Immunoexpression of S100A4 in canine skin melanomas and correlation with histopathological parameters

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Internet based health promotion campaign against skin cancer - Results of www.skincheck.ch in Switzerland

Conventional skin cancer prevention programs appeal to limited populations, and the middle aged male population responds less frequently. Our objective was to establish a complementary health promotion campaign tool for skin cancer prevention. Internet-based education, instruction for self assessment and teledermatological evaluation of skin lesions by an expert commission of dermatologists was used. Compliance and clinical diagnosis was assessed in a subgroup. 12,000 users visited the educational website. There was strong interest among the middle aged male population (53% (N = 262): male; mean age: 42). 28.5% of examined lesions (N = 494) were considered suspicious. Email requests, sent to the group whose lesions where considered suspicious, were answered by 46.0% of females (N = 29) and 59.7% of males (N = 46) with a female distribution predominantly in younger ages (52.6% of females with known age: < 30 years). Males were predominantly represented over 30 years (86.2% of all males). According to user's declarations, at least 8 (8.5%) malignant lesions (1 melanoma in situ, 1 squamous cell carcinoma, 4 basal cell carcinomas, 2 malignant lesions without declared diagnosis) were finally diagnosed by physicians. We conclude that internet-based, interactive, educational programs, in addition to existing health promotion campaigns, can enhance public participation in the middle aged male population in skin cancer prevention.

Recurrent non-melanoma skin cancer: remission of field cancerization after conversion from calcineurin inhibitor- to proliferation signal inhibitor-based immunosuppression in a cardiac transplant recipient

Non-melanoma skin cancers (NMSCs) are the most common malignancies after solid organ transplantation. Their incidence increases with time after transplantation. Calcineurin-inhibitors (CNIs) and azathioprine are known as skin neoplasia-initiating and -enhancing immunosuppressants. In contrast, increasing clinical experience suggests a relevant antiproliferative effect of mammalian target of rapamycin inhibitors, also named proliferation signal inhibitors (PSIs). We report the case of a cardiac allograft recipient with an impressive and consolidated reduction of recurrent NMSC, observed after conversion from CNI-therapy to a PSI-based protocol.

[Swiss clinical practice guidelines for skin cancer in organ transplant recipients]

Swiss clinical practice guidelines for skin cancer in organ transplant recipients Transplant patients have increased over the last decades. As a consequence of long-term immunosuppression, skin cancer, in particular squamous cell carcinoma (SCC), has become an important problem. Screening and education of potential organ transplant recipients (OTRs) regarding prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, OTRs should be seen yearly by a dermatologist to ensure compliance with sun avoidance as well as for treatment of precancerosis and SCC. Early removal is the best treatment for SCC. Reduction of immunosuppression, switch to mTOR inhibitors and chemoprevention with acitretin may reduce the incidence of SCC. The dermatological follow-up of OTRs should be integrated into a comprehensive post-transplant management strategy.

Cutaneous malignant melanoma: A study of skin cancer in the United States from 1973--1997

Cutaneous malignant melanoma (CMM) is the cancer of the melanocytes, the cells that produce the pigment melanin, and is an aggressive skin cancer that is most prevalent in the white population. Although most cases of malignant melanoma are white, black and other non-white populations also develop this disease. However, the etiologic factors involved in the development of melanoma in these lower-risk populations are not well known. Generally, survival rates of malignant melanoma have been found to be lower in blacks than for whites with similar stage of disease at diagnosis. ^ This study presents an analysis of the differences in survival between black and white cases with malignant melanoma of the skin as the only or first primary cancer, found in the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) cancer registry from 1973 to 1997. A total of 54,193 cases of CMM were diagnosed in black and white patients between 1973 and 1997. Black patients tended to be older, with a mean age of 64.46 years, compared to 53.14 years for white patients. Eighty-nine percent of patients were diagnosed with CMM as the only cancer. (Abstract shortened by UMI.)^

Roles of IkappaB kinase alpha in centrosome duplication and skin carcinogenesis

IκB kinase α (IKKα) is one kinase subunit of the IKK complex that is responsible for NF-κB activation. Previous studies have shown that IKKα determines mouse keratinocyte terminal differentiation independent of the NF-κB pathway. Accumulating evidence suggests that IKKα functions as a tumor suppressor in skin carcinogenesis; however, the downstream pathways mediating this function are largely unknown. By using primary cultured keratinocytes, we found that Ikkα-/- cells developed aneuploidy and underwent spontaneous immortalization and transformation while wild type cells underwent terminal differentiation in the same culture condition. Using proteomic analysis we identified nucleophosmin (NPM), a centrosome duplication regulator, as an IKKα substrate. We further demonstrated that IKKα interacted with NPM and colocalized with NPM on the centrosome, suggesting that NPM is a physiological substrate of IKKα. Loss of IKKα reduced centrosome-bound NPM and promoted abnormal centrosome amplification, which contributed to aneuploidy development. Detailed analysis revealed that ablation of IKKα target site serine-125 of NPM induced destabilization of NPM hexamers, disrupted NPM association with centrosomes, and resulted in abnormal centrosome amplification. Re-introduction of IKKα rescued the defect in Ikkα-/- keratinocytes. Thus, IKKα is required for maintaining proper centrosome duplication by phosphorylating NPM. ^ UV is the major etiological agent for human skin cancer and UV-induced mouse skin carcinogenesis is one of the most relevant experimental models for human skin carcinogenesis. Thus, we further evaluated IKKα function in UV-induced skin carcinogenesis in Ikkα+/- mice. We demonstrated that IKKα is also critical in UV skin carcinogenesis, as evidenced by increased tumor multiplicity and reduced tumor latency in Ikkα+/- mice after chronic UVB treatment. Reduced expression of IKKα decreased UV-induced apoptosis and promoted accumulation of P53 mutations in the epidermis. This indicates that IKKα is critical for UV-induced apoptosis in vivo and thus prevents mutation accumulation that is important for tumor development. ^ Together, these findings uncover previously unknown in vivo functions of IKKα in centrosome duplication and apoptosis, thus providing a possible mechanism of how loss of IKKα may contribute to skin carcinogenesis. ^

Psychosocial measures reported by parents in studies of skin cancer prevention

Background. Because it is important to minimize children's sun exposure to reduce skin cancer risk, much of the extensive skin cancer prevention literature consists of studies of children's sun protection, sun avoidance and ultraviolet radiation (UVR) exposure. Little attention has been focused on the measurement of psychosocial constructs in these studies. Identification of the psychosocial correlates or determinants of children's skin cancer risk or risk-reduction behavior is critical to more fully understand and predict behavior. Furthermore, psychosocial variables may be influenced by interventions to reduce risk. Thus, it is important to examine the psychosocial measures used in studies of children's skin cancer prevention. Information on the validity and reliability of psychosocial measures may increase confidence in study findings based on these measures. In particular, self-efficacy and barriers are key constructs in several major theoretical frameworks and parental measures have been associated with children's sun protection. However, there is conceptual overlap of self-efficacy and barriers measures and little is known about the psychometric properties of these measures.^ Study Aims and Methods. The overall goal of this dissertation was to examine the measurement of psychosocial constructs relevant to children's skin cancer prevention. Because children depend primarily on their parents for skin cancer prevention, measures of parents' psychosocial constructs are the focus. Study 1 was a systematic review of parental psychosocial measures used in studies of children's sun protection, sun avoidance and UVR exposure. The specific aims of Study 1 were to (1) describe psychosocial measures reported by parents, including available information on the psychometric properties of these measures and their use in analyses and (2) provide recommendations for the development, refinement and standardized reporting of measures. ^ Study 2 examined the psychometric properties of measures of parental self-efficacy and barriers regarding children's sun protection. Melanoma patients (N=205) who were parents of children ≤ 12 years of age completed a telephone interview that included self-efficacy and barriers measures specific to sunscreen, clothing, shade and limiting time outdoors. The specific aims of Study 2 were to (1) use a confirmatory factor analytic approach to examine the factorial validity of parental self-efficacy and barriers measures, (2) examine the convergent and discriminant validity of behavior-specific measures of self-efficacy and barriers and (3) assess the reliability of item and scale measures.^ Results. In Study 1, a search of standard databases yielded 48 eligible studies. Most studies assessed only one or two psychosocial constructs. Knowledge was measured most frequently. There was little discussion of measure source, development, theoretical background or psychometric properties, besides internal consistency reliability. There was conceptual overlap of some measures. In Study 2, confirmatory factor analytic findings supported the factorial validity of the self-efficacy and barriers measures. When all eight self-efficacy and barriers measures were included in the same model, a modified eight-factor model adequately fit the data, providing preliminary evidence that the measures are distinct. Measure associations supported the convergent validity of all measures and the discriminant validity of most measures. The self-efficacy and barriers measures were reliable.^ Conclusions. Recommendations based on the literature review include developing and refining psychosocial measures based on theory. Describing a measure's theoretical basis and psychometric properties would facilitate critical evaluation. Standardized reporting of source, development, theory, construct, items and analytic role would facilitate comparison of findings, continual refinement and future applications of measures. In the validation study, self-efficacy and barriers measures were examined in a sample of parents with a personal history of melanoma. Findings suggested that these measures are valid and reliable for use in studies of children's sun protection. There was preliminary evidence that these measures are distinct but additional study is needed. ^

Bayesian and survival model for tumor relapse status and disease-specific survival, with applications to breast cancer

Breast cancer is the most common non-skin cancer and the second leading cause of cancer-related death in women in the United States. Studies on ipsilateral breast tumor relapse (IBTR) status and disease-specific survival will help guide clinic treatment and predict patient prognosis.^ After breast conservation therapy, patients with breast cancer may experience breast tumor relapse. This relapse is classified into two distinct types: true local recurrence (TR) and new ipsilateral primary tumor (NP). However, the methods used to classify the relapse types are imperfect and are prone to misclassification. In addition, some observed survival data (e.g., time to relapse and time from relapse to death)are strongly correlated with relapse types. The first part of this dissertation presents a Bayesian approach to (1) modeling the potentially misclassified relapse status and the correlated survival information, (2) estimating the sensitivity and specificity of the diagnostic methods, and (3) quantify the covariate effects on event probabilities. A shared frailty was used to account for the within-subject correlation between survival times. The inference was conducted using a Bayesian framework via Markov Chain Monte Carlo simulation implemented in softwareWinBUGS. Simulation was used to validate the Bayesian method and assess its frequentist properties. The new model has two important innovations: (1) it utilizes the additional survival times correlated with the relapse status to improve the parameter estimation, and (2) it provides tools to address the correlation between the two diagnostic methods conditional to the true relapse types.^ Prediction of patients at highest risk for IBTR after local excision of ductal carcinoma in situ (DCIS) remains a clinical concern. The goals of the second part of this dissertation were to evaluate a published nomogram from Memorial Sloan-Kettering Cancer Center, to determine the risk of IBTR in patients with DCIS treated with local excision, and to determine whether there is a subset of patients at low risk of IBTR. Patients who had undergone local excision from 1990 through 2007 at MD Anderson Cancer Center with a final diagnosis of DCIS (n=794) were included in this part. Clinicopathologic factors and the performance of the Memorial Sloan-Kettering Cancer Center nomogram for prediction of IBTR were assessed for 734 patients with complete data. Nomogram for prediction of 5- and 10-year IBTR probabilities were found to demonstrate imperfect calibration and discrimination, with an area under the receiver operating characteristic curve of .63 and a concordance index of .63. In conclusion, predictive models for IBTR in DCIS patients treated with local excision are imperfect. Our current ability to accurately predict recurrence based on clinical parameters is limited.^ The American Joint Committee on Cancer (AJCC) staging of breast cancer is widely used to determine prognosis, yet survival within each AJCC stage shows wide variation and remains unpredictable. For the third part of this dissertation, biologic markers were hypothesized to be responsible for some of this variation, and the addition of biologic markers to current AJCC staging were examined for possibly provide improved prognostication. The initial cohort included patients treated with surgery as first intervention at MDACC from 1997 to 2006. Cox proportional hazards models were used to create prognostic scoring systems. AJCC pathologic staging parameters and biologic tumor markers were investigated to devise the scoring systems. Surveillance Epidemiology and End Results (SEER) data was used as the external cohort to validate the scoring systems. Binary indicators for pathologic stage (PS), estrogen receptor status (E), and tumor grade (G) were summed to create PS+EG scoring systems devised to predict 5-year patient outcomes. These scoring systems facilitated separation of the study population into more refined subgroups than the current AJCC staging system. The ability of the PS+EG score to stratify outcomes was confirmed in both internal and external validation cohorts. The current study proposes and validates a new staging system by incorporating tumor grade and ER status into current AJCC staging. We recommend that biologic markers be incorporating into revised versions of the AJCC staging system for patients receiving surgery as the first intervention.^ Chapter 1 focuses on developing a Bayesian method to solve misclassified relapse status and application to breast cancer data. Chapter 2 focuses on evaluation of a breast cancer nomogram for predicting risk of IBTR in patients with DCIS after local excision gives the statement of the problem in the clinical research. Chapter 3 focuses on validation of a novel staging system for disease-specific survival in patients with breast cancer treated with surgery as the first intervention. ^

Regulation of apoptosis during the pathogenesis of non -melanoma skin cancer

Previous studies from our lab have shown distinctive patterns of expression of bcl-2 gene family members in human nonmelanoma skin cancer (NMSC). To further evaluate the significance of these observations and to study the effects of cell death deregulation during skin carcinogenesis, we generated a transgenic mouse model (HK1.bcl-2) using the human keratin 1 promoter to target the expression of a human bcl-2 minigene to the epidermis. Transgenic protein expression was confirmed in all the layers of the epidermis except the stratum corneum using immunohistochemistry. Multifocal epidermal hyperplasia, without associated hyperkeratosis, was observed in newborn HK1.bcl-2 mice. Immunofluorescence staining using monoclonal antibodies specific for a variety of differentiation markers revealed aberrant expression of keratin 6 (K6) in the transgenic epidermis. Epidermal proliferative indexes, assessed by anti-BrdUrd immunofluorescence staining, were similar in control and transgenic newborn mice, but suprabasal proliferating cells were seen within the hyperplastic areas of the transgenic mouse skin. Spontaneous apoptotic indices of the epidermis were similar in both control and HK1.bcl-2 transgenic newborn mice, however, after UV-B irradiation, the number of "sunburn cells" was significantly higher in the control compared to the HK1.bcl-2 transgenic animals.^ Adult HK1.bcl-2 and control littermate mice were used in UV-B and chemical carcinogenesis protocols including DMBA + TPA. UV-B irradiated control and HK1.bcl-2 mice had comparable incidence of tumors than the controls, but the mean latency period was significantly shorter in the HK1.bcl-2 transgenic. Both control and transgenic animals included in chemical carcinogenesis protocols required application of both the initiating (DMBA) and promoting (TPA) agents to develop tumors. The frequency, number, and latency of tumor formation was similar in both groups of animals, however, HK1.bcl-2 mice exhibited a rate of conversion from benign papilloma to carcinoma 2.5 times greater than controls.^ Similar carcinogenesis experiments were performed using newborn mice. HK1.bcl-2 mice treated with UV-B plus TPA have a three fold greater incidence of tumor formation compared to controls littermates. HK1.bcl-2 transgenic animals also exhibited a shorter latency for papilloma formation when treated with DMBA plus TPA.^ HK1.bcl-2/v-Ha-ras double transgenic mice shared phenotypic features of both HK1.v-Ha-ras and HK1.bcl-2 transgenic mice, and exhibited focal areas of augmented hyperplasia. These double transgenic mice were susceptible to tumor formation by treatment with TPA alone.^ Cultures of primary keratinocytes were established from control, HK1.bcl-2, HK1.Ha-ras, and HK1.bcl-2/v-Ha-ras newborn mice. Cell viability was determined after exposure of the cells to UV-B irradiation, DMBA, TPA, or TGF-$\beta$1. Internucleosomal DNA fragmentation ("ladders") and morphological cellular changes compatible with apoptotic cell death were observed after the application of all these agents. HK1.bcl-2 keratinocytes were resistant to cell death induction by all of these agents except TGF-$\beta$1. HK1.Ha-ras cells had a higher spontaneous rate of cell death which could be compensated by co-expression of bcl-2.^ These findings suggest that bcl-2 dependent cell death suppression may be an important component of multistep skin carcinogenesis. ^

Increase in skin cancer screening during a community-based randomized intervention trial

Survival from cutaneous melanoma is mainly dependent on the thickness of the lesion at diagnosis. Skin screening may increase detection of thin lesions and hence improve survival. Within a community-based randomized controlled trial of a population screening program for melanoma in Queensland, Australia, 9 communities were randomly assigned to the 3-year intervention and 9 communities to the control group. Skin screening prevalence was monitored by cross-sectional surveys at baseline, 1, 2 and 3 years into the intervention and 2 years later. At baseline, prevalence of whole-body clinical skin examination was similar in intervention and control communities. In intervention communities, the prevalence of whole-body skin examinations increased to 29.2%, an absolute difference of 18% from baseline, with a peak of 34.8% 2 years after baseline, and began to decline again at the end of the intervention period. The largest increases were seen in men and women ≥50 years. Uptake of screening did not differ according to melanoma risk factors; however, the decline in screening was less in participants who reported a number of melanoma risk factors. The prevalence of skin self-examination remained stable during the intervention program. No changes were observed in the control communities. These results indicate that the intervention program significantly increased the prevalence of whole-body clinical skin examinations in intervention communities. Once the intervention program ceased, and particularly after skin clinics ceased, levels of skin screening began to decline. The provision of specialized skin screening clinics may be needed to achieve sufficient screening rates should population based screening for skin cancer be considered. © 2005 Wiley-Liss, Inc.

Long-term increase in sunscreen use in an Australian community after a skin cancer prevention trial

Background. Given the public health burden of skin cancer in white populations, an increase in sun protective behavior is needed. In a highrisk community, we assessed long-term Sunscreen use among people who had participated in a randomized trial of daily Sunscreen application for prevention of skin cancer. Methods. In 1992, 1621 residents of the subtropical Australian township of Nambour were randomly allocated to either daily or discretionary sunscreen use until 1996. From 1997 to 2002, we monitored by questionnaires their ongoing sunscreen use. Results. People who had never or irregularly used sunscreen when in summer sun before the trial were more likely (P < 0.0001) to be sustaining regular application especially to their face (20% vs. 11%) and forearms (14% vs. 5%) if they had been allocated to daily, not discretionary, use of sunscreen for 5 years. Conclusions. Regular voluntary sunscreen use for skin cancer prevention can be sustained by sun-sensitive people in the long term. Habit formation appears to be an important goal for sun protection programs among those living, or on vacation, in sunny places. (c) 2005 Elsevier Inc. All rights reserved.

Skin cancer medicine in primary care: towards an agenda for quality health outcomes

The number of skin cancer clinics functioning within Australia's primary care environment is increasing rapidly, and significant concerns have been raised about the type and quality of work done by some doctors in some clinics. Mainstream general practice is threatened by perceived fragmentation, and specialist practice in dermatology and plastic surgery is threatened by encroachment into their domains of practice. We propose an agenda of training, standards, accreditation, audit and research to ensure that skin cancer clinics provide optimal health outcomes for patients.

Expression of p53 tumor suppressor protein in sun-exposed skin and associations with sunscreen use and time spent outdoors: A community-based study

The p53 gene is a tumor suppressor gene that is commonly mutated in skin cancer and sun-exposed skin, and this can be detected through immunohistochemical expression of the p53 protein. The authors hypothesized that time spent outdoors is associated with p53 protein expression in human skin and that sunscreen use counteracts the association. In 1996, they investigated this in a community-based cross-sectional study in Australia. Detailed information about skin type, time spent outdoors, and sunscreen use was collected from 139 residents of a subtropical township who also provided a skin biopsy from the back of the hand for measurement of p53 expression. Increasing time spent outdoors was positively associated with immuno reactivity in the whole epidermis and in the basal layer of the epidermis. After adjustment for confounders, p53 immunoreactivity was twice as high for people who used sunscreen 1 or 2 days per week as for those who used sunscreen daily (whole epidermis: ratio estimate = 2.0, 95% confidence interval: 1.1, 3.6; basal layer: ratio estimate = 1.7, 95% confidence interval: 0.9, 3.1). The authors conclude that p53 immunoreactivity in the skin is a marker of exposure to ultraviolet light in the past 6 months, but this may be mitigated by regular application of sunscreen.