Bexarotene activates the p53/p73 pathway in human cutaneous T-cell lymphoma.

BACKGROUND: Bexarotene is the first synthetic retinoid X receptor-selective retinoid (rexinoid) approved for the treatment of cutaneous T-cell lymphoma (CTCL). However, little is known about the signalling pathways by which it exerts its anticarcinogenic effect. OBJECTIVES: To characterize the effects of bexarotene in CTCL cell lines and elucidate the underlying molecular pathways of its antineoplastic effect. METHODS: The cell lines Hut-78, HH and MJ were used. Cell viability was assessed with the XTT assay. The self-renewal potential of cells after bexarotene treatment was studied with the methylcellulose clonogenic assay. Flow cytometry was used to analyse the effects on cell cycle, Ki-67 expression and apoptosis induction. Cell cycle and apoptosis-related protein expression were determined by Western blot and immunofluorescence. RESULTS: Bexarotene induced a loss of viability and more pronounced inhibition of clonogenic proliferation in HH and Hut-78 cells, whereas the MJ line exhibited resistance. Bexarotene upregulated and activated Bax in sensitive lines, although not enough to signal significant apoptosis. Instead, all data point to the inhibition of proliferation, rather than apoptosis, as the main mechanistic action of the rexinoid. Bexarotene signals both G(1) and G(2)/M arrest by the modulation of critical checkpoint proteins. We further found that bexarotene activates p53 by phosphorylation at Ser15, which influences the binding of p53 to promoters for cell cycle arrest, induces p73 upregulation, and, in concordance, also modulates some p53/p73 downstream target genes, such as p21, Bax, survivin and cdc2. Bexarotene-mediated ataxia telangiectasia mutated protein (ATM) activation in all studied lines suggests that ATM is likely to be the p53/p73 upstream activator. CONCLUSIONS: Our data indicate for the first time that bexarotene exerts its effect in CTCL mainly by triggering the p53/p73-dependent cell cycle inhibition pathway, probably by upstream ATM activation. Therefore, bexarotene-modulated genes represent potential biomarkers to assess the response to treatment of patients with CTCL.

Cutaneous metastases of hepatocellular carcinoma.

Cutaneous metastases are an unusual finding that may present as the first sign of an internal neoplasia. A case of cutaneous metastases of hepatocellular carcinoma, which may often involve other organs but very rarely metastases to the skin, is reported.

[Clinical experience with efalizumab in the Hospital of Cruces]. / Experiencia clínica con efalizumab en el Hospital de Cruces.

Efalizumab (Raptiva) is one of the biological agents approved recently for the treatment of patients with moderate-severe psoriasis who have not responded to conventional treatments. It is a humanized IgG1 monoclonal antibody which, due to its anti-D11 effect, is capable of blocking the endothelial migration and T cell activation on the skin, fundamental processes in the etiopathogeny of psoriasis. We present the experience we have had in our hospital over the last two years with 23 patients who have initiated treatment with efalizumab.

Prostaglandins and chemotaxis: enhancement of polymorphonuclear leukocyte chemotaxis by prostaglandin F2alpha.

Prostaglandins E1, E2, F1alpha, and F2alpha did not demonstrate direct in vitro chemotactic properties either to rabbit peritoneal polymorphonuclear leukocytes or to rabbit or human polymorphonuclear leukocytes isolated from blood. Prostaglandin F2alpha, however, enhanced the chemotactic responsiveness of human polymorphonuclear leukocytes to the chemotactic agent casein.

Cost-effectiveness analysis of interferon as adjuvant therapy in high-risk melanoma patients in Spain.

In the randomised clinical trial E1684, the administration of interferon (IFN) alpha-2b resulted in prolonged disease-free and overall survival in high-risk melanoma patients following surgical resection. However, and considering the cost and toxicity of IFN, the convenience of its widespread use should be evaluated. The aim of this study was to analyse the cost-effectiveness ratio of adjuvant therapy with IFN alpha-2b in melanoma patients versus an untreated control group. A Markov model was used to compare two hypothetical cohorts of 1000 patients aged 50 years, according to the clinical outcome of the E1684 study. The cohort of patients treated with IFN alpha-2b has an increased overall survival of 1.90 years during the patient's lifetime. The incremental discounted cost per life year gained of IFN versus observation is 9015 Euros according to the projection generated by the model. The sensitivity analysis demonstrated that changes in the most relevant study end-points do not modify the study outcome. In conclusion, in high-risk melanoma patients following surgical resection, the cost-effectiveness of IFN alpha-2b (at a dose of 20 MU/m2/day, 5 days per week for one month, followed by 10 MU/m2 TIW, up to one complete year of therapy) versus an untreated control group is within the limits established in health economics to determine if adoption of a new treatment is economically justified and is comparable with other interventions in which cost-effectiveness is acceptable to the National Health System.

Cutaneous periarteritis nodosa: immunofluorescence studies.

The study of ten cases of cutaneous periarteritis nodosa by direct immunofluorescence microscopy of excision biopsy specimens revealed positive findings in nine. Deposition of IgM was found in the vessel walls in six cases, and C3 was observed in four; however, only in two cases was C3 found with IgM in the vessel walls. Deposits of IgM in the superficial vessels were found in five cases, although only the deep muscular vessels showed evidence of the vasculitis in cutaneous periarteritis nodosa. Serum hepatitis B antigen was absent in the nine cases that were tested. Positive immunofluorescence findings in superficial as well as in deep vessels suggest that although periarteritis nodosa is characterized by an inflammatory panarteritis, occasional vasculitis of small vessels might be expected.

Disabling pansclerotic morphea of children.

Fourteen children with generalized morphea involving all levels of the skin and soft tissues were examined. The term "acral pansclerotic morphea" describes the distribution and the multiple levels of sclerosis. Lymphocytic inflammation and hyaline pannicultitis were observed on biopsy specimens in some cases. Laboratory data were characterized by a polyclonal elevation of gamma-globulin level and by peripheral eosinophilia. Pulmonary changes in five patients and esophageal changes in one imply that acral pansclerotic morphea may be assoicated with mild nonprogressive visceral change. Although cyclophosphamide may retard the process, no satisfactory treatment for progressive, mutilating acral pansclerotic morphea has been found.

Toxic doses of vitamin A for pityriasis rubra pilaris.

Seven patients who were disabled by pityriasis rubra pilaris were given toxic doses of oral vitamin A (1 million IU/day in six of the seven patients) for five to 14 days. Within 72 hours, the patients began to exfoliate the hyperkeratotic and keratodermatous lesions. The desquamative process was completed between ten and 14 days. The skin remained erythematous for several months before assuming a normal color. The skin of six of the seven patients was virtually cleared by the treatment, and none suffered a relapse of the pityriasis rubra pilaris. Serial skin biopsy specimens showed evidence suggestive of an accelerated turnover rate of epidermal cells during treatment. Transient abnormalities of liver function test results were noted in two patients.

Livedo vasculitis (the vasculitis of atrophie blanche). Immunohistopathologic study.

Hyalinizing segmental vasculitis or livedo vasculitis (atrophie blanche) is a clinical entity with a distinctive immunohistopathologic morphology that can be distinguished from other forms of cutaneous vasculitis by histologic and direct immunofluorescent studies. Our studies showed that immunoglobulins and complement components (C-1g, C-3, and properdin) were localized in diseased vessel walls, suggesting an immune pathogenesis.

Serum IgE in dermatitis and dermatosis: an analysis of 497 cases.

Serum IgE values from 497 patients with various forms of dermatitis, dermatosis, and tinea pedis were analyzed statistically and compared with values from 95 normal controls. The median and geometric mean values were significantly elevated (except in acne without atopy, lichen planus, and tinea pedis), even after exclusion of patients with a history of atopy or of cutaneous reaction to food or drugs. Serum IgE levels and atopic dermatitis have a close correlation. A modest positive correlation (p approximately equal to .05) appeared between the log serum IgE level and peripheral blood absolute eosinophil count in 80 cases of atopic dermatitis. A unique group of adult nonatopic patients had acquired generalized dermatitis and markedly elevated serum IgE levels (greater than 12,000 ng/ml). Our results suggest that, in most common dermatologic disorders, elevated serum IgE is a secondary phenomenon rather than a primary causative factor.

Interleukin-2 enhances the growth of human melanoma cells derived form primary but not from metastatic tumours.

Previously, we demonstrated that in vitro treatment of B16F10 murine melanoma cells with interleukin-2 (IL-2) enhances proliferation and metastasis. To further investigate the role played by IL-2 in human melanomas, we studied the expression of IL-2/IL-2 receptor and the effect of IL-2 on the proliferation of melanoma cell lines derived from primary (A375 and RMS cell lines) and metastatic (Hs294T cell line) tumours. We found a constitutive expression of cytoplasmic IL-2 and alpha, beta and gamma-subunits of the IL-2R on the surface of the three melanoma cell lines. The presence of IL-2 in the culture increased the proliferation rate in A375 and RMS cell lines, but no effect was observed in Hs294T metastatic cells. Biologically active IL-2 could be found in the supernatant of the three melanoma cell lines, particularly in A375 and RMS cells, in which an inhibition of the proliferation rate was observed when IL-2 was blocked. Moreover, the combination of anti-IL-2R beta and anti-IL-2R gamma blocking antibodies induced a significant down-regulation of cell proliferation in the three melanoma cell lines, and the combination of anti-IL-2R alpha, anti-IL-2R beta and anti-IL-2R gamma blocking antibodies inhibited IL-2-mediated growth stimulation in A375 and Hs294T cell lines. In RMS cells, a more significant effect was observed when only IL-2R gamma was blocked. Finally, exogenous IL-2 modulated the IL-2 endogenously produced by melanoma cells. These data show that IL-2 may modulate the growth of melanoma cells through autocrine or/and paracrine mechanisms.

[Immunology of bullous diseases (pemphigus vulgaris and bullous pemphigus)]. / Inmunología de las enfermedades ampollosas (Pénfigo vulgar y penfigoide ampolloso)

The immunological aspects of pemphigus vulgaris and bullous pemphigoid are reviewed in this article. In the last few years, the immunoiogical research on these blistering diseases has contributed to a better understanding of the pathogenic mechanisms of these diseases.

[Ackerman's verrucous carcinoma on the lower lip]. / Carcinoma verrucoso de Ackerman en labio inferior.

A patient with Ackerman's verrucous carcinoma located on the transitional epithelium of the lower lip is described. No previous cases have been reported with this location. The clinical course was similar to verrucous carcinoma arising on other areas of skin or mucosae. Viral particles were not found on ultrastructural studies. The response to conservative surgical treatment was excellent.

[Immunology of bullous diseases-II. Cicatricial pemphigoid. Herpes gestationis and dermatitis herpetiformis]. / Inmunología de las enfermedades ampollosas - II. Penfigoide cicatrizal. Herpes gestacional y dermatitis herpetiforme.

The immunological aspects of cicatricial pemphigoid, herpes gestationis and dermatitis herpetiformis are reviewed in this article. The immunofluorescence findings in these diseases are emphasised. The possible implication of the complement system in the pathogonesis of these bullous diseases, as well as the present knowledge about the sequence of actuation of the alternate pathway components are discussed.

[Familial eosinophilic fascitis induced by toxic oil]. / Fascitis eosinofílica familiar inducida por aceite tóxico.

Three of four family members in husband, wife and one of two daughters developed in a short time interval (eleven months) eosinophilic fasciitis. The clinical, analytical and histopathological changes were characteristic of this disease. Familial cases of eosinophilic fasciitis have not been previously published. The process of these patients was probably caused by the ingestion of denatured oil (toxic oil syndrome), although the clinical picture begun two and a half years after the epidemic phase of the toxic oil syndrome declined.

[Bowenoid papulosis in a patient with AIDS]. / Papulosis bowenoide en paciente de SIDA.

A patient with a acquired immunodeficiency syndrome (AIDS) and Kaposi's angiosarcoma developed bowenoid papulosis of the genitalia (BP). The clinical and histopathological criteria were both characteristic of BP. With vinblastine treatment a moderate improvement of Kaposi's lesions was observed, but no significant changes of the BP lesions were noted during this treatment.

[Nail-patella syndrome]. / Síndrome uña-rótula.

Four familiar cases of the Nail-patella syndrome are reported in this article. All the patients displayed clinical and radiographic changes characteristic of this syndrome. All of them had elongated and sharp-pointed postero-inferior iliac prominences. This bony abnormality has not been previously described in this syndrome.

[Ultrastructure of Darier's disease]. / Ultraestructura de la enfermedad de Darier.

Biopsies from four patients with Darier's disease were studied by electron microscopy. The desmosome-tonofilament complex does not seem to be primarily involved in the acantholytic process responsible for the epidermal cells separation with formation of suprabasal lacunae. Grains and corps ronds are consistent histopathological findings in Darier's disease: the ultrastructure of these cells is described.

[Chemotactic activity in the fluid of bullous pemphigoid blisters]. / Estudio de la actividad quimiotáctica en el líquido de ampollas de penfigoide ampolloso

By a modified Boyden technique, chemotactic activity was present in bullous pemphigoid blister fluids but was also present in the corresponding sera. Heat inactivation (56 degrees C for 30 minutes) only partially reduced the blister fluid chemotactic activity, but almost completely inhibited the activity present in pemphigoid sera. Control blister fluids exhibited some chemotactic activity, but in contrast to pemphigoid blister fluids, this activity was almost entirely abolished by heat inactivation. The chemotactic activity remaining in heat inactivated pemphigoid blister fluid was inhibited by N-CBZ-alpha-glutamyl-L-tyrosine and by antiserum to C5 but not with antiserum to C3. Our studies suggest that complement-dependent chemotactic activity is present in bullous pemphigoid blister fluids, findings which further implicate complement activation in the pathogenesis of this disease.