Optimising urinary catecholamine metabolite diagnostics for neuroblastoma

INTRODUCTION: The analysis of urinary catecholamine metabolites is a cornerstone of neuroblastoma diagnostics. Currently, there is no consensus regarding the sampling method, and variable combinations of catecholamine metabolites are being used. We investigated if spot urine samples can be reliably used for analysis of a panel of catecholamine metabolites for the diagnosis of neuroblastoma. METHODS: Twenty-four-hour urine or spot urine samples were collected from patients with and without neuroblastoma at diagnosis. Homovanillic acid (HVA), vanillylmandelic acid (VMA), dopamine, 3-methoxytyramine, norepinephrine, normetanephrine, epinephrine and metanephrine were measured by high-performance liquid chromatography coupled with fluorescence detection (HPLC-FD) and/or ultra-performance liquid chromatography coupled with electrospray tandem mass spectrometry (UPLC-MS/MS). RESULTS: Catecholamine metabolite levels were measured in urine samples of 400 neuroblastoma patients (24-hour urine, n = 234; spot urine, n = 166) and 571 controls (all spot urine). Excretion levels of catecholamine metabolites and the diagnostic sensitivity for each metabolite were similar in 24-hour urine and spot urine samples (p > .08 and >.27 for all metabolites). The area under the receiver-operating-characteristic curve (AUC) of the panel containing all eight catecholamine metabolites was significantly higher compared to that of only HVA and VMA (AUC = 0.952 vs. 0.920, p = .02). No differences were observed in metabolite levels between the two analysis methods. CONCLUSION: Catecholamine metabolites in spot urine and 24-hour urine resulted in similar diagnostic sensitivities. The Catecholamine Working Group recommends the implementation of spot urine as standard of care. The panel of eight catecholamine metabolites has superior diagnostic accuracy over VMA and HVA

Catecholamine metabolites in neuroblastoma patients

Neuroblastoma is a paediatric malignancy of the developing sympathetic nervous system that is characterised by increased production and excretion of catecholamine metabolites such as homovanillic acid (HVA) and vanillylmandelic acid (VMA). Catecholamine metabolites are mainly applied as diagnostics biomarkers for neuroblastoma, other application such as prognosis prediction have rarely been evaluated. In this study, we performed an in-depth analysis of the diagnostic sensitivity of eight urinary catecholamine metabolites [HVA, VMA, dopamine, 3-methoxytyramine, norepinephrine, normetanephrine, epinephrine and metanephrine] and their correlation with clinical factors in a cohort of 301 patients. We studied catecholamine excretion patterns, both in vitro and in vivo, and elucidated their underlying biology. Finally, we evaluated the use catecholamine metabolites as prognostic biomarkers. Our data show that analysis of the panel of eight catecholamine metabolites improves diagnostics sensitivity, enables identification of clinical subgroups and assists in risk assessment of patients with neuroblastoma, thus can improve clinical care for patients with neuroblastoma

Catecholamine metabolites in neuroblastoma patients

Neuroblastoma is a paediatric malignancy of the developing sympathetic nervous system that is characterised by increased production and excretion of catecholamine metabolites such as homovanillic acid (HVA) and vanillylmandelic acid (VMA). Catecholamine metabolites are mainly applied as diagnostics biomarkers for neuroblastoma, other application such as prognosis prediction have rarely been evaluated. In this study, we performed an in-depth analysis of the diagnostic sensitivity of eight urinary catecholamine metabolites [HVA, VMA, dopamine, 3-methoxytyramine, norepinephrine, normetanephrine, epinephrine and metanephrine] and their correlation with clinical factors in a cohort of 301 patients. We studied catecholamine excretion patterns, both in vitro and in vivo, and elucidated their underlying biology. Finally, we evaluated the use catecholamine metabolites as prognostic biomarkers. Our data show that analysis of the panel of eight catecholamine metabolites improves diagnostics sensitivity, enables identification of clinical subgroups and assists in risk assessment of patients with neuroblastoma, thus can improve clinical care for patients with neuroblastoma

Catecholamine Metabolites, Clinical Outcome and A New Insight into Risk Stratification of Patients with Neuroblastoma

Development and application of statistical models for medical scientific researc

Catecholamine Metabolites, Clinical Outcome and A New Insight into Risk Stratification of Patients with Neuroblastoma

Analysis and Stochastic

Catecholamines Profiles at Diagnosis: Increased Diagnostic Sensitivity and Correlation with Biological and Clinical Features in Neuroblastoma Patients

Development and application of statistical models for medical scientific researc

3-Methoxytyramine: An independent prognostic biomarker that associates with high-risk disease and poor clinical outcome in neuroblastoma patients

Development and application of statistical models for medical scientific researc

Urinary 3-Methoxytyramine is a biomarker for MYC activity in patients with neuroblastoma

PURPOSE Elevated urinary 3-methoxytyramine (3MT) level at diagnosis was recently put forward as independent risk factor for poor prognosis in neuroblastoma. Here, we investigated the biologic basis underlying the putative association between elevated 3MT levels and poor prognosis.METHODS Urinary 3MT levels and prognosis were investigated in both retrospective Italian (N = 90) and prospective Dutch (N = 95) cohorts. From the Dutch Cancer Oncology Group cohort (N = 122), patients with available urinary 3MT and gene expression data (n = 90) were used to generate a 3MT gene signature. The 3MT gene signature score was then used to predict survival outcome in the Children's Oncology Group (N = 247) and German Pediatric Oncology Group (N = 498) cohorts and compared with other known gene signatures. Immunohistochemistry of MYCN and dopamine beta-hydroxylase proteins was performed on primary tumors.RESULTS Elevated urinary 3MT levels were associated with poor prognosis in a retrospective cohort and a prospective cohort. Moreover, elevated urinary 3MT levels were associated with eight differentially expressed genes, providing a 3MT gene signature that successfully predicted poor clinical outcome. Even among low-risk patients, high 3MT signature score was associated with poor 5-year overall survival (72% v 99% among low-risk patients with a low 3MT signature score), and the 3MT signature score was correlated with MYC activity in the tumor (R = 82%, P < .0001). Finally, a strong MYCN and weak dopamine beta-hydroxylase staining of tumors derived from patients with elevated urinary 3MT levels was observed, linking MYC activity in the tumor to both catecholamine biosynthesis and elevated urinary 3MT levels.CONCLUSION Elevated urinary 3MT is a promising biomarker for poor prognosis and reflects increased MYC activity in the tumor. Therefore, urinary 3MT levels should be measured at diagnosis and may assist in assessing risk. (C) 2022 by American Society of Clinical OncologyAnalysis and Stochastic

Urinary 3-Methoxytyramine is a biomarker for MYC activity in patients with neuroblastoma

PURPOSE Elevated urinary 3-methoxytyramine (3MT) level at diagnosis was recently put forward as independent risk factor for poor prognosis in neuroblastoma. Here, we investigated the biologic basis underlying the putative association between elevated 3MT levels and poor prognosis.METHODS Urinary 3MT levels and prognosis were investigated in both retrospective Italian (N = 90) and prospective Dutch (N = 95) cohorts. From the Dutch Cancer Oncology Group cohort (N = 122), patients with available urinary 3MT and gene expression data (n = 90) were used to generate a 3MT gene signature. The 3MT gene signature score was then used to predict survival outcome in the Children's Oncology Group (N = 247) and German Pediatric Oncology Group (N = 498) cohorts and compared with other known gene signatures. Immunohistochemistry of MYCN and dopamine beta-hydroxylase proteins was performed on primary tumors.RESULTS Elevated urinary 3MT levels were associated with poor prognosis in a retrospective cohort and a prospective cohort. Moreover, elevated urinary 3MT levels were associated with eight differentially expressed genes, providing a 3MT gene signature that successfully predicted poor clinical outcome. Even among low-risk patients, high 3MT signature score was associated with poor 5-year overall survival (72% v 99% among low-risk patients with a low 3MT signature score), and the 3MT signature score was correlated with MYC activity in the tumor (R = 82%, P < .0001). Finally, a strong MYCN and weak dopamine beta-hydroxylase staining of tumors derived from patients with elevated urinary 3MT levels was observed, linking MYC activity in the tumor to both catecholamine biosynthesis and elevated urinary 3MT levels.CONCLUSION Elevated urinary 3MT is a promising biomarker for poor prognosis and reflects increased MYC activity in the tumor. Therefore, urinary 3MT levels should be measured at diagnosis and may assist in assessing risk. (C) 2022 by American Society of Clinical Oncolog