Clinical validation of urine 3-methoxytyramine as a biomarker of neuroblastoma and comparison with other catecholamine-related biomarkers.

Background Urinary dopamine, homovanillic acid and 4-hydroxy-3-methoxymandelic acid are established tests for diagnosis and monitoring of neuroblastic disease. We compared the diagnostic performance of total urinary 3-methoxytyramine, the O-methylated product of dopamine, to these three established tumour markers. Methods Urinary 3-methoxytyramine, dopamine, homovanillic acid and 4-hydroxy-3-methoxymandelic acid were measured by high-performance liquid chromatography with electrochemical detection on consecutive urine samples from histologically proven neuroblastic patients and controls. Patients with neuroblastic disease were further classified as untreated, advancing, residual or absent disease based on clinical and radiological criteria. Receiver operating characteristic curve analysis was used to compare the diagnostic performance of the four tumour markers. Results Urinary 3-methoxytyramine was well correlated with established tumour markers and its concentration correlated with disease activity. It was the most commonly elevated tumour marker in neuroblastic disease and showed similar sensitivity to dopamine and homovanillic acid. The diagnostic utility of urinary 3-methoxytyramine as measured by area under the receiver operating characteristic curve was similar to dopamine and homovanillic acid. Conclusion Our results support the use of urinary 3-methoxytyramine as a tumour marker in the diagnosis and the monitoring of neuroblastoma disease.

Prognostic significance of biochemical heterogeneity of catecholaminergic clones in neuroblastoma.

BACKGROUND/PURPOSE: Genetic heterogeneity of neuroblastic tumors leads to biochemical changes that manifest themselves in different symptoms and clinical courses, which may vary from spontaneous regression and remission to progression with fatal outcome. METHODS: To test the hypothesis that ratios of dopamine (DA) to noradrenaline and of DA to vanillylmandelic acid reflect the composition of adrenergic clones and tumor heterogeneity, we determined urinary DA/noradrenaline and DA/vanillylmandelic acid ratios that presumably reflect DA-beta-hydroxylase (DBH) activity and the prognostic values thereof. RESULTS: Based on catecholamine metabolism, 4 model situations were defined: (a) complete block of DBH in all cells; (b) block of DBH in some cells; (c) a different enzymatic block; and (d) normal DBH activity in the population of tumor-forming cells. Normal DBH activity was encountered most frequently in children younger than 2 years and in tumors representing favorable prognostic stages (I, II, and IVS). Surviving children with stage IV neuroblastoma presented with tumors composed primarily of cells without the DBH block. Further stratification of 2 prognostically poor groups (stages IV and III + IV) was possible with respect to DBH activity. CONCLUSIONS: Differential production of neurotransmitters in a population of tumor cells may be explained in terms of tumor heterogeneity.

Simultaneous analyses of monoamines and their metabolites in urine specimens of patients with neuroblastoma.

1. Tyrosine and tryptophan, as well as 26 metabolites of these amino acids, were analyzed simultaneously in urine specimens from patients with neuroblastoma and control infants by a three-dimensional HPLC system to develop an early diagnosis. 2. Levels of detected compounds in urine from patients with neuroblastoma were generally higher in the case of catecholamines and lower in the case of indolalkylamines than those in controls. 3. The pathways of Dopamine-3,4-Dihydroxyphenylacetic acid-Vanillylmandelic acid, Dopamine-3-Methoxy-4-hydroxyphenylethylene glycol-Vanillylmandelic acid and Tyrosine-4-Hydroxyphenylacetic acid-4 were, in particular, found to be active in patients with neuroblastoma.

Determination of urinary vanillactic acid and plasma dihydroxyphenylalanine as markers of non-secreting neuroblastoma by high-performance liquid chromatography with electrochemical detection.

An accurate and precise isocratic high-performance liquid chromatographic technique for the analysis of urinary vanillactic acid (VLA) and plasma dihydroxyphenylalanine (DOPA), especially at low concentrations (pmol/l) for VLA and nmol/l for DOPA), is described. The compounds were purified in a single step, (on an anion exchanger for VLA and on aluminium oxide for DOPA), separated by ion-pair reversed-phase liquid chromatography, and detected electrochemically. A single analysis was complete within 18 min. Mean recoveries of 103 and 81% were obtained for VLA and DOPA, respectively, and the limits of detection were 42 and 76 pmol/l, respectively. The mean values of the intra-assay coefficient of variation were 14 and 7.1% for VLA and DOPA, respectively, and the mean values of the inter-assay coefficient of variation were 15.7 and 11.6%, respectively. Modifications of the retention times (between 2 and 42 min) induced by changes in the eluent were determined. Reference values for normal children and children with neuroblastoma or various tumours are given.

Quality assurance for biogenic amines with authentic patient specimens.

The measurement of biogenic amines and metabolites is essential for diagnosis and follow-up of neural crest tumors. A Quality Assurance programme involving the distribution of urine specimens obtained from patients with neural crest and related tumors was conducted by the Australian Association of Clinical Biochemists' Working Party on Biogenic Amines in 1988. Fifty laboratories participated in the programme and measured a number of analytes with a variety of methods. These included high performance liquid chromatography with electrochemical detection (HPLC-EC), spectrophotometry, fluorescence, fluorescence polarization immunoassay (Abbott TDX) and gas chromatography--mass spectroscopy (GC-MS). The results of this survey indicated that fluorimetric methods for catecholamines are unreliable as they are subject to interference particularly by Labetalol. Twice as many laboratories utilized catecholamines rather than metanephrines for detection of pheochromocytoma. 5-HIAA appears to be the analyte measured with the least accuracy, particularly with spectrophotometric methods of analysis. Several laboratories would have failed to diagnose some neural crest tumors and need to improve their performance.

Malignant pheochromocytoma (paraganglioma) of the organ of Zuckerkandl: a study of two cases.

Ten percent of pheochromocytomas are found in extra-adrenal locations and are called paragangliomas. In recent years we have had the opportunity to study two patients with malignant paragangliomas of the organ of Zuckerlandl. Only 13 cases of such neoplasms have been reported previously. Our cases are of interest because of their features of recurrence, distant metastases, response to adjuvant therapy, and long survival.