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.

In vivo long-term effects of retinoic acid exposure in utero on induced tumours in adult mouse skin.

BACKGROUND: Retinoic acid (RA) and its analogues (retinoids) are promising agents in skin cancer prevention following either topical application or oral administration. However, long-term in vivo effects of RA on chemically induced hyperplastic epidermal foci in adult mouse skin have also been described, casting some doubt with regard to its chemopreventive activity. HYPOTHESIS/OBJECTIVES: To characterize chemically induced skin tumours and to investigate the in vivo long-term action and preventive effect of RA on adult mouse skin carcinogenesis. ANIMALS: Fifty-six adult Naval Medical Research Institute mice, exposed (n = 28) or not exposed (n = 28) to RA in utero. METHODS: Mice were treated with a standard two-stage skin carcinogenesis protocol, which included an initiating application of 7,12-dimethylbenz(a)anthracene followed by promotion with 12-O-tetradecanoylphorbol 13-acetate. RESULTS: Retinoic acid administered to pregnant mice showed a long-term inhibitory action on cell differentiation and development of chemically induced tumours on the adult skin of their offspring, as well as a stimulatory effect on cell proliferation and expression of an early marker of malignant progression (keratin 13). CONCLUSIONS AND CLINICAL IMPORTANCE: The results suggest that RA exposure in utero confers long-lasting effects on adult mouse skin carcinogenesis. These include chemopreventive activity (reduced number of tumours), as well as enhancement of squamous papilloma progression, which appears to be due to enhanced keratinocyte proliferation and suppression of epidermal maturation. The clinical significance of these findings is not known for other routes of RA administration at this time.

Surgical removal of the parametrial fat pads stimulates apoptosis and inhibits UVB-induced carcinogenesis in mice fed a high-fat diet.

Removal of the parametrial fat pads (partial lipectomy) from female SKH-1 mice fed a high-fat diet inhibited UVB-induced carcinogenesis, but this was not observed in mice fed a low-fat chow diet. Partial lipectomy in high-fat-fed mice decreased the number of keratoacanthomas and squamous cell carcinomas per mouse by 76 and 79%, respectively, compared with sham-operated control mice irradiated with UVB for 33 wk. Immunohistochemical analysis indicated that partial lipectomy increased caspase 3 (active form) positive cells by 48% in precancerous epidermis away from tumors, by 68% in keratoacanthomas, and by 224% in squamous cell carcinomas compared with sham-operated control mice. In addition, partial lipectomy decreased cell proliferation away from tumors and in tumors. RT-PCR analysis for adipokines revealed that mRNAs for TIMP1, MCP1, and SerpinE1 (proinflammatory/antiapoptotic cytokines) in the parametrial fat pads of sham-operated control mice were 54- to 83-fold higher than levels in compensatory fat that returned after surgery in partially lipectomized mice at the end of the tumor study. Feeding mice high-fat diets for 2 wk increased levels of TIMP1 and other adipokines in serum and epidermis, and these increases were inhibited by removal of the parametrial fat pads. Our results are a unique demonstration that surgical removal of a specific tissue fat results in inhibition of carcinogenesis in obese mice. This inhibition was associated with an increase in apoptosis and a decrease in proliferation in tumors and in precancerous areas away from tumors.

Early detection, prevention and management of cutaneous adverse events due to sorafenib: recommendations from the Sorafenib Working Group.

Cutaneous adverse events commonly reported with tyrosine kinase inhibitors (TKIs) in the treatment of malignancies, represent an important clinical concern since they can limit the optimal use of these novel drugs. Although there are numerous reports in the literature of these events there are no practical guidelines on how they should be managed. The Sorafenib Working Group (SWG) was established with the objective of developing recommendations to allow the early detection, prevention and management of cutaneous adverse events in everyday clinical practice. The SWG was a multidisciplinary team made up of experts in the field who were closely involved in the sorafenib clinical development program. This review provides an overview of the nature and incidence of cutaneous adverse events which manifest with sorafenib treatment and provides recommendations for their early detection and effective management in clinical practice.

Ligand activation of peroxisome proliferator-activated receptor-beta/delta and inhibition of cyclooxygenase-2 enhances inhibition of skin tumorigenesis.

Ligand activation of peroxisome proliferator-activated receptor (PPAR)-beta/delta and inhibition of cyclooxygenase-2 (COX-2) activity by nonsteroidal anti-inflammatory drugs can attenuate skin tumorigenesis. There is also evidence that attenuation of skin tumorigenesis by inhibition of COX-2 activity occurs through PPARbeta/delta-independent mechanisms. The present study examined the hypothesis that combining ligand activation of PPARbeta/delta with inhibition of COX-2 activity will cooperatively inhibit chemically induced skin tumor progression using both in vivo and ex vivo models. A two-stage chemical carcinogenesis bioassay was performed in wild-type and Pparbeta/delta-null mice. After 22 weeks, cohorts of both mouse lines were divided into four experimental groups: (1) control, (2) topical application of the PPARbeta/delta ligand GW0742, (3) dietary administration of the COX-2 inhibitor nimesulide, or (4) both GW0742 and nimesulide. Ligand activation of PPARbeta/delta did not influence skin tumor progression, while a modest decrease in skin tumor multiplicity was observed with dietary nimesulide. Interestingly, the combined treatment of GW0742 and nimesulide increased the efficacy of the decrease in papilloma multiplicity for 6 weeks in wild-type mice, but this effect was not found at later time points and was not found in similarly treated Pparbeta/delta-null mice. Neoplastic keratinocyte lines cultured with GW0742 and nimesulide also exhibited enhanced inhibition of cell proliferation coincident with increased expression of Keratin messenger RNAs. Results from these studies support the hypothesis that combining ligand activation of PPARbeta/delta with inhibition of COX-2 activity can inhibit chemically induced skin tumor progression by modulating differentiation.

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.

[Importance of dermatologic screening within the frame work of a general cancer prevention program]. / Importanza di uno screening dermatologico nell'ambito di un programma di prevenzione oncolologica generale.

BACKGROUND: Skin tumours represent about 11% of all the malignant neoplasms and their frequency is increasing annually. Skin tumours (melanoma, basal and squamous cell carcinoma, etc.) can be used for a good screening activity, but in relation to breast or cervix uteri cancer needs to be better defined. A test on a population of selected patients against skin malignant neoplasms has been carried out in our Centre. All of them had skin lesions and further checks were necessary. METHODS: The diagnostic protocol used in our Centre for Oncological Prevention uses the collection of anamnestic data and an objective examination. Between 1996 and 2000, 222 patients between the ages of 18 and 80 have been selected. All of them had suspected skin lesions. The patients were selected by the oncologist, particularly for pigmentation, asymmetry, irregular borders and heterogeneous colour of their skin lesions. Subsequently, the patients were sent for a further examination to the dermatologist oncologist, who on the basis of the objective dermatological examination with possible dermatoscopy, made a clinical diagnosis of the skin injuries or suggested surgical removal for the histological control of the same. RESULTS: Requested consultations: 222. Exami-nations made: 195. Patients considered: 190. Skin injuries examined: 190. The following skin lesions were identified: melanoma: 4 (2.1%) [2: I Clark level; 2: II Clark level]; basal cell carcinoma: 14 (7.37%); dermatofibrosarcoma: 1 (0.53%); keratoacanthoma: 1 (0.53%); dysplastic nevus: 4 (2.1%); actinic keratosis: 7 (3.68%); benign lesions: 159 (83.68%). CONCLUSIONS: These data were obtained by a screening program and it is therefore not a random study. This study shows interesting results because tumoral skin lesions and in particular melanoma were recognised at early stages. This is more than enough for us to create a specific screening program for skin lesions to cut down the rate of morbidity and mortality.

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.

[Muir-Torre syndrome]. / Muir-Torre-szindróma.

Muir-Torre syndrome patients have multiple visceral malignancies along with cutaneous sebaceous tumors and keratoacanthomas. We describe a history of a 64-year-old male patient with 13 tumours, who survived 13 years. The initial ascending colon adenocarcinoma was followed by some different tumors of the skin: adenoma and carcinoma of sebaceous glands, epidermoid and basaloid carcinoma and other benign tumors. The last time developed rectal adenocarcinoma was operated.

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.

Inhibition of benzoyl peroxide-induced tumor promotion and progression by copper(II)(3,5-diisopropylsalicylate)2.

The ability of a biomimetic superoxide dismutase agent, copper(II)(3,5-diisopropylsalicylate)2 (CuDIPS), to modulate benzoyl peroxide (BzPo)-induced tumor promotion and progression in mouse skin multistage carcinogenesis was evaluated. The results showed a significant inhibition of tumor incidence by CuDIPS pretreatment during promotion-progression. Different types of tumors were developed: papillomas, keratoacanthomas and squamous cell carcinomas. There was a significant increase in the keratoacanthoma-papilloma ratio when the period of treatment with BzPo was prolonged, which was inhibited by CuDIPS pretreatment. CuDIPS induced a significant inhibition of malignant conversion. Our results suggest that reactive oxygen species could be important in BzPo-induced promotion and progression.

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.

[Xeroderma pigmentosum: prevention of tumors with etretinate]. / Xeroderma Pigmentosum: Tumorprophylaxe mit Etretinat.

A 46-year-old woman with xeroderma pigmentosum has had more than one hundred skin tumours in her life, in recent years largely keratoacanthomas. Two and a half years ago, a low-dose prophylactic treatment with etretinate (25 mg/day) was initiated. Since then, no further skin tumours have arisen except for several very small, rapidly resolving keratoacanthomas.