Ongoing Laboratory Research Summary

Surgical Metabolism and Nutrition Research Laboratory

We are investigating the fundamental surgical question as to why patients lose their appetite when they become sick. At present, the loss of appetite and the fact that they cannot eat leads to loss of body weight and increases post-operative complications, length of hospital stay and hospital mortality. We fix this problem temporarily by giving the patient enteral or parenteral nutrition which has a fair number of complications. But imagine if we could figure out the mechanism that controls appetite. Then, we could turn on the sick patients'appetite and they could eat the food they actually like in the amount they wanted according to their ethnic background at a critical time when they require nutrition.

The understanding of how to control appetite will also allow us to treat morbid obesity in a more effective manner. With this as a background, the projects that we are studying in the Surgical Metabolism and Nutrition laboratory involve hypothalamic factors that regulate food intake in the anorexia of disease (eg.cancer) and in a morbid obesity rat model.

These projects have now reached the stage where we are contemplating traditional studies whereby we will apply our basic science understanding in the regulation of appetite gained from anorexia models and morbid obesity models to surgical patients.

Transplant Laboratory

• Effects of Commonly Used Botanical Medicine in Organ Transplantation: We are using a heart transplant model to study the effects herbal medicine may have on the immune system, which in turn, may determine graft viability or rejection.
• Pathophysiology of Hemirenal Transplantation: Due to the shortage of organs for transplant, we will determine if the transplantation of one-half kidneys are a viable alternative to transplanting whole organs.
• Endothelial dysfunction: Occurs in transplanted kidneys from immunological and non-immunological insults. To study this endothelial dysfunction in vitro, we have adapted a model of angiogenesis in which endothelial cells are induced to form capillary tubes on an extra-cellular cell matrix. We have shown that rejecting heart allografts inhibit the formation of the capillary tubes when soluble extracts from the rejected allografts are incubated with endothelial cells.

Our aims are:

1. To develop methods to culture human aortic endothelial cells (HAECs) and to determine if the HAECs will form capillary tubes in a laminin rich extracellular matrix (Matrigel).
2. To determine if various agents including cyclosporine A, tumor necrosis factor and interferon cause dysfunction of the HAECs and inhibit angiogenesis in this in vitro model.
3. To determine if soluble extracts from rejecting hemirenal transplants cause endothelial dysfunction and inhibit angiogenesis in the in vitro model.

Cardiopulmonary Research Laboratory

Our laboratory investigates the pathogenesis and treatment of systemic inflammatory diseases such as the acute respiratory distress syndrome (ARDS), ventilatory induced lung injury (VILI) and cardiac ischemia/reperfusion injury. It is our hypothesis that the majority of the injury caused by systemic inflammation is mediated by proteases released from the neutrophil. Models of cardiopulmonary bypass-induced ARDS as well as chronic models of ARDS have been developed in our laboratory and are currently being utilized to test the efficacy of modified tetracycline (COL-3) which is potent inhibitor of neutrophil protease. Ventilator induced lung injury (VILI) is a significant problem in the management of acute lung injuries. Knowledge of alveolar mechanics is fundamental to understanding the pathophysiology of VILI and establishing the best ventilator strategy to minimize it. We have developed a novel in vivo videomicroscopic technique to observe and quantify dynamic changes in alveolar mechanics in the acutely injured lung which enables us to determine the impact that ventilator strategies have at the alveolar level. The cardiac injury following ischemia/reperfusion is mediated by neutrophil proteases similar to ARDS. Therefore, we are also testing the efficacy of COL-3 in reducing morbidity in a model of ischemic heart injury. Clinical studies will be undertaken to test the anti-inflammatory effects of COL-3 in both cardiopulmonary bypass and trauma patients.

Critical Care Laboratory

The basic science portion of our Critical Care laboratory is currently focusing on the inflammatory response produced by cardioplegic arrest. Most studies involve a global ischemic model. By varying the cardioplegic solution as well as anti-inflammatory additive we are able to reduce the ischemic insult.

The second branch of research is looking at the neurologic complications produced by aortic cross-clamping and cardioplumonary bypass (CPB) itself. For this, our Perfusion Division has developed the ability to place subjects on CPB, which is unique to this institution.

The third section involves research at the molecular level with collaboration from Dr. Dube of the Department of Medicine. We are examining the role of sarcomeric alpha tropomyosin isoforms in cardiomyopathy.

Summary of Ongoing Surgical Clinical Research Trials

Cancer and Leukemia Group B (CALGB) Research Studies

The Cancer and Leukemia Group B (CALGB) is a national clinical research group sponsored by the National Cancer Institute. The CALGB was founded in 1955 with a goal of bringing together medical professionals of all specialties and laboratory investigators to develop better treatments for cancer. Since then, CALGB has grown into a national network of 29 university medical centers, over 185 community hospitals and more than almost 3000 physicians who collaborate in clinical research studies aimed at reducing the morbidity and mortality from cancer, relating the biological characteristics of cancer to clinical outcomes and developing new strategies for the early detection and prevention of cancer. CALGB research is focused on seven major disease areas: leukemia, lymphoma, breast cancer, lung cancer, gastrointestinal malignancies, genito-urinary malignancies and melanoma. In each of these areas, multi-modality treatment programs are designed by national experts in an attempt to cure more patients with cancer. Treatment protocols are often coupled with carefully developed and monitored studies of cancer biology, quality of life, pharmacology and cost-effectiveness measures so that improvement in therapy can be placed in the proper clinical perspective in today's health care marketplace. The Department of Surgery at Upstate focuses on those clinical trials that have a surgical component. Some of the current trials include evaluating PleurX catheters vs chest tubes for pleural effusion patients, lymph node and tissue biopsies for lung cancer patients, itraoperative seninel node mapping in non-small cell lung cancer patients, and selenium supplements as a chemo-preventive agent for diagnosed early lung cancer patients.

American College of Surgeons Oncology Group (ACOSOG) Research Studies

The American College of Surgeons Oncology Group (ACOSOG) was established primarily to evaluate the surgical management of patients with malignant solid tumors.

The ACOSOG includes general and specialty surgeons, representatives of related oncologic disciplines and allied health professionals in academic medical centers and community practices throughout the United States of America and foreign countries.

The Department of Surgery participates in the following ACOSOG trials:

• Lymph node sampling versus complete lymph node dissection in early stage lung cancer patients
• Analyzing the presence of occult micrometastases in patients with resectable non-small cell lung cancer by pleural lavage, bone marrow and tissue sampling
• Evaluating PET scans for esophageal cancer patients.

Cardiac Clinical Research

Clinical research in the Cardiac Service centers around inflammation during Cardiopulmonary Bypass (CPB). Inflammatory marker such as IL-6 and MMP are being measured in patients undergoing CPB which will eventually lead to manipulation of the inflammatory response.

Other studies include radiofrequency surgical ablation for the treatment of atrial fibrillation which is correlated with a clinical study to localize the source of atrial fibrillation led by Dr. Jose Jalife of the Department of Pharmacology.

Additionally, data bases to look at the treatment of aortic disease as well as cardiac tumors are being developed.