Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology.

The incidence of primary cutaneous melanoma has been increasing dramatically for several decades. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is nearly always curative with early detection of disease. In this update of the guidelines of care, we will discuss the treatment of patients with primary cutaneous melanoma. We will discuss biopsy techniques of a lesion clinically suspicious for melanoma and offer recommendations for the histopathologic interpretation of cutaneous melanoma. We will offer recommendations for the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, we will provide recommendations for surgical margins and briefly discuss nonsurgical treatments. Finally, we will discuss the value and limitations of sentinel lymph node biopsy and offer recommendations for its use in patients with primary cutaneous melanoma.

Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In the first 5 parts of the American Academy of Dermatology Psoriasis Guidelines of Care, we have presented evidence supporting the use of topical treatments, phototherapy, traditional systemic agents, and biological therapies for patients with psoriasis and psoriatic arthritis. In this sixth and final section of the Psoriasis Guidelines of Care, we will present cases to illustrate how to practically use these guidelines in specific clinical scenarios. We will describe the approach to treating patients with psoriasis across the entire spectrum of this fascinating disease from mild to moderate to severe, with and without psoriatic arthritis, based on the 5 prior published guidelines. Although specific therapeutic recommendations are given for each of the cases presented, it is important that treatment be tailored to meet individual patients' needs. In addition, we will update the prior 5 guidelines and address gaps in research and care that currently exist, while making suggestions for further studies that could be performed to help address these limitations in our knowledge base.

American Academy of Dermatology evidence-based guideline development process: responding to new challenges and establishing transparency.

BACKGROUND: Evidence-based clinical guidelines are developed to educate and inform physicians about best practices in patient care, and assist providers in the application of treatments and technologies that can improve outcomes. Clinical guidelines also aid appeal of payment decisions; serve as the basis for quality measure development, appropriateness criteria, and maintenance of certification modules; and help identify areas for further clinical research. OBJECTIVE: For guidelines to serve dermatologists effectively in these diverse roles, they must be current, varied in clinical focus, and developed with a high degree of rigor that includes attention to potential conflicts of interest. METHOD: To address these needs and keep pace with advances in medicine, the American Academy of Dermatology (AAD) recently revised the evidence-based guideline development process. RESULTS: Key changes include development of a yearly needs assessment process to determine what guidelines are most needed, the development of focused guidelines that address rapidly evolving clinical topics, a formal method of vetting guidelines produced by other societies, and a scheduled reassessment of existing guidelines to ensure they provide current and practical information. The process for identifying and managing potential conflicts of interest was also revised and expanded to meet current expectations and evolving standards. LIMITATIONS: The impact of these changes to the AAD's guideline development process will not be fully realized for several years. CONCLUSIONS: These changes will help ensure the AAD will be able to provide its members with continued evidence-based guidance to support patient care across the scope of dermatologic practice.

Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this fifth of 6 sections of the guidelines of care for psoriasis, we discuss the use of ultraviolet (UV) light therapy for the treatment of patients with psoriasis. Treatment should be tailored to meet individual patients' needs. We will discuss in detail the efficacy and safety as well as offer recommendations for the use of phototherapy, including narrowband and broadband UVB and photochemotherapy using psoralen plus UVA, alone and in combination with topical and systemic agents. We will also discuss the available data for the use of the excimer laser in the targeted treatment of psoriasis. Finally, where available, we will summarize the available data that compare the safety and efficacy of the different forms of UV light therapy.

Estimating uncertainty in brain region delineations.

This paper presents a method for estimating uncertainty in MRI-based brain region delineations provided by fully-automated segmentation methods. In large data sets, the uncertainty estimates could be used to detect fully-automated method failures, identify low-quality imaging data, or endow downstream statistical analyses with per-subject uncertainty in derived morphometric measures. Region segmentation is formulated in a statistical inference framework; the probability that a given region-delineating surface accounts for observed image data is quantified by a distribution that takes into account a prior model of plausible region shape and a model of how the region appears in images. Region segmentation consists of finding the maximum a posteriori (MAP) parameters of the delineating surface under this distribution, and segmentation uncertainty is quantified in terms of how sharply peaked the distribution is in the vicinity of the maximum. Uncertainty measures are estimated through Markov Chain Monte Carlo (MCMC) sampling of the distribution in the vicinity of the MAP estimate. Experiments on real and synthetic data show that the uncertainty measures automatically detect when the delineating surface of the entire brain is unclear due to poor image quality or artifact; the experiments cover multiple appearance models to demonstrate the generality of the method. The approach is also general enough to accommodate a wide range of shape models and brain regions.

Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this fourth of 6 sections of the guidelines of care for psoriasis, we discuss the use of traditional systemic medications for the treatment of patients with psoriasis. Treatment should be tailored to meet individual patients' needs. We will discuss in detail the efficacy and safety, and offer recommendations for the use of the 3 most commonly used, and approved, traditional systemic agents: methotrexate, cyclosporine, and acitretin. We will also briefly discuss the available data for the use of azathioprine, fumaric acid esters, hydroxyurea, leflunomide, mycophenolate mofetil, sulfasalazine, tacrolimus, and 6-thioguanine in psoriasis.

Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies.

Psoriasis is a common, chronic, inflammatory, multi-system disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this third of 6 sections of the guidelines of care for psoriasis, we discuss the use of topical medications for the treatment of psoriasis. The majority of patients with psoriasis have limited disease (<5% body surface area involvement) and can be treated with topical agents, which generally provide a high efficacy-to-safety ratio. Topical agents may also be used adjunctively for patients with more extensive psoriasis undergoing therapy with either ultraviolet light, systemic or biologic medications. However, the use of topical agents as monotherapy in the setting of extensive disease or in the setting of limited, but recalcitrant, disease is not routinely recommended. Treatment should be tailored to meet individual patients' needs. We will discuss the efficacy and safety of as well as offer recommendations for the use of topical corticosteroids, vitamin D analogues, tazarotene, tacrolimus, pimecrolimus, emollients, salicylic acid, anthralin, coal tar, as well as combination therapy.

Sinecatechins, a defined green tea extract, in the treatment of external anogenital warts: a randomized controlled trial.

OBJECTIVE: To estimate the clinical efficacy of topical sinecatechins, a defined green tea extract, in the treatment of external genital and perianal warts. METHODS: This was a randomized, double-blind, vehicle-controlled trial involving 502 male and female patients aged 18 years and older, with 2-30 anogenital warts ranging from 12 to 600 mm(2) total wart area. Patients applied sinecatechins ointment 15% or 10% or vehicle (placebo) three times daily for a maximum of 16 weeks or until complete clearance of all warts, followed by a 12-week treatment-free follow-up to assess recurrence. RESULTS: Complete clearance of all baseline and newly occurring warts was obtained in 57.2% and 56.3% of patients treated with sinecatechins ointment 15% and 10%, respectively, compared with 33.7% for vehicle (both P<.001). Significance was observed at weeks 4 and 6 and all subsequent visits. Numbers needed to treat were 4.3 and 4.4. Partial clearance rates of at least 50% were reported for 78.4% and 74.0% of patients in the sinecatechins ointment 15% and 10% groups compared with 51.5% of vehicle patients. During follow-up, recurrence of any wart was observed in 6.5%, 8.3%, and 8.8% in the sinecatechins ointment 15% group, sinecatechins ointment 10% group, and vehicle patients, respectively. A total of 3.7%, 8.3%, and 0.0% developed new warts, respectively. A total of 87.7% and 87.3% of patients in the sinecatechins ointment 15% and 10% groups, and 72.1% of vehicle patients experienced application site reactions; 49.2%, 46.2%, and 65.4% of those, respectively, were mild or moderate. CONCLUSION: Topical sinecatechins ointments 15% and 10% are effective and well-tolerated in the treatment of anogenital warts. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00449982. LEVEL OF EVIDENCE: I.

Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this first of 5 sections of the guidelines of care for psoriasis, we discuss the classification of psoriasis; associated comorbidities including autoimmune diseases, cardiovascular risk, psychiatric/psychologic issues, and cancer risk; along with assessment tools for skin disease and quality-of-life issues. Finally, we will discuss the safety and efficacy of the biologic treatments used to treat patients with psoriasis.

Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics.

Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this second of 5 sections of the guidelines of care for psoriasis, we give an overview of psoriatic arthritis including its cardinal clinical features, pathogenesis, prognosis, classification, assessment tools used to evaluate psoriatic arthritis, and the approach to treatment. Although patients with mild to moderate psoriatic arthritis may be treated with nonsteroidal anti-inflammatory drugs and/or intra-articular steroid injections, the use of disease-modifying antirheumatic drugs, particularly methotrexate, along with the biologic agents, are considered the standard of care in patients with more significant psoriatic arthritis. We will discuss the use of disease-modifying antirheumatic drugs and the biologic therapies in the treatment of patients with moderate to severe psoriatic arthritis.

Recent progress on the topical therapy of onychomycosis.

Onychomycosis is a fungal infection of the fingernails and toenails that results in thickening, discoloration, splitting of the nails and lifting of the nail from the nail bed. The disease is caused by dermatophytes and has a high incidence within the general population, especially among older individuals. Present treatment options include both oral and topical drugs, with oral therapies giving better outcomes; however, neither of these treatment options provides high cure rates that are durable. The difficulty in treating onychomycosis results from the deep-seated nature of the infection within the nail unit (nail plate, nail bed and surrounding tissue) and the inability of drugs to effectively reach all sites. Ongoing drug development activities have focused on novel delivery technologies to facilitate penetration of existing antifungal drugs through the nail plate and on the discovery of inherently penetrable antifungals. AN-2690 represents an oxaborole antifungal that is designed to penetrate the nail plate and is showing promising results in clinical trials.

A look at the safety of metronidazole 1% gel: cumulative irritation, contact sensitization, phototoxicity, and photoallergy potential.

Rosacea is a common, recurrent, inflammatory dermatologic disorder characterized by the presence of facial erythema, visible blood vessels, papules, and pustules. The condition may cause serious psychologic morbidity and may significantly affect quality of life. The first topical rosacea therapy approved by the US Food and Drug Administration was metronidazole for the treatment of inflammatory lesions and erythema. Previously, metronidazole was available as a 0.75% gel. Improved solubility was achieved in a new, stable, aqueous gel that permitted the formulation of metronidazole 1.0%. This new formulation is highly spreadable, easy to use, cosmetically friendly, mild to the skin, nondrying, and moisturizing. The safety of metronidazole 1% gel was determined by the evaluation of its cumulative irritation, contact sensitization, phototoxicity, and photoallergy potential in healthy male and female patients. In this formulation, metronidazole was not irritating under occlusive application. Additionally, metronidazole 1% gel had a low potential for causing sensitization reactions, and no evidence suggested phototoxic or photoallergic reactions.

A randomized controlled trial of a replication defective (gH deletion) herpes simplex virus vaccine for the treatment of recurrent genital herpes among immunocompetent subjects.

BACKGROUND: A replication incompetent herpes virus lacking the glycoprotein H gene has been developed as a potential therapeutic vaccine for genital herpes. GOAL: To determine vaccine efficacy on reducing HSV reactivation and clinical disease among immunocompetent persons with recurrent genital HSV-2 infection. STUDY DESIGN: Randomized multicenter placebo-controlled trial. Healthy volunteers who had six or more recurrences of genital herpes per year were randomized to receive injections of vaccine at 0 and 8 or 0, 4, and 8 or 0, 2, 4, and 8 weeks or placebo and were followed for subsequent recurrences for 1 year. RESULTS: The median times to first recurrence of genital herpes (40 days versus 30 days versus 37 days versus 42 days, respectively), mean number of recurrences (3 versus 3 versus 2.4 versus 1.9, respectively), and time to lesion healing of the first recurrence (8 days versus 7.8 days versus 7.4 days versus 7.5 days, respectively), were similar for all treatment groups. Asymptomatic viral shedding was detected by PCR in 61/74 (82%) persons performing daily sample collection following completion of the vaccination series. No differences were noted in the proportion of days with shedding between treatment groups (11.9% versus 17.2% versus 13.1% versus 16.4%, respectively). CONCLUSION: This replication incompetent HSV-2 vaccine lacking the glycoprotein H gene was safe but had no clinical or virologic benefit in the amelioration of genital HSV-2 disease among immunocompetent men and women.

Emerging therapies for herpes viral infections (types 1 - 8).

There are eight members of the herpesviridae family: herpes simplex virus-1 (HSV-1), HSV-2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, human herpes virus-6, human herpes virus-7 and human herpes virus-8. The diseases caused by viruses of the herpesviridae family are treated with and managed by systemic and topical antiviral therapies and immunomodulating drugs. Because these viruses establish a latent state in hosts, antiherpetic agents, such as nucleoside analogues, only control symptoms of disease or prevent outbreaks, and cannot cure the infections. There is a need for treatments that require less frequent dosing, can be taken even when lesions are more advanced than the first signs or symptoms, and can treat resistant strains of the viruses without the toxicities of existing therapies. Immunomodulating agents, such as resiquimod, can act on the viruses indirectly by inducing host production of cytokines, and can thereby reduce recurrences of herpes. The new helicase primase inhibitors, which are the first non-nucleoside antiviral compounds, are being investigated for treatment of HSV disease, including infections resistant to existing therapy.

Once-daily valacyclovir to reduce the risk of transmission of genital herpes.

BACKGROUND: Nucleoside analogues against herpes simplex virus (HSV) have been shown to suppress shedding of HSV type 2 (HSV-2) on genital mucosal surfaces and may prevent sexual transmission of HSV. METHODS: We followed 1484 immunocompetent, heterosexual, monogamous couples: one with clinically symptomatic genital HSV-2 and one susceptible to HSV-2. The partners with HSV-2 infection were randomly assigned to receive either 500 mg of valacyclovir once daily or placebo for eight months. The susceptible partner was evaluated monthly for clinical signs and symptoms of genital herpes. Source partners were followed for recurrences of genital herpes; 89 were enrolled in a substudy of HSV-2 mucosal shedding. Both partners were counseled on safer sex and were offered condoms at each visit. The predefined primary end point was the reduction in transmission of symptomatic genital herpes. RESULTS: Clinically symptomatic HSV-2 infection developed in 4 of 743 susceptible partners who were given valacyclovir, as compared with 16 of 741 who were given placebo (hazard ratio, 0.25; 95 percent confidence interval, 0.08 to 0.75; P=0.008). Overall, acquisition of HSV-2 was observed in 14 of the susceptible partners who received valacyclovir (1.9 percent), as compared with 27 (3.6 percent) who received placebo (hazard ratio, 0.52; 95 percent confidence interval, 0.27 to 0.99; P=0.04). HSV DNA was detected in samples of genital secretions on 2.9 percent of the days among the HSV-2-infected (source) partners who received valacyclovir, as compared with 10.8 percent of the days among those who received placebo (P<0.001). The mean rates of recurrence were 0.11 per month and 0.40 per month, respectively (P<0.001). CONCLUSIONS: Once-daily suppressive therapy with valacyclovir significantly reduces the risk of transmission of genital herpes among heterosexual, HSV-2-discordant couples.