NEXT | Fall 2017

INAUGURAL ISSUE The Future of Discovery at VCU Health

Vitamin C:

Fall 2017

Blazing a Trail to Cure Sepsis

Welcome to NEXT Dear Friends, We’re so pleased to welcome you to the inaugural issue of NEXT, the MCV Foundation’s new publication covering the incredible innovations in patient care, research and education occurring on the MCV Campus at VCU Health. Through this magazine, we hope to share some of the exciting discoveries made by our award-winning healthcare providers, faculty and students, and the positive impact these scientific breakthroughs have on our patients and all Virginians.

Current research awards to the MCV Campus total $483.4 million, with new fiscal 2017 awards to our five health sciences schools of $150.4 million.

This emphasis on leading-edge research is one of the unique benefits our academic health center brings to the community. We have the ability to accelerate the latest scientific breakthroughs from the bench to the bedside so that our patients have access to the most advanced treatments, right here in Richmond, Virginia.

The MCV Campus has grown exponentially since its founding in 1838 into what is now VCU Health, but what has remained constant is our legacy of innovation. This December will mark the 50th anniversary of the first human heart transplant. In this issue, we take a look back at the groundbreaking research of Dr. Richard Lower and the critical role he played in this achievement. He, and physicians like him, helped lay the foundation for the VCU Health Hume-Lee Transplant Center — one of the busiest transplant programs in the nation. Fast-forwarding to the present, our article on islet cell transplantation describes our work with the latest technology to help patients with chronic pancreatitis.

From Dr. Berry Fowler’s transformational work using Vitamin C as a cure for sepsis, to Dr. Kenneth Kendler’s landmark study identifying risk genes for clinical depression, the breadth of the articles in this issue showcase the world-class research being done in every field right here at VCU Health.

We hope the innovative work of these extraordinary healthcare professionals inspires you as much as it inspires us in the philanthropic work we do every day to support VCU Health and the next great discovery.

Margaret Ann Bollmeier

Harry R. Thalhimer

PRESIDENT, MCV FOUNDATION

BOARD CHAIR, MCV FOUNDATION

FALL 2017 / INAUGURAL ISSUE

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VCU Health: First in the Region The cutting-edge technology of islet autotransplantation gives hope to patients with chronic pancreatitis.

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A Look Inside Learn facts, terms and information discussed in this issue.

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The Right Place Professors from the VCU School of Pharmacy and VCU School of Engineering team up to ensure medications properly reach the lungs.

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Identifying Depression Risk VCU Health researchers lead an international team in identifying and studying risk genes for clinical depression.

COVER STORY

Vitamin C:

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Clinical trials may lead the way to less aggressive,

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but still effective, treatment for oropharyngeal cancer.

Blazing a Trail to Cure Sepsis VCU Health researchers, led by Alpha A. “Berry” Fowler III, M.D., find intravenous Vitamin C treatment

A Distinction for Diagnosis

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effective in treating and curing sepsis — the leading

Making History with the Heart In the race to perform the first heart transplant,

cause of death in U.S. hospitals.

a former Medical College of Virginia surgeon plays a vital role.

INAUGURAL ISSUE

About the Cover British photomicrographer Spike Walker uses a Zeiss Ultraphot lll microscope with built-in camera to reveal the beautiful structures

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Massey Leading Paradigm Shift VCU Massey Cancer Center study lays the groundwork for a new look at pancreatic cancer treatment.

that make up Vitamin C.

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VCU Health

First in Region to Launch Islet Autotransplant Program for Chronic Pancreatitis

By Alex Henley

Chronic pancreatitis is a debilitating and painful disease.

Its causes range from gallstones to genetic predisposition, cystic fibrosis or alcohol, but the crippling pain from the inflammation affects a patient’s quality of life, and often necessitates the use of narcotics just to accomplish everyday tasks.

The VCU Health Hume-Lee Transplant Center offers a lifeline to these patients who have tried conventional therapies without success. Marlon F. Levy, M.D., FACS, chair, VCU Health Division of Transplantation Surgery, and director, Hume-Lee Transplant Center, was recruited to VCU Health in 2015 as an expert in cellular transplantation, especially islet cell transplantation.

“What we’ve established here is unique among medical centers,” said Dr. Levy. “We’re offering true rescue therapy for patients who have run out of options. We’ve assembled the clinical and scientific teams to rapidly position ourselves as one of the major islet transplant centers on the East Coast.”

Islet therapy is one of the cutting-edge technologies in the world of transplant medicine. Islets are the cells within the pancreas that produce insulin and glucagon to help maintain healthy blood sugar levels. The procedure Dr. Levy and his team perform is called TPIAT, which stands for total pancreatectomy with islet auto transplant. It allows them to completely remove the pancreas, the source of the patient’s pain. The pancreas is then processed in a laboratory where the islet cells are separated and purified. The islet cells are

Islet Cell Transplant The total pancreatectomy with islet auto transplant (TPIAT) procedure involves removing the pancreas, processing it in a lab where the islet cells are separated and purified, and then reimplanting the islet cells in the patient’s liver.

Infuse islet cells to liver via an IV bag

Isolate and purify islet cells

Remove diseased pancreas VCU University Relations. Based on a diagram produced by the Baylor Health Care System.

Opposite page: The isolation process at the VCU Health Hume-Lee Transplant Center’s dedicated islet cell transplant laboratory separates the islet cells (in red) from the inflamed acinar cells of the pancreas (in yellow). Mazhar A. Kanak, Ph.D./VCU Health

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“What we’ve established here is unique among medical centers. We’re offering true rescue therapy for patients who have run out of options.”

Dr. Marlon F. Levy, Director of VCU Health Hume-Lee Transplant Center

then reimplanted back into the patient, but this time, they’re placed in the liver.

Amazingly, the islet cells return to their role of producing insulin again, which allows the patient to lose their pancreas without becoming a diabetic.

This type of advanced procedure requires state-of-the-art facilities with expert surgical and clinical teams, as the islet cells must be processed while the patient is on the operating table.

“The entire procedure lasts about 10–12 hours,” said Dr. Levy. “We remove the pancreas and take it over to our lab in the Biotech Center at the Virginia Biotechnology Park on the MCV Campus. We extract the islets and bring them back and reinfuse them into the patient asleep in the operating room.

“It’s all one operation. The patient leaves without their pancreas, but with preserved insulin production.”

Dr. Levy reports a success rate above 90 percent in relieving the patient’s pain, and around 70 percent of patients have good to excellent blood sugar control.

Another exciting application for this technology is juvenile diabetes, also known as Type 1 diabetes. For these patients, their pancreas is not inflamed or causing pain, it’s just not producing insulin. Islets from a donor could be placed in their liver to help with insulin production and blood sugar control. In the U.S., this technology is still considered experimental and approval from the FDA is expected in the next few years.

“Our vision is to be the pre-eminent transplant center on the East Coast, and we have a real drive to keep building our transplant research,” said Dr. Levy. “We have active research projects in cell transplantation, ways to better detect liver

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Marlon F. Levy, M.D., FACS, chair, VCU Health Division of Transplantation Surgery, and director, Hume-Lee Transplant Center, was recruited to VCU Health in 2015 as an expert in cellular transplantation. He is pictured in VCU Health’s Islet Transplant Lab. VCU Health

cancer, and organ resuscitation in conjunction with the Division of Trauma within the Department of Surgery.”

The work being done by Dr. Levy and his team continues the legacy established when David Hume, M.D., performed the first kidney transplant in Virginia here on the MCV Campus. This December will mark the 60th anniversary of that groundbreaking surgery. Today, the VCU Health Hume-Lee Transplant Center is one of the busiest transplant programs in the country and celebrated its 5,000th transplant surgery this summer.

Read more about the legacy of innovation in transplant surgery on the MCV Campus on page 25.

A Look Inside Terms and Phrases You’ll Find in this Issue

By Alex Henley

Phases of a Clinical Trial

Terms

PRE-CLINICAL The initial testing of a new treatment idea using in vitro (test tube) and in vivo (animal) experiments to see if further research is warranted.

A few articles in this issue discuss adjuvant versus neoadjuvant therapies.

PHASE I:

SAFETY TRIAL OR FEASIBILITY TRIAL The first phase that involves human participants. The main purpose is to determine what doses can be given safely, without serious side effects. Researchers start with very low doses and may increase them if the treatment is welltolerated. Usually involves less than 100 participants.

Main Question: Is it safe?

PHASE II:

PROOF OF CONCEPT TRIAL The main purpose is to observe the treatment’s effectiveness, and a drug is often compared to a placebo. This phase usually involves 100–300 participants and is also focused on gathering data on safety and side effects.

Main Question: Does it work?

PHASE III:

PRE-MARKETING PHASE This phase compares the safety and effectiveness of the treatment against the current standard. It usually involves multiple centers with thousands of participants over a few years.

Main Question: Is it more effective than the current goldstandard treatment?

PHASE IV:

CONFIRMATORY TRIAL OR POST-MARKETING SURVEILLANCE TRIAL This phase usually occurs after the FDA has approved the drug. It gathers additional information on safety and efficacy to determine if there are any rare or long-term side effects by testing thousands of participants over a longer time range.

Main Question: Are there any rare or long-term side effects?

NEOADJUVANT: Generally means pre-surgical treatment. When treating cancer, it can include radiation, chemotherapy or hormone therapy to shrink the tumor in order to allow for more surgical options or a surgery with a better chance of removing all of the cancer cells.

ADJUVANT: Generally means post-surgical treatment. It can include radiation, chemotherapy or hormone therapy in order to prevent metastasis or recurrence if the cancer is aggressive or if the surgeon is not able to resect all of the cancer cells.

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Michael Hindle, Ph.D., the Peter R. Byron Distinguished Professor in the VCU School of Pharmacy (front) and Worth Longest, Ph.D., a professor in the VCU School of Engineering.

Steinbrenner Photography

The Right Place How Two Researchers are Ensuring Medications Reach the Lungs

By Eric Peters Babies born six or more weeks prematurely commonly develop a disorder known as respiratory distress syndrome (RDS). If these babies are not intubated and treatment squirted into their lungs, the lack of oxygen caused by RDS damages their brain and other organs.

Delivering the treatment noninvasively as an aerosol via a face mask could be a less traumatic route for these critically ill babies. Unfortunately, major barriers exist in delivering medication to infants through a face mask in cases of RDS and other disorders, and these barriers are the throat and nasal passages. Ninety to 99 percent of aerosol medication delivered to babies for any disorder hits the back of the throat or deposits in the nasal cavity and goes no farther. Sometimes physicians don’t know whether any of the medication ever reached its intended target.

In adults, the numbers are not much better. About 60 to 90 percent of any aerosol medication, whether administered through a hand-held inhaler or a face mask, is wasted.

This wasted medication reduces drug effectiveness and can potentially increase side effects such as those seen with antibiotics. There is growing concern that overuse

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or mistargeting with antibiotics can kill helpful bacteria or create drug resistance, so administering an antibiotic for lung infections directly to the lung through an inhaler is intended to protect the rest of a patient’s body from the antibiotic.

When 60 to 90 percent of medication hits the back of the throat, however, the medication is swallowed and still exposes the stomach and other organs to possible adverse side effects.

Challenges like those described above are what brought two VCU Health researchers together in 2009 to begin exploring ways to deliver aerosol medications past the throat and into the lungs where the medications can serve their intended purpose. Today, those researchers — Michael Hindle, Ph.D., the Peter R. Byron Distinguished Professor in the VCU School of Pharmacy, and Worth Longest, Ph.D., a professor in the VCU School of Engineering — hold two patents and several federal grants based on a strategy they developed that better delivers aerosol medication to the lungs.1 They believe that testing their strategy in humans will show the possibility of completely inverting current statistics, delivering very large percentages of medication that currently are wasted.

“As our partnership grows and continues, now there are more engineers coming over to the lab and getting involved. ... It’s cross-fertilization of ideas where pharmacy graduate students are teaching engineering graduate students and vice versa.”

STRATEGY AND DELIVERY Dr. Hindle and Dr. Longest describe their strategy to improve aerosol medication delivery to the lungs as “simple” and “elegant.” The main issue to overcome, they say, is that at around 4 micrometers (0.004 millimeters), aerosol medication particles are simply too big. To combat this issue, Dr. Hindle and Dr. Longest reduce aerosol medication size, allowing those particles to slip easily through airways, past the throat or nasal cavity and into the lungs. Then, after reaching the lungs, the particles have been engineered to triple or quadruple in size, providing the momentum they need to deposit at the desired target site before they’re exhaled.

Their process is different with each drug, but when preparing particles to enter the lungs, Dr. Hindle and Dr. Longest generally target a size below or near 1 micrometer (0.001 millimeter). Once the medication is in the lungs, they generally target a size of 3 to 5 micrometers.

Perhaps the most “simple” or “elegant” part of the process is how Dr. Hindle and Dr. Longest enable that size increase — they use the natural humidity of the airways and lungs.

“The lungs are full of water, so we’re adding something to the formulation, like salt or sugar, which are nonpharmaceutically active and acceptable to be inhaled,” Dr. Hindle said. “Once we combine that addition with our drug particles, the moisture becomes attracted to it and absorbed, and the particles grow.” This process is called controlled hygroscopic growth.

By manipulating the size and growth of aerosol medication particles, Dr. Hindle and Dr. Longest can target different areas of the lungs. Certain diseases require medication in the bronchioles (passageways in the lungs), for example, and others require deeper penetration into the alveoli (air sacs in the lungs).

As Dr. Hindle and Dr. Longest develop these unique medication delivery strategies, they need devices to deliver them. The two researchers have worked together to develop novel aerosol delivery devices2 for adults and children that are applicable for hand-held personal use and for

noninvasive ventilation in healthcare settings. In addition, they 3D-print their own highly detailed anatomical models to use in testing their devices and their medication strategy.

Their collaborative process includes Dr. Hindle and his team in a pharmaceutics lab testing the devices created in Dr. Longest’s lab by shooting aerosols into a laser beam that measures particle size, which is known as laser diffraction.

“As our partnership grows and continues, now there are more engineers coming over to the lab and getting involved and doing not only the design of the device, but then seeing how they’re tested in a pharmaceutics lab,” Dr. Hindle said.

“It’s cross-fertilization of ideas where pharmacy graduate students are teaching engineering graduate students and vice versa.”

By manipulating the size of aerosol drugs, developing novel delivery devices for those drugs, and taking full advantage of a strong interdisciplinary partnership, Dr. Hindle and Dr. Longest are on the cusp of completely inverting expected aerosol medication delivery rates.

Instead of losing more than 90 percent in a baby’s nose and throat, they believe they can deliver more than 90 percent.

Instead of 60 to 90 percent of antibiotics inadvertently dripping to the stomach, they believe they can deliver those antibiotics to the lungs where they belong.

In the coming months and years, they’ll pursue these goals by advancing their strategies toward the clinical setting. That advancement has been accelerated thanks to the National Institutes of Health grants they received this year in the amounts of $2.4 million and $2.5 million.

Dr. Hindle and Dr. Longest will use these grants to test their novel technologies for the first time with human subjects, and also focus specifically on delivering antibiotics to children with cystic fibrosis.

1. Aerosol Science and Technology, April 2010; Pharmaceutical Research, May 2010; and Journal of Pharmacy and Pharmacology, February 2012.

2. Journal of Pharmaceutical Sciences, December 2013; Pharmaceutical Research, February 2014.

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Identifying Depression Risk Expanding on a Landmark Study

By Eric Peters

In 2015, an international team of researchers from VCU Health, UCLA, and throughout China, identified two risk genes for clinical depression for the first time in history. Now, the same research team believes it is on the way to discovering considerably more markers — 10 to 15 times more.

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Depression affects more than 15 million adults each year in the U.S., which is about 6.7 percent of the country’s adult population.

By understanding the causes of depression, researchers and clinicians can gain a better idea of what to target and how to plan when developing new medications and treatments for the millions who battle the disorder each day.

A pivotal moment in the quest to understand these causes came in 2015 when VCU Health researchers were part of an international team that identified, for the first time in history, two risk genes for clinical depression.1 The variants in DNA that they found are clues to the underlying cause of the disorder, which opened new paths for researchers to explore when searching for ways to treat depression and predict who will be at risk.

While the results of this study were groundbreaking, it was immediately clear that there was more work to be done.

The team wrote that major depressive disorder is most probably caused by many additional variants in DNA that remain to be discovered. Now, in continuing its work, the same research team, which is made up of researchers from VCU Health, UCLA, and throughout China, believes it is on the way to discovering considerably more markers — 10 to 15 times more.

“We did a variety of projections, but the expectation would be that with the enlarged sample, we might have between 20 to 30 individual DNA variants,” said Kenneth S. Kendler, M.D., the Rachel Brown Banks Distinguished Professor in Psychiatry at the VCU School of Medicine and a joint senior author on both studies. “That will increase the chances that we can tell a coherent biological story about the underpinnings of the vulnerability to depression.”

Dr. Kendler’s team, which is calling the previous study CONVERGE 1 and the new study CONVERGE 2, has begun collecting data for CONVERGE 2 from what will eventually be 24,000 individuals with major depression and 24,000 individuals who will serve as the control group. The sample sizes for CONVERGE 1 were roughly one-third of these expected totals.

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“When I was a second-year resident in Dublin, I heard an amazing presentation on the genetics of major mental illness from an extraordinary scientist named Dr. Kenneth Kendler. Today, I am proud to be his colleague.

“Dr. Kendler is a pioneer in psychiatric genetics and one of the world’s leading researchers in psychiatry.

Because of the time, energy, passion and intellect he has given to his work, which includes publishing more than 1,200 scholarly articles and leadership in establishing the Virginia Institute of Psychiatric and Behavioral Genetics, Dr. Kendler has helped the world better understand the causes of psychiatric and drug abuse disorders. He is a beacon for this university.”

Peter F. Buckley, M.D., dean of the VCU School of Medicine

The new sample will be made up of, as it was in the first study, Han Chinese women with depression who are at least 30 years old; have had two episodes of major depression; have had no history of alcohol or drug abuse, bipolar illness or psychosis; and have all four grandparents of Han Chinese descent. The team chose to study Han Chinese women because the population is relatively homogeneous from both a genetic and cultural perspective.

Half of the participants will be individuals who report recurrent major depression at mental health centers and hospital psychiatric departments in dozens of Chinese cities and provinces. Individuals in the control group will be patients undergoing minor surgical procedures at general hospitals or local community centers. Postgraduate medical students, junior psychiatrists and senior nurses will interview participants using a computerized assessment system and collect saliva samples.

Next, Dr. Kendler and his team will extract DNA from the saliva samples and conduct high-coverage whole-genome sequencing to identify the risk variants. This process involves determining and carefully analyzing the complete DNA sequence of each study participant’s genome, which contains roughly 3.3 billion bases (letters of the genetic code).

“What stands out about the CONVERGE studies are the careful, detailed analysis and our definitions to ensure that the people affected are relatively severe,” Dr. Kendler said.

“We wish to study more severely ill individuals because they are likely to carry more genetic risk variants and to be more homogeneous (in terms of the cause of their disorder).”

Kenneth S. Kendler, M.D., is the Rachel Brown Banks Distinguished Professor of Psychiatry and director of the Virginia Institute for Psychiatric and Behavioral Genetics at the VCU School of Medicine.

Allen Jones, VCU University Marketing

Dr. Kendler and his team expect to collect data for the next four years and hope to publish their results shortly thereafter. The key collaborator in this ongoing project is Jonathan Flint, M.D., former professor at the Wellcome Trust Centre for Human Genetics at the University of Oxford, and now a professor at UCLA Brain Research Institute.

“The importance of these studies is the degree to which they provide clues to the underlying biology of the vulnerability to depression,” Dr. Kendler said. “From there we can clarify potential novel ways to try to prevent or treat the disorder.”

Preventing and treating major depressive disorder is needed everywhere and can have a major impact on the lives of those who are or could be affected. Dr. Kendler and his team point out in their initial CONVERGE study that major depressive disorder is one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide.

“If you have a family member with depression, there are profound levels of suffering,” Dr. Kendler said. “We need to do better with treatment, and the only way that’s going to happen is by understanding better the etiology (cause) of these conditions.”

1 Nature, July 2015.

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Vitamin C:

Vitamin C:

Blazing a Trail to a Cure for Sepsis

By Alex Henley

Blazing a Trail to Cure Sepsis

By Alex Henley

Sepsis the leading of death U.S. hospitals, Sepsis is theisleading causecause of death in U.S.inhospitals, according according to thetoSepsis the Sepsis Alliance, Alliance, but VCU butHealth VCU Health researchers researchers hopehope to put end that cureathat highly effective, toan put anto end towith that awith cureisthat is highly effective, safe and will hopefully save thousands of lives safe and will, potentially, save thousands of lives.

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“Imagine two fully loaded 747s crashing every day — that’s how many people die of sepsis every year in this country,”

said Alpha A. “Berry” Fowler III, M.D., executive director of the VCU Johnson Center for Critical Care and Pulmonary Research, and professor of medicine, Division of Pulmonary Disease and Critical Care Medicine in the VCU Department of Internal Medicine.

Sepsis is a life-threatening medical condition caused by the immune system’s response to infections from bacteria, viruses or fungi. The body produces proteins called cytokines to fight infection as part of its standard immune response.

In cases of severe infection, the excessive production of these pro-inflammatory proteins causes widespread inflammation, which can lead to microvascular blood clots that impair blood flow and, as a result, damage organs throughout the body. Once one or more organs begin to fail, a patient can spiral downward very quickly.

Of the more than one million cases of sepsis that occur each year in the U.S., approximately 40 percent of patients develop acute lung injury, and 35 percent of those patients die. As sepsis is a disease caused by inflammation, Dr. Fowler and his team have focused their research on using Vitamin C to reduce the underlying inflammation and reverse acute lung injury.

FINDING A CURE “It all started about 12 years ago,” said Dr. Fowler. “We were in Sanger Hall, researching a mouse model of heart attack.

We were experimenting with techniques to boost a protein that protects the heart, called HIF-1. After our studies were submitted to Circulation Research (published January 2006), one of the reviewers asked us to illustrate the opposite effect and show that reducing HIF-1 can damage the heart.”

Ramesh Natarajan, Ph.D., a faculty member in the Division of Pulmonary Disease and Critical Care Medicine

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Vitamin C’s Curative Effect on Acute Lung Injury Figure A

Normal Alveolar-Capillary Membrane

Figure B Injured Alveolar-Capillary Membrane and a close collaborator of Dr. Fowler, went to the literature to try to find a way to do that. He found that ascorbic acid, commonly known as Vitamin C, can inhibit HIF-1. He also came across a study that showed human patients with sepsis have high HIF-1 levels.

That was the team’s eureka moment. “We looked at each other and smiled, and all of a sudden that notebook came off the shelf again,” said Dr. Fowler. “If Vitamin C inhibits HIF-1 in our experiments with the heart, then it should also inhibit HIF-1 in patients with sepsis.”

Dr. Fowler, Dr. Natarajan and research assistant Bernard Fisher consulted the literature and found a study showing sepsis patients exhibit very low Vitamin C levels in their blood plasma, almost approaching what would be defined as scurvy. A European study indicated that low Vitamin C levels were correlated with multiple organ failure and lower rates of survival but, surprisingly, no studies using Vitamin C as a sepsis treatment had been performed.

The team also researched the functioning of the lung to further understand how Vitamin C could be an effective treatment for acute lung injury. As a person breathes, air condenses and turns into a mist, so water is always being created in the lung. A healthy lung has the ability to clear this fluid through tiny sacs, called alveoli, which are connected to the bloodstream via a lymphatic network.

In the case of acute lung injury, the inflammation and ensuing blood clots damage the alveolar-capillary barrier, and plasma and cells from the bloodstream surge into the dry air spaces of the lung. The accumulation of fluid in the lungs is one of the complications that makes sepsis a life-threatening condition.

The VCU Health team designed a preclinical trial and showed that Vitamin C, given intravenously, successfully

Flooded Alveolar Space — inflammatory proteins and lipids fill the air space Activated White Blood Cells

Figure C Vitamin C Infusion Reduces Injury Intravenous Vitamin C clears alveolar flooding

Figure A shows a normal alveolar-capillary membrane. Normal lungs have a barrier between the airspaces and the lung’s capillaries so that the airspaces stay dry. Figure B depicts the lung damage that occurs when sepsis activates an excessive amount of white blood cells, causing them to accumulate in the capillaries and impair the barrier function. This acute damage is compounded when plasma, the watery component of blood, along with more white blood cells flood into the dry airspaces. This flooding causes a patient’s oxygen levels to fall critically low, resulting in respiratory failure. At this point, the person is literally drowning and nearly all patients need a respirator to support breathing.

Figure C illustrates how intravenously infused Vitamin C returns the lung to normal function by reducing the white blood cell activation and helping the lung to clear the flooded plasma.

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Dr. Fowler and his research team gather at their lab in the Molecular Medicine Research Building on the MCV Campus.

reduced vascular lung injury in septic mice. The results showed that the anti-inflammatory properties of Vitamin C enhanced the alveolar-capillary barrier function and increased the lung’s fluid clearance.1 PHASE I HUMAN CLINICAL TRIAL In 2010, Dr. Fowler’s team received approval from VCU’s Institutional Review Board to perform a Phase I randomized, double-blind, placebo-controlled trial. Phase I trials are the first time a treatment is tested on human patients, and safety is the primary concern. The researchers sought to determine if Vitamin C was safe for treatment in critically ill sepsis patients and if it had an impact on organ failure and select biomarkers.

Over a period of one year, they studied 24 patients admitted to VCU Medical Center’s Medical Respiratory

Intensive Care Unit who had been diagnosed with severe sepsis. Patients were equally divided into one of three groups and given intravenous infusions every six hours for four days.

The low-dose group received 50 mg/kg/day of Vitamin C, the high-dose group received 200 mg/kg/day, and the placebo group received a dextrose solution (sugar water).

All patients received the full ICU standard of care support.

The patients’ vital signs were monitored to make sure they were safely tolerating the treatment. Sequential Organ Failure Assessment (SOFA) scores were measured to track overall improvement; C-reactive protein and procalcitonin were used as markers of inflammation; and thrombomodulin was measured to determine the level of vascular injury.

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Vitamin C Decreases Organ Injury Delta SOFA Score

Patients receiving the intravenous Vitamin C treatment showed a dramatic decrease in multi-organ injury, as measured by their daily mean SOFA (Sequential Organ Failure Assessment) scores. While the placebo group showed an increase in organ injury over 96 hours, the low-dose Vitamin C group showed a decrease in organ injury over that time period and the high-dose Vitamin C group illustrated the fastest and most significant decrease in organ injury.

0

Placebo Group

-1

-2

Low-Dose Group

-3

High-Dose Group -4

-5

1 24 48 72 96

hour hours hours hours hours

Time (h)

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Front:

Left to Right:

Alpha “Berry” Fowler III, M.D., executive director of the VCU Johnson Center for Critical Care and Pulmonary Research, and professor of medicine, Division of Pulmonary Disease and Critical Care Medicine in the VCU Department of Internal Medicine

Ramesh Natarajan, professor, Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine Stella Hamman, R.N., clinical research nurse coordinator Bernard Fisher, research assistant

Christine DeWilde, R.N., M.S.N., associate director, clinical research services at VCU Johnson Center for Critical Care and Pulmonary Research Anna Priday, regulatory affairs supervisor

Aamer Syed, M.D., assistant professor, Division of Pulmonary Disease and Critical Care Medicine

RESULTS The Phase I trial showed Vitamin C treatment for sepsis was both safe and effective.2 No patient in either the highor low-dose Vitamin C treatment group was withdrawn or suffered any identifiable negative consequences.

Dr. Fowler’s research team showed that intravenous Vitamin C infusion significantly improved the blood plasma levels of Vitamin C. They demonstrated that SOFA scores, a measure of multi-organ injury, declined significantly in both high- and low-dosage groups. Patients receiving Vitamin C showed a reduction in inflammatory markers: C-reactive protein levels decreased rapidly over the entire four days, and procalcitonin started decreasing at the 12-hour mark. Patients receiving Vitamin C did not demonstrate increased thrombomodulin levels, an indicator of vascular injury, which was observed in the placebo group.

“The results of this study were very exciting. We took the mortality rate from 62 percent to 35 percent, and demonstrated that high doses of intravenous Vitamin C could improve survival, reduce the extent of multi-organ injury and reverse acute lung injury in sepsis patients,” said Dr. Fowler.

PHASE II PROOF OF CONCEPT TRIAL In July 2015, Dr. Fowler’s team was awarded a $3.2 million grant from the National Institutes of Health’s National Heart, Lung and Blood Institute to develop a Phase II proof

of concept trial. Phase II trials study whether a treatment is effective. This multicenter study includes VCU Health as the lead site, along with the Cleveland Clinic, the Medical College of Wisconsin and the University of Kentucky.

For the last two years, the four medical centers have been enrolling patients in a randomized, double-blind, placebo-controlled study to test the efficacy of Vitamin C, given intravenously, as a treatment for acute lung injury in patients diagnosed with sepsis. The goal is to enroll 170 patients across all four sites, and 167 patients have been enrolled to date. Participants are divided into just two groups this time — a placebo and a high-dose Vitamin C group. The high-dose Vitamin C group receives the same treatment as in the Phase I trial.

The research team is tracking SOFA scores and six biomarkers of inflammation and vascular injury. They hope to complete the study by the end of this year and will spend most of 2018 analyzing the data and compiling their findings for publication.

The next step is a Phase III clinical trial, which would involve thousands of patients at multiple sites across the country. After establishing that their treatment is safe (Phase I) and effective (Phase II), the VCU Health researchers will try to show that their treatment is more effective than the current standard of care (Phase III).

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Vitamin C Accelerates Recovery At age 20, patient Kelsey Martin developed acute respiratory failure due to sepsis (her story is on the opposite page). On day 1, her lungs were filled with fluid. The progression of X-rays demonstrates how intravenous Vitamin C enhanced her lungs’ barrier function and ability to clear fluid. The last X-ray shows healthy lungs, filled with air.

DAY 4

ADDITIONAL APPLICATIONS Vitamin C shows promise for treating many other conditions that involve systemic or significant inflammation. Jayanthi N. Koneru, M.D., a cardiologist at VCU Health’s Pauley Heart Center, is currently conducting a study for patients who undergo atrial ablation to treat atrial fibrillation, a condition in which the heart beats irregularly. Pericarditis can be a side effect of this procedure, and his study would determine if Vitamin C treatment could reduce this inflammation of the membrane around the heart.

Another cardiology trial involves elective heart surgery patients. Donald F. Brophy, Pharm.D., chairman of VCU’s Department of Pharmacotherapy & Outcomes Science, is testing whether intravenous Vitamin C could reduce the incidence of atrial and ventricular arrhythmias after open-heart surgery.

Dr. Fowler’s team is in talks with physicians at VCU Massey Cancer Center to develop a trial for patients who receive bone marrow transplants. Graft-versus-host disease is a concern after a transplant because administered donor cells can mistakenly attack a recipient patient’s tissue.

This condition involves severe inflammation that Vitamin C may be able to combat.

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DAY 1

DAY 2

DAY 7

DAY 13 CHECKUP: HEALTHY LUNGS

The VCU Health team is looking into a trial to measure Vitamin C’s effectiveness in treating pulmonary exacerbation (acute respiratory symptoms due to infection) in cystic fibrosis patients. In addition, VCU Health is a member of the PETAL Network, a clinical trials network for the prevention and early treatment of acute lung injury. Dr. Fowler’s team has proposed working with them on a trial involving 2,700 patients to study the use of Vitamin C in preventing acute lung injury.

In addition to sepsis, a number of conditions can cause acute lung injury — toxic inhalation from industrial accidents or house fires, transfusion-associated lung injury and pulmonary aspiration are just a few applications where intravenous Vitamin C treatment could reverse lung damage and save a life.

1. The VCU Health team’s findings were published in Critical Care Medicine (January 2011) and the American Journal of Physiology — Lung Cellular and Molecular Physiology (July 2012).

2. The results of the Phase I trial were published in the Journal of Translational Medicine in 2014 (PMID: 24484547).

Image Credits: Spike Walker/Vitamin C molecule (p. 13); Tom Edwards/illustration (p. 15); Bill Tiernan, The Virginian-Pilot/team photo (p. 16); Alpha A. “Berry” Fowler III, M.D., VCU Health/graph (p. 16), X-rays (p. 18); Leha Byrd, VCU Public Affairs/photo (p. 19).

THE PERSONAL TOUCH

Vitamin C in Action A Positive Outcome Dr. Fowler’s research is already saving lives. He recounted the story of college student Kelsey Martin, who contracted sepsis while abroad.

Though not in his clinical trial, the intravenous Vitamin C treatment protocol established in his research saved her life.

Martin contracted enterovirus D68 while on spring break in Italy. She developed respiratory failure and turned blue on the flight back to the U.S. Despite an expedited landing at Dulles International Airport and being rushed to the emergency room at INOVA Fair Oaks Hospital, the medical team in Northern Virginia was not able to make any progress.

That’s when Vigneshwar Kasirajan, M.D., chair of the VCU Department of Surgery, was called to treat her. He flew up in a VCU LifeEvac helicopter, placed Martin on an extracorporeal membrane oxygenation (ECMO) machine, and brought her back to VCU Medical Center. An ECMO machine adds oxygen and removes carbon dioxide from a patient’s blood.

Martin received Vitamin C treatment the night she arrived at VCU Medical Center. She steadily improved and was off the ventilator by day seven. She was subsequently transferred back to INOVA Fair Oaks Hospital, where she spent one day as an inpatient. When she returned to

her physician in Northern Virginia two weeks later for a checkup, her X-rays revealed two healthy lungs.

“By comparison, the journal Emerging and Infectious Diseases reported a case involving a patient being treated for enterovirus D68 sepsis and acute lung injury at the University of Illinois,” said Dr. Fowler. “That patient spent 42 days on the ventilator and was finally able to leave the hospital on day 55. Kelsey Martin’s case allowed me to see, firsthand, the tremendous results of high-dose, intravenous Vitamin C treatment. We’ve treated other patients and have seen positive outcomes.”

Kelsey Martin (second from left) is now healthy after receiving the high-dose intravenous Vitamin C treatment. Her family, (left to right) Mary Thomson-Martin, Emily Martin and Eric Martin, are also pictured at their home in Clifton, Virginia.

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A Distinction for Diagnosis The Potential to Reduce the Serious Side Effects of Oropharyngeal Cancer

By Eric Peters

A person who battles and survives cancer located in the base of the tongue or tonsillar region (oropharyngeal cancer) will often go on to contend with severe side effects as a result of the radiation therapy they’ve received. They might experience problems digesting or swallowing due to permanently damaged salivary and thyroid glands, or they might suffer bone death in their jaw, which can cause it to become brittle and break.

As frequency of oropharyngeal cancer is rising due to human papillomavirus (HPV) — the most common sexually transmitted infection — these side effects are not going away. Far more people are battling the disease today than they did a generation ago, and many of them might happily trade their cancer in exchange for these possible side effects, but what if they didn’t have to make that trade? What if there were a way to treat people less aggressively to avoid the side effects and still achieve remission?

These are reasonable questions to ask because up to 80 percent of HPV-positive (HPV+) oropharyngeal cancer patients respond very well to treatment, which introduces the possibility that they are being overtreated and could still benefit if they receive less aggressive treatments. A logical step

in exploring this possibility is to begin enrolling individuals in clinical trials that test whether less aggressive treatments are effective (de-escalation trials). The problem with this approach, however, is that until now, no one has been able to predict ahead of time who will be in the group that responds well to treatment and who will be in the group that doesn’t respond well to treatment. This is a serious barrier because those who are in the 20 percent of HPV+ oropharyngeal cancer patients who do not respond well to treatment should not enter de-escalation trials. They need higher levels of treatment in order to have a better chance at survival.

To move toward clinical trials that could alleviate unnecessary side effects for thousands of people, and to allow for better treatment planning, there needs to be a way to identify who will respond well to treatment and who won’t. Iain M. Morgan, Ph.D., director of the VCU School of Dentistry’s Philips Institute for Oral Health Research and member of VCU Massey Cancer Center, together with Brad Windle, Ph.D., associate professor in the Philips Institute and member of VCU Massey Cancer Center, believe they and their team may have found the way to make that identification.

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The research programs at the Philips Institute for Oral Health Research focus on head and neck cancer, bacterial infection and inflammation, bioengineering and health disparities. Here, a research assistant at the institute inspects a petri dish. Allen Jones, VCU University Marketing

MAKING THE DISTINCTION To better understand how to predict which patients will experience positive and negative treatment outcomes, Dr. Morgan and his team set out to determine whether one type of HPV+ oropharyngeal cancer is more aggressive than the other.

They looked at episomal HPV (exists independently in the body) and integrated HPV (has integrated with human DNA). Both episomal and integrated HPV can cause cancer, and in oropharyngeal cancer, neither type has previously been thought to be more aggressive than the other.

Dr. Morgan and his team, however, think this prevailing conclusion about oropharyngeal cancer is wrong, and that integrated HPV+ oropharyngeal cancers do have worse clinical outcomes than the episomal form. This distinction, they believe, is what accounts for the split in patients who respond well and do not respond well to treatment.

In pursuing this conclusion, Dr. Morgan teamed up with Dr. Windle to explore data from The Cancer Genome Atlas project. The Cancer Genome Atlas project was a nationwide collaboration to collect and sequence a host of cancers, including those in the head and neck. Dr. Morgan and Dr. Windle obtained data from more than 500 head and neck cancer samples and analyzed them at the genomic level. Around one-third of the HPV+ samples had episomal

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HPV, and around one-third had integrated HPV. The remaining third showed something unexpected.

“What threw people, and what surprised us, was that we found a third category,” Dr. Morgan said.

The third category they found should have been classified as episomal in the past, but because of a unique interaction it had with human DNA, researchers had always thought it was integrated HPV. This finding was important because when Dr. Morgan’s team properly classified the third category as episomal, the survival rates data showed a clear pattern — integrated HPV is, in fact, more aggressive than the episomal form. This means that by determining whether a patient has integrated or episomal HPV+ oropharyngeal cancer, researchers, clinicians and the patients themselves can be better informed, based on personal needs, when exploring different treatment options such as de-escalation trials.

Identifying the third category also has provided Dr. Morgan and his team information leading to the development of a tool that could enable clinicians to easily make the vital diagnoses mentioned above. When HPV integrates with human DNA, it loses a gene known as E2 and keeps a gene known as E6. Dr. Morgan and his team have developed a fluorescent probe that will show whether E2 and E6 are present in tumors, thus diagnosing whether they are integrated or episomal. His immediate aim is to test

HPV, shown in an artist’s rendering to the right, is viral DNA that occurs in the human body one of two ways. When it first infects a person, it exists and replicates independently in a circle shape — this form is known as episomal. Sometimes the circle breaks and fuses into the host’s human DNA — this form is known as integrated.

this diagnostic tool in HPV+ oropharyngeal cancer samples, and he credits the research’s overall success to the support he’s experienced at VCU Health.

“If we had written a grant to the NIH to support this work, it would not have been funded as it would have been seen as too much of a fishing exercise,” he said. “Only the philanthropic support from the Philips Institute and Massey Cancer Center has allowed us to spend time carrying out this project. In addition, this work was carried out in collaboration with Amy Olex and Dr. Mikhail Dozmorov at the VCU Wright Center for Clinical and Translational Research and, therefore, this project has had input from multiple key centers here at VCU. I think in the end the payoff from this work could be enormous. It’s a new diagnostic approach to HPV+ oropharyngeal cancer that will help stratify patients for correct treatment regimens, which could save them from potentially devastating side effects.”

The Philips Institute The VCU Philips Institute for Oral Health Research was established in 1999 as the Philips Institute for Oral and Craniofacial Molecular Biology.

Original philanthropic gifts of $5 million helped launch the institute.

John F. Philips, D.D.S., an MCV Foundation board member and 1969 School of Dentistry alumnus, made a capstone gift of $1.25 million, honoring the memory of his father who died of throat cancer.

“My hope and mission is

that Dr. Iain Morgan will continue his research focus on head and neck cancer, which will lead to better early detection and treatment,” Dr. Philips said. “There has been very little progress in this area since I graduated in 1969, and I feel that Dr. Morgan is the man to make this progress happen.”

Dr. Morgan has directed the Philips Institute since 2013. Under his leadership, the institute has doubled its number of principal investigators and quadrupled its National Institutes of Health research support.

The research programs in the Philips Institute focus on head and neck cancer, bacterial infection and inflammation, bioengineering

and health disparities. These programs are made possible through close interdisciplinary partnerships with affiliate clinicians and scientists at VCU Health and VCU, including Massey Cancer Center, the Department of Biomedical Engineering, the School of Medicine and the Wright Center for Clinical and Translational Research (CCTR).

Cancer research at the Philips Institute focuses on understanding fundamental genetic and cellular mechanisms that contribute to the formation of cancer and exploring that understanding for therapeutic gain, which is exactly what they’ve done in looking at HPV+ oropharyngeal cancer.

Iain M. Morgan, Ph.D., is the director of the VCU School of Dentistry’s Philips Institute for Oral Health Research and member of VCU Massey Cancer Center. Allen Jones, VCU Marketing

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Making History with the Heart

By Eric Peters

In May 1961, a nationally syndicated article exploring possible scientific breakthroughs for the coming decade predicted the beginning of a race that would change the course of history.

The article, published the same month that President John F. Kennedy declared his intention to send a man to the moon, speculated about a time in the future when heart failure patients might receive heart transplants from car crash victims, and it mentioned two “outstanding” researchers in California who were well on their way to making this science fiction a reality.

“The great heart race has begun,” the article declared.

This Dec. 3 will mark the 50th anniversary of that race’s dramatic conclusion. It is the day the first successful human-to-human heart transplant was performed in 1967.

The procedure’s success was one of the most significant healthcare advancements of the 20th century, and a former Medical College of Virginia surgeon named Richard Lower, M.D., is considered one of its chief architects.

In the late 1950s, Dr. Lower, alongside Norman Shumway, M.D., began extensive research in California to explore the mechanics of what could transform the procedure previously believed to be a surgical impossibility into a feasible practice. The team studied, developed and perfected

many processes critical to heart transplantation, including topical hypothermia, which involved using a machine to oxygenate blood that bypassed the heart so surgeons could remove it, cool it almost to freezing for extended periods of time, and then return the heart to the body in working order.

Another breakthrough came when Dr. Lower suggested that, when removing and replacing a heart, instead of meticulously cutting and suturing every vein, he and Dr. Shumway should cut the heart tissue around the areas where groups of veins connect. Leaving these areas as they were meant Dr. Lower and Dr. Shumway would only have to suture a few times around groups of veins rather than suturing each vein individually.

In 1959, Dr. Lower and Dr. Shumway’s research led them to become the first to successfully complete a heart transplant in an animal model. Their work to hone the procedure is what garnered mention in the 1961 article declaring the beginning of “the great heart race.” At the time, Dr. Lower and Dr. Shumway’s main competitor in the race was Adrian Kantrowitz, M.D., a surgeon at Maimonides Hospital in Brooklyn, New York.

“In those early years they were true explorers, and even icons. … They made the journey into the heart as compelling

Richard Lower, M.D., circa 1977. VCU Libraries

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Richard Lower, M.D. (left), stands with Richard Cleveland, M.D., on the MCV Campus next to a Pemco Heart Pump, which they used to perform the functions of the heart and lungs during heart surgery. VCU Libraries

as the parallel race between the Americans and the Soviets to the moon,” wrote Donald McRae, who authored a book about the race, “Every Second Counts: The Extraordinary Race to Transplant the First Human Heart.”

By 1963, Dr. Lower and Dr. Shumway were well ahead of their closest competitor. They had proven it possible to store a heart in saline for at least seven hours, and were beginning to address the issue of a body rejecting the foreign organ. Newspapers across the country, including The New York Times, had begun to take notice of their work.

“They were moving steadily toward one of the emerging dreams of the twentieth century,” McRae wrote. “Alongside the glorious fantasy of space travel, the heady notion of transplanting a human heart had begun to take hold of America.”

Dr. Lower and Dr. Shumway’s work had also gained the attention of renowned transplant surgeon David Hume, M.D., the chief of surgery at MCV, now called VCU Health.

In 1965, Dr. Hume invited Dr. Lower to join him in Richmond to lead the MCV cardiac surgery program.

With the blessing of Dr. Shumway, Dr. Lower accepted the offer. Suddenly, a new team had entered the race.

Dr. Lower continued his research in Richmond, moving closer each day to the first human-to-human heart transplant. His work at MCV with research partner Richard Cleveland, M.D., included an experiment in which he showed a cadaver’s heart, under certain circumstances, could begin beating again after being transplanted into a living recipient.

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MCV Foundation board member Becky Perdue managed MCV’s transplant program lab in the late 1960s. She said the program was conducting an extensive amount of research at the time, and that Dr. Hume put a premium on proper research that informed decision-making.

“There was no doubt in our mind that we were on the edge of something tremendous,” she said. “We were coming up with proper procedures in donor-matching and other areas.

Many of the procedures were brand-new.”

As Dr. Lower drew closer to his goal, so did his former colleague Dr. Shumway, New York surgeon Dr. Kantrowitz, and several others across the world. During this time, a young South African surgeon named Christiaan Barnard, M.D., visited Richmond for three months to observe and learn from MCV’s transplant team. While in Richmond, Dr. Barnard became intrigued by Dr. Lower’s heart transplant research and studied his techniques intently, eventually becoming infatuated with the idea that he might perform the first human heart transplant. After his brief stay in Richmond, Dr. Barnard returned to South Africa, armed with Dr. Lower’s heart transplant knowledge and a determination to win a race that he knew would bring him immense fame.

“A fevered excitement surged through (Dr. Barnard) that he might beat the cautious Lower and Shumway in replicating the technique in a human,” McRae wrote.

“Barnard could barely believe that Lower and Shumway had not already attempted a transplant in man. He knew that he would be far less cautious than they.”

May 25, 2018, will mark the 50th anniversary of Dr. Richard Lower’s first human-to-human heart transplant, which was the first ever in Virginia.

West Hospital, which opened in 1941, is where Dr. Lower conducted much of his research and performed his first human-to-human heart transplant. Today, West Hospital houses various clinical, administrative and support services of VCU Health. VCU Libraries

The cautiousness McRae referred to had to do with the meticulous patient selection and proper research leading to the informed decision-making that Dr. Lower and Dr. Shumway were especially devoted to. This was evidenced just a few weeks after Dr. Barnard left MCV in 1966 when an opportunity to be the first to cross the finish line presented itself to Dr. Lower and Dr. Hume, who had a patient in need of a heart transplant and a potential donor. The two came as close as anesthetizing the recipient and lining him up next to the brain-dead donor who was soon going to die, but Dr. Lower ultimately refused to proceed because the donor and recipient did not have matching blood types. It was possible for the recipient to survive after an incompatible transplant, but it was also possible that the transplant could cause death.

“This was not how he had imagined the first transplant — marching in despite a blood mismatch,” wrote McRae. “It didn’t feel right.”

By November 1967, Dr. Shumway had identified his own patient who would be an ideal candidate to receive a transplant. He was quoted in the Journal of the American Medical Association saying that the time had come to perform the first human heart transplant trial, and thus he waited for the right donor.

On Nov. 22, 1967, Dr. Barnard had a recipient, Louis Washkansky, and a donor on the operating table, ready to begin his first attempt at the procedure, but the team backed out at the last moment because the donor heart was damaged.

On Nov. 24, 1967, Dr. Kantrowitz also identified a recipient,

a 6-day-old baby. He sent a telegram to 500 hospitals across the U.S. asking for a donor, and then he too waited.

On Dec. 3, 1967, Dr. Barnard found a new donor for Mr. Washkansky and successfully performed the world’s first human-to-human heart transplant in South Africa. The procedure was completed under the same circumstances that the 1961 article predicted. The donor, a 25-year-old woman named Denise Darvall, was brain-dead following a car crash.

During this race, Dr. Lower, Dr. Shumway and Dr. Kantrowitz faced both internal and external hurdles that Dr. Barnard did not. Their attention to donor selection and blood-matching was meticulous, but most limiting was U.S. legislation that could charge a surgeon with murder if he removed the beating heart from a brain-dead patient.

When the circumstances were right, Dr. Kantrowitz subsequently completed his first human-to-human heart transplant on Dec. 6, 1967, and Dr. Shumway completed his on Jan. 6, 1968. Dr. Lower’s first human-to-human heart transplant came in May 1968. It was the first such procedure in Virginia, and he would go on to take part in 393 heart transplants before he retired in 1989.

Dr. Lower and Dr. Shumway were pioneers in the field of heart transplantation, and along with Dr. Hume and others, Dr. Lower was a pioneer at MCV. He helped lay the foundation for what is today one of the busiest transplant programs in the nation — the VCU Health Hume-Lee Transplant Center — and the second oldest heart transplantation program in the U.S., which is part of VCU Health’s Pauley Heart Center.

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Massey Leads Paradigm Shift Pancreatic Cancer Treatment Aims to Improve Outcomes

By Alex Henley

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Pancreatic cancer is not the most common form of

cancer but, sadly, it’s one of the most aggressive. In 2016, an estimated 53,070 people were diagnosed with the disease and 41,780 succumbed to it, according to the National Cancer Institute.

“In this disease, time is of the essence,” said Brian Kaplan, M.D., surgical oncologist and director of VCU Massey Cancer Center’s Pancreas and Biliary Neoplasm Program. “Many patients don’t experience a lot of symptoms in the early stages, before the cancer grows or metastasizes. The location of the pancreas makes surgery difficult to achieve clear margins.”

The pancreas is a pear-shaped gland that aids in digestion and blood sugar regulation. It is located deep in the abdomen, surrounded by the stomach, small intestine, liver, spleen and gallbladder. Tumors are often not felt by the patient or even when palpated by a physician until they become quite large. There is also a high degree of vasculature surrounding the pancreas to supply blood to all of the vital organs in the abdomen.

The traditional standard of care for patients with operable pancreatic cancer is to go quickly to surgery first, and then follow up with chemotherapy and/or radiation therapy.

However, due to the challenging location of the tumor, many patients are left with positive margins after surgery.

What’s a margin? When a tumor is removed, doctors take out extra tissue around the tumor, called the margin.

Pathologists examine the resected tumor and margin to see if all of the cancer cells were removed. The goal is to remove the entire tumor and find that there is a clear margin surrounding the tumor, free of cancer cells. A negative or clear margin means that the tissue surrounding the excised tumor is negative/clear of cancer. A positive margin means that the tissue surrounding the excised tumor has tested positive for cancer cells.

RETROSPECTIVE STUDY LAYS THE GROUNDWORK FOR A PARADIGM SHIFT Emma Fields, M.D., radiation oncologist and member of the Developmental Therapeutics research program at VCU Massey Cancer Center, led a study to look back and analyze patient outcomes using the traditional standard of care.

“I worked with a really dedicated medical student, Justin Anderson. We pulled the charts of all of the patients who had surgery for pancreatic cancer at VCU Health from 2003–2015,” said Dr. Fields.

“Of the 71 patients we studied, about 40 percent had positive margins after surgery. We looked at all of the treatments patients received after surgery — all negative and positive margin patients received chemotherapy, and about half in each group received radiation. We then compared all of this data with patient outcomes to see if giving chemotherapy and/or radiation therapy after surgery made up for having a positive margin.

“It didn’t. We found that the positive margin trumped all, regardless of the amount or type of therapy given after surgery,” said Dr. Fields.

The traditional standard of care for pancreatic cancer involves a Whipple procedure, a drastic surgery that involves removing the head of the pancreas, gallbladder, common bile duct and part of the small intestine, and then reconnecting the remaining digestive organs so the patient can process food.

“That’s a lot to put patients through and still have the possibility of residual cancer cells. This retrospective analysis prompted us to question how we can change the paradigm and investigate giving patients neoadjuvant (pre-operative) therapy to see if we could shrink the tumor before surgery. This not only increases the chance of a negative margin outcome, but also allows us to include some candidates that were previously deemed inoperable.” 1

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“The paradigm shift here is to give as much treatment as possible before the surgery...The goal is to have a successful negative margin surgery, because you only get one shot at a curative surgery for pancreatic cancer.”

Emma Fields, M.D., radiation oncologist

What is a Margin?

In pancreatic cancer, it’s all about the margins and whether the surgeon is able to remove all of the cancer cells during surgery. Surgical resections are classified into two main categories: Negative or Clear Margin: A complete removal of cancerous cells during surgery; the margin of tissue around the tumor is negative/clear of cancer.

Positive Margin: Microscopic or visible amounts of cancerous cells remain after surgery; the margin of tissue around the tumor tests positive for cancer.

The data shows that giving chemotherapy and/or radiation therapy after surgery does not make up for having a positive margin.

Negative

Positive the edge normal tissue cancer cells

Illustration: Tom Edwards

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A SHIFT T O THERAPY BEFORE SURGERY In support of this paradigm shift, Dr. Fields is working on a Phase I clinical trial with Andrew Poklepovic, M.D., medical oncologist and member of the Developmental Therapeutics research program. They are investigating the use of neoadjuvant (pre-surgical) therapy, which consists of at least two months of standard chemotherapy followed by concurrent chemoradiation (chemotherapy and radiation) for five-and-a-half weeks. Radiation is given every day, and the chemotherapy regimen includes three drugs, given in pill form, three times per week. The chemotherapy drugs have been approved by the FDA for other types of cancer, but have not yet been used neoadjuvantly in pancreatic cancer.

As this is a Phase I trial, focused on determining the safety of the treatment, a traditional 3+3 dose escalation is being used. This means three patients start at the lowest dose, and if all three tolerate the treatment well, the researchers move the next three patients up to a higher dosage level, and so on, to test the safety and effectiveness of three dosage levels.

The trial began in 2015 and is expected to run through July 2018. The VCU Health team has enrolled 12 of the expected 36 patients, and the therapy has been well-tolerated to date.

“The paradigm shift here is to give as much treatment as possible before the surgery by targeting the cancer cells from different angles,” said Dr. Fields. “The goal is to have a successful negative margin surgery, because you only get one shot at a curative surgery for pancreatic cancer.”

Lillian Redd (front center), a pancreatic cancer survivor, rejoins her treatment team in VCU Massey Cancer Center’s healing garden. (From left to right) Brian Kaplan, M.D., surgical oncologist and director of VCU Massey Cancer Center’s Pancreas and Biliary Neoplasm Program; Andrew Poklepovic, M.D., medical oncologist; Jennifer Myers, M.D., medical oncologist; Paul Dent, Ph.D., Universal Corporation Chair in Cancer Cell Signaling; and Emma Fields, M.D., radiation oncologist.

Read Lillian’s story on the next page.

Kevin Schindler

ADDING THE CIVASHEET®: VCU HEALTH IS FIRST TEAM IN THE WORLD TO SUCCESSFULLY IMPLANT DEVICE Dr. Fields is also the lead investigator for VCU Health on another Phase I clinical trial using the CivaSheet®, a brachytherapy device, which is a sheet placed near the tumor so radiation can be given at a short distance. The CivaSheet® is implanted in patients during the Whipple procedure if the surgeon is concerned that the margins might be close.

It contains a radioactive isotope, Palladium-103, which releases radiation. With a half-life of 17 days, the palladium decays and becomes inert in 50 –70 days. For this trial, it’s only being used on patients who have received the pre-surgical therapy protocol described previously.

“It’s a very cool technology,” said Dr. Fields. “It delivers the radiation in one direction, where it’s needed, but it’s shielded on the other side so no radiation goes to the surrounding organs. This is especially important because the intestines do not tolerate radiation well. The sheet itself is bioabsorbable and disappears in a few months.”

In May, Dr. Fields, Dr. Kaplan and Dorin Todor, Ph.D., medical physicist and director of the Brachytherapy Program at Massey, led the first team in the world to implant the CivaSheet® in a patient. So far, the Massey team has implanted the device in two patients. You can learn more about one of these patients, Lillian Redd, in the story on the following page.

The Phase I clinical trial is being led by CivaTech Oncology Inc., supported by a $2.3 million grant from

The implantable, bioabsorbable CivaSheet® allows for unidirectional radiation therapy to target cancer cells while shielding healthy tissue.

Courtesy of CivaTech Oncology Inc.

the National Institutes of Health National Cancer Institute Small Business Innovation Research Fast Track Program.

Four centers are enrolled in the two-year study — East Carolina University, Fox Chase Cancer Center, Rush Medical Center and VCU Massey Cancer Center. The study began in September 2016 and the researchers hope to enroll 6–18 patients in the 3+3 dose escalation design.

“There are endless possibilities for this technology,” said Dr. Fields. “It can be used in a targeted way for patients who have recurring gastrointestinal or gynecologic tumors to preserve the health of the intestines, as well as for sarcomas on the nervous system. It’s all about improving the margins and giving people a chance at a better outcome.”

1 The results of this study were published in the Journal of Gastrointestinal Oncology (December 2016).

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THE PERSONAL TOUCH

Lillian Redd is the Second Recipient in the World to Receive the CivaSheet®

Lillian Redd has received two of the clinical trial treatments described previously, and they saved her life.

On Aug. 8, 2016, Redd felt a pain on her right side. She thought maybe she had eaten some bad fish or possibly had appendicitis. “I couldn’t get to sleep and felt restless, so I went to the local emergency room (not VCU Health),” said Redd. “They took my labs and my amylase was elevated, so that led them to focus on my pancreas. They found a mass on my pancreas and I had an endoscopy. The doctor told me right away ‘You have pancreatic cancer.’”

Redd was healthy and hadn’t shown any signs of illness up to that point.

Two years prior, her sister had died of pancreatic cancer in just three short months. Redd decided she was going to do whatever she could to beat this disease.

She began researching the disease to find a treatment center. Redd knows a little about research — she is an electronic resource specialist at VCU Cabell Library in the Metadata and Discovery department. She decided on VCU Massey Cancer Center, partly because it is an NCI-designated center.

“My first appointment with Dr. Kaplan, surgical oncologist, and his resident doctors gave me the opportunity to ask questions about my care and see an actual physical model demonstration of a pancreas

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with a tumor attached — I was impressed!” said Redd.

“I had read about clinical trials during my research and volunteered to participate in two trials: the first was the chemotherapy and radiation before surgery, and the second involved having the CivaSheet® installed during my Whipple surgery on May 22, 2017.

“It just felt good to have people helping you who were so friendly and compassionate. I never felt like a number, and that really helped with the stress. The doctors and nurses took the time to explain everything. Even the man pushing me on the stretcher — everyone would talk to me and you could tell that they really cared.

“Everything went well and I’m feeling great! One time, I forgot that I didn’t have the same stomach capacity as before, so I got a little sick after I ate too much. Dr. Kaplan called me back right away and even gave me his cellphone number. I couldn’t ask for better care.”

The opportunity to give back by participating in clinical trials that could help others was also a motivating factor for Redd. “To help alleviate the pain and suffering of others is a blessing,” said Redd. “That’s what I’m here for — to help others.”

Redd returned to work in August, almost a year after her ordeal began.

Lillian Redd. Kevin Schindler

She wrote this tribute to all of those who helped her.

To Doctors Myers, Kaplan and Fields, who became more than physicians, but attendees in my care, To the clinical trials director and nurses who really provided feedback and insight and who were available most all the time, To the intake receptionist at the oncology clinic who guided me when I lost my direction (a few times), To the medical assistants who took my vitals (all the time; over and over and over), To the valet service driver who gave me a pleasant greeting that made my first drive to Massey Cancer Center more relaxing, Thanks to all of you for what you do.

I have received and continue to receive the best of care from Massey Cancer Center. – Lillian Redd

NEXT is published by the MCV Foundation to share the latest breakthroughs occurring at VCU Health and the positive impact these exciting innovations have on our patients.

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Eric Peters GRAPHIC DESIGN:

Big River Advertising SCIENTIFIC ADVISORY PANEL:

Joseph T. DiPiro, Pharm.D. Alpha A. “Berry” Fowler III, M.D. Steven R. Grossman, M.D., Ph.D. F. Gerard Moeller, M.D. Jerome F. Strauss III, M.D., Ph.D. Wanchun Tang, M.D. The Medical College of Virginia Foundation was established in 1949 to inspire and steward philanthropic resources for our MCV Campus Partners at VCU Health.

The MCV Foundation manages more than $500 million in assets to ensure VCU Health remains at the forefront of excellence and innovation in patient care, research and education as one of the top academic health centers on the East Coast. Through our 1,500 funds, the MCV Foundation provides scholarships, professorships, research and program funds to support the life-saving work occurring at VCU Health every day.

The MCV Foundation’s campus partners include: VCU School of Allied Health Professions, VCU School of Dentistry, VCU School of Medicine, VCU School of Nursing, VCU School of Pharmacy, VCU Massey Cancer Center and VCU Medical Center.

In our next issue, we will explore VCU Health’s latest

To learn more, visit : www.mcvfoundation.org

research on lyme disease and our partnership with

Please address comments or subscription requests to:

the Hunter Holmes McGuire VA Medical Center using

Alex Henley MCV Foundation 1228 East Broad Street Box 980234 Richmond, VA 23298 alex.henley@vcuhealth.org

deep brain stimulation technology to help veterans and members of the community with movement disorders like Parkinson’s disease.

NON-PROFIT ORGANIZATION US POSTAGE PAID PERMIT NO. 1182 RICHMOND, VA Box 980234 Richmond, Virginia 23298-0234

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