Ted A. Hamilton

Restoration of Collagen Formation in Photodamaged Human Skin by Tretinoin (Retinoic Acid)

BACKGROUND Topical tretinoin (retinoic acid) modifies fine wrinkles and certain other features of human skin damaged by exposure to the sun (photodamage), but histologic changes do not account for this improvement. In mice with photodamage induced by ultraviolet light, effacement of fine wrinkles by tretinoin is correlated with dermal collagen synthesis but not with histologic changes. We investigated whether collagen synthesis was reduced in photodamaged human skin and, if so, whether it could be restored by treatment with topical tretinoin. METHODS Biopsies of photodamaged skin from the extensor aspect of the forearm and skin from the buttocks, which had been protected from the sun, were performed on 26 healthy subjects. In addition, 29 patients with photodamaged skin were treated for 10 to 12 months with a daily application of 0.1 percent tretinoin cream (15 patients) or vehicle cream (14 patients). Skin-biopsy specimens obtained at base line and after treatment were assessed immunohistologically for evidence of dermal collagen I formation (collagen synthesis). RESULTS Collagen I formation was 56 percent less in the papillary dermis of photodamaged skin than in skin protected from the sun (P < 0.001) and was correlated with the clinical severity of photodamage (r = -0.58, P = 0.002). Treatment of photodamaged skin with tretinoin produced an 80 percent increase in collagen I formation, as compared with a 14 percent decrease in collagen formation with the use of vehicle alone (P = 0.006). CONCLUSIONS The formation of collagen I is significantly decreased in photodamaged human skin, and this process is partly restored by treatment with tretinoin.

Cyclosporine for plaque-type psoriasis: Results of a multidose, double-blind trial

BACKGROUND Severe plaque-type psoriasis has been successfully treated with orally administered cyclosporine, but there has been no comparative, controlled evaluation of various dosages and their efficacy and side effects. METHODS In a 16-week, double-blind trial, we randomly assigned 85 patients with severe psoriasis to receive 3, 5, or 7.5 mg of cyclosporine per kilogram of body weight per day or a placebo consisting of the vehicle for the drug. After eight weeks the dose could be adjusted to improve safety or efficacy while maintaining blinding. RESULTS The psoriasis improved in a dose-dependent fashion. After eight weeks of fixed-dose therapy, 36, 65, and 80 percent of the patients receiving 3, 5, and 7.5 mg of cyclosporine per kilogram per day, respectively, were rated as being clear or almost clear of psoriasis; each group had significant improvement (P less than 0.0001) as compared with the group receiving vehicle, in which none of the patients were rated as clear or almost clear. The patients who received 5 mg per kilogram were the least likely to require dosage adjustments because of side effects or a lack of efficacy. The glomerular filtration rate, measured in a subgroup of 34 patients receiving cyclosporine, decreased by a median of 16 percent. Higher doses of cyclosporine had greater adverse effects on systolic blood pressure, glomerular filtration rate, and serum levels of creatinine, uric acid, bilirubin, and cholesterol. Delayed-type hypersensitivity reactions to skin-test antigens were reduced by cyclosporine administration. Cyclosporine appears to become concentrated in skin. CONCLUSIONS Cyclosporine therapy leads to a rapid and thorough clearing of psoriasis; an initial dose of 5 mg per kilogram per day seems to be appropriate. However, the safety of cyclosporine for the long-term treatment of psoriasis remains to be determined.

Mohs micrographic surgery for the treatment of dermatofibrosarcoma protuberans. Results of a multiinstitutional series with an analysis of the extent of microscopic spread.

BACKGROUND Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft-tissue tumor of the skin; its microscopic extent of invasion beyond the grossly visible tumor is frequently difficult to appreciate. Although wide local excision has been the standard treatment of DFSP, recurrence rates range from 11% to 53%. Because Mohs micrographic surgery allows the extent of excision to be tailored to the microscopic extent of tumor, we evaluated this technique for the treatment of primary and recurrent DFSP. OBJECTIVE Our purpose was to determine the local recurrence rate and microscopic extent of spread of primary and recurrent DFSP after treatment with Mohs micrographic surgery. METHODS The records of 58 patients with primary and recurrent DFSP treated with Mohs micrographic surgery at three institutions were reviewed and the macroscopic and microscopic extents of tumor were recorded. RESULTS One patient with a twice-recurrent DFSP had another recurrence after Mohs micrographic surgery, for an overall local recurrence rate of 2% (zero for primary tumors and 4.8% for recurrent tumors). There were no cases of regional or distant metastases. Macroscopic tumor size ranged from 0.3 x 0.6 cm to 30 x 20 cm, whereas microscopic (postoperative) size ranged from 1.8 x 1.0 cm to 35 x 40 cm. We calculated the likelihood that a given width of excision around the macroscopic tumor would clear the entire microscopic extent of tumor. Standard wide excision with a width of 1 cm around the primary tumor would have left microscopic residual tumor in 70.7%; a width of 2 cm, 39.7%; 3 cm, 15.5%; and 5 cm, 5.2%. Even an excision width of 10 cm would not have cleared the microscopic extent of some tumors, despite taking a huge excess of normal tissue. CONCLUSION Treatment of primary and recurrent DFSP by Mohs micrographic surgery results in a low recurrence rate because of the ability of the technique to permit the detection and excision of microscopic tumor elements in even the most asymmetric tumors. Whatever type of surgery is chosen to treat DFSP, it is necessary to assess the entire perimeter of the tumor for microscopic extension and to achieve tumor-free margins in all directions.

Topical tretinoin (retinoic acid) improves melasma. A vehicle‐controlled, clinical trial

Melasma is a common disorder of cutaneous hyperpigmentation predominantly affecting the faces of women. Little is known about the aetiology of melasma, and treatment is frequently disappointing. Topical tretinoin is of benefit in treating other forms of hyperpigmentation, for example liver spots, and we therefore investigated its effectiveness in melasma. Thirty‐eight women completed a randomized, vehicle‐controlled study, in which they applied 0.1 % tretinoin (n=19) or vehicle cream (n=19) once daily to the face for 40 weeks.

Oral cyclosporine for the treatment of alopecia areata: A clinical and immunohistochemical analysis

Cyclosporine inhibits the activation of helper T cells that may be pathogenic in alopecia areata. Therefore we treated six patients with alopecia areata (five men, one woman) with oral cyclosporine, 6 mg/kg/day for 12 weeks. Three patients had alopecia universalis, one had alopecia totalis, and two had patchy alopecia areata of the scalp. Hair regrowth in the scalp of all patients occurred within the second and fourth weeks of therapy, followed by hair regrowth of the face and chest (in the male patients), pubic area, extremities, and axillae. Overall, the site of best response was the scalp. Cosmetically acceptable terminal hair regrowth on the scalp occurred in three of six patients. Significant hair loss, however, occurred in all patients within 3 months of discontinuation of cyclosporine treatment. Clinical response correlated with changes in immune cell infiltration of the hair follicles. The number of leukocytes per hair follicle was quantified in transverse scalp biopsy sections stained with a panel of monoclonal antibodies. The degree of terminal hair regrowth correlated significantly with decreases in follicular epithelial human lymphocyte antigen-DR and intercellular adhesion molecule-1 expression, T cells, helper/inducer (CD4) T cells, suppressor/cytotoxic (CD8) T cells and Langerhans cells (CD1+DR+) from the hair follicles during cyclosporine therapy. A significant decrease in the CD4/CD8 ratio occurred early in the course of treatment and was maintained throughout the therapy. This decrease suggests that cyclosporine not only cleared immune cells from the hair follicles but also altered the balance of regulatory lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topical Tretinoin (Retinoic Acid) Therapy for Hyperpigmented Lesions Caused by Inflammation of the Skin in Black Patients

BACKGROUND AND METHODS Irregular disfiguring skin hyperpigmentation due to inflammation may develop in black persons. We investigated the treatment of this hyperpigmentation with topical tretinoin (0.1 percent retinoic acid cream). Fifty-four subjects completed a 40-week randomized, double-blind, vehicle-controlled study. Twenty-four subjects applied tretinoin daily to the face, arms, or both areas, and 30 subjects applied vehicle cream. At base line and after 40 weeks of treatment, each subjects post-inflammatory hyperpigmented lesions and normal skin were assessed by clinical and colorimetric evaluations and by analysis of biopsy specimens. RESULTS The facial post-inflammatory hyperpigmented lesions of the tretinoin-treated subjects were significantly lighter after the 40 weeks of therapy than those of the vehicle-treated subjects (P < 0.001); overall improvement was first noted after four weeks of tretinoin treatment. At the end of treatment, colorimetry demonstrated a 40 percent lightening of the lesions toward normal skin color in the tretinoin-treated lesions, as compared with an 18 percent lightening in vehicle-treated lesions (P = 0.05). The epidermal melanin content in the lesions decreased by 23 percent with tretinoin and by 3 percent with vehicle (P = 0.24). Normal skin was minimally lightened by tretinoin as compared with vehicle, according to both clinical evaluation (0.1 vs. -0.1 unit change on an 8-point scale; P = 0.055) and colorimetry (P < 0.001). Retinoid dermatitis developed in 12 of the 24 tretinoin-treated subjects who completed the study (50 percent) and in 1 tretinoin-treated subject who withdrew from the study, but diminished as the study progressed. CONCLUSIONS Topical application of tretinoin significantly lightens post-inflammatory hyperpigmentation and, to a clinically minimal but statistically significant degree, lightens normal skin in black persons.

Topical Tretinoin (Retinoic Acid) Treatment for Liver Spots Associated with Photodamage

BACKGROUND The hyperpigmented lesions commonly called liver spots distress patients, in part because such lesions are associated with aging. We investigated their treatment with topical 0.1 percent tretinoin (retinoic acid). METHODS Fifty-eight patients completed a 10-month randomized, double-blind study in which they applied either 0.1 percent tretinoin (n = 28) or vehicle (n = 30) cream daily to the face, upper extremities, or both. Fifteen patients who responded well were than randomly assigned to continue tretinoin therapy or use vehicle alone for six more months. Patients were evaluated by physical examination every month and by analysis of biopsy specimens of lesions obtained at base line and at the end of the 10-month trial. RESULTS After one month of treatment the patients treated with tretinoin had significant lightening of hyperpigmented lesions as compared with the patients who received vehicle (P less than 0.002). After 10 months, 20 (83 percent) of the 24 patients with facial lesions who were treated with tretinoin had lightening of these lesions, as compared with 8 (29 percent) of the 28 patients with facial lesions who received vehicle. The results for lesions of the upper extremities were similar. As compared with vehicle, tretinoin caused a significant decrease in the degree of epidermal pigmentation and increases in the degree of compaction of stratum corneum, thickness of the granular cell layer, and epidermal thickness. Reductions in epidermal pigmentation evident on histologic analysis were significantly correlated with the degree of clinical lightening of lesions (r = -0.53, P less than 0.0001). During the 6-month follow-up study, specifically identified lesions that had disappeared during the first 10 months of tretinoin treatment did not return in any patient, and six of seven patients who continued to use tretinoin had further improvement. CONCLUSIONS Topical 0.1 percent tretinoin significantly improves both clinical and microscopical manifestations of liver spots; these lesions do not return for at least six months after therapy is discontinued.

Comparison of urinary 6‐β‐cortisol and the erythromycin breath test as measures of hepatic P450IIIA (CYP3A) activity

The production of 14CO2 in the breath from an intravenous dose of [14C‐N‐methyl] ‐erythromycin (the erythromycin breath test [ERMBT]) and the measurement of the ratio of 6‐β‐cortisol to free cortisol (6‐β‐F/FF) in the urine have each been proposed as means of measuring hepatic P450IIIA catalytic activity in patients. We found that there was a significant correlation between the results of each test (r = 0.59, p < 0.001) in 47 patients who were without liver disease and who were not taking medications believed to influence P450IIIA catalytic activity. In the 24 of these patients who were subsequently treated with the P450IIIA substrate cyclosporine, the ERMBT result was highly correlated with the mean trough cyclosporine blood level observed; however, there was no correlation between urinary 6‐β‐F/FF and the cyclosporine blood levels. In a separate study of a patient during the anhepatic phase of liver transplantation surgery, the ERMBT result decreased by greater than 85%, whereas urinary 6‐β‐F/FF decreased by just 50%. We conclude that the ERMBT and urinary 6‐β‐F/FF do not always provide similar information about P450IIIA catalytic activity in patients, possibly because of extrahepatic production of 6‐β‐F. Of the two tests, the ERMBT appears to provide the most relevant information for cyclosporine administration.

Multiple primary melanomas

BACKGROUND The diagnosis of primary melanoma increases the risk of additional primary melanomas. OBJECTIVE We characterize the subgroup of patients with multiple melanomas. METHODS We reviewed the melanoma database. RESULTS Sixty patients with multiple primary melanomas were identified. Twelve (20%) experienced melanomas in the same regional location, 43 (72%) in different locations, and 5 (8%) in both the same and different locations (> 2 melanomas). Eighteen (30%) were diagnosed concurrently with multiple melanomas, 38 (63%) subsequently, and 4 (7%) concurrently and subsequently (>2 melanomas). Forty-two percent of subsequent melanomas occurred within 3 years of the initial lesion diagnosis, 9 (17%) between 3 and 7 years, and 22 (42%) after more than 7 years. Subsequent melanomas were thinner in 70% of cases (P = .05). The mean age at first melanoma diagnosis was 38 and 59 years, respectively, for those with and without dysplastic nevi (P < .001). CONCLUSION In patients with multiple melanomas, subsequent melanomas often occur in different regional locations several years after diagnosis of the initial lesion.

Sustained improvement with prolonged topical tretinoin (retinoic acid) for photoaged skin.

We performed a 22-month trial of topical tretinoin (retinoic acid) in the treatment of photoaging. Thirty patients participated in a 4-month, randomized, blinded, vehicle-controlled study that has been reported previously; 21 patients continued tretinoin therapy on an open-label basis, participating in the study for a total of 10 months, and 16 patients continued for 22 months. During the open-label study, the statistically significant improvement that had occurred in fine and coarse wrinkling and skin texture during our original study was sustained, despite reductions in dose or frequency of application of tretinoin. The number of discrete lentigines decreased by 71% compared with the number before therapy. Histologic findings included a statistically significant thickening of the epidermis. Side effects were limited to a cutaneous retinoid reaction that diminished as therapy proceeded.