Jan / Feb, 2014 by jo-ann kalaka-Adams

January/February 2014 • Volume 12 • Issue 1 EDITORIAL There Is More to Infection Control Than Just Gloves in the Dermatology Office Parish and Berstein

case studies Palliative Effect of Capecitabine and Cetuximab for Refractory Metastatic Squamous Cell Carcinoma of the Perineum in Epidermodysplasia Verruciformis Lynch, Drabick, Neves, Fox, Mackley, and Anderson

COMMENTARY Current Surgical Management of Basal Cell Carcinoma: A Half-Way Technology? Lambert, Wassef, and Sharma

ORIGINAL CONTRIBUTIONS Cohort Study on the Treatment With Dapsone 5% Gel of Mild to Moderate Inflammatory Acne of the Face in Women Lynde and Andriessen

Laundry Detergents and Skin Irritancy— A Comprehensive Review Crawford and Zirwas

REVIEW Basal Cell Carcinoma

Gupta, Daigle, and Martin

Self Assessment Examination Lambert

Nevus Comedonicus of the Scalp

Kaliyadan, Nambiar, Al Ameer, and Amri

CORRESPONDENCE Disseminated Extragenital Lichen Sclerosus et Atrophicus Treated With Acitretin

de Assis Formiga, de Souza Medeiros Torres, de Oliveira Rocha, Silva, Follador, de Almeida Rêgo, de Oliveira

Bilateral Segmental Eruptive Lentiginosis in a Patient With a History of Hepatocellular Carcinoma Wang, Taylor, Binder, and Mandel

Continuing Medical Education II and What It Is Zachary

More on Continuing Medical Education II Mandy

BOOK REVIEW An Atlas of Hair Pathology With Clinical Correlations Turner

DEPARTMENTS NEW THERAPY UPDATE MIRVASO (Brimonidine Tartrate) Topical Gel 0.33% Abramovits, Prato, Vincent, Scheinfeld, and Gupta

THE HEYMANN FILE Diagnosing Atypical Hand, Foot, and Mouth Disease While Avoiding the Foot in Mouth Syndrome Heymann

NACDS NEWSLETTER North American Clinical Dermatologic Society Is 55 Years Young

Lebanese Dermatological Society

Spielvogel and White, Jr

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

Finacea® (azelaic acid) Gel, 15% is a topical prescription medication used to treat inflammatory papules and pustules of mild to moderate rosacea.

Rosacea is with her wherever she goes. So is Finacea . ®

It’s true. Rosacea is complex and it’s with them for life. Finacea® treats the papules and pustules with associated erythema of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. You have made Finacea® the #1 Dermatologist-prescribed topical brand.1 INDICATION & USAGE Finacea® (azelaic acid) Gel, 15% is indicated for topical treatment of inflammatory papules and pustules of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. IMPORTANT SAFETY INFORMATION Skin irritation (e.g. pruritus, burning or stinging) may occur during use with Finacea®, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists during use with Finacea®, discontinue use and institute appropriate therapy. There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation. Avoid contact with the eyes, mouth, and other mucous membranes. In case of eye exposure, wash eyes with large amounts of water. Wash hands immediately following application of Finacea®. Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Avoid the use of occlusive dressings or wrappings. In clinical trials with Finacea®, the most common treatment-related adverse events (AE’s) were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). Contact dermatitis, edema and acne were observed at frequencies of 1% or less. Finacea® is for topical use only. It is not for ophthalmic, oral or intravaginal use. Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy. Please see Brief Summary of full Prescribing Information on adjacent page. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. 1. According to IMS NPATM (National Prescription Audit) July 2010-August 2013 © 2013 Bayer HealthCare Pharmaceuticals. Bayer, the Bayer Cross and Finacea® are registered trademarks of Bayer. All rights reserved. FIN-10-0001-13b | AUGUST 2013

TABLE OF CONTENTS January/February 2014 • Volume 12 • Issue 1

EDITORIAL

There Is More to Infection Control Than Just Gloves in the Dermatology Office ............................................. 9

Lawrence Charles Parish, MD, MD (Hon); Jack M. Berstein, MD

COMMENTARY

Current Surgical Management of Basal Cell Carcinoma: A Half-Way Technology?........................................ 12

W. Clark Lambert, MD, PhD; Cindy Wassef, BA; Divya Sharma, BS

ORIGINAL CONTRIBUTIONs

Cohort Study on the Treatment With Dapsone 5% Gel of Mild to Moderate Inflammatory Acne of the Face in Women ...................................................................................................................................... 15

Charles W. Lynde, MD, FRCP(C); Anneke Andriessen, PhD

Laundry Detergents and Skin Irritancy—A Comprehensive Review .............................................................. 23

Charles Crawford, PhD; Matthew J. Zirwas, MD

REVIEW

Basal Cell Carcinoma .................................................................................................................................. 33

Aditya K. Gupta, MD, PhD, FRCP(C); Deanne Daigle, MSc; George Martin, MD

Self Assessment Examination ..................................................................................................................... 38

W. Clark Lambert, MD, PhD

Departments New Therapy Update

William Abramovits, MD; Aditya K. Gupta, MD, PhD, Section Editors

MIRVASO (Brimonidine Tartrate) Topical Gel 0.33% ................................................................................... 41

William Abramovits, MD; Ana Prato, MD; Kimberly D. Vincent, MD; Noah Scheinfeld, MD, JD; Aditya K. Gupta, MD, PhD, FRCP(C)

The Heymann File

Warren R. Heymann, MD, Section Editor

Diagnosing Atypical Hand, Foot, and Mouth Disease While Avoiding the Foot in Mouth Syndrome ............... 46

Warren R. Heymann, MD

NACDS Newsletter

North American Clinical Dermatologic Society Is 55 Years Young ............................................................... 49

Richard L. Spielvogel, MD; John W. White, Jr, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Palliative Effect of Capecitabine and Cetuximab for Refractory Metastatic Squamous Cell Carcinoma of the Perineum in Epidermodysplasia Verruciformis ................................................................ 54

Michael C. Lynch, BS; Joseph J. Drabick, MD; Rogerio I. Neves, MD; Edward J. Fox, MD; Heath B. Mackley, MD; Bryan E. Anderson, MD

Nevus Comedonicus of the Scalp................................................................................................................. 59

Feroze Kaliyadan, MD, DNB, MNAMS; Ajit Nambiar, MD, DNB; Ali Al Ameer, MD; Montassar Amri, MD

TABLE OF CONTENTS July/August 2013 • Volume 11 12 • Issue 4 1 January/February 2014 • Volume • Issue

CORRESPONDENCE

Disseminated Extragenital Lichen Sclerosus et Atrophicus Treated With Acitretin ....................................... 62

Aurenita de Assis Formiga, MD; Isabelle de Souza Medeiros Torres, MD; Bruno de Oliveira Rocha, MD; Anete Olivieri Pessoa Silva, MD; Ivonise Follador, MD, MSc, PhD; Vitória Regina Pedreira de Almeida Rêgo, MD, MSc; Maria de Fátima Santos Paim de Oliveira, MD, MSc, PhD

Bilateral Segmental Eruptive Lentiginosis in a Patient With a History of Hepatocellular Carcinoma ............ 64

Yen Tun Wang, MD; Emma Taylor, MD; Scott Binder, MD; Hilary Mandel, MD

Continuing Medical Education II and What It Is ........................................................................................... 65

Christopher B. Zachary, MBBS, FRCP

More on Continuing Medical Education II .................................................................................................... 66

Stephen Mandy, MD

Book Review

Jennifer L. Parish, MD, Section Editor

An Atlas of Hair Pathology with Clinical Correlations .................................................................................. 68

Graham Turner, CBiol, FSB

ABOUT OUR JOURNAL

Editorial

SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760.

MANAGING EDITOR Marla Kipp marla@skinmedjournal.com

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Disclaimer: The Publisher, Editors, and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein do not necessarily reflect those of the Publisher, Editors, and Editorial Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products or services advertised. The Publisher, Editors, Editorial Board, Reviewers, Authors, and Affiliated Agents shall not be held responsible or in any way liable for the continued accuracy of the information or for any errors, inaccuracies, or omissions of any kind in this publication, whether arising from negligence or otherwise, or for any consequences arising thereafter.

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Abstracting & Indexing: The journal is indexed in Index Medicus/ MEDLINE.

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

Simulated image based on patient with locally advanced BCC at Week 24.

BOXED WARNING AND ADDITIONAL IMPORTANT SAFETY INFORMATION Embryo-Fetal Death and Severe Birth Defects • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen • Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant

• Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal ﬂuid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555 Blood Donation • Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge Nursing Mothers • Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother

TRANSFORM THE TREATMENT OF DIFFICULT ADVANCED BASAL CELL CARCINOMA (aBCC) ERIVEDGE IS A UNIQUE ORAL THERAPY E (Not act actual ctual ual size size))

• Due to the nature of aBCC and its clinical factors (ie, lesion recurrence, location/size, and invasiveness) some patients may not be candidates for surgery or radiation1,2 • Erivedge is an oral treatment option dosed as a 150-mg capsule once daily until disease progression or unacceptable toxicity3 • Erivedge reduced lesions in patients with aBCC1,3 Objective response rates (ORR) by IR from ERIVANCE1,3* laBCC (n=63)

mBCC (n=33)

43% (n=27) (30.5-56.0)

30% (n=10) (15.6-48.2)

Complete response

21% (n=13)

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

ORR (95% CI)

Median duration of response (months) (95% CI)

Indication Erivedge® (vismodegib) capsule is a hedgehog pathway inhibitor indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. *Patients received at least 1 dose of Erivedge with independent pathologist-conﬁrmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy. Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. IR=Independent Review; laBCC=locally advanced BCC; ORR=objective response rate; CI=conﬁdence interval; NE=not estimable; mBCC=metastatic BCC.

Adverse Reactions • The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see Brief Summary of Prescribing Information on following page.

See what you can offer your patients with aBCC at www.Erivedge.com References: 1. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012;366:2171-2179. 2. Walling HW, et al. Cancer Metastasis Rev. 2004;23:389-402. 3. Erivedge® (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. © 2013 Genentech USA, Inc. All rights reserved. HED0001655400 Printed in USA.

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

MedDRA Preferred Term

Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)]. 1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

All aBCC1 Patients (N = 138) All Grades 3 Grade 3 Grade 4 (%) (%) (%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

aBCC = Advanced Basal Cell Carcinoma. 2 MedDRA = Medical Dictionary for Regulatory Activities. 3 Grading according to NCI-CTCAE v3.0. Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)]. Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. 7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)]. In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). 8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). t "EWJTF QBUJFOUT UIBU &3*7&%(& FYQPTVSF EVSJOH QSFHOBODZ DBO cause embryo-fetal death or severe birth defects. t *OTUSVDU GFNBMF QBUJFOUT PG SFQSPEVDUJWF QPUFOUJBM UP VTF B IJHIMZ effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t *OTUSVDU BMM NBMF QBUJFOUT FWFO UIPTF XJUI QSJPS WBTFDUPNZ UP VTF condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. t *OTUSVDU QBUJFOUT UP JNNFEJBUFMZ DPOUBDU UIFJS IFBMUIDBSF QSPWJEFS if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. t *OTUSVDU QBUJFOUT UP JNNFEJBUFMZ SFQPSU BOZ QSFHOBODZ FYQPTVSF UP ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. t *OGPSN GFNBMF QBUJFOUT PG UIF QPUFOUJBM GPS TFSJPVT BEWFSTF reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. t "EWJTF QBUJFOUT OPU UP EPOBUF CMPPE PS CMPPE QSPEVDUT XIJMF UBLJOH ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t "EWJTF QBUJFOUT UP TXBMMPX &3*7&%(& DBQTVMFT XIPMF BOE OPU UP crush or open the capsules.

ERIVEDGE ® [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2013 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832301

January/February 2014

EDITORIAL BOARD

EDITOR IN CHIEF

Lawrence Charles Parish, MD, MD (Hon) Philadelphia, PA

DEPUTY EDITORS William Abramovits, MD

W. Clark Lambert, MD, PhD

Larry E. Millikan, MD

Jennifer L. Parish, MD

Dallas, TX

Newark, NJ Vesna Petronic-Rosic, MD, MSc

Meridian, MS Marcia Ramos-e-Silva, MD, PhD

Philadelphia, PA

Chicago, IL

Rio de Janeiro, Brazil

EDITORIAL BOARD Virendra N. Sehgal, MD Delhi, India

Ibrahim Hassan Galadari, MD, PhD, FRCP Dubai, United Arab Emirates

Jasna Lipozencic, MD, PhD Zagreb, Croatia Eve J. Lowenstein, MD, PhD New York, NY

Anthony V. Benedetto, DO Philadelphia, PA

Anthony A. Gaspari, MD Baltimore, MD

George M. Martin, MD Kihei, HI

Charles Steffen, MD Oceanside, CA

Brian Berman, MD, PhD Miami, FL

Michael Geiges, MD Zurich, Switzerland

Marc S. Micozzi, MD, PhD Rockport, MA

Michael H. Gold, MD Nashville, TN

Alexander J. Stratigos, MD Athens, Greece

George F. Murphy, MD Boston, MA

Orin M. Goldblum, MD Pittsburgh, PA

James S. Studdiford III, MD Philadelphia, PA

Venkataram Mysore, MD, FRCP (Hon, Glasgow) Bangalore, India

Robert J. Thomsen, MD Los Alamos, NM

Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Robert L. Baran, MD Cannes, France

Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Joaquin Calap Calatayud, MD Cadiz, Spain

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan Aditya K. Gupta, MD, PhD, FRCP(C) Henry H.L. Chan, MB, MD, PhD, FRCP London, Ontario, Canada Joseph L. Pace, MD, FRCP Hong Kong, China Seung-Kyung Hann, MD, PhD Naxxar, Malta Noah Craft, MD, PhD, DTMH Seoul, Korea Art Papier, MD Torrance, CA Roderick J. Hay, BCh, DM, FRCP, FRCPath Rochester, NY Natalie M. Curcio, MD, MPH London, UK Johannes Ring, MD, DPhil Nashville, TN Warren R. Heymann, MD Munich, Germany Camden, NJ Ncoza C. Dlova, MBChB, FCDerm Roy S. Rogers III, MD Durban, South Africa Tanya R. Humphreys, MD Rochester, MN Bala-Cynwyd, PA Richard L. Dobson, MD Donald Rudikoff, MD Camila K. Janniger, MD Mt Pleasant, SC New York, NY Englewood, NJ William H. Eaglstein, MD Robert I. Rudolph, MD Abdul-Ghani Kibbi, MD Menlo Park, CA Wyomissing, PA Beirut, Lebanon Boni E. Elewski, MD Vincenzo Ruocco, MD Andrew P. Lazar, MD Birmingham, AL Naples, Italy Washington, DC Charles N. Ellis, MD Noah Scheinfeld, MD, JD Ann Arbor, MI New York, NY

Riccarda Serri, MD Milan, Italy

Julian Trevino, MD Dayton, OH Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Michael A. Waugh, MB, FRCP Leeds, UK Wm. Philip Werschler, MD Spokane, WA Joseph A. Witkowski, MD Philadelphia, PA Ronni Wolf, MD Rechovot, Israel

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January/February 2014

Volume 12 • Issue 1

Editorial

There Is More to Infection Control Than Just Gloves in the Dermatology Office Lawrence Charles Parish, MD, MD (Hon);1 Jack M. Berstein, MD2

he 21st century could be easily called the glove era. The omnipresent glove is found on airport screeners, kitchen workers, housekeepers, and, yes, even medical personnel. Latex, vinyl, and laetrile gloves are all used with abandon.

Table. Glove Types Gauntlet Glove Glovelette Mitten

Background Gloves of one fashion or another have been known since at least ancient Greece when Homer recorded Laërtes’ wearing gloves in The Odyssey. Through the centuries, many different types of hand coverings have evolved (Table), but our concern is not the white gloves for formal attire or those protecting a racing driver’s hand, rather the covering of the physician’s. More specifically, the dermatologist’s hand.1

A glove extending to part or all of the forearm A covering with separate covering for each finger and the thumb A glove with most of the fingers uncovered A covering without separation for the fingers

The situation changed dramatically in the 1980s with the recognition of the means for transmission of both the AIDS and hepatitis B viruses.5 Dermatologists generally adhered to hand washing and donning surgical gloves at least for any invasive procedure. Latex allergy and powdered gloves are material for additional consideration.6 Add to the mix the emergence and subsequent recognition of resistant bacteria, including methicillin-resistant Staphylococcus aureus.

The surgical glove appeared in the operating theater toward the end of the 19th century. Whether credit should go to William Stewart Halstead (1852–1922),2—Johns Hopkins’ first Surgeon-in-Chief who devised the rubber covering in 1890 for his scrub nurse Caroline Hampton (1861–1922), who later became his wife, to alleviate her contact dermatitis caused by the disinfectants then used—or Joseph Colt Bloodgood (1867–1935)— his assistant3 who ordered their use in the operating room for everyone involved—or even Abraham Groves (1847–1935)—a Toronto surgeon, who introduced the surgical glove in 18854— is uncertain.

Preventing Infection in the Dermatology Office It has been assumed that adherence to standard aseptic techniques in office-based dermatologic surgery would lead to low infection rates. Implementation of a “sterility upgrade” led to a statistically significant decrease in infections after Mohs surgery.7 This “upgrade” involved restrictions on the wearing of jewelry, an increase in alcohol-based hand scrubs before stages and reconstruction, sterile gloves, masks, sterile drapes, and even the use of sterile gowns. The naysayers lost out, for the increased cost of the upgrade was negligible.

The Dermatology Story The story in dermatology is not any clearer. Some years ago, few dermatologists utilized surgical gloves. Dermatologic surgery was in its infancy, and it was thought that skin was unsterile in the first place. There was little need in the outpatient environment to follow the tenets established in the 20th century for the hospital operating room.

Lasersurgery and electrosurgery have both increased in use over the past several years. An unanticipated risk to staff is the “surgical smoke” generated during these procedures. The electrocautery/laser plume has been shown to contain viable viruses and bacteria, as well as potentially harmful chemicals. A comparative

From the Department of Dermatology and Cutaneous Biology, Jefferson Center for International Dermatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA;1 and the Department of Veterans Affairs Medical Center, and the Department of Medicine, Wright State University of Medicine, Dayton, OH2 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1760 Market Street, Suite 301, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com

SKINmed. 2014;12:9–10

January/February 2014

EDITORIAL

questionnaire study has shown an increased acquisition rate of nasopharyngeal papillomavirus infections in surgeons using carbon dioxide lasers8; however, the acquisition rate of plantar warts remained unchanged. It was proposed that the inhalation of viable papilloma virus from the plume led to the nasopharyngeal infection. Aerosolization of bacteria may also occur and Staphylococcus, Corynebacteria, and Neisseria have been isolated, although no nosocomial infections have been associated with this aerosolization. During these procedures, the use of respiratory protection equipment, such as an N99 Hepa filtered masks, may be beneficial, but few dermatologic surgeons use them. Smoke evacuation systems have been recommended to prevent the transmission of these pathogens to those performing the procedures and have been adopted by some surgical centers. Conclusions The future of infection control in offices and surgical centers is already upon us. Many ambulatory surgical centers (ASCs) are expected to maintain infection control programs directed by health care professionals with training in infection control. Inspection of ASCs by the Center for Medicare and Medicaid Services has not infrequently revealed a failure to follow the stipulated infection control practices. This has led to re-inspection of the facilities and sanctions against noncompliant facilities.

The eventual outcome could be the termination of the facility’s participation in Medicare.9 So, there is more to infection control than just donning gloves. References 1 Schlich T. Negotiating technologies in surgery: the controversy about surgical gloves in the 1890s. Bull Hist Med. 2013;87:170–197. 2 Osborne MP. William Stewart Halsted: his life and contributions to surgery. Lancet Oncol. 2007;8:256–265. 3 Breathnach CS. The centenary of the surgical glove. J Ir Coll Physicians Surg. 1997;26:297–299. 4 Geddes CR, McAlister VC. A surgical review of the priority claims attributed to Abraham Groves (1847–1935). Can J Surg. 2009;52:E126–E130. 5 Wagner RF, Jr. Risks of infection to dermatologists, cosmetic workers, and the public. Int J Dermatol. 1990;29:253–257. 6 Al-Niaimi F, Chiang YZ, Chiang YN, Williams J. Latex allergy: assessment of knowledge, appropriate use of gloves and prevention practice among hospital healthcare workers. Clin Exp Dermatol. 2013;38:77–80. 7 Martin JE, Speyer LA, Schmults CD. Heightened infection-control practices are associated with significantly lower infection rates in office-based Mohs surgery. Dermatol Surg. 2010;36:1529–1536. 8 Lewin JM, Brauer JA, Ostad A. Surgical smoke and the dermatologist. J Am Acad Dermatol. 2011;65:636–641.

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January/February 2014

Volume 12 • Issue 1

COMMENTARY

Current Surgical Management of Basal Cell Carcinoma: A Half-Way Technology? W. Clark Lambert, MD, PhD; Cindy Wassef, BA; Divya Sharma, BS “What we learn is limited by what we think we know.”—Claude Bernard

s reviewed succinctly by Gupta and colleagues in the present issue of SKINmed, surgical excision is currently the treatment of choice, among a number of options available to dermatologists (also well reviewed in this contribution*), for the treatment of basal cell carcinomas.1 For individual patients, dermatologists may, of course, choose among these other options for additional or alternative care: eg, for treatment of a superficial disseminated basal cell carcinoma, in which a tumor may well reside beyond a clear surgical margin, a topical choice such as cryotherapy may be appropriate,2 whereas for some basal cell cancers, such as those of the morpheaform variant, more extensive surgery may be indicated, especially for cases presenting in sites of embryonic fusion planes.

pathway, upregulation of which in basal cell carcinomas enables them to evade normal control mechanisms.1 This approach is being pursued at a number of academic medical centers. New Developments These new developments imply that original thinking “outside of the box” is indicated. For example, cancer cells resistant to these new inhibitors tend to show hypertrophy of mediators of autophagy, a process by which the cell digests debris generated by these and other toxins. It may be useful to consider adjuvant therapy using inhibitors of autophagy, such as those that block cellular phagolysosome activity. Some of these agents, such as dapsone (which blocks fusion of phagosomes and lysosomes to form phagolysosomes) and chloroquine (an antimalarial) are already well-known to dermatologists. They are also Food and Drug Administration (FDA)–approved and have been applied for different indications in a number of patients.

Invasive Variants Even the common nodular form of basal cell carcinoma has at least one much more invasive variant, in which extremely aggressive local invasion is seen. Such cases, once they have been identified, may best be managed by complete excision plus extensive margins;3 however, is complete excision, although almost always effective, really the best that we can offer the patient? Such treatment is sometimes accompanied by extensive morbidity, making this a challenging option. In their careful examination of the molecular advances of recent years studying these tumors,1 Gupta and colleagues imply that we may be able to do better.

Another approach, not yet approved by the FDA but actively pursued in Europe and elsewhere, is electrochemotherapy, in which a drug in a form that is not well absorbed by cells is applied either intratumorally or intravenously followed by application of a brief high-voltage electric charge that produces very brief pores in cell membranes, a process known as electroporation, at sites of tumors, allowing the drugs to enter. There have been individual reports of complete clearing of basal cell carcinomas following this treatment.5,6

Not only are individual inhibitors of genes and gene products specific to basal cell carcinomas and other skin cancers, such as melanomas, now being applied, these agents, such as cetuximab and vismodegib, are being tailor-made for the specific mutations present in tumors of individual patients.1,4 Vismodegib, in particular, attacks the very complex cell signaling “sonic hedgehog”

Questionable Therapy All of this begs the question: Do you introduce a new treatment of uncertain value when you already have a treatment that is effective, but flawed? Lewis Thomas famously identified this

*See page 33. From the Departments of Pathology and Dermatology, Rutgers University – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

SKINmed. 2014;12:12–13

January/February 2014

COMMENTARY

dilemma, terming the older approach a “halfway technology.”7 Also, when you think you know the best way to treat a lesion but a better way, based on a newer technology, appears, does your perception of knowledge inhibit you from understanding the new approach, as Claude Bernard might argue? Ironically, if no older method exists, it may be easier to introduce a new one. But, wait, what if the new approach itself is flawed, perhaps in ways that are not yet apparent when it is first introduced?

2 Jadotte YT, Sarkissian NA, Kadire H, Lambert WC. Superficial spreading basal cell carcinoma of the face: a surgical challenge. Eplasty. 2010;10:e46.

Conclusions

5 Kis E, Baltás E, Kinyó A, et al. Successful treatment of multiple basaliomas with bleomycin-based electrochemotherapy: a case series of three patients with GorlinGoltz syndrome. Acta Derm Venereol. 2012;92:648–651.

What if the limited numbers of reports are wrong and the new treatment is worthless, or even worse? Some of the answers will come from continued advances in the relevant underlying science, but sooner or later someone is going to have to be the first patient to undergo the new treatment. Any volunteers? References 1 Gupta AK, Daigle D, Martin G. Basal cell carcinoma. SKINmed. 2014;12:33–38.

3 Fernandes H, Fernandes N, Bhattacharya S, et al. Molecular signatures linked with aggressive behavior in basal cell carcinoma: a report of six cases. Am J Dermatopathol. 2010;32:550–556. 4 Liu LS, Colegio OR. Molecularly targeted therapies for nonmelanoma skin cancers. Int J Dermatol. 2013;52:654–665.

6 Salwa SP, Bourke MG, Forde PF, et al. Electrochemotherapy for the treatment of ocular basal cell carcinoma; a novel adjunct in the disease management. J Plast Reconstr Aesthet Surg. 2013 Jul 31 [Epub ahead of print]. 7 Thomas L. The technology of medicine. In: The Lives of a Cell: Notes of a Biology Watcher. New York, NY: The Viking Press; 1974.

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January/February 2014

Volume 12 • Issue 1

ORIGINAL CONTRIBUTION

Cohort Study on the Treatment With Dapsone 5% Gel of Mild to Moderate Inflammatory Acne of the Face in Women Charles W. Lynde, MD, FRCP(C);1 Anneke Andriessen, PhD2 Abstract Topical dapsone 5% gel for the treatment of mild to moderate acne has been shown to be effective in randomized controlled studies. A total of 101 adult women with mild to moderate facial inflammatory acne participated in a 12-week cohort study to evaluate the efficacy, tolerability, and safety of dapsone gel 5% in this specific group who often complain of sensitive skin. The women were instructed to apply dapsone 5% gel twice daily after washing their face with a standard noncomedogenic soap-free cleanser. Treatment outcome was evaluated using physicianscored Global Acne Assessment Scale (GAAS) and patient-reported facial skin condition. Ninety-three women completed the study (6 were lost to follow-up and 2 had mild skin irritation). At 12 weeks, significant physician GAAS scores (t55=8.85, P=.001) and patient-reported lesion reductions were shown. Treatment success (GAAS 0 or 1) at 12 weeks was achieved in 69.4% (n=75) of women (t94=4.17, P=.001), improving patient-reported quality-of-life aspects. Topical dapsone gel 5% was shown to be safe, minimally irritating, and effective in the treatment of mild to moderate inflammatory facial acne in adult women with sensitive skin. (SKINmed. 2014;12:15–21)

cne vulgaris remains a common skin problem even past the teenage years, with women being affected at higher rates than men in all age groups 20 years or older.1,2 When compared with adolescent acne, adult acne is often more inflammatory, involving the cheeks and lower half of the face, while comedonal involvement is uncommon.1,2 Patients frequently complain of dry facial skin and may experience skin irritation, possibly related to acne treatment.1,2

A cohort study was designed to evaluate treatment with dapsone 5% gel in women with mild to moderate inflammatory facial acne to assess efficacy, tolerability, and safety in this specific group who often complain of sensitive skin prone to irritation caused by acne treatment.

Topical dapsone 5% gel contains sulfone and has an advanced solvent microparticulate delivery system that enables penetration of the stratum corneum.3,4 The role of this topical treatment may be antibacterial, by inhibiting the bacterial synthesis of dihydrofolic acid, and anti-inflammatory, by blocking neutrophil myeloperoxidase and inhibiting neutrophil chemotaxis. There may also be a role for oxidation to reduce generation of oxygen free radicals.3,4 Its safety and efficacy have been demonstrated over a 12-month period in various randomized controlled studies.3-5

Women aged at least 18 years with mild to moderate inflammatory acne of the face were included in the study. The patients were willing to refrain from exposing their skin to a sun bed or sun lamp and agreed not to schedule any sun destination vacations and refrain from using other topical agents and/or skin care products related to acne treatment. Patients had skin types I to VI. Patients who used oral progestational agents for at least 90 days prior to their baseline visit could continue on their birth control pills so long as their use was not discontinued or altered during the study

Materials and Methods

Patient population

From the Department of Medicine, University of Toronto School of Medicine, Toronto, ON, and the Lynde Centre for Dermatology, Canada;1 and Andriessen Consultants, Malden & UMC St Radboud, Nijmegen, The Netherlands, Zwenkgras 25, 6581RK Malden, The Netherlands2 Address for Correspondence: Anneke Andriessen, PhD, Zwenkgras 25, 6581 RK, Malden, The Netherlands. • E-mail: anneke.a@tiscali.nl

SKINmed. 2014;12:15–21

January/February 2014

ORIGINAL CONTRIBUTION

period. Exclusions included patients with facial skin conditions other than mild to moderate acne; severe nodular acne; or bacterial, viral, or fungal infections requiring antimicrobial intervention. Pregnant or nursing women, those with a history of poor compliance with medical treatment, or those with an allergy to any of the ingredients of the evaluation products were also excluded. Study treatment The treatment regimen consisted of twice-daily cleansing and application of the dapsone 5% gel in a thin layer to the affected area after washing with a standard noncomedogenic soap-free cleanser (Ceramide cleanser, Valeant) twice daily. The study medication was dispensed at baseline and at week 6. The use of cosmetics was permitted, but patients were instructed not to change their use of cosmetic products during the study period. Outcome measures The primary objective of the cohort study was the clinical efficacy of dapsone 5% gel after twice-daily treatment comparing baseline (day 0), week 6, and week 12 (end) scores per patient and per group. For this purpose, physician-reported facial condition using the Global Acne Assessment Scale (GAAS) and patientreported facial condition using an adapted GAAS score (7-point scale: 0=free of acne; 1=some comedones and noninflammed papules; 2=comedones and papules, some inflamed; 3=all of the above and some pustules; 4=all of the above and several pustules; 5=all of the above and many pustules; 6=all of the above and nodules; 7=all of the above and many nodules) was used. The secondary objectives were the percentage of patients who achieved treatment success at 12 weeks (physician GAAS score was 0=none or 1=minimal), patient-reported quality-of-life aspects (questionnaire: 5-point Likert scales) comparing day 0, week 6, and week 12 (end) results, ease of product use, and product features. Finally, product safety was evaluated by recording any adverse events and serious adverse events that occurred during the 12-week evaluation period (Figure 1).

The target group for the study was adult women (mean age, 31.10 years, SD±10.47) with mild to moderate inflammatory acne of the face. Over a 12-month period (April 2012–April 2013), 26 centers across Canada recruited a total of 101 women (average of 5 patients per center). Table I shows patient characteristics at baseline. A total of 93 women were included in the analysis. Eight patients discontinued the study, of which 6 were lost to follow-up and 2 withdrew consent because they experienced mild skin irritation with the study product (Figure 2). A total of 42% of patients at baseline reported that their acne limited their daily activities (5-point Likert scale: 1=strongly disagree to 5=strongly agree). The negative impact of acne on their professional and social life reported at baseline was high, with scores of 41% and 54%, respectively. The same trend was shown for scoring impact on self-image; 74% of women reported to strongly agree or to agree that their facial acne negatively influenced their self-image. The physician GAAS scores indicated that during the course of the study period, the patients’ skin started to clear up and continue to significantly improve (baseline vs week 12 physician GAAS scores (t55=8.85, P=.001) up to the end of the study (Figure 3a). At week 12, 69.4% of women showed significant (t94=4.17, P=.001) treatment success (physician GAAS score of 1 or 0) (Figure 3b). When patients were

Table I. Patient Baseline Characteristics Patient Baseline Characteristics (N=101)

Score

Sex, No. (%) Female

101 (100)

Age, y Mean±standard deviation Median/minimum/maximum

31.19±10.47 51/15/65

Baseline physician-reported skin condition Global Acne Assessment Scale [GAAS]a Mean±standard deviation GAAS, No. (%) 1 = Minimal 2 to 3 = Mild to moderate 3 = Moderate

Statistical analysis Statistical evaluation was performed independently using SPSS statistics software (IBM Corporation, Armonk, NY). Paired t test was used to analyze facial skin condition comparing baseline vs week 6 and week 12 (end) per patient and per group. Tests were carried out at the 5% significance level and a confidence interval of 95%. The assumption was that the treatment regimen would demonstrate a ≥20% improvement in physician-scored (GAAS) skin condition (7) over the 12-week treatment period, improving quality-of-life aspects as reported by the patients. SKINmed. 2014;12:15–21

Results

Baseline patient-reported skin condition Mean±standard deviation 7-point scaleb

2.53±0.62 3 (3.4) 42 (42.1) 56 (54.5) 4.03±1.61

GAAS: 0=none, 1=minimal, 2=mild, 3=moderate, 4=severe.

7-point scale: 0=free of acne; 1=some comedones and noninflammed papules; 2=comedones and papules, some inflamed; 3=all of the above and some pustules; 4=all of the above and several pustules; 5=all of the above and many pustules; 6=all of the above and nodules; 7=all of the above and many nodules.

Cohort Study on the Treatment With Dapsone 5% Gel

January/February 2014 Fig 1.

ORIGINAL CONTRIBUTION

Day 0 Screening and selection

Evaluation facial condition (GAAS) by physician

Patient-‐reported QOL; facial condition; previous treatment

Week 6 Evaluation facial condition (GAAS) by physician

Patient-‐reported facial condition

Week 12 Evaluation facial condition (GAAS) by physician

Fig 2.

Patient-‐reported QOL; facial condition; dapsone properties and use

Figure 1. Visits and assessments. Number of patients=101 (n=5 per center). GAAS indicates Global Acne Assessment Scale; QOL, quality of life.

N=101 women with mild to moderate inflammatory acne

Discontinued N =8: n=2: product related n=6: lost to follow-‐up

N=93 women with mild to moderate inflammatory acne were included in the analysis

Figure 2. Evaluation flow chart.

asked about their facial acne, they reported a similar improvement over the 12-week study period. When comparing patientscored skin condition at baseline vs week 12 (end), the improvement reported was significant (t94=3.69, P=.0001) (Figure 4). At the start of the study, the mean score for tolerance to treatment regimens previously used was 2.68 (SD±1.21) (Is your skin intolerant to skin care products: 1=never, 2=moderate, 3=severe) indicating that patients had mostly sensitive skin. SKINmed. 2014;12:15–21

When scoring patient-reported levels of discomfort and skin irritation experienced during the study period with topical dapsone 5% gel, patients reported to be significantly more comfortable and have less skin irritation (Table II). Patient-reported qualityof-life aspects improved over the 12-week study period, when their acne began to clear (Figure 5a and 5b). The dapsone 5% gel treatment was easy to use and product features such as texture and smell received good ratings (Figure 6).

Cohort Study on the Treatment With Dapsone 5% Gel

Fig 3a:

January/February 2014

ORIGINAL CONTRIBUTION Physician-‐Reported GAAS (mean) Physician-‐Reported GAAS (mean)

(a) 4 3.5 3 2.5 2 1.5 1 0.5 0

Mean GAAS Score

4 3.5 3 2.5 2 1.5 1 0.5 0

*** *

*** * **

Day 0

GAAS score 2.53

week 6

1.88

week 12

1.2

GAAS: 02=none, 2=mild, 3=moderate, 4=severe GAAS: 0=none, 1=minimal, =mild, 13=minimal, =moderate, 4=severe

Failure

Success Failure

Success

Physician-‐Reported GAAS Percentage Improvement

GAAS % of Patients

(b)

70 60 50 Fig 3b 40 30 20 10 0

Fig 3b

Day 0 0

Week 6 0

Week 12 37.6

3.4

40.9

31.8

Mild = 2

42.1

39.8

15.3

Moderate = 3

54.5

19.3

15.3

Severe = 4

Success succes

40.9

69.4

None = 0 Minimal = 1

[TYPE: “SUCCESS” IN TAcne HE LAST ROW FIRST COLUMN IS Smean PELLED INCORRECTLY. PLEASE Figure 3. Physician-reported Global Assessment Scale (GAAS): values at baseline, week F6,IX.] and week 12 (a). Physician-reported GAAS: percentage of patients who demonstrated improvement comparing baseline vs week 6 and week 12 (b). *t59=6.14, P=.001. **t85=–5.03, P=.0001. ***t55=8.85, P=.001.

* t(94) = 4,17, P = 0,001

Discussion In the present cohort study, women with mild to moderate facial acne were successfully treated with twice-daily topical dapsone 5% gel over a 12-week period. Both the physician GAAS scores and the patient facial skin condition scores demonstrated fast and statistically significant results at 6 and 12 weeks. At baseline, most women reported their skin to be intolerant to previously used products. Two patients reported mild skin irritation when using the study product. SKINmed. 2014;12:15–21

The mode of action of topical dapsone in acne treatment is not known. Possibly, as a sulfone with structural similarities to trimethoprimsulfamethoxazole and other sulfonamides, topical dapsone indirectly alters the levels and/or activity of propionibacteria.4 It is also proposed that topical dapsone in acne treatment inhibits leukocyte trafficking and their generation of inflammatory mediators.4 This may explain the rapid onset of especially inflammatory lesion reduction, which was already statistically significant at week 6.

Cohort Study on the Treatment With Dapsone 5% Gel

Fig 4

January/February 2014

ORIGINAL CONTRIBUTION Patient-‐Reported Skin Condition

Mean Score: 7-‐Point Scale

4.5 4

3 2.5 2 1.5 1 0.5 0

Fig 5a

3.5

Baseline baseline

Week week 66

Week week 12 12

4.03

3.01

2.72

Mean mean

Baseline: Patient-‐Reported Quality-‐of-‐Life Aspects TYPE: MEAN, BASELINE, WEEK 6, AND WEEK 12 SHOULD ALL BE CAPITALIZED.

Figure 4. Patient-reported facial skin condition at baseline, week 6, and week 12. 7-point scale: 0=free of acne; 1=some comedones and noninflammed papules; 2=comedones and papules, some inflamed; 3=all of the above and some pustules; 4=all of the above and several pustules; 5=all of the above and many pustules; 6=all of the above and nodules; 70.00% 7=all of the above and60.00% many nodules. *t70=4.57, P=.001. **t94=3.69, P=.0001.

Fig 5a

50.00%

40.00% 30.00% 20.00%

(a)

10.00% 70.00% 0.00% 60.00% 50.00%

Baseline: Patient-‐Reported Quality-‐of-‐Life Aspects

limit daily activities

negatively inﬂuenced professional life

40.00% 30.00%

1=strongly disagree

20.00%

2 = disagree

negatively inﬂuenced social life

3 = neutral

4 = agree

10.00% [TYPE: PLEASE INITIAL CAP ALL WORDS IN FIGURE.] 0.00% Limit Negatively Negatively limit ddaily aily negatively negatively activities influenced influenced activities inﬂuenced inﬂuenced social professional life social professional life life life

Fig 5b Strongly disagree 1=strongly disagree

Disagree 2 = disagree

Neutral 3 = neutral

Agree 4 = agree

negatively inﬂuenced self-‐ image

5 = strongly agree

Negatively negatively influenced inﬂuenced self-‐ self-image image life Strongly agree agree 5 = strongly

Week 12: Patient-‐Reported Quality-‐of-‐Life Aspects [TYPE: PLEASE INITIAL CAP ALL WORDS IN FIGURE.] (b) 70.00% 60.00% 50.00% Fig 5b 40.00% 30.00% 20.00% Week 12: Patient-‐Reported Quality-‐of-‐Life Aspects 10.00% 0.00% Youraacne Areyou yoummore You feel better about treatment Treatment has your cne iiss are ore you feel better has 70.00% uncomfortable confidentaafter youryskin improved your uncomfortable conﬁdent fter about our after skin improved your skin 60.00% productuuse useuse skin condition and product se after product product condition 50.00% and sself-image elf-‐image 40.00% 30.00% Strongly Strongly Disagree Neutral Agree strongly disagree disagree disagree neutral agree strongly agree agree 20.00% 10.00% 0.00% [TYPE: PLEASE INITIAL AP is ALL WORDS FIGURE.] your aC cne are you IN more you feel better treatment has Figure 5. Patient-reported quality-of-life aspects atconﬁdent baseline (a). Patient-reported uncomfortable after about your skin quality-of-life improved your aspects at week 12 (end) (b). product use after product use skin condition and self-‐image

SKINmed. 2014;12:15–21 strongly disagree

disagree 19 neutral

Cohort on the Treatment With Dapsone 5% Gel agree Study strongly agree

ORIGINAL CONTRIBUTION

January/February 2014

Table II. Patient-Reported Treatment Aspects (N=93) Day 0a Skin is intolerant to skin care productsb Mean±standard deviation Paired t test Baseline vs week 6 Baseline vs week 12

2.68±1.21a

Level of discomfort on VAS 10-point scalec Mean±standard deviation Paired t test Baseline vs week 6 Baseline vs week 12

4.55±1.21a

Treated area looks irritatedd Mean±standard deviation Paired t test Baseline vs week 6 Baseline vs week 12

3.39±1.05a

Week 6

Week 12

2.77 (±1.26) t94=0.03, P=97

2.04±1.85 t40=4.87, P=.001

2.20±1.06 t93=8.71, P=.001

t43=5.78, P=.001 2.16±1.95 t43=5.78, P=.001 1.96±0.91 t88=9.34, P=.001

Previous treatment. Tolerance to skin care products: 1=never; 2=moderate; 3=severe. c Level of discomfort (10-point visual analogue scale [VAS]): 0=no discomfort; 10=very uncomfortable. d Skin irritation: strongly disagree=1; disagree=2; neutral=3; agree=4; strongly agree=5. a

Two studies have demonstrated dapsone 5% gel to be effective in the treatment of mild to moderate facial acne, as shown by significantly greater success rates based on the investigator’s GAAS.3 In 2 other 12-week, randomized, double-blind studies, the safety and efficacy of dapsone 5% gel when used in combination with adapalene gel 0.1%, benzoyl peroxide gel 4%, or vehicle was evaluated.5,6 The studies showed that dapsone gel combined with any of the 3 additional treatments reduced lesion counts. Patients treated with dapsone gel combined with adapalene gel had a significantly better response in the reduction of total lesion count compared with patients who received the vehicle combination.5,6 These results indicate that the reduction of inflammatory lesions is the result of dapsone rather than the other components used.5,6

(65%) reported that the treatment had improved their self-image. The result may have had a positive impact on treatment adherence, as was demonstrated by the small number of patients who discontinued the study.9,12 Finally, the use of a noncomedogenic cleanser by all of the study participants also may have favourably affected the incidence of local signs and symptoms, leading to further improvement in acne.13,15

The present cohort study results confirmed topical dapsone 5% gel to be safe, as was also demonstrated in a 1-year follow-up study and a study looking at hematologic safety of dapsone 5% gel.7,8 Facial acne may have a negative influence on patient-reported quality of life.10,12 At baseline, 40 women (41%) reported that their facial acne had a negative impact on their professional and social lives (n=53; 54%). The same trend was shown at baseline for scoring impact on self-image; 74% of women reported to strongly agree or to agree that their facial acne negatively influenced their self-image. At the end of the study, 65 women (60%) reported to feel better about their facial skin after dapsone treatment and 70 women SKINmed. 2014;12:15–21

Limitations Previous randomized, double-blind, vehicle-controlled studies have demonstrated similar trends as those shown in our study; however, as this was a cohort study and, as such, gave descriptions of practice and did not have comparison or control groups, cause and effect relationships cannot be drawn from the present study. Conclusions Topical dapsone gel 5% as a single agent has been shown to have a rapid onset of action, is minimally irritating, and appears to be safe and effective in the treatment of mild to moderate facial acne vulgaris in adult women with sensitive skin. Disclosures and conflicts of interest Valeant Canada provided a scientific grant for conducting the study. Dr Lynde is an adviser for Valeant. He was involved in Cohort Study on the Treatment With Dapsone 5% Gel

January/February 2014

ORIGINAL CONTRIBUTION

development, coordination, and conduct of the study. Dr Andriessen was involved in the development and conduct of the study as well as in writing the presentation.

References 1 Perkins AC, Maglione J, Hillebrand GG, Miyamoto K, Kimball AB. Acne vulgaris in women: prevalence across the life span. J Womens Health (Larchmt). 2012;21:223– 230.

Members of the Canadian Dapsone 5% Gel Study Group

2 Collier CN, Harper JC, Cantrell WC, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58:56–59.

Benjamin Barankin, MD, FRCP(C), Toronto, ON

3 Draelos ZD, Carter E, Maloney JM, et al. Two randomized studies demonstrate the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris. J Am Acad Dermatol. 2007;56:439 e431–439 e410.

Mary Lou Baxter, MD, FRCP(C), Dartmouth, NS Pierre – Luc Dion, MD, FRCP(C), Lévis, QC Maha Dutil, MD, FRCP(C), Toronto, ON

4 Thiboutot DM, Willmer J, Sharata H, Halder R, Garrett S. Pharmacokinetics of dapsone gel, 5% for the treatment of acne vulgaris. Clin Pharmacokinet. 2007;46:697–712.

Karen Diane Edstrom, MD, FRCP(C), Hamilton, ON Anatoli Freiman, MD, FRCP(C), Toronto, ON

5 Tanghetti E, Dhawan S, Green L, et al. Clinical evidence for the role of a topical anti-inflammatory agent in comedonal acne: findings from a randomized study of dapsone gel 5% in combination with tazarotene cream 0.1% in patients with acne vulgaris. J Drugs Dermatol. 2011;10:783–792.

Parbeer Grewal, MD, FRCP(C), FAAD, Edmonton, AB Nhung TC Ho, MD, FRCP(C), FAAD, Toronto, ON H Chih-ho Hong, MD, FRCP(C), Surrey, BC John Kraft, MD, FRCP(C), Markham, ON

6 Fleischer AB Jr, Shalita A, Eichenfield LF, et al. Dapsone gel combination treatment study group. Dapsone gel 5% in combination with adapalene gel 0.1%, benzoyl peroxide gel 4% or moisturizer for the treatment of acne vulgaris: a 12-week, randomized, double-blind study. J Drugs Dermatol. 2010;9:33–40.

Rod Kunynetz, MD, FRCP(C), Barrie, ON Mark Lomaga. MD, PhD, Mississauga, ON Charles Lynde, MD, FRCP(C), Markham and Toronto, ON Eric Mongrain, MD, Dermatologist, Quebec City, QC

7 Lucky AW, Malony JM, Roberts J, et al. Dapsone gel 5% for the treatment of acne vulgaris: safety and efficacy of long term (1 year) treatment. J Drugs Dermatol. 2007;6:981–987.

Adam Natsheh, BSc (Pharmacology), MD, FRCP(C), Toronto, ON Simon Nigen, MD, FRCP(C), Lasalle, QC

8 Piette WW, Taylor S, Pariser D, et al. Hematologic safety of dapsone gel, 5%, for topical treatment of acne vulgaris. Arch Dermatol. 2008;144:1564–1570.

Syed Pirzada, MD, FRCP(C), St. John’s, NL Daniel A. Radin, MD, FRCP(C), Tecumseh, ON

9 Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol. 2003;49:S200–S210.

Linda Rochette, MD, FRCP(C), Quebec City, QC Michael Shaffelburg, MD, FRCP(C), Kentville, NS

10 Klassen AF, Newton JN, Mallon E. Measuring quality of life in people referred for specialist care of acne: comparing generic and disease-specific measures. J Am Acad Dermatol. 2000;43:229–233.

Natalie Shaffer, MD, CM, BCL, LLB, Montreal, QC Christopher Sladden, MBBCh FRCP(C), Corner Brook Newfoundland

11 Lee IA, Maibach HI. Pharmionics in dermatology: a review of topical medication adherence. Am J ClinDermatol. 2006;7:231–236.

Ronald Vender, MD, FRCP(C), Hamilton, ON Louis Weatherhead, BSc, MBBS, FRCP(C), Ottawa, ON

12 Tan JK, Balagurusamy M, Fung K, et al. Effect of quality of life impact and clinical severity on adherence to topical acne treatment. J Cutan Med Surg. 2009;13:204– 208.

Marni C. Wiseman, MD, FRCP(C), Winnipeg, MB Catherine Zip, MD, FRCP(C), Calgary, AB

SKINmed. 2014;12:15–21

Cohort Study on the Treatment With Dapsone 5% Gel

July 18 - 20, 2014 SulAmérica Convention Center Rio de Janeiro Brazil

www.iacdRio2014.com.br

OFFICIAL PUBLICATION

January/February 2014

Volume 12 • Issue 1

Original contribution

Laundry Detergents and Skin Irritancy— A Comprehensive Review Charles Crawford, PhD;1 Matthew J. Zirwas, MD2 Abstract Surface-active agents (surfactants) form the foundation of an effective detergent formulation. As such, surfactants are a major component of laundry detergents. Depending on multiple factors, the amount of residual detergent surfactants in clothing after washing varies but may be sufficient to elicit skin irritation in susceptible individuals and in patients with existing dermatologic disorders. The goal of this review is to examine the relationship between surfactants commonly used in laundry detergent formulations and their potential for skin irritancy. In this context, the role of surfactants in achieving broad-spectrum cleaning performance in laundry is discussed, and currently available methodologies to evaluate and measure the effect of surfactant exposure on the skin are reviewed. (SKINmed. 2014;14:23–31)

ousehold and laundry detergents are highly complex formulations composed of diverse components, including surfactants, builders, buffers, enzymes, polymers, foam control agents, brightening agents, fragrances, and dyes.1,2 Surfactants form the foundation of effective detergency through their ability to solubilize (or emulsify) dirt and soils3; however, their intrinsic surface activity contributes to skin irritation and the development of irritant or allergic contact dermatitis in susceptible individuals. They may exacerbate existing dermatologic disorders, such as atopic dermatitis.3–5 While the skin irritancy potential of surfactants in personal care products is well known and has been reviewed in the scientific literature,3,6 skin irritation caused by residual laundry detergent surfactants in clothing after washing has received considerably less attention. Challenges of Fabric Washing Within the consumer space, laundry is a surprisingly complex process.7 Numerous factors, including different textiles, stains, and soils, as well as varying water conditions, must be taken into account in the development of an effective detergent formulation.7,8 Textiles comprise a broad array of materials, ranging from naturally derived fabrics (eg, cottons, silks, linens, and wools) to synthetics (eg, polyesters and polyamides) and blends of natural

and synthetic fibers. In addition, textile construction—woven vs knit—needs to be considered in the development of a detergent formulation.7,8 An effective laundry detergent must be able to remove different stains and soils, such as outdoor stains (eg, mud, clay, and grass), food-based stains (eg, proteins, carbohydrates, fats/oils, and tannins), and body soils (eg, sebum, urine, fecal matter, and sweat residues).7,8 The quality and hardness of water contribute significantly to the laundry process. Minerals and trace metals, such as calcium and magnesium ions or iron and copper, respectively, can adversely affect detergents and may lead to buildup of precipitates on the clothes. In addition, water temperature, pH value, and the presence of chlorine can affect a detergent’s overall performance.2,7,8 Surfactants in Fabric Washing Surfactants provide the cornerstone of detergency.2,7 They are chemical compounds that exhibit both hydrophobic and hydrophilic properties.8 Driven to interfaces by their amphiphilic character, surfactant molecules act at the surfaces created between the aqueous phase (wash water) and fabric, air, and/or soil. Surfactants reduce aqueous surface tension, which facilitates the wetting of fabrics and soils.6,8 They play an essential role at

From Sun Products Corporation, Trumbull, CT;1 and the Division of Dermatology, Department of Internal Medicine, Ohio State University College of Medicine, Columbus, OH2 Address for Correspondence: Matthew J. Zirwas, MD, Assistant Professor of Dermatology, Director of Contact Dermatitis Center, 540 Officenter Place, Suite 240, Columbus, OH 43230 • Email: matt.zirwas@osumc.edu

SKINmed. 2014;12:23–31

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Hydrophilic exterior

sulfur, and/or phosphorus. Figure 1 Figure 2:

Figure 1 Figure 2:

The hydrophilic head group of anionic surfactants contains a negatively charged functional group, such as a sulfate, sulfonate, carboxylate, or phosphate. Common anionic surfactants include linear alkylbenzene sulfonates (LAS), alkyl ether sulfates (eg, sodium laureth sulfate [SLES]), alkyl sulfates (eg, sodium lauryl sulfate [SLS] and sodium dodecyl sulfate [SDS]), and methyl ester sulfonates. They are highly efficient and cost-effective and, therefore, frequently used in detergents and personal care prodsurfa ucts such as body washes and shampoos. Anionic surfactants are good for the generation of foam, and they are effective in the suspension and removal of a broad range of soils.8 They are, however, sensitive to high levels of calcium (Ca2+) and magnesium (Mg2+). These cations are characteristic of hard water, and the interaction of these positively charged ions with the surfactant’s negatively charged head group results in charge neutralization, surfa deactivating the surfactant and potentially leading to precipitation on fibers, surfaces (“soap scum”), or skin.2,8

Anionic surfactants

for use in detergents fall into 5 categories Surfactants relevant based on their physicochemical properties: anionic, cationic, monomer (A) and a surfactant micelle in water (B).Hydrophobic The amphoteric,Hydrophilic zwitterionic, and nonionic.2 This classification hydrophobic tail is typically a hydrocarbon with a length core largely describes exterior the ionic charge present at the hydrophilic head of 8 to 18 carbon atoms. The hydrophilic head group group of the molecule upon dissociation in water (Figure 2).8 typically contains heteroatoms, such as oxygen, nitrogen, Figure 1. Schematic representation of a surfactant

Hydrophobic core

Hydrophilic head group

Hydrophobic tail

Hydrophilic head group

Hydrophobic tail

interface, surfactants are responsible for the generation or elimination of foam.8 The concentration of free surfactants in detergents is based on the critical micelle concentration (CMC) of the surfactants, a concentration above which surfactant monomers aggregate together in solution to form micelles (Figure 1).8 Simplified, it is the combination of these unique physical and chemical properties that makes surfactants so useful in detergent formulations.

ORIGINAL CONTRIBUTION

Cationic surfactants

Figure 2. Surfactant classes, with examples commonly encountered in detergents.

the water-soil interface by displacing and ultimately solubilizing and removing oily and particulate soils.7 The mechanisms of soil removal are quite complex and can include soil incor poration into surfactant micelles or the creation/elimination of electrostatic interactions, for example.2,6 Lastly, at the water-air

SKINmed. 2014;12:23–31

In contrast to anionics, cationic surfactants possess a positively charged head group. Typical examples of cationic surfactants are quaternary ammonium salts, including benzalkonium chlorides and dialkyl dimethyl ammonium chlorides.6 Their interaction with negatively charged sites, common to most fabrics, makes them useful agents in fabric softeners. Cationic surfactants can be good emulsifying agents and tend not to form insoluble precipitates with hard-water cations.8 In addition, cationic surfactants often possess germicidal properties.6,8 Their interaction with anionic surfactants results in charge neutralization and general incompatibility.8 The incorporation of significant levels of both anionic and cationic surfactants in a single detergent formulation is uncommon.

Laundry Detergents and Skin Irritancy

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ORIGINAL CONTRIBUTION quamation. The SC possesses innate immune and antioxidant mechanisms to prevent or limit cutaneous infection and protect the skin from damage by exogenous, reactive oxygen species, respectively. In addition, melanin and other chemicals in the SC provide photoprotection from UV radiation.10

Amphoteric and zwitterionic surfactants Some surfactants have hydrophilic portions that contain both a positively and negatively charged functional group.8 The primary characteristic of an amphoteric surfactant is the change in charge of the polar head group as a function of conditions, predominantly pH.6 Although similar to amphoterics, zwitterionics maintain this “dual charge” independent of pH, including conditions typically encountered in wash processes.9 Commonly used surfactants in these categories include cocamidopropyl betaine (CAPB), cocoamphodiacetate, and cocoamphoacetate.6

Ionic surfactants are able to interact strongly with keratin in corneocytes, which, in turn, opens up the dense keratin structure and makes it more permeable. Furthermore, ionic surfactants interact with SC lipids and may remove them from the SC, thus creating disorder within the lipid layer.11 By this means, surfactants can affect skin barrier integrity and permeate the SC, resulting in skin dryness, which can further contribute to irritation and inflammation.3

Nonionic surfactants Nonionic surfactants do not carry an electric charge in their hydrophilic head groups.6 Examples of nonionic surfactants include alkyl polyglucosides; polyoxyethylenes; alkoxylated fatty alcohols, such as ethoxylated lauryl alcohol; and methyl ester ethoxylates.6,8 Their detergent and emulsifying properties are optimized by balancing the length of their alcohol chain (ie, the hydrophobic portion of the molecule) with the length of their ethoxylate chain (ie, the hydrophilic portion).8 Although they do not exhibit the broad detergency properties observed with many anionic surfactants, they are highly effective in the dispersion and removal of many prominent soils encountered in laundry, namely, sebum and oily soils. Because they do not carry a charge in their head group, their performance is less affected by hard water ions in solution.2 In addition, in contrast to many anionic surfactants, nonionics tend to exhibit very mild effects on the skin.6 Surfactants and Their Potential for Skin Irritation The properties that confer excellent detergency to surfactants are also the underlying root cause of their intrinsic ability to cause skin irritation. To review, the stratum corneum (SC) is the outermost layer of the epidermis. It mainly consists of corneocytes, which are primarily composed of keratin macrofibrils. Each corneocyte is surrounded by a protective, cornified cell envelope, which is composed of proteins and a covalently bound, outer lipid monolayer. Protein structures called corneodesmosomes connect adjacent corneocytes and anchor them within a layer of intercellular lamellar lipids (ceramides, fatty acids, and cholesterol). The integrity of the SC is vital to its role in providing an epidermal permeability barrier to protect the underlying tissue and in sustaining healthy skin. The SC is responsible for the regulation of transepidermal water loss (TEWL) to maintain the appropriate epidermal water content that is necessary for physiologic desSKINmed. 2014;12:23–31

The interaction of surfactants with SC protein has been studied extensively. Surfactant binding and denaturation of SC proteins lead to transient swelling and hyperhydration. Subsequent evaporation of water results in deswelling, followed by skin dryness, roughness, tightness, and even scaling.3,6 These protein interactions are exacerbated with the surfactant’s increasing charge density.3 Hence, cationic and anionic surfactants—particularly SLS and LAS—are considered to be harsher than amphoteric and nonionic surfactants3,6; however, some studies suggest that nonionic surfactants may still alter the cutaneous lipid layer through their ability to solubilize fatty acids and cholesterol, two of the main lipids of the SC.6 Clinical Assessment of Detergent Surfactants and Skin Safety Evaluating the safety of detergent formulations by assessing their potential for dermal toxicity is part of risk and safety assessment procedures prior to introducing a new product into the marketplace.12 Multiple in vitro and in vivo assays have been developed to assess the cytotoxicity and skin irritation potential of detergent ingredients, such as surfactants, by measuring skin properties, including skin color, blood flow, skin barrier function alterations, and water content of the SC.8 The following section provides a representative overview of currently available testing methods and model systems to gauge the effect of surfactants in cosmetic and common household products, including laundry detergent, on the skin. In vivo assays: direct and indicative Patch testing in human patients involves exposure of the skin to small quantities of the surfactant or detergent formulation. Various modifications of this method allow investigators to assess irritancy under conditions encountered in daily practice.6,13 Occlusive patch testing entails the application of small chambers

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ORIGINAL CONTRIBUTION

Figure 3 Mild Harsh

CIM Value

filled with diluted or undiluted surfactant onto the skin, usually on the back or forearm. In contrast, the open epicutaneous test involves the application of the surfactant on the forearm without occlusion.6 Single or repeated applications of the agents for varying lengths of time allow for the assessment of either their acute irritation potential or their cumulative irritation potential. Irritancy is assessed visually and scored based on the degree of erythema, scaling, and fissures. Although patch testing yields highly relevant results, the scoring system is subjective.4,6,14–16

CIM of Surfactants 80 70

SLES

Water

50 40 30

SDS LAS

20 10

TEWL is an objective measurement of the integrity of SC barrier 0 0.5 1 1.5 2 2.5 Surfactant Concentration function.6 Exposure of the skin to irritant-containing detergent (%) solutions has been shown to result in constant and reproducible increases in TEWL, as measured by evaporimeter, allowing Figure Figure 43. Colorimetric index of mildness (CIM) value of for the ranking of agent irritancy potential. TEWL is capable surfactants: Corneosurfametry was used to determine of detecting early changes in SC integrity and, as such, is more the CIM value for a nonionic surfactant (alcohol ethoxylate) (red circle) surfactants Surfactant source Surfactant-‐induced irritancysodium Exacerbation of ski sensitive than visible scoring.17,18 and the anionicskin laureth sulfate (green triangle), sodium dodecyl sulfate irritancy (blue square), and linear alkylbenzene sulfonate (black • Household cleaners • Binding to SC proteins Mechanical factor In vitro assays: rapid and sensitive diamond) at increasing surfactant concentrations in•dis• Laundry detergent

•

Denaturing of SC proteins

•

Climatic condition

tilled water. The CIM value for distilled water is indicated

care • Personal • Oxidative stress • Delipidation of SC The need to replace animal and human testing models to study (dashed line). • Permeation of SC products • Individual suscept the irritation and toxicity potential of topically applied substances has resulted in the development of suitable in vitro as- Corneocytes SC says. Reconstructed human epidermal models, such as EPISKIN Lipid layer (L’Oreal, Paris, France) and EpiDerm (MatTek Corporation, Ashland, MA), are examples of validated and accepted in vitro late adhesive against the surface of the skin. After several sec Increasing TEWL Cytokine release Stimulation of i model systems to replace the Draize test, which involves repeated onds, the slide is removed, taking with it a layer of corneocytes. application of substances on the skin or in the eye of an immo- Next, the obtained CSSSs are exposed to surfactant for 2 hours Deterioration oblue f skin barrier before being stained with basic fuchsin-toluidine dye solu- integrity bilized rabbit.19-21 tion. The more the corneocytes have been damaged, the more Alternatively, the skin’s electrical impedance is used as a direct the dye is able to penetrate, and the greater is the intensity of the measure of its permeability. A recent study measured skin im- subsequent color reaction. Measurement of the color intensity pedance in vitro on porcine skin using vertical Franz diffusion allows for the determination of the colorimetric index of mildcells. The SC of porcine skin, which is very similar to human ness (CIM).23,24 The CIM of water is 68±4, whereas surfactants SC, was exposed to SDS and SLES at different concentrations, exhibit lower CIM values.23 Surfactants with CIM values over 50 temperatures, and pH levels for varying lengths of time. Skin im- are regarded as mild, whereas surfactants with CIM values below pedance was measured in phosphate-buffered saline before and 30 are considered harsh (Figure 3).24 The prediction of skin irafter surfactant exposure. The ratio of skin impedances after and ritancy potential of surfactants by CSM correlates well with in before surfactant exposure was calculated and reported as relative vivo testing results.23,24 normalized impedance. The study results demonstrated the corIn contrast to CSM, SQM is the colorimetric evaluation of correlation of decreased skin impedance with progressive skin barneocytes collected after skin exposure to a surfactant. Followrier damage.22 ing controlled exposure to the surfactant, an adhesive disc (DCorneosurfametry (CSM) and squamometry (SQM) are also Squame; CuDerm Corporation, Dallas, TX) is applied to the well-accepted, routinely used methods to examine the effects of skin under controlled pressure to harvest a superficial layer of corneocytes. The strippings from surfactant-exposed sites are detergent surfactants on the SC in vitro.23-25 stained and assessed colorimetrically, similar to CSM, and the CSM uses cyanoacrylate skin surface strippings (CSSSs). In brief, CIM is determined. The sensitivity of SQM as a tool to assess a thin layer of healthy SC is harvested from the volar forearm by surfactant mildness under realistic application conditions and pressing a glass slide with a drop of rapidly bonding cyanoacry- reduced exposure time has been demonstrated.24,25

Laundry Detergents and Skin Irritancy

SKINmed. 2014;12:23–31

LAS 0.5

1.5

Surfactant Concentration (%)

2.5

January/February 2014

ORIGINAL CONTRIBUTION

Figure 4

• Binding to SC proteins Denaturing of SC proteins • Delipidation of SC • Permeation of SC

Lipid layer

Increasing TEWL

• Mechanical factors Climatic conditions • Oxidative stress • Individual susceptibility

Cytokine release

Skin barrier dysfunction

•

Corneocytes

Exacerbation of skin irritancy

• Household cleaners • Laundry detergent care • Personal products

Surfactant-‐induced skin irritancy

Surfactant source

• Development of ICD • Worsening of existing dermatologic disorders

20 10 Harsh

Stimulation of inflammatory cascade/oxidative stress response

Deterioration of skin barrier integrity

Figure 4. Schematic for surfactant-induced skin barrier dysfunction. Abbreviations: ICD, irritant contact dermatitis; SC, stratum corneum; TEWL, transepidermal water loss.

Factors that Contribute to the Skin Irritancy Potential of Surfactants

The skin’s susceptibility to irritancy

Irritant contact dermatitis is defined as an inflammatory response of the skin to an exogenous agent without requirement of prior sensitization.5 Surfactants have an innate ability to irritate the skin and cause irritant contact dermatitis.4,6 While the intrinsic properties of the surfactant play an important role, additional specific individual and environment-related variables that affect the skin irritancy potential of surfactants have been identified (Figure 4).5,26,27 The surfactant’s role in skin irritancy The effects of surfactants on the skin have been studied extensively in vitro and in vivo.3,4,6,8,28–30 Surfactants contribute to clinical and subclinical skin conditions by damaging skin barrier function. This, in turn, activates an inflammatory cascade and the oxidative stress response, perceived by patients as redness, roughness, itching, and irritation of the skin.31 Surfactants compromise the integrity of the SC by alteration and/or removal of SC proteins and lipids, with subsequent SC permeation.4–6,8 Cytotoxicity in the form of cellular lysis occurs once skin barrier damage becomes irreparable.6 Depending on their physicochemical properties, surfactants elicit varying levels of irritant and cytotoxic skin reactions.4,6 The ranking order with respect to irritancy potential is as follows: anionic ≈ cationic > amphoteric > nonionic. In contrast, cytotoxicity is ranked as follows: cationic = amphoteric > anionic > nonionic.6 SKINmed. 2014;12:23–31

Various exogenous and endogenous factors can influence the skin’s response to irritants. Exogenous factors relate not only to the type of chemical but also to mechanical, thermal, and climatic influences, as well as the amount of exposure and the exposure site itself.27 The skin’s response to SLS in 10 body regions has shown that the thigh exhibited the highest sensitivity, whereas the palm had the lowest.32 Mechanical factors take into account the roughness of fabrics, such as bed sheets, which have been shown to contribute to facial dermatitis in newborns.33 A study using a hand/forearm immersion test evaluated the irritancy potential of detergent solutions under normal user conditions at 37°C and 40°C. Results demonstrated a stronger response of the skin to detergent solutions, as measured by TEWL assessment, at the higher temperature.34 In addition, climatic factors, such as cold windy climates, can contribute to drying of the skin caused by the reduced capacity of the SC to retain water at lower temperatures.27 While exogenous factors play an important role in affecting skin irritancy, examining endogenous factors may help to explain the differences in the individual’s skin susceptibility to irritants. Using SLS as the model irritant, one group of investigators examined the SC penetration rate of SLS in healthy volunteers in relation to skin water evaporation and inflammation. The skin was evaluated by SQM, TEWL, and manifestation of erythema. The study results showed that the penetration rate of SLS

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ORIGINAL CONTRIBUTION

depended on SC thickness, which determined the variation in barrier impairment and inflammation.35 Another study investigated the effects on TEWL of repeated exposure of the skin of healthy volunteers to a mild detergent (low molar solution of SLS). TEWL was determined before exposure and on the fifth day of exposure. The findings demonstrated that the degree of barrier damage was strongly related to barrier function prior to irritant exposure. Individuals with high pre-exposure TEWL experienced a higher SLS penetration rate and subsequent TEWL at day 5.26

In contrast, a quenched response is one in which the effect is reduced compared with the sum of the expected responses. For the purpose of this review, the focus will be on quenching, or reducing, the skin irritancy potential of detergents by mixing surfactants. Mixed surfactant systems and skin irritancy One study used patch testing with visual scoring and TEWL measurements to assess the skin irritancy potential of surfactant mixtures containing different ratios of 2 anionic surfactants, SLS and sodium lauroyl glutamate (SLG). Described as a milder anionic surfactant, SLG is derived from L-glutamic acid and natural fatty acids. Healthy volunteers were treated with 0.25% to 1% SLS solutions, 1% SLG solution, and 1% surfactant mixture solutions combining SLG and SLS in ratios of 75/25, 50/50, and 25/75. Baseline TEWL was measured before patches were applied for 24 hours. After patch removal, the test sites were assessed visually and by TEWL for 4 consecutive days. Visual scores and TEWL readings were lower for the 1% surfactant mixture solution than for the 1% SLS solution. An increase of SLG concentration in the surfactant mixture further decreased the visual scores and TEWL values. The findings of this study confirm that SLG is a milder surfactant than SLS and that mixing SLG with harsher anionic surfactants, such as SLS, may help to reduce, albeit not quench, the skin irritation potential of the mixture.41

Understanding the role of cytokines in skin irritation may be useful for the identification of factors that determine the individual’s skin irritancy potential in response to detergent surfactants.27,36 In addition to impairing SC integrity, SLS directly affects keratinocytes. In response, keratinocytes release interleukin (IL) 1α, which triggers an inflammatory cascade, leading to the production of other pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8, and tumor necrosis factor α (TNF-α). Of interest, keratinocytes also produce anti-inflammatory cytokines, such as IL-1 receptor agonist (IL-1RA) and IL-10, to block this cascade.36,37 The effects of a single 24-hour 1% SLS irritation test and a repeated 3-week 0.1% SLS irritation test with respect to changes in SC cytokine levels have been investigated. Skin reaction was evaluated by TEWL, SQM, and assessment of cytokines (IL1α, IL-1RA, IL-2, IL-6, IL-8, IL-10, and TNF-α) at exposed and unexposed sites. Although higher baseline IL-1RA and IL-8 levels are likely indicators of higher skin irritability after single exposure to SLS, considerable interindividual variation was observed with respect to skin barrier recovery after repeated exposure.36 The adaptation of the skin to repeated exogenous irritative insults is called the hardening phenomenon. It describes the development of hyporeactivity to the irritant and can differ among individuals.38 Skin Irritancy Potential of Surfactant Mixtures The skin irritancy potential of surfactants is commonly assessed after exposure to a single surfactant39; however, detergents typically consist of a blend of ingredients that may include multiple surfactants.40 This raises questions about how such mixtures affect the skin irritancy potential of the detergent and/or the detergent’s cleaning capabilities. In theory, the effect of surfactant mixtures on the skin can be categorized as additive, synergistic, or quenched. An additive response equals the sum of the expected responses from each irritant. A synergistic response refers to a response that is greater than the sum of the expected responses. SKINmed. 2014;12:23–31

Another group has explored reducing the skin irritancy potential of 2 surfactants. Betaine, a natural product derived from the sugar beet, was added to SLS and CAPB, a zwitterionic surfactant commonly used in personal care products and surface cleaners. The skin irritancy potential of SLS with betaine and CAPB with betaine was assessed after patch testing on healthy patients for 24 hours and compared with that of SLS, CAPB, and betaine alone, as well as with distilled water and an unoccluded control site. In addition to visual assessment and histology of the skin, TEWL and electrical impedance of the skin were measured before and 24 hours after exposure. Although CAPB was found to be less irritating than SLS in general, the addition of betaine reduced the irritancy potential of both SLS and CAPB.42 In a 21-day cumulative irritation patch testing in healthy human volunteers, the responses to SLS alone and in combination with increasing doses of (C12-C14) alkyl, 7-ethoxy sulfate (AEOS7EO), an anionic cosurfactant have been explored. The irritation potential of the tested surfactant mixtures was evaluated by assessing erythema manifestation. The results demonstrated a significant reduction in erythema upon addition of increas-

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ORIGINAL CONTRIBUTION

Table. Anionic-to-Nonionic Surfactant Ratio in Commercially Available Laundry Detergent Formulationsa Commercially Available Laundry Detergents

Surfactant content as ratio anionic:nonionic

76:24

60:40

96:4

D 88:12

60:40

74:26

96:4

98:2

70:30

84:16

The content of the surfactants was determined experimentally using liquid chromatography mass spectrometry.

ing doses of AEOS-7EO to SLS, despite higher surfactant concentration overall. In an attempt to explain their findings, the authors examined the surfactants’ monomer levels in the tested solutions. The investigators found that the observed reduction of erythema correlated with a decrease in SLS monomer concentration caused by increased micellization in the presence of AEOS-7EO.43 Similarly, the acute skin irritation potential of 20% SDS alone or in combination with either N,N dimethyl-n-dodecyl amido betaine (DDAB), a zwitterionic surfactant, or alkyl polyglucoside (APG), a nonionic surfactant, in a 4-hour patch test has been assessed. While 20% DDAB alone demonstrated an acute skin irritation potential similar to that of 20% SDS, mixtures of the 2 surfactants at resulting active levels of 20% or 40% exhibited significantly lower irritation potential. In contrast, the nonionic surfactant APG elicited only a minor skin response on its own. The addition of APG to SDS at resulting active levels of 20% or 40% resulted in a significant reduction of skin irritation potential compared with SDS alone. Assessment of CMC values showed that mixtures of SDS and DDAB have lower CMCs than do the individual surfactants alone. Addition of APG to SDS lowered the CMC compared with SDS alone but did not achieve the low CMC observed with APG alone. The findings of these studies suggest that mixed surfactant systems can lower the skin irritancy potential of anionic surfactants by lowering the CMC, which results in a decrease of skin-reactive surfactant monomers and a possible decrease in affinity of the individual surfactants to skin protein.40

residual laundry detergent in cotton underwear washed with an anionic detergent and rinsed in cold water. Results showed that 100 g of the cotton fabric retained 125 mg of the laundry detergent.44 Similarly, another group washed cotton underwear in cold tap water (10°C) with a commonly used anionic washing detergent and then rinsed the clothes in cold tap water. They observed that a considerable amount of the detergent remained in the fabric, based on the observation that an additional rinse in hot water (42°C) turned the wash water whitely turbid.45 The amount of residual laundry detergent in clothing after washing depends on a multitude of factors, including the wash water temperature, number of rinses, machine configuration, fabric density, and the added amount of laundry detergent.12,45 As a rule, the fraction of detergent deposited on fabric is 2.5% based on a water consumption of 60 L during the wash and an intermediate spinning cycle between the first and second rinse.12 Being the major components of laundry detergents, surfactants are the focus of this review. Surfactant compositions vary among different laundry detergents (Table; C. Crawford, unpublished data, 2013) and are present at concentrations of 1% to 24%.1 It has been shown that residual surfactants on fabrics after washing can prompt skin irritancy.

The Skin’s Response to Residual Detergent Surfactants in Clothing Laundry detergent has the potential to irritate the skin during hand washing of laundry, which allows for direct contact with the skin; however, the skin can indirectly come in contact with laundry detergent from wearing clothes harboring detergent residue.12 A Japanese study used high-performance liquid chromatography to determine the concentration of alcohol-extracted SKINmed. 2014;12:23–31

In an open trial to investigate the effect of residual washing detergent in cotton clothes on dry skin, 148 Japanese patients with atopic dermatitis were studied. Even though dry skin during the winter months is a common phenomenon, the investigators observed that in atopic patients the dryness of the skin during wintertime was more prominent on the trunk, an area typically covered by clothing. All patients in the study were wearing cotton underwear, which had been washed with detergent containing anionic surfactants and additives, such as brighteners and enzymes, before being rinsed in cold tap water. For 2 weeks, patients were asked to wash their underwear with a nonionic, additive-reduced detergent instead. Photographs of patients’ trunks, taken before and after the trial, were used to assess and grade the degree of dry skin after switching to the nonionic launLaundry Detergents and Skin Irritancy

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dry detergent. Seventy-six percent of patients who had dry skin on their trunk at the beginning of the trial showed marked or moderate improvement of dry skin after the 2-week period. The results suggest that residual laundry detergent in clothing after washing has skin irritation potential and that nonionic surfactants in additive-reduced laundry detergents may be beneficial for individuals with sensitive skin.45 Conclusions Blending nonionic surfactants with anionic surfactants has been shown to result in optimized behavior that can improve cleaning performance, along with reducing the skin irritancy potential of the anionic surfactant.40,46 The surfactant composition in laundry detergents can offer broad-spectrum detergency while providing a mild character for sensitive skin. This represents an important benefit for individuals with existing dermatologic disorders or an increased susceptibility for skin irritancy. References 1 Belsito DV, Fransway AF, Fowler JF Jr, et al. Allergic contact dermatitis to detergents: a multicenter study to assess prevalence. J Am Acad Dermatol. 2002;46:200–206. 2 Zoller U, ed. Handbook of Detergents. Part E: Applications. Vol 141. Surfactant Science Series. Boca Raton, FL: CRC Press; 2009. 3 Ananthapadmanabhan KP, Moore DJ, Subramanyan K, Misra M, Meyer F. Cleansing without compromise: the impact of cleansers on the skin barrier and the technology of mild cleansing. Dermatol Ther. 2004;17(suppl 1):16–25. 4 Effendy I, Maibach HI. Surfactants and experimental irritant contact dermatitis. Contact Dermatitis. 1995;33:217-225. 5 Fluhr JW, Darlenski R, Angelova-Fischer I, Tsankov N, Basketter D. Skin irritation and sensitization: mechanisms and new approaches for risk assessment. 1. Skin irritation. Skin Pharmacol Physiol. 2008;21:124–135.

11 Som I, Bhatia K, Yasir M. Status of surfactants as penetration enhancers in transdermal drug delivery. J Pharm Bioallied Sci. 2012;4:2–9. 12 Kwon S, Holland D, Kern P. Skin safety evaluation of laundry detergent products. J Toxicol Environ Health A. 2009;72:1369–1379. 13 Tupker RA, Bunte EE, Fidler V, Wiechers JW, Coenraads PJ. Irritancy ranking of anionic detergents using onetime occlusive, repeated occlusive and repeated open tests. Contact Dermatitis. 1999;40:316–322. 14 Bowman JP, Berger RS, Mills OH, Kligman AM, Stoudemayer T. The 21-day human cumulative irritation test can be reduced to 14 days without loss of sensitivity. J Cosmet Sci. 2003;54:443–449. 15 Robinson MK, Kruszewski FH, Al-Atrash J, et al. Comparative assessment of the acute skin irritation potential of detergent formulations using a novel human 4-h patch test method. Food Chem Toxicol. 2005;43:1703–1712. 16 Sato A, Obata K, Ikeda Y, et al. Evaluation of human skin irritation by carboxylic acids, alcohols, esters and aldehydes, with nitrocellulose-replica method and closed patch testing. Contact Dermatitis. 1996;34:12–16. 17 Pinnagoda J, Tupker RA, Smit JA, Coenraads PJ, Nater JP. The intra- and inter-individual variability and reliability of transepidermal water loss measurements. Contact Dermatitis. 1989;21:255–259. 18 Gabard B, Chatelain E, Bieli E, Haas S. Surfactant irritation: in vitro corneosurfametry and in vivo bioengineering. Skin Res Technol. 2001;7:49–55. 19 Spielmann H, Hoffmann S, Liebsch M, et al. The ECVAM international validation study on in vitro tests for acute skin irritation: report on the validity of the EPISKIN and EpiDerm assays and on the Skin Integrity Function Test. Altern Lab Anim. 2007;35:559–601. 20 Kandárová H, Hayden P, Klausner M, et al. In vitro skin irritation testing: improving the sensitivity of the EpiDerm skin irritation test protocol. Altern Lab Anim. 2009;37:671–689. 21 Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther. 1944;82:377–390.

6 Corazza M, Lauriola MM, Zappaterra M, Bianchi A, Virgili A. Surfactants, skin cleansing protagonists. J Eur Acad Dermatol Venereol. 2010;24:1–6.

22 Lu G, Moore DJ. Study of surfactant-skin interactions by skin impedance measurements. Int J Cosmet Sci. 2012;34:74–80.

7 Miller CA, Raney KH. Solubilization-emulsification mechanisms of detergency. Colloids Surfaces A: Physicochem Eng Aspects. 1993;74:169–215. 8 Broze G, ed. Handbook of Detergents. Part A: Properties. Vol 82. Surfactant Science Series. Boca Raton, FL: CRC Press; 1999.

23 Piérard GE, Goffin V, Hermanns-Lê T, Arrese JE, PiérardFranchimont C. Surfactant-induced dermatitis: comparison of corneosurfametry with predictive testing on human and reconstructed skin. J Am Acad Dermatol. 1995;33:462–469.

9 Zoller U, ed. Handbook of Detergents. Part B: Environmental Impact. Vol 121. Surfactant Science Series. Boca Raton, FL: CRC Press; 2004.

24 Piérard GE, Goffin V, Piérard-Franchimont C. Squamometry and corneosurfametry for rating interactions of cleansing products with stratum corneum. J Soc Cosmet Chem. 1994;45:269–277.

10 Del Rosso JQ, Levin J. The clinical relevance of maintaining the functional integrity of the stratum corneum in both healthy and disease-affected skin. J Clin Aesthet Dermatol. 2011;4:22–42.

25 Paye M, Cartiaux Y. Squamometry: a tool to move from exaggerated to more and more realistic application conditions for comparing the skin compatibility of surfactant-based products. Int J Cosmet Sci. 1999;21:59–68.

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26 Tupker RA, Coenraads PJ, Pinnagoda J, Nater JP. Baseline transepidermal water loss (TEWL) as a prediction of susceptibility to sodium lauryl sulphate. Contact Dermatitis. 1989;20:265–269. 27 Frosch PJ, John SM. Clinical aspects of irritant contact dermatitis. In: Frosch PJ, Menne T, Lepoittevin JP, eds. Contact Dermatitis. 4th ed. Berlin: Springer; 2006:255– 294. 28 Van Scott EJ, Lyon JB. A chemical measure of the effect of soaps and detergents on the skin. J Invest Dermatol. 1953;21:199–203. 29 Blank IH, Gould E. Penetration of anionic surfactants into skin. II. Study of mechanisms which impede the penetration of synthetic anionic surfactants into skin. J Invest Dermatol. 1961;37:311–315. 30 Goffin V, Paye M, Piérard GE. Comparison of in vitro predictive tests for irritation induced by anionic surfactants. Contact Dermatitis. 1995;33:38–41. 31 Walters RM, Mao G, Gunn ET, Hornby S. Cleansing formulations that respect skin barrier integrity. Dermatol Res Pract. 2012;2012:495917. doi:10.1155/2012/495917. 32 Cua AB, Wilhelm K-P, Maibach HI. Cutaneous sodium lauryl sulphate irritation potential: age and regional variability. Br J Dermatol. 1990;123:607–613. 33 Dahlquist I, Fregert S. Skin irritation in newborns. Contact Dermatitis. 1979;5:336–337. 34 Clarys P, Manou I, Barel AO. Influence of temperature on irritation in the hand/forearm immersion test. Contact Dermatitis. 1997;36:240–243. 35 De Jongh CM, Jakasa I, Verberk MM, Kezic S. Variation in barrier impairment and inflammation of human skin as determined by sodium lauryl sulphate penetration rate. Br J Dermatol. 2006;154:651–657. 36 De Jongh CM, Verberk MM, Withagen CET, et al. Stratum corneum cytokines and skin irritation response to sodium lauryl sulfate. Contact Dermatitis. 2006;54:325–333. 37 Steinhoff M, Luger TA. The skin cytokine network. In: Bos JD, ed. Skin Immune System: Cutaneous Immunology

and Clinical Immunodermatology. 3rd ed. Boca Raton, FL: CRC Press; 2004:349–372. 38 Heinemann C, Paschold C, Fluhr J, et al. Induction of a hardening phenomenon by repeated application of SLS: analysis of lipid changes in the stratum corneum. Acta Derm Venereol. 2005;85:290–295. 39 Kartono F, Maibach HI. Irritants in combination with a synergistic or additive effect on the skin response: an overview of tandem irritation studies. Contact Dermatitis. 2006;54:303–312. 40 Hall-Manning TJ, Holland GH, Rennie G, et al. Skin irritation potential of mixed surfactant systems. Food Chem Toxicol. 1998;36:233–238. 41 Lee CH, Kawasaki Y, Maibach HI. Effect of surfactant mixtures on irritant contact dermatitis potential in man: sodium lauroyl glutamate and sodium lauryl sulphate. Contact Dermatitis. 1994;30:205–209. 42 Nicander I, Rantanen I, Rozell BL, Soderling E, Ollmar S. The ability of betaine to reduce the irritating effects of detergents assessed visually, histologically and by bioengineering methods. Skin Res Technol. 2003;9:50–58. 43 Rhein LD, Simion FA, Hill RL, et al. Human cutaneous response to a mixed surfactant system: role of solution phenomena in controlling surfactant irritation. Dermatologica. 1990;180:18–23. 44 Torii K, Nakamura Y. A New Washing Detergent for Irritable Skin [in Japanese]. Osaka, Japan: Sunstar Inc; 1998. Cited by: Kiriyama T, Sugiura H, Uehara M. Residual washing detergent in cotton clothes: a factor of winter deterioration of dry skin in atopic dermatitis. J Dermatol. 2003;30:708–712. 45 Kiriyama T, Sugiura H, Uehara M. Residual washing detergent in cotton clothes: a factor of winter deterioration of dry skin in atopic dermatitis. J Dermatol. 2003;30:708–712. 46 Jadidi N, Adib B, Malihi FB. Synergism and performance optimization in liquid detergents containing binary mixtures of anionic–nonionic, and anionic–cationic surfactants. J Surfact Deterg. 2013;16:115–121.

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Edward L. Keyes Resident Contest for Outstanding Case Reports To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 10th World Congress of the International Academy of Cosmetic Dermatology in Rio de Janeiro, Brazil, July 18-20, 2014. We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The author whose abstract receives the highest score during the review process will be awarded a scholarship by the IACD to present the full paper at the 10th World Congress of the International Academy of Cosmetic Dermatology in Rio de Janeiro, Brazil, July 18-20, 2014. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend. Abstracts should be submitted via email to vrosic@medicine.bsd.uchicago. edu before noon, CDT, March 15, 2014 via e-mail and should be no longer than 2,500 characters including spacing. Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thought-out, and complete presentation. The winner(s) will publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. All applicants will receive e-mail notice of the Resident Case Report Review Committeeâ&#x20AC;&#x2122;s decision by May 1, 2014. Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Associate Professor Ambulatory Practice Medical Director University of Chicago Pritzker School of Medicine Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu

Official publication of IACD

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Basal Cell Carcinoma Aditya K. Gupta, MD, PhD, FRCP(C);1,2 Deanne Daigle, MSc;2 George Martin, MD3 Abstract Basal cell carcinoma (BCC) is a relatively common form of cancer with a favorable prognosis when treated early. Although most BCCs are easily treated by surgical methods, these lesions occasionally progress to an advanced state that is no longer conducive to surgery or radiation therapy. Even more rarely, the lesions spread to distant sites. Until recently, treatment for locally advanced and metastatic BCC were restricted to chemotherapy and radiation; however, the effectiveness of traditional chemotherapeutic methods in treating locally advanced or metastatic BCC is limited at best. Recent discoveries in the fields of molecular biology have found important pathways implicated in the pathogenesis of BCC. Among these are the epidermal growth factor receptor and hedgehog pathways, which are now being targeted by new biologic therapies. Despite a paucity of phase II and III trial data, preliminary evidence demonstrating the disease-stabilizing ability of biologic therapies in locally advanced and metastatic BCC appears promising. (SKINmed. 2014;12:33–38)

asal cell carcinoma (BCC) is the most common cancer, comprising approximately 80% of nonmelanoma skin cancers worldwide1 and affecting roughly 1 million Americans every year.2 As its name implies, BCC is a slow-growing epithelial tumor arising from the basal layers of the epidermis and hair follicles.3 The disease usually presents as one or several small tumors with central depressions. Tumors may be classified histopathologically as nodular, superficial, morpheaform, infiltrating, metatypic, or fibroepithelioma of Pinkus.4 These histopathologic subtypes have been associated with different results and prognoses. BCC rarely metastasizes but has the potential for local invasion and destruction.5

tor in the disease. More cases of BCC have been reported in the southern compared with the northern areas of the United States.8 BCC is also more common among Caucasians, with much lower rates observed among individuals with darker skin pigmentation.13 Individuals with fair skin, red or blonde hair, and light-colored eyes have a higher likelihood for developing BCC.14 The rates of BCC are also higher among persons who had freckling or frequent/severe sunburns as children.15,16 A family history of skin cancer is positively associated with an increased risk for developing the disease.17 The incidence of BCC has been shown to be 10 times greater among transplant recipients compared with the general population, making these patients especially susceptible to the disease.18

Prevalence and Risk Factors

Conventional Management of Nonmetastatic BCC

The yearly incidence rate of BCC in the United States, because registries are not maintained for nonmelanoma skin cancer, is estimated to range from 900,000 to 1,200,000 cases per year with a trend toward an increasing number of cases every year.6 The overall lifetime risk of BCC is approximately 30%,7 and there is a much greater incidence rate among men than women.8,9 BCC is also more common among the elderly, with more than 90% of BCCs detected in patients 60 years and older.10–12 The age-related increase in the incidence of BCC is likely the result of cumulative UV exposure, which is the primary risk factor for the disease.6 The geographic distribution of BCC supports the role of sunlight as a causative fac-

Treatments for the management of BCC include both surgical and nonsurgical options. Surgical methods include surgical excision, Mohs micrographic surgery, and cryosurgery, as well as curettage and electrodessication. Nonsurgical alternatives, such as topical chemotherapy and immune modulators, photodynamic therapy, radiation, and systemic chemotherapy are also indicated, but surgical excision is currently the standard of care for BCC management.19 Surgical excision is successful for the majority of patients and also yields better cosmetic outcomes when compared with most other treatment modalities20; however, there is a small but clinically rel-

See also page 12. From the Department of Medicine, University of Toronto School of Medicine, Toronto, Canada;1 Mediprobe Research Inc, London, Ontario, Canada;2 and the Dermatology and Laser Center of Maui, Kihei, Hawaii3 Address for Correspondence: Aditya K. Gupta, MD, PhD, FRCP(C), FAAD, 645 Windermere Road, London, Ontario, Canada, N5X 2P1 • E-mail: agupta@execulink.com

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evant subset of patients for whom surgery is ineffective or local invasion renders resection unfeasible (locally advanced BCC). In these cases, the lesion may become locally invasive or the cancer may metastasize to the regional lymph nodes, lungs, bone, skin, and liver.21 Conventional Management of Metastatic BCC

ture on the use of these agents for locally advanced BCC or MBCC. There are several classes of chemotherapeutic drugs commonly used in cancer treatment. These include platinum-based agents, taxanes, and anthracyclines, with platinum-based regimens demonstrating the greatest efficacy in the treatment of locally advanced BCC and MBCC.35 Despite the relative efficacy of platinum-based treatment, BCC tumors are generally regarded as being insensitive to chemotherapy, as these methods have high rates of treatment failure, morbidity, and mortality.36,37 Refractory cases often arise in the elderly, a patient population with multiple comorbidities and in whom platinumbased regimens are not well-tolerated. Radiation and systemic chemotherapy with nontargeted standard regimens have shown little clinical efficacy in unresectable BCC.38

Metastatic BCC (MBCC) is defined as the spreading of primary BCC to distant sites via lymphatic or hematological pathways.22 The diagnostic criteria for MBCC specify that the primary lesion should arise in the skin and not in the mucous membrane, the metastasis should be distant and not a consequence of a direct extension, and the primary lesion and the metastasis should have a similar histologic pattern.23 MBCC metastasizes from primary lesions in the head and neck region in approximately 85% of cases, with primary tumors from the face alone accounting for approximately two thirds of MBCCs.24 The median age of onset for a primary tumor is 45 years, and the median age at the time of metastasis is 59 years, while the median interval between appearance of the primary tumor and metastasis is 9 years.25 MBCC is more frequently reported among middle-aged Caucasian men.26 The development of metastatic potential in BCC is multifactorial in etiology. The size of the lesion has been found to be an important risk factor for metastasis.27 For example, the incidence of metastasis is approximately 2% for tumors >3 centimeters in diameter; the incidence increases to 25% for tumors >5 centimeters in diameter and up to 50% for tumors >10 centimeters in diameter.27 Age at presentation, depth of invasion, tumor site, extension of the tumor into adjacent anatomical structures, presence of ulceration, number of lesions, incomplete surgical resection, and recurrence all contribute to the likelihood of metastases.28,29 Specific histologic subtypes (morpheaform, metatypical, and micronodular) and histologic markers of aggression (perineural and/or perivascular invasion) also confer an increased risk of metastases.19,30 Immunosuppression has been shown to heighten the metastasis risk, in that it may contribute to an increased risk of tumor recurrence.31

Cell Signaling and the Use of Biologics in the Management of BCC During the past 2 decades, advancements in cancer genetics have elucidated molecular pathways underlying BCC tumor proliferation. These advancements have resulted in the development of targeted therapies for locally advanced BCC or MBCC. Among these are cetuximab, an antiepidermal growth factor receptor (EGFR) monoclonal antibody, and vismodegib, a hedgehog signaling pathway inhibitor.

Treatment options for MBCC include surgery, radiation, and systemic chemotherapy; yet, these treatments are rarely curative. For patients with resectable MBCC, prolonged survival is possible32; however, the prognosis of unresectable MBCC is generally poor, with a median survival time of less than 1 year.33 Palliative surgery may be recommended in some cases to reduce pain and discomfort.34 Until recently, the treatment of unresectable MBCC has been based solely on traditional methods of systemic chemotherapy and radiation.

EGFR activation plays an essential role in the immune response in human skin, driving cell cycle progression, and impelling cell proliferation, survival, differentiation, and motility.39 EGFR appears to be overexpressed, dysregulated, or mutated in a variety of human cancers including head and neck, brain, bladder, breast, colorectal, kidney, lung, pancreas, prostate, and ovarian cancers.40â&#x20AC;&#x201C;42 Cetuximab is a recombinant human/murine chimeric monoclonal antibody that acts by competitively blocking ligand-induced EGFR activation, thereby preventing uncontrolled cell proliferation and invasion.43 Cetuximab is primarily used in recurrent, locally advanced, or metastatic head and neck squamous cell carcinoma (SCC); however, its use has recently been extended to BCC.39

Experience with systemic chemotherapy in MBCC is limited. Retrospective reviews and case reports comprise the bulk of the literaSKINmed. 2014;12:33â&#x20AC;&#x201C;38

Anti-EGFR monoclonal antibody use in the treatment of BCC has only been documented in case reports.43â&#x20AC;&#x201C;45 Researchers reported on the use of anti-EGFR monoclonal antibody for the palliative treatment of giant nodular midfacial BCC with no sign of metastasis in an 87-year-old man. The patient was treated for 4 months and tumor progression was minor during that time.43 Lesion and metastatic stability was observed in another two palliative patients, one of whom was immunocomprised.44 The immunocompromised patient died of sepsis after 5 months of treatment, while liver metastases developed following the cessation of treatment in the other Basal Cell Carcinoma

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Figure. Hedgehog signaling pathway in normal and basal cell carcinoma (BCC) cells and the mechanism of action of vismodegib. (A) Hedgehog signaling pathway in the absence (left) or presence (right) of hedgehog ligand (soluble hedgehog ligand [SHH]). In the absence of SHH, the PATCHED1 (PTCH) receptor inhibits (red line) the smoothened (SMO) receptor. The SHH ligand binds to and consequently inactivates the PTCH receptor. The active SMO induces a signaling cascade (green arrows) in the cell to promote gene transcription and cell proliferation. (B) Mutations in the PTCH (left) or SMO (right) receptors in BCC result in the overactivation of the SMO signaling pathway leading to uncontrolled cell proliferation. (C) The vismodegib recognizes the SMO receptor and inactivates its cell-proliferating signaling pathway. Narrow arrows: normal activity; bold arrows: over activity; crossed out arrows: inactivation.

patient. Adverse events were limited to head and neck folliculitis in a single patient. Importantly, in all case reports, treatment with cetuximab was implemented after overexpression of EGFR in the primary tumor had been confirmed. A case series of 8 patients treated with cetuximab was also reported.45 Four of these patients had BCC (median age, 84 years; range, 45â&#x20AC;&#x201C;87 years) of which 3 had GorlinGotz syndrome. Two patients had complete remission (CR) and the remaining 2 patients attained partial remission (PR) with treatment. Three patients relapsed after treatment cessation (2 CR and 1 PR) and treatment was then re-initiated. The median disease-free survival for these patients was 1 month. Importantly, high relapse rates were observed on cessation of treatment, which underscores the importance of maintenance treatment in long-term disease control. The hedgehog signaling pathway is important in fetal development and specifically in the formation of the embryonic neural tube, skeleton, hair, and skin.46 It is also involved in adult stem cell differentiation and healing during post-natal life, making it one of the most SKINmed. 2014;12:33â&#x20AC;&#x201C;38

common signal transduction pathways used by mammalian cells.47 When not being used for healing, this pathway is often silenced in adult life. Recent studies have shown that abnormal activity in this pathway may be implicated in the pathogenesis of BCC.48 Upregulation of the hedgehog pathway is a predominant genetic alteration in BCC. The hedgehog signaling pathway hinges on the absence or presence of the soluble hedgehog ligand (SHH). In the absence of SHH, the PATCHED1 (PTCH-1) receptor inhibits the activity of smoothened (SMO) receptors.49 When SHH is present, its binding to PTCH-1 inhibits PTCH-1 suppressive function on SMO.49 SMO then activates the hedgehog signaling cascade, ultimately leading to cell proliferation (Figure). The majority of BCCs carry mutation in the PTCH-1 tumor-suppressor gene resulting in an inactive form of PTCH-1 receptor that results in constitutive hedgehog pathway activation.49 A minority of patients with BCCs carry a mutation in the SMO gene resulting in overactivation of the hedgehog pathway.50,51 As a result, upregulation in hedgehog signal-

Basal Cell Carcinoma

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REVIEW

ing promotes tumor growth, whereas its inhibition promotes tumor suppression and cell cycle arrest. Vismodegib is the latest development in targeted pharmacologic therapy for MBCC. Vismodegib suppresses hedgehog signaling by selectively binding to and inhibiting SMO (Figure).52 Recently approved in the United States, vismodegib has been indicated for the treatment of recurrent BCC, locally advanced BCC, or MBCC and for those who are not candidates for surgery or radiation.53 Only one comparative phase II cohort study has been published to date on the use of vismodegib in locally advanced BCC, recurrent BCC, and MBCC.54 No control group was used in this study because of the low prevalence of the disease. The study was comprised of two cohorts: patients with locally advanced BCC (n=71) and patients with MBCC (n=33). Patients received 150 mg of vismodegib daily for 8 weeks. A reduction in lesion diameter in response to vismodegib was observed in the majority of patients in both cohorts. Objective response rates of 30% and 43% were obtained for patients in the MBCC and locally advanced BCC cohorts, respectively; however, all responses in the MBCC cohort were partial responses. Disease stabilization occurred in 63% of MBCC and 38% of locally advanced BCC patients. During treatment with vismodegib, no residual disease was present in biopsy specimens obtained from 54% of patients with locally advanced BCC. The most frequently reported adverse events of any grade included muscle spasms (68%), alopecia (63%), taste distortion (51%), weight loss (46%), fatigue (36%), nausea (29%), decreased appetite (23%), and diarrhea (22%). Less than 5% of adverse events were grade 3 or 4. The most common reasons for treatment discontinuation were patient decision in 25% of those with locally advanced BCC and disease progression in 18% of MBCC patients. Importantly, because vismodegib can cause tumor shrinkage, it may render previously unresectable locally advanced disease operable.55 Several phase II trials of vismodegib in BCC including the neoadjuvant option are currently underway (NCT01700049, NCT01898598, NCT01367665). Conclusions Locally advanced BCC and MBCC are rare presentations of a common disease. Until recently, treatment for locally advanced BCC and MBCC was restricted to chemotherapy and radiation; however, the effectiveness of these treatments is limited at best. Recent discoveries in the fields of molecular biology have found important pathways implicated in the pathogenesis of BCC. Among these are the EGFR and hedgehog pathways, which are now being targeted by new biologic therapies. Despite a paucity of phase II and III trial data, preliminary evidence demonstrating the disease-stabilizing ability of biologic therapies in locally advanced BCC and MBCC appears promising. SKINmed. 2014;12:33–38

References 1 Lear JT, Smith AG. Basal cell carcinoma. Postgrad Med J. 1997;73:538–542. 2 Skin Cancer Foundation. Basal cell carcinoma. http:// www.skincancer.org/basal-cell-carcinoma.html. Accessed December 1, 2013. 3 Jacobs GH, Rippey JJ, Altini M. Prediction of aggressive behavior in basal cell carcinoma. Cancer. 1982;49:533–537. 4 Heenan PJ, Elder DJ, Sobin LH. Histological typing of skin tumours. In: WHO International Histological Classification of Tumours. 2nd ed. New York, NY: Springer Verlag; 1996. 5 Lo JS, Snow SN, Reizner GT, et al. Metastatic basal cell carcinoma: report of twelve cases with a review of literature. J Am Acad Dermatol. 1991;24:715–719. 6 Vu A, Laub D. Metastatic basal cell carcinoma. InTech. http://www.intechopen.com/books/basal-cell-carconima/metastatic-basal-cell-carcinoma. Accessed December 1, 2013. 7 Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: incidence. J Am Acad Dermatol. 1994;30:774–778. 8 Levine H. Cutaneous carcinoma of the head and neck: management of massive and previously uncontrolled lesions. Laryngoscope. 1983;93:87–105. 9 Harris RB, Griffith K, Moon TE. Trends in the incidence of nonmelanoma skin cancers in southeastern Arizona, 1985–1996. J Am Acad Dermatol. 2001;45:528–536. 10 Betti R, Inselvini E, Carducci M, Crosti C. Age and site prevalence of histologic subtypes of basal cell carcinomas. Int J Dermatol. 1995;34:174–176. 11 Staples MP, Elwood M, Burton RC, et al. Non-melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med J Australia. 2006;184:6–10. 12 Seretis K, Thomaidis V, Karpouzis A, Tamiolakis D, Tsamis I. Epidemiology of surgical treatment of nonmelanoma skin cancer of the head and neck in Greece. Derm Surg. 2010;36:15–22. 13 Urbach F, Davies RE, Forbes PD. Ultraviolet radiation and skin cancer in man. In: Carcinogenesis Advances and Biology of the Skin. Vol. 7. Oxford, UK: Pergamon Press; 1965:195–214. 14 Lear JT, Tan BB, Smith AP, et al. Risk factors for basal cell carcinoma in the UK: case-control study in 806 patients. J R Soc Med. 1997;90:371–374. 15 Gallagher RP, Hill GB, Bajdik CD, et al. Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. Arch Dermatol. 1995;131:157–163. 16 Corona R, Dogliotti E, D’Errico M, et al. Risk factors for basal cell carcinoma in a Mediterranean population. Arch Dermatol. 2002;137:1162–1168. 17 Vitasa BC, Taylor HR, Strickland PT, et al. Association of nonmelanoma skin cancer and actinic keratosis with cumulative solar ultraviolet exposure in Maryland watermen. Cancer. 1990;65:2811–2817.

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18 Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation. 1990;49:506–509. 19 Telfer NR, Colver GB, Morton CA. Guidelines for the management of basal cell carcinoma. Brit J Derm. 2008; 159:35–48. 20 Bath-Hextall FJ, Perkins W, Bong J, Williams HC. Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev. 2007 Jan 24;(1): CD003412. 21 Malone JP, Fedok FG, Belchis DA, Maloney ME. Basal cell carcinoma metastatic to the parotid: report of a new case and review of the literature. Ear Nose Throat J. 2000;79:511–515. 22 Moser S, Borm J, Mihic-Probst D, Jacobsen C, Kruse Gujer AL. Metastatic basal cell carcinoma: report of a case and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013 Jan 10. [Epub ahead of print]. 23 Lattes R, Kessler RW. Metastasizing basal-cell epithelioma of the skin; report of two cases. Cancer. 1951;4:866–878. 24 Snow SN, Sahl W, Lo JS, et al. Metastatic basal cell carcinoma: a report of five cases. Cancer. 1994;73:328–335. 25 Berlin JM, Warner MR, Bailin PL. Metastatic basal cell carcinoma presenting as unilateral axillary lymphadenopathy: report of a case and review of the literature. Derm Surg. 2002;28:1082– 1084. 26 Seo SH, Shim WH, Shin DH, Kim YS, Sung HW. Pulmonary metastasis of basal cell carcinoma. Ann Dermatol. 2011;23:213–216. 27 Snow S. Metastatic BCC. Report of five cases. Cancer. 1994;73:328–335. 28 Farmer ER, Helwig EB. Metastatic basal cell carcinoma: a clinicopathologic study of seventeen cases. Cancer. 1980;46:748–757. 29 Barksdale SK, O’Connor N, Barnhill R. Prognostic factors for cutaneous squamous cell and basal cell carcinoma. Determinants of risk of recurrence, metastasis, and development of subsequent skin cancers. Surg Oncol Clin N Am. 1997;6:625–638. 30 Tuzun Y, Kutlubay Z, Engin B, Serdaroglu S. In Tech. Basal cell carcinoma: skin cancer overview. http://www.intechopen.com/books/skin-canceroverview/basal-cell-carcinoma. Accessed December 1, 2013. 31 Robinson JK, Dahiya M. Basal cell carcinoma with pulmonary and lymph node metastasis causing death. Arch Dermatol. 2003;139:643–648.

34 Fetcher LA. Systemic therapy for inoperable and metastatic basal cell cancer. Curr Treat Options Oncol. 2013;14:237–248. 35 Pfeiffer P, Hansen O, Rose C. Systemic cytotoxic therapy of basal cell carcinoma: a review of the literature. Eur J Cancer. 1990;26:73–77. 36 Haynes HA, Mead KW, Goldwyn RM. Cancers of the skin. In: DeVita VT, Hellman S, Rosenberg SA. Cancer, eds. Principles and Practice of Oncology. Philadelphia, PA: J.B. Lippincott; 1985:1343–1369. 37 Kord JP, Cottel WI, Proper S. Metastatic basal-cell carcinoma. J Dermatol Surg Oncol. 1982;8:604–608. 38 Moeholt K, Aagaard H, Pfeiffer P, Hansen. Platinumbased cytotoxic therapy in basal cell carcinoma—a review of the literature. Acta Oncologica. 1996;35:677– 682. 39 Martinelli E, De Palma R, Orditura M, De Vita F, Ciardiello F. Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Clin Exp Immunol. 2009;158:1–9. 40 Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther. 1999;82:241–250. 41 Yarden Y. The EGFR family and its ligands in human cancer signaling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37:S3–S8. 42 Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000;19:6550– 6565. 43 Muller H, Eisendle K, Gastl G, et al. Palliative therapy of giant basal cell carcinoma with the monoclonal anti-epidermal growth factor receptor antibody cetuximab. Brit J Dermatol. 2008;158:1386– 1388. 44 Caron J, Dereure O, Kerob D, Lebbe C, Guillot B. Metastatic basal cell carcinoma: report of two cases treated with cetuximab. Brit J Dermatol. 2009;161:702– 703. 45 Kalapurakal SJ, Malone J, Robbins KT, et al. Cetuximab in refractory skin cancer treatment. J Cancer. 2012; 3:257–261. 46 Tang JY, So PL, Epstein EH Jr. Novel Hedgehog pathway targets against basal cell carcinoma. Toxicol Appl Pharmacol. 2007;224:257–264. 47 Barakat MT, Humke EW, Scott MP. Learning from Jekyll to control Hyde: hedgehog signaling in development and cancer. Trends Mol Med. 2010;16: 337–348. 48 Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8:743–754.

32 Ducic Y, Marra DE. Metastatic basal cell carcinoma. Am J Otolaryngol. 2011;32:455–458.

49 Liu LS, Colegio OR. Molecularly targeted therapies for nonmelanoma skin cancers. Int J Dermatol 2013;52:654–665.

33 von Domarus H, Stevens PJ. Metastatic basal cell carcinoma: report of five cases and review of 170 cases in the literature. J Am Acad Dermatol. 1984;10:1043– 1060.

50 Caro I, Low J. The role of the hedgehog signaling pathway in the development of basal cell carcinoma and opportunities for treatment. Clin Cancer Res. 2010;16:3335–3339.

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REVIEW 54 Sekulic A, Migden MR, Oro AE, et al. Efficacy and safe-

51 Rudin C. Beyond the scalpel: targeting hedgehog in skin cancer prevention. Cancer Prev Res. 2010;3:1–3.

ty of vismodegib in advanced basal-cell carcinoma. N

52 Macha M, Batra S, Ganti AK. Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma. Cancer Manag Res. 2013;5:197–203.

Engl J Med. 2012;366:2171–2179. 55 Evans MS, Drabick JJ. Systemic treatment in the management of head and neck cutaneous malignancies.

53 Erivedge [package insert]. San Francisco, CA: Genentech Corp; 2012.

Operat Tech Otolaryngol. 2013;24:63–68.

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions for Questions 1–5: For each numbered question, choose the single most appropriate lettered response.

3. The most common site of origin of metastatic basal cell carcinoma is the: a. Extremities. b. Face. c. Nail bed. d. Neck. e. Scalp. f. Trunk

5. Each of the following statements regarding the hedgehog pathway in human basal cell carcinomas is correct, EXCEPT: a. It is directly inhibited by celuximab. b. It is suppressed by vismodegib. c. Its activity hinges on the absence or presence of the soluble hedgehog ligand (SHH). d. The majority of basal cell carcinomas carry a mutation in the PATCHED1(PTCH-1) tumor suppressor gene. e. The PATCHED1(PTCH-1) receptor inhibits the activity of smoothened (SMO) receptors. f. SMO activates the hedgehog signaling cascade. ANSWERS TO CME EXAMINATION: a e b c a

2. Currently the standard of care of non-superficial basal cell carcinomas is: a. Cryosurgery. b. Currettage and electrodessication. c. Immune modulation. d. Mohs’ chemographic surgery. e. Surgical excision. f. Topical chemotherapy.

4. Which of the following classes of chemotherapeutic agent have been most efficacious in treating locally advanced and metastatic basal cell carcinomas? a. Anthracyclines. b. 5-Fluorouracil. c. Platinum based agents. d. Psoralins. e. Taxanes.

1. 2. 3. 4. 5.

1. Each of the following statements regarding basal cell carcinoma is correct, EXCEPT: a. BCC is more common in women than in men. b. BCC is often caused by sun exposure. c. BCC is more common in the southern than in the northern United States. d. BCC is more common in Caucasian than in darkskinned peoples. e. BCC is more common in patients with a family history of skin cancer. f. BCC is more common among persons who had freckling or frequent/severe sunburns as children.

From the Departments of Pathology and Dermatology, Rutgers University – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

SKINmed. 2014;12:33–38

Basal Cell Carcinoma

COMING SOON

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FILLERS Poly-L-Lactic Acid – Present and Future Calcium Hydroxyapatite

Editors: Michael H. Gold, MD Lawrence Charles Parish, MD Wm. Philip Werschler, MD Joel Cohen, MD Dr. Miles Graivier, MD Derek Jones, MD Bruce Katz, MD Mukta Sachev, MD Ava Shamban, MD Danny Vleggaar, MD

Permanent Fillers for Soft Tissue Augmentation Injectable Fat for Soft Tissue Augmentation Soft Tissue Augmentation – NL Folds Soft Tissue Augmentation – Oral Commisures Soft Tissue Augmentation – Lips Soft Tissue Augmentation – Volume Enhancement Soft Tissue Augmentation – Other Indications Injectable Fillers in Skin of Color Complications of Fillers Index

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January/February 2014

Volume 12 • Issue 1

NEW THERAPY UPDATE William Abramovits, MD; Aditya K. Gupta, MD, PhD, Section Editors

MIRVASO (Brimonidine Tartrate) Topical Gel 0.33% William Abramovits, MD;1,2,3 Ana Prato, MD;3 Kimberly D. Vincent, MD;4 Noah Scheinfeld, MD, JD;5 Aditya K. Gupta, MD, PhD, FRCP(C)6,7

osacea is a chronic disease characterized by flushing and persistent facial erythema that has significant negative quality-of-life implications.1,2 Patients may have more than one subtype present. It is estimated that rosacea affects 16 million Americans.3 Patients with rosacea typically experience their first episode between the ages of 20 and 25 years. Rosacea is more common in women and in individuals with Fitzpatrick skin types I and II, although rosacea may still be present in higher Fitzpatrick skin types.4–6 Brimonidine is an α-adrenergic agonist with potent vasoconstrictive activity. It is intended to reduce the persistent erythema observed in rosacea by reversing the dilation of blood vessels.7 Brimonidine topical gel 0.33% is a white to light yellow opaque aqueous gel. Each gram of gel contains 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base. The chemical formula for brimonidine tartrate is 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate. Phase II Clinical Studies

The effect of topical brimonidine tartrate gel on the facial erythema of rosacea was evaluated in a double-blind, randomized, vehicle-controlled, dose-finding study. Erythema severity was assessed using two 5-point scales: Clinician’s Erythema Assessment (CEA) and Patient’s Self-Assessment (PSA). Participants (n=122) with moderate to severe facial erythema from rosacea (CEA and PSA scores ≥3) were randomized to receive a single facial application of brimonidine tartrate gel 0.07%, 0.18%, 0.5%, or vehicle.8,9 The primary outcome measure was the profile of success, defined as 2 grades of improvement on both CEA

and PSA. A single application of topical brimonidine tartrate gel was shown to significantly reduce facial erythema by CEA, PSA, and combined CEA and PSA at hour 12. The response rate for profile of success was 25.0%, 32.3%, and 54.8% for brimonidine tartrate gel 0.07%, 0.18%, and 0.5%, respectively, compared with 12.5% for vehicle. The median duration of effect after a single application of brimonidine tartrate gel 0.5% was 11.53 hours (1 grade of improvement on CEA), 7.00 hours (2 grades of improvement on CEA), and 5.98 hours (profile of success). The treatment-emergent adverse events (TEAEs) were minimal, indicating that brimonidine tartrate gel was well tolerated. The incidence of participants with TEAEs ranged from 6.5% (2 patients) with brimonidine tartrate gel 0.5% to 14.3% (4 patients) with brimonidine tartrate gel 0.07%. Most related AEs were transient, dermatological in nature, and mild in intensity. The safety and efficacy of brimonidine tartrate gel in erythematotelangiectatic rosacea was assessed in a multicenter, doubleblind, randomized, vehicle-controlled phase II study (4 weeks daily treatment/4 weeks follow-up).9,10 Participants (n=269) with moderate to severe facial erythema of rosacea (CEA and PSA scores ≥3) were randomized to 1 of 5 groups: brimonidine tartrate 0.5% once daily (QD), brimonidine tartrate 0.18% QD or twice daily (BID), or vehicle QD or BID. The primary outcome measure was profile of success as defined in the initial phase II trial evaluated on day 29. Brimonidine tartrate 0.5% QD had a significantly superior profile of success compared with vehicle QD on day 29 (primary endpoint, P<.001), and on days 1 and 15 (both P<.001). Success rates at hours 3, 6, 9, and 12

From the Department of Medicine, Baylor University Medical Center, Dallas, TX;1 the Departments of Dermatology & Family Practice, The University of Texas Southwestern Medical School, Dallas, TX;2 Dermatology Treatment & Research Center, Dallas, TX;3 Belle Meade Dermatology, Nashville, TN;4 the Department of Dermatology, Weill Cornell Medical College, New York, NY;5 the Department of Medicine, University of Toronto, Canada;6 and Mediprobe Research Inc, London, Canada7 Address for Correspondence: William Abramovits, MD, Department of Medicine, Baylor University Medical Center, Dallas, TX 75246 • E-mail: DrA@dermcenter.us

SKINmed. 2014;12:41–43

January/February 2014

NEW THERAPY UPDATE

on day 29 were 30.2%, 28.3%, 32.1%, and 18.9%, respectively, for brimonidine tartrate 0.5% QD, compared with 3.6%, 7.3%, 3.6%, and 3.6% for vehicle QD. The other brimonidine tartrate concentrations and dose regimens also showed a trend to efficacy over vehicle. Most related TEAEs were mild and transient and no evidence of tachyphylaxis, rebound, or aggravation of other disease signs (telangiectasias, inflammatory lesions) was observed for any active treatment group. Similar incidences of related TEAEs were reported for the active groups (11.1%â&#x20AC;&#x201C;18.9%) and the vehicle QD group (14.5%). Phase III Clinical Studies Brimonidine tartrate topical gel was evaluated for the treatment of moderate to severe persistent facial erythema of rosacea in 2 phase III multicenter, randomized, double-blind, parallel group, and vehicle control trials, which were identical in design.11,12 The studies included adults aged a minimum of 18 years with a clinical diagnosis of rosacea, fewer than 3 facial inflammatory lesions, and moderate to severe erythema according to both CEA and PSA at both the screening and baseline visits. Participants were required to discontinue medications for inflammatory conditions, rosacea, or acne during a wash-out period prior to the study. Participants were randomized in a 1:1 ratio to brimonidine tartrate gel or vehicle gel applied once daily over the whole face for 4 weeks. The primary efficacy endpoint was evaluated on day 29, and was followed by a 4-week wash-out period. The primary outcome measure for both trials was 2-grade composite success, defined as the proportion of patients with a 2-grade improvement on both CEA and PSA measured at hours 3, 6, 9, and 12 on day 29. Additional CEA and PSA scores were obtained at baseline and on day 15. All efficacy variables were analyzed based on the intent-to-treat (ITT) population. The trials were conducted in 553 patients who were treated once daily for 4 weeks with either brimonidine tartrate gel (0.5% wt/ wt) or vehicle. Overall, 99% of patients were Caucasian and 76% were women. Most patients had a Fitzpatrick skin phototype of II (53.5% and 58.7%, respectively), and the mean age was 48.8 years in study A and 47.5 year in study B. A total of 260 patients were enrolled into study A and 254 (97.7%) completed it normally. Among the 293 patients enrolled into study B, 283 (96.6%) reported normal study completion. Brimonidine tartrate gel was significantly more effective than vehicle for 2-grade Composite Success on day 29 (both P<.001; ITT analyses). During time course analysis, brimonidine tartrate gel was also significantly more effective than vehicle on days 1 and 15, in addition to day 29 (all P<.001). This outcome was also replicated for the secondary study outcome of 1-grade imSKINmed. 2014;12:41â&#x20AC;&#x201C;43

provement on CEA and PSA for all days assessed (all P<.001). Overall, no tachyphylaxis or loss of efficacy was observed during the 4-week treatment period and no rebounding for facial erythema during the follow-up phase was observed for CEA or PSA scores. Participants reported minimal TEAEs during the 4 weeks of active treatment. The majority of TEAEs were cutaneous in nature, transient in duration, and mild in intensity. The most frequent related adverse events included worsening of erythema, pruritus, skin irritation, and worsening of rosacea. Brimonidine tartrate gel produced TEAE rates of 29.5% and 33.8% vs the vehicle rates of 25.2% and 24.1%. No serious TEAEs occurred in any study patients. Overall, once-daily brimonidine tartrate 0.5% gel was well tolerated. Indications and Administration Brimonidine topical gel 0.33% (wt/wt) gel was approved by the Food and Drug Administration (FDA) in August 2013 and is indicated for the topical treatment of persistent erythema of rosacea in adults 18 years and older. It is applied once daily. Patients should apply a pea-size amount to each of the 5 areas of the face: central forehead, chin, nose, and each cheek avoiding the eyes and lips. Discussion Clinical studies of brimonidine tartrate gel at a wide range of concentrations have shown efficacy over vehicle and a strong safety profile. The FDA-approved dosage of 0.33% can be expected to provide patients with comparable results to the phase II and III clinical trials. This product represents a paradigm shift in the approach of the erythema of rosacea, addressing the capillary dilatation that dominates some subtypes of rosacea vs perilesional inflammatory erythema, although it may improve the latter as well. Studies to support a benefit in the erythema related to inflammation have not yet been conducted. Each application has proven to be effective over a 12-hour period, leading to the indication of once-daily application. The studies were conducted with a morning application schedule, but ingenuity on the part of the prescriber or the patient may lead to schedules optimizing the benefits during the peak effect period 3 to 6 hours after application. Patients would be able to apply brimonidine tartrate gel in the afternoon prior to evening social situations to mitigate the flushing associated with alcohol and other predictable triggers. MIRVASO (Brimonidine Tartrate) Topical Gel 0.33%

January/February 2014

NEW THERAPY UPDATE

Further studies and clinical practice may address the observation of sustained benefit upon discontinuation of the gel after months of use. We recognize this product as being a likely major contributor to the treatment of some forms of rosacea. Conclusions Brimonidine tartrate 0.33% gel is an effective and safe treatment for rosacea. It is effective in reducing the appearance of erythema from both a clinical and patient perspective over a single or sustained application. References 1 Crawford GH, Pelle MT, James WD. Rosacea: l. Etiology, pathogenesis, and subtype classification. J Am Acad Dermatol. 2004;51:327–341. 2 Scheinfeld NS. Rosacea. Skinmed. 2006;5:191–194. 3 National Rosacea Society. Rosacea incidence on rise. http://www.rosacea.org/weblog/rosacea_incidence_ on_rise Accessed on October 4, 2013 4 Conde JF, Yelverton CB, Balkrishnan R, Fleischer AB, Feldman SR. Managing rosacea: a review of the use of metronidazole alone and in combination with oral antibiotics. J Drugs Dermatol. 2007;6:495–498. 5 Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol. 1989;69:419–423. 6 Gupta AK, Chaudhry MM. Rosacea and its management: an overview. J Eur Acad Dermatol Venerol. 2005;19:273–285.

7 Rahman MQ, Ramaesh K, Montgomery DNI. Brimonidine for glaucoma. Expert Opin Saf. 2010;9:483–491. 8 Meadows K, Pollack A, Michael, Jarratt M. A single application of brimonidine tartrate gel significantly reduces moderate to severe facial erythema associated with rosacea. J Am Acad Dermatol. 2012;66:4(suppl 1);AB17. 9 Fowler J, Jarratt M, Moore A, et al; Brimonidine Phase II Study Group. Once-daily topical brimonidine tartrate gel 0.5% is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies. Br J Dermatol. 2012;166:633–641. 10 Fowler J Jr, Moore A, Meadows K, Grande K. Once-daily topical brimonidine tartrate gel 0.5% is safe and effcacious in the treatment of moderate to severe persistent facial erythema associated with rosacea. J Am Acad Dermatol. 2012;66:4(suppl 1):AB41 (Poster reference number 4764) (Abstract). 11 Fowler J, Moore A, Meadows K, Jackson M, Leoni M, Jarratt MT, Jones T. Efficacy and safety of once daily brimonidine tartrate 0.5% for moderate to severe facial erythema of rosacea: Two randomized, double-blind, and vehicle controlled Phase III studies. J Am Acad Dermatol. 2013;68:4(suppl 1):1B15 (Poster reference 6178) (Abstract). 12 Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12:650–656.

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MIRVASO (Brimonidine Tartrate) Topical Gel 0.33%

Please forward your completed application for processing to: Larry Millikan, MD, Secretary-Treasurer General Ms Anna Gjeci, Executive Secretary 1508 Creswood Road Philadelphia, PA 19115, USA Tel: 215-677-3060 Cell: 267-438-2543 Fax: 215-695-2254 E-mail: IACDworld@yahoo.com Web: www.IACDworld.org SMCOMP_v10_i2_ADS.indd 396 121 SMCOMP_v10_i1_ADS.indd SMCOMP_v9_i5_ADS.indd 60

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January/February 2014

Volume 12 • Issue 1

The Heymann File Warren R. Heymann, MD, Section Editor

Diagnosing Atypical Hand, Foot, and Mouth Disease While Avoiding the Foot in Mouth Syndrome Warren R. Heymann, MD

ecently, coxsackie virus infections have been in the news, mostly due to the severe illness associated with enterovirus type 71 (which may be fatal secondary to encephalitis, flaccid paralysis, myocarditis, and pulmonary edema). The typical case of hand, foot, and mouth disease (HFMD), caused by type A16, is a milder disorder that affects children, with its characteristic acral football-shaped vesicles. The type caused by A6 (CVA6) may affect children and adults. The eruption may be widespread and demonstrate the phenomenon of “eczema coxsackium,” a vesicular eruption caused by the virus that can be considered the coxsackie virus equivalent of eczema herpeticum. A review of 80 patients with an atypical presentation of HFMD, 17 of which were documented to be caused by CVA6, reported that 55% of all patients demonstrated eczema coxsackium in areas of eczematous dermatitis.1 Various Case Reports One case report described 5 cases of atypical HFMD caused by CA6 in 3 children and 2 adults; both adults had systemic manifestations (fever, chills, myalgias, and diarrhea) severe enough to warrant hospitalization. In 2 children with atopic dermatitis, eczema coxsackium was observed. The authors note that while the diagnosis of typical cases of HFMD is based on history and physical examination, atypical HFMD may require laboratory confirmation. The most sensitive assay is reverse transcriptase polymerase chain reaction (RT-PCR) best obtained from vesicular fluid.2 Another case report described a immunocompetent 37-year-old man with widespread crusted lesions and purpuric, targetoid, vesicular lesions of his hands and feet, accompanied by fever, fa-

tigue, headaches, photophobia, nausea, vomiting, diarrhea, and joint pains. The diagnosis of atypical HFMD caused by CVA6 was confirmed by PCR analysis.3 Importance of Diagnosing the Syndrome It is vital that dermatologists recognize these atypical cases of HFMD, making certain that severely ill patients get the necessary requisite supportive care. Indeed, within the past several weeks, our practice had 2 patients for whom the diagnosis of atypical HFMD was entertained: (1) A 26-year-old man with acral vesicles, targetoid lesions, and purpuric macules of his feet, stated that he had a child who was diagnosed a week earlier with classical HFMD. This diagnosis will remain presumptive as confirmatory RT-PCR was not obtained; (2) A 21-month-old girl with a history of atopic dermatitis and asthma diagnosed with HFMD prior to admission presented with fever and a vesiculopustular eruption with punched out ulcers that were grouped around the mouth, wrists, and flexural extremities. Our clinical suspicion was that of eczema herpeticum vs eczema coxsackium. Results from viral culture were positive for herpes simplex virus type 1 (HSV), and she responded to intravenous acyclovir. Discussion Is a clinician potentially biased in making such a diagnosis when confronted with “new” disorders, such as atypical HFMD caused by CVA6? Considering our latter patient as an example, while we appropriately performed a culture for herpes simplex, clinically I thought the probable diagnosis would be eczema coxsackium. Why was I reaching the wrong conclusion?

From the Departments of Medicine and Pediatrics, Division of Dermatology, Cooper Medical School of Rowan University, Camden, NJ Address for Correspondence: Warren R. Heymann, MD, 100 Brick Road, Suite 306, Marlton, NJ 08053 • E-mail: wrheymann@gmail.com

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January/February 2014

The Heymann File

In a recent fascinating paper4 exploring cognitive errors in dermatology, it appears that I was guilty of cognitive bias based on “availability error” (the disposition to judge things as being more prevalent if they readily come to mind). In this case, I was likely influenced by the flurry of recent reports of the CVA6 outbreaks. Perhaps, subconsciously, I wanted to see what I had been reading about. The best antidote to this bias is to step back and always consider other diagnostic possibilities. Fortunately, we did that in this case. Regardless, I was surprised by the result, confirming my long-held tenet that dermatology is a humbling profession. Unquestionably, it is best to think broadly and methodically to avoid “foot in mouth disease!”

References 1 Mathes EF, Oza V, Frieden IJ, Cordoro KM, et al. “Eczema coxsackium” and unusual cutaneous findings in an enterovirus outbreak. Pediatrics. 2013;132;e149–e157. 2 Lott JP, Liu K, Landry ML, et al. Atypical hand-foot-andmouth disease associated with coxsackievirus A6 infection. J Am Acad Dermatol. 2013;69:736–741. 3 Stewart CL, Chu EY, Intracasso CE, Schaffer A, James WD. Coxsackievirus A6-induced hand-foot-mouth disease. JAMA Dermatology. 2013;149:1419–1421. 4 Dunbar M, Helms SE, Brodell RT. Reducing cognitive errors in dermatology: can anything be done? J Am Acad Dermatol. 2013;69:810–813.

Historical Diagnosis and treatment Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of stereoscopic cards published in 1910 by The Stereoscopic Skin Clinic by, Dr S. I. Rainforth.

(Continued on page 56)

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Diagnosing Atypical Hand, Foot, and Mouth Disease

January/February 2014

Volume 12 • Issue 1

L DE R M ICA A IN

IC SOCI ET LOG TO

IN Y,

C. NOR TH

North American Clinical Dermatologic Society Is 55 Years Young

ERICAN C L AM

NACDS NEWSLETTER

Richard L. Spielvogel, MD;1 John W. White, Jr, MD2

he North American Clinical Dermatologic Society (NACDS) is a not-for-profit organization that was founded in 1959 and whose mission is to provide predominantly clinical dermatology educational opportunities by arranging meetings with academic centers and societies worldwide. This educational experience and travel fosters close friendships while enjoying other cultures. Our 55th Annual Meeting will have taken place in Panama City, Panama, and Havana, Cuba, January 28 to February 9, 2014, with the members of the Panama Dermatology Society and the Cuban National Dermatology Association. Our 2013 meeting was held in Spain at Barcelona, the Basque country, and Porto, Portugal and was highlighted by visits to the dermatology departments at the Universities of Barcelona (Figure 1) and Porto. A complete listing of the locations of our previous annual meetings (Table I) demonstrates the international scope of our activities with memorable visits to many of the most distinguished dermatology academic centers and societies around the globe. Background For more than 50 years, the NACDS has grown into a unique and vibrant society, composed of board-certified dermatologists and dermatopathologists and joined by honorary members and fellows from our foreign visits. Our members share a passion for dermatology and a common interest in the highest standards of both clinical dermatologic practice and quality dermatology continuing medical education. Through fulfillment of our mission, NACDS members enjoy the benefits of good fellowship, develop long-standing close relationships with other members in private practice and academia, and share lifelong memories of travels and colleagues with similar dermatologic interests and experiences. The NACDS was conceived and organized in 1959 by a prominent group of clinical dermatologists who met with Charles A. Oclassen in the Westwood Pharmaceutical suite at the American

Figure 1. April 2013 scientific session at the University of Barcelona, Spain. Professor and Chair Teresa Estrach and Professor J.M. Mascaro, Jr (center) with NACDS Officers. Left to right: President, James B. Stewart, Jr, MD; Vice President and Scientific Program Director, Anthony V. Benedetto, DO; Secretary General, Richard L. Spielvogel, MD; and Historian, John Robert Hamill, Jr, MD.

Academy of Dermatology Annual Meeting in Chicago. Founding Members included Drs Charles Schmitt (Pittsburgh, PA), Marvin E. McRae (Greensboro, NC), Hollis Gerrard (Miami, FL), Royal M. Montgomery (New York, NY), Walter J. Cole (Palo Alto, CA), Charles I. Black (Baton Rouge, LA), Bedford F. Pace (Beaumont, TX), John W. Baird (Memphis, TN), and Edward Finnerty (Boston, MA) and Associate Members Mr Charles O’Classen (Westwood) and Mr Lorne Person (Person and Covey). Dr Finnerty was the first Secretary General and primary annual meeting planner and held that position from 1960 until 1992 (Figure 2). The founders envisioned a society with an emphasis on practical clinical dermatology rather than basic research. Many of the early members, as is still true today, had continuing clinical teaching ties to academic dermatology programs. Thirty-six dermatologists attended the inaugural meeting in Las Vegas, NV, and 9 of the next 11 annual meetings were also held in North America.

From the Departments of Dermatology and Pathology, Drexel University, College of Medicine, Philadelphia, PA;1 and Retired2 Address for Correspondence: Richard L. Spielvogel, MD, 649 Dorset Road, Devon, PA 19333 • E-mail: rlspiel@verizon.net

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January/February 2014

NACDS NEWSLETTER

Table I. North American Clinical Dermatologic Society Annual Meetings, 1960–2014 1960

Las Vegas, Nevada–Stardust

1961

Puerto Rico–Dorado Beach Hotel

1962

Honolulu, Hawaii–Royal Hawaiian Hotel

1963

Hollywood, Florida–Diplomat Hotel

1964

Mexico City, Mexico–Hilton Hotel Acapulco, Mexico–Hilton Hotel

1985

Monterey, California–Hyatt Regency Hotel

1986

Cong, Ireland–Ashford Castle Dublin, Ireland–Burlington Hotel Edinburgh, Scotland–Caledonian Hotel

1987

Munich, W. Germany–Hilton Hotel Rome, Italy–Cavalieri Hilton Hotel

1988

Lisbon, Portugal–Ritz Hotel Algarve, Portugal–Vila Moura Marinotel

1965

Las Vegas, Nevada–Flamingo Hotel

1989

1966

Lisbon, Portugal–Estoril Sol Hotel Madrid, Spain–Plaza Hotel Rome, Italy–Cavalieri Hilton Hotel Paris, France–Continental Hotel

Victoria, British Columbia–Empress Hotel Vancouver, British Columbia–Vancouver Hotel

1990

Leningrad, Russia–Pribaltiiyskaya Hotel Stockholm, Sweden–Royal Viking Hotel

1967

San Francisco, California–Fairmont Hotel

1991

Santa Fe, New Mexico–Santa Fe Hotel

1968

New Orleans, Louisiana–Royal Orleans Hotel

1969

Caribbean Cruise–Nieuw Amsterdam

1992

Lyon, France–Holiday Crowne Plaza Hotel Montreux, Switzerland–Hyatt Intercontinental Hotel

1970

Scottsdale, Arizona–Mountain Shadows Resort

1993

1971

Cartagena, Columbia–Hotel del Caribe Bogota, Columbia–Hotel Tequendama

London, England–Brittania Intercontinental Hotel Edinburgh, Scotland–Balmoral Hotel

1994

1972

Dublin, Ireland–Inter-Continental Hotel London, England–Churchill Hotel

Ottawa, Ontario–Chateau Laurier Hotel Quebec, Quebec–Loews Le Concorde Hotel

1995

Mainz, Germany–Hilton Hotel Brussels, Belgium–SAS Royal Hotel Brugge, Belgium–Holiday Crowne Plaza Hotel

1996

Cappadocia, Turkey–Villa-Kaya Hotel Istanbul, Turkey–Swissotel the Bosphorus Athens, Greece–Hilton Hotel

1997

Madrid, Spain–Hotel Intercontinental Seville, Spain–Hotel Tryp Colon Barcelona, Spain–Hotel Le Meridien

1998

Christchurch, New Zealand–Millennium Hotel Queenstown, New Zealand–Park Royal Hotel Cairns, Australia–Reef Casino Hotel Sydney, Australia–Renaissance Hotel

1999

Jasper, Alberta–Jasper Park Lodge Lake Louise, Alberta–Chateau Lake Hotel Calgary, Alberta–Westin Calgary Hotel

2000

St. Petersburg, Russia–Pre-trip–Astoria Hotel Oslo & Bergen, Norway–Continental Hotel & Radisson SAS Royal Hotel Stockholm & Orebro, Sweden–Sergel Plaza Hotel & Stora Hotellet

2001

Vienna, Austria–Radisson SAS Palais Hotel Budapest, Hungary–Hyatt Regency Krakow, Poland

1973

San Diego, California–Vacation Village

1974

Dakar, Senegal–Hotel Teranga Nairobi, Kenya–Hilton Hotel Rio de Janeiro–Hotel Nacional-Rio

1975

Athens, Greece–Caravel Hotel Dubrovnik, Yugoslavia–Libertas Hotel

1976

Caribbean Cruise–S / S Carla C Puerto Rico–El Conquistador Hotel

1977

Monterey, California–Del Monte Hyatt House

1978

Palm Beach, Florida–The Breakers Hotel

1979

Santo Domingo–Plaza Dominicana

1980

Maui, Hawaii–Wailea Beach Hotel

1981

Marbella, Spain–Atalaya Park Hotel Barcelona, Spain–Avenida Palace Hotel

1982

Orlando, Florida–Dutch Resort Hotel

1983

Nice, France–Hyatt Regency Hotel Paris, France–Hilton International Hotel

1984

Vienna, Austria–Wien Hilton Hotel Budapest, Hungary–Budapest Hilton Hotel Amsterdam, Netherlands–Amsterdam Hilton Hotel

Continued SKINmed. 2014;12:49–52

North American Clinical Dermatologic Society

January/February 2014

NACDS NEWSLETTER

Table I. North American Clinical Dermatologic Society Annual Meetings, 1960–2014 (Continued) 2002

Los Suenos, Costa Rica–Marriot Beach and Golf Resort San Jose, Costa Rica–Marriot Hotel and Resort

2003

Paris, France–Hotel du Louvre Deauville, France–Royal Barriere Hotel

2004

Berlin, Germany–Hilton Berlin Hotel Dresden, Germany–Dresden Hilton Prague, Czech Republic–Hotel Palace

2005

Malta–Hotel Corinthis San Gorg Palermo, Sicily–Hotel Des Palmes Taormina, Sicily–Hotel Capotaormina Sorrento–Hotel Excelsior Vittoria Rome–Starhotel Michaelangelo

2006

Rio de Janeiro, Brazil–Sofitel Rio Palace Iguassu Falls, Argentina–Sheraton Internacional Iguazu Resort Buenos Aires, Argentina–Marriott Plaza Hotel Santiago, Chile–The Ritz Santiago

2007

Hong Kong–Marco Polo Hong Kong Hotel Shanghai–JC Mandarin Hotel Quilin–Lijiang Waterfall Hotel Xian–Xian Hyatt Regency Beijing–Beijing Hotel

2008

Belfast, North Ireland–Europa Hotel Dublin, Ireland–Westbury Hotel Kilarney, Ireland–Killarney Plaza Adare, Ireland–Adare Manor Castle Hotel

2009

Toronto, Canada–Park Hyatt Hotel Halifax, Canada–Halifax Marriott Harbour-Front Hotel Boston, MA–Four Seasons Hotel

2010

Bucharest, Romania–Athenee Palace Hilton Sofia, Bulgaria–Radison Blu Grand Hotel Dubrovnik, Croatia–Grand Villa Argentina

2011

Tokyo and Kyoto meeting cancelled due to the earthquake

2012

Zurich, Switzerland–Hotel Schweizerhof Lucerne, Switzerland–Lucerne Hotel Balance Milan Italy–Star Hotel Stresa, Italy–Grand Hotel Des Ils Borromees

2013

Barcelona, Spain–Hotel El Palace San Sebastian, Spain–Hotel Maria Christina Porto, Portugal–The Yeatman Hotel SKINmed. 2014;12:49–52

Figure 2. Drs Charles Black, Ted Finnerty (Secretary General), and Charles Schmitt, Madrid, Spain, 1966 NACDS Annual Meeting.

Figure 3. NACDS members and spouses arriving in Lisbon, Portugal, for 1966 Annual meeting. Secretary General Ted Finnerty (center).

Figure 4. Professor Robert Degos (right) l’Hôpital St. Louis, Paris, France, lecturing to NACDS members.

North American Clinical Dermatologic Society

January/February 2014

NACDS NEWSLETTER ogy education, department and society visits with social interactions, and the camaraderie of colleagues with similar interests. The Secretary Generals who have followed Finnerty’s remarkable 32-year stint (Table II) have continued the basic traditions of the NACDS while continuing to make modifications to enhance our programs in the face of changing conditions, such as natural disasters, terrorism and dangerous locales, loss of pharmaceutical funding supplementation, and the ever-increasing costs of foreign travel.

Figure 5. British Parliament, the Palace of Westminster, London, England, location of the NACDS 1993 Annual Reception and Banquet.

Table II. North American Clinical Dermatologic Society Secretary Generals 1960–1992 Dr Edmond F. Finnerty 1992–2002 Dr John W. White, Jr 2002–2008 Dr Mark A. Crowe 2009–2015 Dr Richard L. Spielvogel 2016–

Dr Anthony V. Benedetto

Annual Meetings Since 1986, all of the annual meetings have been held outside the United States, except for in 1991 when a conflict in North Africa forced a last-minute shift to Santa Fe, NM, and in 2011 when a tsunami in Japan necessitated a last-minute cancellation. This opportunity to meet with well-known international academic departments was unique and not readily available to practitioners in the United States. More recently, a variety of worldwide meetings and societies have welcomed American dermatologists, including the World Congress of Dermatology and European, Asian, and South American societies. None of these venues, however, offer the same small group setting with a mixture of continuing clinical dermatol-

SKINmed. 2014;12:49–52

Our meetings usually last 10 to 12 days and take place in 2 or 3 locations that explore a region without long distances between cities or countries. Attendance varies, but we strive to maintain a relaxing small group experience with 30 to 50 members along with their spouses and guests. Our scientific sessions take place in the morning in our hotel with presentations by our members, predominantly on clinical topics. Our 1-day visits to academic programs or societies usually consist of presentations by the host faculty members, often with a brief history and tour of the dermatology department in the university and an overview of dermatology in the country. Two regular social events include a president’s reception and dinner early in the meeting schedule and a final annual reception and banquet, which often takes place in a special location. For instance, in 1993, we dined in London’s House of Parliament (Figure 5) and, in 2010, the majestic ballroom of the Hotel Regent Esplanade in Zagreb, Croatia. The Future As we look forward to the next 50 years, it is the goal of the NACDS to continue and expand the vision of the founders. The membership will continue to represent a cross section of all areas of clinical dermatology who enjoy learning from our international colleagues and sharing their experiences in return. It is our hope that this format will allow our members to provide better care to our ever more global population of patients. If you are interested in attending a meeting or joining our society please visit our website, nacds.com, or contact any of our regular or board members. Dr Judith Koperski is our Vice President and Membership Director and will be pleased to provide additional information. She may be reached at jakoperski@yahoo.com or 858-558-0677.

North American Clinical Dermatologic Society

3RD ANNUAL CONGRESS

SUN CITY 2014 SOUTH AFRICA

September 7 â&#x20AC;&#x201C; September 10, 2014

S AV E T HE DAT E For meeting information or to become an industry partner, visit www.theDASIL.org, or contact DASIL headquarters at HQ@theDASIL.org Abstract submissions due by July 7, 2014 and can be submitted to HQ@theDASIL.org

MEDIA PARTNER

January/February 2014

Volume 12 • Issue 1

CASE STUDY Vesna Petronic-Rosic, MD, MSc, Section Editor

Palliative Effect of Capecitabine and Cetuximab for Refractory Metastatic Squamous Cell Carcinoma of the Perineum in Epidermodysplasia Verruciformis Michael C. Lynch, BS;1 Joseph J. Drabick, MD;2 Rogerio I. Neves, MD;3 Edward J. Fox, MD;4 Heath B. Mackley, MD;5 Bryan E. Anderson, MD6

A teenage girl presented with multiple warty skin lesions and had a diagnosis of epidermodysplasia verruciformis made several years later. Later in life she presented with an extensive SCC in situ in her gluteal crease that was surgically resected with wide margins. Despite this treatment, the lesion recurred with extension onto her lower back. Biopsies at the time confirmed SCC in situ of the perianal tissue and invasive SCC above her gluteal cleft. (SKINmed. 2014;12:54–56)

t this time, her disease was treated with 3 months of concurrent mitomycin-C and 5-fluorouracil with radiation therapy, patterned after treatment of SCC of the anus. This treatment resulted in an initial response, but disease progressed into the draining lymph nodes.

Radical, potentially curative hemicorpectomy was discussed with the patient but she declined such extreme surgery; therefore, a neoadjuvant combination regimen of capecitabine and cetuximab was utilized with the hope of achieving a good clinical response that would allow for a less morbid surgery consisting of an anterior flap hemipelvectomy with incorporated vulvectomy. Such a surgery could manage her gross disease load, permit proper wound management, or possibly provide a cure.

A subsequent bilateral inguinal lymph node dissection was conducted that showed right-sided lymph node involvement with locoregional recurrence. Following this recurrence, a second-line chemotherapy regimen of docetaxel and carboplatin for 6 cycles was administered. Unfortunately, despite an initial response, her disease progressed.

The patient had a diverting colostomy and suprapubic urostomy to prevent soiling of the perineum. The cetuximab was given as a loading dose of 400 mg/m2 then weekly at 250 mg/m2. The capecitabine was given initially at 1500 mg/m2 twice a day for 14 days of 21-day cycles.

Her disease continued to progress with greater perianal involvement, widespread confluence of lesions, and increasing ulceration and drainage. Computed tomography (CT) scans showed an extensive soft tissue mass extending from the ischioanal fossa into the perineum bilaterally with associated direct bone invasion and vulvar soft tissue thickening with superior extension into the inguinal region bilaterally. Positron emission tomography (PET) CT identified local and distal lymph node involvement. Brain magnetic resonance imaging (MRI) was negative for metastatic disease and there was no evidence of other visceral involvement.

This treatment soon led to marked reduction of the large firm tumor masses at the edges of the ulcerated lesions. There was increased drainage and bleeding associated with receding tumor masses. She developed grade 4 diarrhea necessitating dose delay and reduction of the capecitabine. Her response was remarkable and showed partial remission for 3 months. The patient was followed-up for 6 months post-therapy. Unfortunately, the patient died from sepsis after 7 months.

From the Pennsylvania State University College of Medicine1 and the Departments of Hematology/Oncology,2 Plastic Surgery,3 Orthopedic Surgery,4 Radiation Oncology,5 and Dermatology,6 Milton S. Hershey Medical Center, Hershey, PA Address for Correspondence: Bryan E. Anderson, MD, Penn State Hershey Dermatology, 500 University Drive, UPC 1, Suite 100, Hershey, PA 17033 • E-mail: banderson@hmc.psu.edu

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CASE STUDY

Discussion Epidermodysplasia verruciformis (EV) is an uncommon, autosomal-recessive genodermatosis characterized by multiple cutaneous skin lesions and marked susceptibility to human papilloma virus (HPV) infection. First described by Lewandowski and Lutz in 1922,1 it presents with a variety of verruciform papules, flat warts, confluent plaques, and scaly pigmented macules.2 The skin lesions develop in early childhood and can become widespread.2

Longstanding and recurrent skin lesions possess the greatest malignant potential and are the source of most SCCs in EV. In fact, SCC develops in 30% to 70% of all EV patients.2 This occurs despite only a few of the HPV genotypes, especially HPV5 and HPV8, being identified in biopsies of skin carcinomas of EV patients.4 Serologic evidence of HPV8 has been shown to carry a 3-fold risk of cutaneous SCC in immunocompetent individuals.3 HPV5 was the first HPV genotype implicated in human cancer4 and is presumed to carry a similar risk. For patients with EV there is an increased susceptibility to all HPV types, but it is these carcinogenic genotypes that are most worrisome. The rates of cutaneous SCC in EV are increased because of a primary immunodeficiency toward HPV and a quantitative increase in skin lesions containing these HPV types.

The extensive HPV-infected lesions undergo malignant transformation with the development of Bowen’s type carcinoma in situ in up to 77% of EV patients.2–5 Invasive squamous cell carcinomas (SCCs) develop from these precancerous lesions in 30% to 70% of patients with EV and usually occur on sun-exposed areas in the third or fourth decade.2,5 Although generally localized tumors, regional and distant metastasis occur in about 25% of patients.5

It is therefore paramount that an effective treatment for invasive and metastatic SCC be developed for the treatment of highly advanced cases such as the one described here. Recent trials have shown clinical response and improved survival with cetuximab, an epidermal growth factor receptor inhibitor, and platin/5-fluorouracil for patients with recurrent and metastatic SCC of the head and neck.10

There are no specific therapies for EV-associated advanced SCC so treatment choices must be extrapolated from cases involving the head and neck and anogenital regions.2 We describe a case of metastatic and locoregionally invasive SCC of the perineum in the setting of EV treated previously with conventional therapies, now treated palliatively with capecitabine and cetuximab. A genome-wide linkage study to search for the genes implicated in EV has identified two susceptibility loci, one located in 17q25.3 and the other in 2p24.6 Two adjacent genes, EVER1 and EVER2, were discovered by analysis of the 17q25.3 region. The EVER genes, members of the novel transmembrane channel-like gene family,6 are partners with zinc transporter 1, a membrane protein important for zinc efflux and a central regulator of zinc homeostasis4; thus zinc is proposed as both a regulator of HPV gene expression, a limiting factor for HPV infectivity,4 and also an essential element of signaling pathways used by keratinocytes and immune cells in response to HPV infections.6 The sensitivity to HPV infections highlights EV as a primary immunodeficiency resulting in widespread cutaneous HPV-infected skin lesions.6 An effective treatment for EV has yet to be described. A number of therapies have shown promising results, including oral isotretinoin (0.8 mg/kg per day),7 a combination of acitretin and interferon alfa-2a,8 and oral cimetidine (40 mg/ kg per day).9 These therapies, however, are not universally accepted and often lead to recurrence of skin lesions after cessation of therapy. SKINmed. 2014;12:54–56

Based on these results, we initiated therapy with cetuximab and capecitabine, a prodrug of 5-fluorouracil, which has its final metabolic step take place within the tumor cell. Capecitabine has the advantage of being oral and can mimic continuous infusional 5-fluorouracil. It has shown activity in proliferative lesions of the oral mucosa.11 During the course of treatment, we saw an immediate palliative benefit with reduced pain and improved activities of daily living. We also noted an objective clinical response, with a reduction in tumor masses and induration. This response occurred in this heavily pretreated patient who underwent unsuccessful prior concurrent chemoradiation. Conclusions Although the skin lesions representative of EV are difficult to treat, early diagnosis and aggressive treatment of these lesions once they undergo malignant transformation is imperative. Cetuximab has been proven to be an effective treatment for SCC of the head and neck, and our case suggests it also has utility in treating recurrent SCC in other locations as well. Of interest, cetuximab has recently been reported to have significant activity in cutaneous SCC as well.12 More research into this combination’s efficacy in similar SCC seems warranted, but the palliative benefit and objective response gained with cetuximab and capecitabine in our case is encouraging and we suggest that this regimen be adopted earlier in the treatment of SCC.

Palliative Effect of Capecitabine and Cetuximab

January/February 2014

CASE STUDY

References 1 Lewandowsky F, Lutz W. Ein Fall einer bisher right beschriebenen Haüterkränkung (Epidermodysplasia verruciformis). Arch Derm Syph. 1922;141:193–203. 2 Gül Ü, Kiliç A, Gönül M, et al. Clinical aspects of epidermodysplasia verruciformis and review of the literature. Int J Derm. 2007;46:1069–1072. 3 Masini C, Fuchs PG, Gabrielli F, et al. Evidence for the association of human papillomavirus infection and cutaneous squamous cell carcinoma in immunocompetent individuals. Arch Derm. 2003;139:890–894. 4 Lazarczyk M, Cassonnet P, Pons C, et al. The EVER proteins as a natural barrier against papillomaviruses: a new insight into the pathogenesis of human papillomavirus infections. Microbiol Mol Biol Rev. 2009;73,2:348– 370. 5 de Oliveira WR, Neto CF, Rady PL, et al. Clinical aspects of epidermodysplasia verruciformis. J Eur Acad Dermatol Venereol. 2003;17:394–398. 6 Orth G. Host defenses against human papillomaviruses: lessons from epidermodysplasia verruciformis. Curr Top Microbiol Immunol. 2008;321:59–83.

7 Rallis E, Papatheodorou G, Bimpakis E, et al. Systemic low-dose isotretinoin maintains remission status in epidermodysplasia verruciformis. J Eur Acad Dermatol Venereol. 2008;22:523–525. 8 Anadolu R, Oskay T, Erdem C, et al. Treatment of epidermodysplasia verruciformis with a combination of acitretin and interferon alfa-2a. J Am Acad Derm. 2001;45:296–299. 9 Micali G, Nasca MR, Dall’Oglio F, et al. Cimetidine therapy for epidermodysplasia verruciformis. J Am Acad Derm. 2003;48:S9–S10. 10 Specenier P, Vermorken JB. Advances in the systemic treatment of head and neck cancers. Curr Opin Oncol. 2010;22:200–205. 11 Salesiotis A, Soong R, Diasio RB, et al. Capecitabine induces rapid, sustained response in two patients with extensive oral verrucous carcinoma. Clin Cancer Res. 2003;9:580–585. 12 Maubec E, Petrow P, Duvillard P, et al. Cetuximab as first-line monotherapy in patients with skin unresectable squamous cell carcinoma: final results of a phase II multicenter study. J Clin Oncol. 2010;28:15s.

Historical Diagnosis and treatment: epithelioma

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(Continued from page 47)

Palliative Effect of Capecitabine and Cetuximab

Finacea® (azelaic acid) Gel, 15% is a topical prescription medication used to treat inflammatory papules and pustules of mild to moderate rosacea.

Rosacea is with her wherever she goes. So is Finacea . ®

January/February 2014

Volume 12 • Issue 1

CASE STUDY

Nevus Comedonicus of the Scalp Feroze Kaliyadan, MD, DNB, MNAMS;1,3 Ajit Nambiar, MD, DNB;2 Ali Al Ameer, MD;1 Montassar Amri, MD1

A 10-year-old boy presented to us with a localized patch of hair loss on the scalp, first noticed by his mother a few months after birth. The lesion had shown very little increase in size since that time. There was a history of occasional redness and discharge from the lesion, which used to be controlled with topical applications. There was no history of any trauma to the site. There was no family history of any similar lesion or any associated systemic problems. On examination, grouped comedonal lesions were seen over a patch of partial alopecia located on the occipital area of the scalp (Figure 1). There was no evidence of inflammation. Systemic examination was normal. Biopsy specimen from the lesion on the scalp showed foci of wide and deep invaginations of the epidermis filled with keratin. There was no evidence of any significant perifollicular inflammatory infiltrate (Figure 2). A possibility of an atypical nevus comedonicus was considered. The patient was started on topical tretinoin 0.05% and is under follow-up. (SKINmed. 2014;12:59–60)

evus comedonicus (NC), first described by Kofmann in 1895, usually presents as groups of closely set dilated follicular openings with dark keratin plugs in the form of comedones.1 Approximately 50% of the cases of NC are evident at birth, with the other 50% developing during childhood, usually in patients before the age of 10 years. NC can occur as

isolated lesions or in combination with abnormalities in the central nervous system, skeletal system, skin, and eyes, called the NC syndrome. This syndrome is extremely rare and belongs to a large group of epidermal nevus syndromes.2 The underlying pathophysiology of NC is not completely understood. Some believe it represents growth dysregulation affecting the mesodermal portion

Figure 1. Alopecia with comedones over the occipital area of scalp.

Figure 2. Wide epidermal keratin-filled invaginations (hematoxylin and eosin stain, original magnification ×10).

From the Departments of Dermatology1 and Pathology,2 King Faisal University, Hofuf, Saudi Arabia; and Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala3 Address for Correspondence: Feroze Kaliyadan, Assistant Professor, Department of Dermatology/Internal Medicine, King Faisal University, Hofuf, Saudi Arabia • E-mail: ferozkal@hotmail.com

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CASE STUDY

of the pilosebaceous unit. NC is considered to belong to the group of epidermal nevi involving the hair follicle or an appendageal nevus of sweat ducts.3 A mutation of a fibroblast growth receptor (FGFR-2) has also been suggested as a possible etiology.4 Lesions are most commonly located on the face, neck, arms, chest, and abdomen, and often arranged in groups, bands, or in a linear pattern along Blaschko’s lines.5 One of the points against the diagnosis of NC in our case is that, as a rule, NC tends to be linear and follows Blaschko’s lines. There are, however, reports of NC occurring as clusters/interrupted lesions, and the only known entity seeming to somewhat satisfy the history, clinical finding, and histopathology taken together was NC.2,6 Our case appears to be similar to a case reported previously.6 Involvement of the scalp is considered to be very rare, although the reason for this is not known. To the best of our knowledge, only 6 cases have been reported in the literature.6–8

References 1 Kofmann S. A case of rare localization and spreading of comedones. Arch Dermatol Syph. 1895;32:177–178. 2 Happle R. The group of epidermal nevus syndromes Part I. Well defined phenotypes. J Am Acad Dermatol. 2010;63:1–22. 3 Lefkowitz A, Schwartz RA, Lambert WC. Nevus comedonicus. Dermatology. 1999;199:204–207. 4 Munro CS, Wilkie AO. Epidermal mosaicism producing localised acne: somatic mutation in FGFR2. Lancet. 1998;352:704–705. 5 Guldbakke KK, Khachemoune A, Deng A, Sina B. Naevus comedonicus: a spectrum of body involvement. Clin Exp Dermatol. 2007;32:488–492. 6 Ghaninezhad H, Ehsani AH, Mansoori P, Taheri A. Naevus comedonicus of the scalp. J Eur Acad Dermatol Venereol. 2006;20:184–185. 7 Peyri J, Ferrandiz C, Palou J, Mascaro JM. Comedo-Naevus of the palmoplantar and scalp regions. Med Cutan Ibero Lat Am. 1978;6:227–230.

Conclusions We present this case to highlight the need to consider NCin the differential diagnosis when suggestive lesions are present, even on atypical sites such as the scalp.

8 Paige TN, Mendelson CG. Bilateral nevus comedonicus. Arch Dermatol. 1967;96:172–175.

Wax Moulage

“Naevi coerulei”, multiple blue nevi in a child with lentiginosis. Moulage No. 250-253, made by Lotte Volger in 1927 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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Nevus Comedonicus of the Scalp

Presented by TSLMS

Music City

January/February 2014

Volume 12 • Issue 1

Symposium for Cosmetic Advances & Laser Education

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Make plans now to attend the 2014 TSLMS meeting featuring world-renowned faculty! Rox Anderson, MD Brian Biesman, MD Michael H. Gold, MD Patrick J. Clark

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SKINmed. 2014;12:000–000

January/February 2014

Volume 12 • Issue 1

correspondence

Disseminated Extragenital Lichen Sclerosus et Atrophicus Treated With Acitretin Aurenita de Assis Formiga, MD;1 Isabelle de Souza Medeiros Torres, MD;2 Bruno de Oliveira Rocha, MD;1 Anete Olivieri Pessoa Silva, MD;1 Ivonise Follador, MD, MSc, PhD;1 Vitória Regina Pedreira de Almeida Rêgo, MD, MSc;1 Maria de Fátima Santos Paim de Oliveira, MD, MSc, PhD1 To the Editor: Lichen sclerosus et atrophicus (LSA) is a chronic cutaneous inflammatory disease of unknown etiology,1,2 occurring especially in postmenopausal women,1-4 commonly at the anogenital region.2-4 Opinions about the utility of acitretin for treating extra-genital LSA found in the literature are controversial, and no clear evidence is available.2,3 A 61-year-old woman presented with a 1-year history of progressive lesions starting on the right thigh and genitalia and evolving

to other areas. Physical examination revealed hypopigmented, atrophic, and shiny extensive plaques involving the breasts, abdomen, elbow, and right thigh (Figure 1a–1c). Hypopigmented macules were also observed in the vulva. Histopathologic examination showed epidermis with hyperkeratosis and marked atrophy, subepidermal edema over a band-like area of fibrosis, papillary dermis with fibrous collagenized tissue, and mononuclear inflammatory infiltration (Figure 1d–1e). Both clinical and histopathologic findings were consistent with the diagnosis of LSA.

Figure 1. Extensive hypopigmented, atrophic, and shiny plaques involving the abdomen (a and b), breast (a) and right thigh (c); Superficial dermis with sclerosis and underlying mild and band-like mononuclear inflammatory infiltrate (hematoxylin and eosin stain, original magnification ×125) (d); Detail of sclerosis in the superficial dermis with a mild and band-like mononuclear inflammatory infiltrate (hematoxylin and eosin stain, original magnification ×250) (e).

From the Department of Dermatology1 and Pathology,2 Complexo Hospitalar Universitário Prof. Edgard Santos, Federal University of Bahia, Salvador, Bahia, Brazil Address for Correspondence: Maria de Fátima Santos Paim de Oliveira, Artesão João da Prata Street, 267, Room 602, Itaigara, Salvador, Bahia, Brazil 41.815-210 • E-mail: mfatimapaim@gmail.com

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Systemic treatment with acitretin was started, with improvement of lesions and itching in the first month of therapy. A 1-year treatment regimen of acitretin was completed, with significant regression and repigmentation of the lesions (Figure 2) without significant side effects or abnormalities in laboratory studies. After 2 years of follow-up, the patient currently remains without recurrence of lesions. LSA was first formally described in 1889 by Hallopeau.5 Later, Darier (1892) described the histopathologic features of this condition.6 It is a chronic inflammatory disease that mainly affects the anogenital region, but 15% to 20% of patients have other sites affected.6-8 Women are affected up to 10 times more than men, especially those who are postmenopausal, when there is a peak of incidence.5–7 Our patient was at the typical age of onset and presented with extensive extra-genital lesions, which occur in a minority of patients.8

Figure 2. The aspect of lesions after 1 year of treatment showing complete improvement of atrophy and significant repigmentation of the lesions in the abdomen (a and b), breast (a), and right thigh (c).

Typical extragenital lesions are small atrophic, hypochromic, and shiny plaques, mainly occurring in the submammary region, shoulders, neck, and wrist. Pruritus of varying degrees can be observed.6 Our patient presented with compatible lesions and anatomopathologic features, but the size of the lesions makes this case unusual.

of our patient reinforces the importance of acitretin as a promising drug for relieving signs and symptoms of not only genital but also extra-genital and extensive LSA. We emphasize that the use of this medication should be restricted to cases of more severe and refractory disease, in an intermittent manner, because of the side effects of the drug, with possible worsening of comorbidities.

Treatment aims to relieve symptoms and prevent disease progression, major sequelae, and malignant transformation of the genital area.2,4 Current available treatment include topical corticosteroids,1–4 testosterone propionate, and topical and systemic retinoids,2-4 with varying responses and sometimes prolonged use.1 Our patient did not respond to the first-line treatment. Because of the disease extension, insisting on the use of topical corticosteroids could lead to serious side effects. The general health status of the patient allowed us to try acitretin.

References 1 Dalziel K, Shaw S. Lichen sclerosus. BMJ. 2010;340:731. 2 Basak PY, Basak K. Lichen sclerosus et atrophicus of the scalp: satisfactory response to acitretin. J Eur Acad Dermatol Venereol. 2002;16:183–185. 3 Bousema MT, Romppanen U, Geiger JM, et al. Acitretin in the treatment of severe lichen sclerosus et atrophicus of the vulva: a double-blind, placebo-controlled study. J Am Acad Dermatol. 1994;30:225–231. 4 Pugliese JM, Morey AF, Peterson AC. Lichen sclerosus: review of the literature and current recommendations for management. J Urol. 2007;178:2268–2276.

The majority of studies on the treatment of LSA demonstrates the effectiveness of acitretin in genital disease, having also been used to control lesions in other locations with varying results.2,4 Although the exact mechanisms of retinoids in autoimmune inflammatory diseases are not completely known, it is proposed that the downregulation of proinflammatory transcription factors (activator protein-1) may lead to decreased transcription of metalloproteinases and collagenases.9 Since acitretin works on cell proliferation and differentiation, it was hypothesized that the effect of acitretin in LSA could be attributed to the improvement of the hyperkeratotic factors related to this condition.3

5 Hallopeau H. Leçons clinique sur les maladies cutanées et syphilitique. Union Med. 1887;43:742–747. 6 Röcken M, Ghoreschi K. Morphea and Lichen Sclerosus. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Bolognia Dermatology. 3rd ed. Philadelphia, PA: Saunders; 2012: chap 96. 7 Habif TP. Psoriasis and other papulosquamous. In: Habif TP, ed. Habif: Clinical Dermatology. 5th ed. Philadelphia, PA: Mosby; 2009: chap 8. 8 Coelho WS, Diniz LM, Souza Filho JB. Líquen escleroso e atrófico – relato de dois casos de apresentação atípica. An Bras Dermatol. 2006;81(5 suppl 3):S297–S300. 9 Pandya AG, Costner MI. Retinoid Therapy and Autoimmune Skin Disease. In: Vahlquist A, Duvic M, eds. Retinoids and Carotenoids. 1st ed. New York, NY: Informa Healthcare; 2007:197–202.

Unfortunately, treatment is not curative,3,4 with possible recurrence,3 and may present a chronic and progressive or cyclical course with periods of remission.4 The improvement in the lesions SKINmed. 2014;12:62–66

Disseminated Extragenital Lichen Sclerosus et Atrophicus

January/February 2014

CORRESPONDENCE

Bilateral Segmental Eruptive Lentiginosis in a Patient With a History of Hepatocellular Carcinoma Yen Tun Wang, MD;1 Emma Taylor, MD;2 Scott Binder, MD;3 Hilary Mandel, MD2 To the Editor: We present a case of a 70-year-old man with a history of hepatocellular carcinoma who developed eruptive bilateral segmental lentigines. Paraneoplastic phenomena in the skin have been well-documented, ranging from malignant acanthosis nigricans to eruptive seborrheic keratoses. These signs may be early clues to internal malignancy, and are therefore important to clinically identify. A few documented cases of eruptive acral lentigines in association with malignant neoplasms have been previously described.1,2 Specifically, these lentigines were associated with large cell lymphoma of the bowel, breast cancer, adenocarcinoma of the stomach, melanoma, and non-Hodgkin’s lymphoma.1,2 To our knowledge, however, there is only one other previous report of segmental lentiginosis in the setting of malignancy.3 Clinical Case We present a rare case of bilateral eruptive lentigines with a segmental, or Blaschkoid, distribution in a 70-year-old Caucasian man with a history of end-stage renal disease and hepatocellular carcinoma secondary to chronic hepatitis C infection that was treated with radiofrequency ablation 1 year prior to the current presentation. During a 3-month period, the patient developed 30 pounds of unintentional weight loss and numerous brown macules on the bilateral temples, central neck, upper back, and upper chest (Figure 1). Interestingly, he also developed light brown macules arranged linearly with a Blaschkoid or segmental distribution on the bilateral arms (Figure 2). These lesions were generally asymptomatic, although the patient occasionally complained of pruritus. There had been no new medications, dietary changes, or recent travel. Histological sampling from a characteristic lesion demonstrated an atrophic epidermis with basilar hyperpigmentation consistent with a lentigo (Figure 3).

Figure 1. Brown macules on the bilateral temples (right temple illustrated here) of our patient over the course of 3 months.

Discussion Skin lesions that often follow Blaschko’s lines include epidermal nevi, hypomelanosis of Ito, lichen striatus, lichen planus, and those seen in incontinentia pigmenti, CHILD syndrome, and systemic lupus erythematosus.4 The Blaschkoid distribution initially led us to believe that the brown macules were flat seborrheic keratoses. Eruptive seborrheic keratoses can be a manifestation of internal malignancy, associated mainly with gastrointestinal adenocarcinomas, but can also be seen in malignancies of the breast, lung, and genitourinary tract in a finding known as the Sign of Leser-Trelat.5,6

From the Division of Dermatology, Ronald Reagan UCLA Medical Center, Los Angeles, CA;1 the Department of Dermatology, Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA;2 and the Department of Pathology and Laboratory Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, CA3 Address for Correspondence: Yen Wang, MD, 200 UCLA Medical Plaza, Suite 450, Los Angeles, CA 90095 • E-mail: ywang@mednet.ucla.edu

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Bilateral Segmental Eruptive Lentiginosis

January/February 2014

CORRESPONDENCE

Figure 3. Characteristic brown macules on the patient’s arm reveals atrophic epidermis with basilar hyperpigmentation, consistent with a diagnosis of lentigo. Hematoxylin and eosin stain section (original magnification ×40).

Figure 2. (a, b) Asymptomatic light brown macules on the bilateral arms following a linear Blaschkoid distribution.

After biopsy results indicated that the lesions in our patient were lentigines and not seborrheic keratoses, we remained concerned that the cutaneous manifestation in our patient may still represent a paraneoplastic process. Luckily for our patient, liver function test results were normal and a computed tomography scan of the abdomen performed for hepatocellular carcinoma follow-up showed no recurrence of the tumor. We will be following the patient closely given the new cutaneous findings. Our case report of eruptive Blaschkoid lentigines or lentiginosis in the setting of hepatocellular carcinoma provides additional documentation that new-onset lentigines may rarely represent a paraneoplastic phenomenon. We encourage clinicians to pursue malignancy screening for patients who present with eruptive segmental lentigines.

References 1 Wolf R, Lipozencic J, Segal Z, Davidovici B. Eruptive acral lentigines—a new paraneoplastic sign? Acta Dermatovenerol Croat. 2008;16:130–132. 2 Wolf R, Orion E, Davidovici B. Acral lentigines: a new paraneoplastic syndrome. Int J Dermatol. 2008;47:168–170. 3 González-Sixto B, Flórez A, Conde Taboada A, et al. Bilateral segmental lentiginosis associated with malignant melanomas. J Eur Acad Dermatol Venereol. 2008;22:1262–1263. 4 Bolognia JL, Orlow SJ, Glick SA. Lines of Blaschko. J Am Acad Dermatol. 1994;31:157–190. 5 Gregory B, Ho VC. Cutaneous manifestations of gastrointestinal disorders. Part I. J Am Acad Dermatol. 1992;26:153–166. 6 Rigel DS, Jacobs MI. Malignant acanthosis nigricans: a review. J Dermatol Surg Oncol. 1980;6:923.

Continuing Medical Education II and What It Is Christopher B. Zachary, MBBS, FRCP To the Editor:

Affordable Care Act

I read with interest the editorial “Continuing Medical Education II: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, Etcetera et Ad Nauseum,1” a sad but accurate assessment of the current requirements placed on physicians and medical education programs in the United States.

The diabolical expansion of healthcare regulations is largely unnecessary, extremely costly, and provides little benefit to patient care. It is intellectually stifling and a major disincentive to technological and pharmaceutical advancement. At this time of cost containment through the ever-changing ro-

From the University of California, Irvine, College of Medicine, Irvine, CA Address for Correspondence: Christopher B. Zachary, MBBS, FRCP, Professor and Chair of Dermatology, University of California, Irvine, College of Medicine, Irvine, CA • E-mail: czachary@uci.edu

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January/February 2014

CORRESPONDENCE

leout of the Affordable Care Act, we need to consider a simplification of regulations concerning compliance and provide our colleagues with comprehensible and logical goalposts that facilitate education without the big stick that currently wags in our faces. Government Inerference Why would any of us go to the trouble of providing lectures at our national meetings only to be subjected to arbitrary inspection to exclude bias and commercialization? I would argue that personal bias is inherent in every lecturer, and blind obfuscation of trade names of drugs and devices only serves to confuse the audience. Professionals need to be professional without being marched through the confessional. And our medical audiences should be expected to have critical analysis as part of their training. We can’t afford to babysit them. They should vote with their feet if a presentation lacks credibility. It’s not unusual for physicians to have to complete 40 hours annually of compliance instruction, ranging from elevator training (Long Beach, VA) to pain management and end-of-life courses. While some of these subjects are incredibly important, mandating individual training sessions tends to trivialize other aspects of patient care that are just as vital. These should all be included during the medical school years.

More Regulation There seems to be a never-ending augmentation of the regulatory process. The recertification process represents a pendulum that has swung all the way to the right . . . and is stuck. Where will it all end? And please, would someone show me how all these regulations have helped our patients? Finally, the private practitioner is drowning in alphabet soup while trying to be a good doctor. These physicians are effectively running small businesses and finding that good medicine is not necessarily a byproduct of overregulation. There is a fear factor, in part related to malpractice issues and in part Medicare/medical audits, that induces wasteful practices and does little to heal the sick. Conclusions Physicians as a group are pretty quiescent and tolerate legislation without being too perturbed. So while my comments will sound reactive and emotional to some, I also understand that it serves no purpose whining. I therefore instead suggest a review of the various requirements and regulations and ask whether each benefits our patients, and let them stand or fall on their own merits. Reference 1 Lambert WC, Parish LC. Continuing medical education II: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, etcetera et ad nauseum. SKINmed. 2013;11:262–263.

More on Continuing Medical Education II Stephen Mandy, MD contrary that the longer we practice the more intuitive we become.

To the Editor: I send you a congratulatory letter on your Editorial in the September–October issue.1

It is quite evident that you are correct in your assertion that money and power flow to regulators in an affront to anyone who appreciates a conflict of interest. This is a flawed system very much in need of reform.

I have repeatedly argued on the Boards of both the American Society for Dermatologic Surgery (ASDS) and the American Academy of Dermatology (AAD) of the absurdity of the entire CME quagmire. Modern medicine insists on “evidence-based” studies but sadly lacking is the hard evidence that physicians actively practicing their specialties lose their once-certified skills. The famous author Malcolm Gladwell argues quite to the

Thanks for having the courage to fly into the wind! Reference 1 Lambert WC, Parish LC. Continuing medical education II: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, etcetera et ad nauseum. SKINmed. 2013;11:262–263.

From Private Practice, Miami Beach, FL Address for Correspondence: Stephen Mandy, MD, 555 Washington Avenue, Suite 210, Miami Beach, FL 33139 • E-mail: steve@mandymd.com

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