Eruptive keratoacanthoma-type squamous cell carcinomas in patients taking sorafenib for the treatment of solid tumors.

BACKGROUND: Protein kinases (PKs) are indispensable for most cellular processes, and deregulation of PKs can lead to activation of oncogenic and anti-apoptotic pathways and immune dysregulation. OBJECTIVE: To report the development of keratoacanthoma (KA)-type squamous cell carcinomas (SCCs) in patients treated with the multikinase inhibitor sorafenib for the treatment of solid tumors, to present the possible mechanisms for induction of these SCCs, and to discuss the implications for discontinuation of therapy and possible cotherapies to decrease this side effect. PARTICIPANTS: Fifteen patients taking the multikinase inhibitor sorafenib for the treatment of solid tumors who developed multiple KA-type SCCs, which continued to develop while the patients were undergoing therapy but stopped with discontinuation of sorafenib. LIMITATIONS: This report is limited because it is a retrospective study that included only patients who developed multiple KA-type SCCs. CONCLUSIONS: Development of cutaneous SCCs appears to be a side effect limited to sorafenib, a multikinase inhibitor that inhibits not only multiple tyrosine kinases (TKs), but also the serine-threonine kinase Raf. The incidence of cutaneous SCCs does not appear greater with multikinase inhibitors that inhibit only TKs.

An assessment of the carcinogenic potential of shea oleine in the rat.

Shea oleine, an oil fraction derived from the nut of the tree Butyrospermum parkii, is used as a frying oil. As part of a series of studies, this investigation examined the carcinogenic potential of 15% (w/w) shea oleine in comparison with 15% (w/w) sheanut oil, and palm oil following dietary administration to rats over 104 weeks. The assessment comprised an evaluation of mortality, clinical signs, body weight, food intake, clinical pathology, organ weights and macroscopic and histopathological examination plus tumour type and incidence evaluation. Results showed that shea oleine produced no adverse effects and no evidence of tumorigenic potential compared to other commercially available sheanut and palm oils in the rat. Notable differences were confined to reduced body weight gain and food intake, reduced cholesterol and increased alkaline phosphatase levels, reduced heart weight and an increased incidence of pulmonary lipidosis with shea oleine diets. The latter effect may reflect a naturally lower incidence of this finding with palm oil diets. Tumour findings, specific to shea oleine diets, were restricted to an increase in the number of hepatomas for females, pancreatic exocrine adenomas for males and skin keratoacanthomas for males fed shea oleine diets. The increase in the incidence of hepatomas with treatment was thought to be related to the high fat content of the diets. The incidence of these tumour findings was similar to that given in published data for the Wistar rat, or the 'in house' values for tumour incidence in rats fed high-fat diets. In conclusion, none of the findings in this study were considered to be adverse effects. In comparison with other commercially available edible oils, shea oleine showed no tumorigenic potential following dietary administration at 7.5 g/kg/day in the rat.

Human papillomavirus and widespread cutaneous carcinoma after PUVA photochemotherapy.

BACKGROUND: Oral psoralen with UV-A (PUVA) photochemotherapy is known to cause cutaneous malignancies and has been associated with cutaneous immunosuppression. Human papillomavirus infection has also been associated with cutaneous malignancies and with immunosuppressed individuals. We therefore sought evidence of human papillomavirus infection in a patient with a long history of PUVA therapy and multiple cutaneous malignancies. OBSERVATIONS: During a 15-year period, an otherwise healthy patient with psoriasis who had undergone a 10-year course of PUVA photochemotherapy developed 13 squamous cell carcinomas, eight lesions diagnosed as "squamous cell carcinoma vs keratoacanthoma," 14 other keratoacanthomas, six basal cell carcinomas, one melanoma in situ, and 18 other keratinocytic dysplasias. Twenty-two of the 30 lesions tested for human papillomavirus DNA by polymerase chain reaction were positive for type 16/18, including six of the seven basal or squamous cell carcinomas tested. CONCLUSION: We hypothesize that PUVA therapy-induced immunosuppression may play an important role in PUVA-related carcinogenesis by affecting the extent and pathogenicity of human papillomavirus infection.

'High single-dose' European PUVA regimen also causes an excess of non-melanoma skin cancer.

We report the results of a long-term (12.8 years) follow-up study of the detection of malignant and benign skin tumours in patients with psoriasis, who were treated with PUVA according to the European, 'high single-dose' regimen. A total of 13 squamous cell carcinomas (SCC) and 24 basal cell carcinomas (BCC) were diagnosed in 11 of 260 patients. The incidence of both SCC and BCC was increased in comparison with the general Dutch population. The ratio of SCC to BCC in the general population was 1:8 but was 1:2.5 in our study group. A positive correlation was observed between the development of SCC and the total UVA dosage, the age of the patient at the start of the PUVA treatment and a history of arsenic use. This dose-related increase in the incidence of SCC, reported in studies from the U.S.A., has not been found in earlier European studies. The average time period between the start of PUVA therapy and the diagnosis of the first malignant skin tumour was 6.0 years for SCC and 4.7 years for BCC. Among the 49 benign skin tumours were actinic keratoses, a keratoacanthoma and 'PUVA keratoses', a newly described hyperkeratotic lesion, especially found in PUVA-treated patients.

Assay of 1-nitropropane, 2-nitropropane, 1-azoxypropane and 2-azoxypropane for carcinogenicity by gavage in Sprague-Dawley rats.

1-Nitropropane (1-NP), 2-nitropropane (2-NP), 1-azoxypropane (1-AP) and 2-azoxypropane (2-AP), were assayed for carcinogenicity by gavage in male Sprague-Dawley rats. 2-NP was given at 1 mmol/kg three times per week for 16 weeks. 1-NP (1 mmol/kg), 1-AP (0.1 mmol/kg), 2-AP (0.1 mmol/kg) or Emulphor EL-620 vehicle was given three times per week for 16 weeks, and then once per week for 10 weeks. In the 2-NP treated group both benign and malignant liver tumors occurred in 100% of the animals. No treatment related tumors occurred in rats receiving 1-NP. In rats treated with 1-AP, a high incidence of skin tumors (100%), mostly keratoacanthomas, and of tumors of the nasal cavity (59%) was observed. Rats which were given 2-AP also showed an increased incidence of skin keratoacanthomas (21%), but not of other tumors. These findings (i) confirm, using the oral route of administration, the results of inhalation studies by others indicating the potent hepatocarcinogenicity of 2-NP, (ii) establish a practical model in which the mechanism of 2-NP carcinogenicity can now be more readily studied, and (iii) demonstrate that 1-AP, and probably 2-AP, like other aliphatic azoxy compounds thus far examined, are carcinogenic in rats.

[Carcinogenic effect of a heavy catalytic gas oil]. / Kantserogennoe deistvie tiazhelogo kataliticheskogo gazoilia.

The carcinogenic effect of treatment with heavy catalytic gasoil on the skin of 120 albino noninbred mice was studied. Skin tumors arose in 97 of 115 animals (84.3%) which survived until the appearance of the first papillomas. In 21 mice, tumors were benign while cancer developed in 76 animals. 116 visceral neoplasms were detected in 99 animals (93.4%). They were found in the upper part of digestive tract of 57, the hematopoietic and lymphatic tissues of 57 and in the lungs of two animals. The study established a high carcinogenicity of heavy catalytic gasoil matched by early appearance and multicentric growth of tumors as well as rapid generalization of the process.

Skin carcinogenesis as a model system: observations on species, strain and tissue sensitivity to 7,12-dimethylbenz(a)anthracene with or without promotion from croton oil.

The pattern of development of tumours was studied in several mice strains, rabbits and pigs. Repeated carcinogen applications caused the appearance of numerous papillomas, keratoacanthomas and squamous cell carcinomas in Swiss, A, ASW/SN Balb/c and C57B1 mice, New Zealand and outbred laboratory rabbits. AKR mice were only little sensitive and Hormel mini pigs unresponsive. Initiation with 7,12-dimethylbenz(a)-anthracene and promotion with croton oil produced in Swiss, A, Balb/c and C3H mice as well as New Zealand rabbits a large number of squamous papillomas. Pigmented or adnexal tumours were not observed, and only a few dermal fibromas and fibrosarcomas.

Bioassay of complex mixtures derived from fossil fuels.

The conversion or processing of shale, coal, or petroleum involves elevated temperatures and altered pressures, and under these conditions polynuclear aromatic hydrocarbons are likely to form. Certain compounds of this type exhibit carcinogenic activity for a variety of organ sites in experimental animals and epidemiological evidence strongly implicates their role as carcinogens in man. It is then not unexpected that many liquid fractions derived from shale and coal are carcinogenic when subjected to bioassay. Benzo(a)pyrene, [B(a)P], is frequently considered to be an indicator substance. It is clear that when a small quantity of B(a)P is present in a fraction, the fraction will exhibit carcinogenic activity in a bioassay (mouse skin). However, it does not follow that the lack of detectable B(a)P insures that the fraction will be noncarcinogenic. Several fractions have been analyzed for their content of B(a)P and then subjected to bioassay. A method for testing complex mixtures for their carcinogenic potential is described. The carcinogenic potency of these fractions are compared to petroleum fractions.