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Lab Overview

The Laparoscopy and Oncology Laboratory of St. Luke’s Roosevelt Hospital
Director, Richard L. Whelan, MD


Introduction


The Laparoscopic Physiology and Oncology Laboratory was first opened in 1996 at Columbia University’s Health Science Campus in Washington Heights. In 2009 the lab was moved to St. Luke’s Roosevelt Hospital where it now resides. Dr. Richard L. Whelan heads the laboratory. The lab is staffed by 2 fulltime PhD’s (Dr. Shantha Kumara and Peter Yan) as well as 2 full time residents or medical students (doing 1 – 2 year long research rotations). There is also a full time research nurse and a clinical data manager/statistician round out the research staff. There are often 1 or 2 post baccalaureate students working with our group as well.


The initial purpose of the lab was to explore the physiologic, immunologic, and oncologic effects of open (large incision) and laparoscopic (minimally invasive) surgery. Stated in layman’s terms, the purpose of the lab was to determine how the methods used to gain access to the abdominal cavity in order to perform surgery alter the body’s ability to heal itself and to deal with cancer cells that may remain in the days and weeks following surgery. Over a 6 to 8 year period we demonstrated that Minimally Invasive Surgical (MIS) methods were less injurious and resulted in fewer and less severe changes in the composition of the blood and immune system function.


The lab’s early study results suggested that major surgery (either open or laparoscopic) resulted in changes that would stimulate the growth of residual cancer in patients who had unforeseen micro metastases or circulating tumor cells after resection of the primary lesion. (See Early Years Summary) Since that time the lab’s purpose has been to better understand why tumor growth is stimulated after surgery and to find anti-cancer therapies that can be used during the month before and immediately following surgery. Toward that end the lab has performed a Phase 1 type clinical trial testing the agent G.M.C.S.F. in cancer patients and is in the process of starting a second clinical phase 1 study. The lab has also investigated more than 8 different anti-cancer drugs (murine and human studies), immunomodulating agents (murine and human studies), and tumor vaccines (murine studies only). In addition to the above research the lab has also, from the start, investigated new minimally invasive surgical methods or looked for ways to improve current cancer resection methods. A summary of the lab’s current major avenues of research follows.


Angiogenesis in the Postoperative Period


One of the major contributions of the lab has been to discover that laparoscopic and open colorectal resection is associated with prolonged (2-4 weeks after surgery) plasma protein changes that collectively render the plasma proangiogenic. Thus far, studies from the lab have been published regarding the proangiogenic proteins VEGF, Angiopoetin 2, and Placental Growth Factor – all of which are elevated for up to a month after minimally invasive large bowel resection. Further, in vitro Endothelial Cell (EC) culture studies have shown that plasma from the second and third weeks after MIS colorectal resection stimulated EC proliferation, migration, and invasion (all critical to neovascularization).


The lab is presently determining perioperative blood levels of a number of proteins that impact angiogenesis. These studies are done via ELISA and utilize blood samples taken from patients preoperatively and, repeatedly, during the first 6 weeks after surgery. Papers and presentations regarding sVCAM, Angiopoietin-Like Protein 4 (ANGPTL4), FGF, HGF, and other proteins will be published and presented this spring. The lab is starting a series of studies that will determine how colorectal surgery for benign indications impacts angiogenesis; we believe that the proangiogenic effects we have noted are related to surgical trauma and are not, therefore, related to the indication for surgery. Toward that end multiple protein assays and in vitro EC culture studies will be done using benign perioperative plasma samples from benign colorectal resection patients.


EGCG and Siliphos Phase 1 Human Study


This year the lab completed a series of murine studies that demonstrated that a combination of green tea extract and a supplement called siliphos, when given for a week before and for 3 weeks after surgery, significantly inhibits the growth of cancer both subcutaneously and in the liver during the perioperative period. It was also determined that this drug combination did not impair or inhibit wound healing (abdominal wall and gastric wound strength was assessed). The results of the final study will be presented at the SAGES meeting this spring. Thus, this drug combination appears safe for perioperative use.


A Phase 1 human Phase 1 study is planned for 2011 in which patients undergoing large bowel resection for cancer will have the opportunity to take these two drugs for the week prior and for 3 weeks after their operation. An IRB study proposal has been submitted and we are soon meeting with the FDA to, hopefully, get permission to use this drug combination in humans. We hope to enroll 30-40 patients.


Other Drug Candidates for the Perioperative Period


The lab has been and continues to investigate the use of CPG (an immunomodulator) and pinocembrin for possible use perioperatively, in addition to other candidate perioperative agents. New drugs are tested for their ability to limit tumor growth subcutaneously and in the liver, in mice, during the perioperative period. If the drugs are effective a wound healing murine study is done wherein the breaking strength of abdominal wounds and the bursting strength of gastrotomy wounds are determined as well as the collagen content. We hope to carry out a series of Phase 1 studies and to select the most promising drug(s) for a Phase 2 study that we would strive to get funded.


Laparoscopic/Colonoscopic Method for Removal of Large Benign Polyps


Large polyps that cannot be removed with a colonoscope in the outpatient setting are usually removed by performing a standard cancer type surgical resection of a segment of the colon or rectum. This is a major operation that carries the risk of infection, bleeding, etc. At St. Luke’s Roosevelt Hospital, we are now carrying out a single center study wherein, using advanced colonoscopic methods (Endoscopic Submucosal Dissection [ESD] and Endoscopic Mucosal Resection [EMR]) combined with simultaneous laparoscopy to inspect and manipulate the outside of the large bowel, we are attempting to fully remove large polyps without performing a cancer type colorectal resection. If successful, a standard resection of a length of the bowel is not required. We have successfully removed about 14 of 28 polyps using these methods. If, after intraoperative evaluation it is determined that the polyp in question cannot be removed using the new method, then a standard colon resection is performed. We are working with the Olympus Corporation to develop new endoscopic tools and methods. This approach, we believe, will spare many future patients from needing colon resections for these polyps.


Tattooing the Distal Margin in Rectal Cancer Patients


The lab is currently investigating the use of endoscopically placed rectal wall tattoos, placed at the time of surgery, to mark the site of distal rectal transection. Whereas tattoos have been used to mark the location of colon cancers, they have not been used for rectal cancers. It has been noted that it is possible to accurately mark the rectum at the desired site of transection (using a through the channel ruler) with a series of low volume tattoos placed via an endoscope. These tattoos, it is believed, notably facilitate and simplify the distal rectal transection, especially during MIS operations, by removing the usual doubt as to how much of a margin one is getting when the stapler is applied. A poster regarding the preliminary results of this study will be presented at SAGES. Further work is ongoing.


Tumor and Blood Sample Bank


It is necessary to have a tissue bank in order to do the types of clinical and basic science cancer studies that the Whelan lab is involved with. Toward that end, the lab and its personnel started a tumor and perioperative plasma bank at St. Luke’s Roosevelt Hospital as of the fall of 2009. Lab personnel, under the supervision of pathologists, harvest samples of colon, lung, and breast cancers (plus samples of normal tissue for each patient) that are frozen and stored in a tumor bank. Further, preoperative blood samples are obtained and processed for cancer patients and the plasma divided into small aliquots and then frozen. Multiple postoperative samples are taken from colorectal resection patients during the first 2 months and similarly processed and stored. These tissue banks permit the periop ELISA, EC culture, Tumor culture studies, antigen discovery, RT-PCR, and other studies the lab is involved with. Further, the tissue is available to other researchers in the institution for studies.


Tumor Antigen Discovery for Vaccine Development


The lab believes that immunotherapy holds great promise for use in the perioperative period. Immunotherapy’s in general have minimal side effects and are not likely to impair wound healing. The lab has published at least 10 articles regarding murine studies that assessed immunomodulating agents as well as a variety of vaccines. Unfortunately, in the human arena, tumor vaccines have proven very difficult to develop and have not been successful, to date. New vaccine targets for colorectal cancer, either peptides or tumor antigens are required. Toward this end, we have been working with the Cancer Research Institute and researchers from Sloan Kettering Hospital over the past 4 years to find promising proteins in human colon and rectal cancers that could be used in an anti-cancer vaccine. Tumor samples that the lab has “banked” from consenting patients who underwent surgery at Columbia Presbyterian Hospital or St. Luke’s Roosevelt Hospital were used for these studies. The first paper regarding 3 potential candidate proteins (MAGE3, GAGE, and PLAC-1) has been submitted for publication (the results have been presented at 2 meetings in 2009 and 1010). A second paper regarding the previously unrecognized Cancer-Testis antigen, IGF2BP3, that the lab discovered is also being prepared for submission.


Participation in Multicenter Clinical Cancer Studies


The Division of Colon and Rectal Surgery is currently involved with 3 different multicenter randomized trials concerning rectal cancer patients. The first is the ACOSOG study that is comparing open and minimally invasive total mesorectal excision (TME) for patients with rectal cancer. The second is a smaller multicenter study that is comparing straight laparoscopic and hand-assisted laparoscopic rectal cancer resection (supported by the Applied Medical and the Olympus Corporations). The third study is investigating whether reinforcement of the circular staple lines with copolymer glycolide (PGA) and trimethylene carbonate (TMC) decreases the leak and abscess rate in patients with rectal cancer who have undergone preoperative radiotherapy and chemotherapy (sponsored by the Gore Corporation).


Publications and Funding


Over 105 peer reviewed papers and over 20 chapters have been published and are attributable to the lab’s basic science and clinical research activity. The bull bibliography of the lab is available upon request. The lab is supported by the St. Luke’s Hospital Department of Surgery, the Breast Surgery and Medical Oncology Divisions at St. Luke’s Roosevelt Hospital, PEER reviewed grants, grateful patients and a number of pharmacologic and surgical device corporations (via study directed support or educational grants).

What Our Patient’s Say…


Our family wishes to express our heartfelt appreciation for the kindness, excellent care and wisdom our mother, Jean Broussard, received during her hospitalization.

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