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23 newly diagnosed patients affected by cutaneous T-cell lymphoma were treated with sub-cutaneous interferon alpha-2a to evaluate the therapeutic efficacy and the toxicity of this agent. IFN was administered daily with dose escalation from 3 to 18 million units for 12 weeks; thereafter, patients induced into complete (CR) or partial (PR) remission were given IFN at maximal tolerated dose 3 times weekly for 6 or 9 months. The objective tumor response was observed in 17 patients (74%): 8 (35%) were CR and 9 (39%) were PR. A 74-yr-old patient died because of neutropenia and sepsis at the end of induction phase, while receiving IFN at dose of 18 million units. Disease stage is the initial feature predictive of response to IFN therapy. The dose schedule of this study was well tolerated: only 3 patients developed liver toxicity, while leukopenia was evident in 6 patients. Only 2 CR patients have relapsed, 18 and 24 months from response; the remaining 6 CR patients are in continuous complete remission with a median follow-up of 41.8 months. 6 PR patients have progressed from 8 to 17 months after response, and in the 3 PR patients not yet progressed the response duration ranges from 20 to 24 months. In conclusion, interferon alpha-2a is a very effective agent in therapy of untreated cutaneous T-cell lymphoma with an overall response rate of 74%.

BACKGROUND Physical urticaria (PU) includes a heterogeneous group of urticarias whose etiopathogenic aspects are still obscure and whose therapeutical management is often difficult. We have previously demonstrated the efficacy of a sequential treatment with nimesulide, a unique nonsteroidal anti-inflammatory drug, and ketotifen in various forms of PU. METHODS The expression of some inflammatory parameters was evaluated in 10 patients affected with some forms of PU. In particular, serum levels of interleukin (IL)-4, IL-1beta, tumor necrosis factor (TNF)-alpha, adhesion molecules (sELAM, sICAM-1 and sVCAM), soluble receptors (sIL-2R, sCD30, sCD23) and IgE were assessed. Moreover, the cutaneous expression of IL-1beta, TNF-alpha and ICAM-1 was studied on biopsy specimens taken from nonlesional skin of patients. The same parameters were further evaluated in both skin and serum following treatment with nimesulide and ketotifen, in order to better understand the possible effects of these agents on the inflammatory network of PU. RESULTS Before therapy we could detect significantly higher serum levels of IL-1beta and TNF-alpha (P < 0.001) and of circulating adhesion molecules in comparison with controls (sELAM, sICAM: P < 0.001; sVCAM: P < 0.02); after treatment, a significant reduction of each was observed (P < 0.05). Simultaneously, a high expression of IL-1beta, TNF-alpha and ICAM-1 was detected in all skin specimens at the baseline, with a relevant decrease following therapy. CONCLUSIONS These results confirm the therapeutical value of treatment with nimesulide and ketotifen in PU and suggest that these agents are able to reduce the release and the expression of some inflammatory molecules that are up-regulated in PU.

Objectives To investigate clinical, serologic, histopathologic and immunopathologic markers of PURPLE (painful purpuric ulcers with reticular pattern of lower extremities) or atrophie blanche. Design Twelve consecutive patients affected with idiopathic PURPLE were studied in the period 1992–1996. Patients with systemic diseases correlated to PURPLE were excluded from the study. Subjects All twelve patients were hospitalized at the Istituto Dermopatico Immacolata in Rome. Results Various and dishomogeneous immunological alterations were detected. Circulating immune complexes, increased serum levels of anticardiolipin and antinuclear antibodies, reduced serum complement levels, and deposition of immunoreactants in dermal vessels, were found in a limited number of patients. The results were not statistically significant. All the patients showed very similar histopathological aspects, characterized by microvascular thromboses, endothelial swelling and segmental hyalinization of small dermal vessels. Conclusion PURPLE is a thrombogenic vasculopathy in which unspecified immunological and laboratory changes are present. The recently suggested pathogenetic role of anticardiolipin and protein C deficiency in the disorder is not confirmed by this study.

A 43-year-old woman was examined in October 1993 for a widespread, large, ulceronecrotic skin eruption with exception of the mucosa (Fig. 1). The skin lesions were round and regular, varied in size from 0.5 to 2 cm, and were partially covered by a brownish-black crust. The patient had a fever ranging from 38 to 40 °C, always preceded by shivering. She had presented with small exfoliating erythematous patches and itching, 8 months before being admitted to our institute, and was treated with topical corticosteroids. After five and a half months, together with the beginning of fever, the above lesions became wet and were covered with squamous crusts. For 2 years the patient had been affected by perianal fistula, but had not referred to this pathology before. She also reported that she had been treated with antibiotic and corticosterod intravenous therapies. A biopsy specimen from a lesion of the right leg showed a widely ulcerous fragment of the skin, characterized by a strong infiltration of lymphocytes, especially in the upper part of the dermis, with neutrophil granulocytes. The epidermis surrounding the ulcer showed acanthosis, orthokeratosic hyperkeratosis, and spreading lymphocyte exocytosis, with a large number of necrotic keratinocytes and the presence of melanophages (Figs 2 and 3), All the above data suggested a diagnosis of pityriasis lichenoides et varioliformis acuta (PLEVA). Direct immunofluorescence carried out on perllesional skin showed the presence of fluorescent bodies on the superficial dermis using antisera anti-immunoglobulin (anti-IgM) and Ciq. Laboratory tests showed the following values: erythrocyte sedimentation rate (ESR), 55 LVh; C-reactive protein, 85 mg/L; white blood cell (WBC), 9200 g/dL; platelets, 476,000; gamma glutamil transferase, 93 U/L; alkaline phosphatase, 185 IU/L; complement C3 fraction, 70.9 mg/L; CP4/CD8 lymphocyte ratio, 6.5; total IgE, 2493 ku/L. Human immunodeficiency virus (HIV), Epstein-Barr virus (EVB), cytomegalovirus, herpes simplex 1 and 2, toxoplasma, rickettsia, and hepatitis markers A, B, and C gave negative results, while blood cultures were positive for Staphylococcus aureus and Pseudomonas aeruginosa. Circulating immune complexes (as C1 binding system), 80 (im/eq/L (normal value, less than 20). Qhest X-ray and total body computed axial tomography (CAT) scan were negative. Antimicrobial therapy with teicoplanin and trimethoprim + sulfamethoxazole for 15 days resulted in a reduction in microbial count in blood cultures, and therapy with prednisone (60 mg/day) for a further 20 days was started. The patient was discharged from hospital in reasonable physical condition, without fever and with an improvement of the skin lesions. Surgery for the treatment of her perianal fistula was not performed as her general condition had improved- The patient continued therapy at home with 50 mg prednisone and a broad spectrum antimicrobial for a further 20 days. One month later, the patient was admitted to hospital in a poor physical condition with fever (peaks of 40/41 °C), preceded by shivering, relapsing skin ulcers, weak respiration, and polypneia. The laboratory tests showed a serious hypoproteinemia, C-reactive protein concentration of 321 mg/L, and high transaminase levels. Blood analysis was positive for Staphylococcus aureus. Therapy was started with 60 mg prednisone, antimicrobials, and albumin, but 24 h later the patient fell into a coma and died from cardiogenic shock. Upon her family's request, no autopsy was performed.

Several skin infiltrating inflammatory cells, such as eosinophils, neutrophils and activated T lymphocytes, are involved in bullous pemphigoid (BP) blister formation. The presence of CD4+ T cells able to produce IL-4 and IL-5 suggests Th2 involvement in the disease. The role of eotaxin in the recruitment of eosinophils into inflammatory sites has been recently described and the specific eotaxin receptor, CCR3, has been documented to be expressed on eosinophils, basophils, and Th2 cells. In this study, we analyzed by immunohistochemistry the expression of both eotaxin and CCR3 in lesional skin from patients with active BP (n = 10) and control subjects affected with pemphigus vulgaris (PV) (n = 3); furthermore eotaxin concentration in BP sera and blister fluids was also evaluated by enzyme-linked immunosorbent assay (ELISA), in comparison to sera from PV and normal donors (n = 10) and to suction blisters from 3 healthy volunteers. A strong immunostaining for eotaxin and CCR3 in BP skin specimens in lesional and, to a lesser extent, in perilesional skin was observed. CCR3 expression was documented on both eosinophils and T cells infiltrating skin lesions. Eotaxin serum levels were significantly higher in BP patients when compared to healthy donors (p = 0.003) and PV patients (p = 0.01). The highest eotaxin concentration was detected in BP blister fluids, in respect to both corresponding BP sera and blister fluids from normal donors (p = 0.003). These results account for the role of eotaxin in the recruitment of activated cells at inflammatory sites during BP and the expression of CCR3 on infiltrating T lymphocytes further supports the involvement of Th2 cells in the pathogenesis of BP.

The AP-2 transcription factor plays a pivotal role in regulating the expression of several genes involved in tumor growth and progression of melanoma. We determined, by Western blot, variation in the level of expression of AP-2 and three of its downstream targets, c-kit, E-cadherin, and p21 in several human melanoma cell lines and, by immunohistochemistry, in a group of 99 histological samples including benign and malignat melanocytic lesions. A significant negative correlation between AP-2 expression level and tumor thickness was found. Moreover, AP-2 expression was positively associated with E-cadherin and c-kit expression. In contrast, there was a significant negative association between AP-2 and p21 expression levels. These findings suggest that p21 is independent of AP-2 transactivator function during the latest phases of melanoma progression. Finally, AP-2, c-kit, E-cadherin, and p21 expression levels did not show to be able to distinguish between dysplastic nevi and nevi without dysplasia. We conclude that changes in the expression of these proteins are involved in the later phases of melanoma progression, and may be responsible for the transition from local invasive melanoma to metastasis. © 2001 Wiley-Liss Inc.

We describe the clinical and laboratory findings of a young man with mycosis fungoides. The disease was associated, since the early stages, with autoimmune purpura. Interferon alfa (IFN-alpha) administration improved this patient's condition, both the purpuric eruption and patchy cutaneous lesions, thus suggesting T-cell abnormalities may be responsible for the development of the disease.

Hereditary nonpolyposis colorectal cancers and a steadily increasing number of sporadic tumors display microsatellite instability. In colorectal tumors, high-frequency microsatellite instability is strictly associated with inactivation of the DNA mismatch repair genes hMSH2, hMLH1, or hPMS2, whereas mutations in the mismatch repair gene hMSH6 have been identified in a subset of tumors with low-frequency microsatellite instability. In addition to epithelial tumors of the colon, endometrium, and ovary, microsatellite instability has been reported to occur also in sporadic melanoma. The relationship between microsatellite instability and mismatch repair in melanoma cells, however, has not been investigated so far. In this study, we analyzed microsatellite instability, mismatch repair activity, and expression of the hMSH2, hMSH6, hMLH1, and hPMS2 proteins in five melanoma cell lines and in tumor specimens from which the cells were derived. Four cell lines displayed normal levels of mismatch repair activity and expressed all the mismatch repair proteins. The extracts of the fifth cell line lacked the hMLH1 and hPMS2 proteins, and were correspondingly deficient in the repair of DNA mismatches. This line displayed high-frequency microsatellite instability, whereas the four mismatch-repair-proficient cell lines displayed either no or low-frequency microsatellite instability. These findings could be confirmed in the tumor specimens, in that only the tumor that did not express hMLH1 and hPMS2 displayed high-frequency microsatellite instability. Our data are consistent with the hypothesis that in melanoma, similarly to epithelial tumors, only the high-frequency microsatellite instability phenotype is strictly dependent on a defective mismatch repair system. Further studies on a large series of tumor specimens are required to establish the frequency of mismatch repair loss in human melanoma.

To the Editor.— Congenital melanocytic nevus is a frequently pigmented lesion that can evolve into malignant melanoma. In this study, we attempted to determine histologic findings that differentiate congenital nevi from other pigmented lesions. Materials and Methods.— From the files of our Institutes, we have randomly chosen 30 malignant melanomas, ten Spitz nevi, 20 adult nevi, and 15 bona fide1,2congenital nevi. Hematoxylin-eosin, Pinkus,3and Weigerts' stains were performed in order to study the cytologic and architectural disposition of the nevocytic cells and the distribution of elastic fibers. Results.— In Spitz nevus, blue nevus, and in the vast majority of adult nevi, the elastic fibers were absent or reduced in number and thickness. In malignant melanoma, they were totally destroyed. A completely different pattern was found in 90% of the congenital nevi. In the dermal component of such nevi, the elastic fibers appeared to increase dramatically in number