A seamless phase I/II dose-finding trial assessing ingenol disoxate (LEO 43204) for field treatment of actinic keratosis on the scalp.

BACKGROUND: Actinic keratosis (AK) is a common sun-related skin condition, which can progress to squamous cell carcinoma and occur in cancerized fields. OBJECTIVES: To investigate in a phase I/II trial the safety and efficacy of ingenol disoxate as topical field therapy for patients with AK on the balding scalp. METHODS: Part 1 was a phase I, open-label, dose-escalation trial investigating up to six doses of ingenol disoxate to determine the maximum tolerated dose (MTD). Part 2 was a phase II, randomized, double-blind, parallel group, vehicle-controlled trial. Patients were randomized 2 : 2 : 1 to receive ingenol disoxate 0·037%, 0·05% or vehicle gel once daily for two consecutive days. Percentage reduction in AK count from baseline, complete clearance (AKCLEAR 100) and partial clearance (≥ 75% AK count reduction; AKCLEAR 75) were assessed at week 8. RESULTS: The MTD in part 1 was 0·075% based on a dose-dependent increase in the number and severity of adverse events. Two lower doses of ingenol disoxate gel (0·037%, 0·05%) were assessed in part 2, which showed a reduction in AK count from baseline to week 8 (0·037%, 72·7%; 0·05%, 78·5% vs. vehicle 12·6; P < 0·001), and rates of AKCLEAR 100 and AKCLEAR 75 were significantly higher in active treatment groups compared with vehicle (P ≤ 0·007). Local skin responses peaked at day 3 and declined rapidly. Adverse events were generally mild to moderate in intensity, and were most commonly application site pain/pruritus. CONCLUSIONS: Ingenol disoxate 0·037% and 0·05% gel was effective and superior to vehicle, and well tolerated as field therapy for AK on the balding scalp.

AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery.

The appropriate use criteria process synthesizes evidence-based medicine, clinical practice experience, and expert judgment. The American Academy of Dermatology in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery has developed appropriate use criteria for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered based on tumor and patient characteristics. This document reflects the rating of appropriateness of MMS for each of these clinical scenarios by a ratings panel in a process based on the appropriateness method developed by the RAND Corp (Santa Monica, CA)/University of California-Los Angeles (RAND/UCLA). At the conclusion of the rating process, consensus was reached for all 270 (100%) scenarios by the Ratings Panel, with 200 (74.07%) deemed as appropriate, 24 (8.89%) as uncertain, and 46 (17.04%) as inappropriate. For the 69 basal cell carcinoma scenarios, 53 were deemed appropriate, 6 uncertain, and 10 inappropriate. For the 143 squamous cell carcinoma scenarios, 102 were deemed appropriate, 7 uncertain, and 34 inappropriate. For the 12 lentigo maligna and melanoma in situ scenarios, 10 were deemed appropriate, 2 uncertain, and 0 inappropriate. For the 46 rare cutaneous malignancies scenarios, 35 were deemed appropriate, 9 uncertain, and 2 inappropriate. These appropriate use criteria have the potential to impact health care delivery, reimbursement policy, and physician decision making on patient selection for MMS, and aim to optimize the use of MMS for scenarios in which the expected clinical benefit is anticipated to be the greatest. In addition, recognition of those scenarios rated as uncertain facilitates an understanding of areas that would benefit from further research. Each clinical scenario identified in this document is crafted for the average patient and not the exception. Thus, the ultimate decision regarding the appropriateness of MMS should be determined by the expertise and clinical experience of the physician.

Poly-L-lactic acid as a facial filler.

Poly-L-lactic acid is a filler recently approved by the US FDA for the correction of facial lipoatrophy in patients infected with the human immunodeficiency virus (HIV). Currently, poly-L-lactic acid, sold under the brand name Sculptratrade mark (Dermik), is the only product approved by the FDA specifically for this indication. The market for poly-L-lactic acid will likely be larger than the HIV-infected population, as physicians use poly-L-lactic acid off-label to correct lipoatrophy associated with the normal aging process in non-HIV-infected patients. The benefits of poly-L-lactic acid are limited by the fact that multiple treatments are necessary to achieve the desired correction; its results are temporary and its cost is high.

LY191704 inhibits type I steroid 5 alpha-reductase in human scalp.

Conversion of testosterone to dihydrotestosterone (DHT) has been demonstrated to be catalyzed by two isoforms of steroid 5 alpha-reductase, designated types I and II. Although several classes of steroid-based inhibitors of the type II isoform have been identified, these agents have not demonstrated highly selective pharmacological activity against human type I 5 alpha-reductase. LY191704 is representative of a series of nonsteroidal agents that have potent [apparent inhibitory constant (Ki) = 11.3 nM] inhibitory activity in human scalp skin homogenates (pH 7.5), a source of type I 5 alpha-reductase. [3H]-DHT production in the presence and absence of LY191704 is consistent with a noncompetitive mode of inhibition. In human prostatic homogenates (pH 5.5), a source of type II 5 alpha-reductase, LY191704 is virtually inactive as an inhibitor [concentration of inhibitor producing 50% inhibition of enzymatic activity (IC50) > 1,000 nM] of [3H]-DHT formation. LY191704 does not inhibit the type I or type II isoforms of rat 5 alpha-reductase, nor does the compound compete for binding to the murine androgen receptor expressed in SF9 cells using a baculo virus expression system. The benzoquinolinones, as exemplified by LY191704, possess exquisite pharmacological selectivity and provide a tool to understand the role of human type I 5 alpha-reductase in normal and pathophysiological states. These agents may also find clinical utility in treating androgen-dependent dermatological conditions.

Quantitative assessment of burn injury in porcine skin with high-frequency ultrasonic imaging.

Early excision and grafting of full thickness burns has been shown to decrease morbidity and mortality. Errors made in assessing acute burn depth are common and result in prolonged hospitalization in expectant healing of full-thickness burns and in unnecessary excision and grafting of potentially regenerative partial-thickness burns. High-frequency ultrasonic imaging may be a noninvasive, convenient means of quantitating burn depth. A depth analysis system for imaging burned skin was developed using a high-frequency 18.5 MHz (nominal 25 MHz) pulse-echo ultrasound system with a longitudinal resolution of 86 mu. Five adult mini-swine (15 kg) were burned with a temperature-(190 degrees C) and pressure-controlled (236 g/cm2) burning iron. A series of burn durations (1-45 seconds) was used to inflict partial- and full-thickness burns of various depths. Ultrasonic scans of the acutely excised burns were performed across the lateral margin of the burn, including adjacent normal skin to serve as control. Direct histologic comparison was made with each scan plane. Average burn and normal skin depth measurements were made by independent observers for 34 scans and corresponding histologic sections. A significant correlation was achieved between burn depth and percent burn (burn depth/adjacent normal skin depth) as measured by ultrasound and histology (R = 0.90, t = 11.2, P less than .001).

Mohs' micrographic surgery and distal urethrectomy with immediate urethral reconstruction for glanular carcinoma in situ with significant urethral extension.

OBJECTIVES: To report the use of conservative extirpative surgical techniques to manage glanular carcinoma in situ with significant urethral extension. METHODS: Over a 5-year period, 2 patients with carcinoma in situ of the glans with significant distal urethral involvement, who refused penectomy, were managed with combined treatment modalities using Mohs' micrographic surgery and distal urethrectomy with immediate urethral reconstruction. RESULTS: At follow-up of 5 years and of 12 months, there has been no evidence of meatal or proximal urethral recurrence. CONCLUSIONS: Mohs' micrographic surgical excision and distal urethrectomy with immediate urethral reconstruction offers an acceptable alternative to partial penectomy in patients with perimeatal carcinoma in situ who fail conservative treatment or refuse penectomy.

Mycobacterium marinum infections treated with tetracycline.

Five cases of Mycobacterium marinum skin infections were successfully treated with 2 gm of tetracycline hydrochloride daily for periods from four to 12 weeks. In each case, the isolated M marinum was sensitive in vitro to tetracycline at levels from 25 to 50 microgram/ml. Tetracycline is recommended as treatment for extensive or sporotrichoid M marinum infections.

Combination therapy for psoriasis. Psoralens plus long-wave ultraviolet radiation with betamethasone valerate.

In the treatment of psoriatic patients with psoralens plus long-wave ultraviolet radiation (PUVA), clearing of psoriatic lesions was obtained more quickly and with smaller doses of ultraviolet light when topically applied corticosteroid therapy was added. Twelve patients with symmetrical plaque-type psoriasis were given PUVA on one side of the body and PUVA plus betamethasone valerate on the other side in a paired comparison study. Ten of the patients had faster clearing of lesions on the side that was treated with PUVA and betamethasone than on the side treated with PUVA alone. The other two patients had equal clearing on both sides. All patients remained clear of lesions during maintenance with PUVA alone for at least five months after steroid therapy was discontinued. Combination therapy may save the patient time, expense, and unnecessary exposure to radiant energy.

Histologic evaluation of preauricular and postauricular human skin after high-energy, short-pulse carbon dioxide laser.

BACKGROUND: Despite its growing use in dermatalogic surgery, the effects of high-energy, short-pulse carbon dioxide laser on human skin have not been well documented. OBJECTIVES: To study the histologic effects of this high-energy, short-pulse CO2 laser on human skin and to compare these changes with the effects of standard chemexfoliation procedures. OBSERVATIONS: Twenty-four hours after laser administration, there was extensive epidermal necrosis and coagulative change in the superficial papillary dermis. With increasing doses of laser energy, there was a statistically significant increase in the depth of dermal wounding (P<.001 for days 1 and 3, F-test). Reepithelialization occurred in most specimens by day 3. By day 90, most specimens showed a subepidermal dermal repair zone consisting of compact new collagen fibers overlying collagen with evidence of solar elastosis. CONCLUSION: This high-energy, short-pulse CO2 laser produces morphologic changes similar to those seen with medium-depth chemical peels. This laser can ablate skin precisely and bloodlessly with little interference in the wound healing process, suggesting that it may serve as an alternative treatment for photoaged skin.

Cutaneous macroglobulinosis.

A patient with Waldenström's macroglobulinemia had firm, translucent papules and nodules on the extremities. Clinically, the skin lesions were suggestive of amyloidosis cutis. Histologically, a homogeneous eosinophilic material was observed in the upper dermis and encasing the hair follicles. Special histochemical stains, electron microscopy, and immunofluorescence microscopy identified the material as IgM.

Repair of surgical defects.

Basic skills in elliptical excision are essential for success in dermatologic surgery. Once the elliptical excision has been mastered, the practitioner should progress to variations on the ellipse. These include "curving" the incision, M-plasty, A-to-T closure, O-to-Z closure, and subcutaneous island pedicle flaps. When one of these methods will not suffice, a local flap or a full-thickness skin graft is often a good alternative.

Morbidity and mortality related to liposuction. Questions and answers.

Reports of fatalities following liposuction have lead to investigations by state medical boards. The risk of complications and fatalities is clearly different for liposuction under local anesthesia and intravenous sedation. Thousands of patients have been treated with true tumescent liposuction as described by dermatologist Dr. Jeffrey A. Klein, with no reports of fatalities. Patients should seek physicians who are experienced in this extremely safe method of liposuction.

The safety of dermatologic liposuction surgery.

The safety of liposuction surgery begins with appropriate preoperative evaluation and patient selection. Operative considerations include the type of anesthesia used, the volume of fat aspirated, and the liposuction technique utilized. Results from a recent survey revealed that liposuction surgery can be extremely safe when done under local anesthesia with conservative fat removal.

Cutaneous resurfacing.

Cutaneous resurfacing can be accomplished with application of acids, abrasive modalities, or the new generation of carbon dioxide lasers. Ultimately, the universal goal is removal and replacement of the epidermis and dermal collagen remodeling. The indications range from therapeutic and reconstruction to the treatment of the stigmata associated with senescence. The indications are not technique-specific, and the art of cutaneous resurfacing is identifying the cutaneous defect and selecting the appropriate tool or tools to realize the optimal clinical results.

Cancer of the scalp.

Carcinomas on the scalp have a tendency to recur following traditional treatment. Their management is often difficult because of the extent of the tumor and the unique anatomy of the area. In order to maximize cure rates for complicated carcinomas, Mohs micrographic surgeons and other surgical specialists have formed interdisciplinary treatment teams. Resection of bone, parotid/facial nerve dissection, and neck dissection are often necessary. Interdisciplinary cooperation in the treatment of skin cancer leads to maximal utilization of expertise and is a major advance in cancer treatment.

Unilateral acquired nevus flammeus in women.

Congenital nevus flammeus is a benign vascular tumor characterized by pink to pale red patches that thicken as the patient ages, producing a dull red to reddish blue, cobblestone-textured plaque. We present the cases of 3 women with unilateral acquired nevus flammeus on the cheek whose lesions resolved after minimal treatment with a 585-nm pulsed dye laser. The etiology of acquired nevus flammeus is reviewed and tumor response rates to laser surgery are discussed.

Nevus leiomyomatosus systematicus.

Leiomyomas of the skin are classified as pilar, genital, or angioleiomyoma depending on the site of origin. Pilar leiomyomas are the most common form, and usually multiple tumors are found in a single patient. An unusual variant of multiple pilar leiomyoma is nevus leiomyomatosus systematicus, a descriptive term used when tumors are wide-spread and patterned, suggesting a nevoid condition. Many of the large pilar tumors are painful and require surgical excision for relief of symptoms.

Skin Cancer in Professional and Amateur Female Golfers.

In brief: Fifty-one female professional golfers and 142 female amateur golfers were evaluated for skin cancer and skin cancer risk. The professionals were considerably younger than the amateurs (average of 28.4 vs 54.5 years) and received five times as much sun exposure as the amateurs. Four of the professionals had already developed basal cell carcinoma (BCC). Their average age was 25.5 years. Eleven amateurs also developed BCC, but their average age was 51.4 years. This study suggests that skin cancer can develop at earlier ages when sun exposure has been heavy. The likelihood of developing a skin I cancer also was related to eye and hair color.