Psoralen plus ultraviolet A +/- interferon-alpha treatment resistance in mycosis fungoides: the role of tumour microenvironment, nuclear transcription factor-kappaB and T-cell receptor pathways.

BACKGROUND: Interferon (IFN)-alpha is widely used in the treatment of mycosis fungoides (MF) and when used in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA) both improved response and duration of complete remission have been reported. However, in spite of encouraging results of the initial studies, currently there is no information available on specific prognostic factors enabling prediction of patients' resistance to PUVA +/- IFN-alpha treatment. OBJECTIVES: To identify factors responsible for resistance to PUVA +/- IFN-alpha treatment in MF patients. PATIENTS/METHODS: The gene expression profiling of pretreatment samples from 29 patients diagnosed as IA, IB or IIA stage of MF enrolled in a randomized PUVA vs. PUVA + IFN-alpha clinical trial was analysed using cDNA microarrays. A Cox model (SAM) and gene set enrichment analysis (GSEA) were used for identification of genes and biologically significant pathways related to resistance to treatment. RESULTS: Genes involved in NF-kappaB signalling, T-cell receptor (TCR) signalling, cytokine signalling and proliferation were differentially expressed between responders and nonresponders. Interestingly, expression of markers representative of those pathways was found not only in the tumoral cells, but also in specific subpopulations of macrophages, dendritic cells and other non-neoplastic cell types constituting the tumour microenvironment, likely involved in the promotion of survival and proliferation of cutaneous T-cell lymphoma. CONCLUSIONS: Gene expression changes in both the tumour and the tumour microenvironment are an important determinant of treatment outcome in early-stage MF patients. Some proinflammatory factors such as NF-kappaB, inflammatory cytokines and their receptors in addition to TCR-associated molecules could be promising targets for MF treatment.

Cutaneous expression of systemic candidiasis.

Skin lesions associated with Candida septicaemia occur only in a minority of patients, who are usually immunocompromised, but they can help to establish a diagnosis rapidly. The lesions form a characteristic maculopapular or nodular rash at the onset of the infection. We report three cases of systemic candidiasis (SC) with cutaneous manifestations in immunocompromised patients. In these patients, the lesions started as asymptomatic or slightly pruriginous macules, papules or nodules localized on the trunk and extremities. The patients' general condition was very poor and they presented a high fever at the onset of the illness. Candida spp. were isolated from blood in all cases, and histology showed yeasts in two of them. Most of the lesions resolved with antifungal treatment. The diagnosis of SC is often delayed or missed because of the absence of useful diagnostic tools, the varying clinical manifestations and the frequent negativity (50-75%) of blood cultures for Candida. Fluconazole is the treatment of choice for Candida albicans, but treatment response is unknown for other Candida spp., which may require treatment with amphotericin B.

Stage IV cutaneous acute graft-versus-host disease. Clinical and histological study of 15 cases.

BACKGROUND: The most severe form of cutaneous acute graft-versus-host disease (aGVHD), stage IV, is characterized by the appearance of vesicles and blisters. OBJECTIVE: To describe the clinicopathological characteristics and evolution of stage IV cutaneous aGVHD presented in our hospital. METHOD: Retrospective study. The following criteria for inclusion were applied: (i) patients subjected to allogeneic stem cell transplantation between 1st January 1984 and 31st of December 2006; (ii) development of vesicles and/or blisters; (iii) extracutaneous coincidental aGVHD manifestations; and (iv) presence of histopathological features consistent with aGVHD. RESULTS: Fifteen cases (10 females and 5 males) were studied. The mean age was 38.1 years. The lesions appeared after a median interval of 19 days, always following a milder stage of GVHD. Two patterns of clinical evolution were found. Mucosal involvement was observed in nine patients. Nikolsky's sign was positive in eight patients. Nine of the patients had biopsies of the vesiculobullous stage which showed a subepidermal blister with epidermal necrosis and basal vacuolar degeneration. Only two patients survived. CONCLUSION: Stage IV cutaneous aGVHD is a severe and unusual complication after haematopoietic stem cell transplantation. Prognosis is poor with a very high mortality rate, although the cause of death is varied and not strictly linked to the cutaneous disease.

Spanish Consensus Document on the Treatment Algorithm for Rosacea. / Documento de consenso español para el algoritmo de tratamiento de la rosácea.

Recent scientific evidence and the incorporation of new drugs into the therapeutic arsenal against rosacea have made it necessary to review and update treatment criteria and strategies. To this end, a panel of 15 dermatologists, all experts in rosacea, was formed to share experiences and discuss treatment options, response criteria, and changes to treatment. Based on a critical review of the literature and a discussion of the routine practices of Spanish dermatologists, the panel proposed and debated different options, with consideration of the experience of professionals and the preferences of patients or equality criteria. Following validation of the proposals, the final recommendations were formulated and, together with the evidence from the main international guidelines and studies, used to produce this consensus document. The goal of this consensus document is to provide dermatologists with practical recommendations for the management of rosacea.

[Septic vasculopathy]. / Vasculopatía séptica.

Sepsis is one of the commonest causes of death around the world. The real frequency of cutaneous lesions in the setting of sepsis is unknown, but when they appear, they are usually one of the earliest signs of sepsis, thus allowing a rapid diagnosis of this potentially life-threatening condition. Four are the main physiopathologic mechanisms that can induce cutaneous lesions in sepsis: a) disseminated intravascular coagulation; b) direct vessel wall invasion by the microorganism; c) immune-mediated vasculitis, and d) septic embolism. We know that more than one of these mechanisms can appear in one single patient. In this review, we analyse these four mechanisms, their clinical presentation, and the histological findings that can be found in the cutaneous biopsy.

Differential expression of the 4F2 activation antigen on human follicular epithelium in hair cycle.

The expression of the 4F2 activation molecule has been studied on keratinocytes of human skin and hair follicle using immunoperoxidase staining with three different anti-4F2 monoclonal antibodies. Membranes of basal layer keratinocytes of the skin uniformly expressed this antigen, whereas a differential expression of this antigen was located in specific areas of the hair follicle. Follicles in the complete anagen phase displayed a strong 4F2 positive staining at the matrix and the outer root sheath cells. This positive staining gradually decreased along the proliferation zone, and became negative at the migration zone. Positivity was recovered in follicular cells at the duct of the sebaceous gland and was maintained in the upper outer root sheath where those cells fuse with the keratinocyte basal monolayer. Changes were also detected on different phases of the hair cycle. Follicles in the catagen-telogen phase expressed a very low number of positive cells in the matrix. Positive labeling progressively increased when the follicle was at the initial anagen stage, reaching a complete staining pattern in hair at the anagen phase. These results suggest that the expression of this activation antigen on hair keratinocytes may be related to the proliferation, active metabolism, and/or activation states of these cell types.

Identification of natural killer (NK) cells in lesions of human cutaneous graft-versus-host disease: expression of a novel NK-associated surface antigen (Kp43) in mononuclear infiltrates.

We performed an immunohistochemical analysis of skin biopsies from 13 allogeneic bone marrow transplant (BMT) recipients, undergoing either acute graft-versus-host-disease (aGVHD, n = 8) or chronic GVHD (cGVHD, n = 5). A panel of different monoclonal antibodies (MoAb) was employed including anti-CD2, -CD3, -CD4, -CD8, -CD11b, -CD16, -CD56, and -CD57, as well as a recently described reagent (HP-3B1) specific for a novel natural killer (NK)-associated cell-surface antigen (Kp43). Our data indicate that in aGVHD lesions the proportions of CD2+ cells often exceeded those detected with anti-CD3 MoAb. Double labeling confirmed the presence of CD2+ CD3- lymphocytes and suggested the coexpression in some cells of CD2 and CD11b. When MoAb specific for non-lineage-restricted NK-associated markers were employed, anti-CD56 and -CD57 occasionally stained variable numbers of lymphocytes (means = 14.6% of mononuclear cells in 0.05 mm2, range less than 1-48% and means = 10.3%, range 2-25%, respectively), whereas no CD16+ lymphocytes were observed. In contrast, most samples consistently displayed substantial proportions of Kp43+ cells (means = 32.8%, range 12-63%), which appeared CD3- and were mainly located at the dermoepidermal junction. On the other hand, sections from most (four of five) cGVHD lichenoid lesions analyzed displayed lower proportions of Kp43+ and CD56+ cells. Our data point out the interest of the anti-Kp43 MoAb to identify NK cells in aGVHD lesions, suggesting their pathogenetic participation.

Late appearance of acute graft-vs-host disease after suspending or tapering immunosuppressive drugs.

BACKGROUND: Graft-vs-host disease (GVHD) is divided into acute and chronic phases based on time and clinical and histological features. The criterion of 100 days after transplantation for separating acute GVHD from chronic GVHD has been challenged on the following points: (1) the lichenoid rash of chronic GVHD may be observed as early as day 31 and acute GVHD may persist after day 100 in some cases, and (2) specific histological features do not consistently separate acute from chronic GVHD defined as the number of days after transplantation. However, the appearance of acute cutaneous GVHD after day 100 is not well established. OBSERVATIONS: Three patients developed a rash with clinical and histological features of acute GVHD between days 153 and 192 after allogeneic bone marrow transplantation or peripheral blood stem cell transplantation. In all patients, the late flare of acute GVHD occurred after tapering or suspending the immunosuppressive regimen with cyclosporine or corticosteroids, and was accompanied by stigmata of chronic GVHD in other target organs. CONCLUSIONS: The rash of acute GVHD may be observed as late as 192 days after transplantation, especially after tapering or suspending the immunosuppressive drugs, and should be considered in the differential diagnosis of late erythematous eruptions after transplantation.

Chemotherapy-induced eccrine squamous syringometaplasia. A distinctive eruption in patients receiving hematopoietic progenitor cells.

BACKGROUND: Eccrine squamous syringometaplasia (ESS) has been associated with characteristic clinical eruption in patients receiving chemotherapy. It has been suggested as a diagnostic clue in the diagnosis of chemotherapy-induced reactions vs acute graft-vs-host disease, as well as other drug reactions. We identified 10 cases of ESS in patients in whom a distinctive clinical eruption developed during or after a pretransplantation conditioning regimen with high-dose chemotherapy. A complete clinical and histologic evaluation was performed in all patients. OBSERVATIONS: All patients developed erythematous and edematous plaques or confluent erythematous macular areas in the axillae and/or groin, with painful areas of well-defined erythema and edema on palms and/or soles in 5 patients. Some discrete papular lesions on the trunk or extremities could also be observed in most patients. The histologic hallmark of the eruption was ESS, with a variable degree of cornification and apoptosis. A vacuolar interface dermatitis and a variable degree of cellular atypica were also consistent findings. CONCLUSIONS: Chemotherapy-induced ESS may be associated with a distinctive clinical eruption and should be considered in the differential diagnosis of erythematous eruptions during or after a pretransplantation conditioning regimen with high-dose chemotherapy.

Induction of hyperacute graft-vs-host disease after donor leukocyte infusions.

BACKGROUND: Infusions of leukocytes obtained from the original bone marrow donor is a new approach for treating patients who have a relapse of leukemia after allogeneic bone marrow transplantation. Up to 90% of patients who achieved remission developed graft-vs-host disease (GVHD). However, any description of the clinical and histologic features in these cases is lacking. OBSERVATIONS: We describe 2 patients in whom a severe, peculiar, hyperacute, fatal GVHD developed after treatment with donor leukocyte infusions and interferon alfa. The patients had not received any additional chemotherapy or GVHD prophylaxis. In both patients, the eruption started with the appearance of erythematous plaques at the interferon alfa injection sites, and a generalized maculopapular eruption subsequently developed. The clinical lesions evolved from acute to lichenoid within several days. The histologic examination also demonstrated unusual findings and showed features of both acute and chronic lichenoid GVHD. CONCLUSIONS: Donor leukocyte infusions without GVHD prophylaxis may provoke a severe fatal hyperacute GVHD. In the cases presented herein, we discuss the significance of the rapid clinical evolution from acute to lichenoid and the combination of histologic features of both acute and chronic GVHD in the biopsy specimens.

[Off-label use of biologic agents in the treatment of dermatosis, part 2: etanercept, efalizumab, alefacept, rituximab, daclizumab, basiliximab, omalizumab, and cetuximab]. / Uso de fármacos biológicos en dermatosis fuera de la indicación aprobada. Segunda parte: etanercept, efalizumab, alefacept, rituximab, daclizumab, basiliximab, omalizumab y cetuximab.

In recent years, a series of new drugs have been developed through the application of molecular biology. These drugs act by blocking specific molecules of the immune system and have been developed to act on specific targets that play an important role in the pathophysiology of the diseases in which their therapeutic use has now been approved. Over time, experience has been accumulated in the use of these drugs in the treatment of skin diseases for which they have not been approved but in which the pathophysiology suggests that they could also be effective. The use of these drugs is increasing in difficult-to-treat cases of skin diseases for which the drugs are not approved. The second part of this review of off-label use of biologic agents in dermatology considers the use of etanercept, efalizumab, alefacept, rituximab, basiliximab, omalizumab, and cetuximab.