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.

Glutaryl-coenzyme A dehydrogenase deficiency: a distinct encephalopathy.

Clinical course, diagnostic and therapeutic management, and neurodevelopmental outcome were evaluated in 11 patients with glutaryl-coenzyme A dehydrogenase deficiency. In 9 patients macrocephalus was present at or shortly after birth and preceded the neurological disease. In 7 children an acute illness resembling encephalitis appeared after a period of normal development; 2 had developmental delay and progressive "dystonic cerebral palsy." Later, all 9 displayed typical signs of a disorder of the basal ganglia. In 1 patient with macrocephalus the disorder was diagnosed before the onset of neurological disease; in another it was diagnosed prenatally. Computed tomography and magnetic resonance imaging scans revealed severe generalized cerebral atrophy, most striking in the frontal and temporal lobes in 10 patients. Further deterioration was halted after initiation of treatment consisting of low-protein diets, special formulas low in lysine and tryptophan, and supplements of riboflavin and L-carnitine. Only 1 patient showed a slight clinical improvement. Later, dietary therapy was discontinued in 2 older patients and relaxed in a third without observed adverse effects. Two patients in whom treatment could be initiated before the onset of neurological symptoms have developed normally. However, duration of follow-up (6 and 29 months) does not yet allow classification of glutaryl-coenzyme A dehydrogenase deficiency as a treatable disorder. Total body production of glutaric acid, reflected in the daily urinary output, was efficiently reduced by therapeutic measures. Levels of glutaric acid in plasma and cerebrospinal fluid remained unchanged, which may in part explain the overall unsatisfactory outcome. All patients presented with a severe secondary deficiency of carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal pyruvate dehydrogenase deficiency with lipoate responsive lactic acidaemia and hyperammonaemia.

A 2-day-old girl developed a severe lactic acidosis with a normal lactate/pyruvate ratio and hyperammonaemia. Plasma arginine and citrulline levels were below the limit of detection. In muscle total pyruvate dehydrogenase complex (PDHC) and pyruvate decarboxylase (E1) activities were reduced to a fraction of lower control values. The acute neonatal period was bridged with peritoneal dialysis, dichloroacetate therapy, supplements of arginine and branched chain amino acids, a complete vitamin B complex and lipoic acid. Lactate homeostasis responded to pharmacological supplements of lipoic acid. At age 1 year the child was hypotonic, showed severe developmental retardation, optic atrophy and cranial dysmorphism. She died aged 1 year 8 months with signs of respiratory paralysis but with normal lactate levels under assisted breathing. Pathological findings at autopsy were suggestive of Leigh syndrome, interstitial pneumonia and extensive fatty infiltration of hepatocytes. Regression analysis of data from 187 plasma amino acid determinations from the patient over a period of 1 year 8 months revealed a persistent-imbalance involving alanine, glutamic acid, glutamine, proline, citrulline and branched chain amino acids. Aspects of acute and long-term therapy in this patient and some implications of the imbalances in plasma amino acids are discussed.