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1.
Methods Mol Biol ; 2265: 475-486, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33704735

RESUMO

MicroRNAs (miRs) are small RNA molecules (18-22 nucleotides) that regulate the transcriptome at a post-transcriptional level by affecting the expression of specific genes. This regulatory mechanism is critical to maintain cell homeostasis and specific functions. Aberrant expression of miRs have been associated with pathobiological processes including cancer. There are few technologies available that are able to profile whole-genome miR expression using minimal amounts of blood samples and without the need for time-consuming extraction steps. Here, we describe the HTG EdgeSeq miR Whole-Transcriptome Assay (WTA) in serum and plasma samples. To identify specific cell-free miR (cfmiR) patterns we have first focused on the analysis of normal donor samples and have then compared these to patients with cutaneous melanoma. The identification of specific cfmiR for melanoma patients will allow for better patient surveillance during targeted and/or checkpoint inhibitor immunotherapy (CII) treatment.


Assuntos
MicroRNA Circulante/sangue , Perfilação da Expressão Gênica , Melanoma/sangue , RNA Neoplásico/sangue , Neoplasias Cutâneas/sangue , Transcriptoma , Humanos
2.
Methods Mol Biol ; 2265: 203-212, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33704716

RESUMO

Early detection of cancer has been a goal of cancer research in general and melanoma research in particular (Birnbaum et al., Lancet Glob Health 6:e885-e893, 2018; Alendar et al., Bosnian J Basic Med Sci 9:77-80, 2009). Early detection of metastasis has been targeted as pivotal to increasing survival rates (Menezes et al., Adv Cancer Res 132:1-44, 2016). Melanoma, though curable in its early stages, has a dramatic decrease in survival rates once metastasis has occurred (Sharma et al., Biotechnol Adv 36:1063-1078, 2018). The transition to metastasis is not well understood and is an area of increasing interest. Metastasis is always premeditated by the shedding of circulating tumor cells (CTCs) from the primary tumor. The ability to isolate rare CTCs from the bloodstream has led to a host of new targets and therapies for cancer (Micalizzi et al., Genes Dev 31:1827-1840, 2017). Detection of CTCs also allows for disease progression to be tracked in real time while eliminating the need to wait for additional tumors to grow. Using a photoacoustic flowmeter, in which we induce ultrasonic responses from circulating melanoma cells (CMCs), we identify and quantify these cells in order to track disease progression. Additionally, these CMCs are captured and isolated allowing for future analysis such as RNA-Seq or microarray analysis.


Assuntos
Citometria de Fluxo/métodos , Melanoma/diagnóstico , Células Neoplásicas Circulantes , Técnicas Fotoacústicas/instrumentação , Técnicas Fotoacústicas/métodos , Reologia/instrumentação , Reologia/métodos , Neoplasias Cutâneas/diagnóstico , Progressão da Doença , Detecção Precoce de Câncer/métodos , Citometria de Fluxo/instrumentação , Biblioteca Gênica , Humanos , Imuno-Histoquímica/métodos , Melanoma/sangue , Melanoma/genética , Melanoma/patologia , Metástase Neoplásica/diagnóstico , Metástase Neoplásica/patologia , Células Neoplásicas Circulantes/patologia , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Ultrassonografia/métodos
3.
Medicine (Baltimore) ; 100(8): e24840, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663104

RESUMO

ABSTRACT: Malignant melanoma is a highly malignant tumor originating from the melanocytes of the neural crest, which is prone to metastasis and has a poor prognosis. Previous research demonstrated that melanoma inhibitory activity (MIA) and lactate dehydrogenase (LDH) could serve as serum markers in malignant melanoma and indicate prognosis in the Caucasian race. Researchers suspected that both MIA and LDH could prompt the prognosis of malignant melanoma in the Chinese population. This study aimed to investigate the value of MIA and LDH in the prognosis of acral malignant melanoma.From January 1, 2014, to December 31, 2017, in Jiangsu Province, 44 acral malignant melanoma patients with complete data were chosen from the clinic. The LDH levels were extracted from their clinical data, and MIA levels were measured by enzyme-linked immunosorbent assay method. 8 paired advancing samples before and after metastasis were examined. 22 health donors were matched to the patient group. Receiver operating characteristic (ROC) curves of MIA and LDH were drawn to determine acral malignant melanoma tumorigenesis and metastasis and finally got the cut-off value. Cumulative survival was illustrated with the Kaplan-Meier plot, and factors were compared using the Log-rank test.Compared with age-matched healthy donors, MIA was significantly high in patients (P < .001). Moreover, serum MIA was significantly higher in III-IV stage patients than I-II stage patients (P < .001). However, there was no such association between LDH and melanoma stage and risk. Further study indicated that the MIA cut-off > 914.7pg/mL predicted disease progression with 86.4% specificity and 95.5% sensitivity. In the Kaplan-Meier analysis, MIA levels were independent risk factors for long-term mortality of acral malignant melanoma patients.It concluded that the quantification of MIA in the serum should be performed as a general standard of care in patients at risk of developing metastatic melanoma.


Assuntos
Proteínas da Matriz Extracelular/sangue , Melanoma/sangue , Melanoma/genética , Proteínas de Neoplasias/sangue , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Idoso , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , Estudos de Casos e Controles , China , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Estimativa de Kaplan-Meier , L-Lactato Desidrogenase/sangue , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade
4.
Drug Discov Ther ; 14(3): 117-121, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32595179

RESUMO

The advent of immune checkpoint inhibitors such as anti-PD-1 antibodies had a striking impact on the treatment for advanced malignant melanoma. However, less than half of the patients benefited from those antibodies, and biomarkers that could sensitively differentiate responders from non-responders are urgently needed. Herein, we explored such biomarkers by retrospectively analyzing clinical data from patients with advanced malignant melanoma treated with nivolumab and pembrolizumab. We found that anti-PD-1 antibody was especially effective for those with metastasis only to soft tissues. Although no significant difference was found in the baseline value of relative neutrophil count (RNC), relative lymphocyte count (RLC), neutrophil to lymphocyte ratio (NLR), and relative eosinophil count (REC) between responders and non-responders, responders after anti-PD-1 therapy revealed the increase of lymphocytes and eosinophils and the decrease of neutrophils within the first 6 weeks of the treatment. We also calculated the change of RNC and RLC 3 weeks and 6 weeks after the initiation of the therapy and designated as NΔ3-LΔ3 and NΔ6-LΔ6 respectively. NΔ3-LΔ3 was significantly decreased in responders, which suggest that the neutrophil decrease and lymphocyte increase after as early as 3 weeks of anti-PD-1 therapy might be a useful clinical indicator. In addition, the difference of NΔ6-LΔ6 between responders and non-responders was even more robust. These data suggest that change of RNC, RLC, and REC together with the combination of NΔ3-LΔ3 and NΔ6-LΔ6 might be a useful tool for early and sensitive biomarkers for anti-PD-1 therapy.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Autoanticorpos/sangue , Autoanticorpos/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Melanoma/sangue , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptor de Morte Celular Programada 1/sangue , Estudos Retrospectivos , Neoplasias Cutâneas/sangue , Resultado do Tratamento
5.
Sci Rep ; 10(1): 7478, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366871

RESUMO

Advanced melanoma remains a disease with poor prognosis. Several serologic markers have been investigated to help monitoring and prognostication, but to date only lactate dehydrogenase (LDH) has been validated as a standard prognostic factor biomarker for this disease by the American Joint Committee on Cancer. In this work, we built a semi-mechanistic model to explore the relationship between the time course of several circulating biomarkers and overall or progression free survival in advanced melanoma patients treated with adjuvant high-dose interferon-[Formula: see text]. Additionally, due to the adverse interferon tolerability, a semi-mechanistic model describing the side effects of the treatment in the absolute neutrophil counts is proposed in order to simultaneously analyze the benefits and toxic effects of this treatment. The results of our analysis suggest that the relative change from baseline of LDH was the most significant predictor of the overall survival of the patients. Unfortunately, there was no significant difference in the proportion of patients with elevated serum biomarkers between the patients who recurred and those who remained free of disease. Still, we believe that the modelling framework presented in this work of circulating biomarkers and adverse effects could constitute an additional strategy for disease monitoring in advance melanoma patients.


Assuntos
Biomarcadores Tumorais/sangue , Melanoma , Modelos Biológicos , Neoplasias Cutâneas , Adulto , Idoso , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melanoma/sangue , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Taxa de Sobrevida
6.
Melanoma Res ; 30(2): 159-165, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32142497

RESUMO

Histone posttranslational modifications (PTMs) have been shown to be dysregulated in multiple cancers including melanoma, and as they are abundant and easily detectable, they make ideal biomarkers. The aim of this study was to identify histone PTMs that could be potential biomarkers for melanoma diagnosis. Previously, we utilized mass spectrometry to identify histone PTMs that were dysregulated in matched melanoma cell lines and found two modifications, H3 lysine 27 trimethylation (histone H3K27me3) and H4 lysine 20 monomethylation (histone H4K20me), that were differentially expressed in the more aggressive compared to the less aggressive cell line. In this study, we performed immunohistochemistry on tissue microarrays containing 100 patient tissue spots; 18 benign nevi, 62 primary, and 20 metastatic melanoma tissues. We stained for histone H3K27me3 and histone H4K20me to ascertain whether these histone PTMs could be used to distinguish different stages of melanoma. Loss of histone H4K20me was observed in 66% of malignant patient tissues compared to 14% of benign nevi. A majority (79%) of benign nevi had low histone H3K27me3 staining, while 72% of malignant patient tissues showed either a complete loss or had strong histone H3K27me3 staining. When we analyzed the staining for both marks together, we found that we could identify 71% of the benign nevi and 89% of malignant melanomas. Histone H3K27me3 or histone H4K20me display differential expression patterns that can be used to distinguish benign nevi from melanoma; however, when considered together the diagnostic utility of these PTMs increased significantly. The work presented supports the use of combination immunohistochemistry of histone PTMs to increase accuracy and confidence in the diagnosis of melanoma.


Assuntos
Histonas/sangue , Imuno-Histoquímica/métodos , Melanoma/diagnóstico , Processamento de Proteína Pós-Traducional/genética , Neoplasias Cutâneas/diagnóstico , Humanos , Melanoma/sangue , Melanoma/patologia , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/patologia
7.
PLoS One ; 15(2): e0228751, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049976

RESUMO

BACKGROUND: Primary cutaneous CD30+ lymphoproliferative disorders (CD30CLPD) are the second most common type of cutaneous T cell lymphoma (CTCL) and include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL). Case reports and small patient series suggest an association of CD30CLPD with atopic disorders. However, the prevalence of atopy in patients with CD30CLPD in retrospective studies depends on patients' recall which is not always reliable. More objective criteria of atopy include evidence of skin reactivity to allergens (positive prick test) and evidence of allergen-specific IgE in serum. This study was undertaken to test the hypothesis that atopy is prevalent in patients with CD30CLPD using serologic criteria of allergen-specific IgE antibodies to aeroallergens and Staphylococcal aureus enterotoxin superantigens (SSAgs). METHODS: We tested serum samples of CD30CLPD for common IgE-specific airborne allergens with the Phadiatop test, which if positive, is regarded as serologic evidence of atopy in adults. Sera were also tested for IgE antibodies reactive to three Staphylococcal enterotoxins with superantigenic properties (SSAg-IgE). Control sera were obtained from adult subjects evaluated for rhino-sinusitis and a negative Phadiatop test. Patients' history of an atopic disorder was obtained by retrospective chart review. FINDINGS: Nearly 50% of patients with the most common LyP types (A and C) had a positive Phadiatop test for allergic sensitization to common airborne allergens, and total serum IgE (IgE-t) was increased compared to non-atopic controls. At the IgE antibody concentration generally used to define serologic atopy (≥ 0.35 kUA/L), 8/31 (26%) samples of CD30CLPD and 7/28 (25%) samples of LyP were reactive to at least one SSAg-IgE compared to 3/52 (6%) control specimens (P = 0.016 and P = 0.028, respectively). TSST1-IgE was detected in 7 (23%) specimens of CD30CLPD, often together with SEB-IgE; SEA-IgE ≥ 0.35 kUA/L was not detected. For control specimens, TSST1-IgE exceeded the 0.35 kUA/L threshold in 3 (6%) specimens. CONCLUSIONS: Patients with LyP types A and C have serologic evidence of atopy against common airborne antigens and SSAgs when compared to control adult subjects who had rhino-sinusitis and a negative Phadiatop test for aero-IgEs. Serologic evidence of atopy exceeded that determined by LyP patients' personal history. The findings support our hypothesis that an atopic diathesis may contribute to the pathogenesis of the most common types of LyP (A and C).


Assuntos
Antígenos de Bactérias/imunologia , Papulose Linfomatoide/imunologia , Neoplasias Cutâneas/imunologia , Staphylococcus aureus/imunologia , Superantígenos/imunologia , Adolescente , Corticosteroides/farmacologia , Adulto , Idoso , Feminino , Humanos , Imunoglobulina E/imunologia , Papulose Linfomatoide/sangue , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Neoplasias Cutâneas/sangue , Fumar , Adulto Jovem
8.
BMJ Case Rep ; 13(2)2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32102892

RESUMO

Testicular choriocarcinoma (CC) is a malignant germ cell tumour which most frequently presents with disseminated metastasis, often involving the lungs, brain and liver. Metastatic are characterised by extensive vascularity, often causing patients to present emergently with potentially life-threatening haemorrhagic complications. We report a patient with disseminated testicular CC, presenting with haemorrhage from a dermal metastatic focus involving the lower lip and mentum, requiring surgical intervention. This unique case illustrates the potential utility of palliative surgery, for the management of symptomatic metastatic disease, such as those caused by testicular CC.


Assuntos
Coriocarcinoma/patologia , Neoplasias de Cabeça e Pescoço/secundário , Hemorragia/etiologia , Neoplasias Cutâneas/secundário , Neoplasias Testiculares/patologia , Adulto , Queixo/cirurgia , Neoplasias de Cabeça e Pescoço/sangue , Humanos , Lábio/cirurgia , Masculino , Neoplasias Embrionárias de Células Germinativas/patologia , Cuidados Paliativos , Neoplasias Cutâneas/sangue
9.
Cancer Immunol Immunother ; 69(4): 559-568, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31974724

RESUMO

OBJECTIVES: The neutrophil-lymphocyte ratio (NLR) is an inflammatory biomarker which is useful in cancer prognostication. We aimed to investigate the differences in baseline NLR between patients with localised and metastatic cutaneous melanoma and how this biomarker changed over time with the recurrence of disease. METHODS: This multicentre cohort study describes patients treated for Stage I-III cutaneous melanoma over 10 years. The baseline NLR was measured immediately prior to surgery and again at the time of discharge or disease recurrence. The odds ratios (OR) for sentinel node involvement are estimated using mixed-effects logistic regression. The risk of recurrence is estimated using multivariable Cox regression. RESULTS: Overall 1489 individuals were included. The mean baseline NLR was higher in patients with palpable nodal disease compared to those with microscopic nodal or localised disease (2.8 versus 2.4 and 2.3, respectively; p < 0.001). A baseline NLR ≥ 2.3 was associated with 30% higher odds of microscopic metastatic melanoma in the sentinel lymph node [adjusted OR 1.3 (95% CI 1.3, 1.3)]. Following surgery, 253 patients (18.7%) developed recurrent melanoma during surveillance although there was no statistically significant association between the baseline NLR and the risk of recurrence [adjusted HR 0.9 (0.7, 1.1)]. CONCLUSION: The NLR is associated with the volume of melanoma at presentation and may predict occult sentinel lymph metastases. Further prospective work is required to investigate how NLR may be modelled against other clinicopathological variables to predict outcomes and to understand the temporal changes in NLR following surgery for melanoma.


Assuntos
Linfócitos/patologia , Melanoma/sangue , Neutrófilos/patologia , Neoplasias Cutâneas/sangue , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Metástase Linfática , Masculino , Melanoma/patologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia
10.
Int J Mol Sci ; 21(2)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936623

RESUMO

Melanoma is one of the most lethal and malignant cancers and its incidence is increasing worldwide, and Japan is not an exception. Although there are numerous therapeutic options for melanoma, the prognosis is still poor once it has metastasized. The main concern after removal of a primary melanoma is whether it has metastasized, and early detection of metastatic melanoma would be effective in improving the prognosis of patients. Thus, it is very important to identify reliable methods to detect metastases as early as possible. Although many prognostic biomarkers (mainly for metastases) of melanoma have been reported, there are very few effective for an early diagnosis. Serum and urinary biomarkers for melanoma diagnosis have especially received great interest because of the relative ease of sample collection and handling. Several serum and urinary biomarkers appear to have significant potential both as prognostic indicators and as targets for future therapeutic methods, but still there are no efficient serum and urinary biomarkers for early detection, accurate diagnosis and prognosis, efficient monitoring of the disease and reliable prediction of survival and recurrence. Levels of 5-S-cysteinyldopa (5SCD) in the serum or urine as biomarkers of melanoma have been found to be significantly elevated earlier and to reflect melanoma progression better than physical examinations, laboratory tests and imaging techniques, such as scintigraphy and echography. With recent developments in the treatment of melanoma, studies reporting combinations of 5SCD levels and new applications for the treatment of melanoma are gradually increasing. This review summarizes the usefulness of 5SCD, the most widely used and well-known melanoma marker in the serum and urine, compares 5SCD and other useful markers, and finally its application to other fields.


Assuntos
Biomarcadores Tumorais/metabolismo , Cisteinildopa/metabolismo , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Cisteinildopa/sangue , Monitoramento de Medicamentos , Humanos , Melanoma/sangue , Melanoma/patologia , Metaboloma , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/patologia
11.
PLoS One ; 15(1): e0227187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31917795

RESUMO

Receptor tyrosine kinase AXL is a one-pass transmembrane protein upregulated in cancers and associated with lower survival and therapy resistance. AXL can be cleaved by the A Disintegrin and Metalloproteinases (ADAM)10 and ADAM17, yielding a soluble version of the protein. Elevated soluble AXL (sAXL) has been reported to be associated with disease progression in hepatocellular carcinoma, renal cancer, neurofibromatosis type 1 and inflammatory diseases. In the present work, we analyzed sAXL levels in blood from melanoma patients and showed that sAXL increases with disease progression. Additionally, increased sAXL levels were found correlated with shorter two-year survival in stage IV patients treated with ipilimumab. Furthermore, we showed that sAXL levels were related to the percentage of cells expressing AXL in resected melanoma lymph node metastases. This finding was verified in vitro, where sAXL levels in the cell media corresponded to AXL expression in the cells. AXL inhibition using the small-molecular inhibitor BGB324 reduced sAXL levels, while the cellular expression was elevated through increased protein stability. Our findings signify that quantification of sAXL blood levels is a simple and easily assessable method to determine cellular AXL levels and should be further evaluated for its use as a biomarker of disease progression and treatment response.


Assuntos
Progressão da Doença , Melanoma/sangue , Melanoma/mortalidade , Proteínas Proto-Oncogênicas/sangue , Receptores Proteína Tirosina Quinases/sangue , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Benzocicloeptenos/farmacologia , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral , Feminino , Humanos , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/química , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Solubilidade , Taxa de Sobrevida , Triazóis/farmacologia
12.
Clin Pharmacol Ther ; 107(4): 978-987, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31721173

RESUMO

Lower clearance of immune checkpoint inhibitors is a predictor of improved overall survival (OS) in patients with advanced cancer. We investigated a novel approach using machine learning to identify a baseline composite cytokine signature via clearance, which, in turn, could be associated with OS in advanced melanoma. Peripheral nivolumab clearance and cytokine data from patients treated with nivolumab in two phase III studies (n = 468 (pooled)) and another phase III study (n = 158) were used for machine-learning model development and validation, respectively. Random forest (Boruta) algorithm was used for feature selection and classification of nivolumab clearance. The 16 top-ranking baseline inflammatory cytokines reflecting immune-cell modulation were selected as a composite signature to predict nivolumab clearance (area under the curve (AUC) = 0.75; accuracy = 0.7). Predicted clearance (high vs. low) via the cytokine signature was significantly associated with OS across all three studies (P < 0.01), regardless of treatment (nivolumab vs. chemotherapy).


Assuntos
Antineoplásicos Imunológicos/sangue , Citocinas/sangue , Aprendizado de Máquina , Melanoma/sangue , Nivolumabe/sangue , Neoplasias Cutâneas/sangue , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Prognóstico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico
13.
Cancer Chemother Pharmacol ; 85(3): 615-620, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31786653

RESUMO

Purpose To validate a plasma vemurafenib steady-state trough concentration (Css,min) threshold that predicts survival outcomes of patients with BrafV600 mutated melanoma. METHODS: A pooled analysis of individual patient data from two advanced melanoma trials involving vemurafenib ± cobimetinib therapy was performed. Day 23 was chosen as the landmark time when steady-state concentration reached. Optimal Css,min threshold was determined via assessment of discriminative performance and model fitting. Association between vemurafenib Css,min and survival was modelled using Cox proportional hazards regression. RESULTS: Vemurafenib plasma concentration data were available for 402 patients who were on stable dose for the first 3 weeks. When compared to a previously described plasma vemurafenib Css,min threshold of 42 mg/L, we identified that a cutoff concentration of 50 mg/L by day 23 was strongly associated with progression-free survival and overall survival. The association remained statistically significant after adjusting for important clinical confounding variables. Sub-group analysis showed that while the addition of cobimetinib resulted in a lower day 23 plasma vemurafenib Css,min, the threshold was still associated with overall survival and not in the monotherapy cohort. CONCLUSION: A plasma vemurafenib Css,min threshold of 50 mg/L is strongly associated with survival outcomes in patients with advanced melanoma. This new threshold needs to be validated prospectively in future studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Melanoma/sangue , Melanoma/mortalidade , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/mortalidade , Vemurafenib/sangue , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/genética , Pessoa de Meia-Idade , Mutação/genética , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Resultado do Tratamento , Vemurafenib/uso terapêutico
14.
Clin Exp Dermatol ; 45(5): 539-543, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31755143

RESUMO

Lactate dehydrogenase (LDH) is used in dermatology practice, particularly as a prognostic marker for cutaneous lymphoma. LDH is an intracellular enzyme involved in anaerobic glycolysis, and is found at low concentrations in the blood. LDH is produced in every tissue, thus cell damage releases LDH into the circulation, so the causes of elevated LDH levels are multiple. The utility of LDH in dermatology practice is reviewed, alongside current diagnostic and staging guidelines.


Assuntos
L-Lactato Desidrogenase/sangue , Linfoma/diagnóstico , Melanoma/patologia , Neoplasias Cutâneas/diagnóstico , Adolescente , Criança , Pré-Escolar , Dermatologia , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , L-Lactato Desidrogenase/metabolismo , Linfoma/sangue , Masculino , Melanoma/secundário , Estadiamento de Neoplasias/métodos , Valores de Referência , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/patologia
15.
J Invest Dermatol ; 140(2): 327-337.e2, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31425707

RESUMO

A lack of basic resources within a society (deprivation) is associated with increased cancer mortality, and this relationship has been described for melanoma. We have previously reported the association of smoking and low vitamin D levels with melanoma death. In this study, we further explored the associations of these with melanoma in addition to deprivation and socio-economic stressors. In this analysis of 2,183 population-ascertained primary cutaneous melanoma patients, clinical, demographic, and socio-economic variables were assessed as predictors of tumor thickness, melanoma death and overall death. Using the Townsend deprivation score, the most deprived group did not have thicker tumors compared to the least deprived. Of the World Health Organization 25x25 risk factors for premature death, smoking and body mass index (BMI) were independently associated with thicker tumors. Low vitamin D was also independently associated with thicker tumors. No socio-economic stressors were independent predictors of thickness. Smoking was confirmed as a key predictor of melanoma death and overall death, as were low vitamin D levels, independent of other measures of deprivation. Neither BMI nor the Townsend deprivation score were predictive in either survival analysis. We report evidence for the role of smoking, vitamin D, and BMI in melanoma progression independent of a postcode-derived measure of deprivation.


Assuntos
Melanoma/mortalidade , Neoplasias Cutâneas/mortalidade , Fumar/epidemiologia , Classe Social , Deficiência de Vitamina D/epidemiologia , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Feminino , Seguimentos , Humanos , Estilo de Vida , Masculino , Melanoma/sangue , Melanoma/etiologia , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Fatores de Risco , Fatores Sexuais , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/etiologia , Fumar/efeitos adversos , Análise de Sobrevida , Vitamina D/sangue , Deficiência de Vitamina D/complicações
16.
Int J Dermatol ; 59(3): 345-351, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31663123

RESUMO

BACKGROUND: Mycosis fungoides (MF) skin lesions are characterized by low-grade inflammation, which may be sustained by proinflammatory cytokines as probably interleukin-33 (IL-33). We compared serum concentrations of IL-33 and its receptor ST2 and the frequency of selected IL-33 single nucleotide polymorphisms (SNPs) between patients with MF and healthy controls. METHODS: In 88 patients with MF and 66 healthy controls, we analyzed SNPs in the 9894 and 11877 loci of the IL-33 gene. Moreover, we measured serum concentrations of IL-33 and its receptor ST2. RESULTS: There were no statistically significant differences in the frequencies of both IL-33 SNPs between patients and controls. Compared with controls, patients with MF had similar IL-33 serum concentrations (P = 0.71) but significantly increased ST2 concentrations (P < 0.001). Patients in MF-IA stage had significantly lower ST2 serum concentrations than those with the remaining MF stages (P = 0.002). The studied variables were not related to pruritus severity. Patients with the C(+) IL-33 11877 SNP had lower ST2 serum concentrations than patients with the C(-) 11877 SNP (P = 0.043). CONCLUSIONS: It was published before that the knockout of the ST2 gene after injection of IL-33 is associated with a reduced inflammatory reaction in the skin, as well as that IL-33 plays a role in allergic and neoplastic disorders. Concerning the difference in ST2 concentration between control and MF group, and C IL-33 11877 SNP possibly influencing the ST2 concentration, the role of IL-33/ST2 signaling, needs further studies.


Assuntos
Interleucina-33/sangue , Interleucina-33/genética , Micose Fungoide/sangue , Micose Fungoide/genética , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/genética , Feminino , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
17.
Cancer Res ; 79(23): 5986-5998, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31690667

RESUMO

1α,25-Dihydroxyvitamin D3 signals via the vitamin D receptor (VDR). Higher serum vitamin D is associated with thinner primary melanoma and better outcome, although a causal mechanism has not been established. As patients with melanoma commonly avoid sun exposure, and consequent vitamin D deficiency might worsen outcomes, we interrogated 703 primary melanoma transcriptomes to understand the role of vitamin D-VDR signaling and replicated the findings in The Cancer Genome Atlas metastases. VDR expression was independently protective for melanoma-related death in both primary and metastatic disease. High tumor VDR expression was associated with upregulation of pathways mediating antitumor immunity and corresponding with higher imputed immune cell scores and histologically detected tumor-infiltrating lymphocytes. High VDR-expressing tumors had downregulation of proliferative pathways, notably Wnt/ß-catenin signaling. Deleterious low VDR levels resulted from promoter methylation and gene deletion in metastases. Vitamin D deficiency (<25 nmol/L ∼ 10 ng/mL) shortened survival in primary melanoma in a VDR-dependent manner. In vitro functional validation studies showed that elevated vitamin D-VDR signaling inhibited Wnt/ß-catenin signaling genes. Murine melanoma cells overexpressing VDR produced fewer pulmonary metastases than controls in tail-vein metastasis assays. In summary, vitamin D-VDR signaling contributes to controlling pro-proliferative/immunosuppressive Wnt/ß-catenin signaling in melanoma and this is associated with less metastatic disease and stronger host immune responses. This is evidence of a causal relationship between vitamin D-VDR signaling and melanoma survival, which should be explored as a therapeutic target in primary resistance to checkpoint blockade. SIGNIFICANCE: VDR expression could potentially be used as a biomarker to stratify patients with melanoma that may respond better to immunotherapy.


Assuntos
Calcitriol/deficiência , Melanoma/imunologia , Receptores de Calcitriol/metabolismo , Neoplasias Cutâneas/imunologia , Deficiência de Vitamina D/imunologia , Animais , Calcitriol/sangue , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Progressão da Doença , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Melanoma/sangue , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Pele/metabolismo , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Fatores de Tempo , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/patologia , Via de Sinalização Wnt , beta Catenina/metabolismo
18.
Eur J Cancer ; 121: 74-84, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31563729

RESUMO

PURPOSE: High plasma levels of YKL-40 might be associated with mortality in patients with melanoma, and it is unknown if YKL-40 is causally related to mortality. EXPERIMENTAL DESIGN: We studied two cohorts: 2618 patients with melanoma from hospital clinics and 1413 general population patients with melanoma, totalling 4031 patients followed up for mortality end-points for up to 20 years. All were genotyped for CHI3L1 rs4950928, highly predictive of lifelong plasma YKL-40, and plasma YKL-40 levels were measured in 2165 patients. We tested the hypotheses that measured and genetically predicted high plasma YKL-40 are associated with increased mortality in patients with melanoma. RESULTS: For the hospital melanoma cohort, age- and sex-adjusted hazard ratios for death in individuals with measured plasma YKL-40 in the 96-100th percentile versus 1-95th percentile and per 10-percentile increase were 1.52 (95% confidence interval, 1.07-2.16) and 1.07 (1.02-1.11), respectively, most pronounced for patients with localised melanomas. Each C-allele of the CHI3L1 rs4950928 genotype was associated with plasma YKL-40 level increases of 32% in the hospital melanoma cohort (p = 6 × 10-48) and 43% in the general population melanoma cohort (p = 7 × 10-13). Multifactorially adjusted ratios for these increases in the combined cohorts were 1.04 (1.00-1.09) observationally for measured plasma YKL-40 and 0.98 (0.86-1.12) for the genetically predicted plasma YKL-40. CONCLUSION: Measured, but not genetically predicted, increasing plasma YKL-40 was associated with increased mortality in patients with melanoma. Plasma YKL-40 is a marker but less likely to be a cause of increased mortality in patients with melanoma.


Assuntos
Proteína 1 Semelhante à Quitinase-3/sangue , Proteína 1 Semelhante à Quitinase-3/genética , Melanoma/mortalidade , Neoplasias Cutâneas/mortalidade , Adulto , Idoso , Biomarcadores/análise , Biomarcadores/sangue , Causas de Morte , Proteína 1 Semelhante à Quitinase-3/análise , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Melanoma/sangue , Melanoma/diagnóstico , Melanoma/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Análise de Sobrevida
19.
Cancer Biomark ; 26(3): 333-342, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31561328

RESUMO

BACKGROUND: To date, serological markers to monitor melanoma progression and response to therapy are lacking. In this context cytokines appear to be promising biomarkers of the disease. OBJECTIVE: To compare cytokine and chemokine levels in melanoma patients and in healthy controls and to assess possible variations according to melanoma stage. METHODS: Serum chemokine and cytokine levels were determined by ELISA in 34 patients diagnosed histologically of malignant melanoma. Seven healthy volunteers were used as controls. RESULTS: We found a subset of cytokines (CCL3, CCL4, IFN-γ and IL-10) to be significantly higher in melanoma patients than in control group, thus confirming the importance of the inflammation in cancer. While CCL3 increased with tumor progression, IFN-γ and IL-10 showed higher levels in stage I patients. Moreover, we noticed a direct correlation between CCL3 level and the presence of ulceration in the primary tumor; on the contrary, CCL4, IL-10 and IFN-γ were lowered down in patients with ulcerated melanoma. CONCLUSIONS: These results expand and confirm observations made in other studies focusing on a more limited number of molecules. This extended panel of cytokines examines the potential roles of type2 cytokines (such as IL-4) and many chemokines (mainly CCL3) as biomarkers in melanoma progression.


Assuntos
Biomarcadores Tumorais/sangue , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Estudos de Casos e Controles , Quimiocina CCL3/sangue , Quimiocina CCL4/sangue , Progressão da Doença , Feminino , Voluntários Saudáveis , Humanos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-4/sangue , Masculino , Melanoma/sangue , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/patologia
20.
Eur Arch Otorhinolaryngol ; 276(12): 3467-3475, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31482332

RESUMO

PURPOSE: The clinical significance of cytokeratin fraction 21-1 (CYFRA 21-1) for patients with head and neck cutaneous squamous cell carcinoma (CSCC) is unknown. Thus, the aim of the study was to evaluate the clinical value of CYFRA 21-1 in the context of treatment and follow-up for these patients. METHODS: The clinical, histological and laboratory data of a total of 55 patients with the first diagnosis of head and neck cutaneous squamous cell carcinoma (T1-T4, N0-N2b, M0-1) between 2003 and 2017 were retrospectively analyzed. In 25 cases, the primary tumor could be treated successfully without residual or recurrent disease in the further course. The average follow-up period was 2.3 years. In all patients, pretherapeutic determination of CYFRA 21-1 was performed using the ECLIA test kit. The cut-off value was set at 3.3 ng/ml. RESULTS: In 18 patients (32.7%), regional recurrence was found in the course of treatment. Distant metastases could be observed in two patients (3.6%). In these cases, no significant increase of CYFRA 21-1 blood concentration was detected at the time of recurrence/metastasis. At the time of the first diagnosis, the mean value of CYFRA 21-1 blood concentration was 2.4 ng/ml; and in cases of regional recurrence or distant metastases, the initial mean CYFRA 21-1 concentration was 2.0 ng/ml. There was no statistically significant relationship between CYFRA 21-1 blood concentration and analyzed tumor characteristics. CONCLUSIONS: According to current knowledge, the tumor marker CYFRA 21-1 is not clinically significant for treatment and follow-up of patients with head and neck CSCC.


Assuntos
Antígenos de Neoplasias/sangue , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Queratina-19/sangue , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Adulto , Assistência ao Convalescente , Idoso , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/sangue , Progressão da Doença , Feminino , Neoplasias de Cabeça e Pescoço/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Retrospectivos , Neoplasias Cutâneas/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue
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