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PURPOSE: Human melanoma is a highly aggressive incurable cancer due to intrinsic cellular resistance to apoptosis, reprogramming, proliferation and survival during tumour progression. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, plays a role in carcinogenesis in many cancer types. However, the cytotoxic molecular mechanisms and gene expression profiles promoted by SFN in human melanoma remain unknown. METHODS: Three different cell lines were used: two human melanoma A375 and 501MEL and human epidermal melanocytes (HEMa). Cell viability and proliferation, cell cycle analysis, cell migration and invasion and protein expression and phosphorylation status of Akt and p53 upon SFN treatment were determined. RNA-seq of A375 was performed at different time points after SFN treatment. RESULTS: We demonstrated that SFN strongly decreased cell viability and proliferation, induced G2/M cell cycle arrest, promoted apoptosis through the activation of caspases 3, 8, 9 and hampered migration and invasion abilities in the melanoma cell lines. Remarkably, HEMa cells were not affected by SFN treatment. Transcriptomic analysis revealed regulation of genes involved in response to stress, apoptosis/cell death and metabolic processes. SFN upregulated the expression of pro-apoptotic genes, such as p53, BAX, PUMA, FAS and MDM2; promoted cell cycle inhibition and growth arrest by upregulating EGR1, GADD45B, ATF3 and CDKN1A; and simultaneously acted as a potent inhibitor of genotoxicity by launching the stress-inducible protein network (HMOX1, HSPA1A, HSPA6, SOD1). CONCLUSION: Overall, the data show that SFN cytotoxicity in melanoma derives from complex and concurrent mechanisms during carcinogenesis, which makes it a promising cancer prevention agent.
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Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Brassicaceae/química , Sobrevivência Celular , Isotiocianatos/farmacologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/terapia , Sulfóxidos , TiocianatosRESUMO
PURPOSE: Only a few reports in the literature have investigated the presence of ocular abnormalities in neurofibromatosis type 1 (NF-1) patients. The aim of this study was to evaluate the prevalence of ocular abnormalities in a large population of NF1 patients, focusing on the choroidal changes. METHODS: This study was conducted on 160 consecutive patients with NF1 and 106 sex- and age-matched healthy subjects (control). Each patient underwent a complete ophthalmological examination inclusive of best-corrected visual acuity, intraocular pressure measurement, slit-lamp biomicroscopy, indirect fundus biomicroscopy, and near-infrared reflectance (NIR) retinography by using the spectral domain OCT. Moreover, all patients underwent complete dermatological exam and 1.5-Tesla MRI scan of the brain to assess the presence of optic nerve gliomas. RESULTS: Choroidal abnormalities were detected in 97% of patients, with a positive predictive value of 100% and a negative predictive value of 96.4%. Interestingly, a small number of patients (4/160; 2.5%) showed Lisch nodules without choroidal abnormalities, whereas a larger number of patents (22/160; 13.75%) presented choroidal lesions in absence of Lisch nodules. None of the patients showed the absence of both choroidal lesions and Lisch nodules. The number of choroidal lesions increased with age (r = 0.364, p = 0.0001) and with the severity of pathology (r = 0.23, p = 0.003). Any statistically significant correlation between choroidal lesions, visual acuity, and intraocular pressure was observed. CONCLUSIONS: NIR imaging represents an in vivo, non-invasive, sensitive and reproducible exam to detect choroidal nodules in NF-1 patients, suggesting that choroidal changes may represent an additional diagnostic criteria for NF1.
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Doenças da Coroide/diagnóstico , Corioide/patologia , Raios Infravermelhos , Neurofibromatose 1/diagnóstico , Oftalmoscopia/métodos , Tomografia de Coerência Óptica/métodos , Adulto , Doenças da Coroide/etiologia , Estudos Transversais , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Neurofibromatose 1/complicações , Curva ROC , Reprodutibilidade dos Testes , Pele/patologia , Fatores de Tempo , Acuidade VisualRESUMO
Cultured primary human keratinocytes are frequently employed for studies of immunological and inflammatory responses; however, interpretation of experimental data may be complicated by donor to donor variability, the relatively short culture lifetime, and variations between passages. To standardize the in vitro studies on keratinocytes, we investigated the use of HaCaT cells, a long-lived, spontaneously immortalized human keratinocyte line which is able to differentiate in vitro, as a suitable model to follow the release of inflammatory and repair mediators in response to TNFα or IL-1ß. Different treatment conditions (presence or absence of serum) and differentiation stimuli (increase in cell density as a function of time in culture and elevation of extracellular calcium) were considered. ELISA and Multiplex measurement technologies were used to monitor the production of cytokines and chemokines. Taken together, the results highlight that Ca2+ concentration in the medium, cell density, and presence of serum influences at different levels the release of proinflammatory mediators by HaCaT cells. Moreover, HaCaT cells maintained in low Ca2+ medium and 80% confluent are similar to normal keratinocytes in terms of cytokine production suggesting that HaCaT cells may be a useful model to investigate anti-inflammatory interventions/therapies on skin diseases.
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Mediadores da Inflamação/metabolismo , Queratinócitos/imunologia , Anti-Inflamatórios/farmacologia , Cálcio/metabolismo , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Citocinas/biossíntese , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismoRESUMO
Paraneoplastic pemphigus is a rare autoimmune skin disease that is always associated with a neoplasm. Usually, oral, skin, and mucosal lesions are the earliest manifestations shown by paraneoplastic pemphigus patients. The pathogenesis of paraneoplastic pemphigus is not yet completely understood, although some immunological aspects have been recently clarified. Because of its rarity, several diagnostic criteria have been proposed. Besides, several diagnostic procedures have been used for the diagnosis, including indirect immunofluorescence, direct immunofluorescence, and ELISA. We reviewed the most recent literature, searching on PubMed "paraneoplastic pemphigus". We included also papers in French, German, and Spanish. We found 613 papers for "paraneoplastic pemphigus". Among them, 169 were review papers. Because of its varying clinical features, paraneoplastic pemphigus still represents a challenge for clinicians. Furthermore, diagnosis and management of paraneoplastic pemphigus requires close collaboration between physicians, including dermatologist, oncologist, and otorhinolaryngologist.
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Síndromes Paraneoplásicas/diagnóstico , Pênfigo/diagnóstico , Diagnóstico Diferencial , Humanos , Fatores Imunológicos/uso terapêutico , Síndromes Paraneoplásicas/etiologia , Síndromes Paraneoplásicas/terapia , Pênfigo/etiologia , Pênfigo/terapiaRESUMO
Non-melanoma skin cancer is the most common skin cancer with an incidence that varies widely worldwide. Among them, actinic keratosis (AK), considered by some authors as in situ squamous cell carcinoma (SCC), are the most common and reflect an abnormal multistep skin cell development due to the chronic ultraviolet (UV) light exposure. No ideal treatment exists, but the potential risk of their development in a more invasive form requires prompt treatment. As patients usually present with multiple AK on fields of actinic damage, there is a need for effective, safe, simple and short treatments which allow the treatment of large areas. To achieve this, daylight photodynamic therapy (DL-PDT) is an innovative treatment for multiple mild actinic keratosis, well tolerated by patients. Patients allocated to the PDT unit, affected by multiple mild-moderate and severe actinic keratosis on sun-exposed areas treated with DL-PDT, were clinically evaluated at baseline and every three months with an Antera 3D, Miravex(©) camera. Clinical and 3D images were performed at each clinical check almost every three months. In this retrospective study, 331 patients (56.7% male, 43.3% female) were treated with DL-PDT. We observed a full clearance in more than two-thirds of patients with one or two treatments. Different responses depend on the number of lesions and on their severity; for patients with 1-3 lesions and with grade I or II AK, a full clearance was reached in 85% of cases with a maximum of two treatments. DL-PDT in general improved skin tone and erased sun damage. Evaluating each Antera 3D images, hemoglobin concentration and pigmentation, a skin color and tone improvement in 310 patients was observed. DL-PDT appears as a promising, effective, simple, tolerable and practical treatment for actinic damage associated with AK, and even treatment of large areas can be with little or no pain. The 3D imaging allowed for quantifying in real time the aesthetic benefits of DL-PDT's increasing compliance.
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Ceratose Actínica/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Idoso , Ácido Aminolevulínico/química , Ácido Aminolevulínico/uso terapêutico , Feminino , Humanos , Imageamento Tridimensional , Ceratose Actínica/patologia , Luz , Masculino , Fotoquimioterapia , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Trichoscopy is the term coined for the dermoscopic imaging of scalp and hair. This diagnostic technique, simple and noninvasive, can be used as a handy bedside tool for the diagnosis and follow-up of hair and scalp disorders. It allows the recognition of morphologic structures not visible by the naked eye and provides the clinician with a range of dermoscopic findings necessary for differential diagnosis. Trichoscopy observation can be broadly grouped as interfollicular patterns and follicular patterns. Recently, a third mixed class, called the follicular plus interfollicular pattern, has been introduced. Some of these features are specific to a certain scalp disease, while others can be found in many hair disorders. Although studies suggest that the use of trichoscopy can improve clinical accuracy, further investigation is needed. This review provides update information on the trichoscopic features of the most common scalp disorders, striving to show a histopathological and clinical correlation.
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Dermoscopia/métodos , Dermatoses do Couro Cabeludo/diagnóstico , Couro Cabeludo/patologia , Diagnóstico Diferencial , HumanosRESUMO
In this study, we analyzed multiple somatic mutations in 10 genes relevant in melanoma tumorigenesis and targeted therapies. Overall, 45% of the tumors showed mutations and, in particular, 33% had multiple mutations. Based on our results, we conclude that the assessment of mutation status of multiple genes, including CDKN2A, could provide a genetic profile that can be useful as a prognostic and therapeutic marker in melanocytic tumors.
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Genes p16 , Melanoma/genética , Neoplasias Cutâneas/genética , Quinases Proteína-Quinases Ativadas por AMP , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , GTP Fosfo-Hidrolases/genética , Humanos , Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas p21(ras)/genéticaAssuntos
Antineoplásicos/administração & dosagem , Carcinoma Basocelular/tratamento farmacológico , Imiquimode/administração & dosagem , Fotoquimioterapia/métodos , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Carcinoma Basocelular/patologia , Feminino , Humanos , Masculino , Neoplasias Cutâneas/patologia , Luz Solar/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The prevalence of latex allergy varies according to the population studied from 3% to 64%. No data exist in the present literature about elderly people because they were not considered among populations at risk. We report a retrospective observational study of 88 elderly patients of our centre of Dermatology and Allergology at Policlinico Umberto I, University of Rome, Sapienza. RESULTS: First and second level diagnostic tests showed latex positivity in 11,4% of patients studied for latex allergy in the elderly population. CONCLUSIONS: Our study demonstrates a prevalence of elderly-latex sensitization of 11,4%, showing that allergy to latex is a growing disease that can occur at any age. So, we propose these patients as an additional risk category for latex allergy.
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BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder involving aberrant proliferation of multiple tissues of neural crest origin. Retinal vascular alterations in NF1 have rarely been reported in the literature and their nature is not clear. This study describes distinctive retinal microvascular alterations and their relationship to choroidal nodules in patients with neurofibromatosis type 1. METHODS: This was a retrospective study where records of seventeen consecutive patients with diagnosis of NF1, presenting Lisch nodules and choroidal alterations, and 17 age and gender-matched healthy control patients were evaluated. Fundus photographs, near infrared reflectance and enhanced depth imaging - optical coherence tomography images were reviewed. Retinal microvascular abnormalities and choroidal and retinal alterations in proximity of the retinal microvacular alterations were carefully noted. RESULTS: 6 patients (35%) presented distinctive microvascular abnormalities. These consisted of small, tortuous vessels with a "spiral" or "corckscrew" aspect. They were second or third order, small tributaries of the superior or inferior temporal vein. These vessels were all located overlying choroidal alterations as observed with near infrared reflectance. Enhanced depth imaging - optical coherence tomography showed alteration of choroidal vasculature due to the presence of choroidal nodules but otherwise retinal and choroidal cross-sections were unremarkable for morphology. CONCLUSIONS: Retinal microvascular alterations overlying choroidal nodules in patients with NF1 can be considered another distinctive characteristic of the disease. Although the nature of these alterations is not clear, the authors speculate that functional disorders of vasomotor nerve cells, which originate in the embryonal neural crest can lead to their formation.
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Doenças da Coroide/diagnóstico , Neurofibromatose 1/diagnóstico , Doenças Retinianas/diagnóstico , Vasos Retinianos/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia de Coerência ÓpticaRESUMO
INTRODUCTION: Few studies have explored the intricate connections between vitamin D receptor (VDR) gene polymorphisms, VDR, tight junction (TJ) protein expression and clinical features of atopic dermatitis (AD). METHODS: From 43 adult AD patients, VDR polymorphisms were genotyped from peripheral blood samples using polymerase chain reaction-restriction fragment length polymorphism. VDR, occludin, claudin-1 and ZO-1 protein expression from skin lesion biopsies were assessed by immunohistochemistry. RESULTS: The A1012G heterozygous VDR polymorphism exhibited a lower odds ratio (OR) for juvenile AD onset (OR: 0.046, 95% CI 0.004-0.51, p=0.012). In contrast, the presence of ≥2 homozygous VDR polymorphisms were significantly associated with positive skin prick test (SPT) (10/20, 50%) vs. negative SPT (1/23, 4.3%; p=0.0003). The most highly expressed TJ proteins in lesions of AD patients were claudin-1 and zonulin-1 (ZO-1), while VDR and occludin were less prevalent. A significant correlation was observed between ZO-1 expression and a body mass index ≥30 kg/m2 (OR: 12.1, 95% CI 1.06-137.9, p=0.045). Claudin-1 expression was associated with a positive SPT (OR: 8.23, 95% CI 1.04-65.5, p=0.046) and serum 25(OH)D levels were negatively correlated with ZO-1 expression (rho= -0.43, p=0.0058). CONCLUSION: This study provides novel insights into the relationship between VDR gene polymorphisms, VDR, TJ protein expression, and clinical features in adult AD patients, highlighting a significant role of vitamin D in the pathophysiology of this disease.
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Ácido Aminolevulínico/análogos & derivados , Anti-Inflamatórios não Esteroides/uso terapêutico , Diclofenaco/uso terapêutico , Ácido Hialurônico/uso terapêutico , Ceratose Actínica/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Pele/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Ácido Aminolevulínico/efeitos adversos , Ácido Aminolevulínico/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Diclofenaco/efeitos adversos , Feminino , Géis , Humanos , Ácido Hialurônico/efeitos adversos , Ceratose Actínica/diagnóstico , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Fotoquimioterapia/efeitos adversos , Fármacos Fotossensibilizantes/efeitos adversos , Qualidade de Vida , Cidade de Roma , Índice de Gravidade de Doença , Pele/patologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Psoriasis is a common chronic relapsing inflammatory cutaneous disease; the main role in the inflammation of this condition is played by lymphocyte Th1, Th17 and their cytokines. The activity of these cells is modulated by a particular kind of T cells recently described: the T regulatory cells (Treg). These are able to inhibit the immunological response and to maintain the cutaneous immunological homeostasis, thus preventing autoimmunity against self antigens. Few data are available in the literature as to Treg in psoriasis; several studies demonstrate that the function of these cells is impaired in this condition and treatments for psoriasis may increase the number and activity of Treg. The role of these cells in the pathogenesis of psoriasis is very important to understand how they may contribute to the development of this cutaneous disorder. In the near future it would be possible to target therapies at these defects, improving the activity of these cells and maintaining cutaneous homeostasis, preventing psoriasis or other inflammatory cutaneous conditions.
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Imunidade Celular , Psoríase/imunologia , Pele/imunologia , Linfócitos T Reguladores/imunologia , Humanos , Psoríase/patologia , Pele/patologiaRESUMO
BACKGROUND: Electrochemotherapy (ECT) is an emerging treatment for cutaneous lesions of different tumor types. The combination of chemotherapy and electroporation enhances drug uptake into tumoral cells. However, its role in the treatment of Kaposi sarcoma (KS) has not yet been well defined, and to date, literature reports are scarce. We prospectively evaluated clinical activity and safety of ECT in KS patients. METHODS: Twenty-three patients with histologically confirmed unresectable KS, not treatable by radiotherapy or intralesional vincristine therapy, were enrolled onto the study according to the European Standard Operating Procedures of Electrochemotherapy (ESOPE) guidelines and treated with a pulse generator. RESULTS: A response to the first ECT session was obtained in all patients, with a complete response (CR) in 14 (60.9%) of 23 patients. A second ECT was performed in 5 (21.7%) and a third in 2, with a median interval between two sessions of 5.1 (range 2.5-25.5) months. Overall, a total of 15 patients (65%) experienced a CR. After a median follow-up of 1.5 years (range 2 months to 4.2 years), 16 patients maintained the response, 4 after repeated courses. Sustained local control of treated lesions was present in 20 of 23 patients. The overall survival rate was 74.4% at 2 years. CONCLUSIONS: ECT represents an additional therapeutic tool for the management of KS cutaneous lesions, characterized by a definite clinical activity and long-lasting remissions. The absence of systemic side effects and the low impact on the immune system also make this treatment suitable for elderly people, even with repeated courses.
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Antineoplásicos/uso terapêutico , Eletroquimioterapia , Sarcoma de Kaposi/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/mortalidade , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/mortalidade , Taxa de SobrevidaRESUMO
BACKGROUND: Insulin-like growth factor (IGF) binding protein (IGFBP)-3 is the main carrier of circulating IGFs and the main modulator of their activity. IGFBP-3 controls cellular availability of IGFs, which cannot exert their pro-proliferative activity while bound to IGFBP-3. Proteolysis of IGFBP-3 is one mechanism to control IGF release. A reduction of serum IGFBP-3 levels and the associated increased availability of IGFs may represent a strategy whereby melanoma increases its metastatic potential. OBJECTIVE: The aim of our study was to evaluate the correlation between the IGFBP-3 serum level and melanoma stage. METHODS: The study included 41 patients, 24 male and 17 female, with median age of 60 years (range 24-80), affected by cutaneous melanoma. Blood samples were taken from each patient and IGFBP-3 serum levels were measured using Western blot analysis with commercial antibodies. Values were normalized using commercial IGFBP-3. RESULTS: The statistical analysis showed that full-size, glycosylated IGFBP-3 concentrations were significantly lower in the sera of patients with stage IV melanoma. Low serum levels of IGFBP-3 correlated with both disease progression and presence of disease at the time of sample collection. In patients who underwent follow-up visits with further collections of blood samples, the concentrations of glycosylated IGFBP-3 decreased only in those who showed progression of disease. LIMITATIONS: Our study shows only preliminary results on a limited number of patients. CONCLUSION: We demonstrate that there is a significant inverse correlation between the serum concentration of full-size, glycosylated IGFBP-3 and disease progression in patients with melanoma.
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Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Melanoma/sangue , Neoplasias Cutâneas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Progressão da Doença , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Curva ROC , Neoplasias Cutâneas/patologia , Adulto JovemRESUMO
The standard methods used to diagnose scalp psoriasis vary in sensitivity, reproducibility, and invasiveness. Videodermoscopy can be used to explore microcirculatory modifications in skin diseases. Psoriasis presents three pathognomonic vascular patterns: red dots, hairpin vessels and red globular rings. Our aim was to create a videodermoscopy scalp psoriasis severity index (VSCAPSI) for evaluation of scalp psoriasis, especially mild and moderate forms that often are not clinically appreciable. VSCAPSI takes into account the area of the scalp affected by psoriasis, the presence and morphology of vascular patterns, the erythema and desquamation. Videodermoscopy images obtained between November 2009 to June 2010 from 900 participants with various scalp and hair disorders were reviewed for distinguishing features. During the 2010 Italian congress on psoriasis, in order to assess the reproducibility and efficacy of the VSCAPSI, 146 dermatologists were asked to evaluate 16 videodermoscopy images of scalp psoriasis using the VSCAPSI. Of the 900 patients, 85 new cases of scalp psoriasis were diagnosed. The other 815 patients were found to be suffering from different scalp and hair diseases. Of 146 dermatologists, 28 did not recognize erythema, 15 desquamation and 7 the vascular patterns. The VSCAPSI provides important evidence for early diagnosis, differential diagnosis, for follow-up and screening.
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Dermoscopia/métodos , Psoríase/diagnóstico , Dermatoses do Couro Cabeludo/diagnóstico , Gravação em Vídeo , Diagnóstico Diferencial , Humanos , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Estatísticas não ParamétricasRESUMO
BACKGROUND: Regulatory T-cells (T-reg) play a central role in the immunopathogenesis of psoriasis. T-reg cells are both functionally and numerically impaired in psoriasis and they are up-regulated by drug therapy. OBJECTIVE: To analyse the circulating CD4+CD25 bright FOXP3+ subset in 14 patients with vulgaris/arthropathic psoriasis treated with biological drugs and to investigate their relationship with the clinical response. METHODS: The CD4+ CD25 bright FOXP3+ expression was determined in peripheral blood by flow cytometry at baseline and during treatment. RESULTS: A response was obtained in 10/14 patients with increased CD4+ CD25 bright FOXP3+ (T-reg) in peripheral blood after the first month and then 4 months after therapy with biological drugs. This increase is associated with the achievement of a clinical response and with a reduction in the Psoriasis Activity and Severity Index (PASI) score. 2/14 patients showed a decrease in T-reg after drug therapy and this decrease correlated with a worsening of the clinical skin. CONCLUSION: Biological drugs induce circulating T-reg up-regulation in psoriatic patients; such an increase is an early predictive marker of clinical response.
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Produtos Biológicos/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Psoríase/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/metabolismo , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Linfócitos T Reguladores/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Second primary melanomas (SPMs) are new developed primary melanomas occurring in a subset of patients affected by BRAF-mutated metastatic melanoma during treatment with BRAF-inhibitors. A drug-induced paradoxical activation of mitogen-activated protein kinase (MAPK) signaling pathway in BRAF-wild type/RAS-mutated cells have been proposed as a possible molecular mechanism but data on the mutational status of SPMs are lacking. In order to better understand genetic alterations affecting the biological mechanism of SPMs, we performed a personalized and targeted next-generation sequencing analysis of a patient affected by metastatic melanoma who developed multiple SPMs during treatment with encorafenib (LGX818). METHODS: Using a cancer panel of 50 genes for solid tumors enriched with a custom panel of 10 genes specifically involved in melanoma pathogenesis, we analyzed the primary melanoma, two SPMs, one benign compound nevus and the normal DNA extracted from blood lymphocytes of the patient. RESULTS: We identified HRAS Q61 somatic mutation in one SPM developed in a pre-existing nevus. In the primary melanoma, besides the BRAF mutation, we identified the clinically actionable IDH1 R132C somatic mutation. Both SPMs were BRAF wild type. The patient harbors the recently recognized pathogenetic germline variant KDR Q472. We observed that mutations detected in tumor samples involving genes related to melanoma pathogenesis (TP53, PIK3CA, FGFR3, ATF1, KIT, HRAS and MAP2K2) were present in heterozygosis in the germline status of the patient. CONCLUSIONS: Our results support the paradoxical mechanism of MAPK pathway for SPMs under BRAF inhibitors. Moreover, they suggest that targeted mutational assessment based on matching somatic and germline analysis represent a promising approach to detect the neoplastic landscape of the tumor and to identify most accurate treatment in metastatic melanoma patient.
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Melanoma , Segunda Neoplasia Primária , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas , Análise Mutacional de DNA , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/genética , Nevo de Células Epitelioides e Fusiformes , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genéticaRESUMO
BACKGROUND: Cancer survivors are rising up, but this better survival is accompanied by possible treatments side-effects. In particular, cardiovascular effects are commonly reported, even if vascular damage is not necessarily connected to clinical manifestations. Periungual microcircle evaluation through capillaroscopy could identify asymptomatic patients with high risk of cerebro-cardio-vascular disease. The aim of this pivotal study was to evaluate videocapillaroscopy in patients who undergo chemotherapy, in order to understand if it could represent in future a prognostic tool to predict the risk of cardio-cerebro-vascular events. METHODS: We conducted an open-label, uncontrolled study. Patients affected by solid tumors were enrolled. Each subject underwent a clinical evaluation and a videocapillaroscopic examination. RESULTS: We selected 25 patients. Mean age was 55.48 years. Time interval between the start of chemotherapy and capillaroscopy: average 41 months. From our analysis it emerges that ectasia and hemorrhages could be a possible marker of capillary insult caused by chemotherapy. CONCLUSIONS: Our study showed the presence of capillaroscopic features that may be peculiar in chemotherapy-induced endothelial damage. The individuation of capillaroscopic alteration specific for chemotherapy-induced endothelial injury could be an important tool to identify patients with high cardiovascular risk.