Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial

Background The use of sunscreens on the skin can prevent sunburn but whether long-term use can prevent skin cancer is not known. Also, there is evidence that oral betacarotene supplementation lowers skin-cancer rates in animals, but there is limited evidence of its effect in human beings. Methods In a community-based randomised trial with a 2 by 2 factorial design, individuals were assigned to four treatment groups: daily application of a sun protection factor 15-plus sunscreen to the head, neck, arms, and hands, and betacarotene supplementation (30 mg per day); sunscreen plus placebo tablets; betacarotene only; or placebo only. Participants were 1621 residents of Nambour in southeast Queensland, Australia. The endpoints after 4.5 years of follow-up were the incidence of basal-cell and squamous-cell carcinomas both in terms of people treated for newly diagnosed disease and in terms of the numbers of tumours that occurred. Analysis of the effect of sunscreen was based only on skin cancers that developed on sites of daily application. All analyses were by intention to treat. Findings 1383 participants underwent full shin examination by a dermatologist in the follow-up period. 250 of them developed 758 new skin cancers during the follow-up period. There were no significant differences in the incidence of first new shin cancers between groups randomly assigned daily sunscreen and no daily sunscreen (basal-cell carcinoma 2588 vs 2509 per 100 000; rate ratio 1.03 [95% CI 0.73-1.46]; squamous-cell carcinoma 876 vs 996 per 100 000; rate ratio 0.88 [0.50-1.56]). Similarly, there was no significant difference between the betacarotene and placebo groups in incidence of either cancer (basal-cell carcinoma 3954 vs 3806 per 100 000; 1.04 [0.73-1.27]; squamous-cell carcinoma 1508 vs 1146 per 100 000; 1.35 [0.84-2.19]). In terms of the number of tumours, there was no effect on incidence of basal-cell carcinoma by sunscreen use or by betacarotene but the incidence of squamous-cell carcinoma was significantly lower in the sunscreen group than in the no daily sunscreen group (1115 vs 1832 per 100 000; 0.61 [0.46-0.81]). Interpretation There was no harmful effect of daily use of sunscreen in this medium-term study. Cutaneous squamous-cell carcinoma, but not basal-cell carcinoma seems to be amenable to prevention through the routine use of sunscreen by adults for 4.5 years. There was no beneficial or harmful effect on the rates of either type of skin cancer, as a result of betacarotene supplementation.

Parotidectomy: review of treatment and outcomes

Background: Parotidectomy is a common surgical procedure performed for a wide array of benign and malignant tumours. The aim of the present study was to review a single-institution experience with parotidectomy over a 10 year period. Methods: We retrospectively reviewed 170 patients who had parotidectomy performed. The preoperative investigations, clinicopathological parameters, perioperative morbidity and mortality were assessed. Results: One hundred and six (62%) of the patients were men. The mean age was 54 years (range 21-80). Indications for parotidectomy included benign tumour (44%), malignant tumour (42%), inflammatory parotid disease (7%) and miscellaneous (5%). The most common benign tumour was pleomorphic adenoma (25%). The most common malignant tumour was metastatic cutaneous squamous cell carcinoma (SCC) (19%). Fine needle aspiration cytology was performed in 83% patients with a sensitivity and specificity for benign tumours of 76% and 97%, respectively. The sensitivity and specificity for malignant tumours was 90% and 99%, respectively. One (0.6%) patient died in the postoperative period. Postoperative complications included wound infection (2.3%), wound haematoma (3.5%) and seroma (6.6%). Six patients (3.5%) developed temporary complete facial paresis, while 33 patients (20%) developed temporary partial facial palsy in the immediate postoperative period. The 2-year disease-free and disease-specific survival for those patients with metastatic cutaneous SCC were 75% and 76%, respectively. Conclusions: The most common indications for parotidectomy were pleomorphic adenoma and metastatic cutaneous SCC. Our perioperative morbidity and survival for patients with malignant parotid disease compare favourably with other institutional series.

The effect of skin examination surveys on the incidence of basal cell carcinoma in a Queensland community sample: A 10-year longitudinal study

Skin cancers pose a significant public health problem in high-risk populations. We have prospectively monitored basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) incidence in a Queensland community over a 10-y period by recording newly treated lesions, supplemented by skin examination surveys. Age-standardized incidence rates of people with new histologically confirmed BCC were 2787 per 100,000 person-years at risk (pyar) among men and 1567 per 100,000 pyar among women, and corresponding tumor rates were 5821 per 100,000 pyar and 2733 per 100,000 pyar, respectively. Incidence rates for men with new SCC were 944 per 100,000 pyar and for women 675 per 100,000 pyar; tumor rates were 1754 per 100,000 pyar and 846 per 100,000 pyar, respectively. Incidence rates of BCC tumors but not SCC tumors varied noticeably according to method of surveillance, with BCC incidence rates based on skin examination surveys around three times higher than background treatment rates. This was mostly due to an increase in diagnosis of new BCC on sites other than the head and neck, arms, and hands associated with skin examination surveys and little to do with advancing the time of diagnosis of BCC on these sites as seen by a return to background rates following the examination surveys. We conclude that BCC that might otherwise go unreported are detected during skin examination surveys and thus that such skin cancer screening can influence the apparent burden of skin cancer.

Merkel-cell carcinoma of the skin

Merkel-cell carcinoma (MCC) is a rare form of skin cancer of neuroendocrine origin that has been described as the most aggressive cutaneous malignancy. The cell of origin is thought to be the Merkel cell or skin-pressure receptor. It has the propensity for dermal-lymphatic invasion, and nodal and haematogenous spread. Factors that have been implicated in its cause include exposure to sunlight and immunosuppression. The tumour has many similarities to small-cell carcinoma of the lung, with intrinsic sensitivity to ionising radiation and chemotherapy, and an aggressive metastatic potential. The best treatment outcomes can be achieved with early diagnosis and the integration of surgery, radiation, and chemotherapy. The treatment challenges for the clinician are often enormous because many of the patients are elderly and because lesions occur in difficult sites such as the head and neck region and the lower leg.

Does chemotherapy improve survival in high-risk Stage I and II Merkel cell carcinoma of the skin?

Purpose: The effectiveness of synchronous carboplatin, etoposide, and radiation therapy in improving survival was evaluated by comparison of a matched set of historic control subjects with patients treated in a prospective Phase II study that used synchronous chemotherapy and radiation and adjuvant chemotherapy. Patients and Methods: Patients were included in the analysis if they had disease localized to the primary site and nodes, and they were required to have at least one of the following high-risk features: recurrence after initial therapy, involved nodes, primary size greater than 1 cm, or gross residual disease after surgery. All patients who received chemotherapy were treated in a standardized fashion as part of a Phase II study (Trans-Tasman Radiation Oncology Group TROG 96:07) from 1997 to 2001. Radiation was delivered to the primary site and nodes to a dose of 50 Gy in 25 fractions over 5 weeks, and synchronous carboplatin (AUC 4.5) and etoposide, 80 mg/m(2) i.v. on Days 1 to 3, were given in Weeks 1, 4, 7, and 10. The historic group represents a single institution's experience from 1988 to 1996 and was treated with surgery and radiation alone, and patients were included if they fulfilled the eligibility criteria of TROG 96:07. Patients with occult cutaneous disease were not included for the purpose of this analysis. Because of imbalances in the prognostic variables between the two treatment groups, comparisons were made by application of Cox's proportional hazard modeling. Overall survival, disease-specific survival, locoregional control, and distant control were used as endpoints for the study. Results: Of the 102 patients who had high-risk Stage I and II disease, 40 were treated with chemotherapy (TROG 96:07) and 62 were treated without chemotherapy (historic control subjects). When Cox's proportional hazards modeling was applied, the only significant factors for overall survival were recurrent disease, age, and the presence of residual disease. For disease-specific survival, recurrent disease was the only significant factor. Primary site on the lower limb had an adverse effect on locoregional control. For distant control, the only significant factor was residual disease. Conclusions: The multivariate analysis suggests chemotherapy has no effect on survival, but because of the wide confidence limits, a chemotherapy effect cannot be excluded. A study of this size is inadequately powered to detect small improvements in survival, and a larger randomized study remains the only way to truly confirm whether chemotherapy improves the results in high-risk MCC. (c) 2006 Elsevier Inc.

A for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study

Purpose: The aims of this randomized controlled trial were to determine whether there were differences in the disease-free survival (DFS) and toxicity between conventional radiotherapy (CRT) and a continuous 3 week accelerated radiotherapy regimen (ART) in stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, larynx and hypopharynx. Patients and methods: Patients from 14 centres throughout Australia and New Zealand were randomly assigned to either CRT, using a single 2 Gy/day to a dose of 70 Gy in 35 fractions in 49 days or to ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days. Treatment allocation was stratified for site and stage. The accrual began in 1991 and the trial was closed in 1998 when the target of 350 patients was reached. Results: The median potential follow-up time was 53 months (range, 14-101). The DFS at 5 years was 41% (95% CI, 33-50%) for ART and 35% (95% CI, 27-43%) for CRT (P = 0.323) and the hazard ratio was 0.87 in favour of ART (95% CI, 0.66-1.15). The 5-year disease-specific survival rates were 40% for CRT and 46% for ART (P = 0.398) and the loco-regional control was 47% for CRT vs. 52% for ART (P = 0.300). The respective hazard ratios were 0.88 (95% CI, 0.65-1.2) and 0.85 (0.62-1.16), favouring the accelerated arm. In the ART arm, confluent mucositis was more severe (94 vs. 71%; P < 0.001) and peaked about 3 weeks earlier than in the CRT arm, but healing appeared complete in all cases. There were statistically significant reductions in the probability of grade 2 or greater late soft tissue effects over time in the ART arm (P < 0.05), except for the mucous membrane where late effects were similar in both arms. Conclusions: Differences in DFS, disease-specific survival and loco-regional control have not been demonstrated. ART resulted in more acute mucosal toxicity, but this did not result in greater prolongation of the treatment time compared with the CRT arm. There were less late effects in the ART arm, with the exception of late mucosal effects. This trial has confirmed that tumour cell repopulation occurs during conventionally fractionated radiotherapy for head and neck cancer. However, it has also provided additional evidence that overall improvements in the therapeutic ratio using accelerated fractionation strategies are seriously constrained by the need to limit total doses to levels that do not exceed acute mucosal tolerance. The accelerated schedule tested has been shown in this trial to be an acceptable alternative to conventionally fractionated irradiation to 70 Gy. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Role of dietary factors in the development of basal cell cancer and squamous cell cancer of the skin

The role of dietary factors in the development of skin cancer has been investigated for many years; however, the results of epidemiologic studies have not been systematically reviewed. This article reviews human studies of basal cell cancer (BCC) and squamous cell cancer (SCC) and includes all studies identified in the published scientific literature investigating dietary exposure to fats, retinol, carotenoids, vitamin E, vitamin Q and selenium. A total of 26 studies were critically reviewed according to study design and quality of the epidemiologic evidence. Overall, the evidence suggests a positive relationship between fat intake and BCC and SCC, an inconsistent association for retinol, and little relation between beta-carotene and BCC or SCC development. There is insufficient evidence on which to make a judgment about an association of other carotenoids with skin cancer. The evidence for associations between vitamin E, vitamin C, and selenium and both BCC and SCC is weak. Many of the existing studies contain limitations, however, and further well-designed and implemented studies are required to clarify the role of diet in skin cancer. Additionally, the role of other dietary factors, such as flavonoids and other polyphenols, which have been implicated in skin cancer development in animal models, needs to be investigated.

E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

Squamous differentiation of keratinocytes is associated with decreases in E2F-1 mRNA expression and E2F activity, and these processes are disrupted in squamous cell carcinoma cell lines. We now show that E2F-1 mRNA expression is increased in primary squamous cell carcinomas of the skin relative to normal epidermis, To explore the relationship between E2F-1 and squamous differentiation further, we examined the effect of altering E2F activity in primary human keratinocytes induced to differentiate. Promoter activity for the proliferation-associated genes, cdc2 and keratin 14, are inhibited during squamous differentiation. This inhibition can be inhibited by overexpression of E2F-1 in keratinocytes, Overexpression of E2F-1 also suppressed the expression of differentiation markers (transglutaminase type 1 and keratin 10) in differentiated keratinocytes, Blocking E2F activity by transfecting proliferating keratinocytes with dominant negative E2F-1 constructs inhibited the expression of cdc2 and E2F-1, but did not induce differentiation. Furthermore, expression of the dominant negative construct in epithelial carcinoma cell lines and normal keratinocytes decreased expression from the cdc2 promoter. These data indicate that E2F-1 promotes keratinocyte proliferation-specific marker genes and suppresses squamous differentiation-specific marker genes. Moreover, these data indicate that targeted disruption of E2F-1 activity may have therapeutic potential for the treatment of squamous carcinomas.

EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer

EDD (E3 isolated by differential display), located at chromosome 8q22.3, is the human orthologue of the Drosophila melanogaster tumour suppressor gene 'hyperplastic discs' and encodes a HECT domain E3 ubiquitin protein-ligase. To investigate the possible involvement of EDD in human cancer, several cancers from diverse tissue sites were analysed for allelic gain or loss (allelic imbalance, AI) at the EDD locus using an EDD-specific microsatellite, CEDD, and other polymorphic microsatellites mapped in the vicinity of the 8q22.3 locus. Of 143 cancers studied, 38 had AI at CEDD (42% of 90 informative cases). In 14 of these cases, discrete regions of imbalance encompassing 8q22.3 were present, while the remainder had more extensive 8q aberrations. AI of CEDD was most frequent in ovarian cancer (22/47 informative cases, 47%), particularly in the serous subtype (16/22, 73%), but was rare in benign and borderline ovarian tumours. AI was also common in breast cancer (31%), hepatocellular carcinoma (46%), squamous cell carcinoma of the tongue (50%) and metastatic melanoma (18%). AI is likely to represent amplification of the EDD gene locus rather than loss of heterozygosity, as quantitative RT-PCR and immunohistochemistry showed that EDD mRNA and protein are frequently overexpressed in breast and ovarian cancers, while among breast cancer cell lines EDD overexpression and increased gene copy number were correlated. These results demonstrate that AI at the EDD locus is common in a diversity of carcinomas and that the EDD gene is frequently overexpressed in breast and ovarian cancer, implying a potential role in cancer progression.

Anthropometric measures in relation to Basal Cell Carcinoma: a longitudinal study

Background: The relationship between anthropometric indices and risk of basal cell carcinoma ( BCC) is largely unknown. We aimed to examine the association between anthropometric measures and development of BCC and to demonstrate whether adherence to World Health Organisation guidelines for body mass index, waist circumference, and waist/ hip ratio was associated with risk of BCC, independent of sun exposure. Methods: Study participants were participants in a community- based skin cancer prevention trial in Nambour, a town in southeast Queensland ( latitude 26 degrees S). In 1992, height, weight, and waist and hip circumferences were measured for all 1621 participants and weight was remeasured at the end of the trial in 1996. Prevalence proportion ratios were calculated using a log- binomial model to estimate the risk of BCC prior to or prevalent in 1992, while Poisson regression with robust error variances was used to estimate the relative risk of BCC during the follow- up period. Results: At baseline, 94 participants had a current BCC, and 202 had a history of BCC. During the 5- year follow- up period, 179 participants developed one or more new BCCs. We found no significant association between any of the anthropometric measures or indices and risk of BCC after controlling for potential confounding factors including sun exposure. There was a suggestion that short- term weight gain may increase the risk of developing BCC for women only. Conclusion: Adherence to World Health Organisation guidelines for body mass index, waist circumference and waist/ hip ratio is not significantly associated with occurrence of basal cell carcinomas of the skin.

De novo mutations of the Patched gene in nevoid basal cell carcinoma syndrome help to define the clinical phenotype

The demonstration that mutations in the Patched (PTCH) gene cause nevoid basal cell carcinoma syndrome (NBCCS) has led to the identification of the exact molecular lesion in a percentage of individuals with the syndrome, In addition, it has been possible to determine, through molecular analysis of parents and other relatives of these individuals, if the mutation is inherited or has arisen de novo, We have previously reported 28 mutations in individuals with NBCCS, and here we present an additional 4 novel mutations, We have also analyzed relatives of a number of the individuals in whom we have found mutations, In total we have identified 8 individuals who carry a de novo mutation in the PTCH gene, In 5 of these cases, clinical and radiological examination had not unequivocally ruled out a diagnosis in one of the parents, This helps to define the clinical phenotype and suggests that diagnostic criteria in this complex syndrome may require review. (C) 1997 Wiley-Liss, Inc.

CDKN2A is not the principal target of deletions on the short arm of chromosome 9 in neuroendocrine (Merkel cell) carcinoma of the skin

The majority of small-cell lung cancers (SCLCs) express p16 but not pRb, Given our previous study showing loss of pRb in Merkel cell carcinoma (MCC)/neuroendocrine carcinoma of the skin and the clinicopathological similarities between SCLC acid MCC, we wished to determine if this was also the case in MCC, Twenty-nine MCC specimens from 23 patients were examined for deletions at 10 loci on 9p and I on 9p. No loss of heterozygosity (LO H) was peen in 9 patients including 2 for which tumour and cell line DNAs were examined. Four patients had LOH for all informative loci on 9p, Ten tumours showed more limited regions of loss on 9p, and from these 2 common regions of deletion were determined, Half of all informative cases had LOH at D95168, the most telomeric marker examined, and 3 specimens showed loss of only D9S168, A second region (InFNA-D9S126) showed L0H in 10(44%) cases, and case MCC26 showed LOH for only D9S126, implicating genes centromeric of the CDKN2A locus. No mutations in the coding regions of p16 were seen in 7 cell lines tested, and reactivity to anti-p16 antibody was seen in all Il tumour specimens examined and in 6 of 7 cell lines from 6 patients. Furthermore, all cell lines examined reacted with anti-p 14' antibody, These results suggest that neither transcript of the CDKN2A locus is the target of deletions on 9p in MCC and imply the existence of tumour-suppressor genes mapping both centromeric and telomeric of this locus. (C) 2001 Wiley-Liss, Inc.