Victor Tron

Systemic cyclosporine and low-dose prednisone in the treatment of chronic severe alopecia areata: A clinical and immunopathologic evaluation

1. Ramsay DL, Halpefin PS, Zeleniuch-Jacquotte A. Topical mechlorethamine therapy for early stage mycosis fungoides. J Am Acad Dermatol 1988;19:684-91. 2. Vonderheid EC. Topical mechlorethamine chemotherapy: considerations on its use in mycosis fungoides. Int J Derrnatol 1984;23:180-6. 3. Price NM, Deneau DG, Hoppe RT. The trealrnent of mycosis fungoides with ointment-based mechlorethamine. Arch Dermatol 1982; 118:234-7. 4. Goday JJ, Aguirre A, Raton JA, et al. Local buUous reaction to topical mechlorethamine (musfine). Contact Dermatitis 1990;22:306-7. 5. Daughters D, Zackheim H, Maibach H. Urticaria and anaphylactoid reactions after topical application of mechlorethamine. Arch Dermatol 1973;107:429-30. 6. Lee LA, Fritz KA, Golitz L, et al. Second cutaneous malignancies in patients with mycosis fungoides treated with topical nitrogen mustard. J Am Acad Dermatol 1982; 7:590-8. 7. Shelley WB. Induction of tinea cruris by topical nitrogen mustard and by systemic chemotherapy. Acta Dermatol 1981 ;61:164-5. 8. Assier H, Bastuji-Garin S, Revuz J, et al. Erythema multiforme with mucous membrane involvement and StevensJohnson syndrome are clinically different disorders with distinct causes. Arch Dermatol 1995;131:539-43. 9. Bauer MJ, McEvoy BF, Mitus WJ. Hypersensitivity to nitrogen mustards in the form of erythema multiforme: a unique adverse reaction. Arch Intern Med 1967;120:499503. 10. Roujeau J-C. What is going on in erythema multiforme? Dermatology 1994;188:249-50. 11. Bruynzeel I, Van der Raaij EMH, Boorsma DM, et al. Increased adherence to keratinocytes of peripheral blood mononuclear leucocytes of a patient with drag-induced erythema multiforme. Br J Dermatol 1993;129:45-9. 12. Sayarna K, Watanabe Y, Tohyama M, et al. Localization of pefforin in viral vesicles and erythema multiforme. Dermatology 1994;188:305-9. 13. Fisher AA. Erythema multiforme-like eruptions due to topical medications. Curls 1986;37:158-60. 14. Friedman SJ, Perry HO. Erythema multiforme associated with contact dermatitis. Contact Dermatitis 1985;12: 21-23. 15. Torinuki W. Generalized erythema multiforme--like eruption following allergic contact dermatitis. Contact Dermatitis 1990;23:202-3.

Histopathology in erythroderma: review of a series of cases by multiple observers

This study examines the utility of objective histopathological studies in the evaluation of adult patients with erythroderma. A series of 56 skin biopsies, from 40 erythrodermic patients, was reviewed sequentially by 4 Canadian dermatopathologists who were unaware of clinical details of the cases. The final diagnosis (gold standard), in each instance, had already been determined by others, based on clinicopathologic data and response to therapy. Direct comparison revealed that the mean accuracy of I he histopathological diagnoses was 53% (range: 48‐(i6%). a favorable result in view of the difficulty of the task at hand. Additional points of information which evolved from the study are as follows: (i) identification, by microscopy alone, of spongiolic dermatitis, cutaneous T‐cell lymphoma and psoriasis, as underlying causes of eryihroderma was more successful than that of drug eruptions and pilyriasis rulira pilaris; (ii) the1 epidermotropism which characterizes cutaneous T‐cell lymphoma may be mistaken for inflammatory interface changes seen in drug eruptions and vice versa, thus constituting a pitfall in diagnosis; (iii) finally, it appears dial submission of multiple simultaneous biopsies, rather than a single specimen, from patients with erythroderma would be likely to enhance the accuracy of histopathological diagnosis.

Eosinophilic ulcer of the oral mucosa

BACKGROUND The eosinophilic ulcer is a rare lesion of the oral mucosa that has been infrequently described in the literature. OBJECTIVE We attempted to characterize the history, demographics, clinical features, histologic features, pathogenesis, and treatment of the eosinophilic ulcer. METHODS We observed three new cases of eosinophilic ulcer and reviewed the English-language literature. RESULTS Eosinophilic ulcer occurs in any age group, without sex preference. The most common site in the oral cavity is the tongue, and the average size at diagnosis is 1.6 cm2. These lesions are often ulcerated, may be tender, and are sometimes multiple. The histologic features are characteristic but likely represent a spectrum of related disorders. Most eosinophilic ulcers will resolve spontaneously within a month. Recurrences are uncommon (< 15%). CONCLUSION The eosinophilic ulcer is a benign, self-limited, reactive process of the oral mucosa of unknown origin. Its histologic features are characteristic but may be confused with atypical histiocytic granuloma and angiolymphoid hyperplasia with eosinophilia or, more importantly, lymphoma. This condition most likely represents a spectrum of related disorders with overlapping clinical and histologic features. After the diagnosis has been histologically confirmed, conservative management is suggested.

Analysis of HMB‐45 immunoreactivity in common and cellular blue nevi

HMB‐45 is generally thought of as a melanoma specific antibody; however, there are certain exepdons. It is known that most dermal nevi show no reactivity; however, the dermal nevus component within dysplastic nevi and certain Spitz nevi show positive reactivity. In order to further examine this observation, we undertook a study to examine blue nevi, both common and cellular, for the expression of HMB‐45. Cases were stained with antibodies directed at both HMB‐45 and SI00 protein. Of 16 common blue nevi studied, 14 were positive with HMB‐45, as were 6 of 6 cellular blue nevi. Staining for HMB‐45 was quite variable in intensity amongst cases labelled common blue nevi. In contrast, cellular blue nevi were uniformly strongly positive. It is therefore concluded that blue nevi, including cellular blue nevi, exhibit an activated phenotype as demonstrated by HMB‐45 reactivity.

Treatment of chronic severe alopecia areata with topical diphenylcyclopropenone and 5% minoxidil: a clinical and immunopathologic evaluation.

BACKGROUND Topical diphenylcyclopropenone (DPCP) and minoxidil have been used in the treatment of alopecia areata with variable results. OBJECTIVE This study was designed to evaluate the efficacy of DPCP alone or in combination with topical 5% minoxidil for the treatment of chronic severe alopecia areata. The effect of therapy on cutaneous T-cell and Langerhans cell subpopulations and intercellular adhesion molecule-1 (ICAM-1) expression was also examined. METHODS Fifteen patients with chronic (more than 2 years), severe (more than 50% scalp involvement) alopecia areata participated in a 24-week trial. Half of the scalp was treated with DPCP once weekly and with either 5% minoxidil solution or a vehicle solution twice daily in a randomized double-blind design. Skin biopsy specimens from each half of the scalp were obtained before therapy and after 12 and 24 weeks of therapy for histologic and immunophenotypic analysis. RESULTS Thirteen patients completed the study. Five of 13 patients (38%) showed marked regrowth of coarse terminal hair after 24 weeks of treatment with DPCP. The addition of topical 5% minoxidil did not produce any significant clinical benefit in this 24-week trial. Immunophenotypic analysis showed no differences between responders and nonresponders at baseline. During treatment, Leu-4, Leu-2, Leu-3, and keratinocyte ICAM-1 expression were significantly reduced in biopsy specimens of responders versus nonresponders. CONCLUSION DPCP treatment showed a 38% success rate in producing cosmetically acceptable regrowth in patients with chronic severe alopecia areata.

Melanocytes in human skin express bcl‐2 protein

The bcl‐2 gene was initially identified through its participation in the translocation 14:18 in B‐cell lymphomas of follicular center cell origin. This classic translocalion juxtaposes the transcriptionally active immunoglobulin heavy‐chain locus on chromosome 14 to the bcl‐2 gene on chromosome 18, resulting in overexpression of bcl‐2 protein. The oncogene bcl‐2 is thought to prolong cell survival through interference with programmed cell death. To date, bcl‐2 expression has been reported in normal lymphoid, hemopoietic, neural, breast and prostatic tissues. Since melanocytes are neural crest derivatives and have an extended life‐span, our objective was to determine whether the bcl‐2 protein is expressed in human melanocytes. We analyzed normal skin biopsies for bcl‐2 expression using standard immunohistochemistry. As hypothesized, dendritic cells in the basal epidermal layer stained strongly for bcl‐2. The distribution and morphology of these cells was typical for melanocytes. Additionally, eccrine sweat glands, lymphocytes and the dermal papilla of hair follicles demonstrated bcl‐2 positivity. We believe this to be the first report of bcl‐2 expression in normal melanocytes.

Vincristine-induced dermal toxicity is significantly reduced when the drug is given in liposomes.

Abstract A problem associated with the intravenous delivery of vincristine concerns drug extravasation at the site of injection or infusion. This can result in extensive local soft-tissue damage. A new formulation of vincristine has recently been developed based on encapsulation of the drug in liposomes. The liposomal drug is somewhat less toxic and substantially more efficacious than free drug. The studies described here assessed, using a murine model of drug extravasation, whether vincristine encapsulation in liposomes influences drug-induced dermal toxicity. It was shown that subcutaneous injection of vincristine in liposomes does not result in the gross skin necrosis and ulceration observed following injection of free drug. Histological analysis of the dermal tissue surrounding the injection site suggests that free drug induces a pronounced inflammatory reaction as judged by the presence of infiltrating leukocytes. In contrast, the liposomal formulation of vincristine engenders a mild prolonged inflammatory condition. These toxicological studies were correlated with an evaluation of drug retention at the site of administration. It was shown using radiolabelled vincristine as a drug marker, that free vincristine is rapidly eliminated from the injection site. In contrast, the level of drug at the site of injection was far greater when the drug was given in liposomal form.

p53-dependent regulation of nucleotide excision repair in murine epidermis in vivo.

Background: p53 protects the integrity of the genome by inducing programed cell death or by promoting DNA repair. We have previously shown that loss or mutation of p53 leads to reduced DNA repair in keratinocytes. Objective: The hypothesis that p53 regulates repair of ultraviolet light-induced epidermal DNA damage in vivo was tested in mice. Methods: An immunohistochemical assay for pyrimidine dimers and 6–4 photoproducts was performed on ultraviolet-irradiated skin from p53 null (−/−) and wild type (+/+) mice. Immunostaining for photoproducts was quantified using computer-assisted imaging. The level of DNA repair was then expressed as the percentage of positive cells remaining as compared to the zero hour time point. Results: p53+/+ mouse skin exposed to 1000 J/m2 retained ≈ 25% of epidermal cyclobutane dimers at 48 h, whereas approximately 50% remained in p53−/− cells. Using the same UV dose, p53+/+ mice retained 20% of detectable 6–4 photoproducts by 24 h, whereas about 50% remained in epidermal cells of p53-deficient mice. Conclusion: Using in situ labelling of UV-damaged cells, we confirm our earlier conclusion that p53 regulates DNA repair within the epidermis after exposure to UV light.

Effect of N-acetylcysteine on UVB-induced apoptosis and DNA repair in human and mouse keratinocytes.

Abstract The incidence of skin cancer is increasing rapidly, particularly in the Caucasian population. Epidemiological and experimental studies demonstrated that ultraviolet radiation (UVR) is the primary cause for the increasing incidence of skin cancer. It is well known that UV irradiation induces DNA damage. If the damage is not repaired or removed in time, it can lead to mutations and skin carcinogenesis. N‐acetylcysteine (NAC) has been shown to be an effective protector against UVB‐induced immunosuppression and to modulate the expression of some oncogenes and tumor suppressor genes. To test further the protective effect of NAC against UVR, we used both in vitro and in vivo models to investigate the effect of NAC on UVB‐induced apoptosis and repair of DNA damage in human and mouse keratinocytes. Our data indicate that the intracellular glutathione level was increased after treatment with NAC at 10–20 mM but decreased with 40 mM NAC treatment due to the toxicity. At concentrations up to 20 vaM NAC did not have a significant effect on UVB‐induced apoptosis of cultured human keratinocytes. In addition, in an in vivo mouse model, topical application of NAC (3 μ.mol cm‐2) that has been shown to inhibit UVB‐induced immunosuppression did not have any effect on UVB‐induced apoptosis and did not reduce the formation or enhance the repair of UVB‐induced cyclobutane pyrimidine dimers and (6‐4) photoproducts. Our results indicate that NAC is ineffective in preserving the genomic stability of keratinocytes against UVB irradiation.

p53 mutation in metastatic melanomas and primary melanomas from sun-exposed and sun-protected sites

Background p53 mutation has been observed in many human malignancies, including skin cancers. However, the data in melanoma has been conflicting. Material and methods We have examined, by immunohistochemistry, using the DO7 and CM1 antibodies, the frequency of p53 overexpression in 14 metastatic melanomas and 61 primary melanomas, of which 30 were from sun-protected sites and 31 from sun-exposed sites. Results Ten of 14 metastatic melanomas showed p53 overexpression compared to only eight of 61 primary melanomas (P < 0.004). No significant difference in p53 expression was found between primary melanomas from sun-protected (230) and sun-exposed sites (631). We have also examined p53 mutation by single-strand conformation polymorphism (SSCP) analysis of four melanoma cell lines. One cell line established from a primary melanoma from a sun-protected site showed evidence of an altered migration pattern in exon 7. Sequencing analysis of this region confirmed a point mutation in codon 244, showing a G to C transversion. This mutation is unlikely to be due to ultraviolet (UV) radiation since mutations caused by UV radiation are predominantly CC → TT or C → T transitions. Conclusions In summary, p53 mutation in primary melanoma is uncommon and does not appear to be related to UV radiation. p53 mutation is more common in metastatic melanomas suggesting that it may be involved as a late event in melanoma progression.