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Application of an LC–MS/MS Method for the Simultaneous Quantification molecules Article Application of an LC–MS/MS Method for the Simultaneous Quantification of Homovanillic Acid and Vanillylmandelic Acid for the Diagnosis and Follow-Up of Neuroblastoma in 357 Patients Narae Hwang 1,† , Eunbin Chong 1,†, Hyeonju Oh 1, Hee Won Cho 2, Ji Won Lee 2 , Ki Woong Sung 2,* and Soo-Youn Lee 1,3,4,* 1 Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; [email protected] (N.H.); [email protected] (E.C.); [email protected] (H.O.) 2 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; [email protected] (H.W.C.); [email protected] (J.W.L.) 3 Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea 4 Department of Health Science and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul 06351, Korea * Correspondence: [email protected] (K.W.S.); [email protected] (S.-Y.L.); Tel.: +82-2-3410-3529 (K.W.S.); Citation: Hwang, N.; Chong, E.; Oh, +82-2-3410-1834 (S.-Y.L.); Fax: +82-2-3410-0043 (K.W.S.); +82-2-3410-2719 (S.Y.L.) H.; Cho, H.W.; Lee, J.W.; Sung, K.W.; † These authors contributed equally to this work. Lee, S.-Y. Application of an LC–MS/MS Method for the Abstract: Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are end-stage metabolites of Simultaneous Quantification of catecholamine and are clinical biomarkers for the diagnosis of neuroblastoma. For the first time Homovanillic Acid and in Korea, we implemented and validated a liquid chromatography tandem mass spectrometry Vanillylmandelic Acid for the (LC–MS/MS) assay to measure urinary concentrations of HVA and VMA according to Clinical and Diagnosis and Follow-Up of Laboratory Standards Institute guidelines. Our LC–MS/MS assay with minimal sample preparation Neuroblastoma in 357 Patients. Molecules 2021, 26, 3470. was validated for linearity, lower limit of detection (LOD), lower limit of quantification (LLOQ), https://doi.org/10.3390/ precision, accuracy, extraction recovery, carryover, matrix effect, and method comparison. A total molecules26113470 of 1209 measurements was performed to measure HVA and VMA in spot urine between October 2019 and September 2020. The relationship between the two urinary markers, HVA and VMA, was Academic Editors: Farid Chemat, analyzed and exhibited high agreement (89.1% agreement, kappa’s k = 0.6) and a strong correlation James Barker and Iltaf Shah (Pearson’s r = 0.73). To our knowledge, this is the first study to utilize LC–MS/MS for simultaneous quantitation of spot urinary HVA and VMA and analyze the clinical application of both markers on a Received: 9 April 2021 large scale for neuroblastoma patients. Accepted: 1 June 2021 Published: 7 June 2021 Keywords: mass spectrometry; validation; vanillylmandelic acid; homovanillic acid; neuroblas- toma; urine Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Neuroblastoma is the most common extracranial solid tumor in children and ac- counts for 7–10% of pediatric malignancies [1]. Neuroblastoma cells synthesize excess catecholamines including norepinephrine, epinephrine, and dopamine [2]. These cells Copyright: © 2021 by the authors. contain small amounts of storage vesicles; hence, storage of synthesized catecholamines Licensee MDPI, Basel, Switzerland. is limited [2]. Therefore, most catecholamines produced by neuroblastoma cells are me- This article is an open access article tabolized to 4-hydroxy-3-methoxyphenylglycol (MHPG) by catechol-O-methyltransferase distributed under the terms and conditions of the Creative Commons (COMT) and monoamine oxidase (MAO) [3]. MHPG secreted by neuroblastoma cells Attribution (CC BY) license (https:// is metabolized to vanillylmandelic acid (VMA) mainly by hepatic alcohol dehydroge- creativecommons.org/licenses/by/ nase [3]. Dopamine is completely metabolized to homovanillic acid (HVA) by COMT and 4.0/). MAO within neuroblastoma cells [4]. These metabolites of catecholamines are produced Molecules 2021, 26, 3470. https://doi.org/10.3390/molecules26113470 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 3470 2 of 10 in relatively large amounts with micromolar concentrations and are mainly excreted in urine, allowing ease of measurement [4]. HVA and VMA serve as useful clinical biomark- ers for diagnosis and follow-up of neuroblastoma [5]. Biochemical detection of urinary HVA and VMA allows diagnosis of neuroblastoma with high sensitivity (66–100%) and specificity (>99%) when the two markers are combined [6,7]. High-performance liquid chromatography coupled with electrochemical detection (HPLC–ECD) has been utilized for quantification of HVA and VMA in urine. The HPLC–ECD method requires a complex sample extraction such as solid-phase or liquid–liquid extraction and has a long data acquisition time (approximately 10 to 20 min) [8]. Recently, an LC–MS/MS method was introduced for the quantification of HVA and VMA. This method allows simple sample preparation procedures, such as the dilute-and-shoot method, and rapid data acquisi- tion (3 to 8 min), which are useful features in a clinical environment, especially when a large number of tests have to be performed. [8–11]. Up to now, HPLC–ECD has been predominantly used in Korea to quantify urinary HVA and VMA. Two laboratories utilize LC–MS/MS to measure urinary VMA, and only our laboratory measures both analytes simultaneously [12]. Since HVA and VMA are both used as biomarkers of neuroblastoma and have similar characteristics, it is more convenient to quantitate both analytes in the same specimen [13]. Clinically, the utility of HVA and VMA quantitation in spot urine is increasing due to the convenience of sample collection. However, to the best of our knowledge, there are no studies regarding the clinical application of urinary HVA and VMA in neuroblastoma patients on a large scale. Herein, we validated an LC–MS/MS method for simultaneous measurement of uri- nary HVA and VMA for diagnosis and follow-up of neuroblastoma patients and analyzed the clinical applications of HVA and VMA using 1209 measurements. 2. Results and Discussion 2.1. Method Validation The total chromatographic run time was 6 min/sample. The calibration curves were linear over 0.5–100 mg/L, with a coefficient of linearity (R2) >0.99 for both HVA and VMA (Table1). The HVA and VMA LLOQ and LOD were 0.5 mg/L and 0.1 mg/L, respectively. Intra-assay CVs (n = 5) were 3.7 and 2.5% for HVA and 1.8 and 1.1% for VMA, respectively; inter-assay CVs (n = 25) were 3.9 and 3.6% for HVA and 4.1 and 3.0% for VMA at low and high concentrations, respectively (Table1). The method showed good accuracy with a bias of −9.1% to 11.3% for HVA and −9.9% to 6.3% for VMA. Extraction recoveries ranged from 97.0% to 107.0% for HVA and 97.0% to 106.0% for VMA. Although an ion suppression effect was observed, the matrix effect bias (%) with IS normalization was acceptable with values from 93.0% to 112.0% for HVA and 97.0% to 110.0% for VMA. No significant carryover effect was observed. Our laboratory previously used HPLC–ECD for measurement of VMA for more than 10 years. Therefore, we performed method comparison between HPLC–ECD and LC–MS/MS and obtained comparable results for urinary concentrations of VMA in 41 urine specimens (r = 0.98, p < 0.0001, Figure S1, Supplementary Materials). There have been several attempts to measure urinary HVA and VMA by LC–MS/MS [8–11]. Most studies used a C18 or C16 column with an acetonitrile or methanol gradient (Table1 and Table S1, Supplementary Materials). Our method development for measurement of HVA and VMA was comparable to those of previous studies in terms of AMR, precision, accuracy, LLOQ, run time, and sample volume. Two studies evaluated matrix effect with post-column infusion and reported no matrix effect in their study [8,9]. Our study used a post-extraction spiking method to evaluate the matrix effect, which used IS to compensate for the possible ion suppression. Recovery was comparable to that in other studies [9,10]. Molecules 2021, 26, 3470 3 of 10 Table 1. Summary of analytical performance of LC–MS/MS methods for quantification of HVA and VMA. Precision Precision Clinical Accuracy Extraction Reference Item LOD (mg/L) LLOQ (mg/L) AMR (mg/L) (Intra-Assay) (Inter-Assay) Matrix Effect Specimen (Bias %) Recovery CV% CV% Number a This study HVA 0.1 0.5 0.5–100.0 2.5–3.7 3.6–3.9 −9.1–11.3 93–112% 97–107% 1209 VMA 0.1 0.5 0.5–100.0 1.1–1.8 3.0–4.1 −9.9–6.3 97–110% 97–106% Clark et al., HVA 0.1 0.5 0.5–100.0 0.8–2.7 1.6–3.8 <15 NA 2017 [8] None * NA VMA 0.2 0.5 0.5–100.0 1.0–2.7 1.9–4.1 <15 NA Shen et al., HVA 0.3 0.1 0.1–182.2 3.7–3.8 2.3–3.8 <13.3 86–100% 2019 [9] None * 19 VMA 0.3 0.1 0.1–99.1 1.4–3.9 2.2–2.9 11.4 85–109% Grouzmann HVA NA 0.1 0.1–36.4 4.0–8.0 4.1–4.7 1.8 NA 100% et al., 2018 [10] NA VMA NA 0.1 0.1–39.6 2.3–2.6 5.1 −3.8 NA 100% Manini et al., HVA 0.03 0.1 0.1–25.0 1.4–3.4 2.6–5.2 2.8–3.9 NA NA 2000 [11] NA VMA 0.07 0.5 0.5–50.0 0.8–1.2 1.1–1.8 2.1–3.3 NA NA Abbreviations: AMR, analytical measurement range; CV, coefficient of variation; HVA, homovanillic acid; LOD, lower limit of detection; LLOQ, lower limit of quantitation; NA, not available; VMA, vanillylmandelic acid; * post-column infusion; a number of samples generated from neuroblastoma patients.
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