A DE RMATOL OGY FO UNDA TION PUBLICAT IO N SPONSORED BY MEDICIS, A DIVISION OF VALEANT PHARMACEUTICALS VOL. 32 NO. 1 SPRING 2013 DERMATOLOGYDERMATOLOGY ™ DF Also In This Issue DF: Strong Specialty FFOOCCUUSS Support Continues $3.2 Million in Research Funding Awarded for 2013 DF Clinical Symposia: DF Honors Dr. Robert A. Silverman and Proceedings 201 3–Part I Dr. C. William Hanke

inadequately excised. The adventure had a happy ending because ADVANCES IN DERMATOLOGY “accurate diagnosis was at the time of biopsy rather than a decade The Dermatology Foundation presented its annual later, after a catastrophe had occurred.” The basis for molecular diagnosis. Cancer is a disease 3-day symposia series in February. This highly regarded of the genome. Most typically, DNA—either whole chromosomes cuttin g-edge CME program provides the most clinically or specific segments—has been lost and/or multiplied. Losses tend relevant knowledge and guidance for making the to involve tumor suppressors and pro-apoptotic genes. Gains, or newest research advances accessible and usable. A repetitions, frequently involve oncogenes and anti-apoptotic daily provocative keynote talk precedes topic-focused, genes. The amplified sequences may involve normal or mutant peer-reviewed caliber presentations. This year’s DNA. Not all such changes, however, signify a malignant process. topics were: Women’s & Children’s Dermatology; Cancer is commonly associated with multiple rather than single CPC; Emerging Therapies; Revisiting Old Therapies; Medical Dermatology; and Cutaneous Oncology & Copy Number Changes in Immunology. The Proceedings appear in the Spring Melanocytic Neoplasm s—Assumptions (Part I) and Summer (Part II) issues. • Cancer is a disease of the genome Janet A. Fairley, MD, and • Most cancers have gains/losses of whole Jack S. Resneck, Jr., MD —Program Co-Chairs chromosomes, or focused gains/losses • CGH may not be able to detect either small gains/losses or translocations WERNER K. STIEFEL LECTURESHIP • Multiple aberrations favor cancer more than Molecular Diagnosis of Melanocytic Neoplasms: single ones do • Amplifications (ie, high level gains) are stronger Adventures and Misadventures evidence of malignancy than are low level gains Philip E. LeBoit, MD Background. Although the high degree of correlation be - • Gains/losses that have “edges” at important cancer tween morphology and outcome enables H&E staining to determine genes are more significant than random ones the nature of roughly 99% of melanocytic lesions, morphology for the remaining 1%—the borderline melanocytic neoplasms—is inconclu - sive or misleading. “These are the most difficult cases in melanocytic CGH Points to Genetic Hotspots neoplasms, and cannot be solved by even the best expert,” Dr. in Melanoma Progression LeBoit said. Relying on H&E staining here is highly vulnerable to serious, sometimes catastrophic, diagnostic error. Accuracy requires • Gains/amplifications can lead to increased molecular diagnosis, which is based on the lesion’s DNA fingerprint. protein expression LeBoit discussed the two most common molecular tech - • Losses reflect loss of function niques, then presented several illustrative cases referred to his lab. • Loci identified by CGH can be investigated Two misadventures involved the metastatic consequences of an with more refined techniques earlier melanoma erroneously diagnosed as a dysplastic nevus and Who Inspired You? DF Accepting Nominations for 2013 Honorary Awards

Each year, the Foundation honors those extraordinary dermatologists who have left a lasting imprint on the specialty. The DF’s honorary awards provide an opportunity to recognize dermatology’s formative teachers and clinicians—true role models—who have inspired and trained generations of dermatologists. Clark W. Finnerud Award. This award honors the exceptional clinician who has also been a dedicated and highly effective volunteer or part-time teacher for residents and medical students. Practitioner of the Year. This dermatologist is an exemplary clinician in private practice with significant involvement in professional organizations, and participation in medical teaching and/or research. Your nomination letter, along with the nominee’s . CV, are due at the Dermatology Foundation by August 1, 2013. The 2013 Honorary Awards will be presented at the DF Annual Meeting of Membership in March 2014. Contact the DF staff with any questions: 847-328-2256 or [email protected]

Malignant n=133 Skin 2008

Small Bowel 2011 Benign n=54

Case: an excised lesion diagnosed by H&E as a dysplastic nevus in 2008 was retrospectively diagnosed as a primary melanoma 3 years later, when CGH analysis matched the more re cent bowel melanoma.

Pooled CGH plots: 133 melanomas vs 54 nevi. Each lane represents a chromosome. 6), gain of 1q—noting their significance, then contrasting this to The melanoma plot reveals characteristic widespread DNA gains and losses. The benign the changes that characterize Spitz nevi. nevi show only 2 minimal gains, which characterize the Spitz nevi subset. FISH and CGH. The molecular dermatopathology lab at aberrations; many rather than few repeats; gains and losses that UCSF (founded by Dr. Boris Bastian) relies on FISH (fluorescent in have “edges” at important cancer genes. In addition, “the genomic situ hybridization) and CGH (comparative genomic hybridization) damage in melanoma is not random.” LeBoit enumerated the for detecting changes in DNA copy number. FISH appeared in the most common melanoma-associated aberrations—loss of 9p (the early 1980s, and CGH roughly a decade later. Although they both short arm of chromosome 9), loss of the entire chromosome 9, use fluorescent-labeled DNA probes that bind with relevant areas loss of chromosome 10, loss of 6q (the long arm of chromosome of DNA, FISH uses focused probes that home in on a narrowly

2 Spring 2013 Dermatology Foundation defined area of the genome and bind to complementary se - quences. CGH, on the other hand, can screen the entire genome in a single session and is also better than FISH at detecting DNA DERMA TOLOGY FOCUS losses. LeBoit describes CGH as a competitive binding assay in A PUBLICATION OF THE DERMATOLOGY FOUNDATION DF Sponsored by which the tumor DNA is microdissected out and fluorescently labeled with an identifying color, then hybridized with a refer - Medicis, A Division of Valeant Pharmaceuticals ence sample of normal DNA—or more frequently now, a DNA Editors-in-Chief array—that has been fluorescently labeled with a different identi - David J. Leffell, MD— Professor of Dermatology fying color, and with control DNA. Yale School of Medicine, New Haven, CT Misadventures. A 22-year-old woman with intussuscep - Mary M. Tomayko, MD, PhD— Assistant Professor of Dermatology tion of her small bowel was found to have a large tumor mass. Al - Yale School of Medicine, New Haven, CT though it stained positively for the melanoma marker HMB-45, Heidi A. Waldorf, MD— Director, Laser and Cosmetic Dermatology she denied any history of melanoma but mentioned a dysplastic The Mount Sinai Medical Center, New York, NY nevus removed from her shoulder 3 years earlier. A slide from the excisional biopsy lacked any clear melanoma indicators, Executive Director making the diagnosis of dysplastic nevus “very understandable.” Sandra Rahn Benz With immunohistochemical stains, this melanocytic tissue Deputy Executive Director showed a high proliferation rate and the absence of protein from Christine M. Boris the tumor suppressor p16. CGH analyses of both this tissue and Please address correspondence to: the bowel tumor produced strikingly similar chromosomal pro - Editors-in-Chief files, “proof that this bowel tumor metastasized from the misdi - Dermatology Focus agnosed skin lesion.” c/o The Dermatology Foundation A 65-year-old woman—who had had what was interpreted as a 1560 Sherman Avenue, Evanston, Illinois 60201 Tel: 847-328-2256 Fax: 847-328-0509 dysplastic nevus removed 11 years earlier—now had a huge peri - e-mail: dfgen@de rmatologyfoundation.org anal mass that was obviously a melanoma. The highly unlikely pos - sibility that it was a metastasis to this site rather than a primary Published for the Dermatology Foundation by tumor had to be explored, because treatment would differ signifi - Robert B. Goetz— Designer, Productio n cantly. Reviewing tissue from the 11-year-old biopsy, morphology Sheila Sperber Haas, PhD— Managing Editor, Writer was similar—except for the presence of melanoma-associated giant This issue of Dermatology Focus is distributed without charge through melanocytes that should have sounded the alarm. Now, CGH on tis - an educational grant from Medicis, A Division of Valeant Pharmaceuticals. sue from both lesions showed “an almost identical pattern” of gains The opinions expressed in this publication do not necessarily reflect those of and losses. Thus the perianal melanoma was metastatic disease, the Dermatology Foundation or Medicis, A Division of Valeant Pharmaceuticals. and the original surgical plan—to remove the patient’s anus and © Copyright 2013 by the Dermatology Foundation rectum—would not provide benefit. Adventures. After discussing the typical histology and Spitz nevus or not.” He illustrated this with H&E-stained tissue from clear-cut variants for Spitz nevi, LeBoit noted those uncertain a 31-year-old man that was typical except for a nest of cells with cases—especially in adults—with very subtly aberrant features by “dusty looking melanin”—a tip-off to look further. CGH analysis H&E staining. “CGH can determine whether the lesion is really a identified melanoma. (Continued on page 6) Deferred Giving: The Benefits of a Bequest to the DF

Contributing to There are a variety of ways to establish a be - the Dermatology quest, and your attorney and/or financial advisor Foundation this year is the best way to ensure can recommend the best option for you. Once that the newest generation of physician scientists you have determined the best approach, be sure and investigators has the support they need to identify the Dermatology Foundation, a 501(c)3 now to initiate work that will ultimately advance organization, as the recipient of this gift in your patient care. A simple, effective way to provide will or other instrument. Please note that the DF this much-needed funding well into the future is able to accept only monetary donations. is a bequest to the Dermatology Foundation. If you have questions about establishing A bequest enables you to leave a legacy that a bequest for the Dermatology Foundation, will impact future generations of dermatologists feel free to address them to Sandra Benz, and patients. By reducing your estate, it also has DF Executive Director, at 847-328-2256 or the potential to reduce estate taxes. [email protected]. www.dermatologyfoundation.org Spring 2013 3 201 2: Looking Back—Strong Specialty Support Continues

Newly elected President Dr. Michael D. Tharp had good news to share at the Dermatology Foundation’s annual membership meeting in Miami. “While concerns about a ‘fiscal cliff’ emerged in 2012 and colored the economic outlook, I am happy to report that all of our supporters were generous and enabled the Foundation to accomplish its mission this year— to identify and launch the early careers of the most promising future leaders in dermatology.”

Member Dermatologists: The Heart of the DF Board of Trustees Elects DF Officers The Board of Trustees is grateful to Dr. Richard L. Edelson Dr. Tharp was pleased to announce that for his long-term volunteer service to the Dermatology individual member contributions remained stable Foundation as an Executive Committee member and most and substantial in 2012, totaling $2.9 million. recently, as President. Following completion of his term, “This ongoing support reflects the tremendous the Board of Directors elected the following officers to lead commitment individual physicians have to the the work of the DF. health and growth of the specialty, and has President Michael D. Tharp, MD Chairman, Board ensured the Foundation’s funding capacity Bruce U. Wintroub, MD despite the notable difficulties currently faced of Trustees by many non-profits.” Vice President Stuart R. Lessin, MD Secretary– Dr. Tharp thanked all DF members for their Elizabeth I. McBurney, MD participation and support in 2012. As a group, Treasurer those giving at the leadership level had the greatest impact on the Foundation’s results: giving. Each Sustaining member has gone • Leaders Society members, about 1,000 strong, beyond their $25,000 AC pledge with an annual comprise the largest sector of physicians contribution of $5,000; many have pledged to supporting the specialty and provided nearly repeat this annual gift for nearly 20 more years. half of the DF’s individual giving revenue, about Industry Supporters $1.4 million. Industry giving remains an essential part • The Annenberg Circle reached a new high of of DF annual fundraising activities despite 600 members and accounted for nearly 20% of the significant changes wrought by corporate individual contributions in 2012. mergers and reduced budgets for charitable • Annenberg Circle Sustaining members grew donations. Dr. Tharp emphasized the Founda - at a rate beyond all others, rising to a total of 124 tion’s gratitude for all industry support, which and providing an additional 24% of individual totaled $2.7 million in 2012.

Honorary Awardees DF President Dr. Michael D. Tharp ( on right in each photo ) was delighted to present the Foundation’s honorary awards, the annual recognition of exemplary dermatologists who have helped the specialty be the best it can be.

2012 Clark W. Finnerud Award 2012 Practitioner of the Year Award 2012 Lifetime Career Educator Robert A. Silverman, MD C. William Hanke, MD Vera H. Price, MD

4 Spring 2013 Dermatology Foundation 2013: Looking Forward—$3.2 Million Invested in the Future

“Every member and supporter of the DF in 2012 made it possible for the Dermatology Foundation to award over $3.2 million in research awards for 2013,” Dr. Bruce U. Wintroub, Chairman of the DF Board of Trustees, announced.

Dr. Wintroub expressed his great pleasure in presenting 2013 Research Awards the list of research awards Career Development Awards that have been approved for ($55,000 annual salary support) funding by the Dermatology 3 Health Care Policy 3 Dermatologic Surgery Bruce U. Wintroub, MD Foundation Board of Trustees. “This investment will go to 13 Physician Scientist support 66 promising individuals and worthy projects,” he 5 Science of Human Appearance noted. “We are extremely proud of our 2013 award recipients.” 10 Medical Dermatology 3 Dermatopathology The great majority of DF funding now goes to the highly 3 Women’s Health competitive and effective Career Development Awards 12 Basic Science Research (CDAs). Eighty percent (80%) of past CDA recipients have Fellowships remained in academics, and most have earned federal ($30,000–$45,000 salary support) research funding that translates to $10 of federal funding 4 Dermatologist Investigator for every $1 invested by the DF. 2 Pediatric Dermatology Dr. Tharp added that “our ability to maintain a funding Grants level of $3.2 million is quite an accomplishment in the current ($20,000 project support) economic environment, and we have all of our members 1 Patient-Directed Investigation and industry supporters to thank for making this possible.” 6 Basic Science Research For a list of the 2013 award recipients and projects, 1 Epidermolysis Bullosa Research visit www.dermatologyfoundation.org

Especially generous is the DF’s Cornerstone society contributors for their substantial support: Benefactor Galderma Laboratories. Galderma the American Academy of Dermatology; contributed over $500,000 to the DF to support Women’s Dermatologic Society; Society for Inves - the Research Awards Program, the Clinical tigative Dermatology; The American Society of Symposia, and several other key membership Dermatopathology; and DEBRA of America, Inc. programs. Dr. Tharp thanked the Foundation’s The Time to Do More Platinum Benefactors for their support at the $200,000 level: AbbVie, Amgen Pfizer, Medicis, The Foundation is the primary funding Unilever, and Valeant Dermatology. He also source for new physician-scientists and recognized The Allergan Foundation, Merz, investigators in the specialty. “Without the and SkinMedica as the DF’s Gold Benefactors, DF, many of those who received awards today who each contributed $100,000 or more. would never have considered an investigative career,” Dr. Tharp emphasized. Given the Society Partners: pending decreases in federal research funding, Important Supporters “we have set the bar high this year and are Dr. Tharp noted “how fortunate the DF is asking every DF member to contribute at the to receive significant support for the Research highest level possible. Awards Program from our national, regional, and The only way to be certain the science local society partners each year. Each of these base of dermatology continues to expand organizations believes in the DF’s capability to is to ensure that those entering our field identify promising individuals who have the have the early career funding they need. potential and motivation to keep dermatology After all, if we do not fully support our field— advancing.” He recognized the following national who will?”

www.dermatologyfoundation.org Spring 2013 5 Conclusions. Molecular analysis will alter our perspective est mortality, in 10–12 days. When skin involvement (vesicular) on melanocytic lesions by promoting awareness that low-risk (eg, is present, it is a primary diagnostic source. Treat with high-dose spitzoid tumors in young children) and intermediate-risk tumors parenteral acyclovir. exist between the extremes of benign and frankly malignant. Within a decade, molecular studies (not FISH or CGH, but others under development) should become routine for all questionable Neonatal HSV cases and may well replace H&E staining entirely in 20–30 years.

MINI-SYMPOSIUM: WOMEN’S & CHILDREN’S DERMATOLOGY Five Diagnoses Not to Miss Anthony J. Mancini, MD Introduction. Delayed/incorrect diagnosis of these condi - tions—which often involve the skin—can have significant conse - quences. The dermatologist can be instrumental in preventing this. For each, Dr. Mancini discussed typical and atypical presentations and outcomes, subtypes, diagnostics, cautions, and treatment. Langerhans cell histiocytosis. LCH ranges from benign and self-limited to disseminated organ involvement, risking signifi - cant morbidity and possible mortality. LCH can occur anywhere on the skin, with scalp, palms/soles, and intertriginous zones most Summary common. Be aware of refractory seborrheic dermatitis or inter - • Think of LCH: refractory seborrheic dermatitis/intertrigo, trigo, look for lichenoid papules and for punctate erosions in fold purpura, flexural erosions, palm/sole crusted papules, areas. Neonates have a more vesicular, often hemorrhagic, presen - hemorrhagic vesiculopustules (neonate) tation. LCH is diagnosed relatively easily from skin histopathology • Consider immunodeficiency: recalcitrant dermatitis; and immunostaining. “We often refer these patients to our oncol - resistance to therapy; GVHD; growth failure; ogy colleagues for treatment.” recurrent/unusual infections Congenital immunodeficiency. Mancini discussed and illustrated the various cutaneous manifestations. In general, severe • Recognize Kawasaki disease: unexplained high fever; atopic or seborrheic dermatitis, erythroderma, or intertrigo resist - rash, conjunctivitis, lip/tongue changes; perineal ant to proven treatment triggers concern, as well as growth failure, accentuation; “sick” child alopecia, and recurrent and/or unusual infections (especially with • Diagnose DRESS syndrome: facial/periorbital edema; less common organisms). Biopsy results of graft-vs-host disease hepatitis; reactive lymphocytes/eosinophilia; 3–8 weeks (GVHD) in an infant may indicate severe combined immunodefi - after aromatic anticonvulsant/sulfa drug started. ciency. Treatments may include IVIG and stem cell transplantation. Treatment: drug withdrawal, consider steroids/IVIG Kawasaki disease. This acute vasculitis in young children— • Don’t miss neonatal herpes: newborn with vesicles aka mucocutaneous lymph node syndrome—involves medium- (may be hemorrhagic or pustular); sometimes sized arteries. Coronary artery aneurysm is the most feared widespread erosions, polycyclic patches. Diagnosis: complication. “Have a high index of suspicion for this disease—you cultures, DFA, PCR. Treatment: institute parenteral do not want to miss it.” Diagnosis—which is clinical—is based on acyclovir if considering unexplained high fever >5 days plus 4/5 additional criteria: con - junctivitis; lip/tongue changes; extremity changes (edema, then desquamation); polymorphous skin eruption with perineal accen - Big Rashes in Little Patients tuation; and cervical adenopathy >1.5 cm. High-dose aspirin and Julie V. Schaffer, MD single infusion high-dose IVIG are the first-line therapy. Introduction. Sudden onset of an extensive rash in a young Drug hypersensitivity syndrome. Aka DRESS ( drug child often frightens parents, pediatricians, and even dermatolo - reaction with eosinophilia and systemic symptoms), this severe gists. Recognition of clinical clues to the diagnosis enables der - cutaneous adverse reaction of altered drug metabolism is most ma tologists to provide reassurance in many of these situations, often associated with the aromatic anticonvulsants but can occur and facilitates initiation of appropriate evaluation and treatment. Dr. with other agents. Marked cytokine-mediated inflammation— Schaffer discussed four such rashes referred to her as emergencies. occasionally misdiagnosed as a bacterial or viral infection— Urticaria “multiforme.” A 10-month-old boy had a low- presents 3–8 weeks after treatment begins. Look for facial edema grade fever and widespread eruption of pink edematous annular (particularly periorbital), skin rash (often erythrodermic), fever, plaques, some quite large. Many lesions had a central dusky pur - lymphadenopathy, and hepatitis. Withdraw the drug. Systemic plish color, while central clearance in others was a clue to the tran - steroids may be required. sient nature of this condition—urticaria. Frequently misdiagnosed Neonatal herpes simplex infection. HSV infection of as erythema multiforme or serum sickness-like reactions, giant the newborn—presenting 10 days to 3 weeks after birth—is caused annular urticaria (urticaria “multiforme”) in infants and young most often by HSV-2 and usually acquired intrapartum. SEM children is often virally triggered and has a benign course. Angio- disease (skin, eyes, mouth) appears in 1 0–12 days; CNS disease edema (hands/feet/face), pruritus, dermatographism, and low- (encephalitis) in 16–19 days; disseminated disease, with the high - grade fever are common. If unsure of the diagnosis, outlining

6 Spring 2013 Dermatology Foundation lesions in pen reveals their hourly or daily changes. Antihistamines a work-up that confirmed the diagnosis of neonatal lupus, which speed resolution and represent the therapeutic mainstay. usually presents with skin changes at ≥1 month of age. Anti-Ro an - Reaction to molluscum. A 5-year-old boy had sudden onset tibodies were positive in both mother and patient; skin biopsy was of extremely pruritic, edematous papulovesicles on his extensor typical for lupus. Schaffer discussed the spectrum of cutaneous arms and legs. Although the eruption brought to mind Gianotti- and extracutaneous manifestations. Crosti syndrome (GCS) or an id reaction, Schaffer identified mol - luscum lesions in separate locations. This GCS-like inflammatory Vulvar Manifestations of Systemic Disease reaction develops in ~5% of molluscum patients, signaling an effec - tive immune response that heralds resolution of the molluscum. Bethanee J. Schlosser, MD, PhD Introduction. In addition to primary inflammatory der - matoses, vulvar skin and mucosa can be involved in systemic in - Molluscum: The Bump That Rashes flammatory disorders. Vulvar inflammation commonly results in agglutination • Retrospective study of 696 patients with molluscum scarring ( ), with loss of tissue mass and architectural seen in NYU pediatric dermatology practice distortion. Recognizing vulvar pathology requires familiarity with normal vulvar anatomy. Dr. Schlosser discussed vulvar manifesta - – Mean age 5.5 yr (range 7 mo–17 yr) tions of three systemic inflammatory conditions. – Atopic dermatitis (in 37%) associated with Metastatic Crohn’s disease. Mucocutaneous findings, higher # of MC lesions most often genital, occur in ≤44% of Crohn’s patients. Metastatic – Molluscum dermatitis in 39%: 51% with Crohn’s disease presents with knife-like ulcerations of the skin folds AD vs 32% without AD (genital, buttock, axillary, inframammary) and painful vulvar – Inflamed MC lesions in 22%: associated with edema, erythema, and purulent discharge. These skin lesions pre - ȇ# of MC lesions over next 3 months cede detectable bowel involvement in 20% of patients, and the – Gianotti-Crosti syndrome-like reaction in 5%: course of mucocutaneous and GI disease can differ significantly. heralded resolution of MC lesions Treatment of vulvar metastatic Crohn’s disease involves systemic EM Berger et al. Arch Dermatol. 2012;148:125764. immunosuppressive agents and anti-TNF therapies. Acute vulvar ulcers of the nonsexual female (Lip - Coxsackievirus A6. A 1-year-old boy presented with fever schutz ulcers). Acute vulvar ulcers affect nonsexual young and a widespread vesicular eruption affecting his extremities (in - women (teens, early 20s) and are classically associated with an cluding palms/soles) and trunk, with crusted papules around his acute febrile illness. Triggering infections include group A strepto - mouth and within pre-existing diaper dermatitis. The distribution coccal pharyngitis, acute EBV infection, and acute Mycoplasma in - of the extensive vesicular exanthem—eg, the perioral region and fection. Patients present acutely with painful aphthous ulcers of the sites of dermatitis ( eczema coxsackium ) as well as classic locations labia majora, labia minora, and vaginal introitus. Variable scarring of hand-foot-and-mouth disease (HFMD)—pointed to a recently occurs, but functional compromise is uncommon. The diagnosis is recognized variant due to coxsackievirus A6, which now has a clinical; pathology is nonspecific. Treatment entails analgesia and significant presence in the U.S., Asia, and Europe. Despite the anti-inflammatory topical/oral agents. Recurrence occurs in <50% more severe skin findings, this form of HFMD typically resolves without complications after a mean of 12 days. ~ The Normal Vulva Enteroviral Exanthem: Coxsackievirus A6

• CDC report (3/12): “severe and extensive” HFMD Illustrated by due to coxsackie A6 in the U.S. (Prior outbreaks Dawn Danby and in Europe and Asia.) Paul Waggoner. • 80 patients from 7 pediatric dermatology centers in the U.S. (7/11–6/12) – Median age 1.5 yr (range 4 mo–16 yr), 50% with AD Vulvar Agglutination* – >10% BSA in 60%; intraoral lesions in 50% • Loss of tissue mass – Extremities (100%), buttocks (75%), face (80%), trunk (>50%) – Fever in 75%; no serious systemic/neurologic manifestations • Destruction of normal – Mean duration 12 days (range 3–35) architecture CDC. MMWR Morb Mortal Wkly Rep. 2012;61:213–4; K. Flett et al. Emerg Infect Dis. • Clitoral hood, labia minora, 2012;18:1702–4; EW Mathes et al. Pediatrics. (in press) posterior fourchette, introitus Neonatal lupus. A 12-hour-old girl born at 35 weeks to a • Vagina healthy mother was extremely small for gestational age, with a pur - • Can occur without symptoms puric eruption and concerning coagulation profile—“definitely *Any vulvar disease can scar. scary looking.” Noting atrophy in affected skin was key in initiating www.dermatologyfoundation.org Spring 2013 7 DF Honors the Specialty’s Role Models

Each year the Dermatology Foundation pays tribute to dermatologists whose exemplary capabilities and dedication have helped to make the specialty what it is today. Presentation of the 2012 awards was a highlight of the DF Annual Meeting on Saturday, March 2 in Miami. The leaders honored by their peers for their outstanding contributions to dermatology are: Practitioner of the Year—C. William Hanke, MD Clark W. Finnerud Award—Robert A. Silverman, MD Lifetime Career Educator Award—Vera H. Price, MD (Dr. Price was highlighted in the Winter 2012/13 issue.)

2012 Practitioner of the Year Award: Hawaii. With each opportunity he took to improve his C. William Hanke, MD knowledge and skills, the more dermatology appealed to him. His new interest was further piqued by two This annual award recognizes dermatologists for exemplary inspirational dermatologists, Drs. Harry Arnold and service as a private practitioner Allan Azumi, who also helped launch his early career. combined with significant contri - Dr. Hanke completed his residency and fellowship train - butions to the specialty through ing at the Cleveland Clinic Foundation and then joined leadership and teaching. the full-time dermatology faculty at Indiana University “Bill Hanke has dedi - School of Medicine. He rapidly rose to Professor cated his professional of Dermatology, Pathology, and Otolaryngology. Dr. career to his patients and Hanke left academia in 1998 to found the Laser & to bettering the world of Skin Surgery Center of Indiana, which includes a der - C. William Hanke, MD dermatology,” a colleague matopathology lab and clinical trials center. He also notes. “He provides stellar founded a one-year ACGME-accredited Procedural patient care in his state-of-the-art private med - Dermatology Training Program at St. Vincent Hospital ical/surgical practice in Indianapolis, has been in Indianapolis. “Training procedural dermatology president of 11 major medical organizations, fellows has been a highlight of my career,” he shares. holds several part-time academic positions, and Dr. Hanke has always believed that service to the teaches fellows in a private setting. He conducts profession is important, and has spent a significant clinical research, and has authored over 400 portion of his career doing just that. He established a medical publications—including 91 book chap - Dermatology Professorship at the University of Iowa and ters and more than 20 books.” served on more than 20 organizational boards. His pres i- Dermatology is especially fortunate, because dencies include the American Academy of Dermatology, Dr. Hanke’s interest in the specialty began purely by American Society for Dermatologic Surgery, American chance. Although he had chosen cardiology by the College of Mohs Surgery, and International Society for time he graduated from the University of Iowa College Dermatologic Surgery. His many awards include these of Medicine, his military service assigned him to der - organiza tion’s highest honors, including the AAD’s Gold matology responsibilities at Hickam Air Force Base in Medal. Of Dr. Hanke’s accomplishments, he finds his of patients and should prompt evaluation for other causes of vulvar Conclusions. Vulvar edema, erosions, and ulcers may be the aphthae (ie, inflammatory bowel disease, Behçet’s). presenting signs of systemic inflammatory disorders. Assessment of Graft-vs-host disease. Vulvovaginal GVHD affects 1/3 of patients requires thorough history and review of systems, detailed vul - women at 1 year post-hematopoietic stem cell transplant and var examination, and clinicopathologic correlation of skin pathology. almost 50% by 2 years, but likely continues to be underdiag - Multidisciplinary care is imperative for optimal treatment and preser - nosed and undertreated. Patients most often present with ery - vation of quality of life for patients with inflammatory vulvar disease. thema and erosions; significant scarring (clitoral agglutination, vaginal narrowing/obliteration) is not uncommon. Most women with vulvovaginal GVHD will have concomitant GVHD of the Summary conjunctiva, oral cavity, and skin, but a minority will have GI or • Vulvar edema, erosions, or ulcers may be the liver GVHD. Treatment of vulvovaginal GVHD involves modula - initial manifestation of systemic disease tion of systemic immunosuppressives, use of potent topical cor - • Obtaining a thorough history and ROS is ticosteroids and calcineurin inhibitors, as well as adjunctive essential to making an accurate diagnosis local estrogen therapy and vaginal dilators. To ensure timely di - • Multidisciplinary care of patients with vulvar agnosis and appropriate treatment, Schlosser advises dermatol - lesions is imperative ogists to “keep female transplant patients high on your radar.”

8 Spring 2013 Dermatology Foundation focused work on patient safety—that began in the 1990s “It was my very last elective of my fourth year, and I and reached a high point during his AAD presidency— had already committed to pediatrics. The dermatolo - most meaningful. “Safety is critically important. When gists and residents I worked with were so energetic, I be came president of the AAD, I knew this was my op por - and knowledgeable—and so happy with their work.” tu nity to heighten the specialty’s focus on this area.” They ultimately influenced his career choice. A colleague praised all that Dr. Hanke has When Dr. Silverman began his pediatric resi - accomplished. “Bill Hanke provides the very dency at the University of Buffalo, he formed a close best of care to his patients. I also greatly admire relationship with the dermatology department. Main - the fact that he is able to maintain an active taining a strong interest in dermatology, he went on practice and yet serve dermatology as a dedi - to complete a two-year pediatric dermatology fellow - cated teacher and spokesperson for all of us.” ship at Harvard’s Children’s Hospital in Boston to study congenital nevi, “just as pediatric dermatology 2012 Clark W. Finnerud Award: was congealing into a sub-specialty.” Dr. Silverman Robert A. Silverman, MD completed his dermatology residency at University This annual award recognizes Hospitals of Cleveland, then became the first Director the exceptional dermatologist of Pediatric Dermatology at Rainbow Babies and who is both an exemplary Children’s Hospital and taught pediatric dermatology clinician and a dedicated at Case Western Reserve University. volunteer or part-time teacher. In 1989, Dr. Silverman entered private practice A fellow pediatric in Washington, DC. He also began to teach dermatol - dermatologist lauds Dr. ogy to pediatric residents at Georgetown University Silverman’s “extraordinary and University of Virginia pediatric residents at contributions to dermatol - INOVA Fairfax Hospital. He also spent substantial ogy as a part-time teacher time training residents in his office. He has given Robert A. Silverman, MD and clinician, a leader in the field of pediatric countless grand rounds, published 25 book chapters, dermatology who has worked tirelessly as an regularly organized and taught in seminars and CME advocate for children with skin disease, and an courses at AAD meetings. Dr. Silverman has held educator and role model.” Dr. Silverman’s impact leadership positions in a variety of specialty organi - is amplified by the scope of his expertise, which zations, including the presidencies of the Washington, includes atopic dermatitis, contact dermatitis, nail DC Dermatological Society and the Society for and hair diseases, acne, hemangiomas, inherited Pediatric Dermatology, and is currently a Director skin diseases, skin conditions of newborns, and of the American Board of Dermatology. precursors to skin cancer. A renaissance man of pediatric dermatology, Dr. Silverman’s life-changing connection to der - Dr. Silverman admits that his clinical interests matology began with his elective at the University have always been wide and varied. He especially of Virginia School of Medicine—fascinating, inspira - loves to learn about the subtleties of pediatric tional, and an excellent fit for this highly visual skin disease “from my youngest patients and individual. The problem for Dr. Silverman was timing. their parents.”

Perioral Rejuvenation in Women Dana L. Sachs, MD Facial Muscle Targets for Introduction. Dr. Sachs discussed the nature and appropri - Botulinum Toxin Injection ate treatment of age-related changes in the perioral region of the face, aesthetically the second most important part of the face after the eyes/eyebrows. She described the age-related changes in skin, collagen, subcutaneous fat, muscles, cartilage, and bone that all contribute, and focused on ways to improve the perioral region without enhancing the lips (responding to the common patient fear of overly enlarged lips). After explaining the underlying Depressor Orbicularis changes that produce perioral rhytides, downturned oral commis - anguli oris oris sures (drooping mouth corners), a prominent mental crease, cob - (DAO) blestone chin, and labiomental folds (marionette or puppet lines), Depressor Sachs provided guidance, tips, and cautions for minimizing each labii Mentalis of them, advising combining procedures for optimal results. inferioris www.dermatologyfoundation.org Spring 2013 9 Mark Your Calendar! 2014 DF Clinical Symposia—Advances in Dermatology, February 5–9, Naples, FL

Here is why past attendees never miss this meeting: • Difficult Diseases in Medical Dermatology “This is the best and most well-rounded CME • Surgery and Aesthetics program I attend.” • Immunologic Skin Diseases “This meeting teaches real dermatology.” • Pediatric Dermatology • How to Avoid Harming Your Patient: “Erudite and fresh perspectives.” Safety Issues in Dermatology Discover the latest advances in dermatology that will • Cutaneous Oncology: Clinical Challenges benefit your practice in these 7 Mini-Symposia: • Infectious Diseases and the Skin Registration begins in September 2013. Visit www.dermatologyfoundation.org

Tools and targets. Botulinum toxin A: Although its full-face procedure or, in appropriate patients, limited to one use for the perioral region is off-label, “we use it all the time” to region. The fractionated ablative laser is beginning to supplant treat wrinkles (inject the orbicularis oris), labiomental folds (in - the conventional CO 2 laser. ject the depressor anguli oris), and cobblestone chin plus the Illustrations. Sachs presented 12 cases, women ranging mental crease (inject the mentalis muscle). Avoid for patients from their mid-40s to mid-70s, illustrating patient concerns, her who cannot risk any muscle weakening in this area (eg, a profes - assessment and treatment, and before and after photographs. sional wind instrument player). Onabotulinum toxin, abobotu - linum toxin, and incobotulinum toxin are all FDA approved. Soft tissue injectables: This option for the lower face can be used to reconstitute the philtral columns, turn up oral commisures, MINI-SYMPOSIUM: CPC improve the lips, and fill out perioral lines, mental crease, and Julie V. Schaffer, MD labiomental crease. Cross-linked hyaluronic acid fillers are “the Case 1. An 11-year-old Chinese immigrant girl had an ~1.5-year workhorse for this part of the face.” Calcium hydroxylapatite can history of episodic outbreaks of vesiculated, purpuric, necrotic, rel - also be used, but not for the lips. Prepare for possible occlusion atively pruritic skin lesions that healed with punched out scars. Dur - or compression of vascular structures—which can result in local ing attacks—mostly in summertime and on exposed sites—she was tissue necrosis—by having warm compresses, nitroglycerin paste, febrile, sometimes with neutropenia. Biopsy findings included a and hyaluronidase on hand. Resurfacing: This option is espe - dense perivascular and interstitial infiltrate with enlarged lympho - cially useful for improving and softening rhytides, either as a cytes and prominent eosinophils. Her blood contained extremely high levels of EBV DNA. Key was that many lesional lymphocytes were positive for EBV RNA via in situ hybridization. Her diagnosis Perioral Region—Botulinum Toxin A combined necrotic hypersensitivity to mosquito bites (which favors • Perioral rhytides —inject orbicularis oris Asian > Hispanic children) and atypical hydroa vacciniforme. Dr. • Labiomental folds —inject depressor anguli oris (DAO) Schaffer discussed these conditions and the distressing prognosis of • Chin —inject mentalis severe hydroa. “As we see patients from increasingly international backgrounds, this is important to have on one’s radar.” • FDA approved agents: onabotulinum toxin, abobotulinum toxin, incobotulinum toxin The Lower Face—Soft Tissue Injectables EBV and Necrotic • Lips Mosquito Bite Hypersensitivity • Philtral columns • Predilection for Asian children • Perioral lines – Japan > Taiwan, Korea – One previous report in a 7-yr-old Hispanic boy in Texas • Oral commissures • Mental crease • Bullous/necrotic skin lesions + systemic symptoms (eg, fever, lymphadenopathy) • Labiomental creases – Asymptomatic between episodes • Agents : cross-linked hyaluronic acid, calcium – Punched-out ulcer s Ǟ scars hydroxylapatite (not for lips) • Proliferation of EBV + NK cells: often progresses to Resurfacing NK/T-cell lymphoma or hemophagocytic syndrome • Perioral rhytides SE Pacheco et al. J Allergy Clin Immunol. 2005;116:470–2. • Regionally in select patients

• Lasers: conventional CO 2 is gold standard, fractionated ablative and nonablative • +/- botulinum toxin A, soft tissue injectables • Risks: HSV, scarring, dyspigmentation

10 Spring 2013 Dermatology Foundation Case 2. An 11-year-old otherwise healthy girl had a 1-month Mark D.P. Davis, MD history of asymptomatic unilateral swelling of her vulva unre - Case 1. This patient had an allogeneic hematopoietic cell sponsive to antibiotics. Schaffer observed erythema, induration, transplantation 2 months previously and had developed a wide - and a few linear erosions/superficial ulcerations toward the per - spread itching rash over the past 6 days. Was this GVHD or a drug ineal area. Biopsy findings included a superficial and deep granu - reaction? Studies have demonstrated the impossibility of distin - lomatous dermatitis, with giant cells and some peripheral guishing the two entities clinically or—for drug reactions that show lymphocytes. The patient had mild iron deficiency anemia, a high interface changes—by biopsy. Try to distinguish them via the pres - sedimentation rate, and ASCA antibodies (associated with ence/absence of diarrhea plus liver function tests (GI tract and liver Crohn’s disease). A GI evaluation with endoscopy confirmed are the most commonly affected by GVHD). If this fails, treat as Crohn’s disease with involvement of the terminal ileum. In con - GVHD because delay, or stopping the immunosuppressive drug, trast to adults with Crohn’s disease, extra-intestinal mucous find - could be fatal. Biopsy does not have to be done before reaching ings are the first sign of disease in ~85% of pediatric cases. Genital a treatment decision. involvement includes swollen labia, scrotum, or penis. Case 2. Calciphylaxis (involving vascular calcification and skin necrosis) is an under-recognized and devastating syndrome occurring in dialysis patients—and recently reported to occur in Genital Crohn’s Disease in Children many other situations. It presents “a marked therapeutic dilemma.” • Persistent, nontender induration & erythema Dr. Davis illustrated the difficulties and challenges via a patient on of the vulva (often unilateral) > scrotum/penis dialysis for chronic renal failure who suddenly developed extraor - • DDx dinarily painful ulcerations involving his legs, thighs, and abdomi - – Cellulitis, lymphedema nal pannus. Recognition is emerging that calciphylaxis is not – Child abuse primarily a problem of calcium and phosphate deposition in vessel walls, but a clot in the middle of these vessels—akin to a myocardial • Clues to CD Dx infarct. Clot-busting drugs should be considered if the patient can – Perianal involvement tolerate them. Prognosis is dismal and pain is severe; multidiscipli - – Poor growth, Fe deficiency anemia nary care should include pain control and palliative care teams. – Anti-ASCA antibodies • Often associated with colorectal CD DD Sackett et al. J Pediatr Urol. 2012;8:e55–8; AL Pinna et al. Pediatr Dermatol. 2006;23:49–52; Calciphylaxis S Keiler et al. Pediatr Dermatol. 2009;26:604–9; RM Vaid et al. Pediatr Dermatol. 2010;27:279–81; MG Reinders et al. JAAD. 2011;65:49–50; A Porzionato et al. Forensic Sci Int. 2005;155:24–7. • Under-recognized syndrome occurring in 4% of Case 3. An adopted 2-year-old Asian girl with mild develop - hemodialysis patients mental delay of unknown etiology had a 7-month history of per - sistent acral papulovesicles and erosions. She was commonly • Dismal prognosis: indoors, where temperature was maintained at 68°. Although the – 1-year survival: 46% lesions were reminiscent of coxsackievirus infections, the pro - – 2-year survival: 20% longed course eliminated this possibility. Biopsy showed a vacuo - lar interface dermatitis with necrotic keratinocytes and a • No treatment has been shown to help consistently superficial and deep perivascular lymphocytic infiltrate. She was – Treatment strategies: ANA positive; a brain MRI showed white matter changes. Her – Correct calcium/phosphate levels diagnosis combined Aicardi-Goutières syndrome (an inherited – Consider thrombolysis inflammatory encephalopathy mimicking a congenital viral infec - – Pain control/palliative care tion) and familial chilblain lupus. “This links garden-variety lupus to AGS, giving us insights into the pathogenic role of nucleic acid – Multidisciplinary care metabolism.” Case 3. This adult case of widespread atopic dermatitis (AD) was presented to highlight widespread misconceptions in man - Aicardi Goutières Syndrome agement. The patient wanted to control her current flare and avoid future ones. She should use wet dressings to decrease crusting and • Inherited inflammatory encephalopa thy mimicking discomfort. But for adult patients, approaches intended to identify a congenital viral infection food allergens (elimination diet, prick or RAST allergy testing) are – Developmental delay (often progressive) not useful because, as has been documented, food allergy is not with white matter changes ± microcephaly relevant to adult flares, and test results are likely to be highly mis - – Sterile pyrexia with CSF lymphocytosis leading. For pediatric patients, however, 30%–40% have immediate and elevated interferon levels hypersensitivity reactions to food allergens, and elimination is – Chilblain lupus acrally (onset 1–2 yr) appropriate. Low- and mid-potency topical corticosteroids are safe to use long term. • Mutations in genes encoding proteins that regulate innate immune responses via processing of nucleic acid debris Christopher J. Arpey, MD Case 1. Dr. Arpey noted that despite this case’s poor ending, – TREX1, RNASEH2A-C, SAMHD1, ADAR1 he had learned the most from it. An 80-year-old man with multiple – Usually autosomal recessive comorbidities—long-term multiple myeloma the most significant— JS Prendiville et al. JAAD. 2009;61:727–8; GM Abdel-Salam et al. Neuropediatrics. that also included severe bilateral lower limb edema, rapidly de - 2010;41:18–23. C Chahwan et al. Clin Genet. 2012 ;81:413–20. veloped a 1-cm crusted plaque in his left shin. Arpey immediately www.dermatologyfoundation.org Spring 2013 11 biopsied this well-differentiated but fairly proliferative squamous working without them does the patient an injustice.” It is especially cell carcinoma (SCC), planning a review in 2 weeks and excision important in correctly diagnosing inflammatory skin diseases. at 6 weeks. By 2 weeks the lesion had grown fairly quickly, but after Case 1. The patient had smooth-surfaced erythematous le - discussion the original plan was maintained. By surgery, the lesion sions on the shoulder. Several were annular. The suspected di - was 4–5 cm with a much worse appearance. In retrospect, earlier agnosis was atypical erythema annulare centrifugum (EAC). and more aggressive surgery would have been desirable. Initial The biopsy appeared consistent with EAC until LeBoit used a good healing was quickly replaced by an aggressive recurrence. CD123 stain to visualize plasmacytoid dendritic cells, immune Arpey described the rapidly deteriorating situation (including cells that produce IFN- ␣. Most inflammatory diseases have very metastatic disease by 12 weeks post-op), and emphasized the early small clusters of these cells, but this patient had notably large warning signs of aggressive SCC. clusters—key to diagnosing tumid lupus erythematosus. LeBoit believes that we should reappraise EAC and its diagnosis. For the patient with an annular eruption and gyrate erythema, spon - Aggressive SCC giotic dermatitis reflects EAC. If superficial and deep with lym - phocytes, think of tumid lupus and erythema migrans. With an interface reaction, think of subacute cutaneous lupus and an - nular lichen planus. Case 2. A 6-year-old girl had multiple skin lesions (arms, but - tocks, abdomen, thighs) that also occurred in other family mem - bers. The clinician suspected xanthomas or histiocytosis. LeBoit’s review of the biopsy pointed to papular mucinosis until he re - ceived clinical photographs showing the lesions’ slightly yellowish Week 2: at time of Week 6: at time of color. Staining for elastic tissue highlighted prodigiously thick col - preoperative assessment scheduled procedure lagen bundles that appeared welded together, identifying Buschke- Ollendorff syndrome. The patient has been sent for skeletal films Case 2. A 61-year-old man presented with a back mass that to look for osteopoikilosis. appeared to be an epidermoid cyst but was in fact a poorly differ - entiated sebaceous cell carcinoma. Difficulty in obtaining clear margins brought him to Arpey. This was his first extra-ocular case, Buschke-Ollendorff Syndrome although he learned that this incidence is rising, especially below the neck ( ~20% of these tumors). Recent data on the metastatic po - tential of poorly differentiated sebaceous cell carcinoma moti - vated Arpey to request a SLNB, which was negative. The patient healed well, with no recurrence at 6 months. A recent review of pa - tients treated at the Mayo Clinic found a trend for improved prog - nosis with Mohs surgery vs WLE. As extra-ocular sebaceous cell carcinomas differ in architecture from those on the eyelid—very Clinical photo showing dermal papules and nodules, with histopathology well lobulated rather than pagetoid—Arpey suspects that “this may showing thick collagen bundles consistent with Buschke-Ollendorff syndrome. actually be something different.” Case 3. A 50-year-old immunocompetent man had a 10-year Case 3. A 9-year-old boy had annular lesions clinically history of an enlarging mass in his left breast that had been treated thought to be granuloma annulare. Histopathology disagreed and, with topical antifungals. He finally sought treatment when the cen - along with clinical images, raised the possibility of mycosis fun - tral area eroded. The nipple was obliterated. Biopsy identified a very goides (MF). LeBoit does not normally do immunohistochemistry aggressive basal cell carcinoma affecting the nipple and areola—ex - for MF, but atypical aspects prompted him to stain for CD56, which ceedingly rare in this area—with no evidence of chest wall invasion was positive. LeBoit noted a reflex among histopathologists to iden - and no metastases. The patient underwent WLE, a left axillary SLNB tify CD56 positivity with natural killer cell lymphoma, an extremely that found 2/11 nodes positive, and then complete node dissection. aggressive disease. This case highlights that in a patient with char - He healed uneventfully and was still alive at 7 years. acteristics clinically compatible with MF, CD56 positivity does not define the disease. It is just an MF variant and is treated the same as other cases of MF. Nipple/Areola BCC • Very rare: 25–30 cases in 2005 Taiwanese review Mycosis Fungoides Variant • 10–20% metastatic rate to axilla, but no deaths—all men YI Zhu et al. Dermatol Surg. 2001;27:971–4. CW Huang et al. Kaohsiung J Med Sci. 2005;21:480–3. N Rosen et al. Dermatol Surg. 2005;31:480–3. • There have only been a couple of reported cases of SNLB used to detect metastatic BCC M Harwood et al. JAAD. 2 005;53:475–8.

Philip E. LeBoit, MD Dr. LeBoit emphasized the irreplaceable value of clinical Clinical photo showing annular lesions in a 9-yr-old boy that were shown histopathologically to be a mycosis fungoides variant. images, which he often receives by email. “This has opened up another dimension in the practice of dermatopathology, and (Continued on page 15)

12 Spring 2013 Dermatology Foundation Significant AK lesion reductionuction at 1, 2, and 4 weeks

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Carac is indicated for the topical treatment of multipleple actinic or solar keratoses of the face and anterior scalp. Important Safety Informationformation Carac is contraindicatecontraindicateded in women who are nursing, pregnantp or may become pregnantnant as fluorouracil may cause fetal harm. Carac should not be ususedsed in patients with dihydropyrimdihydropyrimidinemidine dehydrogenase (DPD) enzymenzyme deficiency. Rarely, unexpected, syssystemicstemic toxicity (e.g., stomatitis, ddiarrhea, neutropenia, and neuneurotoxicity)rotoxicity) associated with parenteral administratioadministrationon of fluorouracil has been attribattributedbuted to deficiency of dihydropdihydropyrimidinepyrimidine dehydrogenase “DPD” activity. SymptomSymptomsms included severe abdominal pain, bloody diarrhea, vomiting,g, fever, and chills. Carac should be discondiscontinuedntinued if severe abdominal papain,ain, bloody diarrhea, vomiting, fefever,ever, or chills develop when using the product. Application of Carac too mucous membranes should bbee avoided due to the possibilityy of local inflammation and ulceration. In clinical trials, the mosmostst common drug-related adversadversese events were application site reactionsr (94.6%), which included: erythema, drdryness,yness, burning, erosion, pain, anandnd edema, and eye irritation (5.(5.4%).4%). Patients using Carac shshouldhould avoid prolonged exposuree to sunlight or other forms of ultultraviolettraviolet irradiation during treatment, as the intensintensitysity of the reaction maybe increincreased.eased. Please see brief sumsummarymmary of full Prescribing IInformationnformation on adjacent ppage.ageage.

References: 1. Weiss J, MenteMenterer A, Hevia O, et al. Effective treatmentreatmentnt of actinic keratosis with 0.5% fluorourafluorouracilacil cream for 1, 2, or 4 weeks. Cutis. 2002;70(suppl 2):2229. 2. JJorizzoorizzo JJ,, SStewarttewart D, Bucko A, et al. Randomized trial evaluating a new 0.5%% fluorouracil formulation ddemonstratesemonstrates efficacy after 1-, 2-, or 4-week treatment in patients wwithith aactinicctinic kkeratosis.eratosis. Cutis. 2002;70:335-339.39.

Except as where otherwise indicated,d, all product names, slogans, and otherer marks are trademarks of the Valeant family of companies. © 2013 All rights reserved. CRC 13-005 6/30/2014 Carac® Cream, 0.5% Rx Only Pregnancy (fluorouracil cream) Teratogenic Effects: Pregnancy Category X BRIEF SUMMARY See CONTRAINDICATIONS IMPORTANT NOTE: This information is a BRIEF SUMMARY of the complete prescribing Nursing Women information provided with the product and therefore should not be used as the basis ,W LV QRW NQRZQ ZKHWKHU IOXRURXUDFLO LV H[FUHWHG LQ KXPDQ PLON %HFDXVH PDQ\ GUXJV DUH H[FUHWHG LQ for prescribing the product. This summary has been prepared by deleting information KXPDQ PLON DQG EHFDXVH RI WKH SRWHQWLDO IRU VHULRXV DGYHUVH UHDFWLRQV LQ QXUVLQJ LQIDQWV IURP IOXRURXUDFLO from the complete prescribing information such as certain text, tables, and references. 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Rx Only JHQHWLF GLVHDVHV &DUDF VKRXOG QRW EH XVHG LQ FKLOGUHQ 7KH VDIHW\ DQG HIIHFWLYHQHVV RI &DUDF KDYH QRW 'LVWULEXWHG E\ EHHQ HVWDEOLVKHG LQ SDWLHQWV OHVV WKDQ  \HDUV ROG 9DOHDQW 3KDUPDFHXWLFDOV 1RUWK $PHULFD //& Geriatric Use %ULGJHZDWHU 1-  1R VLJQLILFDQW GLIIHUHQFHV LQ VDIHW\ DQG HIILFDF\ PHDVXUHV ZHUH GHPRQVWUDWHG LQ SDWLHQWV DJH  DQG ROGHU $OO RWKHU WUDGHPDUNV DUH WKH WUDGHPDUNV RU WKH UHJLVWHUHG WUDGHPDUNV RI WKHLU UHVSHFWLYH RZQHUV FRPSDUHG WR DOO RWKHU SDWLHQWV  9DOHDQW 3KDUPDFHXWLFDOV 1RUWK $PHULFD //& © CRC 13-006 6/30/2014 MINI-SYMPOSIUM: Pay Online EMERGING THERAPIES With the From Empirical to Precision DF Contribution Melanoma Medicine Boris C. Bastian, MD Center Introduction. The 3 stages of medical care—intuitive (solving medical problems via intuitive experimentation and Save time, paper, and postage while pattern recognition), empirical, ie, evidence-based (trial data supporting the specialty. provide response likelihoods, but not individualized predic - tion), and precision (deep understanding of all aspects enables It is easy to become a member of the precisely targeted treatments and predictable individual out - Dermatology Foundation or renew your sup - comes). Dr. Bastian used the field of infectious disease to illus - port through the DF’s Contribution Center. trate progress from “intuitive” to “precision,” beginning with Leeuwenhoek’s documentation of microbes, to the first tar - Simply visit www.dermatologyfoundation.org geted therapy (ie, penicillin), to precise diagnostics, an array of and select “Contribute Now.” It will take only targeted agents, and eradication of some diseases. As treatment a minute to set up your DF account* using has improved, the cost of diagnosis and treatment has steadily your current email address and zip code. declined. Although most dermatologic care is in the intuitive category, “the field as a whole—particularly regarding cancer— Have your Visa or MasterCard ready to make is striving for this precision.” your payment. Once complete, the password- Looking at Cancer. The evolution of a given cancer ex - protected system allows you to view your presses a variety of individual differences, including the originating current membership information and make cell, the signaling networks it relies on, the initial mutation, the spe - any future payments via credit card. cific secondary mutations and their order of occurrence. Thus can - cers in the same tissue can vary considerably in prognosis, making Need Assistance? diagnostic clarity the precondition for treatment precision. Please contact the DF staff at 847.328.2256 “Melanoma” is currently a mixed bag of distinct types reflecting dif - or [email protected]. ferent cells of origin, different initial mutations, and different sec - ondary mutations, and “we are not sufficiently able to distinguish *For security purposes, the system will not store your credit card information. those that are really dangerous from those that are not.” Bastian dis - cussed the best-characterized mutations and altered signaling The New Assay. Bastian described the power of whole pathways. The mutational burden in melanoma genomes on sun- genome sequencing, “the revolution taking place” enabling mil - exposed sites is 1–2 orders of magnitude greater than in most other lions of molecules to be sequenced simultaneously, and at a solid tumors. The task now is to separate the relevant from the minuscule fraction of earlier times and costs. The Human “passenger” mutations, ie, those that do not actively contribute Genome Project took 13 years and $3 billion; today, sequencing a to tumor progression. single human genome takes <1 week and ~$5,000, and provides a far greater abundance of information in a single measurement. It is being applied to a broad range of problems in cancer and Cancer Genome Analysis beyond. is expected to have a far-reaching impact on our understanding of cancer biology and will likely prompt new approaches to the detec - tion, diagnosis, treatment, and possibly prevention of the disease. Molecularly Targeted Therapies in the Treatment of Nonmelanoma Skin Cancers Oscar R. Colegio, MD, PhD Introduction. Dr. Colegio discussed the molecular under - standing and rationally targeted treatment for basal cell carcinoma (BCC), dermatofibrosarcoma protuberans (DFSP), Kaposi’s sar - coma (KS), and squamous cell carcinoma (SCC). BCC. Although still uncertain whether the epithelial cell of origin is in the interfollicular epidermis, hair unit, or sebaceous gland, all 26 subtypes involve mutations in the hedgehog signal - ing pathway. Most inactivate the patched gene’s tumor suppressor activity, thus releasing the smoothened gene’s proliferative stimu - lation via gli. Sometimes smoothened itself becomes mutated and no longer responds to patched’ s inhibition. Although the gli- inhibiting molecule vismodegib—approved in 2012 for treating advanced and metastatic BCC—recently showed efficacy in re - ducing tumor burden in basal cell nevus syndrome, side effects caused ~50% of enrolled patients to stop treatment. DFSP. This fairly rare, typically low-grade, sarcoma is of Reprinted with permission from M R Stratton Science 2011;331:1553 –8. fibroblast or myofibroblast origin; 10% of cases are fibrosarcoma - www.dermatologyfoundation.org Spring 2013 15 tous and thus more aggressive. A chromosomal translocation pathogenic mechanisms and his research progress in clarifying this fuses collagen and the mitogen PDGF ␤ (platelet-derived growth relationship and pathophysiology. The goal is identifying patients factor- ␤). The collagen promoter upregulates PDGF ␤ expression, at risk to ensure proper monitoring and preventive care. increasing protein levels and ultimately activating its kinase re - Evolving View of Psoriasis. In the increasingly complex ceptor—PDGFR ␤—to drive cell cycle progression and prolifera - conception and systemic context of psoriasis, it is not a 1-way tion. Surgery remains the principal treatment (with Mohs most street in which lymphocytes drive keratinocyte pr oliferation, but effective), but repeated recurrences are common. Imatinib, bi-directional, with keratinocytes and lining macrophages ex - which blocks this receptor, is approved for DFSP that does not pressing factors that reach the vasculature. It is not a simple Th1 respond to surgery or is unresectable. response (driven by IFN-expressing T cells), but a complex and KS. Endothelial cells are infected by human herpesvirus 8 interactive cellular and cytokine milieu. This includes a compo - (HHV8) in all four common variants (classic, African endemic, in nent of the composite IL-12 p40 molecule—blocked by the psoria - the iatrogenically immunosuppressed, and AIDs related). HHV8 sis treatment ustekinumab—that also partners with a different in fection leads to activation of mTOR—the master regulator of sig - molecule to create IL-23, ultimately turning regulatory T cells into nals controlling cell growth, metabolism, and longevity. Sirolimus— inflammatory IL-17-producing Th17 cells. The several experimen - which inhibits mTOR in T cells to prevent an adaptive immune tal IL-17-targeting drugs—brodalumab, ixekizumab, and secuk - response after organ transplantation—also inhibits mTOR in HHV8- inumab—work remarkably well and rapidly, neutralizing just this infected endothelial cells. Its profound therapeutic value in KS minuscule slice of the T-cell repertoire without affecting the rest was recognized in 2005. of the immune system. SCC. This epidermal cell cancer is particularly significant in The Psoriasis–CVD Link. Because “all of these mecha - immunosuppressed populations, especially solid organ trans - nisms are also implicated in atherosclerosis” and Dr. Joel Gelfand plant recipients (reported as 65–250-fold the norm). Vulnerability and others documented the risk for cardiac events and early is significantly greater in sunnier climates ( ~70% incidence in death for psoriasis patients, Cooper assessed his psoriasis popu - renal transplant patients in Australia vs ~40% in the Netherlands). lation. Demonstrable atherosclerosis was significantly more fre - Replacing a calcineurin inhibitor with sirolimus in renal trans - quent, especially among younger patients (ages 30–49), the plant recipients reduced SCC development by ~50% at 2 years. vulnerable group in the Gelfand study. “Younger patients with Transplant recipients with only a single prior SCC saw greatest psoriasis who seem fairly healthy, may not be,” and require mon - benefit. Severe adverse effects led to 23% of subjects discontinu - itoring by their PCPs for blood pressure, LDLs, and triglycerides. ing it in a recent trial. Another iatrogenically induced SCC derives Cooper provided his acronym—LOP-D-CAL’S—for the full spec - from BRAF-inhibiting melanoma drugs that risk unmasking trum of psoriasis-associated comorbidities. RAS mutations culminating in SCC, an uncommon mutation in spontaneous SCC. LOP – D – CAL’S Inhibiting the Hedgehog Pathway in Patients L – Liver and Lipids With the Basal Cell Nevus Syndrome O – Obesity (Hossler, BJD, ’12: 2/3 bariatric surgery improved) P – Psychiatric Baseline D – Diabetes C – Cardiovascular and peripheral vascular disease A – Arthritis L – Lymphomas S – Sleep apnea or Stroke

Month 5 of vismodegib treatment Emerging Therapies in Pediatric Dermatology Anthony J. Mancini, MD Introduction. Dr. Mancini discussed the off-label use of four newer therapies for treating some challenging conditions in infants and children. Sirolimus. Also called rapamycin, it inhibits mTOR (mam - malian target of rapamycin), a serine/threonine kinase in multi - ple mitogenic signaling pathways affecting cellular proliferation, From JY Tang et al. NEJM. 366:2180–8. © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. growth, and angiogenesis. Sirolimus also inhibits vascular en - dothelial growth factor (VEGF). Used primarily to prevent renal allograft rejection, recognition emerged of dramatic benefit for Emerging Therapeutic Targets in Psoriasis: patients with facial angiofibromas—a potentially severe and dev - Skin and Beyond astating cutaneous manifestation of tuberous sclerosis, a geno - Kevin D. Cooper, MD dermatosis involving constitutive mTOR activation—when a Introduction. Dr. Cooper discussed the relationship between patient with tuberous sclerosis received sirolimus to prevent re - psoriasis and inflammatory-based comorbidities in patients with a jection of a kidney transplant. Facial lesion improvement was susceptible genetic background. He focused on atherosclerosis confirmed in trials. A 1% topical ointment is applied twice daily and lesional psoriasis, the best understood, outlining their shared (Continued on page 18)

16 Spring 2013 Dermatology Foundation Dermatology Foundation 201 2 Corporate Honor Society Partners in Shaping Dermatology’s Future

The Dermatology Foundation is grateful to the following corporations for their generous contributions last year. Their support furthers the DF’s mission to develop and retain tomorrow’s leaders in the specialty and advance patient care.

Cornerstone Benefactor ($500,000)

Platinum Benefactor ($200,000)

Gold Benefactor ($100,000) The Allergan Foundation Merz SkinMedica, Inc.

Silver Benefactor ($50,000) Avon Products, Inc. Obagi Medical Products Stiefel, a GSK company

www.dermatologyfoundation.org Spring 2013 17 for 12 weeks (although many use longer periods). Lab values have been normal to date; drug levels are undetectable. Relapse HOT TOPIC tends to follow discontinuation, possibly necessitating chronic treatment. Mancini noted success in treating this disease’s sys - Health Care Reform and Dermatology, temic manifestations (including brain tumors), and noted good A Post-Inauguration Update treatment outcomes in a variety of complicated vascular tumors Jack S. Resneck, Jr., MD and malformations. Introduction. Now that the Affordable Care Act (ACA) is Sildenafil. This active ingredient in Viagra inhibits phos - remaining in place, health care politics and constraints are entering phodiesterase-5, decreasing smooth muscle contraction. Its abil - a new phase. Dr. Resneck surveyed the aspects potentially affecting ity to treat lymphatic malformations was discovered when a the shorter and longer range economic and regulatory pressures 10-week-old girl with a massive lymphatic malformation of the facing the medical community and provided his best sense of what right chest and arm, in heart failure, developed secondary pul - awaits on the horizon. He concluded by characterizing dermatol - monary hypertension. This was treated with sildenafil (approved ogy’s imminent challenges and advice for meeting them effectively for adults, used off-label in children), and her malformation di - “to make sure we can continue to take care of our patients.” minished greatly. Mancini discussed examples. The risk of a po - tentially severe ophthalmologic toxicity (non-arteric ischemic optic neuropathy) requires scrupulous monitoring. A prospective Dermatology and the Broader trial is being planned. Medical Community’s Choice Beta-blockers. Propranolol, a nonselective beta-blocker, • Traverse our dysfunctional political system and take has become standard of care for treating infantile hemangiomas responsibility for integrating care, reshaping the (IH) since its fortuitous discovery in 2008, when its effectiveness payment system, and deciding where to achieve savings, was observed in 2 French infants with IH who were receiving it for or cardiac indications. Effects are both immediate (likely reflecting a component of vasoconstriction) and long term. Treatment often • Insist on the status quo, drive off the fiscal cliff, and continues until 12–15 months of age to prevent recurrence. It is also watch as others reshape the system effective for associated liver hemangiomas, and helps reverse heart This will not be easy… failure and associated hypothyroidism when present. Mancini dis - • We are used to thinking of ourselves as advocates for cussed prevention of hypoglycemia, the primary toxicity of con - an individual patient in front of us (not as stewards of cern. Propranolol may help inadequately involuted hemangiomas resources, not as responsible for system integration) in older children, albeit more slowly and less completely. Consen - sus guidelines for propranolol use in IH were just published (BA • We are used to helping defend pharma, device makers, Drolet et al. Pediatrics. 2013;131(1):128–40). The nonselective beta- and hospitals blocker timolol—in a gel-forming solution approved for treating If we succeed… glaucoma—treats smaller or flatter IH lesions (mostly in the 0.5% • Our specialty and practices will continue to thrive concentration). There is no evidence to date of significant absorp - and maintain access for patients to high quality tion in this setting. Monitoring is not generally recommended. dermatologic care

Summary Spheres of ACA activity. States are occupied with their (all off-label) approach to the health care exchange—the online market for em - • Sirolimus (rapamycin)—promising option for facial ployees in small companies and individuals who will be buying pri - angiofibromas (topical) and complicated vascular anom - vately—to be ready for the beginning of 2014. Some are developing alies (oral); caution: mucositis, hypercholesterolemia their own, within a complex context of rules and responsibilities; others are ceding this to the federal government. States are also as - • Sildenafil —appears to benefit severe lymphatic mal - sessing participation in the expansion of Medicaid. Washington, formations; caution: hearing loss, optic neuropathy DC activity is being watched carefully for evidence of evolution. • Propranolol —has evolved into the standard-of-care Resneck discussed the problematic SGR (Sustainable Growth Rate for problematic infantile hemangioma therapy; board) and the emerging IPAB (Independent Payment Advisory caution: hypoglycemia, bronchospasm Board), including the presence of only two physicians in this new • Timolol —is a reasonable topical option for smaller, group. He reviewed issues associated with emerging local Ac - flatter infantile hemangiomas countable Care Organizations (ACOs)—some physician-driven, some hospital-driven—for physician payment reform. Other pressures. Resneck discussed the runaway costs of health care and insurance since 1999, unsustainable entitlement 2013 DF Clinical Symposia Faculty Disclosures costs, and the anticipated fallout from sequestration. Within the (Part I) SGR, the physician community is the remaining target for further Christopher J. Arpey, MD: None. Boris C. Bastian, MD: Abbott Molecular, cost cutting. DermTech, Novartis. Oscar R. Colegio, MD, PhD: None. Kevin D. Cooper, MD: Dermatology’s vulnerability. Inevitable major deficit re - Avon, Anacor Pharmaceuticals, Astellas Pharma US, Inc., Estée Lauder, duction efforts will make “our image and perception among our Fluence Therapeutics, L.E.K. Consulting, L’Oréal USA Inc., Takeda. Mark D.P. Davis, MD: None. Philip E. LeBoit, MD: None. Anthony J. Mancini, MD: Galderma, peers more important than ever.” Dermatology needs to look be - Pierre Fabre, Quinnova Pharmaceuticals, Top MD, Topaz Pharmaceuticals, yond the status quo, seizing an active role in reshaping the payment Valeant Pharmaceuticals. Jack S. Resneck, Jr., MD: None. Dana L. Sachs, MD: and entitlement systems and becoming “a steward of resources” None. Julie V. Schaffer, MD: None. Bethanee J. Schlosser, MD, PhD: None. to enable a functional system and top care for our patients. I

18 Spring 2013 Dermatology Foundation CLINICAL SYMPOSIA 20 13 FACULTY Corporate Supporters Proceeding s— Part I 2013 DF Clinical Symposia

Christopher J. Arpey, MD Professor of Dermatology Mayo Clinic Diamond Supporter Boris C. Bastian, MD ($100,000) Professor Departments of Dermatology and Pathology Valeant Dermatology University of California, San Francisco Oscar R. Colegio, MD, PhD Emerald Supporters Assistant Professor of Dermatology Yale University ($50,000) Kevin D. Cooper, MD Amgen Pfizer Professor and Chair Department of Dermatology Galderma Laboratories, L.P. Case Western Reserve University Mark D.P. Davis, MD Obagi Medical Products Professor of Dermatology Mayo Clinic SkinMedica Philip E. LeBoit, MD Professor Sapphire Supporters Departments of Dermatology and Pathology University of California, San Francisco ($25,000) Anthony J. Mancini, MD Bayer HealthCare Professor of Pediatrics and Dermatology Northwestern University DUSA Pharmaceuticals Inc. Jack S. Resneck, Jr., MD Medicis, Associate Professor & Vice Chair of Dermatology Core Faculty, Philip R. Lee Institute for A Division of Valeant Pharmaceuticals Health Care Policy Studies Merz University of California, San Francisco Dana L. Sachs, MD Ranbaxy Laboratories Associate Professor Department of Dermatology University of Michigan Julie V. Schaffer, MD Associate Professor The Ronald O. Perelman The DF is pleased to Department of Dermatology recognize Unilever for New York University their educational grant of Bethanee J. Schlosser, MD, PhD Assistant Professor of Dermatology $300,000 supporting the Northwestern University 2013 DF Clinical Symposia Resident Program. PROGRAM CO-CHAIRS

Janet A. Fairley, MD Professor and Head DF CLINICAL SYMPOSIA Department of Dermatology PROCEEDINGS 2 013—PART II University of Iowa Will Appear in the Summer Jack S. Resneck, Jr., MD “Dermatology Focus” Associate Professor and Vice Chair Department of Dermatology Revisiting Old Therapies Core Faculty, Philip R. Lee Institute Medical Dermatology for Health Policy Studies Cutaneous Oncology & Immunology University of California, San Francisco Keynote Talks www.dermatologyfoundation.org Spring 2013 19 Dermatology Focus c/o Dermatology Foundation Non-Profit U.S. Postage DF 1560 Sherman Avenue PAID Evanston, Illinois 60201 -4808 Permit No. 236 Melrose Park, IL ADDRESS SERVICE REQUESTED

Giving Back—Profile of a DF Volunteer David R. Byrd, MD –“Investing in My Specialty”

The Dermatology dermatologist father in practice. Just six years Foundation’s out - later, in 2009, he made a commitment to join the standing success in Annenberg Circle. The following year Dr. Byrd launching careers of accepted the invitation to help lead his state’s tomorrow’s thought annual Leaders Society campaign. Since then, leaders convinced he has inspired many of his colleagues to join Dr. David R. Byrd, him in furthering the specialty. David R. Byrd, MD a dermatologic sur - Dr. Byrd finds his practice focused on cancers geon in Rochester and aesthetic concerns to be “very gratifying Hills, Michigan, to support the DF just as soon and rewarding. It has all the facets of medicine as he could. “Innovation is what enables us I enjoy—I can be the clinician, the pathologist, to be the best dermatologists we can be,” and the surgeon.” As a clinical instructor he he points out, “and research drives innovation. teaches dermatology residents from a handful “As a dermatologist,” he adds, “there is no of neighboring medical schools, he is also an better investment I can make than in my associate clinical professor of dermatology at specialty—and the Dermatology Foundation Wayne State University. provides a way for me to do that.” Dr. Byrd encourages his colleagues to give Dr. Byrd became a DF Leaders Society back and support “those who are advancing member in 2003 only three years after completing our field through research and maintaining his residency at the Mayo Clinic. He had our ability to be the premier specialists treat - remained at the Mayo for a fellowship in Mohs ing the skin. The DF is a great organization, surgery before returning to Michigan to join his and I’m happy to be a part of it.” The DF is exceptionally grateful to its many volunteers who give generously of their time and inspiration to keep dermatology at the forefront of medicine.

A DE RMATOL OGY FO UNDA TION PUBLICAT IO N SPONSORED BY MEDICIS, A DIVISION OF VALEANT PHARMACEUTICALS VOL. 32 NO. 1 SPRING 2013