Dr. Kwatra Awarded Funding in the Fight Against Glioblastoma

Madan M. Kwatra, PhDDelMar Pharmaceuticals has awarded Dr. Madan Kwatra a three-year, $715,500 grant, titled “Development of VAL-083, alone or in combination with other agents, to inhibit the growth of specific subsets of glioblastoma (personalized drug development).”

Glioblastoma (GBM) is a deadly brain cancer, and attempts to control its progression have been limited. The current standard of care consists of surgery followed by radiation and chemotherapy using temozolomide. However, temozolomide only works for about 40 percent of GBM patients who have a methylated MGMT promoter.  In contrast, VAL-083 is a novel chemotherapeutic agent that has activity against GBM with both methylated and unmethylated MGMT promoters. Thus, VAL-083 is a more versatile chemotherapeutic agent that may help a wider subset of GBM patients.

The completion of the proposed pre-clinical studies will identify molecular characteristics of GBM tumors that are more likely to respond to VAL-083 therapy either alone, or through combination therapies. This personalized medicine approach will be used to initiate clinical trials in newly diagnosed GBM patients.

Chris KeithDr. Kwatra Awarded Funding in the Fight Against Glioblastoma
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Dr. Taekman Awarded Funding for Microbiome Clinical Trial

Jeffrey M. Taekman, MDClasado/Host Therabiomics has awarded Duke Anesthesiology’s Dr. Jeffrey Taekman $69,885 in funding for a clinical trial titled, “Exploring the Impact of Perioperative Galacto-Oligosaccharides (GOS) on Stress, Anxiety and Cognition.”

Studies link the gut microbiota to the function of the central nervous system, both in behavior and cognition. Prebiotics stimulate growth of beneficial bacteria in the gut. The overall objective of this proposal is to explore, in the perioperative period, the association between the administration of the prebiotic GOS and pain, anxiety and cognitive function. His central hypothesis is subjects who consume GOS in the perioperative period will demonstrate lower levels of salivary cortisol before, during, and after their operative procedures. In addition, he expects subjects who consume GOS to have lower perceived levels of anxiety during the perioperative period. Finally, he hypothesizes that subjects who consume perioperative GOS will perform better on tests of cognition in the postoperative period.

Dr. Taekman is a professor of anesthesiology, the assistant dean for educational technology, and the director of the Duke Human Simulation and Patient Safety Center. He is currently a fellow in the University of Arizona’s Center for Integrative Medicine where he is pursuing his interests in the medicinal use of food as well as mind-body medicine.

Chris KeithDr. Taekman Awarded Funding for Microbiome Clinical Trial
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Faculty Awarded Grant to Advance Field of Transplantation

Anne Cherry, MDThe Transplantation and Immunology Research Network (TIRN), an American Society of Transplantation (AST) program, has awarded Duke Anesthesiology’s Dr. Anne Cherry a one-year, $50,000 AST TIRN Basic Science Faculty Development Research Grant for her proposal titled, “Interface of Mitochondrial Dysfunction and Immune Activation in Heterotopic Mouse Heart Transplant.”

Primary graft dysfunction (PGD) after cardiac transplant occurs in about 7.5 percent of recipients; there is concern that the rate is increasing due to a) extension of ischemic time to facilitate organ distribution and b) increasing use of high risk donor organs due to increasing mismatch in organ demand vs. availability. Graft dysfunction is a devastating complication, resulting in prolonged post-transplant hospitalization (often requiring invasive mechanical circulatory support or re-transplant) and 35 percent one-year mortality.

The long term goal of Dr. Cherry’s research is to identify and manipulate signaling targets that control the interface between impaired mitochondrial quality control after ischemia/reperfusion (I/R) injury and inflammatory activation in PGD to a) improve donor selection (prediction of PGD), b) implement pre-organ harvest donor interventions to stimulate mitochondrial quality control pathways, and c) intervene by specifically targeting key modulators of the mitochondrial-inflammatory interface to prevent excessive immune activation.

Through this research, Dr. Cherry aims to 1) characterize the impact of deficits in mitochondrial function and recovery on PGD in a syngenic transgenic heterotopic mouse heart transplant model and 2) characterize subsequent inflammatory activation attributable to those pre-existing mitochondrial regulation deficits acutely (24 hours) and at mid- to longer-term time points (7 and 21 days). She will serially investigate and compare changes in mitochondrial structure/distribution (electron microscopy); oxidative damage, cell death and fibrosis; molecular mitochondrial quality control markers; and graft function (echocardiography) will help illustrate the PGD phenotype in this model. Differences in the temporal course (particularly focused on macrophage phenotypes), magnitude, cellular composition, and functionality of the immune phenotype for PGC-1ɑ +/- vs. WT grafts will be evaluated using histology, markers for neutrophil infiltration, and flow cytometry characterization of both serum and graft infiltrates. Together, these aims will allow identification and, most importantly, manipulation of key modulators of the mitochondrial-inflammatory interface in cardiac transplant patients.

Overall, this investigation into the interaction of mitochondrial quality control and oxidative stress with inflammatory injury will also translate to patients with graft dysfunction of other transplanted organs and to ischemia/reperfusion injury in other pathologic processes (i.e. myocardial infarction). Dr. Cherry will use the novel mechanisms to identify new interventions to modulate I/R injury and graft dysfunction, promote recovery, and prevent consequent immune activation.

The AST is the largest transplant organization in America, dedicated to advancing the field of transplantation and improving patient care by promoting research, education, advocacy and organ donation. Dr. Cherry, assistant professor of anesthesiology in Duke’s Cardiothoracic Anesthesia Division, will accept this grant award at the AST Excellence in Transplantation Reception at the 2017 American Transplant Congress in Chicago on May 1. Her research for this project will begin on July 1.

Chris KeithFaculty Awarded Grant to Advance Field of Transplantation
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Researcher Awarded Grant to Study the Most Aggressive Cancer

Madan M. Kwatra, PhDAstraZeneca has awarded Duke Anesthesiology’s Madan Kwatra, PhD, a $97,109 grant for his project titled, “Efficacy of AZD9291 against EGFRvIII-positive glioblastoma.”

Glioblastoma (GBM) is a deadly brain cancer, and according to Dr. Kwatra, all attempts to control it have failed so far. GBMs exhibit significant inter- and intratumoral heterogeneity, and to control this type of tumor, he believes a personalized approach is required.

According to the research statement, one target, whose gene is amplified and mutated in a large number of GBMs, is the epidermal growth factor receptor (EGFR). But, all attempts to target it have been unsuccessful. Dr. Kwatra attributes this failure to the extreme molecular heterogeneity of EGFR, as well as to the poor brain penetration of previously tested EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs). Recently, a third generation EGFR-TKI, known as AZD9291, was reported to have good brain penetration. AZD9291 also blocks EGFRvIII, a mutant EGFR present in 20 percent of GBM tumors, with high affinity. Dr. Kwatra’s preliminary studies (conducted under a collaborative agreement among his laboratory, NIH, and AstraZeneca) indicate AZD9291 is active against EGFRvIII-positive GBMs intracranially transplanted in nude mice.

This study will test if AZD9291’s efficacy against EGFRvIII-positive GBMs can be improved by giving 25mg/kg AZD9291 twice a day. Finally, before conducting studies in GBM patients, Dr. Kwatra will examine whether EGFRvIII-positive GBMs differ in their response to AZD9291. This way the compound is tested only in those GBM patients expressing the sensitive form of EGFRvIII (precision medicine approach).

Dr. Kwatra is an associate professor in anesthesiology and the director of the Molecular Pharmacology Laboratory where researchers focus to understand the role of G protein-coupled receptors in human diseases.

Chris KeithResearcher Awarded Grant to Study the Most Aggressive Cancer
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Anesthesia Faculty Awarded Health Innovation Grant

Drs. Annemarie Thompson and Madhav SwaminathanThe Duke Institute for Health Innovation (DIHI) has awarded a multidisciplinary team from the Duke departments of anesthesiology, surgery, medicine and statistical sciences a $50,000 grant for their project titled, “PROMISE – Perioperative Risk Optimization with Machine learning for an Improved Surgical Experience.”

The goal of the project is to use machine learning tools to develop risk stratification models using patient level data to predict surgical risk and direct optimization interventions to reduce this risk. The funding will be used to develop risk stratification tools, and help providers in surgery clinics with optimization goals for their at-risk surgical populations.

The team of investigators includes Duke Anesthesiology’s Drs. Annemarie Thompson and Madhav Swaminathan (both of the Cardiothoracic Anesthesia Division), as well as Dr. Mitchell Heflin, Erich Huang, Shelley McDonald, Mark Sendak, Katherine Heller and Dr. Sandhya Lagoo-Deenadayalan.

The mission of the DIHI is to promote transformative innovation in health and health care, and to help cultivate a community of entrepreneurship across Duke University and its health enterprise. Proposed projects address actual and important problems encountered by care providers, patients and their loved ones in the Duke University Health System and represent urgent health challenges nationally.

Chris KeithAnesthesia Faculty Awarded Health Innovation Grant
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Regional Division Chief Receives Funding for Opioid Study

Jeffrey C. Gadsden, MDMallinckrodt Pharmaceuticals has awarded Duke Anesthesiology’s Dr. Jeffrey Gadsden $199,734 in funding for a clinical trial titled, “Comparison of Multimodal Analgesic Regimen with Intravenous Acetaminophen to Standard Oral Multimodal Therapy in Primary Total Hip Arthroplasty: A Randomized Controlled Double Blind Trial.”

Little robust data exists comparing the efficacy of oral versus intravenous acetaminophen for postoperative pain following major surgical procedures such as joint replacement. In this double-blind, randomized controlled trial, Dr. Gadsden’s hypothesis is that use of the intravenous formulation will result in a 20 percent reduction in opioid consumption in the first 24 hours.

60 patients scheduled for primary total hip arthroplasty will be enrolled in this trial. Subjects will receive a standardized anesthetic and postoperative analgesic regimen, and prior to surgery will be randomized to receive four doses of acetaminophen every six hours either by the oral or intravenous route. Placebo controls will ensure blinding. Subjects will be evaluated while in hospital for pain scores, satisfaction, opioid use, and rehab outcomes such as range of motion and ability to sit, stand, and walk in the postoperative period. Other outcomes will include total hospital cost, pharmacy-related costs, costs due to opioid-related adverse events, hospital length of stay (raw and criteria-based readiness) and ER presentations/admissions due to pain in the first 30 days.

Dr. Gadsden is an associate professor of anesthesiology and chief of Duke Anesthesiology’s Division of Orthopaedics, Plastics and Regional Anesthesiology. He’s also the associate director of the department’s Regional Anesthesiology and Acute Pain Medicine Fellowship.

Chris KeithRegional Division Chief Receives Funding for Opioid Study
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