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BU Publications Evans Medicine

1988 Evans Medicine: Summer 1988 v. 4, no. 1

https://hdl.handle.net/2144/22461 BOSTON UNIVERSITY MEDICAL CENTER EVANSI MEDICINE

Evans Memorial Department of Clinical Research and Preventive Medicine VOLUME 4, NUMBER 1 SUMMER 1988 Enthusiasm and a broad research program characterize growing Dermatology Department

In just three years the Department of Derma• tology has grown from one to 11 members and its research programs and clinical activi• ties have been expanded to make it one of the top dermatology groups in the nation. The Department The force behind this growth is Dermatology capitalizes on chief Barhara A. Gilchrest, M.D., who joined members' innovation the Department in 1985 from Tufts Univer• and collaborative sity and the New England Medical Center (where she still heads a laboratory at the projects with other USDA Human Nutrition Research Center on Evans groups. Aging). Her energy and innovation have made the Department a great place to be, ac• cording to one member who feels "very lucky to he a part of it." A sampling of the types of research and clinical activities under way in the Depart• ment includes: • Exploration of new laser applications in dermatology. • Treatment of difficult skin cancers hy a Monica Peacocke, M.D., discusses her research on new microscopically controlled surgical tech• melanocytes and nerve growth factor. nique known as Mohs surgery. • The estahlishment of a Clinical Test Center for studies of new dermatologic treat• Laboratory group at ments, including a trial of retin A for photo- aged skin. forefront of human • Formation of two innovative training programs: A unique joint training program in melanocyte biology dermatology with Tufts University and the New England Medical Center and a new As principal investigator of a program project year-long certificate program in dermatology grant on the cellular basis of aging, one of for foreign health-care professionals, sched• Dr. Gilchrest's principal interests has been uled to hegin this summer. the biology of the human melanocyte, an Crucial to the success of the Department, area to which she has made some pioneering says Dr. Gilchrest, are three factors: the contributions. Although melanocytes are a quality of its members, the strong interactive minority cell type in the epidermis after ker- links between laboratory research and clini• atinocytes and fibroblasts, they nevertheless cal practice, and the multidisciplinary char• play a key role in photoprotection, photoag- acter of projects under way. ing and photocarcinogenesis. It is in this last This issue of Evans Medicine highlights capacity that molecular biologist Monica three members of the Department of Derma• Peacocke, M.D., recruited to pursue research tology whose work symbolizes important as• in this area, finds them so interesting. pects of the discipline and the Evans in gen• Dr. Peacocke, who joined the Department The eral: hasic research, education and patient last year, heads the laboratory group on cuta- University care. • Continued on page 2 Hospital neous gerontology. She is posing questions— there is an effect of NGF on melanocytes at many for the first time—ahout the growth certain points in their life cycle." Ultraviolet EVANS and differentiation of normal melanocytes irradiation, a stimulus for tanning of normal MEDICINE and the possihle mechanisms involved in skin, also stimulates NGF receptor produc• malignant transformation. tion in cultured melanocytes. "The most interesting thing ahout melano• Nerve growth factor receptors have been cytes for us is not their role in tanning, hut found on many human melanoma cell lines, the fact that they can hecome malignant," but it is not clear whether NGF is related to says Dr. Peacocke, "and melanoma is a can• the malignant transformation or is just a cer that is galloping in terms of incidence. marker of cellular maturity. To explore this We are prohably the first group to investigate question. Dr. Peacocke is beginning a series aspects of melanocyte gene expression—ex• of experiments that involve inserting an am• amining which genes are involved in normal plified version of the gene for nerve growth growth and which may he involved in trans• factor receptor into normal melanocytes and formation." observing the changes. After three weeks of Thanks to hreakthrough contributions by growth, Dr. Peacocke hopes to notice Dr. Gilchrest over the past several years, the changes in morphology to the nerve cell type ability to culture melanocytes has been and unusual growth patterns, particularly vastly improved. Using these techniques. Dr. clumping, which is generally the first sign of Peacocke and her colleagues are looking malignancy. As a final step, the abnormal closely at the role of nerve growth factor in cells will be injected into nude mice to see if melanocyte biology and at the cell-cell inter• tumors develop. actions between keratinocytes and melano• cytes. According to Dr. Gilchrest, the group TPA-stimulated melano• was the first to demonstrate in culture that cytes stain positive for keratinocytes produce a series of substances NGF receptors with im- muno fluorescent mono• that influence melanocyte morphology, pig• clonal antibody. ment production and growth rate. Melano• cytes are attracted by what keratinocytes make and these factors are critical to melan• ocyte survival. Exactly what these mediators are and how they work on melanocytes are the subjects of further studies in Dr. Pea- cocke's lab. Dr. Peacocke's current studies began seren- dipitously, she says. When, working with Dr. Mina Yaar at Tufts University, she noticed that melanocytes treated with the tumor promoting phorbol ester, TPA, differentiated to look like nerve cells. (As neural crest-de• In collaboration with Dr. Yaar, Dr. Pea• rived cells, melanocytes migrate early in em• cocke has shown that keratinocytes produce bryonic development to the skin where, in NGF as well, and she is pursuing investiga• contact with keratinocytes, they assume a tions to elucidate the complex relationships polygonal, somewhat dendritic character.) between keratinocytes and melanocytes. For This nerve cell-like morphology suggested instance, if skin is exposed to sunlight in to Dr. Peacocke that receptors for nerve amounts necessary to produce a tan, do the growth factor (NGF) could be found on me• keratinocytes make more NGF, and is in• lanocytes. Gollaborating with a colleague at creased NGF production involved in melano• Cornell University who had cloned the hu• cyte transformation? She also is interested in man NGF receptor, Dr. Peacocke found that the proteins that enable melanocytes to normal melanocytes were negative for NGF maintain their long dendritic processes and receptor. However, cells that had been ex• is looking especially at fihronectin and lami- posed to the tumor promoter made the re• nin, which are two large extracellular matrix ceptor protein. Further experiments revealed proteins synthesized hy neighboring keratin• both the presence of protein of the correct ocytes. The hypothesis is that as melano• molecular weight for the NGF receptor and cytes encounter these proteins, the melano• the expression of the gene for the receptor in cytes differentiate and a sequence of genes TPA-stimulated cells. involved in the differentiation program are "If you give nerve growth factor to an un• induced. stimulated melanocyte, nothing happens; Although Dr. Peacocke is looking at the NGF cannot interact with the cell because specific genetic steps involved in the melan• there is no receptor. What we are discovering ocyte differentiation from normal polygonal now is that we can induce the receptor in a to dendritic nerve-cell form, particularly the variety of ways," says Dr. Peacocke. By re• events that occur in the first 30 minutes to moving for a period of time the serum or one hour after exposure to TPA, she also is basic fibroblast growth factor—the major me• looking at the sequence of gene activation in lanocyte mitogen—needed to grow melano• normal melanocytes. cytes in culture, and then giving the melano• "Only through a meticulous exploration of cytes NGF, she found that the cells grew normal growth and differentiation can we better. "Not as well as if they had serum or come to understand the abnormal growth in• basic fibroblast growth factor, hut clearly volved in malignancy," she says. • Dermatologist studies can Cancer Society. Similar campaigns have proved effective for breast cancer detection melanoma prevention, and prevention and, according to Dr. Koh, should work as well for melanoma. blood cancer treatment In addition to his public health work. Dr. Koh is the director of photopheresis at the Research in the Department of Dermatology University Hospital. Photopheresis is a new is not restricted to the laboratory bench, and technique used to treat people with a severe the work of Howard Koh, M.D., is a case in form of the skin cancer cutaneous T cell Screening has the potential lymphoma. Cutaneous T cell lymphoma is a point. Dr. Koh is board certified in internal to catch melanoma before medicine, hematology, and derma• relatively uncommon tumor compared to it becomes deadly. tology and presently has appointments in the melanoma, but it can appear in a wide range School of Puhlic Health and the Departments of forms. The most advanced phase, called of Medicine and Dermatology. He is putting Sezary's syndrome, occurs when malignant T his broad training to good use in the study of cells in the skin move into the bloodstream skin cancer, particularly melanoma, and its and the patient develops leukemia as well. prevention. (Dr. Koh recently was awarded a Whitaker "My overall interest is in the public-health Health Sciences Fund grant in collaboration aspects of cancer and the early detection and with Dr. Herman Eisen of the prevention of cancer. Melanoma is an excel• Institute of Technology to explore the basis lent tumor model to study because even of photopheresis' beneficial effect.) though the rate of incidence is increasing The University Hospital is one of 10 cen• faster than any other cancer, except for lung ters in the country offering photopheresis. cancer in women, and the number of deaths The technique involves removing a patient's from melanoma is increasing, the potential blood by a dialysis machine, separating out for early detection and prevention is great." the malignant T cells and shining long wave Dr. Koh and colleagues in the School of ultraviolet light on these cells, which acti• Puhlic Health are researching how to im• vates the drug, psoralen, that the patients prove the early detection and prevention of have taken prior to the procedure. The pho- melanoma and whether screening helps to toactivated drug affects the malignant cells 'Although the number control the number of deaths. Dr. Koh is a and the blood is then returned to the patient. of deaths from member of a national committee of the Exactly how the process works is unknown, melanoma is rising, American Academy of Dermatology (AAD) but it is thought that by damaging cells with the potential for early that is looking into skin cancer prevention. light, photopheresis allows for more rapid de• detection and The AAD has organized yearly nationwide struction of the malignant cells, conceivably screening clinics as part of this effort. through an immunologic mechanism. prevention is great/ According to Dr. Koh, more than 100,000 The treatment helped approximately 75 people, including approximately 2,500 in percent of the patients in a first series stud• Massachusetts, have been screened in the ied at . "In theory this might past three years during limited screening work with other, more common diseases, campaigns. Such clinics will be held again such as chronic lymphocytic leukemia and this year at a number of sites, including at chronic rheumatoid arthritis," says Dr. Koh, BUMC, where dermatologists in the Evans who plans to start protocols this summer Medical Group have donated their time to with collaborators in the Evans Sections of conduct examinations for skin cancer. (Last Hematology and Arthritis. • year, 116 people were screened during two days at the Evans Medical Group; 25 percent were thought to have clinically suspicious lesions and were referred to their own physi• cians for follow-up.) Dr. Koh is active in co• ordinating the Massachusetts melanoma screening efforts in order to obtain hard data on whether the screening programs work. This effort includes tracking what happens to individuals following the screening— whether cancer was diagnosed and what the pathology and outcomes were. Dr. Koh uses the term "applied epidemiol• ogy" to describe his prevention efforts, which involve using all available data on melanoma, including who is at risk for it and what the risk factors are, in order to prevent the disease or at least keep it from reaching an incurable stage. In addition to screening, educational ef• forts have been aimed at teaching individu• als, primary care physicians and nurse practi• tioners to routinely check for signs of melanoma. Dr. Koh has contributed to these Howard Koh, M.D., is pursuing research in mela• efforts as a member of the board of directors noma prevention and photopheresis, a new therapy of the Massachusetts Ghapter of the Ameri• for patients with Sezary's syndrome. Noteworthy

Internationally known expert on hyperten• on the increasing frequency of adenocarci• sion Aram Chobanian, M.D., chief of the Ev• noma of the esophagus in Massachusetts at ans Hypertension Section and professor of the recent annual meeting of the American medicine and pharmacology, became the Society of Clinical Oncology, also in New 16th dean of Boston University School of Orleans. Medicine, effective May 1. Among other recent achievements. Dr. Mark Moskowitz, M.D., has heen appointed Chobanian presented the 1988 Report of the chief of the Evans General Internal Medicine Joint National Committee (JNC IV) on the Section. Dr. Moskowitz previously had been Detection, Evaluation and Treatment of Hy• in charge of the Health Care Research Unit pertension at an April press conference in in that Section. Bethesda, Md., sponsored by NHEBl. Dr. Chobanian is chairman of the JNC IV com• Karen Freund, M.D., also of the General In• mittee, and the report was scheduled to ap• ternal Medicine Section, has heen named di• Aram V, Chobanian, M.D. pear as a special article in the May 1988 is• rector of the Women's Health Group, effec• sue of the Archives of Internal Medicine. tive July 1, 1988. She replaces Linda Lesky, Dr. Chobanian also received the 1987 East• M.D., who is leaving to pursue research in man Kodak Award of the National Academy clinical epidemiology at Harvard Medical of Clinical Biochemistry for his research on School. the relationships between hypertension and atherosclerosis. Evans member Michael Rosenbaum, M.D., an associate clinical professor of dermatol• David Beller, Ph.D., who heads the Evans ogy, has heen elected secretary-treasurer of Research Immunology Unit, has heen invited the New England Dermatological Society. to speak at the Second International Work• shop on Macrophage Biology and Activation Neil Ruderman, M.D., Ph.D., head of the this July. Diahetes-Metabolism Unit in the Evans Sec• tion of Endocrinology and Metabolism, was a Richard D. Diamond, M.D., chief of the In• visiting professor at Louisiana State Univer• fectious Disease Section, recently was sity and the University of Tennessee Schools elected a member of the American Associa• of Medicine in March. Anthony McCall, tion of Physicians. Richard A. Cohen, M.D., M.D., an assistant professor of medicine and of the Peripheral Vascular Section, and physiology in the same Section, is an invited Thomas Rothstein, M.D., Ph.D., of the He• speaker for the Symposium on Hypoglycemi; matology Section, were elected to member• organized by the International Diabetes Fed• ship in the American Society for Clinical In• eration, to be held in Sydney, Australia, in vestigation. Both organizations encompass all November. specialties and election to them recognizes outstanding research accomplishments and David Salant, M.D., a professor of medicine national and international reputation. and pharmacology, was named head of the Renal Unit and the Renal Section of the De• Matt Fenton, Ph.D., recently joined the Ev• partment of Medicine in 1987. ans as a research professor of medicine in the Immunology Section. His interest is in mo• R. Knight Steel, M.D., chief of the Evans lecular mechanisms of regulating lE-l ex• Geriatric Section, is serving as chairman of pression. the Gertifying Examination Committee in Geriatric Medicine of the American Board ol William Kannel, M.D., chief of the Section of Internal Medicine and the American Board o Preventive Medicine and Epidemiology, re• Family Practice. In April, Dr. Steel was ceived a Distinguished Service Award this among a panel of experts discussing issues spring from the American College of Cardiol• related to aging and health care during an in ogy at the College's annual meeting in At• teractive video teleconference, moderated by lanta. Ted Koppel of ABG. The program, entitled "Aging in America: Dignity or Despair," was Evans Director Norman G. Levinsky, M.D., broadcast live to special conference centers Wade Professor of Medicine and chairman of across the country. the Division of Medicine at BUSM, recently was elected a Master of the American Col• Joseph Stokes, M.D., a member of the Sec• lege of Physicians. He also is serving as pres• tion of Preventive Medicine and Epidemiol• ident of the Association of Professors of ogy, received medals from the Swedish Soci• Medicine for the 1988-89 term. ety of Medicine and the Society for Prospective Medicine in recognition of his Ronald McCaffrey, M.D., chief of the Section research in preventive medicine and epide• of Medical Oncology, served as chairman of miology. In addition. Dr. Stokes, who directs the Leukemia Society of America's annual the Framingham Offspring Study, presented a meeting in New Orleans in March. Paul Hes- lecture in April on the National Cholesterol keth, M.D., an assistant professor of medi• Education Program at Prevention '88. cine in the same Section, presented a lecture Skin graft technique holds promise for patients with chronic wounds

Since joining the Department a year and a half ago, geriatric dermatology fellow Tania Phillips, M.D., has been heading a clinical research program using cultured skin allo• grafts to treat intractable skin ulcers. It has been estimated that 1.5 million Americans suffer from chronic, nonhealing wounds. People with diabetes, older people with poor circulation and cancer chemotherapy pa• tients may be especially prone to delayed or failed healing. Dr. Phillips' approach involves culturing small pieces of discarded foreskins from newborns into large sheets of cells that can be placed directly onto wounds. Before coming to the United States, ex• With patient looking on, Tania Phillips, M.D., describes cultured plains Dr. Phillips, she was a clinical derma• allograft procedures. tologist at the London Hospital in London, England, where she treated many patients "The interesting thing," says Dr. Phillips, with persistent leg ulcers. "One of the ways "is the way the allograft works, because this to treat these problems is with a split-thick• is foreign tissue." At first, she says, the re• ness skin graft, using skin from the thigh to sults were so dramatic that she thought the cover the wound. The problem with this ap• graft must be taking. Further studies have in• proach, especially with older patients, is that dicated, however, that the allografts do not you leave a wound in the thigh, which itself remain in place permanently, but are slowly can he painful and take a long time to heal." rejected as the host tissue repairs itself. Biop• The split-thickness approach also limits the sies performed after three or four weeks do size of the wound that can be treated. not reveal any foreign tissue at all. When she arrived in Boston, Dr. Phillips "We think the combination of a biological spent time in the laboratory of Dr. Howard dressing, which keeps the wound moist and So far, more tlian 70 Green of Harvard University, where she protects it from the air, and the rich mix of learned how to grow the cells in culture. growth factors secreted by the neonatal cells percent of her "Dr. Green developed the method of taking a stimulate the patient's own skin cells to be patients treated with tiny piece of skin from a person, growing it more active and fill in the wound, which cultured allografts to many times its original size and then us• they couldn't do before," says Dr. Phillips. experienced complete ing this bigger piece to treat the wound. In It also is possible that the loss of the donor wound healing. early trials this worked pretty well, but the skin's Langerhans cells during the culture problem again was that with older patients process makes the graft much less antigenic the skin cells are older and just don't grow as than a conventional graft of noncultured tis• well," Dr. Phillips explains, "so people won• sue. dered what else could he tried." Another positive aspect of the allograft Drawing on Dr. Gilchrest's findings of age- treatment, according to Dr. Phillips, is the related losses in the proliferative potential of almost immediate relief from pain that many skin cells. Dr. Phillips decided that a good patients experience—pain that for many has possibility might be to use newborn fore• heen constant during the months or years skins because young cells grow so much bet• during which the ulcer has failed to heal. ter in culture than older skip and because Until now. Dr. Phillips has been doing an newborn cells generate large amounts of uncontrolled trial of this treatment, follow• growth factors. ing the wound healing process in each pa• She has treated about 40 patients so far at tient, tracking the time the process takes and the University Hospital using cultured neo• the pattern of healing. A comparison of ul• natal cells, and has been getting excellent re• cers that heal completely and those that sults—over 70 percent of patients' wounds don't showed a pattern of dramatic improve• have healed completely and most of the rest ment in both during the first two weeks, fol• have shown improvement. First, the ulcer is lowed by a tapering off in some cases. "If a cleaned with conventional topical treat• wound is going to heal at all, you can usu• ments, then the layer of cultured cells at• ally tell in the first four weeks," she says. tached to a gauze backing is applied and ban• Beginning this summer, she will head a daged over. If the patient can rest at home large randomized study in collaboration with and stay off his or her feet for the first week, groups at the Boston Veterans Administra• there is no need for hospitalization; if not. tion Medical Center and Brown University's Dr. Phillips does her best to have the patient Roger Williams Hospital in which some pa• admitted. After the first week, the gauze is tients will receive cultured allografts while removed and the patients can continue to others will only receive the gauze dressing. dress the wound themselves until healing is At the moment, she is seeking patients to complete. include in this next phase of research. • Evans Memorial Department Nonprofit Org. of Clinical Research U.S. Postage The University Hospital PAID 88 East Newton Street Boston, MA Boston, MA 02118 Permit No. 3469

Jay D. Coffman M.D. Peripheral Vascular E411

Evans/Transition

Kenneth Steinherg, M.D., has been named Joseph Polito, M.D., Medical College of Vir• chief resident for the 1988-1989 academic ginia year. Born in Brooklyn, N.Y., and raised in Bruce Randazzo, M.D., State University of Stamford, Conn., Dr. Steinberg received his New York at Stony Brook School of Medi• medical degree from New York Medical Col• cine lege. He is just finishing his third year as a Lisa Renfro, M.D., University of Connecticut resident in internal medicine and will start School of Medicine his chief residency July 1. Monique Roth, M.D., University of Connect• Following his year as chief medical resi• icut School of Medicine dent. Dr. Steinberg expects to begin a pulmo• Jeffrey Silver, M.D., Boston University nary medicine fellowship, although he is not School of Medicine yet sure where. His research interests focus Lynn Sydor, M.D., University of Pittsburgh on vascular mediators and their role in pul• School of Medicine New chief medical resident monary vascular disease. Dr. Steinberg also is Robert Tarpy, M.D., University of Massachu• Kenneth Steinberg, M.D. interested in the development and treatment setts Medical School of interstitial lung disease. Arthur Zerbey, M.D., University of Minne• In addition to patient-care duties. Dr. sota School of Medicine Steinberg helps teach the advanced cardio• pulmonary life support course of the Ameri• Thirteen Evans memhers complete their resi• can Heart Association to nurses, interns and dencies in July. The graduates and their fu• other residents at the Medical Center, and he ture pursuits are: instructs second-year medical students in Manuel Anton, M.D., (cardiology) physical diagnosis. Andrew Chodos, M.D., Boston University Evans Medicine is published "I definitely would like to get a position in Medical Center (cardiology) by the Evans Memorial De• academic medicine. 1 enjoy teaching, thrive Peter Francis, M.D., National Cancer Insti• partment of Clinical Research on patient care and have research interests as tute (oncology) and Preventive Medicine of The University Hospital, a well, so 1 would prefer a situation that com• Russel Gerry, M.D., private practice in Con• member of Boston University bines all three." cord, Mass. Medical Center. Editor is Jay A total of 20 interns have joined the Evans Eric Manning, M.D., Boston University Med• D. Coffman, M.D., associate ical Center (research fellowship in bio• director of the Department; this year. They are: associate editor is Caroline Christopher dlFilippi, M.D., University of chemistry) Lupfer; designer is Kredlow Rochester School of Medicine Craig Morita, M.D., Brigham &. Women's &. Gonzalez. Evans Medicine Judy Fine, M.D., Tufts University School of Hospital, Boston (rheumatology) is produced by Boston Univer• sity Medical Center's Office of Medicine Joanne Murabito, M.D., Framingham Heart Publication Services, Owen f. John Freedman, M.D., University of Pennsyl• Study McNamara, director. Send any vania School of Medicine Margaret O'Donoghue, M.D., Harvard Uni• correspondence to the Evans Howard Goldberg, M.D., Albert Einstein Col• versity (neurology) Memorial Department of Clinical Research, 88 East lege of Medicine Alan Steele, M.D., Beth Israel Hospital, Bos• Newton St., Boston, MA Robert Goldberg, M.D., University of Cali• ton (renal medicine) 02118. Norman G. Levinsky, fornia-San Diego School of Medicine Kenneth Steinberg, M.D., The University M.D., is director of the Department. James Hoffman, M.D., Boston University Hospital, Boston (chief medical resident) School of Medicine Richard Taikowski, M.D., Mt. Sinai Hospi• Photo credits: Pages 1, 3, 5, 6, Michael Hollett, M.D., Duke University tal, New York (cardiology) Bradford F. Herzog; Page 2, School of Medicine Robert Weiss, M.D., (gastroenterology) courtesy of Monica Peacocke, Abram Kirschenbaum, M.D., New York Uni• Anthony White, M.D., (infectious disease) • M.D.; Page 3 top, courtesy of versity School of Medicine Howard Koh, M.D. Glenn Levine, M.D., Columbia College of Physicians and Surgeons Wendy Livingston, M.D., Columbia College of Physicians and Surgeons Mary Manning, M.D., George Washington University School of Medicine

Andrew Nichols, M.D., Boston University •^4- 1 8 5 5 School of Medicine • fiEAVO^ '