians without expertise in pediatric cancer may not recognize the need to provide appropriate surveillance-guided care, such as yearly screening evaluation for thyroid studies and diabetes mellitus, and to emphasize appropriate lifestyle modifications to address or prevent obesity. However, the Children’s Oncology Group Long-Term Follow Up Guidelines serves as a useful tool with helpful information for providers caring for childhood cancer survivors.

The current study raises awareness among adult primary care physicians about the importance of continued risk-based endocrine screening. For example, a 25-year-old survivor with previous history of total body or abdominal radiation during childhood should increase awareness regarding risk of early onset insulin resistance and type 2 diabetes mellitus. Therefore, once the screening values suggest pre-diabetes or early diabetes, initiating treatment at earlier stages is important as it can markedly reduce future life threatening cardiovascular outcomes, particularly at a younger age.

While currently there are new approaches to pediatric cancer diagnosis and treatments that have evolved over the past decade, raising the possibility that the risks for endocrine disorders in recent generations of cancer survivors may be lower than what was reported in this study, the authors point out that “the chemotherapy and radiotherapy treatments used in the CCSS study cohort remain the backbone of many therapeutic protocols for common childhood malignancies.”

Future research should focus on clinical trials aimed at finding ways to intervene at earlier stages to help prevent negative outcomes that are the direct consequences of cancer therapy, Dr. Mostoufi-Moab said. If successful, these results may contribute to many additional years to blow out more birthday candles.

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Neuroblastoma Drug Candidates Target Key Henchmen of a Supervillain Oncogene


The oncogene MYC is a supervillain of the cancer world. This gene is known to power the activities of cancer cells in many types of tumors in children and adults. Its variant MYCN, which is active in the childhood cancer neuroblastoma, is associated with the most high-risk forms of the disease. Although many scientists have tried to fight cancer by attacking MYC, the gene is active in so many different ways that it has so far managed to evade such direct attacks. As a result, many researchers are also trying to stop MYC by attacking some of its henchmen instead.

A recently published study by researchers at The Children’s Hospital of Philadelphia showed promising preclinical results with just such an approach, blocking the synthesis and speeding the breakdown of molecules that MYCN uses, called polyamines. Some of the drug candidates they studied are already in Phase 1 and 2 clinical trials for neuroblastoma.

“Polyamines have been an area of growing interest in the last several decades,” said Nicholas Evageliou, MD, an attending physician at CHOP. “Previous data in lymphomas and also in colon cancer suggested that these molecules were good targets for cancer therapies.”

Dr. Evageliou, who is now medical director of the Hematology/Oncology Clinic at CHOP’s Specialty Care Center in Voorhees, New Jersey and an assistant professor of Clinical Pediatrics in Hematology and Oncology at the Perelman School of Medicine at the University of Pennsylvania, is first author of the new study published in the September issue of Clinical Cancer Research. He worked on the project during his fellowship in the lab of Michael Hogarty, MD, a CHOP pediatric oncologist and associate professor of Pediatrics at the Perelman School of Medicine.

Before the start of the project, Dr. Hogarty’s and several other labs had performed in vitro studies showing that drugs blocking polyamine synthesis also had potential in neuroblastoma, a cancer of the peripheral nervous system that is one of the deadliest childhood cancers. Then, over a span of several years, Dr. Hogarty, Dr. Evageliou, and colleagues put several of these drugs through their paces, alone and in combination, on a variety of in vitro and in vivo preclinical models of neuroblastoma.

They tested two drugs that block MYC-regulated enzymes that are needed for synthesis of polyamines, difluoromethylornithine (DFMO) and SAM486, and one drug, celecoxib, that induces an enzyme that breaks polyamines down. DFMO is already approved by the Food and Drug Administration (FDA) for an infectious disease, African sleeping sickness, and celecoxib has FDA approval for treating pain and inflammation, typically in arthritis.

In the team’s in vitro studies, the drugs were effective at killing MYCN-driven neuroblastoma cells. In in vivo studies, the combination of DFMO and SAM486 delayed onset of neuroblastoma in mice predisposed to the cancer. The drugs also regressed the tumors in mice that already had cancer, and DFMO did so even more strongly when given in combination with known-effective chemotherapy drugs.

Combining DFMO with the drug celecoxib added to its effectiveness at regressing or slowing tumors in the mouse model, and the pair of drugs did so even more strongly when combined with standard chemotherapy treatments. The researchers suggested that by limiting uptake of polyamine molecules from the environment outside the cell, celecoxib could keep polyamine levels in the tumor cells low even if those cells tried to compensate for DFMO blocking their synthesis.

The researchers were especially enthusiastic about the findings when they repeated these experiments and saw similar results in mice grafted with human neuroblastoma tumor cells. Similar drug combinations were not only effective on MYCN-driven grafted tumors, but also in a variety of neuroblastoma tumors representing the different genetic subtypes that clinicians typically see.

A Phase 1 clinical trial for DFMO and celecoxib combined with chemotherapy is underway, sponsored by the New Approaches to Neuroblastoma Therapy consortium (NANT). Discussions of how to proceed with a Phase 2 trial are ongoing with both NANT and the Children’s Oncology Group (COG). A key question that will shape the design of the ideal Phase 2 trial of these drugs is whether they have the most potential to kill cancer cells directly when given in high doses alongside chemotherapy, or to do so indirectly in more moderate doses to help an immunotherapy work better. Dr. Hogarty and COG are carefully reviewing the available data about the drugs’ activity mechanisms to determine the best path forward for clinical testing.

Dr. Hogarty also cautioned that, although he is enthusiastic about the strength of the preclinical findings with these drugs, he is far from certain that this success will translate to clinical effectiveness.

“I think it’s humbling to see how difficult it is to predict what drugs will work in the clinic,” Dr. Hogarty said. “But compared to a lot of other potential new drugs, we know a lot about DFMO’s safety, we know a lot about its impact on children’s bodies because it’s been used as an infectious disease drug for a long time, and we have, in my experience, as much depth and breadth of preclinical data of any drug that I’ve been associated with. It’ll have to prove itself in the clinic, but it has a good running start.”

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Fresh Hope for Treating a Rare Progressive, Lysosomal Storage Childhood Disease


It took nearly a decade and the loss of two infants before Khalid and Jabin Shaikh finally learned what was going wrong. Their third child, Zain, a son, was born in 2007 and immediately whisked away to a pediatric hospital for testing in an effort to identify the disease that took the lives of his siblings. While Zain survived infancy and beyond and met his major developmental milestones, it still took years of testing and inconclusive interpretations of unusual test results before the Shaikh family finally heard of Niemann-Pick Disease Type C (NPC).

Getting this diagnosis for Zain was a critical step for the Shaikh family, but solutions were still lacking. There is no cure for NPC. This genetic neurodegenerative condition is progressive, irreversible, and chronically debilitating. It is caused by a defect in lipid transportation within the cell, which leads to excessive accumulation of lipids in the brain, liver and spleen. It can lead to difficulty eating and breathing, and often seizures. The majority of people with NPC die by their late teens or 20s. Was the Shaikh family destined to lose their surviving child, too?

“I have been pulled to this place,” said Khalid Shaikh, who is now taking a sabbatical year from his job in the software industry in his native India to be in Philadelphia with his wife and son, pursuing a new hope for a better outcome for Zain.

Now a quiet 9-year-old with deep brown doe eyes, Zain is one of just over 50 children in the world are enrolling in an international multi-site clinical trial of an investigational treatment for NPC sponsored by Vtesse Inc. He is the first to enroll at the study site at The Children’s Hospital of Philadelphia in this Phase 2b/3 clinical trial.

“We are feeling very confident that CHOP will successfully help this child to better health because some power, some almighty, is planning this stuff,” Khalid said. “Very few families get an opportunity like this.”

There is no FDA approved therapy for NPC, and most interventions only help manage its symptoms, which can vary across a broad spectrum. Sometimes the condition initially appears as liver disease detected in newborns or even during fetal development. A majority of children with NPC have an eye-movement symptom called vertical supranuclear gaze palsy, in which children are initially slow to shift their gaze to look up, and control over eye movement degenerates over time due to neurological damage. Often, children exhibit problems with neurological development and experience progressive losses after initially appearing to be healthy for the first few years of life.

“You have a walking child, all of a sudden, losing milestones,” said Can Ficicioglu, MD, PhD, director of the newborn metabolic screening  and lysosomal storage disease programs at CHOP and associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, who is the lead investigator for the CHOP site of the NPC trial.

Zain Shaikh, so far, has been lucky. He has full control over his movements and showed relatively few symptoms of NPC until he had major seizures within the last year. More subtle symptoms affecting his intellectual development may have impacted his behavior and academic performance at school. For some children with NPC, belligerent behavior is an early sign that is misdiagnosed as a behavioral disorder until ongoing major cognitive decline makes it clear they are experiencing serious neurological degeneration.

NPC causes such brain damage as a result of one of two possible genetic mutations that affect how cells store cholesterol. By mechanisms that have not yet been fully explained, cholesterol and other lipids become trapped inside brain cells due to the mutated gene’s dysfunctional protein product; as a result, patients experience severe neurological decline.

The clinical trial for NPC is evaluating a drug candidate called VTS-270, which is a well-characterized mixture of 2-hydroxypropyl-beta-cyclodextrin (HPbCD) with a specific compositional fingerprint that distinguishes it from other HPbCD mixtures. Other versions of cyclodextrins have already been shown to be useful in medicine (such as sugammadex [BRIDION, Merck]), as well as different and entirely unexpected places such as the odor-neutralizing ingredient in Febreze.

In cell culture, VTS-270 has been shown to remove cholesterol from cells, so scientists have studied its potential as a treatment for NPC. Intrathecally injected VTS-270 has been shown to slow the disease in animal models. Last year, a team of researchers from multiple institutions including the University of Pennsylvania School of Veterinary Medicine showed that cats that have a naturally occurring version of NPC had dramatic improvements after treatment with VTS-270. Hearing loss was a side effect in cats and impact on high-frequency hearing is an expected side effect in children, although this effect is ambiguous; due to the neurodegeneration involved in NPC, some hearing loss may result from the disease itself. The translational step of testing as a veterinary therapy for affected cats was essential in establishing that the compound was safe enough to proceed with the clinical trials in children that are underway at sites worldwide, now including CHOP.

“When I talk with physicians who have been treating patients with this compound, they told me that it does something for affected kids,” Dr. Ficicioglu said. “But of course it is not a miracle. Since there is no treatment available, whatever you have is extremely promising.”

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New Neuroblastoma Research Scholars Program Supports Young Scientist


Young scientists may have passion and brilliant ideas, but unfortunately, they often do not add up to federal funding dollars. This is particularly problematic in pediatric cancer research, which receives just 4 percent of the National Cancer Institute’s $4.95 billion budget.

Enter the Evan’s Victory Against Neuroblastoma Foundation (The EVAN Foundation) into the equation. In 2015, the foundation established the Evan Lindberg Neuroblastoma Research Scholars Program to support exceptional early career scientists at The Children’s Hospital of Philadelphia who are dedicated to finding a cure for neuroblastoma. A rare childhood cancer that 700 new patients are diagnosed with each year in the U.S., neuroblastoma is a tumor of nerve tissue that typically presents in the adrenal gland.

After months of searching for the right candidate, Yael Mossé, MD, a CHOP pediatric oncologist and physician-scientist specializing in neuroblastoma who is leading the new program, announced that the first scholar recipient is Olivia Padovan-Merhar, PhD, a postdoctoral fellow at the CHOP Research Institute. Dr. Padovan-Merhar’s skills and background in computational biology and genomics paired with her interest in medicine and passion for helping others made her an exceptional choice.

“We are thrilled that Olivia is the first beneficiary of the scholar’s program bearing Evan’s name,” said Gavin Lindberg, president of The EVAN Foundation. “Not only is she an incredibly talented scientist, but she is passionate about helping children with neuroblastoma. We are impressed by the contributions she is currently making in the CHOP lab, and even more excited about her potential to become a future leader in the fight against neuroblastoma.”

In 2011, Wendy and Gavin Lindberg established The EVAN Foundation in honor of their son who passed away from neuroblastoma at age 7. During his treatment at CHOP, the family met remarkable researchers who had groundbreaking ideas for treating neuroblastoma, including Dr. Mossé. She shared many of Evan’s qualities: an amazing spirit, curiosity, energy, and compassion.

The Lindbergs realized that engaging more scientists with these traits and cultivating their enthusiasm for neuroblastoma research is essential to finding a cure. Frustrated by the shortage of opportunities for such promising scientists to get financial support from industry or government sources, the Lindbergs made a long-term commitment to help fill the gap in funding for pediatric cancer research.

“When I met Dr. Mossé, I was struck by the fact that she was so young and yet a world-renowned neuroblastoma researcher,” Gavin Lindberg said. “I think that planted a seed in my mind.”

Dr. Padovan-Merhar is thrilled and honored to have received the scholarship. This support will allow her to carry out her current projects and develop as a neuroblastoma researcher, enabling her to better serve the children and parents affected by childhood cancer. She is working with genetic data from families that has been collected over the span of a decade to identify genetic variants that may predispose children to developing neuroblastoma.

As Dr. Mossé demonstrated with the gene ALK, a better understanding of the genetic causes of the disease can lead to improved targeted therapies in the future. In 2010, Evan was one of the first children to receive an experimental drug in a clinical trial that targeted his tumor’s rare ALK mutation. Today, CHOP offers testing for the ALK mutation to children with a diagnosis of neuroblastoma to help customize their treatment approaches.

“We found hope at CHOP,” Wendy Lindberg said. “We had been battling Evan’s neuroblastoma for years, and we were at the point where we had exhausted everything. We always wondered, wouldn’t it be great if there was a personalized medicine approach for Evan’s tumor? Dr. Mossé’s work on the ALK mutation made that possible. Although treatment did not yield the result we were all hoping for in Evan, we knew that we had helped open up a new frontier in the fight against this awful disease.”

In turn, Dr. Mossé and her team learned a great deal from Evan and his courage. They have made significant advances in understanding the role of ALK in the growth of neuroblastoma tumors, and they have developed several treatment strategies that have translated into clinical trials. Evan’s lack of response to the very first ALK inhibitor developed against neuroblastoma has fueled Dr. Mossé’s lab with the drive and perseverance to understand why and to do better for other children.

“The EVAN Foundation Neuroblastoma Research Scholar Program provides an unmatched opportunity to impart this determination and grit to a young investigator, and Olivia is precisely the person to inaugurate this program,” Dr. Mossé said.

To date, The EVAN Foundation has raised $400,000 in support of promising neuroblastoma studies, including several at CHOP. In addition, the Foundation sponsors the weekly “Treats and Treasures Carts” program at their local children’s hospital in Washington, DC. Every Wednesday, the Lindbergs visit each room on the oncology floor at Children’s National Medical Center with two oversized carts full of toys, games, candy, chocolate, stuffed animals, and other fun items. Patients, parents, and siblings all choose as much as they want at no cost. Since the program’s inception, the Lindbergs have made more than 6,000 visits to young children enduring long and difficult stays in the hospital.

Visit the organization’s website to learn more about Evan and the Foundation he inspired.

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Produced by The Children’s Hospital of Philadelphia Research Institute.

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