Cutaneous malignancies are the most frequent human malignancy with an increasing incidence reaching epidemic proportions among Caucasians in Europe, America and Australia. The most common cutaneous... Show moreCutaneous malignancies are the most frequent human malignancy with an increasing incidence reaching epidemic proportions among Caucasians in Europe, America and Australia. The most common cutaneous malignancy is basal cell carcinoma, followed by squamous cell carcinoma (cSCC) and melanoma.(1-3) There are also other, less common cutaneous malignancies which consist of less than 5% of the cutaneous malignancies. Some of these rare cutaneous malignancies are still considered skin cancer such as sebaceous carcinoma,while others are classified as soft tissue sarcoma (DFSP, angiosarcoma). In this thesis, I aimed to analyse outcome after surgical procedures for rare cutaneous malignancies and the rare locally advanced cases of cSCC. Show less
Background Artificial intelligence (AI)-based mobile phone apps (mHealth) have the potential to streamline care for suspicious skin lesions in primary care. This study aims to investigate the... Show moreBackground Artificial intelligence (AI)-based mobile phone apps (mHealth) have the potential to streamline care for suspicious skin lesions in primary care. This study aims to investigate the conditions and feasibility of a study that incorporates an AI-based app in primary care and evaluates its potential impact. Methods We conducted a pilot feasibility study from November 22nd, 2021 to June 9th, 2022 with a mixed-methods design on implementation of an AI-based mHealth app for skin cancer detection in three primary care practices in the Netherlands (Rotterdam, Leiden and Katwijk). The primary outcome was the inclusion and successful participation rate of patients and general practitioners (GPs). Secondary outcomes were the reasons, facilitators and barriers for successful participation and the potential impact in both pathways for future sample size calculations. Patients were offered use of an AI-based mHealth app before consulting their GP. GPs assessed the patients blinded and then unblinded to the app. Qualitative data included observations and audio-diaries from patients and GPs and focus-groups and interviews with GPs and GP assistants. Findings Fifty patients were included with a median age of 52 years (IQR 33.5-60.3), 64% were female, and 90% had a light skin type. The average patient inclusion rate was 4-6 per GP practice per month and 84% (n = 42) successfully participated. Similarly, in 90% (n = 45 patients) the GPs also successfully completed the study. GPs never changed their working diagnosis, but did change their treatment plan (n = 5) based on the app's assessments. Notably, 54% of patients with a benign skin lesion and low risk rating, indicated that they would be reassured and cancel their GP visit with these results (p < 0.001). Interpretation Our findings suggest that studying implementation of an AI-based mHealth app for detection of skin cancer in the hands of patients or as a diagnostic tool used by GPs in primary care appears feasible. Preliminary results indicate potential to further investigate both intended use settings. Show less
Although clinical aspects of melanoma have been extensively studied, the literature largely concerns relatively healthy 20-70 years old patients. Special populations, such as the elderly, children,... Show moreAlthough clinical aspects of melanoma have been extensively studied, the literature largely concerns relatively healthy 20-70 years old patients. Special populations, such as the elderly, children, patients with multiple primary melanoma and those with familial melanoma, are frequently excluded from clinical studies. The studies presented in this thesis were aimed to assess prognostic factors and management of patients with clinically localized melanoma, in particular among the aforementioned special populations. Show less
Skin cancer is the most common type of cancer in fair-skinned populations. Cutaneous squamous cell carcinoma (SCC) comprises about 15% of all skin cancer diagnoses. Treatment associated with the... Show moreSkin cancer is the most common type of cancer in fair-skinned populations. Cutaneous squamous cell carcinoma (SCC) comprises about 15% of all skin cancer diagnoses. Treatment associated with the high and rising prevalence of cutaneous SCC puts an increasingly high financial burden on society, marking a pressing need for advancements in skin cancer drug development. For screening of novel therapeutics, representative models of human cutaneous SCC are required. The aim of the research described in this thesis was to develop a representative in vitro model of human SCC for screening therapeutics, without the unnecessary use of animals. To this end, we generated three-dimensional in vitro SCC models in which the malignant epidermal cancer cells were either represented by intact primary human cutaneous or by established, spontaneously immortalized cutaneous SCC cell lines. The dermal microenvironment in our models was seeded with either primary normal human dermal fibroblasts or primary SCC-associated fibroblasts. In verifying human cutaneous SCC representation by these in vitro models, we focused on hyperproliferation, cytological and architectural atypia and invasion as three main features of primary SCC. The in vitro skin cancer models presented in this thesis add to the spectrum of available in vitro models for therapeutic screening. Show less
Transplant recipients generally require lifelong treatment with immunosuppressive medication to prevent rejection of the graft by their immune system. Inhibitors of the enzyme calcineurin,... Show moreTransplant recipients generally require lifelong treatment with immunosuppressive medication to prevent rejection of the graft by their immune system. Inhibitors of the enzyme calcineurin, including cyclosporin A and tacrolimus, constitute a very potent class of immunosuppressants that has revolutionized transplant medicine. However, their reputation has been showing cracks due to the severe side-effects associated with long-term use of these drugs, including an explosively increased risk of developing skin cancer. The pathophysiological mechanism of this phenomenon is not known, although a number of hypotheses have been put forward. In this dissertation, we show that oxidative stress, mainly derived from exposure to UVA radiation, may locally augment the effects of the calcineurin inhibitors; we propose that overly strong suppression of calcineurin activity may result in malignancy formation due to disruption of tumor-suppressive signaling pathways or disturbed immunosurveillance in skin. Show less
Raimondi, S.; Gandini, S.; Fargnoli, M.C.; Bagnardi, V.; Maisonneuve, P.; Specchia, C.; ... ; SKIP Study Grp m 2012
Skin cancer is a serious problem for many organ transplant recipients. Half of them develop skin cancer within 20 years after the transplantation. The main cause of this increased skin cancer risk... Show moreSkin cancer is a serious problem for many organ transplant recipients. Half of them develop skin cancer within 20 years after the transplantation. The main cause of this increased skin cancer risk is thought to be suppression of the immune system, a necessity to prevent rejection of the transplanted organ. This thesis focuses on the effects of immunosuppressive drugs on the responses of skin cells to UV irradiation and how these altered responses would affect UV-induced skin cancer development. The goal was to compare several immunosuppressants and identify the least hazardous one. Human skin cultures and mice were used as experimental models to study short and long term effects in successive stages of tumor development. These studies have yielded several unexpected findings. Foremost, none of the tested immunosuppressants increased skin cancer development in mice when administrated in the diet; remarkably, cyclos porin even delayed tumor onset. And furthermore, seemingly discordant effects of the drugs on different putative stages of tumor development evoked a new perspective on the step-wise process leading up to skin cancer. More specifically and contrary to the prevailing consensus, this study showed that UV-induced early microscopic clusters of skin cells overexpressing the mutant-p53 tumorsuppressor protein are not early stages or precursors of ensuing skin carcinomas with mutant-p53. Surprisingly, some immunosuppressants affected the number of these clusters without corresponding effects on tumor onset. Show less
The risk of (skin) cancer is highly increased in organ-transplant recipients who are kept on immunesuppressive drugs to prevent graft rejection. This thesis dealt with the epidemiologic aspects and... Show moreThe risk of (skin) cancer is highly increased in organ-transplant recipients who are kept on immunesuppressive drugs to prevent graft rejection. This thesis dealt with the epidemiologic aspects and risk factors for cancer focused on cutaneous squamous cell carcinoma and basal cell carcinoma. Show less
Skin carcinomas develop at a high rate in organ-transplant recipients who are kept on immune suppressive drugs to prevent graft rejection. The present study dealt with a broad range of aspects of... Show moreSkin carcinomas develop at a high rate in organ-transplant recipients who are kept on immune suppressive drugs to prevent graft rejection. The present study dealt with a broad range of aspects of this elevated carcinoma risk, starting from the earliest oncogenic events to the ultimate therapy. Advancements on any of these aspects may be of significant benefit to the patient and his/her physician in the management of multiple and progressive skin carcinomas. The studies presented in Chapter 2 - 4 focused on the early pathogenesis of skin cancer in organ-transplant recipients to gain a better understanding of the underlying mechanism(s) of the increased skin cancer risk in these patients. We specifically focused on the role of p53 and beta-PV in early skin carcinogenesis. The clinical studies in Chapter 5 - 7 investigated the management of skin cancer in organ-transplant recipients. Show less
Sunlight has many beneficial effects. However, from a biological point of view, solar UV radiation has also detrimental effects, especially at high doses of exposure. Because of its genotoxic... Show moreSunlight has many beneficial effects. However, from a biological point of view, solar UV radiation has also detrimental effects, especially at high doses of exposure. Because of its genotoxic properties, UV radiation plays an important role in the induction of skin cancer. In the last decennia, the incidence of skin cancer is rapidly increasing. This can partly be explained by an ageing population. However, the rise in skin cancer incidence appears to be primarily due to a change in human lifestyle in which sunbathing has become very popular. Our skin is continuously challenged by UV radiation, which may lead to irreversible damage. In order to withstand sustained physical, chemical and biological damage from the environment, among which UV radiation, the skin is continuously renewed. The regenerative capacity of skin is conferred by stem cells, which persist throughout the organism__s lifetime. Because of their long residency and unlimited capacity to replicate, stem cells might accumulate DNA damage and generate the multiple genetic lesions necessary for tumour development, despite efficient cellular defence mechanisms against DNA damage. Thus, stem cells may play an important role in carcinogenesis. The aim of this study is to investigate the role of stem cells in skin carcinogenesis. Show less
Through epidemiological and biochemical studies the role of mucosal HPV types in human cancer has been confirmed and the molecular mechanisms underlying the transformation process have been... Show moreThrough epidemiological and biochemical studies the role of mucosal HPV types in human cancer has been confirmed and the molecular mechanisms underlying the transformation process have been elucidated. However, although research on the cutaneous HPV types is progressing fast, many questions remain unanswered regarding their potential role in human skin carcinogenesis.This thesis describes the characterization of the biological properties of E6 and E7 proteins from mucosal and cutaneous HPV types using novel or previously described assays and models. First, we describe the development and use of an in vitro systems to evaluate and quantify the ability of the oncoprotein E7 to associate with pRb (chapter 2). However, we show that this binding although indicative of a high risk HPV type, does not necessarily correlate with in vivo carcinogenicity (chapter 3) and that other in vitro studies are essential to asses the carcinogenicity of any given HPV type. Next we focused on the cutaneous HPV type 38, which displays in vitro transforming properties and appears to be frequently present in NMSC. We show that this cutaneous HPV type can increase the risk for development of skin cancer (chapter 4)and we describe a novel HPV transformation mechanism (chapter 5). Show less
