Long-term clinical outcomes of imiquimod 5% cream vs. diclofenac 3% gel for actinic keratosis on the face or scalp: a pooled analysis of two randomized controlled trials.

BACKGROUND: Actinic keratosis (AK) is an early in situ epidermal cancer which can progress to invasive squamous cell carcinoma (SCC). Imiquimod 5% cream (IMIQ) and diclofenac 3% gel (DIC) are frequently used to treat AK; however, their long-term effects following repeated treatment cycles have never been compared. OBJECTIVE: To compare IMIQ and DIC in the treatment of AK with respect to the risk of change to grade III AK or invasive SCC, after 3 years. METHODS: Data were pooled from two randomized, active-controlled, open-label, multicentre, multinational, phase IV studies (Clinicaltrials.gov NCT00777127/NCT01453179), with two parallel groups. Studies were conducted between 2008 and 2015 and were almost identical in design. Patients eligible for inclusion were immunocompetent adults with 5-10 visible AK lesions on the face/scalp and grade I/II AK. The primary endpoint was inhibition of histological change to grade III AK or invasive SCC in the study treatment area, observed until month 36. Patients applied either IMIQ or DIC for a maximum of six treatment cycles. RESULTS: In total, 479 patients (IMIQ 242; DIC 237) were included in the full analysis set. Histological change to grade III AK or invasive SCC was observed until month 36 in 13 (5.4%) patients treated with IMIQ, compared with 26 (11.0%) patients treated with DIC (absolute risk difference -5.6% [95% confidence interval -10.7%, -0.7%]). Time to histological change was greater in the IMIQ group than the DIC group (P = 0.0266). Frequency of progression to invasive SCC was lower with IMIQ than with DIC at all time points. Initial clearance rate was higher in the IMIQ group compared with the DIC group, while recurrence rate was lower. Both treatments were well tolerated. CONCLUSIONS: Over 3 years, IMIQ was superior to DIC in clearing AK lesions and preventing histological change to grade III AK or invasive SCC and recurrence.

Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version.

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies. RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

Value of diffusion-weighted imaging in central pontine and extrapontine myelinolysis.

INTRODUCTION: Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) are rare neurological disorders characterized by demyelination in and/or outside the pons. Whether diffusion-weighted imaging (DWI) might facilitate an earlier diagnosis has not yet been studied systematically. METHODS: We describe demographics, clinical presentation, and early magnetic resonance imaging (MRI) findings with special emphasis on the relevance for diagnosis of CPM and/or EPM in eight patients. RESULTS: Of the analysed eight patients (aged 37-70 years; two men, six women), CPM was diagnosed in three, EPM in one, and a combination of CPM and EPM in four patients. Aetiology was rapid correction of sodium in two patients; a combination of hyponatremia, alcoholism and alcohol withdrawal in five patients and unclear in one patient. Seven patients suffered from chronic alcoholism and four from malnutrition. Demyelinating lesions were found in the pons, thalamus, caudate nucleus, putamen and midbrain. While the lesions could be clearly delineated on T2- and T1-weighted images, DWI demonstrated a strong signal in only six patients. Furthermore, DWI demonstrated lesions only to some extent in two patients and was completely negative in two patients on initial MRI. In none of the patients did the demonstration of hyperintense lesions on DWI precede detection on conventional MRI sequences. Apparent diffusion coefficient (ADC) values were heterogenous with a decrease in two cases and an increase in the remainder. CONCLUSIONS: We conclude that early DWI changes are a common finding in CPM/EPM but do not regularly precede tissue changes detectable on conventional MRI sequences. Heterogenous ADC values possibly represent different stages of disease.

Low-dose 5-fluorouracil in combination with salicylic acid as a new lesion-directed option to treat topically actinic keratoses: histological and clinical study results.

BACKGROUND: Actinic keratoses (AKs) arise after chronic sun exposure. Because long-term ultraviolet (UV) damage may induce proliferation of atypical keratinocytes, treatment of AKs is recommended. OBJECTIVES: To compare 5-fluorouracil 0·5%/salicylic acid 10·0% [low-dose 5-FU/SA (Actikerall®)] with diclofenac 3% in hyaluronic acid (diclofenac HA) and vehicle for the treatment of AKs. METHODS: This was a randomized, placebo-controlled, double-blind, parallel-group, multicentre trial. Patients received topical low-dose 5-FU/SA once daily, its vehicle or diclofenac HA twice daily for a maximum of 12 weeks. The final evaluation was at week 20. The primary objectives were to demonstrate the histological clearance rate of one predefined lesion. The secondary objectives were the improvement of treated lesions, tolerability and safety. RESULTS: There were 470 patients with 4-10 AK lesions each (grade I or II) on the face/forehead or bald scalp included in the study. Low-dose 5-FU/SA was superior to diclofenac HA (P < 0·01) and vehicle (P < 0·0001) for histological clearance of one representative lesion 8 weeks post-treatment. In 72·0%, 59·1% and 44·8% of patients in the low-dose 5-FU/SA, diclofenac HA and vehicle groups, respectively, the week-20 biopsy revealed no AKs. Significantly more lesions were cleared with low-dose 5-FU/SA (74·5%) compared with diclofenac HA (54·6%; P < 0·001) or vehicle (35·5%; P< 0·001). Low-dose 5-FU/SA was superior in terms of complete clinical clearance: 55·4%, vs. diclofenac HA (32·0%, P < 0·001) and vehicle (15·1%P < 0·001). Application-site disorders (mainly burning and inflammation) were more frequent with low-dose 5-FU/SA but mainly of mild to moderate intensity. CONCLUSIONS: Topical low-dose 5-FU/SA demonstrated higher histological and clinical clearance rates vs. diclofenac HA or vehicle. Low-dose 5-FU/SA is an effective lesion-directed treatment for AKs.

[A child's birthday with consequences]. / Ein Kindergeburtstag mit folgen.

Foreign body ingestion is a common pediatric emergency and if the foreign body cannot be detected radiologically or endoscopically further investigations are required. In this article the case of a radiolucent, ingested foreign body (mini-candleholder of a birthday cake) is presented. The foreign body could not initially be identified via X-ray and endoscopy due to its parapharyngeal localization but was finally visualized by magnetic resonance imaging (MRI) which additionally uncovered the co-existence of acute mediastinal inflammation.

Treatment with 311-nm ultraviolet B accelerates and improves the clearance of psoriatic lesions in patients treated with etanercept.

BACKGROUND: Some patients with plaque-type psoriasis respond slowly to treatment with etanercept. In such cases combining etanercept with conventional treatments might be helpful. OBJECTIVES: To investigate whether treatment with 311-nm ultraviolet (UV) B can improve the therapeutic response in patients treated with etanercept. METHODS: Four women and one man (mean age 57 years, range 48-66) with moderate to severe plaque-type psoriasis who had received standard treatment with etanercept 50 mg twice weekly for 6 weeks without Psoriasis Area and Severity Index (PASI) reduction of 75% or greater (of initial mean PASI of 16.0, range 15.4-20.4) were enrolled in the study. Starting at 6 weeks, 311-nm UVB treatment was given to a randomly selected body half (left or right, excluding the head) for another 6 weeks, while all patients continued receiving etanercept. The patients were monitored by half-body PASI at weekly intervals. RESULTS: During the 6-week irradiation regimen, 311-nm UVB significantly bolstered the therapeutic response in the patients on etanercept treatment. After 6 weeks of 311-nm UVB, the patients had a mean PASI on their UV-irradiated body halves of 1.6 (range 0.6-3.3) vs. 4.7 (range 1.4-8.6) on nonirradiated body halves (P = 0.0192, paired two-tailed t-test), compared with 10.7 (range 6-16.4) and 10.5 (range 5.2-16.4) at start of 311-nm UVB treatment. The overall mean PASI reduction from baseline (i.e. at etanercept start) was 89% vs. 68%, respectively (P = 0.0009 and P = 0.0088). CONCLUSIONS: Treatment with 311-nm UVB significantly accelerates and improves the clearance of psoriatic lesions in patients responding slowly to etanercept monotherapy.

The prognosis of early mycosis fungoides is not influenced by phenotype and T-cell clonality.

BACKGROUND: The influence of phenotype and detection of clonality on prognosis in early mycosis fungoides has never been addressed in large studies. OBJECTIVES: To correlate immunophenotype and detection of clonality with clinical outcome. METHODS: We analysed 73 biopsy specimens from 68 patients with early mycosis fungoides (stage Ia or Ib) and at least 10 years of follow up (or dead of disease). RESULTS: Four phenotypic groups could be identified: group A (alpha/beta+ CD4+ CD8- TIA1-), 51 patients; median survival time 160 months; group B (alpha/beta+ CD4- CD8+ TIA1+), 10 patients; median survival time 195 months; group C (alpha/beta- CD4- CD8+/- TIA1+), five patients; median survival time 165 months; and group D (alpha/beta+ CD4- CD8- TIA1-), two patients; median survival time 130 months. Survival curves did not show statistical differences among the groups. Monoclonality was detected in 36 of 67 tested biopsies (54%), and statistical analyses did not show prognostic differences between the clonal and nonclonal cases. CONCLUSIONS: We conclude that cytotoxic phenotype and detection of monoclonal T-cell receptor-gamma gene rearrangement in early lesions of mycosis fungoides do not have any prognostic significance.

Feasibility and acceptance of telemedicine for wound care in patients with chronic leg ulcers.

We examined the feasibility and acceptance of teledermatology for wound management of patients with chronic leg ulcers by home-care nurses. Forty-one chronic leg ulcers of different origin in 14 patients were included. After an initial in-person visit in which leg ulcers were assessed and classified, and underlying diseases noted, follow-up visits were done by home-care nurses. Once a week 1-4 digital images of the wound and surrounding skin and relevant clinical information were transmitted via a secure Website to an expert at the wound care centre. The experts provided an assessment of wound status and therapeutic recommendations. In 89% of the 492 teleconsultations, the quality of images was sufficient or excellent and the experts were confident giving therapeutic recommendations. Treatment modalities were changed or adapted in one-third of the consultations. There was a significant decrease in visits to a general physician or the wound care centre. The acceptance of teledermatology was high in patients, home-care nurses and wound experts. Teledermatology offers great potential for chronic wound care and seems to be accepted both by patients and health-care persons.

Two years' experience with Web-based teleconsulting in dermatology.

A non-commercial teledermatology network based on store-and-forward operation was established in April 2002. The aim was to create an easy-to-use platform for teleconsultation services, where physicians could seek diagnostic advice in dermatology from a pool of expert consultants and where they could present and discuss challenging dermatology cases with special emphasis on diagnosis and therapy. An online moderated discussion forum was added in October 2003. During the first two years, 348 health-care professionals from 45 countries registered to use the Website. A total of 783 requests for consultations were answered; 285 requests concerned pigmented skin lesions, 440 requests were from the whole range of clinical dermatology and 58 requests were about non-melanoma skin cancer. Of a total of 133 requests analysed, 80 (60%) were answered within one day, 47 (35%) within one week, five (4%) within two weeks and one (1%) consultation was answered in more than two weeks. Our experience with a discretionary, non-commercial, multilingual Website for open-access teleconsulting in dermatology appears to be successful. The Website represents an example of user-generated content, together with active interaction between users, who can present and discuss cases with remote colleagues.

Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group.

PURPOSE: Patients with primary cutaneous melanoma with a Breslow thickness > or = 1.5 mm have only a 30% to 70% probability of survival after surgery, and no adjuvant therapy has so far improved this outcome. Since interferon alfa-2a (IFNalpha2a) exhibits antitumor activity in metastatic melanoma, we investigated whether adjuvant IFNalpha2a diminishes the occurrence of metastases and thus prolongs disease-free survival in melanoma patients after excision of the primary tumor. PATIENTS AND METHODS: In a prospective randomized study, 311 melanoma patients with a Breslow thickness > or = 1.5 mm were assigned to either adjuvant IFNalpha2a treatment (n = 154) or observation (n = 157) after excision of the primary tumor. IFNalpha2a was given daily at a dose of 3 mIU subcutaneously (s.c.) for 3 weeks (induction phase), after which a dose of 3 mIU s.c. three times per week was given over 1 year (maintenance phase). RESULTS: Prolonged disease-free survival was observed in patients treated with IFNalpha2a versus those who underwent surgery alone. This difference was significant (P = .02) for all patients enrolled onto the study (intention-to-treat analysis) at a mean observation time of 41 months. Subgroup analysis showed that Breslow tumor thickness had no influence on treatment results in the groups of patients investigated. CONCLUSION: Adjuvant IFNalpha2a treatment diminishes the occurrence of metastases and thus prolongs disease-free survival in resected primary stage II cutaneous melanoma patients.

bcl-2 protein expression and correlation with the interchromosomal 14;18 translocation in cutaneous lymphomas and pseudolymphomas.

The interchromosomal 14;18 translocation occurs in approximately 70-80% of follicular lymphomas and in a lower proportion of high-grade non-Hodgkin lymphomas of the lymph nodes. This translocation results in the fusion of the bcl-2 oncogene on chromosome 18 with immunoglobulin heavy chain genes on chromosome 14, and in the expression of higher amounts of normal bcl-2 protein. We studied bcl-2 expression in biopsies of 108 patients with benign and malignant cutaneous lymphoproliferative diseases (B-cell lymphoma, primary cutaneous, 42; secondary cutaneous, 21; primary cutaneous T-cell lymphoma, 21; B-cell pseudolymphoma, 24), using a monoclonal anti-bcl-2 antibody on paraffin-embedded tissue sections, bcl-2 protein was detected immunohistochemically in 16 of 63 cases of cutaneous B-cell lymphoma, whereas cutaneous T-cell lymphomas and B-cell pseudolymphomas were negative. The proportion of bcl-2 protein expression was significantly higher in secondary (11/21) than in primary cutaneous B-cell lymphomas (5/42; chi 2 test, p < 0.001). Biopsies from 25 of these patients (B-cell lymphoma, 22; B-cell pseudolymphoma, three) were analyzed previously on the molecular level for the t(14;18), using polymerase chain reaction amplification of DNA obtained from paraffin-embedded sections. In four of 11 cases of bcl-2 protein-positive B-cell lymphoma (primary, one; secondary, three) the t(14;18) was detected by polymerase chain reaction. All other cases of B-cell lymphoma, including seven cases where bcl-2 protein was detected by immunohistology, and B-cell pseudolymphoma were negative. These results demonstrate: 1) bcl-2 protein is expressed in a small portion of cutaneous B-cell lymphomas; 2) bcl-2 protein expression is significantly more frequent in secondary than in primary cutaneous B-cell lymphoma; 3) only approximately one-third of cases expressing the bcl-2 protein are characterized also by the t(14;18). bcl-2 protein expression might indicate that the cutaneous manifestation of the lymphoma represents a secondary spread from a node-based lymphoma.

Development of a highly specific and sensitive molecular probe for detection of cutaneous lymphoma.

Using DNA from formalin-fixed paraffin-embedded tissue of a patient with mycosis fungoides, a highly specific and sensitive molecular probe for the malignant lymphoid cells of this patient was developed. Polymerase chain reaction (PCR) was used to selectively amplify the region of the rearrangement of TCR-gamma genes. Randomly inserted nucleotides between rearranged segments (N-region) were used as a specific marker for the malignant lymphoid clone of this patient. Clonal cells in paraffin-embedded tissue of previous and later biopsies were detected. This technique provides a new and unique tool for retrospective detection of early evolving cutaneous lymphoma, as well as for detection of minimal residual and systemic disease.

Langerhans cell density in epithelial skin tumors correlates with epithelial differentiation but not with the peritumoral infiltrate.

We investigated the intraepithelial density of Langerhans cells in 17 epithelial skin tumors by immunohistologic and morphometric methods. There was a significant difference between seborrheic keratosis (Langerhans cell density 431 +/- 31/mm2; normal epidermis: 378 +/- 20/mm2), basal cell carcinoma (28 +/- 6/mm2), and squamous cell carcinoma (100 +/- 21/mm2). No correlation was found between the Langerhans cell density and the number of intraepithelial T lymphocytes or the extent of the peritumoral inflammatory infiltrate. A significant inverse correlation was demonstrated between mean nuclear area of the epithelial tissue and the Langerhans cell density (r = -0.7; p less than 0.05). These data indicate that the number of Langerhans cells does not influence the extent of the antitumoral immune response. The correlation with the level of epithelial differentiation may be due to different homing conditions.

Monoclonality of intraepidermal T lymphocytes in early mycosis fungoides detected by molecular analysis after laser-beam-based microdissection.

The identification of neoplastic lymphocytes in early lesions of mycosis fungoides is difficult because of the scarcity of the infiltrate and the presence of reactive T lymphocytes admixed with neoplastic cells. Molecular analysis of the T cell receptor gene rearrangement using the polymerase chain reaction technique demonstrates monoclonality only in a proportion of these cases. The exact location of the malignant clone is unknown, and at present it is not clear whether neoplastic cells in early lesions reside within the epidermis, the superficial dermis, or both. We analyzed skin lesions from five patients with early mycosis fungoides using the polymerase chain reaction technique after microdissection of the specimens. In each case the epidermis was separated from the dermis using a laser-beam microdissection technique. Three samples were prepared from each lesion: one containing only the epidermis, one only the superficial dermis, and one the entire specimen. A distinct band could be observed in the epidermal sample in four cases, indicating the presence of an intraepidermal monoclonal population of T lymphocytes. The dermal sample revealed a monoclonal pattern in two cases (both of them showing clonality also within the epidermis). Analysis of the entire specimen revealed a monoclonal pattern only in two cases. Our results demonstrate that intraepidermal lymphocytes in early mycosis fungoides often show a monoclonal pattern of T cell receptor gene rearrangement. Microdissection of biopsy specimens may enhance the sensitivity of the polymerase chain reaction technique.

Differential expression of cytokine mRNA in skin specimens from patients with erythema migrans or acrodermatitis chronica atrophicans.

Erythema migrans, the characteristic skin manifestation of acute Lyme borreliosis, is a self-limited lesion. In contrast, acrodermatitis chronica atrophicans, the typical cutaneous manifestation of late Lyme borreliosis, is a chronic skin condition. In an effort to understand pathogenic factors that lead to different outcomes in dermatoborrelioses, skin biopsy samples from 42 patients with erythema migrans and 27 patients with acrodermatitis chronica atrophicans were analyzed for mRNA expression of five pro-inflammatory cytokines (tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interferon-gamma, and interleukin-2) and two anti-inflammatory cytokines (interleukin-4 and interleukin-10) by in situ hybridization with cytokine-specific riboprobes. Among the 27 patients who had erythema migrans alone with no associated signs or symptoms, the major cytokines expressed in perivascular infiltrates of T cells and macrophages were the pro-inflammatory cytokine interferon-gamma and the anti-inflammatory cytokine interleukin-10. In the 15 erythema migrans patients who had associated signs and symptoms, including headache, elevated temperature, arthralgias, myalgias, or fatigue, a larger number of macrophages and greater expression of macrophage-derived pro-inflammatory cytokines, tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6, were also found. In comparison, infiltrates of T cells and macrophages in the skin lesions of acrodermatitis chronica atrophicans patients had very little or no interferon-gamma expression. Instead, they usually expressed only the pro-inflammatory cytokine tumor necrosis factor alpha and the anti-inflammatory cytokine interleukin-4. Thus, the activation of pro-inflammatory cytokines in erythema migrans lesions, particularly interferon-gamma, seems to be important in the control of the spirochetal infection. In contrast, the restricted pattern of cytokine expression in acrodermatitis chronica atrophicans, including the lack of interferon-gamma, may be less effective in spirochetal killing, resulting in the chronicity of this skin lesion. J Invest Dermatol 115:1115-1123 2000

Microsatellite instability and loss of heterozygosity in melanoma.

Alterations in the repeat length of microsatellites have been identified recently in tumors arising in patients with hereditary nonpolyposis colon cancer and in several human sporadic tumors. We examined 40 sporadic melanomas and their corresponding nontumorous skin for microsatellite instability (MSI) and loss of heterozygosity (LOH) at chromosomes 2q, 3p25-26, 5q11.2-13.3, 5q21, 6q27, 9p21, 9p22-pter, 17p12, 17p12-p11.1, and 18q23. Specific loci were amplified by polymerase chain reaction, electrophoresed on polyacrylamide gels, transferred onto nylon membranes, and hybridized with 33P-end-labeled oligonucleotides. MSI was observed in eight of 40 (20%) melanomas at one of 10 loci examined. LOH was found at chromosome region 9p21 in 40%, at 9p22 in 22%, and at 17p in 13% of the informative cases. Comparison between clinicopathologic features of patients with and without MSI revealed no obvious differences. LOH at 9p21 was observed only in lesions greater than 1.5 mm in depth, suggesting that it does not represent an early event in sporadic melanoma. Our results indicate that 1) MSI is a genetic alteration in a proportion of sporadic melanoma, which may reflect a defect in genes involved in DNA replication fidelity; and 2) LOH at chromosome region 9p21 is a significant event in sporadic melanoma. The latter finding further supports the hypothesis that the 9p21 region may contain one or more tumor suppressor genes (e.g., MTS1/CDNK2) involved in the pathogenesis of melanoma.

Nuclear size and shape parameters correlate with proliferative activity in cutaneous melanocytic tumors.

Proliferative activity and morphometric data have previously been shown to be related with the degree of malignancy in melanocytic skin tumors. In the present study, the proliferative activity, as defined by Ki 67 monoclonal antibody (reactive with all actively cycling cells), has been determined by immunohistologic and morphometric methods in cutaneous melanocytic tumors. Quantitative morphologic features of Ki 67-positive and Ki 67-negative nuclei were separately assessed using computer-assisted image analysis. Comparing morphometric features and proliferative activity, the most significant correlation was found between mean nuclear volume and the percentage of Ki 67-positive nuclei in each lesion (linear regression analysis: r = 0.73; p = less than 0.05). On multidimensional discriminant analysis, tumors with high proliferative activity (more than 5 X 10(3) Ki 67-positive cells per mm3 tumor tissue) were detected at a specificity of 92% and a sensitivity of 75%. Within one lesion, Ki 67-positive nuclei showed an increase in nuclear volume (Wilcoxon test: p = less than 0.05), a more spheroid shape (p = less than 0.05), and a wider dispersion of nuclear volume values (Siegel-Tukey test: p = less than 0.05) than negative nuclei. Discriminant analysis on the basis of nuclear volume density functions facilitated an estimation of the proliferative state (resting or cycling) of a given nucleus. The results are consistent with increased cellular synthetic activity in highly proliferating lesions and particularly in actively cycling cells. The association of proliferative activity and quantitative nuclear features may be helpful in the interpretation of morphometric studies concerning melanocytic skin tumors.

Ultraviolet exposure as the main initiator of p53 mutations in basal cell carcinomas from psoralen and ultraviolet A-treated patients with psoriasis.

Basal cell carcinoma, the most frequent skin cancer in humans, is often linked to chronic sun exposure. In psoralen and ultraviolet A-treated psoriatic patients, basal cell carcinomas may occur even more frequently; however, the exact etiology and mechanisms of tumorigenesis in psoriatic patients are unclear because psoralen and ultraviolet A is not only a carcinogen but also an immunosuppressor and because psoralen and ultraviolet A-treated psoriatic patients often have other (co)carcinogenic risk factors (e.g, therapeutic exposure to ultraviolet B, X-ray radiation, arsenic, tar, and/or chemotherapeutic agents such as methotrexate). In this study, we analyzed the DNA of 13 basal cell carcinomas from five psoralen and ultraviolet A-treated psoriatic patients for mutations of the p53 tumor suppressor gene. DNA sequencing revealed a total of 11 mis-sense, two non-sense, and four silent mutations in seven of the 13 basal cell carcinomas (54%). Of the 13 total mis-sense or non-sense mutations, 12 (92%) occurred at dipyrimidine sites and nine (69%) were of the ultraviolet fingerprint type (eight C-->T transitions and one CC-->TT transition). Three of the C-->T transitions occurred at dipyrimidine sites opposite a 5'-TpG sequence (a potential psoralen-binding site and target for psoralen and ultraviolet A mutagenesis). Thus, whether these mutations were induced by ultraviolet or psoralen and ultraviolet A was not clear. In addition, two other mutations (15%) occurred at 5'-TpG sites, one (8%) occurred at a 5'-TpA site (the most frequent site of psoralen binding and mutagenesis in cell and murine studies), and one (8%) involved a G-->T transversion. These results suggest that (i) the major initiator of p53 mutations in basal cell carcinoma in psoralen and ultraviolet A-treated psoriasis patients is environmental and/or therapeutic ultraviolet(B) exposure, and that (ii) psoralen and ultraviolet A itself causes only a smaller portion of p53 mutations in psoralen and ultraviolet A-associated basal cell carcinomas.