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February 2013 Osteoimmunology Research Yields Significant SPECIAL EDITION Findings Affecting Diverse Group of Diseases

Weill Cornell Medical College, a teaching affiliate of NewYork-Presbyterian Hospital, is among the top-ranked clinical and medical research centers in the country. The advanced research at Weill ­Cornell Medical College furthers medical science and improves clinical practice, and many of the physi- cians with academic appointments at the College also practice medicine at NewYork-Presbyterian/ Weill Cornell Medical Center. Here, the Dean of Weill Cornell Medical College discusses research SAVE THE DATE that explores both the immune and skeletal systems, with wide-ranging implications. Brain Attack and Cerebrovascular Disease e are undertaking advanced research in Update 2013 “Wareas such as inflammatory arthritides March 8, 2013 and lupus, and are engaged in important research New York Academy of Medicine in skeletal biology, particularly as it relates to lining scalloped edges of . New York, NY inflammatory diseases, cancer, , and Brain Tumor Biotech osteoarthritis,” Laurie H. Glimcher, MD, said. cells of the immune and skeletal systems are Summit 2013 She added, “At Weill Cornell Medical College, explored, which has led to discoveries that increase June 7, 2013 we have a very vigorous rheumatology research understanding of the basic science and eventually Weill Cornell Medical College group. I think it is very important for the academic may lead to advanced therapeutics for a range of New York, NY community to realize that we are fully committed disorders.1 Such discoveries have led to her elec- Advanced Endoscopic to strengthening our research even further, and one tion into several prominent scientific institutions, Skull Base and Pituitary way we will do that is through additional recruits.” including the National Academy of Sciences and Surgery, Hands-on As Stephen and Suzanne Weiss Dean of Weill the Institute of Medicine. Symposium Cornell Medical College, where she is also Profes- Osteoimmunology centers on the fact that the June 14-15, 2013 sor of Medicine, Dr. Glimcher is clearly well posi- skeleton is continually engaged in -medi- Weill Cornell Medical College tioned to state these goals, but she also happens ated coupled with -­ New York, NY to be an example of this commitment herself. Dr. mediated bone deposition. “The osteoblast has been For more information and to Glimcher was recruited a year ago from her posi- shown to be the niche where hematopoietic stem register, visit nyp.org/pro or tion as the Irene Heinz Given Professor of Immu- cells emerge within the ,” Dr. Glim- e-mail [email protected] nology at the Harvard School of Public Health, cher explained. “The osteoblast creates factors and where she was Director of the Division of Biologi- provides the environment that allows hematopoietic cal Sciences. She was also Professor of Medicine at stem cells to differentiate, and supports the immune Harvard Medical School, directing its system. Correspondingly, the cells of the immune program, and Senior Physician and Rheumatolo- system—T and B cells and macrophages—secrete gist at Brigham and Women’s Hospital, in Boston. inflammatory that activate the osteoclast Dr. Glimcher’s research laboratory has made sev- and lead it to resorb bone. So, for example, in rheu- eral notable discoveries, many of which have cen- matoid you find activated macrophages that tered on the pathophysiologic immune responses differentiate into osteoclasts under inflammatory Top Ranked Hospital in New York. affecting autoimmune, infectious, and malignant signals as well as signals from , which Twelve Years Running. diseases. In an emerging field that has been called cause bony erosive lesions.” osteoimmunology, the interrelationships between See Skeletal Biology, page 3 Advances in Rheumatology

Robotic Applications and Operating Room Technology Are Transforming the Post-Op Surgical Experience

uilding on the concept of mini- minimally invasive approach to treat Weill Cornell. Dr. Tewari, who is Direc- B mally invasive procedures, robotic uterine fibroids, as well as other gyneco- tor of the Prostate Cancer Institute and surgical approaches performed at logic surgeries—reported that real-time the LeFrak Center for Robotic Surgery, NewYork-Presbyterian Hospital are imaging has been fundamental to creat- has performed more than 5,000 robotic- vastly improving the patient experi- ing the modern OR, which is capable of assisted urologic procedures, and is ence. Real-time imaging in the oper- offering minimally invasive endovascular widely recognized for this work. Data ating suite combined with continually procedures, as well as radiologic-guided from a recently published meta-analysis advancing robotic systems offer the interventional, cardiothoracic hybrid, of 79 studies suggested robotic-assisted potential for greater precision with less and robotic procedures. prostatectomies are at least as effective by trauma, less scarring, less blood loss, “ORs for minimally invasive endo- essentially any measure, particularly in and quicker healing. Surgeons are driv- vascular procedures provided a head regard to the proportion of patients who ing the advances, and there are pro- start because they were set up for real- achieve cancer-free margins, but generate grams at both NewYork-Presbyterian/ time imaging and had the structure fewer complications.1 Columbia University Medical Center and size to accommodate the equip- “Robotic surgery was initially attrac- and NewYork-Presbyterian/Weill Cor- ment and connectivity that we need tive because of the visualization,” nell Medical Center that create an envi- for robotic procedures,” explained Dr. Dr. Tewari explained. “While the pre- ronment that encourages their rapid Evanko, who works to assist OR innova- cision of robotic excisions is an impor- implementation. tion at NewYork-Presbyterian/Columbia. tant advantage, the ability to visualize “Our surgeons are the ones driving “Minimally invasive surgery overall and the anatomy in the structural context robotic applications. My goal is simply robotics in particular are now being used that can be lost in an open approach has to ensure we are setting up our operating effectively across specialties, including been the most important attribute. There rooms [ORs] to facilitate these innova- gynecology, urology, otolaryngology, and is also significantly less bleeding, which tions,” said John C. Evanko, MD, MBA, thoracic and general surgery.” can also obscure the anatomy when per- who is Medical Director of Periopera- forming a reconstruction.” However, tive Services at NewYork-Presbyterian/ Urology other advantages, such as reduced blood Columbia and a gynecologic surgeon. In urology, Ashutosh K. Tewari, loss, have followed. Dr. Evanko—whose expertise with the MD, led much of the pioneering work The work by Dr. Tewari has greatly da Vinci Surgical System includes a in robotics at NewYork-Presbyterian/ advanced the use of robotic proce- dures for a broad array of urologic sur- gical procedures, including resection of benign hypertrophy, and he has now ­assembled one of the most important facilities in the world for this approach. NewYork-Presbyterian/Weill Cornell’s LeFrak Center for Robotic Surgery has several unique features. In addition to a large endowment that has permitted the Center to upgrade imaging capabilities and to employ multiple robotic systems, a comprehensive therapeutic program includes a multidisciplinary team to focus on recovery with emphasis on sus- taining a good quality of life. “There are several exciting develop- ments that will generate further evolu- tion in the field,” Dr. Tewari said. “For example, I think there will be synergy between the technological advances made

NewYork-Presbyterian Hospital is improving its patient care by implementing new, advanced r­obotic in robotics and genomic advances, which systems that help to improve the patient experience. will allow us to provide individualized

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care to the characteristics of the malig- able to debulk a patient’s ovarian cancer “Increasingly, imaging such as CT [com- nancy. However, robotic-assisted surgery robotically. She was rendered in complete puted tomography] scanning is an intra- in urology is a mature platform at our clinical remission with a surgery that operative tool to guide the procedure. Center. Our outcomes validate that this lasted about 2 hours and she didn’t have The modern OR has to be large enough approach provides advantages over an to stay in the hospital overnight. I think to accommodate the imaging systems, open approach.” that is a huge benefit and it isn’t being the displays, the robotic devices, as well offered in many places.” as the monitoring equipment that would Oncology be found in a conventional OR. This “A major focus for us at Weill Cor- Orthopedic, Gastrointestinal, requires planning and the infrastruc- nell Cancer Center is working to improve Neurologic ture that allows the OR to function effi- the quality of our patients’ lives, leav- At NewYork-Presbyterian/Colum- ciently.” Simply running the wires to ing them with less morbidity from our bia, robotic-assisted surgery is now being an increasingly complex and sophisti- treatments so they go on to live fruit- employed for some common orthope- cated array of devices limits the degree to ful lives without any long-standing det- dic diseases, for resections of a vast array which the OR can be retrofitted as needs riment. I think in that regard, robotics of malignancies, and for gastrointesti- evolve. plays a major role,” said Kevin Holcomb, nal diseases, including resections of the “We have been deeply involved in MD, Director of Minimally Invasive Sur- bowel. The precision of robotic-assisted attempting to anticipate these changes gery of the Department of Obstetrics surgery has long made it attractive for and to approach the development of a and Gynecology, NewYork-Presbyterian/ neurologic applications, but the expan- modern OR with a prospective approach. Weill Cornell. He added that his team is sion to such a broad array of organ sys- This has allowed us to stay at the front of studying robotic-assisted surgery, which tems is attributed primarily to its role the curve in expanding robotic-assisted involves the use of the da Vinci Surgi- in taking minimally invasive surgery to surgery where it has advantages for the cal System, in gynecologic cancers other the next step. Although the laparoscope patient,” Dr. Evanko said. than those for which it has already dem- brought momentum to minimally inva- onstrated benefit, such as in endometrial sive surgery, modern imaging systems Reference cancer. “We’ve been performing many allow visualization without a scope. It is 1. Novara G, Ficarra V, Mocellin S, et al. Sys- robotic surgeries for recurrent ovarian a new approach that demands ORs with temic review and meta-analysis of studies cancer, and really pioneering this,” said different capabilities. reporting oncologic outcome after robot- Dr. Holcomb, who instructs other sur- “Imaging was once a preoperative assisted radical prostatectomy. Eur Urol. geons on the technology. “Recently I was device to plan surgery,” Dr. Evanko said. 2012;62:382-404. continued from Skeletal Biology, page 1 A focus of Dr. Glimcher’s research vastly undertreated,” Dr. Glimcher said. We have ongoing research at Weil Cornell is this fundamental skeletal biology “One out of 2 women over the age of 55 that is dedicated to doing just that.” and the interplay between the immune years has low bone mass, whether it is Indeed, Dr. Glimcher and her col- and skeletal systems, which necessarily from the tendency to resorb bone with leagues discovered a gene that controls touches on diseases as diverse as osteo- age, or from a bony bone mass, finding that if the gene is porosis, osteoarthritis, inflammatory erosion caused by inflammation, or from inhibited there will be a vast increase arthritides, and cancers, such as multi- cancer.… We need to figure out how to in bone mass and protection from age- ple myeloma. Dr. Glimcher pointed out make more bone. related bone loss.2 that some of the same therapeutics are used across some of these disease states, “We very much need to enhance and expand the including the bisphosphonates, whose research we are doing on those diseases that arise from major target is the osteoclast, and deno- sumab, FDA-approved for prevention of dysregulation of bone formation.” ­skeletal-related events in patients with —Laurie H. Glimcher, MD solid tumor bone metastases. Deno- sumab is a receptor activator of nuclear “There are two ways to do that. Several Schnurri-3 (Shn3) is a large zinc fin- ­factor κ-B ligand (RANKL) inhibitor, researchers at Weill Cornell Medical Col- ger protein that, among other functions, which is the major factor that stimulates lege and the Hospital for Special Surgery is an adapter protein within the immune osteoclastogenesis. are targeting the osteoclast and work- system. Very few genes have been found “The most important point I want ing to inhibit it. Another approach is to to regulate postnatal osteoblast-mediated to emphasize is that these diseases are make the osteoblast produce more bone. See Skeletal Biology, page 4

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continued from Skeletal Biology, page 3 display heightened osteoblastic bone for- to join her when she accepted the posi- ; one such gene is the mation. They also found that mesen- tion of Dean at the College, and several did, transcription factor Runx2. Dr. Glimcher chymal cells lacking the protein were and she continues to actively work to fur- and her colleagues found that mice that defective in promoting osteoclastogene- ther strengthen research, in ­rheumatology were developed with a null mutation of sis, and that Shn3 controls the expression as well as other areas. “There is a lot of the Shn3 gene, with no Shn3 mRNA or of RANKL, the key osteoclastogenic cyto- cross-talk between the and protein, were born healthy without gross kine, in mesenchymal cells. the skeletal system and between the skele- abnormalities, but at maturity showed This finding is very promising, and tal system and the endocrine system,” she increased bone mass at various points research is ongoing. “You can imagine said. “We very much need to enhance and along the skeleton. They found that Shn3 that when you have inflammatory immune expand the research we are doing on those controlled protein levels of Runx2, and cells that are making RANK ligand, or diseases that arise from dysregulation of discovered that it is a “central regulator of , then that is going bone formation, which happens, for exam- postnatal bone mass.” to cause osteoclastic activation and bone ple, in inflammatory arthritis, patients who “The most attractive route for research is resorption, and that is of course what we take steroids, women after menopause, in to activate the osteoblast because you need see,” Dr. Glimcher said. “You can pre- the setting of cancer, and in some inherited to form new bone,” Dr. Glimcher observed. serve bone mass if you can block inflam- diseases.” “Halting bone resorption by targeting the mation in these inflammatory diseases, and References osteoclast is a very good first step, but ulti- the gold standard for testing whether new mately bone resorption and bone formation therapeutic agents can do that is radio- 1. Jones D, Glimcher LH, Aliprantis AO. are coupled, so if you decrease osteoclast graphic evidence that erosive lesions have Osteoimmunology at the nexus of arthri- activity you will eventually decrease osteo- been halted. So inflammation is a key part tis, osteoporosis, cancer, and infection. J Clin blast activity as well. However, if you of regulating the skeletal system, which in Invest. 2011;121:2534-2543. increase osteoblast activity it is possible turn can regulate and mediate the conse- 2. Jones DC, Wein MN, Oukka M, et al. Reg- that there are circumstances where you will quences of inflammation.” ulation of adult bone mass by the zinc fin- not also increase osteoclast activity, or, if Dr. Glimcher is very optimistic about ger adapter protein Schnurri-3. Science. you do, there is still a net positive.” the research program at Weill Cornell Med- 2006;312:1223-1227. Indeed, Dr. Glimcher’s laboratory found ical College, although she noted, “the field 3. Wein MN, Jones DC, Shim J-H, et al. that Shn3 concurrently activates the osteo- of skeletal biology in general is very under- Control of bone resorption in mice by blast and inhibits the osteoclast.3 Their populated with talented scientists.” She had Schnurri-3. Proc Natl Acad Sci USA. research confirmed that mice lacking Shn3 invited a number of those talented people 2012;109:8173-8178.

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