Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group Study.

PURPOSE: To prospectively analyze the outcome of patients with Stage A neuroblastoma (NB) treated with surgery alone, especially with regard to the prognostic significance of age, tumor site, MYCN copy number, tumor cell ploidy, and histology. PATIENTS AND METHODS: The clinical course of 329 patients with Stage A disease registered on the POG NB Biology Study #9047 between February, 1990 and October, 1997 were evaluated. Age, tumor site, MYCN copy number, tumor cell ploidy, and histology were analyzed for their impact on event-free survival (EFS) and survival (S). RESULTS: The 5-year estimated EFS and S rates for the 329 patients were 91% (+/-3%) and 96% (+/-2%), respectively. The EFS rate was similar for infants younger than 12 months and children age 12 months or older, but age older than 12 months was predictive of lower S rates (P = 0.044). Patients with adrenal, abdominal non-adrenal, thoracic, and cervical tumors had similar S rates. The majority of patients had tumors with favorable biologic features, and only 3% had MYCN amplification. For infants with diploid tumors, the EFS rate was 82% (+/-16%), but effective therapy yielded an S rate of 100%. Rate of S was 80% (+/-26%) and 64% (+/-27%) for patients with unfavorable tumor histology and MYCN-amplified tumors, respectively. CONCLUSION: The outcome for patients with Stage A NB treated with surgery alone is excellent. Although EFS and S rates were significantly worse for patients with MYCN-amplified tumors, a subset achieved long-term remission after surgery alone. For patients with Stage A and MYCN amplification, additional factors are needed to distinguish the patients who will achieve long-term remission with surgery alone from those who will develop recurrent disease.

FH Tulsa-1 and -2: two unique alleles for familial hypercholesterolemia presenting in an affected two-year-old African-American male.

A two-year-old African American boy presented with cutaneous xanthomata and extreme hypercholesterolemia. Subsequent studies revealed that the LDL-cholesterol was 1,001 mg/dl and apoB 507 mg/dl. LDL-receptor activity was almost undetectable, which is compatible with the finding of two newly described defective alleles on exon 4 of the LDL-receptor gene coding for part of the ligand-binding domain. One allele contained a 21 base-pair insertion from codon 200 to 207 whereas the other had a point mutation at codon 207. The rarity of genes for FH reported in individuals of African ancestry is discussed.

Comparison of antibody, antigen, and metabolite assays in rat models of systemic and gastrointestinal candidiasis.

We compared serial measurements of antibodies to mannan and to a cytoplasmic antigen (enzyme-linked immunosorbent assays), detection of mannan and an unidentified candidal antigen (latex agglutination), and assays of mannose and arabinitol (gas chromatographic assay of per-O-acetylated aldonitrile derivatives). In a high-inoculum intravascular-infection model, antimannan assays were consistently positive beginning on day 2 postinoculation, anti-cytoplasmic antigen assays followed the same time course but were less sensitive, mannan was detected in all samples beginning on day 2 postinoculation, and serum mannose concentrations peaked on day 3 postinoculation and were less sensitive than mannan detection. Other assays were not useful. In a lower-inoculum intravascular-infection model, the antibody assays became positive after a similar interval and remained positive for 28 days, with antimannan again being the more sensitive. Mannan and mannose tests were positive in week 1 postinoculation only, with mannan detection being the more sensitive. In a gastrointestinal-colonization model, antimannan assays become positive after 2 weeks of colonization, whereas anti-cytoplasmic antigen and mannan tests remained negative. In a model of gastrointestinal colonization followed by invasive infection produced by induction of neutropenia, only mannan detection was diagnostically useful. These data, comparing this panel of modern serodiagnostic techniques in controlled models of clinically relevant syndromes of candidiasis, enhance understanding of previous efforts in serodiagnosis of candidiasis and provide a foundation for further prospective studies in patients.

Hydroxyl free radical adduct of deoxyguanosine: sensitive detection and mechanisms of formation.

DNA or 2-deoxyguanosine reacts with hydroxyl free radical to form 8-hydroxy-deoxyguanosine (8-OH-dG). We found that 8-OH-dG can be effectively separated from deoxyguanosine by high pressure liquid chromatography and very sensitively detected using electrochemical detection. The sensitivity of electrochemical detection is about one-thousand fold enhanced over optical detection. Utilizing deoxyguanosine in bicarbonate buffer it was found that ferrous ion, but not ferric ion, was effective in forming 8-OH-dG. The hydroxyl free radical scavenging agents, thiourea and ethanol, were very effective in quenching Fe(11) mediated 8-OH-dG formation, but superoxide dismutase had very little effect.

Familial central diabetes insipidus: vasopressin and nicotine stimulated neurophysin deficiency with subnormal oxytocin and estrogen stimulated neurophysin.

Five members of a family with dominantly inherited diabetes insipidus were diagnosed and treated with deamino-d-arginine vasopressin (DDAVP), a vasopressin analogue given intranasally. All subjects demonstrated subnormal levels of arginine vasopressin (AVP) by radioimmunoassay in response to cigarette smoke inhalation, a standardized nicotine stimulation test. Levels of oxytocin (OT) were found to be normal and unstimulated after cigarette inhalation in two subjects, but when two affected male siblings ingested Ovulen, OT and ESN were stimulated to subnormal levels. After twelve months of DDAVP treatment, the low AVP response to nicotine was preserved whereas the carrier protein, nicotine stimulated neurophysin (NSN) remained undetectable.

Oral chloramphenicol in the treatment of Haemophilus influenzae meningitis.

We conducted a prospective, randomized evaluation of oral chloramphenicol administration for completion of therapy of Haemophilus influenza type b meningitis in 44 children: 21 received drug by this route after the second day of therapy, the remainder continued to receive the drug intravenously. Resolution of clinical manifestations and cerebrospinal fluid indicators of meningitis was equivalent with both routes in 43 patients. One infant failed to achieve efficacious serum concentrations by either route of administration. Paired analysis of the area under the serum concentration versus time curve in 13 patients after oral and intravenous administration indicated equivalent bioavailability. Neutropenia was the only observed drug-related toxicity and correlated with the highest observed serum concentration. We conclude that: (1) chloramphenicol can be used by the oral route to complete treatment of H. influenzae type b meningitis; (2) a dose of 75 mg/kg/day is effective and less likely than higher doses to cause neutropenia; and (3) the measurement of serum chloramphenicol concentrations is important, regardless of route of administration.

1-Deamino-8-D-arginine vasopressin and urine cyclic adenosine monophosphate excretion in diabetes insipidus.

The response to 1-deamino-8-D-arginine vasopressin (DDAVP), an intranasally administered analogue of vasopressin, was investigated in children and adults with central diabetes insipidus. To assess the action of DDAVP on the distal nephron, cyclic adenosine monophosphate (cAMP) excretion was assayed in urine collected 4 hr before and during four subsequent 4-hr periods after intranasal administration of 5 micrograms DDAVP. Maximal effects on urine volume and concentration were observed between 4 and 12 hr, coinciding with an elevated cAMP excretion in seven subjects. The pretreatment 4-hr cAMP excretion (micrograms/gm creatinine) correlated inversely with age (p less than 0.02) and surface area (p less than 0.001). Subsequent cAMP excretion after DDAVP increased inconsistently with no relationship to duration of antidiuresis, indicating that urinary cAMP is a poor index of antidiuretic hormone action on the distal nephron. We also confirmed that DDAVP intranasally induces antidiuresis in patients with diabetes insipidus over approximately 12 hr.

Familial absorptive hypercalciuria and renal tubular acidosis.

Hypercalciuria was considered as a secondary condition when associated with familial renal tubular acidosis. Later studies suggested that hypercalciuria could lead to renal tubular acidosis and nephrocalcinosis. Selected members of a family spanning five generations were studied. Renal tubular acidosis was present in eight subjects in three consecutive generations. Increased 24-hour urinary calcium excretion was present in nine subjects in three consecutive generations, alone in the younger generation, and in combination with renal tubular acidosis and nephrocalcinosis in the older generation. Calcium loading tests showed the absorptive nature of hypercalciuria in nine of 18 subjects studied. This report suggests that in this family the absorptive hypercalciuria is an autosomal dominant genetic defect with complete penetrance and variable expressivity which leads to renal tubular acidosis and nephrocalcinosis.

Premature onset of labor, neonatal patent ductus arteriosus, and prostaglandin synthetase antagonists--a rat model of a human problem.

Premature labor and patent ductus arteriosus are two potentially fatal hazards of the human newborn infant. Prostaglandin synthetase antagonists have thus been used to suppress early labor and to close the ductus of the neonate. Indomethacin has been most effective but not free of significant complications. Neuronal necrosis may result from numerous systemic aberrations. A controlled rat model study was therefore devised to investigate fetal neuronal necrosis in relation to maternal indomethacin dose. Dams were given various treatments of 2 mg/kg of 4 mg/kg indomethacin within the last 3 days of gestation. Liquid chromatography was used to assess serum maternal and fetal drug levels. From light microscopy of more than 200 brains it was apparent that fetal neuronal necrosis correlates with maternal dose.

Combined oral L-dopa and propranolol for growth hormone provocation.

A convenient test of growth hormone (GH) provocation using oral doses of L-dopa and propranolol (L + P) is compared with insulin-induced hypoglycemia (IIH) in 28 children and adolescents with short stature. In eight of these children, growth hormone deficiency was diagnosed when GH failed to rise above 7 ng/ml. The GH levels of the remaining GH-responsive children were significantly higher after administration of L + P (P less than .05) when compared with IIH given before L + P on the same morning or on a separate day.