The performance of solarscan : an automated dermoscopy image analysis instrument for the diagnosis of primary melanoma

Objective To describe the diagnostic performance of SolarScan (Polartechnics Ltd, Sydney, Australia), an automated instrument for the diagnosis of primary melanoma.

Design Images from a data set of 2430 lesions (382 were melanomas; median Breslow thickness, 0.36 mm) were divided into a training set and an independent test set at a ratio of approximately 2:1. A diagnostic algorithm (absolute diagnosis of melanoma vs benign lesion and estimated probability of melanoma) was developed and its performance described on the test set. High-quality clinical and dermoscopy images with a detailed patient history for 78 lesions (13 of which were melanomas) from the test set were given to various clinicians to compare their diagnostic accuracy with that of SolarScan.

Setting Seven specialist referral centers and 2 general practice skin cancer clinics from 3 continents. Comparison between clinician diagnosis and SolarScan diagnosis was by 3 dermoscopy experts, 4 dermatologists, 3 trainee dermatologists, and 3 general practitioners.

Patients Images of the melanocytic lesions were obtained from patients who required either excision or digital monitoring to exclude malignancy.

Main Outcome Measures Sensitivity, specificity, the area under the receiver operator characteristic curve, median probability for the diagnosis of melanoma, a direct comparison of SolarScan with diagnoses performed by humans, and interinstrument and intrainstrument reproducibility.

Results The melanocytic-only diagnostic model was highly reproducible in the test set and gave a sensitivity of 91% (95% confidence interval [CI], 86%-96%) and specificity of 68% (95% CI, 64%-72%) for melanoma. SolarScan had comparable or superior sensitivity and specificity (85% vs 65%) compared with those of experts (90% vs 59%), dermatologists (81% vs 60%), trainees (85% vs 36%; P =.06), and general practitioners (62% vs 63%). The intraclass correlation coefficient of intrainstrument repeatability was 0.86 (95% CI, 0.83-0.88), indicating an excellent repeatability. There was no significant interinstrument variation (P = .80).

Conclusions SolarScan is a robust diagnostic instrument for pigmented or partially pigmented melanocytic lesions of the skin. Preliminary data suggest that its performance is comparable or superior to that of a range of clinician groups. However, these findings should be confirmed in a formal clinical trial.

Frequency of excisions and yields of malignant skin tumors in a population-based screening intervention of 360 288 whole-body examinations

Objective To explore the frequency of excisions and yields of histopathologically confirmed skin cancer.

Design A population-based skin cancer screening intervention (the SCREEN project) in the German state of Schleswig-Holstein (July 1, 2003, to June 30, 2004).

Setting Physician offices. Participants could choose between nondermatologist physicians and dermatologists for their initial whole-body skin examination. All screening physicians received a mandatory 8-hour training course.

Participants Inhabitants of Schleswig-Holstein 20 years or older with statutory health insurance (N = 360 288).

Main Outcome Measures Frequency of excisions and yields of malignant skin tumors (malignant melanomas [MMs], basal cell carcinomas [BCCs], and squamous cell carcinomas [SCCs]), stratified by sex and age.

Results Overall, 15 983 excisions were performed (1 of 23 screenees). A total of 3103 malignant skin tumors were diagnosed in 2911 persons: 585 MMs, 1961 BCCs, 392 SCCs, and 165 other malignant skin tumors. Overall, 116 persons (3103 of 360 288) had to be screened to find 1 malignant tumor, with 1 of 620 for MM, 1 of 184 for BCC, and 1 of 920 for SCC. Twenty excisions were performed to find 1 melanoma in men 65 years and older, but more than 50 excisions were required to find 1 melanoma in men aged between 20 and 49 years.

Conclusions The results of SCREEN suggest a high yield of malignant skin tumors in a large-scale population-based screening project. We found that a high number of excisions was performed in the youngest screenees with an associated low yield, suggesting a need in screener training to emphasize a more conservative attitude toward excisions in young screenees.

Allelic imbalance studies of chromosome 9 suggest major differences in chromosomal instability among nonmelanoma skin carcinomas

CONTEXTO: Vários estudos de perda de heterozigozidade na região 9p21-p22, que abriga os genes supressores tumorais CDKN2a/p16INK4a, p19ARF e p15INK4b, têm sido realizados em uma ampla série de tumores humanos, incluindo os melanomas familiares. Perdas e ganhos em outras regiões do cromossomo 9 também têm sido observados com freqüência e podem indicar mecanismos adicionais no processo de tumorigênese dos carcinomas basocelulares da pele. OBJETIVO: Investigar o equilíbrio alélico existente na região 9p21-p22 em carcinomas basocelulares. TIPO DE ESTUDO: Análise molecular de marcadores de microssatélites em tumores e controles. LOCAL: Dois serviços de dermatologia de atendimento terciário em universidades públicas de São Paulo e o Laboratório de Genética Molecular do Câncer da Universidade Estadual de Campinas (UNICAMP), Brasil. PARTICIPANTES: Examinamos 13 casos benignos, incluindo 4 queratoses solares, 3 queratoacantomas, 3 nevos melanocíticos, 2 doenças de Bowen e 1 neurofibroma cutâneo, além de 58 tumores malignos da pele: 14 de células escamosas, 40 carcinomas basocelulares e 4 melanomas; em pacientes consecutivamente encaminhados à clínica de Dermatologia da Unicamp e que concordaram em participar do estudo. VARIÁVEIS ESTUDADAS: O tumor principal e uma porção normal de pele não-adjacente foram removidos cirurgicamente de pacientes que consecutivamente procuraram os ambulatórios de dermatologia da Universidade Estadual de Campinas (UNICAMP) e da Universidade Estadual de São Paulo (Unesp), São Paulo, por causa de lesões cutâneas. Extraímos DNA tanto de tecido tumoral como do correspondente tecido normal de cada paciente. Para amplificar regiões de repetição polimórfica de microssatélites do cromossomo 9, foram utilizados quatro pares de primers, sendo dois deles destinados à região 9p21-p22. RESULTADOS: Identificamos oito casos (20%) de desequilíbrio alélico entre os carcinomas basocelulares, sendo dois casos de perda de heterozigozidade e seis casos de instabilidade de microssatélite na região 9p21-p22. Outros marcadores também mostravam anormalidades em três destes tumores, enquanto nenhuma alteração foi detectada entre os casos benignos e nos outros tumores malignos. CONCLUSÃO: Esta dependência fenotípica sugere que existem diferenças importantes no comportamento das formas mais comuns de tumores cutâneos não-melanocíticos em relação à sua tendência para instabilidade de microssatélite no cromossomo 9. Considerando-se que os genes CDKN2a/p16INK4a, p19ARF e p15INK4b não parecem responsáveis pelas anormalidades observadas, outros genes em 9p21-p22 podem estar envolvidos na etiopatogenia e na progressão dos carcinomas basocelulares.

Characterization of texture in image of skin lesions by support vector machine

Due to the increased incidence of skin cancer, computational methods based on intelligent approaches have been developed to aid dermatologists in the diagnosis of skin lesions. This paper proposes a method to classify texture in images, since it is an important feature for the successfully identification of skin lesions. For this is defined a feature vector, with the fractal dimension of images through the box-counting method (BCM), which is used with a SVM to classify the texture of the lesions in to non-irregular or irregular. With the proposed solution, we could obtain an accuracy of 72.84%. © 2012 AISTI.

Técnicas de imagem para triagem de melanoma

Pós-graduação em Pesquisa e Desenvolvimento (Biotecnologia Médica) - FMB

Metastatic melanoma of the tongue: a case report with immunohistochemical profile

BackgroundMelanoma of the skin is characterised by a high metastatic potential, but reports of metastasis to the tongue are rare. We report a case of skin melanoma with metastasis to the lymph nodes, tongue and brain.ObjectivesThis report highlights the clinical and histological features of oral metastatic melanoma.Case reportA 72-year-old man was seen with a nodule on the tongue. The differential diagnosis included salivary gland tumour, lymphoma and metastatic melanoma. His medical history revealed treatment for melanoma in the periumbilical region and micrometastases in the inguinal lymph nodes. An incisional biopsy was obtained and histological analysis showed the presence of a solid, epithelioid malignant tumour of monotonous appearance infiltrating the skeletal musculature. Immunohistochemistry showed reactivity of neoplastic cells to anti-HMB45, anti-melan A and anti-S100 antibodies and negativity for anti-PAN cytokeratin, confirming the diagnosis of metastatic melanoma.ConclusionThe present findings highlight the importance of a complete medical evaluation of the patient by anamnesis to identify possible oral repercussions of primary diseases in other organs and/or systems.

Terapia fotodinâmica - Aplicações em lesões cutâneas

Photodynamic therapy is a method of healing skin lesions , in addition to radiotherapy and brachytherapy are commonly used in the treatment of skin cancers , but it is still little known in Brazil , consisting of the application to the skin of a drug in the form of cream or lotion ( photosensitizer ) . It is absorbed by tumor cells and subsequently activated by light device , that wavelength of light in the order of 630 nanometers , promoting the selective destruction of cancer cells while preserving healthy cells around the lesion . It can be considered highly effective for treatment of skin cancer types of non-melanoma ( basal cell carcinoma , 85-100 % success in curing [ 3 ] , and Bowen's disease), actinic keratoses , which are precancerous lesions and still no studies that prove also action in the treatment of acne and aging caused by the sun . And the advantage of this treatment is that , when indicated , replace the surgical procedure , selectively treating the diseased cells . Thus, it offers better cosmetic results, reducing the risk of scarring [ 4 ]

Nanotechnology-based drug delivery systems for melanoma antitumoral therapy: a review

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Antisense-mediated melanoma inhibitor of apoptosis protein downregulation sensitizes G361 melanoma cells to cisplatin

Malignant melanoma is an aggressive form of skin cancer that is highly resistant to conventional therapies. The melanoma inhibitor of apoptosis protein is a potent inhibitor of apoptosis and is overexpressed in melanoma cells, but undetectable in most normal tissues including melanocytes. We designed 20-mer phosphorothioate antisense oligonucleotides complementary to five putatively single-stranded sites on the melanoma inhibitor of apoptosis protein mRNA and investigated their ability to sensitize G361 melanoma cells to cisplatin. Inhibition of melanoma inhibitor of apoptosis protein mRNA and protein expression were measured by real-time polymerase chain reaction and immunoblotting. Cell viability and apoptosis were quantitated by colorimetric viability assays and by annexin V staining, respectively. Oligonucleotide M706 was identified as the most efficient antisense sequence which downregulated melanoma inhibitor of apoptosis protein mRNA and protein levels in G361 cells by 68 and 78%, respectively. The specificity of target downregulation was confirmed using scrambled sequence control oligonucleotides that only marginally decreased melanoma inhibitor of apoptosis protein expression. Whereas downregulation of melanoma inhibitor of apoptosis protein moderately inhibited cell growth by 26%, in combination with cisplatin, this resulted in a supra-additive effect with almost 57% reduction in G361 cell viability compared with cisplatin alone (17%) (P<0.05). Cell death was mainly due to apoptosis as demonstrated by a 3- to 4-fold increase in annexin V-positive cells and typical morphological changes compared with controls. In summary, we describe a new antisense oligonucleotide that efficiently downregulates melanoma inhibitor of apoptosis protein expression and sensitizes melanoma cells to cisplatin.

Targeting autophagy as a potential therapeutic approach for melanoma therapy

Melanoma, occurring as a rapidly progressive skin cancer, is resistant to current chemo- and radiotherapy, especially after metastases to distant organs has taken place. Most chemotherapeutic drugs exert their cytotoxic effect by inducing apoptosis, which, however, is often deficient in cancer cells. Thus, it is appropriate to attempt the targeting of alternative pathways, which regulate cellular viability. Recent studies of autophagy, a well-conserved cellular catabolic process, promise to improve the therapeutic outcome in melanoma patients. Although a dual role for autophagy in cancer therapy has been reported, both protecting against and promoting cell death, the potential for using autophagy in cancer therapy seems to be promising. Here, we review the recent literature on the role of autophagy in melanoma with respect to the expression of autophagic markers, the involvement of autophagy in chemo- and immunotherapy, as well as the role of autophagy in hypoxia and altered metabolic pathways employed for melanoma therapy.

Histological review of skin cancers in African Albinos: a 10-year retrospective review.

BACKGROUND Skin cancer is rare among Africans and albinism is an established risk for skin cancer in this population. Ultraviolet radiation is highest at the equator and African albinos living close to the equator have the highest risk of developing skin cancers. METHODS This was a retrospective study that involved histological review of all specimens with skin cancers from African albinos submitted to The Regional Dermatology Training Center in Moshi, Tanzania from 2002 to 2011. RESULTS A total of 134 biopsies from 86 patients with a male to female ratio of 1:1 were reviewed. Head and neck was the commonest (n = 75, 56.0%) site affected by skin cancers. Squamous cell carcinoma (SCC) was more common than basal cell carcinoma (BCC) with a ratio of 1.2:1. Only one Acral lentiginous melanoma was reported. Majority (55.6%) of SCC were well differentiated while nodular BCC (75%) was the most common type of BCC. CONCLUSIONS Squamous cell carcinoma is more common than basal cell carcinoma in African albinos.

Risk of second primary tumors following treatment of non-small cell lung cancer

Background. The rise in survival rates along with more detailed follow-up using sophisticated imaging studies among non-small lung cancer (NSCLC) patients has led to an increased risk of second primary tumors (SPT) among these cases. Population and hospital based studies of lung cancer patients treated between 1974 and 1996 have found an increasing risk over time for the development of all cancers following treatment of non-small cell lung cancer (NSCLC). During this time the primary modalities for treatment were surgery alone, radiation alone, surgery and post-operative radiation therapy, or combinations of chemotherapy and radiation (sequentially or concurrently). There is limited information in the literature about the impact of treatment modalities on the development of second primary tumors in these patients. ^ Purpose. To investigate the impact of treatment modalities on the risk of second primary tumors in patients receiving treatment with curative intent for non-metastatic (Stage I–III) non-small cell lung cancer (NSCLC). ^ Methods. The hospital records of 1,095 NSCLC patients who were diagnosed between 1980–2001 and received treatment with curative intent at M.D. Anderson Cancer Center with surgery alone, radiation alone (with a minimum total radiation dose of at least 45Gy), surgery and post-operative radiation therapy, radiation therapy in combination with chemotherapy or surgery in combination with chemotherapy and radiation were retrospectively reviewed. A second primary malignancy was be defined as any tumor histologically different from the initial cancer, or of another anatomic location, or a tumor of the same location and histology as the initial tumor having an interval between cancers of at least five years. Only primary tumors occurring after treatment for NSCLC will qualified as second primary tumors for this study. ^ Results. The incidence of second primary tumor was 3.3%/year and the rate increased over time following treatment. The type of NSCLC treatment was not found to have a striking effect upon SPT development. Increased rates were observed in the radiation only and chemotherapy plus radiation treatment groups; but, these increases did not exceed expected random variation. Higher radiation treatment dose, patient age and weight loss prior to index NSCLC treatment were associated with higher SPT development. ^

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. ^

ROLE OF STAT3 IN KERATINOCYTE STEM CELLS DURING SKIN TUMORIGENESIS

STATs play crucial roles in a wide variety of biological functions, including development, proliferation, differentiation, migration and in cancer development. In the present study, we examined the impact of Stat3 deletion or activation on behavior of keratinocytes, including keratinocyte stem cells (KSCs). Deletion of Stat3 specifically in the bulge region of the hair follicle using K15.CrePR1 X Stat3fl/fl mice led to decreased tumor development by altering survival of bulge region KSCs. To further understand the role of KSCs in skin tumorigenesis, K5.Stat3C transgenic (Tg) mice which express a constitutively active/dimerized form of Stat3 called Stat3C via the bovine keratin 5 (K5) promoter were studied. The number of CD34 and α6 integrin positive cells was significantly reduced in Tg mice as compared to non-transgenic (NTg) littermates. There was a concomitant increase in the progenitor populations (Lgr-6, Lrig-1 and Sca-1) in the Tg mice vs. the stem cell population (CD34 and Keratin15). To investigate the mechanism underlying the increase in the progenitor population at the expense of bulge region KSCs we examined if Stat3C expression was involved in inducing migration of the bulge region KSCs. There was altered β-catenin and α6-integrin expression in the hair follicles of Tg mice, which may have contributed to reduced adhesive interactions between the epithelial cells and the basement membrane facilitating migration out of the niche. To further study the effect of Stat3 on differentiation of keratinocytes we analyzed the epidermal keratinocytes in K5.Cre X Stat3fl/fl mice. There was an increase in the expression of epidermal differentiation markers in the Stat3 knockout mice. These data suggest that deletion of Stat3 in the epidermis and hair follicle induced differentiation in these cells. Preliminary studies done with the BK5.Stat3C mouse model suggests that multiple hair follicle stem/progenitor populations may be involved in skin tumor development and progression in this model of skin tumorigenesis. Overall, these data suggest that Stat3 plays an important role in differentiation as well as migration of keratinocytes and that these effects may play a role during epithelial carcinogenesis.

Alterations in the ras oncogene and the p53 tumor suppressor gene in ultraviolet radiation-induced skin carcinogenesis

A rapid increase of the ultraviolet radiation (UVR)-related skin cancer incidence has attracted more and more public attention during the last few decades. Prevention and treatment of UVR-related skin cancer has become an important public health issue in the United States. Recent studies indicate that mutations in ras and/or p53 genes may be involved in UVR-induced skin tumor development but the precise molecular mechanism remains unclear. In this study, alterations of H-ras and p53 genes were investigated in different stages of carcinogenesis in a chronic UVR (solar simulator) exposure-induced Sencar mouse skin carcinogenesis model in order to clarify the role of the alterations of these genes during the skin carcinogenesis process and to further understand the mechanisms by which UVR causes skin cancer.^ Positive ras-p21 staining in cell membranes and cytosol were detected in 18/33 (55%) of squamous cell carcinomas (SCCs), but were not detected in UV-exposed skin, papillomas, or spindle cell tumors (SCTs). Positive staining of the malignant progression marker K13 was found in 17/33 (52%) of SCCs only. A significant positive correlation was observed between the K13 and the ras-p21 expression. Polymerase chain reaction (PCR)-based single strand conformation polymorphism (SSCP) analysis and gene sequencing analysis revealed three point mutations, one (codon 56) in UV-exposed non-tumor bearing skin and the other two (codons 21 and 13) in SCCs. No UV-specific mutation patterns were found.^ Positive p53 nuclear staining was found in 10/37 (27%) of SCCs and 12/24 (50%) of SCTs, but was not detected in normal skin or papillomas. PCR-based SSCP and sequencing analysis revealed eight point mutations in exons 5 and 6 (four in SCTs, two in SCCs, and two in UV-exposed skin) including six C-T or C-A transitions. Four of the mutations occurred at a dipyrimidine (CC) sequence. The pattern of the mutations indicated that the mutagenic lesions were induced by UVR.^ These results indicate that overexpression of ras-p21 in conjunction with aberrant expression of K13 occurred frequently in UVR-induced SCCs in Sencar mouse skin. The point mutation in the H-ras gene appeared to be a rare event in UVR skin carcinogenesis and may not be responsible for overexpression of ras-p21. UVR-induced P53 gene alteration is a frequent event in UVR-induced SCCs and later stage SCT tumors in Sencar mice skin, suggesting the p53 gene mutation plays an important role in skin tumor malignant progression. ^