DOPA Metabolism in Neuroblastoma

Blood plasma samples from 60 neuroblastoma patients prior to, during, and following treatment were studied for their content of circulating DOPA using a radioenzymatic assay. Normal values were established from children who were tumor-free or had other nonneurogenic tumors. The highest plasma DOPA concentration in tumor-free or nonneuroblastoma controls was 5.3 ng/ml with a mean of 2.15 ng/ml. Most neuroblastoma patients (28/31) with active disease had DOPA values above this level. Only one out of 30 “successfully” treated patients without evidence of disease was encountered with an abnormally high level. In treated patients, elevated values forewarned of impending clinical recurrence or persistent tumor. Cerebrospinal fluid DOPA levels in one patient with cerebral neuroblastoma were extraordinarily high and suggests that this assay may prove useful to distinguish neuroblastoma from other central neuroectodermal or metastatic tumors. Plasma DOPA appears to be a reliable predictive and diagnostic test for neuroblastoma.     

Bilateral pheochromocytoma. Is there stimulation of an extra-adrenal adrenaline liberation after bilateral adrenalectomy?]

BACKGROUND: In order to determine plasma and urine epinephrine levels after bilateral adrenalectomy, we examined a 16 year old young man with bilateral pheochromocytoma. Bilateral removal of the adrenals was performed because of a left sided pheochromocytoma relapse. An extra-adrenal pheochromocytoma could be excluded by scintigraphy. Macroscopically all adrenal tissue was removed during surgery. METHODS: A modified radioenzymatic determination of the free catecholamines epinephrine, norepinephrine and dopamine was used according to Peuler and Johnson. Sulfoconjugated catecholamines were measured after addition of 60 microU arylsulfatase type VI. Urine catecholamine levels were determined fluorometrically. RESULTS: The elevated plasma andurine norepinephrine levels before surgery returned to normal after surgery. In contrast, plasma epinephrine levels returned to subnormal values thereafter but increases 5-fold at the end of anesthesia suggesting an extra-adrenal source of epinephrine. Urine epinephrine levels remained in the lower normal range. An insulin induced hypoglycemia was performed resulting in adrenergic symptoms of hypoglycemia and a subnormal increase of epinephrine. CONCLUSIONS: We conclude, that epinephrine mediated physiological regulations occur inspite of bilateral adrenalectomy probably by a regulated extra-adrenal source of epinephrine. The kidney could be the site of extra-adrenal epinephrine production.     

Inhibition of catecholamine biosynthesis by carbidopa and metyrosine in neuroblastoma

In three patients with neuroblastoma and high circulating levels of dopamine and dopa, we interfered pharmacologically with catecholamine biosynthesis either at the tyrosine hydroxylase or dopa decarboxylase step in an attempt to 1) improve the efficacy of antitumor therapy and 2) avoid the potential arrythmogenic interaction between elevated circulating catecholamines and an halogenated hydrocarbon anesthetic during surgery. Biochemical evidence indicated that inhibition of catecholamine biosynthesis had occurred but there was no associated significant change in clinical status or response to other therapy.     

Methylated catecholamine metabolites for diagnosis of neuroblastoma

Assays of urinary catecholamines and their metabolites (HVA, VMA, dopamine) permit biochemical diagnosis of neuroblastoma in approximately 80% of patients. The urinary methylated catecholamine metabolites normetanephrine (NMN), metanephrine (MN), and 3-methoxytyramine (3-MT) were analyzed in 18 patients with neuroblastoma and compared with reference values established for 69 healthy pediatric controls. All 18 neuroblastoma patients had raised urinary excretion of at least one of the three commonly assayed metabolites (HVA, VMA, dopamine). Similarly, raised urinary excretion of a methylated metabolite was noted in all but one of the neuroblastoma patients. The 3-MT level was pathologic in 16 of the 18 patients (89%). In this series, 3-MT assay sensitivity was sufficient to warrant trials on a larger population including comparison with patients considered nonsecretors by routine assay procedures. © 1992 Wiley-Liss, Inc.     

Methylated catecholamine metabolites for diagnosis of neuroblastoma.

Assays of urinary catecholamines and their metabolites (HVA, VMA, dopamine) permit biochemical diagnosis of neuroblastoma in approximately 80% of patients. The urinary methylated catecholamine metabolites normetanephrine (NMN), metanephrine (MN), and 3-methoxytyramine (3-MT) were analyzed in 18 patients with neuroblastoma and compared with reference values established for 69 healthy pediatric controls. All 18 neuroblastoma patients had raised urinary excretion of at least one of the three commonly assayed metabolites (HVA, VMA, dopamine). Similarly, raised urinary excretion of a methylated metabolite was noted in all but one of the neuroblastoma patients. The 3-MT level was pathologic in 16 of the 18 patients (89%). In this series, 3-MT assay sensitivity was sufficient to warrant trials on a larger population including comparison with patients considered nonsecretors by routine assay procedures.     

Plasma and urinary catecholamines in patients with cystic fibrosis

In 43 patients with cystic fibrosis (age 8-23 yr, 26 boys and 17 girls) attending a summer camp in a mountain rehabilitation center and in 25 parents (heterozygotes) plasma epinephrine, norepinephrine, dopamine and plasma activity of dopamine-beta-hydroxylase were determined as well as the 24-h excretion of the free urinary amines (epinephrine, norepinephrine, dopamine), their O-methylated products (metanephrine, normetanephrine, 3-methoxytyramine) and the urinary phenolic acids (vanilmandelic and homovanillic). Also the metabolic breakdown product of serotonin in urine, the 5-hydroxyindoleacetic acid, was determined. Significantly elevated plasma dopamine (0.03-0.45 nmol/liter for controls versus 1.70-2.21 nmol/liter for cystic fibrosis) and slightly higher plasma norepinephrine levels were found in patients with cystic fibrosis. An increased 5-hydroxyindoleacetic acid excretion was noticed in adolescent patients which correlated with the disease state and the extent of lung involvement. No abnormalities of plasma amine levels were seen in the parents of the patients. Despite controversial results, CF patients seem to have an alteration in catecholamine metabolism which is reflected in higher plasma dopamine levels.     

Neuropeptide Y as a marker in pediatric neuroblastoma

Neuropeptide Y (NPY) was investigated as a possible tumor marker in pediatric patients with tumors of the sympathetic nervous system. Seven patients with neuroblastoma, 3 patients with ganglioneuroblastoma, and 2 with ganglioneuroma, were compared with 12 matched healthy controls and 34 tumor controls. NPY-like immunoreactivity (NPYLI) was analyzed in extracted plasma using a competitive radioimmunoassay. At diagnosis, plasma NPYLI was significantly increased (p less than .001) in the neuroblastoma patients (352 +/- 99 pM; mean +/- SEM) when compared with healthy controls (36 +/- 4 pM) and tumor controls (30 +/- 2 pM). Ganglioneuroblastoma and ganglioneuroma patients had lower levels (57 +/- 8 pM) than neuroblastoma patients but still significantly higher than the controls. In all patients with sympathetic tumors, the NPYLI level was decreased after treatment. Five neuroblastoma patients relapsed; all had increasing NPYLI levels. In 3 of these patients, incresing NPYLI was the first sign of relapse. Plasma NPYLI correlated well to urinary levels of homovanillic acid. NPY in plasma (NPYLI) may be a clinically useful marker of pediatric neuroblastoma for diagnosis and differential diagnosis. NPYLI correlates well with the clinical course and can be the first sign of relapse. Plasma determinations of NPYLI make it possible to monitor rapid alterations of disease.     

Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients

BACKGROUND: Urinary catecholamine metabolites are well-known to be elevated in patients with neuroblastoma. Some investigators have described different patterns in favorable and unfavorable cases. However, extended studies have not been published. PROCEDURE: We investigated urinary catecholamine patterns and their correlation to stage, biological features, and outcome in 114 consecutively clinically diagnosed neuroblastoma patients. RESULTS: Sensitivity of vanillylmandelic acid (VMA), homovanillic acid (HVA), and dopamine (DA) was 80.7, 71.9, and 61.3%, respectively. In 91.2% of patients at least one parameter was above normal. High VMA levels were associated with favorable biological features, high DA levels were predominantly found in biologically unfavorable disease. Whereas patients with normal HVA levels had a significant better outcome, the other parameters showed no significant association with prognosis. For disseminated neuroblastoma of infancy, DA/VMA ratio proved to be helpful for the discrimination of stage 4 versus stage 4s. CONCLUSION: Urinary catecholamines appear to be useful to give a first but important hint about the biological behavior and thus the prognosis of the underlying disease. Particularly DA/VMA ratio may serve as a tool for "biological grading"-especially in disseminated disease of infancy. In addition, it may be speculated that HVA negativity and low DA/VMA ratio may be helpful for the decision of a "wait and see" strategy in selected neuroblastoma patients with localized disease.     

Effect of diet on urinary excretion of VMA, HVA, metanephrine, and total free catecholamine in normal preschool children.

Quantitation of the urinary metabolites of catecholamines, including VMA, HVA, and metanephrines, from six normal preschool children was performed during a normal diet, a restricted diet, and a diet with increased amounts of vanilla, vanillin, and phenolic acids. Ingestion of these substances has been suspected of producing elevated values of urinary catecholamines and their metabolites. Urine was collected on the fourth day of each diet in two consecutive 12-hour aliquots, beginning at 8:00 AM. Statistically significant diurnal variation in excretion of all three metabolites and total free catecholamines (epinephrine, norepinephrine, and dopamine) was demonstrated. Diet did not alter exceretion of total free catecholamines or any of the three metabolites. This study suggests that a three-day restricted diet is not necessary prior to screening children for neuroblastoma when using quantitative assay methods and that all screening tests should be performed on a 24-hour urine sample.     

Urinary Catecholamines and Their Metabolites in Management of Neuroblastoma

Measurements of urinary total catecholamines expressed as dopamine (TC) and their metabolites, total metadrenalines (TM) and 3-methoxy-4-hydroxy mandelic acid (HMMA) were made on 24-h urine collections from 56 previously untreated children with neuroblastoma. All results were expressed as a ratio to the creatinine excretion and were compared with “smoothed” age-related reference ranges derived from results in 704 children with other illnesses. Urinary catecholamines/metabolites excretion was elevated in 55 of the 56 patients, the exception being a baby with opsomyoclonus. TC was raised in 47, HMMA in 41, and TM in 37. Eleven patients had elevations of one parameter (TC in 10, HMMA in 1), 15 had 2 elevated levels, and 29 had elevations of all three. The TM level was the least contributory, as in no patient was it the only parameter elevated. Serial measurements were performed in 40 children, and the results correlated closely with the clinical progress of the disease and in some children permitted early detection of recurrence.     

Transient elevation of urinary catecholamine excretion and cholestatic liver disease in a neonate with hypopituitarism.

Hypothalamic hypopituitarism was diagnosed in a 3-month-old boy presenting with cholestatic liver disease, which resolved 5 weeks after the start of replacement therapy with hydrocortisone and human growth hormone. Clinical and pathohistological features of liver disease associated with neonatal hypopituitarism in this patient are compared to those of patients reviewed from the literature. Urinary excretion of dopa and 3-methoxytyramine but not of other catecholamine metabolites was elevated during cholestatic liver disease. 3-Methoxytyramine excretion normalized when cholestasis resolved. Altered hepatic metabolism of catecholamines due to growth hormone and cortisol deficiency may explain this observation.     

Update on basic research and clinical experience with metaiodobenzylguanidine

I 131-metaiodobenzylguanidine (MIBG) is an aralkylguanidine with certain structural similarities to norepinephrine (NE). It is concentrated, stored, and released from chromaffin granules in a manner almost identical with that of NE. It will image the enlarged adrenal medullae of adrenal medullary hyperplasia when the CAT and NMR scans are normal. It is more sensitive in detecting extra-adrenal pheochromocytomas than CAT and NMR imaging. Because 46% of our 176 patients with histopathologically proved "benign" pheochromocytomas (pheos) have developed demonstrable metastases, with or without elevated plasma and urinary catecholamines, we now image all patients with "benign" pheos yearly. As of January 22, 1986 we had treated 28 patients with malignant pheos 71 times with MIBG. As of July 24, 1986, we had given 34 neuroblastoma patients 55 tracer doses. In some cases MIBG demonstrates more neuroblastoma than all other imaging modalities and this is helpful in staging. We have had 30-50% objective regressions in neuroblastoma tumor mass in 3 out of the first 12 patients treated. These three patients had slower-growing tumors and a lower body burden than the nonresponders. We also record the sensitivity of MIBG imaging of neuroendocrine tumors other than pheos and neuroblastomas.     

Dopaminergic Instability in Children with Orthostatic Dysregulation

Effects of postural change on plasma catecholamine levels were examined in 53 children with orthostatic dysregulation (OD). Special interest was focused on plasma dopamine and dopamine-β-hydroxylase (DBH) activity, since one patient showed a prominent rise in plasma dopamine from 822 pmol/L to 126 nmol/L in postural change. She had a wide fluctuation of plasma dopamine from 209 pmol/L to 305 nmol/L during 12 hours of observation period, but plasma norepinephrine and epinephrine remained within the normal range as well as urinary excretion of catecholamines. Of 52 children with OD, 11 had a marked increase in plasma dopamine, whereas 11 showed a reduction of it by postural change. Plasma DBH activity was significantly decreased in the former (81±14 nmol/h/ml), while it was elevated in the latter (320±48 nmol/h/ml, P<0.001 vs the former), although DBH activity in individuals was not affected by postural change. These results indicate the involvement of dopaminergic instability as a cause of OD in childhood.     

The value of catecholamine metabolite determination on untimed urine collections in the diagnosis of neural creast tumours in children

Abstract There is still controversy regarding the relative merits of catecholamine metabolite estimations on 24 h versus untimed urine collections. The former has the advantage of taking into account diurnal variation in the rate of metabolite excretion but has the disadvantages of delaying results and of being affected by errors in collection. In this study percentile values were established for a reference population of 181 children for urinary 4-hydroxy-3-methoxyphenylacetic acid (HVA) creatinine and 163 children for 4-hydroxy-3-methoxymandelic acid (VMA)/creatinine, using untimed urine collections. Results of similar determinations performed as part of the diagnostic work up of 23 consecutive children subsequently proven to have neural crest tumours showed that all patients had the value of at least one metabolite concentration at or above the highest reference value. In neuroblastoma all patients' VMA/creatinine exceeded the highest reference value and in neural crest tumors overall, this ratio was greater than the highest reference value in 96% of patients. These results are as good as, or better than, previously published results and demonstrate the practical value of using catecholamine metabolite determinations expressed as 'creatinine equivalents' on untimed urine specimens in the diagnosis of neuroblastoma and related tumours in children.     

The value of catecholamine metabolite determination on untimed urine collections in the diagnosis of neural crest tumours in children

There is still controversy regarding the relative merits of catecholamine metabolite estimations on 24 h versus untimed urine collections. The former has the advantage of taking into account diurnal variation in the rate of metabolite excretion but has the disadvantages of delaying results and of being affected by errors in collection. In this study percentile values were established for a reference population of 181 children for urinary 4-hydroxy-3-methoxyphenylacetic acid (HVA)/creatinine and 163 children for 4-hydroxy-3-methoxymandelic acid (VMA)/creatinine, using untimed urine collections. Results of similar determinations performed as part of the diagnostic work up of 23 consecutive children subsequently proven to have neural crest tumours showed that all patients had the value of at least one metabolite concentration at or above the highest reference value. In neuroblastoma all patients' VMA/creatinine exceeded the highest reference value and in neural crest tumours overall, this ratio was greater than the highest reference value in 96% of patients. These results are as good as, or better than, previously published results and demonstrate the practical value of using catecholamine metabolite determinations expressed as 'creatinine equivalents' on untimed urine specimens in the diagnosis of neuroblastoma and related tumours in children.     

Serum ferritin in stage IV neuroblastoma

Serum ferritin is known to be one of the tumor markers for neuroblastoma. Serum ferritin is elevated in most children with neuroblastoma who are in stages III or IV, but it is not elevated in those in stage I or II. It has also been observed that iron load caused by blood transfusion shows a greater effect on serum ferritin levels than tumor activity due to neuroblastoma. Thus, serum ferritin increases in a linear fashion in children given repeated blood transfusions but the levels increase exponentially in children who have bulky neuroblastomas. Thus, serum ferritin values must be interpreted with caution in patients with advanced stages of neuroblastoma who inevitably require blood transfusions. The authors propose that the pretransfusion and posttransfusion serum ferritin values be in comparison with other tumor markers such as urinary VMA, urinary HVA, and neuron specific enolase. The serum ferritin level should not be used as a sole indicator of tumor activity in neuroblastoma.     

Development of hypertension in neuroblastoma during therapy: A case report

A case of stage 4 neuroblastoma that developed excessive hypertension on day 120 of chemotherapy is presented. The tumor initially had responded well to chemotherapy; however, while the tumor mass decreased, plasma and urine catecholamines and the blood pressure increased. The plasma concentrations of noradrenaline, adrenaline, and dopamine increased to 26.4, 1.8, and 36.2 μg/l, respectively. The profile of catecholamine metabolites changed: on day 150 of therapy, noradrenaline, adrenaline, and dopamine levels were increased, whereas HVA and VMA levels were decreased when compared to day 1 of therapy. The only residual neuroblastoma tissue visible on MIBG scintigraphy on day 150 of treatment was a metastasis in the left tibia which was irradiated with 24 Gy. The adrenaline concentration in the left femoral vein was twice as high compared to the right femoral vein. A treatment, possibly radiation-associated tumor cell alteration resulting in a different catecholamine production, is discussed. © 1993 Wiley-Liss, Inc.     

Population-based and controlled study to evaluate neuroblastoma screening at one year of age in Germany: interim results

BACKGROUND: The German Neuroblastoma Screening Project is the first controlled and population-based screening study to evaluate the presumed benefit of neuroblastoma mass screening at 1 year of age (10-18 months). PROCEDURE: Screening takes place in 6 of the 16 German states; children from the remainder serve as controls. The German Childhood Cancer Registry enables a mostly complete follow-up and detection of false-negative patients. RESULTS: Up to December, 1999, 1,199,165 children were examined for urinary catecholamine metabolites and 124 cases of neuroblastoma were detected preclinically, giving a detection rate of 10.3/100,000. Within this cohort, 33 false-negative cases were found. CONCLUSIONS: The results of this screening program will be crucial for further implementation of neuroblastoma screening.     

Evaluation of catecholamine metabolites, mIBG scan, and bone marrow cytology as response markers in stage 4 neuroblastoma

BACKGROUND: The early biological response has been proved an excellent predictor in acute lymphoblastic leukemia and nephroblastoma. We asked whether catecholamine metabolites, mIBG scan, and bone marrow evaluation might be relevant response markers in disseminated neuroblastoma. PROCEDURE: Three hundred sixty-seven unselected stage 4 neuroblastoma patients treated according the German cooperative trial NB90 were entered into the study. Catecholamine plasma and urine levels were centrally determined by gas chromatography/ mass spectrometry. Bone marrow cytology and mIBG scans were evaluated by local investigators. RESULTS: At diagnosis, mIBG scan was positive in 306 patients (92%), borderline in seven patients (2%), and negative in 19 patients (6%). Bone marrow aspirates were cytologically positive in 292 patients (84%) and negative in 57 patients (16%). Plasma catecholamine levels were elevated in 79% (206 of 260 patients.), urinary levels in 91% (307 of 338 patients). The outcome of patients with normalized mIBG scan after four courses of chemotherapy [5 year EFS (event free survival) 0.22 +/- 0.07] was not superior to the outcome of patients with still abnormal uptake (5 year EFS 0.30 +/- 0.05). The event free survival of patients with still positive bone marrow aspirates after four courses (0.16 +/- 0.06) was inferior to the EFS of patients with negative bone marrow aspirates (0.26 +/- 0.04, P = 0.0054). Urinary catecholamine normalization after four cycles of chemotherapy (5 year EFS 0.35 +/- 0.06 versus 0.26 +/- 0.10) had no influence on outcome, whereas plasma catecholamine normalization after the first (5 year EFS 0.40 +/- 0.09 versus 0.14 +/- 0.07, P= 0.0364) or the fourth cycle (5 year EFS 0.35 +/- 0.06 versus 0.26 +/- 0.10, P = 0.0242) indicated a better outcome. CONCLUSIONS: These data show that serial plasma catecholamine levels and bone marrow aspirates in the course of the disease are useful tools in predicting outcome.     

MIBG in neuroblastoma diagnosis and treatment

Neuroblastoma is a heterogenous disease, with solid tumors arising in the adrenal gland or paraspinal regions in young children. Neuroblastoma is unique, with varied presentation and prognosis based on primary location and tumor stage. Tumor behavior and response to treatment ranges from spontaneous regression to disseminated, lethal disease depending on the individual biology of a patient’s tumor. Stratification of the disease has changed, with patients now placed in low, intermediate, and high-risk categories depending on age, stage, and tumor biology. Long-term survival for the high-risk subset of patients with metastatic disease is <40% despite aggressive multimodal therapy. Derived from sympathoadrenal cells of the adrenal medulla and sympathetic nervous system, both malignant neuroblastoma and differentiated tumors have specialized norepinephrine transporter (NET) receptors which are naturally occurring in the sympathetic nervous system throughout the body. Metaiodobenzylguanidine (MIBG) is a norepinephrine analog that undergoes active uptake by NET receptors resulting in accumulation in neuroblastoma as well as tissues normally expressing the NET receptor. When radioiodine labeled, MIBG can be used for both diagnosis and treatment. This article describes the history of MIBG use in neuroblastoma, including its utility as an imaging modality for diagnosis as well as the varied ways in which is it included in the multimodal treatment algorithm.