Mass screening for neuroblastoma in infants.

Neuroblastoma (NB) is the only pediatric tumor that is screened for nationwide by detecting the urinary levels of homovanillic acid and/or vanillylmandelic acid; however, whether NB screening reduces the mortality rate has not been established. This review compared the incidence and mortality rates among data from international mass screening for NB, as well as an analysis of differences in age of screening, detection methods, and diagnostic biomarkers. A well-designed trial exploring possible benefits and hazards is warranted prior to resuming mass screening for NB.

Is Preoperative Biochemical Testing for Pheochromocytoma Necessary for All Adrenal Incidentalomas?

This study examined whether imaging phenotypes obtained from computed tomography (CT) can replace biochemical tests to exclude pheochromocytoma among adrenal incidentalomas (AIs) in the preoperative setting.We retrospectively reviewed the medical records of all patients (n = 251) who were admitted for operations and underwent adrenal-protocol CT for an incidentally discovered adrenal mass from January 2011 to December 2012. Various imaging phenotypes were assessed for their screening power for pheochromocytoma. Final diagnosis was confirmed by biopsy, biochemical tests, and follow-up CT.Pheochromocytomas showed similar imaging phenotypes as malignancies, but were significantly different from adenomas. Unenhanced attenuation values ≤10 Hounsfield units (HU) showed the highest specificity (97%) for excluding pheochromocytoma as a single phenotype. A combination of size ≤3 cm, unenhanced attenuation values ≤ 10 HU, and absence of suspicious morphology showed 100% specificity for excluding pheochromocytoma.Routine noncontrast CT can be used as a screening tool for pheochromocytoma by combining 3 imaging phenotypes: size ≤3 cm, unenhanced attenuation values ≤10 HU, and absence of suspicious morphology, and may substitute for biochemical testing in the preoperative setting.

Retrospective study of neuroblastoma in Chinese neonates from 1994 to 2011: an evaluation of diagnosis, treatments, and prognosis : a 10-year restrospective study of neonatal neuroblastoma.

PURPOSE: The purpose of the study is to review the clinical features, treatments, and outcomes of neonatal neuroblastoma (NB). METHODS: A retrospective analysis was performed on 42 patients with NB between January 1994 and December 2011. RESULTS: MYCN amplification was detected in nine tumor samples. The ratio of unfavorable histology to favorable histology was 1:2 in NB patients. The 5-year overall survival (OS) of NB patients was 85.7 %. The 5-year OS in patients in the operation group was 83.3 %, chemotherapy group was 83.3 %, and the "wait-and-see" group was 100 % (P = 0.04). Overall, the prognosis was favorable, except in patients with elevated MYCN amplification or vanillylmandelic acid. CONCLUSIONS: NB patients were more sensitive and vulnerable to chemotherapy and operation. The "wait-and-see" strategy should be highlighted in the treatment of NB.

[Biological diagnosis of pheochromocytomas and paragangliomas]. / Diagnostic biologique des phéochromocytomes et paragangliomes.

Pheochromocytomas and/or paragangliomas are rare, heterogeneous tumors of the chromaffin cells. Thirty percent of the patients presented with these diseases in a hereditary context. The biological diagnosis relies on the identification of excessive secretion of the metanephrines which are more sensitive and specific than those of catecholamines The published recommendations give the opportunity to choose between the free metanephrines and the fractionated metanephrines in sera or urines. The concentrations of the free plasmatic metanephrines reflect the ongoing production of tumor. They are little sensitive to the renal failure. The assay of the vanillylmandelic acid should be dropped because of its inefficiency. The assay of the chromogranin A in serum should be used in association with those of metanephrines in the diagnosis but also in the follow-up. Its role still has to be precised.

The use of enzyme immunoassays for the detection of abzymatic activities. Application to an enantioselective thioacetal hydrolysis activity.

Relying on the particularly high specificity displayed by antibodies, enzyme immunoassays have proved to be one of the most efficient tools for early detection of the catalytic activities displayed by antibodies. We took advantage of such an assay, namely the Cat-enzyme-linked immunoassay (EIA) approach developed in our laboratories, both to exhibit and characterise an antibody-catalysed thioacetal hydrolysis. Monoclonal antibody (mAb) H3-32 was thus identified to accelerate the hydrolysis reaction of thioacetal substrate (NC9) to vanillylmandelic acid (VMA), with a k(cat) of 0.148 h(-1) (k(uncat) = 6.85 x 10(-5) h(-1)), and a K(M) of 720 microM. Taking advantage of the enantiomeric discrimination between (R)- and (S)-VMA displayed by some of the anti-H3 monoclonal antibodies, we were also able to determine that (S)-VMA was preferentially formed during this abzymatic hydrolysis with a 47% enantiomeric excess. All these EIA measurements were confirmed through HPLC analyses.

Induction of catecholamine synthesis in human neuroblastoma cells by replication inhibitors and sodium butyrate.

Various inhibitors of DNA synthesis induced neurite extension in human neuroblastoma cells. In order to clarify morphology-function relationship in differentiation of neuroblastoma cells, the effect of the replication inhibitors on inducibility of catecholamine synthesis was examined. The reagents alone did not affect production of dopamine and noradrenaline, but joint administration of each inhibitor and sodium butyrate considerably promoted the catecholamine synthesis, without additional change in neurite profile. Although inactive in neurite extension, sodium butyrate was moderately active in catecholamine production. The promoting effect of thymidine (or hydroxyurea) and sodium butyrate was repealed by alpha-amanitin, actinomycin D or cycloheximide.

[Effects of aluminum on neurobehavioral function and metabolism of monoamine neurotransmitter].

OBJECTIVE: To evaluate the effects of occupational exposure to aluminum on neurobahavioral function and metabolism of monoamine neurotransmitter. METHODS: Thirty-three workers exposed to aluminum and 40 controls were studied. Air aluminum concentrations in workplace environment were detected with an atomic absorption spectrophotometer, homovanillic acid (HVA) and vanilylmandellic acid (VMA) in urine and aluminum in serum and urine were detected with high perfolmance liquid chromatography. Neurobehavioral function was tested with Neurobehavioral Core Test Battery recommended by WHO. RESULTS: Geometric time-weighted average of aluminum in workplace environment was 0.95 mg/m3, ranging from 0.31 to 4.12 mg/m3, and urine aluminum levels in workers exposed to aluminum averaged 12.25 micrograms/L, significantly higher than that in controls (5.78 micrograms/L). There was no significant difference in serum aluminum between the exposed and controls. Both urine VMA and HVA levels were higher in the workers exposed to aluminum, and urine VMA level in the exposed was significantly higher than that in controls. There was significant difference in neurobehavioral test, including Santa Ana, digit symbol and Benton tests between the exposed and control workers. CONCLUSION: It suggests that occupational exposure to low level of aluminum can affect the neurobehavioral function and metabolism of monoamine neurotransmitter.

Effects of N-ethyl,N-nitrosourea on monoamine concentrations and metabolizing enzymes in mouse brain regions.

N-ethyl,N-nitrosourea is a well known alkylating agent and produces central nervous system-specific tumors in several laboratory animal species. In the present study, young male CD-1 mice were treated by i.p. injections of 0, 2, 8, or 32 mg/kg body weight N-ethyl,N-nitrosourea, twice a week for 3 weeks. Endogenous levels of brain monoamine neurotransmitters and their selected metabolites; norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), vanillylmandelic acid (VMA), dihydroxyphenyl acetic acid (dopac), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and dihydroxyphenylalanine (dopa) were measured using HPLC with electrochemical detection. N-ethyl,N-nitrosourea treatment caused an increase of NE and 5-HT in the hypothalamus and striatum. Increased levels of 5-HIAA were noticed in the same brain regions. Elevated levels of NE were also observed in the cerebral cortex, medulla oblongata and the cerebellum. The major metabolite of NE, VMA, was decreased in several brain regions to non-detectable levels. Histopathological examination of brain tissue did not reveal any pathologic lesions. The increases in brain amines were associated with increased activity of tryptophan hydroxylase in the hypothalamus and corpus striatum. Dopa-decarboxylase was elevated in the cerebral cortex at a low dose of N-ethyl,N-nitrosourea only, whereas the monoamine oxidase activity was unaltered. Results indicated that N-ethyl,N-nitrosourea exposure may cause an elevation of steady state levels of various biogenic amines in brain areas and these changes to some extent are consistent with the altered activity of metabolizing enzymes.

Functionally active ganglioneuroma with increased plasma and urinary catecholamines and positive iodine 131-meta-iodobenzylguanidine scintigraphy.

Ganglioneuromas are usually considered not to be functionally active. Studies of their catecholamine excretory pattern and of their imaging by means of the adrenergic tracing agent 131-I-MIBG have been therefore sparse. We report on a case of secretory ganglioneuroma, as demonstrated by the increased urinary excretion of the catecholamine metabolites HVA and VMA, increased plasma dopamine and epinephrine levels, and positive 131-I-MIBG scintigraphy. We must therefore be aware that a functionally active tumor is not necessarily a neuroblastoma, and that the diagnosis should be biopsy proven.

Hypothalamic-pituitary-adrenocortical axis activity and immune function after oral exposure to benzene and toluene.

Benzene and toluene, commonly used solvents, possess neurotoxic and immunotoxic effects. Male CD-1 mice were continuously fed drinking water containing 0, 31, 166 and 790 mg/l benzene and 0, 17, 80 and 405 mg/l toluene, respectively. The concentrations of hypothalamic norepinephrine (NE) and its metabolite vanillylmandelic acid (VMA), circulating corticosterone and adrenocorticotropic hormone (ACTH), and lymphocyte-derived interleukin-2 (IL-2) activity were evaluated after 28 days of exposure to each solvent. Serum corticosterone was also measured at pretreatment, 2, 7, and 14 days of exposure. The concentrations of NE, VMA, ACTH and corticosterone were increased following exposure to these solvents. Benzene increased corticosterone levels in mice after 7 days (166 and 790 mg/l) and at 28 days (790 mg/l). Toluene elevated corticosterone levels at 14 and 28 days at the 405 mg/l exposure. IL-2 production by mouse T-lymphocytes was suppressed in the two higher benzene-treated groups, while toluene decreased IL-2 synthesis at the highest level only. Both benzene and toluene exposures stimulated hypothalamic-pituitary-adrenocortical (HPA) activity. Elevated corticosterone has been reported to inhibit IL-2 production and impair immunocompetence. Organic solvents may have, at least partially, an additive adverse effect on immune function via activated HPA status.

Asymptomatic adrenal tumor; 386 cases in Japan including our 7 cases.

To clarify the indication of surgery in incidentally discovered asymptomatic adrenal masses, we analyzed 386 Japanese cases, 379 cases reported in Japan during the past 25 years (from 1964 to 1988) and 7 cases from our own experience. From a total of 460 patients, we carefully selected 379 patients satisfying our criterion of the absence of symptoms and signs suggestive of active hormone over-secretion as described in each case report. From the Japanese series, there was a high incidence of pheochromocytoma patients (20 of 37 patients) who had no symptoms and signs but had high plasma or urine catecholamines. Scintigraphy with 131I-meta-iodo-benzyl-guanidine was useful in the diagnosis of pheochromocytoma. For the other asymptomatic adrenal tumors, except for myelolipoma and adrenal cyst, differential diagnosis between malignant and benign adrenal lesions by imaging procedures such as whole body computed tomography (CT), ultrasonography (US), adrenocortical scintigraphy, and angiography was not always possible. In addition, among the 109 patients with cortical tumors whose hormonal data were reported, no clear-cut differentiation of malignant tumor from benign by means of these data could be obtained. Since 1980 whole body CT scanner and high resolution US scanner have become widely available, and there have been 283 cases of asymptomatic adrenal tumors who satisfied our criterion. Cortical carcinomas smaller than 3 cm and 6 cm in diameter account for 3.8% and 6.6%, respectively, of the total of 101 cases of cortical carcinoma, cortical adenoma, ganglioneuroma, and hemangioma during this period. The size of the smallest cortical carcinoma with metastasis was 2 cm in diameter in this series. Pre-operatively, an adrenocortical carcinoma 2.8 cm in diameter in our patient could not be diagnosed as such by imaging techniques and measurement of plasma hormones. These findings suggest that an adrenal mass larger than 3 cm should be removed and a patient with a smaller cortical tumor should be carefully followed up.

A case of malignant pheochromocytoma treated with 131I-metaiodobenzylguanidine and alpha-methyl-p-tyrosine.

A 47-year-old man had surgery for paraaortic paraganglioma in 1980 and 1985. In 1987, his urinary excretion of catecholamines and metabolites was extremely high. Scintigraphy with 131I-metaiodobenzylguanidine (MIBG) showed multiple bone and liver metastases. He was treated twice with infusions of 3.7 GBq of 131I-MIBG. After the first treatment, he had transient hypertension and pain in the back and right leg. Subsequent 131I-MIBG scintigraphy showed that the number of metastatic tumors had decreased. The second treatment was less effective. Excess catecholamines were treated with alpha-methyl-p-tyrosine (MPT), a catecholamine synthesis inhibitor, at doses between 250 and 2000 mg/day, which significantly decreased urinary NE excretion. This is the first case treated with 131I-MIBG in Japan.

Hepatic hemangioendothelioma of infancy associated with elevated alpha fetoprotein and catecholamine by-products.

Five cases of hepatic hemangioendothelioma (HH) were seen in infants ranging from 2 days to 5 months of age. The cases were studied by clinical chemistry, immunohistochemical staining, and electron microscopic techniques. Serum alpha-fetoprotein (AFP) levels were elevated in each of the four patients in whom levels were obtained. The highest elevation was noted in a 2-day-old infant with a diffuse, unresectable lesion involving the right lobe. Two patients who underwent complete resections of their solitary HH had normalization of their AFP levels. This study suggests that AFP levels in patients with HH are closely related to the patients' age, with the youngest patient having the highest levels of AFP. Catecholamine by-products (VMA and HVA) were elevated in one of four patients in whom levels were obtained, this infant was 3 months old at the time of presentation. She also had an elevated AFP level, a diffuse unresectable lesion involving the entire liver, multiple pulmonary nodules, and cutaneous hemangiomas. Immunohistochemical study failed to demonstrate the source of AFP or the catecholamine by-products in the tumor of this patient, suggesting that the source of catecholamine by-products could be stress-induced catecholamine secretion.

Effect of furosemide on urinary excretion of 4-hydroxy-3-methoxymandelic acid (VMA).

Excretion of VMA was measured in 10 healthy volunteers before and after intake of 40 mg furosemide and in 3 patients with congestive heart failure who were intermittently treated with 80 mg furosemide. In healthy volunteers furosemide caused an increase in VMA excretion from 5.0 +/- 0.5 to 7.8 +/- 0.9 mg/24 h and from 2.0 +/- 0.2 to 2.9 +/- 0.3 mg/g creatinine (mean +/- SE). Excretion of catecholamines was slightly increased in some subjects, but did not reach the upper limit of normal in any case. Furosemide induced an acute increase in urinary VMA that could have derived from inhibition of renal tubular reabsorption. Administration of furosemide might result, on occasion, in a false positive test for pheochromocytoma.