Melanomas in renal transplant recipients: the London experience, and invitation to participate in a European study.
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Adult↗
Biomedical subjects
C M Proby
Publications and source records attributed to C M Proby.
Treatment of post-transplant premalignant skin disease: a randomized intrapatient comparative study of 5-fluorouracil cream and topical photodynamic therapy.
BACKGROUND: Organ transplant recipients (OTR) are at high risk of developing nonmelanoma skin cancer and premalignant epidermal dysplasia (carcinoma in situ/ Bowen's disease and actinic keratoses). Epidermal dysplasia is often widespread and there are few comparative studies of available treatments. OBJECTIVES: To compare topical methylaminolaevulinate (MAL) photodynamic therapy (PDT) with topical 5% fluorouracil (5-FU) cream in the treatment of post-transplant epidermal dysplasia. METHODS: Eight OTRs with epidermal dysplasia were recruited to an open-label, single-centre, randomized, intrapatient comparative study. Treatment with two cycles of topical MAL PDT 1 week apart was randomly assigned to one area of epidermal dysplasia, and 5-FU cream was applied twice daily for 3 weeks to a clinically and histologically comparable area. Patients were reviewed at 1, 3 and 6 months after treatment. The main outcome measures were complete resolution rate (CRR), overall reduction in lesional area, treatment-associated pain and erythema, cosmetic outcome and global patient preference. RESULTS: At all time points evaluated after completion of treatment, PDT was more effective than 5-FU in achieving complete resolution: eight of nine lesional areas cleared with PDT (CRR 89%, 95% CI: 0.52-0.99), compared with one of nine lesional areas treated with 5-FU (CRR 11%, 95% CI: 0.003-0.48) (P = 0.02). The mean lesional area reduction was also proportionately greater with PDT than with 5-FU (100% vs. 79% respectively). Cosmetic outcome and patient preference were also superior in the PDT-treated group. CONCLUSIONS: Compared with topical 5-FU, MAL PDT was a more effective and cosmetically acceptable treatment for epidermal dysplasia in OTRs and was preferred by patients. Further studies are now required to confirm these results and to examine the effect of treating epidermal dysplasia with PDT on subsequent development of squamous cell carcinoma in this high risk population.
Administration, Topical↗
Overexpression of the Axl tyrosine kinase receptor in cutaneous SCC-derived cell lines and tumours.
The molecular mechanisms that underlie the development of squamous cell skin cancers (SSC) are poorly understood. We have used oligonucleotide microarrays to compare the differences in cellular gene expression between a series of keratinocyte cell that mimic disease progression with the aim of identifying genes that may potentially contribute towards squamous cell carcinoma (SCC) progression in vivo, and in particular to identify markers that may serve as potential therapeutic targets for SCC treatment. Gene expression differences were corroborated by polymerase chain reaction and Western blotting. We identified Axl, a receptor tyrosine kinase with transforming potential that has also been shown to have a role in cell survival, adhesion and chemotaxis, was upregulated in vitro in SCC-derived cells compared to premalignant cells. Extending the investigation to tumour biopsies showed that the Axl protein was overexpressed in vivo in a series of SCCs.
Biomarkers, Tumor↗
Specialist dermatology clinics for organ transplant recipients significantly improve compliance with photoprotection and levels of skin cancer awareness.
BACKGROUND: Organ transplant recipients (OTRs) have 100-fold increased risk of developing squamous cell carcinomas. Cumulative exposure to ultraviolet radiation is the main risk factor and there is evidence that lack of dermatological surveillance may be responsible for poor levels of knowledge and photoprotection among OTRs. OBJECTIVES: This study evaluated whether routine consultation in a specialist OTR dermatology clinic improves understanding of skin cancer risk and compliance with photoprotection measures. METHODS: A cross-sectional questionnaire-based study was performed in a specialist OTR dermatology clinic at Bart's and the London NHS Trust, London, U.K. The subjects were 399 white-skinned patients under surveillance in a renal transplant clinic, who were sent a postal questionnaire from the renal transplant clinic. The main outcome measures were responses to the questionnaire regarding photoprotective practices and skin cancer risk awareness. RESULTS: Two hundred and ninety-two of 399 (73%) responded, of whom 89% had previously attended the specialist dermatology clinic. Ninety-six per cent recalled receiving photoprotection advice at least once (85% from dermatologists); 92% reported use of sunscreen; 88% specifically dressed to photoprotect themselves; 96% directly avoided sun exposure during summer; 68% were aware that an increased risk of skin cancer was the reason that extra photoprotective measures were important after a transplant. Photoprotective measures and level of skin cancer awareness were significantly lower in those responders who had never attended the specialist clinic. No obvious bias was identified among nonresponders. CONCLUSIONS: Skin cancer awareness and compliance with photoprotective measures in our patient population is generally greater than previously reported, suggesting that delivery of educational messages regarding skin cancer may be improved if provided in a specialist dermatological setting.
Cross-Sectional Studies↗
Treatment of basal cell carcinoma with topical methylaminolaevulinate photodynamic therapy in an organ-transplant recipient.
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Administration, Topical↗
Imiquimod cream 5% for recalcitrant cutaneous warts in immunosuppressed individuals.
BACKGROUND: Viral warts may cause significant morbidity in individuals unable to mount an adequate T-helper 1 cell-mediated immune response to human papillomavirus. Imiquimod is a potent inducer of antiviral cytokine activity which has shown significant efficacy in the treatment of genital warts. Similar efficacy in cutaneous warts is not yet established. OBJECTIVES: To assess the response of persistent cutaneous warts to 5% imiquimod cream in immunosuppressed individuals. METHODS: Fifteen immunosuppressed patients with warts on the hands and/or feet present for more than 18 months, which had failed to respond to a minimum of 12 weeks of topical salicylic acid and four cycles of cryotherapy, were recruited. Imiquimod 5% cream was applied in an open label, right vs. left comparison study for 24 weeks (three times weekly for 8 weeks, daily for 8 weeks, then daily with occlusion for 8 weeks). RESULTS: Twelve (80%) patients completed the study protocol. Benefit was seen in five patients [36% in the intent-to-treat analysis (14 patients)], including more than 30% clearance of warts in three patients and reduction in overall size of warts in two further cases. Local skin reactions occurred in four (29%) patients and were usually mild. A transient rise in creatinine (11-29% above baseline) was measured in three renal transplant recipients, but we did not consider that this was related to imiquimod exposure. CONCLUSIONS: This is the first controlled study to assess therapeutic efficacy of topical 5% imiquimod cream in persistent warts associated with immunosuppression. It provides preliminary evidence that topical imiquimod may benefit a subgroup of immunosuppressed patients with recalcitrant cutaneous warts.
Administration, Cutaneous↗
Atypical fibroxanthoma in a renal transplant recipient.
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12E7 Antigen↗
Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin.
BACKGROUND: Human papillomaviruses (HPVs) are found in normal skin and in benign and malignant skin conditions. Epidermodysplasia verruciformis (EV) HPV types are those most plausibly linked to the development of squamous cell carcinomas of the skin. OBJECTIVES: To assess the risk of nonmelanoma skin cancer (NMSC) associated with the presence of EV HPV in normal skin in immunocompetent (IC) individuals and renal transplant recipients (RTRs). METHODS: Using a degenerate and nested polymerase chain reaction technique, HPV DNA was sought in 124 normal skin samples from sun-exposed and nonsun-exposed sites, from 39 IC individuals and 38 RTRs, both with and without NMSC. Data were analysed using the Mantel-Haenszel test and by logistic regression analysis. RESULTS: HPV DNA was detected in 58/67 (87%) and 20/57 (35%) samples from renal transplant and IC patients, respectively. There was no difference in either the prevalence or spectrum of HPV types found in sun-exposed and nonsun-exposed normal skin. However, there was significant association between NMSC and the presence of EV HPV DNA. Multivariate analysis provided an odds ratio of 6.41 (95% confidence interval 1.79-22.9) for the association of EV HPV DNA in normal skin (irrespective of site) and NMSC status, even after stratifying for patient group and adjusting for the clustering effect of multiple sampling. Conversely, there was no association between skin cancer status and the presence of cutaneous or mucosal HPV types in either sun-exposed or nonsun-exposed skin. CONCLUSIONS: HPV DNA is widespread in normal adult skin, particularly in transplant patients. In our study, the presence of EV but not cutaneous HPV DNA in normal skin was significantly associated with NMSC status and may prove to be of predictive value for skin cancer risk. These data provide reason to focus on EV HPV types as causal agents in skin cancer.
Adult↗
Dermatofibrosarcoma protruberans in a renal transplant recipient.
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Antigens, CD34↗
Lack of mutations within ST7 gene in tumour-derived cell lines and primary epithelial tumours.
ST7 is a candidate tumour suppressor gene at human chromosome locus 7q31.1. We have performed mutational analysis of ST7 in a wide-range of cell lines and primary epithelial cancers and detected only one missense change in a breast cancer cell line. Other mutations previously found in cell lines and primary tumours were not evident in our analysis. These results imply that another tumour suppressor gene at this locus may be more important than ST7 in carcinogenesis.
Adenocarcinoma↗
Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals.
The role of human papillomavirus (HPV) in anogenital carcinogenesis is established firmly, but a similar role in non-melanoma skin cancer remains speculative. Certain immunosuppressed individuals have an increased incidence of both viral warts and non-melanoma skin cancer, that has prompted the suggestion that HPV may play a pathogenic role. Differences in the techniques used to detect HPV DNA in skin, however, have led to discrepancies in the prevalence and spectrum of HPV types reported in these malignancies. This study describes the use of a comprehensive degenerate PCR technique to compare the HPV status of 148 Non-melanoma skin cancers from immunosuppressed and immunocompetent individuals. HPV DNA was detected in 37/44 (84.1%) squamous cell carcinomas, 18/24 (75%) basal cell carcinomas and 15/17 (88.2%) premalignant skin lesions from the immunosuppressed group compared with 6/22 (27.2%) squamous cell carcinomas, 11/30 (36.7%) basal cell carcinomas and 6/11 (54. 4%) premalignancies in the immunocompetent group. Epidermodysplasia verruciformis HPV types prevailed in all lesion types from both groups of patients. In immunosuppressed individuals, cutaneous HPV types were also identified at high frequency, and co-detection of multiple HPV types within single tumours was commonly observed. This study represents the largest and most comprehensive analysis of the HPV status of non-melanoma skin cancers yet undertaken; whereas there are clearly significant differences in non-melanoma skin cancers from immunosuppressed and immunocompetent populations, we provide evidence that the prevalence and spectrum of HPV types does not differ in squamous cell carcinomas, basal cell carcinomas or premalignancies within the two populations. These data have important implications for future investigation of the role of HPV in cutaneous carcinogenesis at a functional level.
Adult↗
Spontaneous keratinocyte cell lines representing early and advanced stages of malignant transformation of the epidermis.
A unique series of epidermal cell lines representing different stages of malignant transformation were spontaneously derived from a single adult immunosuppressed individual. Four keratinocyte lines (PM1-4) established from forehead skin are here compared with 4 squamous cell carcinoma (SCC) lines (MET1-4) derived respectively from a primary cutaneous tumour, two local recurrences and a distant metastasis of invasive SCC. Despite altered growth properties, the PM lines retained many features of normal keratinocytes including keratin phenotype, differentiation capacity and non-tumorigenicity in athymic mice. In contrast, from early passage, the MET lines displayed markedly reduced growth requirements, abnormal differentiation, aberrant K18 expression and tumorigenicity in athymic mice. The abnormal keratin profile of individual MET lines closely reflected the keratin phenotype of the tumour of origin. Although unusual HPV types were identified in the original tissue, there was no evidence of persistent virus within any cell line and it appears that HPV is not critical for maintenance of the immortal phenotype. The PM lines were distinctly different from invasive SCC lines and are likely to be useful for studies of mutations important early in neoplastic progression. The SCC series represent primary, recurrent and metastatic carcinoma. Availability of such a series from the same individual will facilitate genetic analysis of the malignant process.
Adaptation, Physiological↗
Development of chimeric molecules for recognition and targeting of antigen-specific B cells in pemphigus vulgaris.
Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by circulating pathogenic IgG antibodies against desmoglein 3 (Dsg3). The purpose of this study was to develop chimeric molecules for specific recognition and elimination of autoimmune B cells in PV. Mouse hybridoma cell lines producing anti-Dsg3 antibody (5H10, 12A2) were developed as an in vitro model system for targeting B cells. Dsg3-GFP, a baculoprotein containing the entire extracellular domain of Dsg3 fused with green fluorescence protein, recognized and targeted the hybridoma cells through their surface immunoglobulin receptors in an antigen-specific way. The epitopes of these monoclonal antibodies were mapped on the amino terminal EC1 and part of EC2, a region considered functionally important in cadherins. Chimeric toxin molecules containing the mapped region (Dsg3deltaN1) and modified Pseudomonas exotoxin were produced in bacteria (Dsg3deltaN1-PE40-KDEL, PE3 7-Dsg3deltaN1-KDEL) and tested in vitro on hybridoma cell lines. The chimeric toxins, but not Dsg3deltaN1 alone, showed dose-dependent toxic activity with a reduction in hybridoma cell number to 40-60% of toxin-negative control cultures, compared with little or no effect on anti-Dsg3-negative hybridoma cells. Furthermore, these toxins showed toxic effects on anti-Dsg3 IgG-producing B cells from Dsg3deltaN1-immunized mice, with a 60% reduction in cell number compared with Dsg3deltaN1 alone. Thus, specific recognition and targeting of antigen-specific B cells in PV was demonstrated; this strategy may hold promise as a future therapeutic option for PV and other autoimmune diseases.
ADP Ribose Transferases↗
The promoter of a novel human papillomavirus (HPV77) associated with skin cancer displays UV responsiveness, which is mediated through a consensus p53 binding sequence.
An aetiological role has been proposed for human papillomavirus (HPV) in skin carcinogenesis within the immunosuppressed patient population. To examine this possibility, we have focused on an HPV type that, to date, has been identified only in the cutaneous lesions of renal transplant recipients despite a high degree of sequence homology with other HPVs commonly found in warts in the general population. We report that the non-coding region of this virus, HPV type 77, contains a consensus binding site for the tumour suppressor protein p53, and we show by gel-retardation analysis that this sequence does indeed bind p53. Furthermore, using reporter gene assays, we demonstrate that HPV77 promoter activity is stimulated by UV radiation and that this response is mediated through the p53 binding site. This is the first report of a p53-dependent positive response element within a viral genome. Our results suggest a possible novel mechanism by which specific types of HPV might act as cofactors with UV radiation in cutaneous transformation.
Adult↗
Degenerate and nested PCR: a highly sensitive and specific method for detection of human papillomavirus infection in cutaneous warts.
The role of human papillomavirus (HPV) in anogenital carcinogenesis is firmly established, but evidence that supports a similar role in skin remains speculative. Immunosuppressed renal transplant recipients have an increased incidence of viral warts and nonmelanoma skin cancer, and the presence of HPV DNA in these lesions, especially types associated with the condition epidermodysplasia verruciformis (EV), has led to suggestions that HPV may play a pathogenic role. However, differences in the specificities and sensitivities of techniques used to detect HPV in skin have led to wide discrepancies in the spectrum of HPV types reported. We describe a degenerate nested PCR technique with the capacity to detect a broad spectrum of cutaneous, mucosal, and EV HPV types. In a series of 51 warts from 23 renal transplant recipients, this method detected HPV DNA in all lesions, representing a significant improvement over many previously published studies. Cutaneous types were found in 84.3% of warts and EV types were found in 80.4% of warts, whereas mucosal types were detected in 27.4% of warts. In addition, the method allowed codetection of two or more distinct HPV types in 94.1% of lesions. In contrast, single HPV types were detected in all but 1 of 20 warts from 15 immunocompetent individuals. In summary, we have established a highly sensitive and comprehensive degenerate PCR methodology for detection and genotyping of HPV from the skin and have demonstrated a diverse spectrum of multiple HPV types in cutaneous warts from transplant recipients. Studies designed to assess the significance of these findings to cutaneous carcinogenesis are under way.
Base Sequence↗
Human papillomavirus and the development of non-melanoma skin cancer.
Human papillomaviruses (HPV) are increasingly recognised as important human carcinogens. The best established association with human malignancy is that of high-risk mucosal HPV types and anogenital cancer. HPV-induced transformation of anogenital epithelia has been the subject of intense research which has identified the cellular tumour suppressor gene products, p53 and pRB, as important targets for the viral oncoproteins E6 and E7 respectively. Certain HPV types are also strongly associated with the development of non-melanoma skin cancer in the inherited disorder epidermodysplasia verruciformis (EV). However, in contrast with anogenital malignancy the oncogenic mechanisms of EV-HPV types remain uncertain, and there appears to be a crucial additional requirement for ultraviolet radiation. Cutaneous HPV types in the general population are predominantly associated with benign viral warts, but a role in non-melanoma skin cancer has recently been postulated. Polymerase chain reaction based HPV detection techniques have shown a high prevalence of HPV DNA, particularly in skin cancers from immunosuppressed patients and to a lesser extent in malignancies from otherwise immunocompetent individuals. No particular HPV type has yet emerged as predominant, and the role of HPV in cutaneous malignancy is unclear at present. It remains to be established whether HPV plays an active or purely a passenger role in the evolution of non-melanoma skin cancer.
Carcinoma, Squamous Cell↗
Detection of human papillomavirus DNA in PUVA-associated non-melanoma skin cancers.
Psoralen and UVA (PUVA) photochemotherapy is associated with a dose-dependent increased risk of nonmelanoma skin cancer in patients treated for psoriasis. Like ultraviolet B radiation, PUVA is both mutagenic and immunosuppressive and may thus act as a complete carcinogen; however, the reversed squamous to basal cell carcinoma ratio (SCC:BCC) in PUVA-treated patients, also seen in immunosuppressed renal transplant recipients, suggests a possible cofactor role for human papillomavirus (HPV) infection. In this study we examine a large series of benign and malignant cutaneous lesions for the presence of HPV DNA from patients treated with high dose (> or =500 J per cm2) ultraviolet A. A panel of degenerate primers based on the L1 (major capsid protein) open reading frame was employed, designed to detect mucosal, cutaneous, and epidermodysplasia verruciformis HPV types with high sensitivity and specificity. HPV DNA was detected in 15 of 20 (75%) non-melanoma skin cancer, seven of 17 (41.2%) dysplastic PUVA keratoses, four of five (80%) skin warts, and four of 12 (33%) PUVA-exposed normal skin samples. The majority of HPV positive lesions contained epidermodysplasia verruciformis-related HPV including HPV-5, -20, -21, -23, -24, and -38. Possible novel epidermodysplasia verruciformis types were identified in further lesions. Mixed infection with epidermodysplasia verruciformis, cutaneous, and/or mucosal types was present in six of 30 (20%) of all HPV positive lesions, including in normal skin, warts, dysplastic PUVA keratoses, and squamous cell carcinomas. The prevalence and type of HPV infection in cutaneous lesions from PUVA-treated patients is similar to that previously reported in renal transplant-associated skin lesions, and suggests that the role of HPV in PUVA-associated carcinogenesis merits further study.
Adult↗
Detection and typing of human papillomaviruses in mucosal and cutaneous biopsies from immunosuppressed and immunocompetent patients and patients with epidermodysplasia verruciformis: a unified diagnostic approach.
AIM: To develop a unified diagnostic approach for the detection of human papillomavirus (HPV) DNA in skin and mucosal biopsies from both immunocompetent and immunosuppressed individuals using a degenerate polymerase chain reaction (PCR) method. METHODS: The sensitivity and specificity of three published degenerate primer sets (HVP2/B5 and F14/B15; MY09/MY11; CP62/69 outer and CP65/68 nested primer pairs) were evaluated in PCR reactions with serial dilutions of 12 representative cloned HPV types. This combination of primers was then used to detect HPV DNA in 49 benign and malignant lesions of cutaneous and mucosal origin from immunosuppressed, immunocompetent, and epidermodysplasia verruciformis (EV) patients, and compared with detection rates using single primer sets alone. RESULTS: The observed sensitivity of MY09/MY11 and CP62/69 + CP65/68 was high for mucosal and EV HPV types, respectively. The sensitivity of all primer sets for cutaneous types was low, but nonetheless the use of this combination of primers allowed HPV DNA detection in all of the benign warts analysed. Several mixed infections were also identified. A high prevalence of HPV DNA was similarly detected in squamous cell carcinomas from immunocompromised patients; the HPV types found were exclusively EV related. CONCLUSIONS: The use of a combined degenerate primer PCR approach considerably improves HPV DNA detection over individual primer sets and allows detection of mixed infections. The findings may help explain the discrepancies in published reports relating to HPV DNA detection in benign and malignant skin lesions. Further modifications to this method are in progress which should significantly improve comprehensive HPV detection and typing for diagnostic purposes.
Biopsy↗