Progress Report
Reports of the Vice Chairmen
Research and Information Systems
Henry M. Spotnitz, MD
Surgical research employs state-of-the-art technologies, pharmaceuticals and molecules, computer science and data management, animal experiments and basic science to solve clinical issues affecting patients. The complexities of modern surgical problems are most likely to yield to multidisciplinary and translational approaches. Recent examples at Columbia included basic and applied science of surgical inflammation and clinical effects of left ventricular assist devices. Current research includes ground-breaking clinical studies of percutaneous aortic valve insertion in the PARTNER trial and reversal of angiogenesis for control of devastating cancers of infancy. The future of research in the Department of Surgery is likely to include innovative use of simulation techniques in surgical training and time management, new approaches to Outcomes and Clinical Effectiveness Research, and important advances in the immunology of organ transplantation.
The Reemtsma Center for Innovation and Outcomes Research (RCIOR) under the leadership of Dennis L. Fowler, MD, MPH is rebuilding on a long tradition of effective Outcomes Research in the Department of Surgery. Dr. Fowler has formed important alliances with New York Presbyterian Hospital allowing direct access to hospital data, including costs, complications, and the Electronic Medical Record. Dr. Fowler brings a wealth of experience as former operating room director, developer of minimally invasive surgery, and innovator in surgical simulation. This latter experience has already led to opening of new simulator facilities and plans for important simulation facilities in the new Medical Education Building being developed by the medical school.
The Transplant Clinical Research Center (TCRC)
The Transplant Clinical Research Center (TCRC) resides in the Department of Surgery / Division of Abdominal and Liver Transplantation. Clinical research overseen by the TCRC includes adult and pediatric liver transplantation and liver diseases. TCRC studies include kidney transplant, lung transplant and most recently pediatric heart transplant. More than 35 active protocols include:
- Immunosuppressive therapy in solid organ transplantation
- Immunosuppression withdrawal in pediatric liver transplantation
- Clinical and quality of life in living donor and deceased donor liver transplants
- Techniques for predicting likelihood of solid organ transplant rejection
- Advanced organ preservation methods
- Patent safety in liver transplantation
- Hepatitis B and C therapy pre- and post-transplant
- Hepatocellular carcinoma
- Liver assist devices in end-stage liver disease
- Hepatic encephalopathy
Furthermore, there is a close collaboration with the Columbia Center for Translational Immunology (CCTI), under the leadership of Dr. Megan Sykes. Currently, a translational research protocol in tolerance induction is being jointly conducted by CCTI and the TCRC. Total clinical research revenue brought in through the TCRC for fiscal year 2009-2010 is $1.3 million, approximately $760,000 from government grants, and $540,000 from industry sponsored research.
The CCTI is a multi-departmental, multidisciplinary research center aimed at optimizing translation of advances in basic immunology from the laboratory to the clinic, understanding immunological diseases and events in humans and optimizing transfer of information and methodologies to achieve synergy between different disciplines of applied immunology. The Center was established in April 2010, and will continue to develop over the next 5 years. The completed Center will include 11 independent laboratories working in various areas of organ transplantation, hematopoietic cell transplantation, Type I diabetes, other areas of autoimmunity, tumor immunology and basic immunology.
The CCTI currently consists of three laboratories and three cores, including a Sample Repository, a Human Studies Core and a Flow Cytometry Core. CCTI investigators have expertise at all levels of immunology and transplantation, from molecular biology to large animal and clinical transplantation studies. Extensive collaborations are carried out among these laboratories and between clinicians and basic scientists, including close interactions with the transplant physicians and surgeons in the Columbia Transplant Initiative.
The mission of the CCTI is to accelerate translation of basic advances in immunology into new clinical therapies for immune diseases by creating a center that: 1) Fosters "horizontal" integration of information and advances between immunological disciplines and "vertical" integration between scientists and clinicians; 2) Trains a new generation of scientists and clinicians with the skills to lead the translation of future advances in immunology into clinical therapies.
Dr. Mark Hardy
Dr. Mark Hardy has continued his studies on induction of tolerance to organ transplantation using immature Dendritic Cells (imDC) primed against donor immunodominant antigens in vitro in rodent models of heart and pancreatic islet transplantation. He has extended these studies with his fellows to evaluating human imDC's and shown that they suppress allogeneic responses in mixed lymphocyte reactions (microcosm of allograft rejection between donor and recipient cells in a dish). He further showed that instead of imDC's which is somewhat laborious to produce, regular human DC's can be used for the same purpose if they are first lightly UVB irradiated. It appears from these in vitro studies that the "false" antigen presentation by either imDC's or by UVB-DC's which are easily obtained from the peripheral blood of recipients via leukopheresis, leads to production of donor specific regulatory T cells which inhibit reactions allograft reactions between donor and recipient in an in vitro system (in a dish). Dr. Hardy and colleagues are now planning to evaluate whether this suppression of reaction to a foreign graft (rejection) using human cells can be produced in vivo in a humanized mouse and eventually in a pig or a small monkey before applying this technique to transplantation in humans.
Another type of Dr. Hardy's research is being conducted along with Dr. Shanta Modak and surgical fellows looking at potential increase in the rate of wound healing, both clean, and infected in rats. These studies have followed a preliminary clinical study in humans which showed that Thymosin B-4, a thymic hormone, .accelerates healing of decubiti ulcers. Using rat skin-wound model and combinations of Thymosin B-4 with various analogues of Silvadene cream, the group showed that there appears to be an accelerated rate of healing of both clean and of infected (controlled) wounds in the rat. This study is being extended to study other infected wounds and modified preparations and mixtures of the topical hormone-antibiotic cream mixtures prior to returning to clinical studies of decubiti ulcers in humans.
Dr. Hardy has also been an active participant in clinical multiinstitutional studies of new immunosuppressive agents in renal transplant recipients. He has completed the study of Certican R (Novartis), a Sirolimus preparation, approved by FDA late in 2010, and distributed in the US as Zortress R. He has also continued a study for Bristol Myer Squibb comparing Cyclosporine and Belatecept (a new anti-signaling agent) in renal transplant recipients, which may be soon approved by FDA for clinical use.
Cardiothoracic Research
CT research includes: minimally invasive surgery, valve surgery, ventricular assist devices, heart transplant, the maze procedure, coronary artery bypass surgery, congenital surgery, and animal models of arrhythmias. Our research includes overall outcomes analysis, pre-operative risk prediction models, and assessment of surgical techniques.
With regards to minimally invasive surgery, we have reported on the evolution of our surgical approach over the past 10 years with respect to incision site and cannulation techniques and the resulting clinical outcomes. In an effort to better categorize appropriate candidates for minimally invasive cardiac surgery, we have examined the relationship between measurements of anatomic relationships taken from preoperative chest x-rays as predictors of operative difficulty. Furthermore, we are prospectively investigating the effect of both cardiac surgery and minimally invasive cardiac surgery on patient Quality of Life.
Heart failure research has included assessing scoring systems predicting right heart failure in LVAD patients. We explored the relationship between pre-transplant MELD score and heart transplant outcomes in the UNOS database as well as the relationship between MELD score and Columbia VAD outcomes. We examined whether tricuspid valve repair performed at LVAD insertion affects RV function. Currently, we are clarifying the relationship between pre-operative arrhythmias and outcomes in heart transplant patients. We have also investigated the impact of metabolic syndrome and lipid profile on long-term survival in heart transplant patients.
With respect to the aortic valve we have explored the outcomes of intraoperative minimally invasive technique, the 3f bioprosthetic aortic valve, and valve-sparing root replacement vs. bioroot composite biologic conduit. We investigated the impact of low EF on patients undergoing mitral valve surgery. We addressed whether patients undergoing left-sided valve surgery should also undergo surgery for tricuspid regurgitation. Furthermore, we are exploring the management of mitral regurgitation during CABG.
Our translational work is also diverse. We are exploring the feasibility of rehabilitating and enhancing human endothelial progenitor cells (EPCs) endothelialization capacity through histone deacetylases (HDACi) inhibition via in vitro and in vivo models. We are extending our basic science work in stem cells into translational research in tissue engineering. We continue to study vasopressin in hemorrhagic shock and seek to develop a partial agonist of vasopressin receptors as a therapeutic agent in hemorrhagic shock. Our animal models for arrhythmias focus on the targeting of channels by selective drug agents to decrease the incidence and duration of atrial fibrillation as well as reperfusion arrhythmias in an ischemia-reperfusion model.
We are investigating the outcomes of the Maze procedure as it progresses and have recently reported the outcomes in a cohort of lone atrial fibrillation patients as well as the elderly. Present work in congenital cardiac surgery reviews our experience with an extracellular matrix and its clinical outcomes.
Clinical trials sponsored by the NIH Cardiothoracic Surgery Network are in progress with CUMC as a clinical center. These focus on results of surgery for ischemic mitral regurgitation and related topics. The multisite PARTNER trial in collaboration with CRF has demonstrated equivalence of percutaneous or transapical aortic valve replacement and conventional surgical replacement in high risk candidates with aortic stenosis. The BiPACS, BiPOP, and related trials are examining benefits of temporary biventricular pacing for acute left and/or right ventricular dysfunction after cardiopulmonary bypass.
Breast Surgery Trials
- ABLATE: Intraoperative radiofrequency ablation to extend negative margins of tumors during breast conservation surgery. Hope reduce re-excisions for close or involved surgical margins and reduce to need for adjuvant radiation for early stage breast cancer.
- Experimental vaccine to use for metastatic melanoma to prevent progression and growth through the BioVex study. Vaccine might decrese systemic therapies and invasive surgeries.
- ACOSOG Z071: Sentinel node biopsy in neoadjuvant chemotherapy for locally advanced breast cancer. Might avoid axillary node dissection and reduce risk of lymphedema.
- MicroRNA: Open for patients with breast cancer undergoing surgery. Uses blood, tumor and nipple aspirate fluid to identify a microRNA profile as a future screening tool for women at risk for developing breast cancer and potentially to monitor patients for cancer recurrence.
- Ductal anatomy mapping study is being performed on mastectomy specimens to define unique ductal/lobular anatomical breast units. Methylation signatures for individual units will be analyzed to determine potential sites of increased risk for breast cancer development. This is the initial work towards performing anatomical specific segmental breast resections for cancer.
Pediatric Surgery
Pediatric Surgery (Jessica Kandel): Our laboratory focuses on mechanisms of progression (metastasis and invasion) in pediatric solid tumors, in response to anti-angiogenic treatments.
Specific pathways of interest include vascular endothelial growth factor (VEGF), Notch, angiopoietin/Tie2, and activin signaling. Strategies for evaluation include gene expression studies, novel molecular imaging modalities, and tissue analysis.
Pediatric Surgery (Bob Cowles): Basic Science research into the role of the enteric nervous system (ENS) in the response of the small intestine to stress. Focus on the role of Serotonin, a ubiquitous neurotransmitter in the bowel, in mucosal growth and repair. Related projects are aimed at understanding the fate of neurons and glial cells of the ENS after surgical trauma.
Clinical Research interests include the treatment of intestinal failure and biliary diseases in infants and children. Several projects evaluate outcomes in patients with short gut as well as a biliary atresia database covering nearly 40 years of experience.
Pediatric Surgery (Gudrun Aspelund): Projects include studies on the use of MRI in diagnosis of acute appendicitis in children, study of sonographic lung-head ratio as a prognostic marker in congenital diaphragmatic hernia (CDH), and assessment of surgical practice patterns for infants with biliary atresia.
Vascular Surgery
Vascular Surgery (Roman Nowygrod):
2 IRB approved studies in progress
- oscillation therapy for patients with peripheral vascular disease
- systemic coagulation in patients with prosthetic and autogenous vein grafts
Plastic Surgery
Plastic Surgery (Christine Rohde): In three separate studies, we are investigating the effects of pulsed electromagnetic field (PEMF) therapy on post-operative pain and pain narcotic use after transverse rectus abdominus myocutaneous (TRAM) flap, breast reduction, and axillary lymph node dissection (ALND) surgeries. PEMF is FDA approved for pain and edema relief and has been shown to be effective in the acceleration of fracture healing, relief of pain in acute sprains and whiplash injuries, the improvement of skin blood flow, healing of venous stasis ulcers, and reduction of post-mastectomy lymphedema, without significant side effects. Dr. Rohde has already published a paper demonstrating the utility of PEMF for decreasing pain and pain medication use after breast reduction. The current study for PEMF after breast reduction seeks to maximize the effect of PEMF on pain relief. For the TRAM flap and breast reduction PEMF studies, we will analyze JP wound exudate for levels of cytokines and growth factors involved in wound healing. For the ALND study, we will assess subjects' objective and subjective shoulder and arm symptoms, including: pain, arm movement, arm strength, edema, and loss of sensitivity.
We are also conducting two studies using the Breast-Q, an internationally recognized and validated questionnaire that helps surgeons scientifically assess patient satisfaction after breast surgery. One study assesses patient satisfaction among adolescents who have undergone breast reduction. The other study will compare patient satisfaction after breast reconstruction following nipple-sparing mastectomy with patient satisfaction after nipple and breast reconstruction following total mastectomy.
Plastic Surgery (June K. Wu): Our laboratory focuses on vascular anomalies, a heterogeneous group of lesions comprising vascular tumors and vascular malformations. Vascular tumors affect infants, and vascular malformations are congenital and can have lifelong consequences. Our laboratory is interested in the pathogenesis of infantile hemangiomas (IH), the most common benign tumor of infancy. We currently are investigating the Notch signaling system in the pathophysiology of IH. In particular, we are interested in the role of Notch signaling in the differentiation of the hemangioma stem cell (HemSC), a hematopoietic stem cell, to the different cell types seen in IH. On a broader scale, IH has a disease model will allow the study of stem cell biology in the hematopoietic lineage.
Another project focuses on the role of propranolol in the treatment of IH. Despite its prevalence, there are no FDA-approved treatment for problematic IHs. All current medical treatments are off-label uses of FDA-approved medications. Recent reports have shown efficacy of using propranolol in treating problematic IH, but the mechanism of action is poorly understood. We use our in vitro and ex vivo animal model to study the mechanisms by which propranolol exerts its effects. These models will also allow us to test other potential drug therapies
The Center for Innovative Cancer Management
The Center for Innovative Cancer Management is engaged in groundbreaking research, testing tumor vaccines for metastatic kidney cancer and melanoma, and exploring ways to prevent tumor recurrences in colorectal cancer patients.
A promising approach to pancreatic cancer now allows surgeons to perform resections in a substantial number of patients who were previously considered inoperable. This discovery has led to a multi-center clinical trial.
Other trials focus on minimally invasive techniques refined or developed here at Columbia-Carotid Artery Angioplasty and Stenting, an alternative method of stroke prevention, a Thoracic Aortic Stent-graft for patients with thoracic aortic aneurysms, an Endobronchial Valve for Emphysema Palliation (the VENT trial), and gastric banding for patients who are not considered morbidly obese.
In the area of General Surgery, researchers are exploring wound healing, cancer immunotherapy and the immunological aspects of minimal access surgery.
We hope to increase applications of medical informatics in the operating room, including use of heads-up displays, similar to fighter pilots' screens, to provide real time access to hemodynamic data, ultrasound images, angiograms, lab results, and clinical profiles. This project is a prime opportunity for collaboration with industry.
Surgeons of the future will perform more minimal access and robotic procedures and increasingly practice remote telemedicine. Columbia is positioned as a leader in these emerging fields.
