Neuroblastoma in Europe: differences in the pattern of disease in the UK. SENSE. Study group for the Evaluation of Neuroblastoma Screening in Europe

BACKGROUND: Neuroblastoma is a major contributor to childhood cancer mortality, but its prognosis varies with age and stage of disease, and some tumours regress spontaneously. Urinary screening programmes or clinical examination may detect the disease before symptoms appear, but the benefit of early diagnosis is uncertain. We examined the incidence, pattern, and presentation of neuroblastoma in four European countries. METHOD: Population-based incidence rates were derived for France, Austria, Germany, and the UK. Age, sex, and stage distribution were analysed by Mantel-Haenszel techniques and Poisson regression. The proportion of incidental diagnoses (cases without symptoms found at routine health checks or during investigation of other disorders) and mortality rates were also compared. FINDINGS: Between 1987 and 1991, 1672 cases of neuroblastoma were diagnosed in children under 15 years old (France, 624; Austria, 69; Germany, 493; UK, 486). Age-standardised annual incidence was significantly lower in the UK (10.1/million) than in France (12.5) and Germany (11.4). In the UK a deficit of low-stage disease in infants was accompanied by an excess of stage IV in older children. The UK had significantly fewer incidental diagnoses (8%) than Austria (27%) and Germany (34%). UK mortality rates were significantly higher than German or French rates. INTERPRETATION: In the UK, neuroblastoma diagnosis is delayed, possibly because of a less rigorous system of health checks for children. Although some overdiagnosis occurs in mainland Europe, our data suggest that in the UK some low-stage cases, undetected in infancy, may later present as advanced disease. This finding has implications for screening programmes and organisation of routine surveillance of infant health in the UK.     

Cocaine and metabolites in amniotic fluid may prolong fetal drug exposure

OBJECTIVE: Cocaine and metabolites can be found in the amniotic fluid after maternal use, presumably as a result of fetal urination. The fetus may be repeatedly exposed to the effects of these drugs through contact with amniotic fluid that contains these substances. The purpose of this study was to determine whether the naive fetal lamb generates detectable fetal blood levels of cocaine and metabolites when cocaine is placed directly into the amniotic fluid and, if so, whether fetal swallowing accounts for these findings. STUDY DESIGN: Six pregnant ewes with singleton fetuses of 120 to 125 days' gestation were chronically catheterized for daily sampling of cocaine and metabolite levels in maternal venous plasma, fetal venous plasma, and amniotic fluid over a 7-day period. Esophageal ligation was performed in three additional animals similarly instrumented to evaluate the role of fetal swallowing in the distribution of amniotic fluid cocaine and its metabolites. In each case, at the time of surgery, an Alzet osmotic pump delivering cocaine at 0.5 mg/kg estimated fetal weight per hour into the amniotic fluid was secured to the fetal back. Cocaine and metabolites (benzoylecgonine, ecgonine methyl ester, and norcocaine) were measured daily in material and fetal plasma, amniotic fluid, and meconium by solid-phase extraction and derivatization and quantified by high-performance gas chromatographic techniques. RESULTS: The concentrations of ecgonine methyl ester were highest in the amniotic fluid followed by cocaine and benzoylecgonine. In the normal and esophagus-ligated groups, cocaine, benzoylecgonine, and norcocaine were found in fetal plasma in concentrations of approximately 3% that of amniotic fluid. Ecgonine methyl ester was not detected in fetal plasma from either group. Meconium samples from sheep with and without esophageal ligation demonstrated high levels of norcocaine. CONCLUSION: We conclude that cocaine and metabolites in amniotic fluid enter the fetal circulation to produce detectable plasma levels through routes other than swallowing. Moreover, the results of meconium analyses in the two groups of fetuses suggest that fetal swallowing is not the primary mechanism by which cocaine and metabolites enter the intestine.     

True trisomy 15 mosaicism, detected by amniocentesis at 12 weeks of gestation and fetal echocardiography

A case of mosaicism of trisomy 15, with two-thirds of the cells trisomic, was detected at 12 weeks of gestation in amniotic fluid cell cultures obtained with the filtration technique. Ultrasound examination at 13 weeks showed a nodule protruding into the amniotic cavity which was speculated to be remnants of a co-twin, causing the trisomic cell line. At 20 weeks of gestation, a malformation scan (level III) was normal, but supplementary fetal echocardiography revealed a severe cardiac defect (mitral atresia and a ventricular septal defect). Fetal lymphocytes obtained by cordocentesis showed trisomy 15 mosaicism, but only in 5 per cent of the mitoses. After termination, the same percentage of trisomy 15 mosaicism was found in cells from skin and tendon as in the original early amniocentesis. No sign of earlier twinning was found in the placenta or membranes. We conclude that mosaicism in early amniotic fluid obtained by the filter technique in this case reflected the true karyotype accurately and that supplementary echocardiography added significantly to the interpretation of the clinical implications.     

Recovery of ventilatory response to carbon dioxide after thiopentone, morphine and fentanyl in man

Ventilatory responses to CO2 (delta VI/delta PCO2) were measured half, one, two and four hours after infusions of thiopentone, morphine, fentanyl and saline in healthy men in order to test the idea that variation in clinical recovery and control of breathing after anaesthetic drugs are associated with interindividual differences in control measurements of delta VI/delta PCO2. Ventilatory response to CO2 was profoundly reduced one half hour after each drug, in contrast to the observation during air breathing that ventilation and end tidal PCO2 had returned to within 10 per cent of control. Mean delta VI/delta PCO2 increased progressively at one, two, and four hours, returning to near control after thiopentone, but remaining less than 80 per cent of control four hours after morphine and fentanyl. From the regression equations of each ventilatory response, ventilation at PCO2 of 58 and 70 mmHg (VI58 and VI70) were computed to estimate displacement of the response curves by the drugs. Following thiopentone there was no significant change of V158. In contrast ther was a highly siginificant fall of VI58 one half hour after fentanyl (p less than 0.01), with progressive return towards control at one, two, and four hours; similar changes were observed after morphine. For each drug, changes of VI70 were substantially greater than corresponding changes of V158. At all times during these recovery measurements, subjects were conscious and co-operative and, by traditional clinical criteria, were judged to have recovered from the effects of the drugs. Differences between high and low responding subjects were assessed by plotting control measurements against values obtained half and one hour after drugs. No systematic differences were found. These findings suggest that delta VI/delta PCO2 is a sensitive indicator of central nervous activity, but do not support the concepts that individuals with low delta VI/delta PCO2 might be more susceptible to the ventilatory depressant effects of anaesthetic drugs, or that low delta VI/delta PCO2 might be associated with delayed return of spontaneous breathing after general anaesthesia. Plasma thiopentone levels at half, one, and four hours were highly reproducible, in contrast to the wide variation of delta VI/delta PCO2 among subjects in this study. These findings together support the notion that wide variation in clinical recovery from anaesthesia may have a primary physiological basis in addition to variation caused by interindividual differences in drug dosage, biotransformation and excretion.     

Thickness of human cornea measured by topographic pachometry

In the hands of trained user, the topographic pachometer proves to be an instrument of acceptable clinical precision (standard deviation = 0.006mm). An examination of corneal thinning during waking hours revealed a rate of thinning which was greatest upon lid opening and which declined uniformly throughout the day (p = 0.01). An investigation into menstrually related change in corneal thickness revealed that at least 122 subjects would be required to investigate this change on an acceptable statistical basis (p = 0.05).     

The response of cells in culture to fractionated radiation: a theoretical approach

A mathematical model has been constructed to simulate the response of cells in vitro to fractionated doses of radiation. The model is capable of describing most of the radiobiological functions that are commonly studied. Input data are measurable cell properties. The details of the model and methods of acquiring the input data are outlined and a comparison with experimental observations on two radiobiological functions, survival curves and recovery curves are discussed in some detail.     

Study on the relationship between plasma prolactin levels and androgen metabolism in man

The purpose of the study was to investigate the effect of hyperprolactinemia on the metabolism of androgens in man. A group of 6 normal men was treated for 4 consecutive days, on separate periods, with Sulpiride which is known to raise plasma prolactin (PRL) concentration. The effect of the treatment on plasma steroids was verified in basal conditions and under stimulation by HCG. In the controls, a parallel rise in testosterone (T) and dihydrotestosterone (DHT) was observed in response to HCG stimulation. In experimental hyperprolactinemia, the rise in T in response to HCG, similar to that of the controls, was accompanied by a markedly diminished rise in DHT. Similar results were observed in a patient with hyperprolactinemia following apparent accidental section of the pituitary stalk. These data demonstrate the interference of increased levels of PRL in the metabolism of testosterone into the active DHT form by 5alpha-reductase. They suggest that this mechanism could possibly impair the gonadal function in man.     

Anisocytosis and the C-1000 Channelyzer in macrocytic anaemia

Red cell anisocytosis as assessed using the Coulter Channelyzer C-1000 showed an increase with progressive anaemia in 25 patients with macrocytosis due to B12 and/or folate deficiency. In deficiency of a single factor, the degree of anisocytosis increased with progressive anaemia. In five cases with B12 and folate deficiency combined, anisocytosis was markedly increased out of proportion to the degree of anaemia present. Iron stores were also reduced in four of these cases. It is suggested that objective measurement of anisocytosis is of early diagnostic value in the assessment of multiple haematinic factor deficiency, for example, in macrocytic anaemia associated with malabsorption states and unexpected multiple deficiency states.