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.

Inhibition of 7,12-dimethylbenzanthracene-induced skin tumors by a nutrient mixture.

The annual incidence of all forms of skin cancer, the most common of all human cancers, is increasing yearly. A unique nutrient mixture (NM) was shown to exhibit anticancer activity in vivo and in vitro. We examined the effect of NM on the development of skin cancer induced by 7,12-dimethylbezanthracene (DMBA) in female SENCAR mice by a complete carcinogenesis protocol. Mice (n=55) were divided into four groups and carefully shaved on dorsum. After 2 days, the mice in Groups 1 (n=10), 3 (n=20), and 4 (n=20) were treated topically with 100 nM DMBA in 0.2 ml of acetone twice a week for 4 weeks; Group 2 (n=5), the control group, was treated with acetone 0.2 ml. Groups 1 and 2 were fed the regular diet. Group 3A (n=10) was fed a diet containing 0.5% NM from the day of DMBA treatment and 3B (n=10) the regular diet and received NM (75 mg in 0.4 ml of 1:1 acetone/water) topically to the shaved area 15 min before DMBA application twice a week for 4 weeks. Group 4 mice were fed a diet containing 0.5% NM for 2 weeks prior to the application of DMBA and then divided into two groups: 4A (n=10) was fed the 0.5% NM diet as in 3A, and 4B (n=10) the regular diet as described for 3B. Body weight and diet consumption of the mice were monitored and the skin tumors (papillomas) were counted and recorded. Ten weeks thereafter the mice were euthanized, skinned, and tumors were processed for histology. NM significantly (P<0.0001) inhibited DMBA-induced skin tumor multiplicity by 59, 62, 69, and 86% in NM-treated Groups 3A, 3B, 4A, and 4B, respectively. These results suggest that NM has strong potential as a useful therapeutic regimen for skin cancer by significantly inhibiting the incidence and tumor multiplicity of DMBA-induced skin tumors.

Effects of oral administration of tea, decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk SKH-1 mice previously treated with ultraviolet B light.

Treatment of SKH-1 mice with ultraviolet B light (UV-B, 30 mJ/cm2) twice a week for 22-23 weeks resulted in tumor-free animals with a high risk of developing malignant and nonmalignant tumors during the next several months in the absence of further UV-B treatment (high-risk mice). In three separate experiments, oral administration of green tea or black tea (4-6 mg tea solids/ml) as the sole source of drinking fluid for 18-23 weeks to these high-risk mice inhibited the formation and decreased the size of nonmalignant squamous cell papillomas and keratoacanthomas as well as the formation and size of malignant squamous cell carcinomas. In one experiment all these inhibitory effects of tea were statistically significant, whereas in the two other experiments many but not all of the inhibitory effects of tea were statistically significant. The decaffeinated teas were inactive or less effective inhibitors of tumor formation than the regular teas, and adding caffeine back to the decaffeinated teas restored biological activity. Oral administration of caffeine alone (0.44 mg/ml) as the sole source of drinking fluid for 18-23 weeks inhibited the formation of nonmalignant and malignant tumors, and this treatment also decreased tumor size in these high-risk mice.

Effects of tea, decaffeinated tea, and caffeine on UVB light-induced complete carcinogenesis in SKH-1 mice: demonstration of caffeine as a biologically important constituent of tea.

Oral administration of green or black tea inhibited UVB light-induced complete carcinogenesis in the skin of SKH-1 mice. Green tea was a more effective inhibitor than black tea. Oral administration of decaffeinated green or black tea resulted in substantially less inhibitory activity than did administration of the regular teas, and in one experiment, administration of a high-dose level of the decaffeinated teas enhanced the tumorigenic effect of UVB. Oral administration of caffeine alone had a substantial inhibitory effect on UVB-induced carcinogenesis, and adding caffeine to the decaffeinated teas restored the inhibitory effects of these teas on UVB-induced carcinogenesis. In additional studies, topical application of a green tea polyphenol fraction after each UVB application inhibited UVB-induced tumorigenesis. The results indicate that caffeine contributes in an important way to the inhibitory effects of green and black tea on UVB-induced complete carcinogenesis.

Effect of immunosuppressive agents and sunscreens on UV carcinogenesis in the hairless mouse.

The effect of two immunosuppressive agents, azathioprine and cyclophosphamide, with and without UVB sunscreen protection on UV-induced skin carcinogenesis was studied in the albino hairless mouse. In a daily treatment regime spanning 9 weeks, groups of mice were immunosuppressed with either drug, and were exposed to minimally erythemal doses of a light source simulating the UV portion of the solar spectrum. The accumulated UV exposure alone induced skin tumours in 77% of mice. Azathioprine, but not cyclophosphamide, significantly enhanced the incidence of UV tumorigenesis. Photoprotection by topical application of one of two commonly used UVB sunscreens, 2-ethyl-hexyl-p-methoxycinnamate (2-EHMC) or octyl-N-dimethyl-p-aminobenzoate (o-PABA), reduced the UV tumour incidence to zero in immunologically normal mice and to 8-15% in immunosuppressed mice. Unexpressed latent tumour initiations were revealed in all sunscreen-protected groups by the subsequent application of a tumour promoter, croton oil. In immunologically normal mice 2-EHMC had allowed initiations in 39% of UV-irradiated mice, and o-PABA in 16.5%. However, in UV-irradiated mice immunosuppressed with azathioprine there had been initiations in 78% of mice protected with 2-EHMC and 65% of mice protected with o-PABA. Photoprotected mice immunosuppressed with cyclophosphamide did not show the same increase in UV-initiations (22% with 2-EHMC, 23% with o-PABA). These results provide evidence that azathioprine increases the susceptibility of the skin to UV carcinogenesis. However, UVB sunscreens afford effective protection from overt tumour expression in the absence of a tumour promoter.