Mauro Alaibac

Prognostic Factors in Primary Cutaneous B-Cell Lymphoma: The Italian Study Group for Cutaneous Lymphomas

PURPOSE Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors. PATIENTS AND METHODS The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification. RESULTS Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94% and 85%, respectively. Compared with FCL/MZL, DLBCL, leg type, was characterized by statistically significant lower complete response rates, higher incidence of multiple cutaneous relapses and extracutaneous spreading, shorter time to progression, and shorter OS rates. The only variable with independent prognostic significance on the OS was the clinicopathologic diagnosis according to the WHO-EORTC classification (DLBCL, leg-type, showed a significantly worse prognosis v FCL and MZL; P < .001), whereas the only variable with independent prognostic significance on disease-free survival was the presence of a single cutaneous lesion (P = .001). CONCLUSION Our study identifies a possible PCBCL subclassification and the extent of cutaneous involvement as the two most relevant prognostic factors in PCBCL. These data can be considered reasonably as the clinical background for an appropriate management strategy.

Skin cancer in heart transplant recipients: frequency and risk factor analysis

BACKGROUND The frequency of skin cancer is increased among organ transplant recipients, but the predisposing risk factors are controversial. It is also unclear whether heart transplant patients face an increased risk compared to recipients of other organs, e.g. kidney transplants. METHODS We performed univariate and multivariate analysis of risk factors for skin cancer in 252 heart transplants and in a control series of 228 kidney transplants followed up at a single center. An extensive dermatologic examination was carried out; baseline features, type of immunosuppression, number of 3A rejection episodes, extent of sunlight exposure and skin type were recorded. Multivariate analysis (Cox regression) included: age at transplantation, sex, skin type (Fitzpatricks criteria), presence of solar keratosis, presence of warts, type of organ, sunlight exposure. RESULTS During follow up skin cancer was more common among heart transplants (40, 16 %) than in kidney transplants (16, 7%, p = 0.004). The cumulative incidence of skin cancer by life table analysis increased from 16% after 5 years to 33% after 10 years in heart transplant patients and from 6% to 17% in kidney transplants (p 10000 hours (relative risk = 2.8), but not organ type were significant risk factors. CONCLUSION Age at transplant, skin type and sunlight exposure, but not type of organ and type of immunosuppressive regimen, are associated with increased risk of skin cancer in heart transplantation.

Phase II trial of interferon‐α‐2a plus psolaren with ultraviolet light A in patients with cutaneous T‐cell lymphoma

To evaluate the efficacy and side effects of psolaren with ultraviolet light A (PUVA) and interferon‐alpha‐2a (IFN‐α‐2a) in patients with mycosis fungoides (MF) and Sézary syndrome (SS).

Eruptive melanocytic nevi in patients with renal allografts: report of 10 cases with dermoscopic findings.

Eruptive nevi have been reported after renal allograft transplantation, particularly in children and adolescents, and immunosuppression has been suggested to favor both benign and malignant melanocyte proliferation. In this study, we describe the dermoscopic features of eruptive melanocytic nevi in 10 children, adolescents, and young adults with renal allografts in whom multiple melanocytic nevi developed during a short period after transplantation. Dermoscopy of the eruptive pigmented lesions revealed a peripheral rim of brown globules. This rim of peripheral globules was present in 80% of the patients with eruptive nevi and in most of the lesions of the same patient. The other standard dermoscopic criteria for melanocytic nevi were normal. In our study, we confirm previous reports concerning the development of eruptive nevi in children and adolescents receiving immunosuppressive therapies. In particular, we showed by dermoscopy the presence of a characteristic symmetrical rim of peripheral brown globules. This finding is consistent with the hypothesis that a symmetrical peripheral rim of globules may indicate rapid enlargement of melanocytic lesions. Moreover, we have identified a new group of patients characterized by this dermoscopic feature. These patients are children, adolescents, and young adults with renal allografts receiving immunosuppressive therapy and it is plausible that this dermoscopic characteristic may be found in eruptive nevi developed in association with immunosuppression from any cause.

Tumour necrosis factor α is expressed in refractory skin lesions from patients with subacute cutaneous lupus erythematosus

Objectives: To investigate whether tumour necrosis factor α (TNFα) is expressed in subacute cutaneous lupus erythematosus (SCLE) skin lesions. Methods: The in situ expression of TNFα in refractory lesional and non-lesional skin biopsy specimens from patients with SCLE was analysed using an immunohistochemical approach. At the time of biopsy these patients were receiving treatment with systemic medications such as antimalarial agents, immunosuppressive drugs, and thalidomide. Expression of TNFα was also evaluated in cutaneous lesions of patients with other inflammatory and neoplastic skin diseases as controls. Results: The data showed that refractory lesional skin tissue from patients with SCLE displays a strongly positive distribution of TNFα, particularly within the epidermis. No prominent staining was seen in non-lesional skin from the same group of patients or in cutaneous lesions from the control group. Conclusions: These findings suggest that TNFα is localised and produced by epidermal cells within SCLE skin lesions and support its potential role in the pathogenesis of SCLE. The tissue localisation of TNFα may represent a potential therapeutic target providing a new perspective in the treatment of refractory skin lesions in patients with SCLE.

Immunosuppression and melanocyte proliferation.

Melanocytes are pigmented cells derived from the neural crest; their proliferation is restrained by immune system. The eruption of nevi after an immunosuppressive condition is a peculiar phenomenon indicating that the immune system may play a major role in limiting proliferation of melanocytes. In this review, we analyze the role of immunosuppressive regimens on melanocyte proliferation. In particular, we discuss the eruptive nevi phenomenon, which is determined by the inability of the immune system to inhibit melanocyte proliferation. These clinical observations indicate that the immune system has a pivotal role in restraining melanocyte proliferation. However, although the role of the immune system in the development of nonmelanoma skin cancer has been shown clearly in several studies involving organ transplant patients, the role of immunosuppression in melanoma genesis has not yet been established. Further investigations are required to establish the real immunogenicity of melanoma, particularly in the light of the dichotomy between the eruptive nevi phenomenon in immunosuppressed patients and the low incidence of melanoma in transplanted patients.

Detection of autoantibodies against recombinant desmoglein 1 and 3 molecules in patients with pemphigus vulgaris: correlation with disease extent at the time of diagnosis and during follow-up.

The recent availability of cDNA clones for pemphigus antigens has allowed the production of recombinant desmoglein 1 and desmoglein 3 molecules and the development of an ELISA approach in order to determine levels of antibodies to them. The aim of the study was to determine the relationship between autoantibodies levels and the extent of both mucosal and skin lesions in 20 patients with pemphigus vulgaris at the time of diagnosis and during follow-up. For the detection of autoantibodies by ELISA we used the recombinant proteins expressing overlapping sequences with the entire extracellular desmoglein 1 and desmoglein 3 domains. We showed that in presence of mucosal lesions there was a correlation between extension of mucosal involvement and autoantiboidies titres against both desmoglein 1 and desmoglein 3, whereas in presence of skin lesions there was a statistically significant correlation between extension of skin lesions and autoantibodies titres against desmoglein 3, but not against desmoglein 1. A not negligible number of patients showed variations of the desmoglein 3 autoantibodies titre which did not correlate with the severity of both cutaneous and mucosal involvement. Similar results were obtained analyzing autoantibodies titres against desmoglein 1. In conclusion, we believe that the utilization of recombinant desmoglein 1 and desmoglein 3 proteins by ELISA should be used with caution to monitor disease severity and response to therapy, although it remains a high specific test for the initial diagnosis of pemphigus and the identification of a change in the clinical phenotype of this condition.

Sunscreen tests: Correspondence between in vitro data and values reported by the manufacturers

BACKGROUND In vitro sunscreen tests are diffusively used to test both the sun protection factor (SPF) and the photo-stability of filters. Spectrophotometric measurements of the absorbance of ultraviolet radiations through a sunscreen applied on a suitable substrate allow a rapid evaluation of its protection factor both at short and long wavelength ultraviolet radiation (UVB and UVA). OBJECTIVES The objective of this study has been to demonstrate if Teflon can be adopted as substrate both for SPF evaluation and photo-stability tests. Moreover, we have investigated if there is a correspondence between in vitro SPF measurements and values reported by manufacturers on sunscreens. MATERIAL AND METHODS Teflon has been used to perform several photo-stability tests by irradiating the filters with different wavebands and analyzing the combined effect of UV and infrared (IR) light. Similar analyses have been carried out using PMMA Plates, which is the standard substrate for UVA in vitro test. RESULTS We have demonstrated that it is possible to establish a good correspondence between in vitro SPF and values reported by manufacturers on sunscreens. We have also verified that the in vitro/label SPF correlation curve depends on the quantity of product applied while this does not seem to be true for other parameters like Critical Wavelength and UVA ratio. With regard to photo-stability studies, our results indicate for the first time that IR irradiation may have a role on photo-degradation. CONCLUSIONS The results show that there is a good correlation between the in vitro SPF determined by the present method and the SPF reported by the manufacturer. The compatibility of the results obtained using Teflon and PMMA Plates demonstrates that Teflon can be utilized for both SPF determination and photo-stability tests.

Glutathione S-transferase and CYP1A1 gene polymorphisms and non-melanoma skin cancer risk in Italian transplanted patients.

Abstract:  Solid organ transplant recipients are at higher risk of non‐melanoma skin cancer (NMSC), especially basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Genetic alterations in the production of detoxifying enzymes such as glutathione S‐transferase (GST) and CYP1A1 may enhance this risk. We investigated the frequency of GST genotypes (GSTM1, GSTM3, GSTT1 and GSTP1) and CYP1A1 in 239 transplant recipients: 107 cases with NMSC and 132 controls free from NMSC matched for type of transplanted organ, duration of transplantation, sex and age. Allele GSTP1*A was associated with a higher risk of NMSC [odds ratio (OR) 1.7 (1.1–2.5); P = 0.017]. Homozygosity for allele GSTP1 Val105 was lower in cases [OR 0.3 (0.1–0.8); P = 0.012], especially in patients with SCC [OR 0.1 (0.0–0.7); P = 0.012]. A higher risk of BCC was found in patients with GSTM1 null/null [null/null versus A + B, OR 3.1 (1.4–6.8); P = 0.003]. Analysis of allelism and interaction between allelic variants showed significant association between combined GSTM1 and CYP1A1 Val462 genotypes, where individuals homozygous for the risk allele GSTM1 null and carrying also the allele CYP1A1 Val462, show a higher risk of developing NMSC [OR 4.5 (1.1–21.4); P = 0.03], especially SCC [OR 6.5 (1.4–34.4); P = 0.01]. GSTP1 polymorphisms are associated with both BCC and SCC risk. GSTM1 polymorphisms seem to be involved in BCC risk, while GSTM1 null/null genotype combined with CYP1A1 allele Val462 are associated with a higher risk for SCC, indicating that allelism and/or interactions between allelic variants at other loci may also influence the risk of NMSC, particularly SCC.

C2 is superior to C0 as predictor of renal toxicity and rejection risk profile in stable heart transplant recipients

To assess whether cyclosporine A (CsA) 2‐h peak (C2) is superior to trough levels (C0) for Neoral dose monitoring in heart transplantation (HT), we studied 928 C0–C2 paired determinations from 313 stable HT patients (257 male, aged 50 ± 14 years at HT, follow‐up 6.9 ± 4 years), on a C0‐based regimen. Our target C0 levels (ng/ml) were 150–400 (first 3 months), 150–300 (4–12 months), 100–250 (>12 months). Mean C0 and C2 levels were 268 ± 80 and 1031 ± 386, respectively (first 3 months); 230 ± 49 and 955 ± 239 (4–12 months); 157 ± 53 and 745 ± 236 (>12 months). For patients within the target C0, the corresponding C2 were 600–1500 (first 3 months), 600–1300 (4–12 months), 400–1100 (>12 months). C2 correlated with C0 (r = 0.64, P = 0.0001). C2 correlated better with CsA dose than C0 (r = 0.41, P = 0.0001 vs. r = 0.33, P = 0.0001). Between patients, CsA dose varied by a factor of 9.3; the C/dose ratio varied by a factor of 8.5 for C2 and of 15.6 for C0. Patients with higher C2 (>740) had higher severe rejection score at 2 years (P = 0.02) than patients with lower C2. This did not apply to C0. Both C2 and C0 correlated with blood urea (r = −0.18, P = 0.0001; r = −0.12, P = 0.0002) and creatinine (r = −0.19, P = 0.0004; r = −0.19, P = 0.0001 respectively). By logistic regression higher C2 (>740) was associated with higher total severe rejection score at 2 years (P = 0.006). C2 showed better correlation with CsA dose, renal function, rejection profile and less variability between patients than C0. C2 may improve CsA‐based immunosuppression in HT.