Advance Research Digest - Summer 2016

ADVANCING RESEARCH FROM LAB TO LIFE A Biannual Research Digest of the University of Tennessee Medical Center

Improving Patient Outcomes Through Research

On the Horizon: Advanced Liver Cancer Clinical Trial

Research Spotlight: Collmann Research Success

Studies in Brief:

• Alzheimer’s Trial • Pot of Gold Awards • Dr. Zite Receives Grant Funding • Therapeutic Approaches to Hypogonadism • Seed Funding for Collaboration

Summer 2016

Wisdom for Your Life.

Spirit of Discovery…

Observations

Table of Contents

The current issue of advance highlights a theme that is integral to research success at UTMC-collaboration.

Collaboration such as that exemplified by the Pot of Gold grants is the mainstay of current research efforts. Team research is emphasized by the NIH when funding is considered.

Understanding that less than 20% of new NIH R01 applications are funded, it is felt that the chances for funding are increased when a team of scientists is working on a research projects. One of the requirements of the Pot of Gold grants was that two laboratories one from UTGSM, UTK or UTIA had submit a novel collaborative proposal for consideration. As a result, three innovative projects from collaborations with UTGSM researchers that could have profound impact on vascular disease, cervical cancer and colonic endoscopy were funded. Collaboration also comes in the form of clinical trials. UTMC has been involved in some trials that are on the cutting edge of cancer therapy, Alzheimer’s disease and hypogonadism, leading the way to provide advanced therapy to our patients. Funding for research is always a project and UTMC researchers strive to get a good percentage funded through grants. However, even the best research medical organizations are dependent on clinical dollars, state funding or generous donors. We continue to strive to meet the “discovery” mission of the Medical Center.

Featured Researcher: Bruce Ramshaw 2 Advanced Liver Cancer Clinical Trial Collmann Research Success In Brief: Alzheimer’s Trial In Brief: Pot of Gold Awards In Brief: Dr. Zite Receives Grant Funding

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In Brief: Therapeutic Approaches to Hypogonadism

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In Brief: Seed Funding for Collaboration

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News

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Advance

Issue 12: Summer 2016 Publishers James Neutens, Ph.D. Mitch Goldman, M.D. Managing Editors Kristen Vandergriff, M.S. Rachel Echols Contributors Mitch Goldman, M.D. Kandi Hodges Photography Kandi Hodges Design Jerry Tracy/J Squared Graphics Advance is produced by the University of Tennessee Graduate School of Medicine. The mission of the digest is to spotlight research programs at the institution and explain how the work of our researchers impacts health care in East Tennessee and beyond.

Institutional Review Board All research using human volunteers follows stringent federal regulations that require a review by an Institutional Review Board (IRB) before it is approved. The IRB committee is comprised of physicians, pharmacists, scientists, researchers and non-scientific community representatives. The members review research protocol to ensure protections are in place.

Faculty from the UT Graduate School of Medicine influence medical care across the world by publishing and presenting.

For a comprehensive list of publications and presentations, visit http://gsm.utmck.edu/scholars Contact Us Advance UT Graduate School of Medicine Kristen Vandergriff 1924 Alcoa Hwy., Box 93, Knoxville TN, 37920 Telephone: 865-305-9749 E-mail: klvandergriff@utmck.edu Web: http://gsm.utmck.edu

Mitchell H. Goldman, M.D.

Assistant Dean of Research University of Tennessee, Graduate School of Medicine

Wisdom for Your Life.

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FEATURED RESEARCHER »»»»»»

New Surgery Chairman Dr. Bruce Ramshaw Improving Patient Outcomes Through Research and decrease costs. In researching hernia repair specifically, patient outcomes have been negative, often requiring the patient to undergo multiple surgeries. Dr. Ramshaw hopes to use the data and research to discover the best methods to improve patient care but also decrease the number of future surgeries.

One of the main components of improvement is developing better materials for hernia repair with the assistance from biomedical engineers.

The project will be presented this spring to engineers at the University of Missouri.

A native of Florida, Dr. Ramshaw completed his undergraduate and graduate degrees at the University of Florida in Gainesville, Florida. Both his General Surgery internship and residency were completed at Georgia Baptist Medical Center in Atlanta, Georgia. Prior to his appointment at the University of Tennessee Graduate School of Medicine, Dr. Ramshaw was Chairman of Halifax Health General Surgery Residency Program in Daytona Beach, Florida. He has held previous appointments as Clinical Associate Professor at Florida State University School of Medicine, Assistant Professor at Emory University School of Medicine and Clinical Assistant Professor at the Medical College of Georgia.

Hospital appointments included Director of the Emory Hernia Institute and Director of Education for the Endosurgery Unit at Emory University Hospital and Director of Telemedicine and Robotic Surgery at Atlanta Medical Center.

The Department of Surgery recently named Bruce Ramshaw, M.D., FACS, Chairman and Professor of the Department of Surgery. Dr. Ramshaw began his position on October 1, 2015 and is eager to bring his ideas to an evergrowing department.

One of Dr. Ramshaw’s main focus for the future of the department is measuring the value of patient care in order to improve healthcare; by understanding the patient’s perspective, addressing problems, and working as a team. “I see an opportunity to develop an infrastructure to support improving the value of care we provide for patients and to support bringing innovative ideas to the patient through the commercialization process” he said. He does not view these goals as too challenging, citing the unique leadership between surgeons, the Graduate School of Medicine, hospital leaders and patients in our complex healthcare environment. Dr. Ramshaw is also focused on targeting disparities and improving value for the underprivileged populations in east Tennessee.

Currently Dr. Ramshaw is coordinating a major research project on clinical outpatient improvement with a group of researchers and engineers from both the University of Tennessee, Knoxville, campus and the University of Missouri, Columbia, where he previously served as Chief of General Surgery.

The research will focus on real world patient data and how to affectively measure data in order to improve the outpatient experience 2

Dr. Ramshaw is also the founder and former Chairman and Chief Medical Officer for Surgical Momentum, an AHRQ designated Patient Safety Organization, based in Daytona Beach, Florida. He previously served as Co-Director for Advanced Hernia Solutions and for the Biomaterials, Innovation, Characterization and Analysis of Missouri Lab (a Biomaterials Laboratory).

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FEATURED RESEARCHER »»»»»»

Advanced Liver Cancer

Liver cancer (hepatocellular carcinoma, or HCC) is the third most common cause of cancer deaths worldwide. The cancer results primarily from fibrosis and damage of the liver, is managed through either transplant, surgical resection, or by a variety of interventional radiology procedures characterized as “liver directed therapy”.

These treatments have good results for management of liver cancer when the tumors are limited in size or distribution in the liver.

However, patients that relapse or do not respond to these therapies, or who have too high a cancer burden for these treatments are left with only one FDA approved chemotherapy treatment in the form of sorafenib (Nexavar). Life expectancy in patients with a new diagnosis of HCC is 6 to 9 months, on average.

While sorafenib has been shown to provide

a clinically significant increase in survival time for patients with advanced HCC, this benefit is measured in months, and the agent does not provide a cure. Researchers are actively pursuing improved survival from HCC in the form of novel therapies, because the rate of HCC is growing due to increases in rates of viral hepatitis and obesity in the population. Importantly, HCC is one of the only cancers with an increasing rate in developed countries, with 25,000 new cases in the United States each year.

The University of Tennessee Medical Center is fortunate to have an opportunity to participate in a Phase III clinical trial of a novel HCC treatment agent in the form of Pexa Vec. This agent is a form of “oncolytic immunotherapy”, meaning that it is a common vaccine that has been changed to have a specific affinity for replicating in and 4

Clinical Trial

destroying cancer cells. It has also been shown to damage the blood supply to the tumors, and stimulate the body’s own immune system to fight the tumors.

The technique for delivery of the treatment agent is by injection directly into liver tumors.

Using a CT scanner for guidance, a needle is inserted through the skin and into the liver, and directly into the tumor. Through the needle, a liquid containing the treatment drug is injected, allowing the therapy to be delivered directly to its site of activity. The treatment includes 3 separate injections of the agent, two weeks apart. Following the injection series, patients are placed on the standard of care medication, sorafenib, and are followed over time for response to therapy.

The active agent in Pexa Vec has been tested in 13 clinical trials, and there have been hundreds of prior intravenous and

intratumoral injections to date. In this trial, 600 patients will be randomly assigned to standard of care (sorafenib) or Pexa Vec followed by sorafenib, so that 300 patients will be treated in each “arm” of the study, to compare the outcomes between the two treatment options.

“Having been involved in a prior clinical trial using Pexa-Vec, I remain excited about the potential this new cancer immunotherapy holds,” said Laura Findeiss, M.D., Chair of the Department of Radiology and principal investigator of the study at The University of Tennessee Medical Center and UT Graduate School of Medicine. “At The University of Tennessee Medical Center, we are at the forefront of bringing innovative cancer treatments to patients, as exemplified by having enrolled the first North American patient into the PHOCUS trial.”

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Student Research Program Inspires a Future Physician A summer research opportunity turned into a year-long research position and helped change the course of an aspiring doctor’s career goals.

Adrianna Eder participated in the 2015 I. Reid Collmann, MD, Research Endowment program, learning about basic science research through Surgery’s Division of Trauma and Critical Care under the direction of Michael Karlstad, PhD, whose research is supported by National Institutes of Health funding. The goal of the Collmann program is to equip medical students with a solid foundation in research so that they can see firsthand how basic science research affects patient care.

Eder said that as a Collmann fellow, she was able to see physiology in action, investigating the factors that affect pancreatic beta cell function (the pancreatic cells that control blood glucose), ultimately helping patients with diabetes.

“Clinical relevance gives this research special significance, and each experiment was designed with the diabetic patient in mind,” Eder said. “My experience as a Collmann fellow solidified my interest in both clinical medicine and basic research.”

After the summer program concluded, Eder continued working in Dr. Karlstad’s lab as a research assistant and was recently awarded a competitive travel grant by the Shock Society to attend the 39th Annual Conference on Shock in June 2016 for her first-authored abstract, “Atmospheric Plasma: A Novel Approach to Wound

Disinfection in a Murine Model,” coauthored by M Wintenberg, A Wintenberg, J Collier, E Karlstad, P Mitchell, P Coan and Dr. Karlstad.

In the fall, Eder will begin medical school at the UT Health Science Center in Memphis, with the hopes of pursuing a career in academic medicine.

She said, “Physician-scientists impact more than the quality of their own patients’ lives; they change the way medicine is practiced by all physicians, and that is why I want to incorporate research into my clinical career.”

Eder’s career path wasn’t always obvious to her. Before she discovered her passion for research, she planned to pursue a dual MD/ MBA degree because she was interested in healthcare management. However, before she ever envisioned herself as a doctor, she wanted to heal people through nursing. She said, “I realized I wanted an education that would allow me to contribute to integrated medicine and improved patient care. My interests were fashioned into an Integrated Studies degree, with concentrations in biology, pre-medicine and accounting. For better or worse, medicine and business are becoming increasingly integrated, so my coursework was carefully designed to prepare me for a career in healthcare as the kind of physician-leader I wanted to be.”

Then, Eder worked in a research lab at UT Chattanooga as part of her senior thesis project and received an Honorable Mention for the Barry Goldwater Scholarship, the 6

premier undergraduate scholarship for students doing research in the sciences.

“I learned the importance of understanding why, in addition to knowing what,” Eder said. “I found myself excited about the clinical relevance of the skills I acquired in the lab, and it was then that my interest shifted from the integration of medicine and business to the integration of medicine and basic research.”

Eder said the Collmann experience solidified her new career path as a physician

in academic medicine, and she learned that working in a lab allows her to apply business management skills, too. “Dr. Karlstad is an amazing mentor. I learned not only about research but also about the resources needed to keep a lab running. He’s extremely business savvy.”

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IN BRIEF »»»»»»

Alzheimer’s Trial

Alzheimer’s disease (AD) is a progressive Center, Associate Professor of Neurology. neurodegenerative disorder characterized by “This clinical study is an important step in cognitive decline and behavioral disturbances our effort to find potentially meaningful that eventually result in a person’s inability treatments for this disease.”

A novel and key aspect of this study, is that to perform daily activities. An estimated 5.3 it takes advantage of new imaging compounds million Americans have Alzheimer’s disease1. designed specifically for Evidence suggests that normal brain amyloid imaging in the pathophysiological changes brain to assess patient typically begin years prior to eligibility and drug efficacy, the symptoms that lead to said Dustin Osborne, PhD, a clinical diagnosis. As the Director of the Molecular disease progresses, cognitive Imaging and Translational impairments, behavioral Research Program. Use changes and functional of these novel tracers disability commonly requires advanced imaging associated with AD begin capabilities and a particular to manifest.

The University of level of expertise with the Tennessee Medical Center’s use of novel tracers.

Brain and Spine Institute The ENGAGE and and UT Graduate School EMERGE trials is a global of Medicine’s Molecular Phase 3 clinical study Imaging and Translational to assess the potential Research Program are efficacy and safety of an actively participating in investigational compound amyloid positive a clinical research study being developed for the designed to evaluate the treatment of Alzheimer’s safety and potential efficacy disease. The trial is being of an investigational conducted at approximately medication to determine 150 sites in more than 20 whether it slows the countries in North America, progression of symptoms of Europe and Asia Pacific.

Alzheimer’s disease, such as For more problems with memory or information, visit thinking clearly. adacanumabclinicaltrials.

“We have a longstanding com or clinicaltrials.gov commitment to improve (NCT02477800). the treatment and care ENGAGE/EMERGE Site of those affected with Recruitment Template Alzheimer’s disease,” said Press Release Dr. John H. Dougherty, August 10, 2015 Director, Cole Neuroscience AD-US-0168(1)

Why this matters:

Early Alzheimer’s intervention is critical to stopping or slowing the progression of disease.

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IN BRIEF »»»»»»

Pot of Gold Awards

2015-2016 “Pot of Gold” teams are: • Shawn Campagna, PhD (UTK) and Brynn Voy, PhD (UTIA) - “Cholesterol Metabolites-Metabolic Mediators of Adipocyte Metabolism”

Six collaborative University of Tennessee research projects have received $10,000 grants through the “Pot of Gold” program.

The “Pot of Gold” is sponsored and equally funded by the UT Graduate School of Medicine (UTGSM); UT, Knoxville (UTK); and the UT Institute for Agriculture (UTIA), to foster new and innovative research projects involving cross-campus collaborations that demonstrate a strong potential of eventually attracting significant extramural funding.

This internal funding opportunity evolved from an idea put forth by Mitchell Goldman, MD, Assistant Dean for Research at UTGSM, to researchers asking, “What would you do if you had some funding to support an entirely new collaborative research project?” In its inaugural year, the program funded two projects with a total of $15,000.

Dr. Goldman and Janet Nelson, PhD, Associate Vice Chancellor for Research and Development, aimed to significantly increase funding for the second year. They put a team of staff members together to update the proposal criteria and hosted an information session for all faculty members.

This year, the program has expanded and exceeded expectations. The institutions were able to increase funding to this year’s “Pot of Gold,” which is equally funded through UTK, UTGSM and UTIA, to support six one-year grants of $10,000 each, selected from 22 high-quality proposals.

• Shigetoshi Eda, PhD (UTIA), Jayne Wu, PhD (UTK), and James McLoughlin, MD (UTGSM) - “Proof-of-Concept Study for Development of a Cervical Cancer SelfTesting Device” • Tim Sparer, PhD (UTK) and Tom Masi, PhD (UTGSM) - “CMV’s Infection and Alteration of Stem Cell Adipogenesis” • Deidra Mountain, PhD (UTGSM) and Michael Best, PhD (UTK) - “The Development of a Dual-Ligand PEGylated Liposome Nanotechnology for CellSelective Targeted Vascular Gene Therapy” • Daniel Caleb Rucker, PhD (UTK) and Andrew Russ, MD (UTGSM) - “A Robotic System for Colonoscopic Surgery” • Andy Sarles, PhD (UTK) and Scott Lenaghan, PhD (UTIA) - “Tissue-like Biomimetic Materials Incorporating PlantBased Aquaporins” UTGSM Dean James Neutens, PhD; UTK Associate Vice Chancellor for Research Development Janet Nelson, PhD; and UTIA Ag Research Dean William Brown, PhD, congratulate the recipients for their awards and commend all of the applicants for their innovative ideas and excellent applications.

Why this matters:

Funding collaborative grants helps researchers put together stronger applications for larger scale funding.

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IN BRIEF »»»»»»

Dr. Zite Receives Grant Funding

Nikki Zite, M.D., Professor of Obstetrics and Gynecology at University of Tennessee Medical Center has received a grant from The National Institute of Reproductive Health (NIRH).

Last spring, NIRH put out an announcement for proposals aiming to help advocates work towards making immediate post-partum Long Acting Reversible Contraception (LARC), such as intrauterine devices (IUD) and implants, available in their states. Dr. Zite had already been working with Tenncare and advocating on a series of contraceptive initiatives to decrease unplanned pregnancy in Tennessee, and knew that this proposal was a perfect fit for her research and advocacy goals.

Dr. Zite, along with colleagues from Vanderbilt and SisterResearch (a Reproductive Justice Not-for-profit based in Memphis, Tennessee), were each awarded $20,000 specifically to advocate to make postpartum LARC a reality in Tennessee. Most of the funding will be used to meet with stakeholders in Nashville and to produce material to educate key decision makers, physicians, and women about immediate post-partum LARC. As of July, 2016, Dr. Zite’s advocacy has led to women on CoverKids getting access to all forms of contraception. Prior to these changes, CoverKids recipients had pregnancy coverage only and could not obtain any contraception after the delivery of their child, even a tubal ligation at the time of a cesarean section.

Now they have the same benefits as other Tenncare recipients and will be at lower risk for a rapid repeat pregnancy or any unintended pregnancies. In addition, as of August 2016, CoverKids and Bluecare will cover LARC insertions in the postpartum period. This means women desiring LARC while they are in the hospital for their delivery or within 8 weeks of their delivery can obtain those devices, making these safe and effective options a possibility.

Why this matters:

The availability of post-partum LARC will decrease unplanned pregnancies in Tennessee.

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IN BRIEF »»»»»»

Therapeutic Approaches to Hypogonadism The use of testosterone therapy has become commonplace for hypogonadal men. These men typically have symptoms such as low libido, fatigue, erectile dysfunction and decreased energy, accompanied by two low morning serum testosterone levels. Current therapies such as injections, topical gels, and subcutaneous pellets can effectively raise serum testosterone levels, but have the unwanted side effect of decreasing sperm production. Hypogonadism is a common problem in men wishing to become fathers.

For men interested in maintaining their potential to become fathers and to avoid testicular shrinkage, use of testosterone therapies is less than ideal.

A focus of Dr. Kim’s research has been with alternatives to testosterone replacement. Use of selective estrogen receptor modulators (SERMs) can restore testicular production of testosterone, rather than simply replacing deficient serum testosterone levels. Currently, there are not FDA-approved SERMS for treating men, although clomiphene citrate has been used off-label. SERMS have an additional advantage of being a pill, rather than a shot or a topical product. Dr. Kim has worked extensively with oral enclomiphene and fispimiphene.

His research paper “Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men,

unlike topical testosterone: restoration instead of replacement” was selected as the Article of the Month for the BJU International. This study represents level 1 evidence as presented in a prospective, randomized, active comparator trial. The significance of this work is that it provides the most detailed analysis of a selective estrogen receptor modulator for the treatment of secondary hypogonadism due to excess weight, which has become epidemic worldwide. Oral enclomiphene effectively raises serum testosterone levels without suppressing spermatogenesis.

The path to FDA-approval of novel therapies is a long and arduous process.

However, there is a clear patient need for novel therapies.

Why this matters:

Replacing the current forms of testosterone therapies with alternatives would allow male patients the benefit of increasing testosterone levels without the unwanted side effects, especially those which affect reproduction.

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IN BRIEF »»»»»»

Seed Funding for Collaboration

A team of researchers from Oak Ridge National Laboratory (ORNL), ProNova, and the University of Tennessee’s Medical Center have won a $100,000 seed funding award that is part of a larger NIH funded Clinical and Translational Science Award (CTSA) project, including the Georgetown School of Medicine.

This award will be used to develop early publications and feasibility testing of multiple motion correction technologies that can be used to improve proton therapy targeting in the presence of motion. This work will examine multiple imaging modalities combined with multiple internal and external tracking technologies, all coupled with patient motion simulation to provide accurate assessment of patient motion during proton therapy. Funding for this project will be used to cover student and materials cost to perform this early

assessment work which will be used in larger grant submissions.

Funds allocated to the Graduate School of Medicine, will be used to fund a Computer Science Ph.D. candidate in the Molecular Imaging and Translational Research Program (MITRP) beginning in August. This student will work with Dusting Osborne, Ph.D., focusing on the further development of patentpending tracking technologies developed by the MITRP, as well as technologies being developed in conjunction with other consortium collaborators. The primary goal is to create clinically useful, real-time methods of assessment for proton therapy planning and delivery. As part of this work, the student will have a unique educational experience that will combine aspects of imaging and therapy across multiple institutions and imaging systems.

Why this matters:

Accurate dose delivery in proton therapy is critical for a successful treatment outcome.

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News»

Completion of major Siemens PET/CT

Datta Receives Award

research collaboration

At the end of December, researchers in the molecular imaging program completed a million dollar research collaboration with Siemens Medical Solutions. This collaboration provided novel PET/CT imaging technologies at the University of Tennessee Medical Center that has provided novel research publications as well as true clinical benefits to our patients. One example of the clinical impact of this collaboration was the expansion of patient access to advanced imaging technologies for respiratory motion correction.

Prior to this collaboration, motion corrected studies were only performed when specifically requested. Following this collaboration, we were able to provide motion corrected imaging on all lung, pancreatic, gastric, and liver patients which improved imaging for approximately 60% of our patient population. The advantages of respiratory motion correction on imaging studies is improved quantification, improved image quality and resolution, and improved diagnostic confidence for physicians making patient decisions.

Subimal Datta, PhD, Professor of Anesthesiology, received the 2015 B. K. Anand Oration Award at the All India Institute of Medical Sciences in Asari Nagar, New Delhi.

The international award is given annually to an eminent basic medical scientist with special contributions related to neurosciences.

UT Research Foundation Recognizes Innovation

The UT Research Foundation (UTRF) recognized 88 University of Tennessee researchers, including several UT Graduate School of Medicine faculty and staff, for their discoveries and commercialization efforts made within the last two years during the 2016 Innovation Award Ceremony. From the UT Graduate School of Medicine, Jonathan Wall, PhD, Director of the Preclinical and Diagnostic Molecular Imaging Laboratory, and Stephen Kennel, PhD, Associate Professor in the PDMIL, received a plaque in recognition of their patent “Inhibitory Peptides of Viral Infection.” Alison McNabb, Director of Health Information Management and Services, received a License Certificate for Medical Examiner Data Dashboard; Alexander Pasciak, PhD, Clinical Associate Professor of Radiology, received a License Certificate for An Affordable Digital X-Ray Detection System Based on a ConsumerGrade DSLR Camera; and Carmen Lozzio, MD, Retired Professor of Medicine, received a certficate for K562 Cell Line.

Radioactive Drug Research Committee Formed

A new committee has been developed at the University of Tennessee Medical Center (UTMC) that enables local approval of small studies involving radioactive drugs, typically for imaging.

The first meeting of the UTMC RDRC occurred in November of 2015. During this meeting, RDRC members voted on the approval of the first locally approved RDRC study involving an IRB approved study by PIs Keith Gray and Dustin Osborne.

This study involves the use of a PET drug, fluorocholine (FCH), which highlights regions of increased choline kinase expression which is a hallmark of certain types of cancer. This study will be examining the biodistribution and kinetics of FCH in pancreatic cancer patients to provide information on its utility in the management of pancreatic cancer patients.

Your Chance to Advance The people at the UT Graduate School of Medicine would be happy to discuss our research programs and how your support can help advance healthcare. For information about philanthropic giving to the UT Graduate School of Medicine Office of Research, please contact the development office at 865-305-6611 or development@utmck.edu.

If you would like more information about any research programs described in this issue of Advance, please contact the UT Graduate School of Medicine’s Research Coordinator, Kristen Vandergriff, at 865-305-9749 or visit online: http://gsm.utmck.edu/research/main.cfm.

Thank you.

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