Treatment approaches in immunosuppressed patients with advanced cutaneous squamous cell carcinoma.

Immunosuppression, both iatrogenic and disease-related, is associated with a greatly increased incidence of cutaneous SCC (cSCC) and with aggressive cSCC and worse disease outcomes. Consequently, rapid access to skin cancer services and prudent surgical choices, such as circumferential margin assessment, is essential when treating advanced cSCC in an immunosuppressed patient. For high-risk cancers and control of cSCC multiplicity, additional strategies should be actively considered within the multidisciplinary clinical care team. These include minimization or revision of immunosuppressive medications, systemic chemoprevention (including retinoids, nicotinamide, capecitabine) and adjuvant therapies such as radiotherapy. Unfortunately, there is a relative paucity of good evidence for many of these treatments in the immunosuppressed. Systemic treatments for metastatic cSCC are often contraindicated in organ transplant recipients, notably checkpoint inhibitor immunotherapy. There are also toxicity concerns with some conventional chemotherapies and EGFR inhibitors. Until recently, clinical trials have largely excluded immunosuppressed individuals. Development of more effective treatment for advanced cSCC in this high-risk group and prospective clinical trials are now research priorities.

Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.

Although tremendous progress has been made in recent years in skin cancer care for organ transplant recipients, significant gaps remain in data-driven clinical guidelines, particularly for the treatment and prevention of cutaneous squamous cell carcinoma (cSCC), the most common malignancy among this population. In this review, we aim to summarize current knowledge around the management of cSCC and highlight the most significant gaps in knowledge that continue to pose challenges in the delivery of skin cancer care for organ transplant recipients. We suggest future directions for research that will bridge existing gaps and establish evidence-driven guidelines for primary prevention, screening and treatment of cSCC in this high-risk patient population.

The breeding systems of diploid and neoautotetraploid clones of Acacia mangium Willd. in a synthetic sympatric population in Vietnam.

Colchicine-induced neoautotetraploid genotypes of Acacia mangium were cloned and planted in mixture with a set of diploid clones in an orchard in southern Vietnam. Following good general flowering, open-pollinated seed was collected from trees of both cytotypes and microsatellite markers were used to determine the breeding system as characterised by the proportion of outcrosses in young seedling progeny. As predicted from the literature, the progeny of diploid clones were predominantly outcrossed (t(m) = 0.97). In contrast, the progeny of the tetraploid clones were almost entirely selfs (t(m) = 0.02; 3 of 161 seedlings assayed were tetraploid outcrosses and there were no triploids). Segregation at loci heterozygous in the tetraploid mothers followed expected ratios, indicating sexual reproduction rather than apomixis. Post-zygotic factors are primarily responsible for divergence of the breeding systems. Commonly, less than 1 % of Acacia flowers mature as a pod, and after mixed pollination, diploid outcrossed seed normally develops at the expense of selfs. Selfs of the tetraploid trees appear to express less genetic load and have a higher probability of maturing. However, this does not fully explain the observed deficiency of outcross tetraploid progeny. Presumably, there are cytogenetic reasons which remain to be investigated. In nature, selfing would increase the probability of establishment of neotetraploids irrespective of cytotype frequency in the population. Breeders need to review their open-pollinated breeding and seed production strategies. It remains to be seen whether this is an ephemeral problem, with strong fertility selection restoring potential for outcrossing over generations.

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.

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.