RESUMEN
BACKGROUND: Neoadjuvant therapy improves recurrence-free survival (RFS) in resectable stage III cutaneous melanoma. However, accurately predicting individual recurrence risk remains a significant challenge. We investigated circulating tumour DNA (ctDNA) as a biomarker for recurrence in measurable stage IIIB/C melanoma patients undergoing neoadjuvant immunotherapy. METHODS: Plasma samples were collected pre-neoadjuvant treatment, pre-surgery and/or six weeks post-surgery from 40 patients enrolled in the OpACIN-neo and PRADO clinical trials. Patients received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before surgery. Cell free DNA (cfDNA) underwent unbiased pre-amplification followed by tumour-informed mutation detection using droplet digital polymerase chain reaction (ddPCR) with the Bio-Rad QX600 PCR system. RESULTS: Pre-treatment ctDNA was detectable in 19/40 (48%) patients. Among these, 17/19 (89%) zero-converted within six weeks of surgery and none recurred. Positive ctDNA post-surgery (N = 4), irrespective of pre-treatment ctDNA status, was 100% predictive of recurrence (sensitivity 44%, specificity 100%). Furthermore, ctDNA cleared prior to surgery in 7/9 (78%) patients who did not recur, warranting further investigation into ctDNA-guided surgical management. CONCLUSION: Post-surgery ctDNA positivity and zero-conversion are highly predictive of recurrence, offering a window for personalised modification of adjuvant therapy.
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ADN Tumoral Circulante , Inmunoterapia , Melanoma , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Humanos , Melanoma/terapia , Melanoma/sangre , Melanoma/patología , Melanoma/genética , Melanoma/tratamiento farmacológico , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Terapia Neoadyuvante/métodos , Masculino , Femenino , Persona de Mediana Edad , Inmunoterapia/métodos , Anciano , Adulto , Biomarcadores de Tumor/sangre , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genéticaRESUMEN
This study addresses the diagnostic and therapeutic challenges in malignant melanoma (MM) and non-melanoma skin cancers (NMSC). We aim to identify circulating proteins causally linked to MM and NMSC traits using a multicenter Mendelian randomization (MR) framework. We utilized large-scale cis-MR to estimate the impact of numerous plasma proteins on MM, NMSC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). To ensure robustness, additional analyses like MR Steiger and Bayesian colocalization are conducted, followed by replication through meta-analytical methods. The associations between identified proteins and outcomes are also validated at the tissue level using Transcriptome-Wide Association Study methods. Furthermore, a protein-protein interaction analysis is conducted to explore the relationship between identified proteins and existing cancer medication targets. The MR analysis has identified associations of 13 plasma proteins with BCC, 2 with SCC, and 1 with MM. Specifically, ASIP and KRT5 are associated with BCC, with ASIP also potentially targeting MM. CTSS and TNFSF8 are identified as promising druggability candidates for BCC. This multidimensional approach nominates ASIP, KRT5, CTSS, and TNFSF8 as potential diagnostic and therapeutic targets for skin cancers.
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Proteínas Sanguíneas , Melanoma , Análisis de la Aleatorización Mendeliana , Proteoma , Neoplasias Cutáneas , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/metabolismo , Humanos , Melanoma/genética , Melanoma/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/sangre , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Estudio de Asociación del Genoma CompletoRESUMEN
Malignant melanoma (MM) is known for its abundance of genetic alterations and a tendency for rapid metastasizing. Identification of novel plasma biomarkers may enhance non-invasive diagnostics and disease monitoring. Initially, we examined copy number variations (CNV) in CDK genes (CDKN2A, CDKN2B, CDK4) using MLPA (gDNA) and ddPCR (ctDNA) analysis. Subsequently, low-coverage whole genome sequencing (lcWGS) was used to identify the most common CNV in plasma samples, followed by ddPCR verification of chosen biomarkers. CNV alterations in CDK genes were identified in 33.3% of FFPE samples (Clark IV, V only). Detection of the same genes in MM plasma showed no significance, neither compared to healthy plasmas nor between pre- versus post-surgery plasma. Sequencing data showed the most common CNV occurring in 6q27, 4p16.1, 10p15.3, 10q22.3, 13q34, 18q23, 20q11.21-q13.12 and 22q13.33. CNV in four chosen genes (KIF25, E2F1, DIP2C and TFG) were verified by ddPCR using 2 models of interpretation. Model 1 was concordant with lcWGS results in 54% of samples, for model 2 it was 46%. Although CDK genes have not been proven to be suitable CNV liquid biopsy biomarkers, lcWGS defined the most frequently affected chromosomal regions by CNV. Among chosen genes, DIP2C demonstrated a potential for further analysis.
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Biomarcadores de Tumor , Variaciones en el Número de Copia de ADN , Melanoma , Humanos , Melanoma/genética , Melanoma/patología , Melanoma/diagnóstico , Biopsia Líquida/métodos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/sangre , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/genética , Anciano de 80 o más Años , Secuenciación Completa del Genoma/métodos , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genéticaRESUMEN
Background: Circulating metabolites, which play a crucial role in our health, have been reported to be disordered in basal cell carcinoma (BCC). Despite these findings, evidence is still lacking to determine whether these metabolites directly promote or prevent BCC's progression. Therefore, our study aims to examine the potential effects of circulating metabolites on BCC progression. Material and methods: We conducted a two-sample Mendelian randomization (MR) analysis using data from two separate genome-wide association studies (GWAS). The primary study included data for 123 blood metabolites from a GWAS with 25,000 Finnish individuals, while the secondary study had data for 249 blood metabolites from a GWAS with 114,000 UK Biobank participants.GWAS data for BCC were obtained from the UK Biobank for the primary analysis and the FinnGen consortium for the secondary analysis. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Results: In the primary analysis, significant causal relationships were found between six metabolic traits and BCC with the inverse variance weighted (IVW) method after multiple testing [P < 4 × 10-4 (0.05/123)]. Four metabolic traits were discovered to be significantly linked with BCC in the secondary analysis, with a significance level of P < 2 × 10-4 (0.05/249). We found that all the significant traits are linked to Polyunsaturated Fatty Acids (PUFAs) and their degree of unsaturation. Conclusion: Our research has revealed a direct link between the susceptibility of BCC and Polyunsaturated Fatty Acids and their degree of unsaturation. This discovery implies screening and prevention of BCC.
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Carcinoma Basocelular , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Neoplasias Cutáneas , Humanos , Carcinoma Basocelular/sangre , Carcinoma Basocelular/genética , Carcinoma Basocelular/epidemiología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/epidemiología , Polimorfismo de Nucleótido Simple , Femenino , Masculino , Predisposición Genética a la Enfermedad , Factores de Riesgo , Finlandia/epidemiologíaRESUMEN
Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma (CTCL) with its etiology not yet fully understood. Interleukin (IL)-35 is an inhibitory cytokine that belongs to the IL-12 family. Elevated IL-35 in the plasma and the tumor microenvironment increases tumorigenesis and indicates poor prognosis in different types of malignancies. The objective of this study is to estimate the expression levels of IL-35 in tissue and serum of MF patients versus healthy controls. This case-control study included 35 patients with patch, plaque, and tumor MF as well as 30 healthy controls. Patients were fully assessed, and serum samples and lesional skin biopsies were taken prior to starting treatment. The IL-35 levels were measured in both serum and tissue biopsies by ELISA technique. Both tissue and serum IL-35 levels were significantly higher in MF patients than in controls (P < 0.001) and tissue IL-35 was significantly higher than serum IL-35 in MF patients (P < 0.001). Tissue IL-35 was significantly higher in female patients and patients with recurrent MF compared to male patients and those without recurrent disease (P < 0.001). Since both tissue and serum IL-35 levels are increased in MF, IL-35 is suggested to have a possible role in MF pathogenesis. IL-35 can be a useful diagnostic marker for MF. Tissue IL-35 can also be an indicator of disease recurrence.
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Interleucinas , Micosis Fungoide , Neoplasias Cutáneas , Humanos , Micosis Fungoide/sangre , Micosis Fungoide/diagnóstico , Micosis Fungoide/patología , Interleucinas/sangre , Interleucinas/metabolismo , Femenino , Masculino , Estudios de Casos y Controles , Persona de Mediana Edad , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Adulto , Piel/patología , Piel/metabolismo , Anciano , Biopsia , Biomarcadores de Tumor/sangreRESUMEN
In patients with resected non-metastatic melanoma, the liquid biopsy for the assessment of molecular residual disease (MRD) by circulating tumour DNA (ctDNA) represents a promising tool to stratify the risk and to monitor tumour evolution. However, its validation requires the demonstration of analytical validity, clinical validity and utility. Indeed, the development of sensitive and specific assays can optimize prognostication and eventually help clinicians to modulate adjuvant treatments, in order to improve clinical outcomes. Data about ctDNA-guided prognosis stratification is emerging, but clinical trials assessing ctDNA-guided therapeutic decisions are still ongoing. This review aims to depict the role of ctDNA-based MRD assessment in patients with non-metastatic melanoma and to provide a roadmap to face challenges for its introduction into clinical practice.
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ADN Tumoral Circulante , Melanoma , Neoplasia Residual , Humanos , Melanoma/genética , Melanoma/sangre , Melanoma/patología , Neoplasia Residual/diagnóstico , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Pronóstico , Biopsia Líquida/métodos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patologíaRESUMEN
Comparison of the 2007 EORTC/ISCL and the 2022 EORTC/ISCL/USCLC blood staging guidelines for cutaneous T-cell lymphoma at a single institution reveals the newer guidelines fail to detect a subset of patients with Sézary syndrome with low blood burden.
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Linfoma Cutáneo de Células T , Estadificación de Neoplasias , Síndrome de Sézary , Neoplasias Cutáneas , Humanos , Síndrome de Sézary/patología , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/sangre , Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/sangre , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Guías de Práctica Clínica como AsuntoRESUMEN
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cancer with often poor outcomes. Limited biomarkers exist for predicting clinical outcomes. The Merkel cell polyomavirus (MCPyV) serum antibody test (AMERK) has shown potential for indicating better recurrence-free survival in a single-institution study. The study aimed to evaluate the link between initial AMERK serostatus and survival. Secondary objectives included examining the relationship between initial AMERK titer levels and tumor burden. METHODS: A retrospective cohort study across two institutions analyzed patients tested with AMERK within 90 days of MCC diagnosis. Regression models assessed the association of survival outcomes with serostatus, considering various factors. The relationship between AMERK titer and tumor burden indicators was evaluated using ANOVA. Significance testing was exploratory, without a fixed significance level. RESULTS: Of 261 MCC patients tested, 49.4% were initially seropositive (titer ≥75). Multivariable analysis showed that seropositivity improved recurrence, event-free, overall, and MCC-specific survival rates. Strong associations were found between initial AMERK titer and clinical, tumor, and nodal stages, tumor size, and disease extent. Notably, improved survival with seropositivity was observed only in patients with localized disease at initial presentation. CONCLUSION: Circulating antibodies to MCPyV oncoproteins, as indicated by the AMERK test, are linked with better survival in MCC patients with localized disease at presentation. This could enhance patient risk profiling and treatment personalization. The study's retrospective nature and exploratory analysis are key limitations. PLAIN LANGUAGE SUMMARY: Merkel cell carcinoma (MCC) is a potentially aggressive skin cancer, and tools to predict patient outcomes are limited. A blood test called anti-Merkel cell panel (AMERK), which checks for specific antibodies related to this cancer, might give us some clues. In this study, we looked at 261 MCC patients who took the AMERK test within 90 days of diagnosis. We found that patients with an initial positive AMERK result tended to have better outcomes, especially if their cancer was in the early stages. However, it is important to note that this study has limitations, including using retrospective data and exploratory analyses.
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Anticuerpos Antivirales , Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Neoplasias Cutáneas , Humanos , Carcinoma de Células de Merkel/virología , Carcinoma de Células de Merkel/sangre , Carcinoma de Células de Merkel/mortalidad , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/inmunología , Poliomavirus de Células de Merkel/inmunología , Poliomavirus de Células de Merkel/aislamiento & purificación , Femenino , Masculino , Estudios Retrospectivos , Anciano , Pronóstico , Persona de Mediana Edad , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/virología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Anticuerpos Antivirales/sangre , Anciano de 80 o más Años , Infecciones Tumorales por Virus/virología , Infecciones por Polyomavirus/sangre , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/inmunologíaRESUMEN
INTRODUCTION: Age-related differences in the safety profile of cemiplimab for patients with locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) have not been well described. We investigated the association of increasing age with immune related adverse events (irAE) from cemiplimab, efficacy outcomes, and the prognostic significance of pre-treatment blood biomarkers in contemporary practice. MATERIALS AND METHODS: Patients starting first-line cemiplimab for locally advanced or metastatic cSCC at British Columbia Cancer between April 2019 and January 2023 were identified. Landmark four-month logistic regression analysis compared the odds of developing irAE or sequelae amongst patients aged <75 years to those aged 75-84 or ≥ 85. Objective responses were determined using Response Evaluation Criteria in Solid Tumors version 1.1. Univariable Cox proportional hazard (PH) regression modelling of factors associated with overall survival (OS) was performed. RESULTS: Of 106 patients, the proportions aged <75, 75-84, and ≥ 85 years were 34%, 45%, and 21%, respectively. Overall, the proportion of patients with irAE ≥ grade 3, cemiplimab discontinuation, and hospitalization for immune toxicity was 27.4%, 31.1%, and 11.3%, respectively. There was no clear association between age and the odds of high grade irAE. However, increased odds of cemiplimab discontinuation was observed in patients aged 75-84 years (p = 0.05). Patients ≥85 years had increased hospitalizations due to irAE (OR = 5.00, 95% CI = 0.97-37.52) with two treatment-related deaths. Objective responses were similar across age cohorts (50.0%, 60.4%, and 54.5%) but progressive disease was higher in the age ≥ 85 group (22.2%, 18.8%, and 31.8%). On Cox PH regression analysis, age ≥ 85 years (vs. <75), Eastern Cooperative Oncology Group performance status 2-3 (vs. 0-1), and neutrophil to lymphocyte ratio (NLR) ≥7.80 (vs. <7.80) were associated with shorter survival. DISCUSSION: While the odds of high grade irAE were similar across age groups, significant age-related differences in treatment discontinuation and hospitalization due to immune toxicity were observed. Despite a higher incidence of primary progression and shorter OS in the oldest cohort, cemiplimab yielded robust objective responses regardless of age. Higher pre-treatment NLR was associated with shorter survival and the cut-point identified requires further study.
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Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos , Carcinoma de Células Escamosas , Neoplasias Cutáneas , Humanos , Anciano , Anciano de 80 o más Años , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/sangre , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/sangre , Factores de Edad , Pronóstico , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Biomarcadores de Tumor/sangre , Colombia Británica , Estudios Retrospectivos , Persona de Mediana EdadRESUMEN
BACKGROUND: Especially in the era of successful systemic therapy, there is an urgent need to detect early disease recurrence in stage III melanoma patients. This study investigates if serum S100 calcium-binding protein B (S100B) can detect disease recurrence in stage III melanoma patients. METHODS: A retrospective cohort study was conducted at the University Medical Center Groningen (UMCG). Adult AJCC 8th stage III melanoma patients in whom serum S100B was measured as part of follow-up from January 2010 until April 2023 were included. The association between serum S100B and disease recurrence was evaluated using standard definitions for sensitivity and positive predictive value (PPV). RESULTS: Overall, 147 patients were included (mean age was 60.4 years, 53.1 % were female). Most patients were classified as stage IIIB (39, 26.5 %) and IIIC (73, 49.7 %). During median follow-up of 56 months, 69 (46.9 %) patients experienced disease recurrence. Seventeen out of 18 patients with elevated serum S100B (≥0.15 µg/L) experienced disease recurrence (PPV of 94.4 %). However, 52 out of 69 patients with disease recurrence had normal serum S100B (sensitivity of 24.6 %). Eight out of 17 (47.1 %) patients were asymptomatic (P = 0.608), twelve (70.6 %) patients had at least four distant metastases (P < 0.001). CONCLUSION: The clinical value of serum S100B to detect disease recurrence in stage III melanoma patients is negligible since only one out of four patients with disease recurrence have elevated serum S100B. Furthermore, half of stage III melanoma patients with elevated S100B experienced symptoms, and most patients already have multiple distant metastases.
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Biomarcadores de Tumor , Melanoma , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Subunidad beta de la Proteína de Unión al Calcio S100 , Neoplasias Cutáneas , Humanos , Melanoma/sangre , Melanoma/patología , Melanoma/diagnóstico , Subunidad beta de la Proteína de Unión al Calcio S100/sangre , Femenino , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Estudios Retrospectivos , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patología , Biomarcadores de Tumor/sangre , Anciano , Adulto , Valor Predictivo de las PruebasRESUMEN
We aimed to unveil the underlying pathogenic mechanisms of skin cancer in relation to metabolic factors and pathway mechanisms. This study utilized the TwoSample Mendelian randomization (MR) method to investigate the causal relationship between 1400 plasma metabolites and skin cancer. The primary method employed was the inverse variance weighting (IVW). Through IVW analysis, we found 105 plasma metabolites associated with Basal Cell Carcinoma (BCC), with the highest association observed for Prolylglycine levels (OR [95% CI]: 1.1902 [1.0274, 1.3788]). For Malignant Melanoma of Skin (MSS), 68 plasma metabolites were linked, with the highest causal relationship seen for 3-Hydroxybutyrate levels (OR [95% CI]: 1.0030 [1.0013, 1.0048]). Regarding actinic keratosis (AK), and the highest association observed for Hexadecadienoate (16:2n6) levels (OR [95% CI]: 1.3302 [1.0333, 1.7125]). Glycerol to palmitoylcarnitine (16: n6) levels (OR [95% CI]: 1.3302 [1.0333, 1.125]) were found to be significant for BCC and AK. Palmitoylcarnitine (C16) had the most positive causal effect for BCC (OR [95% CI]: 1.1777 [1.0493, 1.3218]), while 5-hydroxy-2-methylpyridine sulfate levels had the highest effect for AK (OR [95% CI]: 1.1788 [1.0295, 1.3498]). And 4-guanidinobutanoate levels had the largest positive causal effect (OR [95% CI]: 1.0857 [1.0417, 1.1317]) for BCC, and X-11880 levels for MSS (OR [95% CI]: 1.0013 [1.0000, 1.0025]). The study revealed a positive association between hereditary Glycerol to palmitoylcarnitine (C16) and 5-hydroxy-2-methylpyridine sulfate levels with the risk of developing BCC and AK. Additionally, 4-guanidinobutanoate levels and X 11880 levels were found to be positively associated with the risk of BCC and MMS.
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Carcinoma Basocelular , Análisis de la Aleatorización Mendeliana , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/epidemiología , Carcinoma Basocelular/sangre , Carcinoma Basocelular/genética , Carcinoma Basocelular/epidemiología , Melanoma/sangre , Melanoma/genética , Melanoma/epidemiología , Queratosis Actínica/sangre , Queratosis Actínica/genética , Ácido 3-Hidroxibutírico/sangre , Predisposición Genética a la Enfermedad , Melanoma Cutáneo MalignoRESUMEN
The aim of this study was to apply a state-of-the-art quantitative lipidomic profiling platform to uncover lipid alterations predictive of melanoma progression. Our study included 151 melanoma patients; of these, 83 were without metastasis and 68 with metastases. Plasma samples were analyzed using a targeted Lipidyzer™ platform, covering 13 lipid classes and over 1100 lipid species. Following quality control filters, 802 lipid species were included in the subsequent analyses. Total plasma lipid contents were significantly reduced in patients with metastasis. Specifically, levels of two out of the thirteen lipid classes (free fatty acids (FFAs) and lactosylceramides (LCERs)) were significantly decreased in patients with metastasis. Three lipids (CE(12:0), FFA(24:1), and TAG47:2-FA16:1) were identified as more effective predictors of melanoma metastasis than the well-known markers LDH and S100B. Furthermore, the predictive value substantially improved upon combining the lipid markers. We observed an increase in the cumulative levels of five lysophosphatidylcholines (LPC(16:0); LPC(18:0); LPC(18:1); LPC(18:2); LPC(20:4)), each individually associated with an elevated risk of lymph node metastasis but not cutaneous or distant metastasis. Additionally, seventeen lipid molecules were linked to patient survival, four of which (CE(12:0), CE(14:0), CE(15:0), SM(14:0)) overlapped with the lipid panel predicting metastasis. This study represents the first comprehensive investigation of the plasma lipidome of melanoma patients to date. Our findings suggest that plasma lipid profiles may serve as important biomarkers for predicting clinical outcomes of melanoma patients, including the presence of metastasis, and may also serve as indicators of patient survival.
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Lipidómica , Lípidos , Melanoma , Humanos , Melanoma/sangre , Melanoma/patología , Masculino , Femenino , Persona de Mediana Edad , Lípidos/sangre , Lipidómica/métodos , Anciano , Biomarcadores de Tumor/sangre , Adulto , Metástasis de la Neoplasia , Metástasis Linfática , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patologíaRESUMEN
The prognostic value of the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio in patients with melanoma has yielded controversial results in the literature. A retrospective single-centre cohort study was conducted from 1998 to 2020, including patients diagnosed with invasive melanoma. A total of 2,721 patients were included in the study. The median follow-up was 8.23 years (IQR 4.41-13.25). The median baseline neutrophil- lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio values increased significantly (p < 0.001) with the increasing American Joint Committee on Cancer stage. The optimal cut-off values for neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio were determined as 2.1, 184 and 0.2, respectively. In the multivariate analysis, high levels of neutrophil-lymphocyte ratio (≥ 2.1), platelet-lymphocyte ratio (≥ 184) and monocyte-lymphocyte ratio (≥ 0.2) were independently associated with significantly shorter melanoma-specific survival (neutrophil-lymphocyte ratio: HR 1.30, 95% CI 1.06-1.60, p = 0.013; platelet-lymphocyte ratio: HR 1.37, 95% CI 1.06-1.76, p = 0.014; monocyte- lymphocyte ratio: HR 1.29, 95% CI 1.05-1.58, p = 0.015) and overall survival (neutrophil-lymphocyte ratio: HR 1.39, 95% CI 1.19-1.64, p < 0.001; platelet- lymphocyte ratio: HR 1.44, 95% CI 1.19-1.74, p < 0.001; monocyte-lymphocyte ratio: HR 1.42, 95% CI 1.21-1.66, p < 0.001). High levels of neutrophil- lymphocyte ratio and monocyte-lymphocyte ratio were also associated with poor relapse-free survival, while platelet-lymphocyte ratio was not. In conclusion, baseline neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio were identified as independent predictors for the prognosis of melanoma.
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Linfocitos , Melanoma , Monocitos , Neutrófilos , Neoplasias Cutáneas , Humanos , Melanoma/sangre , Melanoma/mortalidad , Melanoma/patología , Melanoma/inmunología , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/inmunología , Pronóstico , Recuento de Linfocitos , Recuento de Plaquetas , Plaquetas/patología , Anciano , Adulto , Valor Predictivo de las Pruebas , Recuento de Leucocitos , Estadificación de Neoplasias , Factores de TiempoAsunto(s)
Carcinoma de Células Escamosas , ADN Tumoral Circulante , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/diagnóstico , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Estadificación de Neoplasias , Biomarcadores de Tumor/sangreRESUMEN
BACKGROUND: The treatment of melanoma has been revolutionized by the use of immune checkpoint inhibition (ICI), but many patients do not benefit. Furthermore, immune-related adverse events may occur during therapy. A predictive biomarker is needed to reliably identify patients benefitting. In lung, renal cell and bladder cancer early C-reactive protein (CRP) kinetics were shown to be a predictive biomarker for ICI. OBJECTIVE: Here, we investigate early CRP kinetics as predictive biomarker for ICI in melanoma patients. METHODS: Two independent prospectively collected cohorts were analysed: Cohort 1 (n = 87) with advanced and Cohort 2 (n = 99) with completely resected melanoma. Patients were stratified by in the dynamics of CRP after ICI initiation: A doubling of baseline CRP within 30 days followed by at least a 30% drop within 3 months was classified as a CRP flare. If no doubling of CRP was reported, but a 30% drop within 3 months, patients were classified as CRP responders and all others as CRP non-responders. Analysed factors included clinical characteristics like S100B and LDH. Median follow-up was 1.5 and 1.7 years for Cohorts 1 and 2. RESULTS: In Cohort 1 CRP flare (n = 12), CRP responders (n = 43) and CRP non-responders (n = 32) with a progression-free survival (PFS) of 0.7, 0.6 and 0.2 years (p = 0.017) and an overall survival (OS) of 2.2, 1.5 and 1.0 years (p = 0.014), respectively. Multivariable Cox analysis showed an independent risk reduction of progression for CRP responders by 62% compared to CRP non-responders (p = 0.001). In Cohort 2 CRP flare (n = 13), CRP responders (n = 70) and CRP non-responders (n = 16) the log-rank analysis showed a significant difference between OS and recurrence-free survival (RFS) curves (p = 0.046 and p = 0.049). CONCLUSION: Early CRP kinetics could indicate a response to ICI with improved OS and RFS/PFS. CRP flare and CRP response indicating significantly improved outcomes compared to CRP non-responders.
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Proteína C-Reactiva , Inhibidores de Puntos de Control Inmunológico , Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Melanoma/sangre , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Masculino , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Persona de Mediana Edad , Anciano , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/sangre , Adulto , Estudios Prospectivos , Biomarcadores de Tumor/sangre , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Cutaneous melanoma (CM) has long been recognized as a lethal form of cancer. Despite persistent research endeavors, the precise underlying pathological mechanisms remain largely unclear, and the optimal treatment for this patient population remains undetermined. OBJECTIVES: This study aims to examine the causal associations between CM and 486 metabolites. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted to ascertain the causal relationship between blood metabolites and CM. The causality analysis involved the inverse variance weighted (IVW) method, followed by the MR-Egger and weighted median (WM) methods. To increase the robustness of our findings, several sensitivity analyses, including the MR-Egger intercept, Cochran's Q test, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were performed. The robustness of our results was further validated in independent outcome samples followed by a meta-analysis. Additionally, a metabolic pathway analysis was carried out. RESULTS: The two-sample MR analysis yielded a total of 27 metabolites as potential causal metabolites. After incorporating the outcomes of the sensitivity analyses, seven causal metabolites remained. Palmitoylcarnitine (OR 0.9903 95% CI 0.9848-0.9958, p = 0.0005) emerged as the sole metabolite with a significant causality after Bonferroni correction. Furthermore, the reverse MR analysis provided no evidence of reverse causality from CM to the identified metabolites. CONCLUSIONS: This study suggested a causal relationship between seven human blood metabolites and the development of CM, thereby offering novel insights into the underlying mechanisms involved. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Asunto(s)
Melanoma , Análisis de la Aleatorización Mendeliana , Neoplasias Cutáneas , Humanos , Melanoma/genética , Melanoma/sangre , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/sangre , Melanoma Cutáneo Maligno , Femenino , Medición de RiesgoRESUMEN
Immune checkpoint inhibitors (ICIs) bring prognostic benefits to patients with malignancies. However, there is a substantial number of patients whose lesions are not improved by ICIs. In addition, ICIs may cause immune-related adverse events (irAEs), which could lead to an unfavorable prognosis with fatal consequences. Therefore, we conducted a retrospective study to evaluate the utility of circulating sPD-L1 (soluble programmed cell death 1 ligand 1) as a biomarker in patients with advanced melanoma treated with anti-PD-1 (programmed cell death 1 protein) antibodies. Sera from 31 consecutive patients were prospectively collected before and after anti-PD-1 antibody treatment and the serum level of sPD-L1 was evaluated. We found that high sPD-L1 levels before treatment were associated with better prognosis, and this association was observed only in patients with a low tumor burden. We also found that sPD-L1 levels were elevated in patients who developed severe irAEs after treatment, and the patients with severe irAEs had significantly higher fluctuations in sPD-L1 (delta sPD-L1) than those without severe irAEs. Our study suggests that serum sPD-L1 level is a useful biomarker to predict tumor response and irAE development in patients with advanced melanoma treated with anti-PD-1 antibodies.
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Antígeno B7-H1 , Biomarcadores de Tumor , Inhibidores de Puntos de Control Inmunológico , Melanoma , Receptor de Muerte Celular Programada 1 , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Melanoma/sangre , Melanoma/inmunología , Masculino , Femenino , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/sangre , Antígeno B7-H1/inmunología , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Anciano , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Estudios Retrospectivos , Biomarcadores de Tumor/sangre , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/sangre , Adulto , Anciano de 80 o más Años , Pronóstico , Resultado del Tratamiento , Carga TumoralRESUMEN
Background Vitamin D deficiency associates with the risk of developing many diseases, including cancer. At the molecular level, vitamin D appears to have an antineoplastic effect. However, the role of vitamin D deficiency in cancer pathogenesis remains unelucidated and numerous studies have resulted in discordant results. This study aimed to determine whether vitamin D deficiency during melanoma diagnosis increases the risk of developing non-cutaneous second primary cancers (SPC). Materials and methods A retrospective study on 663 patients diagnosed with melanoma between 1 January 2011 and 31 October 2022. The effect of each variable on the development of a subsequent non-cutaneous cancer was performed using KaplanMeier curves and differences were assessed by log-rank tests. Cox proportional hazard univariate and multivariate models were used to quantify the effect of each variable in the time to develop a non-cutaneous neoplasia. Results Out of 663 patients, 34 developed a non-cutaneous SPC. There was no statistically significant association between vitamin D levels and non-cutaneous SPC development (log-rank, p=0.761). Age>60 years, stage III/IV, and nodular melanoma subtype were significantly associated with the development of a SPC. After multivariate analysis, only age>60 years (HR 3.4; HR CI 95%: 1.57.6) and nodular melanoma subtype (HR 2.2; HR CI 95%: 1.04.8) were included in the final model. Conclusions Our results suggest that vitamin D deficiency is not associated with an increased risk of developing non-cutaneous SPC in melanoma patients. However, age over 60 years and nodular melanoma subtype increase the risk for non-cutaneous SPC development (AU)
Antecedentes El déficit de vitamina D se asocia con un mayor riesgo de padecer varias enfermedades, incluido el cáncer. Molecularmente, esta parece tener un efecto antineoplásico. Sin embargo, el papel que juega en la patogénesis del cáncer no está bien esclarecido y hay resultados dispares en los estudios publicados. El objetivo del presente fue determinar si unos niveles de vitamina D deficientes en el momento del diagnóstico del melanoma aumentaba el riesgo de desarrollar un cáncer no cutáneo (CNC). Material y método Se diseñó un estudio retrospectivo de 663 pacientes diagnosticados de melanoma entre el 1 de enero de 2011 y el 31 de octubre de 2022. El efecto de cada una de las variables seleccionadas en el desarrollo de un CNC durante el seguimiento tras el diagnóstico del melanoma se realizó mediante el estudio de supervivencia con el método de Kaplan-Meier y las diferencias se evaluaron con la prueba de los rangos logarítmicos. Se elaboraron modelos uni y multivariados de riesgos proporcionales de Cox para cuantificar el efecto de cada valor de las variables de estudio en el tiempo para desarrollar un CNC. Resultados De los 663 pacientes, 34 desarrollaron un CNC tras el melanoma. No hubo diferencias estadísticamente significativas entre los grupos definidos por los niveles de vitamina D (log-rank, p = 0,761). Sin embargo, una edad > 60, el estadio III/IV, y el tipo nodular se asociaron significativamente al desarrollo de un CNC. Tras el análisis multivariado, solo la edad > 60 (hazard ratio [HR] 3,4; intervalo de confianza [IC] 95% HR:1,5-7,6) y el subtipo nodular de melanoma (HR 2,2; IC 95% HR:1,0-4,8) se mantuvieron en el modelo predictivo final. Conclusiones Nuestros resultados sugieren que unos niveles de vitamina D deficientes en el diagnóstico de melanoma no se asocian a un mayor riesgo de desarrollar un CNC. Sin embargo, en una edad > 60 y el subtipo nodular sí que aumentan el riesgo de desarrollar un CNC (AU)
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patología , Melanoma/sangre , Melanoma/patología , Vitamina D/sangre , Estudios Retrospectivos , Estudios Longitudinales , Factores de RiesgoRESUMEN
Antecedentes El déficit de vitamina D se asocia con un mayor riesgo de padecer varias enfermedades, incluido el cáncer. Molecularmente, esta parece tener un efecto antineoplásico. Sin embargo, el papel que juega en la patogénesis del cáncer no está bien esclarecido y hay resultados dispares en los estudios publicados. El objetivo del presente fue determinar si unos niveles de vitamina D deficientes en el momento del diagnóstico del melanoma aumentaba el riesgo de desarrollar un cáncer no cutáneo (CNC). Material y método Se diseñó un estudio retrospectivo de 663 pacientes diagnosticados de melanoma entre el 1 de enero de 2011 y el 31 de octubre de 2022. El efecto de cada una de las variables seleccionadas en el desarrollo de un CNC durante el seguimiento tras el diagnóstico del melanoma se realizó mediante el estudio de supervivencia con el método de Kaplan-Meier y las diferencias se evaluaron con la prueba de los rangos logarítmicos. Se elaboraron modelos uni y multivariados de riesgos proporcionales de Cox para cuantificar el efecto de cada valor de las variables de estudio en el tiempo para desarrollar un CNC. Resultados De los 663 pacientes, 34 desarrollaron un CNC tras el melanoma. No hubo diferencias estadísticamente significativas entre los grupos definidos por los niveles de vitamina D (log-rank, p = 0,761). Sin embargo, una edad > 60, el estadio III/IV, y el tipo nodular se asociaron significativamente al desarrollo de un CNC. Tras el análisis multivariado, solo la edad > 60 (hazard ratio [HR] 3,4; intervalo de confianza [IC] 95% HR:1,5-7,6) y el subtipo nodular de melanoma (HR 2,2; IC 95% HR:1,0-4,8) se mantuvieron en el modelo predictivo final. Conclusiones Nuestros resultados sugieren que unos niveles de vitamina D deficientes en el diagnóstico de melanoma no se asocian a un mayor riesgo de desarrollar un CNC. Sin embargo, en una edad > 60 y el subtipo nodular sí que aumentan el riesgo de desarrollar un CNC (AU)
Background Vitamin D deficiency associates with the risk of developing many diseases, including cancer. At the molecular level, vitamin D appears to have an antineoplastic effect. However, the role of vitamin D deficiency in cancer pathogenesis remains unelucidated and numerous studies have resulted in discordant results. This study aimed to determine whether vitamin D deficiency during melanoma diagnosis increases the risk of developing non-cutaneous second primary cancers (SPC). Materials and methods A retrospective study on 663 patients diagnosed with melanoma between 1 January 2011 and 31 October 2022. The effect of each variable on the development of a subsequent non-cutaneous cancer was performed using KaplanMeier curves and differences were assessed by log-rank tests. Cox proportional hazard univariate and multivariate models were used to quantify the effect of each variable in the time to develop a non-cutaneous neoplasia. Results Out of 663 patients, 34 developed a non-cutaneous SPC. There was no statistically significant association between vitamin D levels and non-cutaneous SPC development (log-rank, p=0.761). Age>60 years, stage III/IV, and nodular melanoma subtype were significantly associated with the development of a SPC. After multivariate analysis, only age>60 years (HR 3.4; HR CI 95%: 1.57.6) and nodular melanoma subtype (HR 2.2; HR CI 95%: 1.04.8) were included in the final model. Conclusions Our results suggest that vitamin D deficiency is not associated with an increased risk of developing non-cutaneous SPC in melanoma patients. However, age over 60 years and nodular melanoma subtype increase the risk for non-cutaneous SPC development (AU)
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/patología , Melanoma/sangre , Melanoma/patología , Vitamina D/sangre , Estudios Retrospectivos , Estudios Longitudinales , Factores de RiesgoRESUMEN
Elevated neutrophil-to-lymphocyte ratio (NLR) is associated with diminished immunotherapy response in metastatic melanoma. Although NLR assessment in peripheral blood is established, tissue dynamics remain insufficiently explored. This study aimed to evaluate tissue NLR (tNLR)'s predictive potential through immunohistochemistry in immunotherapy-treated melanoma. Fifty melanoma patients who underwent anti-programmed cell death 1 (PD-1) therapy were assessed. Hematological, clinical and tumor features were collected from medical records. Responses were categorized using the Response Evaluation Criteria in Solid Tumors for immunotherapy (iRECIST) guidelines. Immunohistochemistry for tumor-infiltrating T cells (cluster differentiation 3) and neutrophils (myeloperoxidase) was performed on formalin-fixed paraffin-embedded tumor samples. NLR, derived NLR (dNLR) and tNLR were calculated. Overall survival (OS) and survival following immunotherapy (SFI) were calculated from diagnosis or immunotherapy start to loss of follow-up or death. Patients with high tNLR presented improved OS ( Pâ =â 0.038) and SFI with anti-PD-1 therapy ( Pâ =â 0.006). Both NLR and dNLR were associated with OS ( Pâ =â 0.038 and Pâ =â 0.046, respectively) and SFI ( Pâ =â 0.001 and Pâ =â 0.019, respectively). NLR was also associated with immunotherapy response ( Pâ =â 0.007). In conclusion, tNLR emerged as a novel potential biomarker of enhanced survival post anti-PD-1 therapy, in contrast to classical NLR and dNLR markers.