1,721,130 research outputs found
Clinical markers and driving mechanism in melanoma progression: VEGF-C, RhoC, c-Ski/SnoN and EGFR
No full textMelanoma appears to be a complex multigenic disease which is determined by several parallel and stepwise progressive pathways. Better understanding of molecules and pathways involved in melanoma progression can contribute to better prognostic information and identification of possible new therapeutic targets.
Cutaneous malignant melanoma spreads preferentially through the lymphatic vessels. Vascular Endothelial Growth Factor-C has been found to promote tumour-associated lymphatic vessel growth. We investigated VEGF-C protein expression in primary cutaneous melanoma tissues of 113 patients with known clinicopatological follow up. High VEGF-C expression levels in melanoma cells and tumour-associated macrophages were correlated with the presence of a positive sentinel lymph node. The presence of VEGF-C expression in melanoma cells was associated with reduced disease free and overall survival.
RhoC belongs to the family of Ras-homologous (Rho) proteins, wich are important regulators of the organization of the actin filament system. We observed RhoC mRNA and protein expression to be upregulated in a highly metastatic melanoma cell line, whereas only low expression levels were found in a melanoma cell line with low proliferative and invasive capacity. RhoC expression in melanoma tissue was associated with high Breslow tumour thickness and the presence of ulceration.
Loss of TGF-b growth control is frequently observed in several human neoplasms, including melanoma. C-Ski and SnoN have been identified as negative regulators in the TGF-b pathway. When studying the subcellular c-Ski localization in melanoma tissues, a significant association was observed between the presence of nuclear c-Ski and thicker, ulcerated melanomas indicating nuclear c-Ski might be involved in the process of melanoma growth. SnoN expression was associated with the presence of ulceration and a positive sentinel lymph node.
Epidermal Growth Factor Receptor (EGFR) expression has been associated with tumour progression and poor outcome in a variety of solid tumours. We found EGFR immunoreactivity in melanoma tissue to be more frequently present in patients with a positive sentinel lymph node. The presence of EGFR gene polysomy was associated with higher Breslow tumour thickness. Treating BLM melanoma cells with different concentrations of cetuximab (anti-EGFR antibody) reduced the invasive capacity of the melanoma cells, without impact on cell viability and growth
Preventive landscape of skin cancer in Belgium : a clinical and health economical analysis
Full text linkA translational exploration of melanoma immunology focused on indoleamine 2,3-dioxygenase : lessons for immunoprofiling and immunotherapy
Full text linkStudy of the mechanisms of melanocyte destruction in melanoma, halo nevi and vitiligo
No full textIn this thesis we investigated the different aspects of the in vivo immune responses against benign and malignant melanocytes. The aim of this research project was to gain more insights into an adequate skin immunosurveillance of melanocytes. Therefore, we chose distinct models that reflect a depressed (melanoma), an efficient (halo nevi) and an overactive (vitiligo) immune response against melanocytes.
In chapter 4.1 we assessed the role of indoleamine 2,3-dioxygenase (IDO) and Forkhead Box P3 (Foxp3) - both factors associated with immunosuppression - in the sentinel nodes of melanoma patients. High IDO expression was an independent prognostic factor of worse outcome in our study. This effect was more pronounced in sentinel negative patients, which suggests that a deficient immune response develops early in the disease process. An associated network of immunosuppression was confirmed by an enhanced percentage of Foxp3+ cells in sentinel nodes expressing IDO and higher CTLA-4 levels in the circulating regulatory T-cells of these patients.
In chapter 4.2 we describe a patient with a history of melanoma and the dysplastic nevus syndrome who showed regression of almost all nevi. As the patient did not receive systemic therapy, this was most likely a spontaneous phenomenon. We found both in the regressing nevus as in the blood Gp100+ CD8+ T-cells, confirming the presence of an anti-melanocyte immune response. These findings substantiate the hypothesis that regressing nevi may be a sign of efficient immunosurveillance.
In chapter 4.3 we investigated whether in analogy to melanoma-associated leukoderma, patients with multiple halo nevi show additional depigmentations not corresponding to classic vitiligo. We observed indeed in a subpopulation of halo nevi patients remarkable limited depigmentations, which developed at the same time of the halo nevi and did not progress over time. This phenomenon is most likely due to a subgroup of circulating melanocyte-specific T cells, which become active during the halo process for example due to release of oxidative factors (such as H2O2). Oxidative stress has earlier been shown to play a crucial role in the development of depigmentation by inducing a process of haptenation that elicits strong immune responses.
In chapter 4.4 we developed an in vivo model to investigate koebner-induced depigmentation in vitiligo patients. This model lends itself to investigate the pathophysiological aspects of koebner-induced vitiligo and to assess the efficacy of therapeutic strategies. The results were reproducibly showing depigmentation after all 3 koebner induction methods, which could be prevented by anti-inflammatory treatment. Our pilot study pointed to tacrolimus and corticosteroids as significantly better inhibitors of the koebner process compared to pimecrolimus.
In chapter 4.5 we investigated the clinical significance of Koebner’s phenomenon in vitiligo patients. Patients with Koebner’s phenomenon had more active vitiligo. They displayed a younger age of onset and had a higher affected body surface area. These patients were more susceptible for further depigmentation despite treatment. Moreover, patients with Koebner’s phenomenon due to friction had a marked enhanced frequency of thyroid disease.
In conclusion, we believe this work contributes to the insights into the development of immune reactions against benign and malignant melanocytes. Therefore, it has implications both for melanoma, halo nevi and vitiligo
Comparison of ex vivo and in vivo dermoscopy in dermatopathologic evaluation of skin tumors
Full text linkIMPORTANCE: Ex vivo dermoscopy (EVD) can be a valuable tool in routine diagnostic dermatopathologic evaluation.
OBJECTIVES: To compare in vivo dermoscopy (IVD) and EVD and to provide guidance for routine dermatopathologic evaluations.
DESIGN, SETTING, AND PARTICIPANTS: This observational study collected 101 consecutive IVD and EVD images of skin tumors from a private dermatology practice from March 1 to September 30, 2013. Four observers (3 dermatologists and 1 dermatopathologist) blinded to the histopathologic diagnoses independently scored and compared the colors, structures, and vessels of EVD images with those of the corresponding IVD images. Data were analyzed from January 1 to March 31, 2014.
MAIN OUTCOMES AND MEASURES: Concordance between the EVD and IVD images and gain or loss of colors, structures, and vessels on EVD relative to IVD images.
RESULTS: The final analysis included 404 observations of 101 images. The EVD image was generally similar to the corresponding IVD image but clearly darker, with new areas of blue in 130 of 404 observations (32.2%) and white in 100 of 404 observations (24.8%) and loss of red in 283 of 404 observations (70.0%). Most structures were well preserved. New structureless areas were found in 78 of 404 observations of EVD images (19.3%), and new crystalline structures were detected in 68 of 404 observations of EVD images (16.8%). On EVD images, squames and crusts were lost in 56 of 404 observations (13.9%) and 43 of 404 observations (10.6%), respectively. Blood vessels were lost in 142 of 404 observations of EVD images (35.1%).
CONCLUSIONS AND RELEVANCE: The EVD image is an important new tool in dermatopathology and may give direction to targeted tissue processing and examination of skin tumors
Integrating neural networks as diagnosis support in dermatology
No full textSinds enkele decennia is de incidentie van huidkanker wereldwijd in opmars, en zo ook in België. Dit heeft een grote impact, zowel maatschappelijk, als op niveau van het individu. Zo komt het zorgsysteem steeds meer onder druk te staan. Bovendien kan huidkanker leiden tot drastische gevolgen op persoonlijk vlak. Melanoma, de gevaarlijkste vorm, heeft een grote kans zich te verspreiden tot andere delen van het lichaam in een vergevorderd stadium. In dat geval daalt de overlevingskans aanzienlijk. Vroege detectie is dus van vitaal belang! Aangezien dergelijke detectie visueel gebeurt, kan computergestuurde beeldherkenning, tegenwoordig aangevoerd door artificiële intelligentie (AI), hierin een grote rol spelen. Meer specifiek halen neurale netwerken uitstekende resultaten. Echter kunnen deze soort modellen niet zomaar in de praktijk worden toegepast. In dit doctoraat halen we hiervoor drie redenen aan: het gebrek aan een uitleg, het gebrek aan onzekerheid, en de moeilijkheid bij sensor upgrades. In de op onderzoek gebaseerde hoofdstukken reiken we bij elk van deze problemen een oplossing aan, en dit via visualitatietechnieken voor neurale netwerken, een nieuwe metriek voor onzekerheid, en een data-efficiënt sensor upgrade pad
Pathologic evaluation of skin tumors with ex vivo dermoscopy with derm dotting
Full text linkIMPORTANCE : Ex vivo dermoscopy (EVD) with derm dotting (DD) improves clinicopathologic correlation and the quality of diagnosis in skin tumors.
OBJECTIVE : To compare the diagnostic performance of the standard method of skin biopsy processing with the practice of EVD with DD.
DESIGN, SETTING, AND PARTICIPANTS : This retrospective study compares the diagnostic performance in 6526 skin biopsy specimens examined from 2008 to 2010 with a standard method of processing with 8584 biopsy specimens examined in 2015 with EVD and DD. Data were analyzed from January 1 to March 31, 2016. A total of 15 110 skin biopsy specimens were included. The biopsy specimens from 2008 to 2010 were processed in a hospital-based general pathology laboratory; the biopsy specimens from 2015 were processed in a private dermatopathology laboratory. Biopsy specimens from both periods were diagnosed by the same dermatopathologist.
MAIN OUTCOMES AND MEASURES : The primary outcome measures were clinicopathological characteristics, usefulness of EVD with DD, and turnaround times (TATs).
RESULTS : Use of EVD with DD increased the detection of positive section margins in nonmelanoma skin cancer from 8.4% to 12.8%. The most significant increase was seen in Bowen disease, invasive squamous cell carcinoma, and a superficial type of basal cell carcinoma (BCC). With EVD and DD, a specific clinicopathologic diagnosis was made in 27.7% of nevi compared with only 10.3% using the standard method. The incidence of moderately and severely dysplastic nevi increased from 1.0% to 7.2% and from 0.6% to 1.4%, respectively. The detection of ulceration in melanomas with thicker than 1 mm increased from 24.0% to 31.3%. The number of nevi-associated melanomas increased from 15.5% to 33.3%. The number of collision lesions from 0.07% to 1.07%. The TAT for nevi decreased from 2 days to 1 day, for melanomas from 5 days to 2 days, and for BCC from 2 days to 1 day.
CONCLUSIONS AND RELEVANCE : Ex vivo dermoscopy and DD with adapted sectioning in a dermatopathology setting allows a more accurate and less time consuming histopathologic diagnosis of skin tumors. These findings suggest that pathologists involved in skin tumor evaluation should be encouraged to learn dermoscopy and replace random transverse cutting with lesion-specific and DD-guided cutting
Ex vivo dermoscopy with derm dotting : a new method for lesion specific and targetted cutting
No full textBiomarkers in immuno-oncology : from melanoma to other cancer types, from tissue to liquid biopsy, from late stage to early stage disease
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