Multifocal urothelial cancers with the mutator phenotype are of monoclonal origin and require panurothelial treatment for tumor clearance

Purpose: UC is a disease of the entire urothelium, characterized by multiplicity and multifocality. The clonal relationship among multiple UCs has implications regarding adjuvant chemotherapy. It has been investigated in studies of chromosomal alteration and single gene mutation. However, these genetic changes can occur in unrelated tumors under similar carcinogenic selection pressures. Tumors with high MSI have numerous DNA mutations, of which many provide no selection benefit. While these tumors represent an ideal model for studying UC clonality, their low frequency has prevented their previous investigation. Materials and Methods: We investigated 32 upper and lower urinary tract UCs with high MSI and 4 nonUC primary cancers in 9 patients. We used the high frequency and specificity of individual DNA mutations in these tumors (MSI at 17 loci) and the early timing of epigenetic events (methylation of 7 gene promoters) to investigate tumor clonality. Results: Molecular alterations varied among tumors from different primary organs but they appeared related in the UCs of all 9 patients. While 7 patients had a high degree of concordance among UCs, in 2 the UCs shared only a few similar alterations. Genetic and epigenetic abnormalities were frequently found in normal urothelial samples. Conclusions: Multiple UCs in each patient appeared to arise from a single clone. The molecular order of tumor development varied from the timing of clinical presentation and suggested that residual malignant cells persist in the urinary tract despite apparent curative surgery. These cells lead to subsequent tumor relapse and new methods are required to detect and eradicate them.

Effects of whole body cryotherapy and cold water immersion on knee skin temperature

This study sought to a) compare and contrast the effect of 2 commonly used cryotherapy treatments, 4 min of − 110 °C whole body cryotherapy and 8 °C cold water immersion, on knee skin temperature and b) establish whether either protocol was capable of achieving a skin temperature ( < 13 °C) believed to be required for analgesic purposes. After ethics committee approval and written informed consent was obtained, 10 healthy males (26.5 ± 4.9 yr, 183.5 ± 6.0 cm, 90.7 ± 19.9 kg, 26.8 ± 5.0 kg/m 2 , 23.0 ± 9.3 % body fat; mean ± SD) participated in this randomised controlled crossover study. Skin temperature around the patellar region was assessed in both knees via non-contact, infrared thermal imaging and recorded pre-, immediately post-treatment and every 10 min thereafter for 60 min. Compared to baseline, average, minimum and maximum skin temperatures were significantly reduced (p < 0.001) immediately post-treatment and at 10, 20, 30, 40, 50 and 60 min after both cooling modalities. Average and minimum skin temperatures were lower (p < 0.05) immediately after whole body cryotherapy (19.0 ± 0.9 ° C) compared to cold water immersion (20.5 ± 0.6 ° C). However, from 10 to 60 min post, the average, minimum and maximum skin temperatures were lower (p < 0.05) following the cold water treatment. Finally, neither protocol achieved a skin temperature believed to be required to elicit an analgesic effect.

Investigating epidermogenesis in a human skin equivalent model

Skin is the largest, and arguably, the most important organ of the body. It is a complex and multi-dimensional tissue, thus making it essentially impossible to fully model in vitro in conventional 2-dimensional culture systems. In view of this, rodents or pigs are utilised to study wound healing therapeutics or to investigate the biological effects of treatments on skin. However, there are many differences between the wound healing processes in rodents compared to humans (contraction vs. re-epithelialisation) and there are also ethical issues associated with animal testing for scientific research. Therefore, the development of skin equivalent (HSE) models from surgical discard human skin has become an important area of research. The studies in this thesis compare, for the first time, native human skin and the epidermogenesis process in a HSE model. The HSE was reported to be a comparable model for human skin in terms of expression and localisation of key epidermal cell markers. This validated HSE model was utilised to study the potential wound healing therapeutic, hyperbaric oxygen (HBO) therapy. There is a significant body of evidence suggesting that lack of cutaneous oxygen results in and potentiates the chronic, non-healing wound environment. Although the evidence is anecdotal, HBO therapy has displayed positive effects on re-oxygenation of chronic wounds and the clinical outcomes suggest that HBO treatment may be beneficial. Therefore, the HSE was subjected to a daily clinical HBO regime and assessed in terms of keratinocyte migration, proliferation, differentiation and epidermal thickening. HBO treatment was observed to increase epidermal thickness, in particular stratum corneum thickening, but it did not alter the expression or localisation of standard epidermal cell markers. In order to elucidate the mechanistic changes occurring in response to HBO treatment in the HSE model, gene microarrays were performed, followed by qRT-PCR of select genes which were differentially regulated in response to HBO treatment. The biological diversity of the HSEs created from individual skin donors, however, overrode the differences in gene expression between treatment groups. Network analysis of functional changes in the HSE model revealed general trends consistent with normal skin growth and maturation. As a more robust and longer term study of these molecular changes, protein localisation and expression was investigated in sections from the HSEs undergoing epidermogenesis in response to HBO treatment. These proteins were CDCP1, Metallothionein, Kallikrein (KLK) 1 and KLK7 and early growth response 1. While the protein expression within the HSE models exposed to HBO treatment were not consistent in all HSEs derived from all skin donors, this is the first study to detect and compare both KLK1 and CDCP1 protein expression in both a HSE model and native human skin. Furthermore, this is the first study to provide such an in depth analysis of the effect of HBO treatment on a HSE model. The data presented in this thesis, demonstrates high levels of variation between individuals and their response to HBO treatment, consistent with the clinical variation that is currently observed.

Cutaneous markers of photo-damage and risk of basal cell carcinoma of the skin : a meta-analysis

BACKGROUND: Epidemiologic research has demonstrated that cutaneous markers of photo-damage are associated with risk of basal cell carcinoma (BCC). However there has been no previous attempt to calculate pooled risk estimates. METHODS: We conducted a systematic review and meta-analysis after extracting relevant studies published up to January 2013 from five electronic databases. Eligible studies were those that permitted quantitative assessment of the association between histologically-confirmed BCC and actinic keratoses, solar elastosis, solar lentigines, or telangiectasia. RESULTS: Seven eligible studies were identified and summary odds ratios (OR) were calculated using both random and quality effects models. Having more than ten actinic keratoses was most strongly associated with BCC, conferring up to a 5-fold increase in risk (OR: 4.97; 95% CI: 3.26, 7.58). Other factors, including solar elastosis, solar lentigines, and telangiectasia had weaker but positive associations with BCC with ORs around 1.5. CONCLUSIONS: Markers of chronic photo-damage are positively associated with BCC. The presence of actinic keratoses was the most strongly associated with BCC of the markers examined. IMPACT: This work highlights the relatively modest association between markers of chronic ultraviolet exposure and BCC.

Determinants of uptake of whole-body skin self-examination in older men

Early detection through whole-body Skin Self-Examination (wbSSE) may decrease mortality from melanoma. Using the Health Action Process Approach (HAPA) or Health Belief Model (HBM) we aimed to assess determinants of uptake of wbSSE in 410 men 50 years of older who participated in the control group of a randomized trial. Overall, the HAPA was a significantly better predictor of wbSSE compared to the HBM (p < .001). The construct of self-efficacy in the HBM was a significant predictor of future wbSSE (p = .001), while neither perceived threat (p = .584) nor outcome expectations (p = .220) were. In contrast, self-efficacy, perceived threat, and outcome expectations predicted intention to perform SSE, which predicted behavior (p = .015). The HAPA construct volitional self-efficacy was also associated with wbSSE (p = .046). The use of the HAPA model for future SSE interventions for this population is warranted.

The HealthyTexts study : A randomized controlled trial to improve skin cancer prevention behaviors among young people

Several randomized trials have found behavior change programs delivered via text messaging to be efficacious to improve preventive health behaviors such as physical activity and stopping smoking; however few have assessed its value in skin cancer prevention or early detection. The HealthyTexts study enrolled 678 participants 18–42 years, and assigned them to receive 21 text messages about skin cancer prevention, skin self-examination or physical activity(attention control) over the course of one year. Baseline data have been collected and outcomes will be assessed at three months and twelve months post intervention. The trial aims to increase the mean overall sun protection habits index score from 2.3 to 2.7 with a standard deviation of 0.5 (effect size of 0.5) and the proportion of people who conduct a whole-body skin self-examination by an absolute 10%. This paper describes the study design and participants' baseline characteristics. In addition, participants' goals for their health, and strategies they apply to achieve those goals are summarized.

Enhanced skin self-examination : a novel approach to skin cancer monitoring and follow-up

Advances in mobile telephone technology and available dermoscopic attachments for mobile telephones have created a unique opportunity for consumer-initiated mobile teledermoscopy. At least 2 companies market a dermoscope attachment for an iPhone (Apple), forming a mobile teledermoscope. These devices and the corresponding software applications (apps) enable (1) lesion magnification (at least ×20) and visualization with polarized light; (2) photographic documentation using the telephone camera; (3) lesion measurement (ruler); (4) adding of image and lesion details; and (5) e-mail data to a teledermatologist for review. For lesion assessment, the asymmetry-color (AC) rule has 94% sensitivity and 62 specificity for melanoma identification by consumers [1]. Thus, consumers can be educated to recognize asymmetry and color patterns in suspect lesions. However, we know little about consumers' use of mobile teledermoscopy for lesion assessment.

Chitosan-collagen scaffolds with nano/microfibrous architecture for skin tissue engineering

In this study, a hierarchical nano/microfibrous chitosan/collagen scaffold that approximates structural and functional attributes of native extracellular matrix (ECM), has been developed for applicability in skin tissue engineering. Scaffolds were produced by electrospinning of chitosan followed by imbibing of collagen solution, freeze-drying and subsequent cross-linking of two polymers. Scanning electron microscopy showed formation of layered scaffolds with nano/microfibrous architechture. Physico-chemical properties of scaffolds including tensile strength, swelling behavior and biodegradability were found satisfactory for intended application. 3T3 fibroblasts and HaCaT keratinocytes showed good in vitro cellular response on scaffolds thereby indicating the matrices′ cytocompatible nature. Scaffolds tested in an ex vivo human skin equivalent (HSE) wound model, as a preliminary alternative to animal testing, showed keratinocyte migration and wound re-epithelization — a pre-requisite for healing and regeneration. Taken together, the herein proposed chitosan/collagen scaffold, shows good potential for skin tissue engineering.

Developing an adaptive radiotherapy technique for virally mediated head and neck cancer

Purpose Virally mediated head and neck cancers (VMHNC) often present with nodal involvement and are highly radioresponsive, meaning that treatment plan adaptation during radiotherapy (RT) in a subset of patients is required. We sought to determine potential risk profiles and a corresponding adaptive treatment strategy for these patients. Methodology 121 patients with virally mediated, node positive nasopharyngeal (Epstein Barr Virus positive) or oropharyngeal (Human Papillomavirus positive) cancers, receiving curative intent RT were reviewed. The type, frequency and timing of adaptive interventions, including source-to-skin distance (SSD) corrections, re-scanning and re-planning, were evaluated. Patients were reviewed based on the maximum size of the dominant node to assess the need for plan adaptation. Results Forty-six patients (38%) required plan adaptation during treatment. The median fraction at which the adaptive intervention occurred was 26 for SSD corrections and 22 for re-planning CTs. A trend toward 3 risk profile groupings was discovered: 1) Low risk with minimal need (< 10%) for adaptive intervention (dominant pre-treatment nodal size of ≤ 35 mm), 2) Intermediate risk with possible need (< 20%) for adaptive intervention (dominant pre-treatment nodal size of 36 mm – 45 mm) and 3) High-risk with increased likelihood (> 50%) for adaptive intervention (dominant pre-treatment nodal size of ≥ 46 mm). Conclusion In this study, patients with VMHNC and a maximum dominant nodal size of > 46 mm were identified at a higher risk of requiring re-planning during a course of definitive RT. Findings will be tested in a future prospective adaptive RT study.

A meta-analysis of pigmentary characteristics, sun sensitivity, freckling and melanocytic nevi and risk of basal cell carcinoma of the skin

Objective: To calculate pooled risk estimates of the association between pigmentary characteristics and basal cell carcinoma (BCC) of the skin. Methods: We searched three electronic databases and reviewed the reference lists of the retrieved articles until July 2012 to identify eligible epidemiologic studies. Eligible studies were those published in between 1965 and July 2012 that permitted quantitative assessment of the association between histologically-confirmed BCC and any of the following characteristics: hair colour, eye colour, skin colour, skin phototype, tanning and burning ability, and presence of freckling or melanocytic nevi. We included 29 studies from 2236 initially identified. We calculated summary odds ratios (ORs) using weighted averages of the log OR, using random effects models. Results: We found strongest associations with red hair (OR 2.02; 95% CI: 1.68, 2.44), fair skin colour (OR 2.11; 95% CI: 1.56, 2.86), and having skin that burns and never tans (OR 2.03; 95% CI: 1.73, 2.38). All other factors had weaker but positive associations with BCC, with the exception of freckling of the face in adulthood which showed no association. Conclusions: Although most studies report risk estimates that are in the same direction, there is significant heterogeneity in the size of the estimates. The associations were quite modest and remarkably similar, with ORs between about 1.5 and 2.5 for the highest risk level for each factor. Given the public health impact of BCC, this meta-analysis will make a valuable contribution to our understanding of BCC.

Polymorphisms of the VDR gene are associated with presence of solar keratoses on the skin

Background Vitamin D has a range of biological effects including antiproliferative functions that are mediated through its receptors, encoded by the VDR gene. Objectives We investigated polymorphisms within the VDR gene for association with solar keratosis (SK), a biomarker for skin cancer, and examined interactions with skin phenotype. Methods Among participants of the community-based Nambour Skin Cancer Study, we genotyped 190 people with SKs and 190 without for ApaI, TaqI and FokI polymorphisms. Results We found a significant difference in genotype frequencies of the TaqI polymorphism between affected and unaffected populations (P = 0Æ008). The TT ⁄tt genotype group was associated with a twofold increase in odds of being affected by one or more SK. Individuals with fair skin and the TT ⁄tt genotype had about a sevenfold increase, whereas fair-skinned people with the Tt genotype had a fourfold increase in odds of being affected by SK. Individuals with the TT ⁄tt genotype who were prone to burn and not tan on acute sun exposure had about a sixfold increase in odds of SK. Fair-skinned people with VDR-Apa AA ⁄aa genotypes had about an eightfold increase in odds of being affected by SK compared with a fivefold increase in individuals with the Aa genotype and fair skin. Conclusions The trend for homozygote genotypes to increase the odds of SK suggests that intermediate VDR activity is important in protection or that the heterodimer formed by a heterozygous genotype may have an altered binding potential. Overall, these analyses indicate that VDR may be important in SK development.

Principle components analysis with covariance matrix on regional differences for mortality and percentages of cancers in Shandong province [山东省恶性肿瘤死亡率和构成比地区差异协方差矩阵主成分分析]

Objective To explore the characteristics of regional distribution of cancer deaths in Shandong Province with the principle components analysis. Methods The principle components analysis with co-variance matrix for age-adjusted mortality rates and percentages of 20 types of cancer in 22 counties （cities） were carried out using SAS Software. Results Over 90% of the total information could be reflected by the top 3 principle components and the first principle component alone represented more than half of the overall regional variances. The first component mainly reflected the area differences of esophageal cancer. The second component mainly reflected the area differences of lung cancer， stomach cancer and liver cancer. The value of the first principal component scores showed a clear trend that the west areas possessed higher values and the east the lower values. Based on the top two components，the 22 counties （cities） could be divided into several geographical clusters. Conclusion The overall difference of regional distribution of cancers in Shandong is dominated by several major cancers including esophageal cancer， lung cancer， stomach cancer and liver cancer. Among them，esophageal cancer makes the largest contribution. If the range of counties （cities） analyzed could be further widened， the characteristics of regional distribution of cancer mortality would be better examined. Abstract in Chinese 目的 利用主成分分析探讨山东省恶性肿瘤死亡的地区分布特征. 方法 利用SAS软件对山东省22个县市区2004～2006午的20种恶性肿瘤标化死亡率和构成比分别进行协方差矩阵主成分分析. 结果 前3个主成分就反映了总体差异90%以上的信息,其中仅第1主成分就提供了总体差异一半以上的信息.第1主成分主要反映了食管癌的地区差异,第2主成分主要反映肺癌的地区差异,兼顾胃癌和肝癌.各地区第1主成分得分呈现西高东低的趋势,根据第1和第2主成分可以将调查地区分为若干类别,表现为明显的地理聚集性. 结论 山东省各地区恶性肿瘤死亡的总体差异主要取决于少数高发肿瘤,包括食管癌、肺癌、胃癌、肝癌等,其中以食管癌地位最为突出.如能进一步扩大分析范围,可更好地查明恶性肿瘤死亡的地区特征.

An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers

Background: To directly assess tumor oxygenation in resectable non - small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes. Methods: Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes. Results: The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO 2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001). Conclusions: Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors. © 2006 American Association for Cancer Research.

Skin cancer prevention and fashion – frontier bedfellows

Problem Queensland has the highest rates of skin cancer in the world, even after wide-ranging public programs promoting sun safety awareness. To-date, public awareness campaigns on the dangers of excessive sun exposure have been highly successful. For adolescents, however, where a significant amount of lifetime sun exposure occurs, perilous exposure still ensues, despite awareness of the risks. New frontier approaches are required to target this key audience cluster, for this significant national problem. Approach For the majority of adolescents, being part of a collective norm defines their visual, attitudinal and behavioural actions and fashion has been validated as one of the most powerful forces that can form, shape and bolster these norms. Considering clothing is the easiest method to limit the amount of skin exposed to UV, fashion (in its many subtle, yet influential guises) is proposed as an avenue to advance positive sun safe practices for adolescents. Through an action-led methodology, this research explores the potential of fashion, as one of the key parts of a complex equation, to be a prime driver to facilitate sun safety for adolescents. Findings This paper advocates that fashion, as distinguishable from clothing, has the potential to positively influence sun protective behaviour. The findings go further and recommend the use of fashion as a stealth driver for sun safety advancement, for adolescents in particular, via shifts in norms of beauty and targeted generational communication strategies. This frontier approach has the potential to significantly reduce risky sun exposure in adolescence.