Cancer-Pain Discovery at Duke Makes Headlines

Ru-Rong Ji, PhDOnce hailed as a breakthrough in cancer treatment, immunotherapies are now raising concerns as doctors note new side effects like severe allergic reactions, acute-onset diabetes and heart damage.

These drugs, which work by unleashing the immune system to fight cancer, are only effective in about a fifth of cases, prompting many patients to wonder if they are worth the risk.

But a new study from Duke University researchers, featured in Duke TODAY and The San Diego Union-Tribune, suggests there may be a quick and easy way to predict which cancer patients are likely to benefit from immunotherapy treatments.

The researchers showed that a molecule called PD-L1, which is blocked by the popular immunotherapy drug, nivolumab, acts not only on immune cells but also on the nerve cells that signal pain. That insight could lead to a simple test that measures subtle differences in pain sensitivity to gauge whether or not the body is responding to treatment.

The findings, published May 22 in the journal, Nature Neuroscience, underscore the surreptitious nature of cancer, which uses a variety of tricks to evade detection by the body’s natural defense mechanisms.

“Cancer cells are smart. We already knew that they produced PD-L1 to suppress the immune system,” said senior study author Ru-Rong Ji, Ph.D., professor of anesthesiology and neurobiology at Duke University School of Medicine. “But there’s another defense system at play as well, and that is pain. We showed that this well-known molecule can mask pain, so that cancers can grow without setting off any alarms before metastasis.”

In its early stages, when cancer cells are just starting to grow and multiply in a given tissue or organ, the disease is not usually painful. But as the cancer becomes more aggressive and spreads throughout the body, these cells secrete thousands of pain-inducing chemicals, which either trigger pain-sensing nerve fibers or, in the case of molecules like nerve growth factor, generate entirely new ones. The pain can become so unbearable that some cancer patients die from opioid overdoses.

Ji has been studying pain for over twenty years. Recently, his group noticed that mouse models of melanoma didn’t show the typical signs of pain that he observed in mice with other kinds of cancer, which would flinch or lick their hind paws whenever they were in discomfort.

Ji also knew that melanoma cells could produce a molecule called PD-L1, which latched onto a receptor called PD-1 on the surface of white blood cells, effectively putting the brakes on the immune response. Ji wondered whether there was a connection. So his team treated mice with nivolumab, a drug that prevents PD-L1 from binding to PD-1. Then they poked the animals’ hind paws with a calibrated filament and measured how much force it took for them to withdraw their hind paws. They found that the mice responded to much lower forces than before treatment, indicating they had become more sensitive to pain. In addition, they also found that nivolumab caused spontaneous pain in mice with melanoma, which made them tend to their affected hindpaws like never before.

Next, the researchers performed the opposite experiment. They injected PD-L1 — the pain-masking factor in this equation — into the hind paws or spinal cord of mouse models of three different kinds of pain — inflammatory, neuropathic and bone cancer pain. In every case, the injections of PD-L1 had an analgesic effect, deadening the mice’s sensitivity to pain.

“The effect was surprisingly fast,” said Ji. “We saw a reduction of pain in under half an hour.”

To figure out the mechanism behind this quick response, Ji’s team examined the sensory neurons of the dorsal root ganglion (DRG), a collection of nerves and neurons near the top of the spinal cord. They isolated these cells from mouse DRGs as well as human DRGs from donors and cultured them in a dish, with or without PD-L1, and then recorded their electrical activity. The researchers found that PD-L1 impaired the ability of sodium channels to fire neurons (action potentials) in response to pain.

Ji believes the finding could potentially lead to new treatments for pain, as well as new ways to predict the efficacy of already existing treatments based on PD-1 and PD-L1. “The response to cancer drugs can take a long time, weeks to months,” he said. “The response to pain happens in minutes to hours.”

Sensory neurons from human dorsal root ganglia, a collection of nerves and neurons near the top of the spinal cord, show red for PD-1, a binding site for immunotherapies against cancer. The blue stain shows cell nuclei. Photo credit: Ru-Rong Ji Lab, Duke Anesthesiology

Sensory neurons from human dorsal root ganglia, a collection of nerves and neurons near the top of the spinal cord, show red for PD-1, a binding site for immunotherapies against cancer. The blue stain shows cell nuclei. Photo credit: Ru-Rong Ji Lab, Duke Anesthesiology

In the future, Ji would like to explore whether the mechanism uncovered in this study also applies to other immunotherapy treatments. He is also interested in working with clinicians to measure changes in patients’ pain sensitivity after treatment, a first step toward developing a diagnostic test.

The study was a collaboration between Duke University and two Chinese universities, Fudan University and Nantong University. Professor Yu-Qiu Zhang from Fudan University, the co-senior author of the paper, is a well-known expert in cancer pain. The lead author, Dr. Gang Chen, was an Assistant Professor at Duke  and is now a Professor at Nantong.

The research was supported by the National Institutes of Health (NS87988, DE17794, and DE22743), the National Science Fund of China (31420103903), and the National Research Foundation of Korea (2013R1A6A3A04065858)

CITATION:  “PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1,” Gang Chen, Yong Ho Kim, Hui Li, Hao Luo, Da-Lu Liu, Zhi-Jun Zhang, Mark Lay, Wonseok Chang, Yu-Qiu Zhang, and Ru-Rong Ji. Nature Neuroscience, May 22, 2017. DOI: doi:10.1038/nn.4571

Source: Duke University Office of News and Communications (Durham, N.C. – Tuesday, May 23, 2017)

Chris KeithCancer-Pain Discovery at Duke Makes Headlines
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Duke Anesthesiology Marks Academic Evening’s Silver Anniversary

A special 25th anniversary edition of Academic Evening was held on May 16 at the Millennium Hotel in Durham. All training levels and divisions of Duke Anesthesiology were represented by the 102 poster abstracts, presented by the department’s junior-level investigators and faculty. The annual event supports research and discovery with the overall goal of advancing anesthesia, critical care and pain management.

A key element to the evening was guest judge Dr. Aman Mahajan, the executive chairman of the Department of Anesthesiology & Perioperative Medicine at the UCLA David Geffen School of Medicine, and the Ronald L. Katz Professor of Anesthesiology and Bioengineering. Dr. Mahajan’s expertise is in cardiothoracic anesthesiology, cardiac electrophysiology and echocardiography. As director of the UCLA Perioperative Services at UCLA, he coordinates a multidisciplinary team of physicians involved in the care of patients undergoing surgical and interventional procedures. Dr. Mahajan’s research focuses on autonomic neural modulation of cardiac electrophysiology and assessment of cardiac mechanical function in heart failure.

After 23 years of service to Academic Evening, Dr. David Warner served as program director for the final time. Dr. Jeffrey Gadsden co-directed for the first time and will assume the event’s future leadership. “It was a pleasure and honor to work alongside Dr. Warner. He essentially built this event into what it is today,” says Dr. Gadsden.

“Academic Evening allows us to celebrate our academic successes and often serves to foster new and exciting research ideas and collaborations between departmental subspecialties,” says senior resident, Dr. Kendall Smith, winner of the Bill White Resident Research Award. “To receive this award among the many excellent resident entries this year was both a surprise and a great honor.”

At the night’s conclusion, Drs. Gadsden and Warner thanked all of the participants and everyone who helped make this event possible, especially those who served as abstract judges, moderators, mentors, and support staff. “Just when you think you couldn’t be more proud of the department you work in, you receive more than 100 abstracts of original research. It’s humbling,” says Dr. Gadsden.

Congratulations to each of the award winners and teams, listed below.

2017 Academic Evening Winners

1st Place
Martin Sigurdsson, MD

Runner-Up
Shu Yu, MD

Runner-Up
Chao Xiong, MD

1st Place
Rebecca Scholl, MD

Runner-Up
Hassan Amhaz, MD

Runner-Up
Claudia Villalpando, MD

1st Place
Kendall Smith, MD

Runner-Up
Jon Andrews, MD

Runner-Up
Rebecca Anderson, MD

1st Place
Benjamin Andrew, BS, RD

Runner-Up
Andrea Ansari, BS

1st Place
Michael Young, MD

1st Place
Benjamin Dunne, MD

Runner-Up 
James Kim, MD

1st Place
Suraj Yalamuri, MD
Michael Plakke, MD

Runner-Up
Tera Cushman, MD

Runner-Up
Jennifer Lee, MD

View the 25th Annual Academic Evening Photo Gallery

View the Academic Evening 25th Anniversary Video

Chris KeithDuke Anesthesiology Marks Academic Evening’s Silver Anniversary
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Dr. Habib Appointed to SOAP Board of Directors

Ashraf S. Habib, MBBCh, MSc, MHSc, FRCAThe Society for Obstetric Anesthesia and Perinatology (SOAP) has elected Duke Anesthesiology’s Dr. Ashraf Habib to serve as the director at large on its board of directors. The announcement was made at the society’s 49th annual meeting, titled “Beyond the Obstetric Suite.”

SOAP’s mission is to improve the pregnancy-related outcomes of women and neonates through the support of obstetric anesthesiology research, the provision of education to its members, other providers, and pregnant women, and the promotion of excellence in clinical anesthetic care.

Dr. Habib is the chief of Duke Anesthesiology’s Women’s Anesthesia Division. He has been a SOAP member for the past 17 years in which he has been active in a number of SOAP committees, including the international outreach committee (member 2004-2008, chairman since 2008), the research committee (since 2008), and the resident affairs committee (since 2009). He has also  served on a number of the American Society of Anesthesiologists (ASA) committees related to obstetric anesthesia, including the ASA abstract review subcommittee on obstetric anesthesia and perinatology (member 2009-2013, chair since 2013), and the ASA education track subcommittee (since 2013).

Dr. Habib says the experience he has gained through his work, participating in and leading several international outreach trips teaching obstetric anesthesia overseas (Croatia, Egypt and Romania), has made him appreciate the opportunities that SOAP can have as a leader in improving the care of pregnant women worldwide.

Chris KeithDr. Habib Appointed to SOAP Board of Directors
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New Information Technology Director Named

Dan Cantrell - IT DirectorWe are pleased to announce that Dan Cantrell officially joined Duke Anesthesiology on March 6 as the anesthesiology and perioperative information technology director, bringing 20 years of experience to his new role in our department.

Cantrell specializes in infrastructure systems, significant-sized server and storage clusters, large data set management, information security, and building complex systems from multiple disparate technologies. He has notably been part of three start-ups, including Hotmail, which was the largest email service in the world until 2012. As manager of data storage, he directed the design and cost analysis for all storage and backup systems for more than 100 million global email users. He went on to become the senior systems engineer at Microsoft and the director of technical consulting and system architect at Redbridge IT, Incorporated. In 2008, Cantrell was appointed as the senior information technology manager at the Duke University School of Law; a position he held for nine years in which he oversaw the primary infrastructure technologies and provided support via the web, media and desktop information technology groups.

In his new role at Duke Anesthesiology, Cantrell will work to support the mission of the department, primarily focusing on data analytics, software development and IT support. “We must direct our resources through this time of incredible opportunity with terrific technological resources such as the vast electronic health care records system, virtually limitless computer and storage capacity, and cutting-edge artificial intelligence,” says Cantrell. “During this era of unequaled expansion and growth of technology in health care, our team and resources will ensure success for this department’s great initiatives.”

Cantrell’s primary goals for his IT team include fostering automation to improve efficiency, and deploying and promoting creative solutions to solve the rapidly-evolving health care strategies such as cost control population care management and preventative measures.

Cantrell is originally from Michigan. He currently resides in Apex with his wife and two young girls. Please join us in welcoming him to Duke Anesthesiology!

Chris KeithNew Information Technology Director Named
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Dr. Nicoara Receives Inaugural Echocardiography Award

Alina Nicoara, MD, FASEThe Society of Cardiovascular Anesthesiologists (SCA) has selected Duke Anesthesiology’s Alina Nicoara, MD, FASE, as the recipient of the inaugural Echo Week Co-Directors’ Award!

This honor is awarded to a mid-career anesthesiologist. Dr. Nicoara was chosen to be the first-ever recipient of this award based on her nationally-recognized expertise in perioperative echocardiography, her contributions to research in this field, and her potential to continue performing at this high level.

“I am honored to receive this award from friends and mentors, people I try to emulate every day in many ways,” says Dr. Nicoara, who will accept her award at the 20th Annual Echo Week in Atlanta on May 25. “I consider myself very lucky that, although the SCA Echo Week is an intense work experience for both faculty and participants, it’s also an opportunity to have fun and spend time with my colleagues.”

The SCA is an international organization of physicians that promotes excellence in patient care through education and research in perioperative care for patients undergoing cardiothoracic and vascular procedures.

Dr. Nicoara is the director of the Duke Perioperative Echocardiography Service. Its mission is to promote excellence in perioperative cardiac ultrasound imaging, and inspire and educate future generations of anesthesiologists and critical care physicians.

Chris KeithDr. Nicoara Receives Inaugural Echocardiography Award
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