Population density and childhood leukaemia: results of the EUROCLUS Study.

The EUROCLUS study assembled incidence data for 13,551 cases of childhood leukaemia (CL) diagnosed between 1980 and 1989 in 17 countries (or regions of countries). These were referenced by location at diagnosis to small census areas of which there were 25,723 in the study area. Population counts, surface area and, hence, population density were available for all these small areas. Previous analyses have shown limited extra-Poisson variation (EPV) of case counts within small areas; this is most pronounced in areas of intermediate population density (150-499 persons/km2). In this study, the data set was examined in more detail for evidence that variations in incidence and EPV of CL are associated with population density. Incidence showed a curvilinear association with population density and was highest in areas which were somewhat more densely populated (500-750 persons/km2), where the incidence rate ratio relative to areas having > or = 1000 persons/km2 was 1.16 (95% confidence interval 1.07-1.26) and the P value for quadratic trend across eight strata of population density was 0.02. Incidence in these areas is uniformly elevated and showed no evidence of heterogeneity (i.e. EPV). Statistically significant evidence of EPV was evident amongst some of the areas previously classified as intermediate density areas (specifically, those with a density of 250-499 persons/km2, P < 0.001 for CL). These results were interpreted in terms of the current aetiological hypotheses for CL which propose that exposure to localised epidemics of one or more common infectious agent may contribute to the development of leukaemia. They suggest that such epidemics arise regularly in moderately densely populated areas and also sporadically in areas which are somewhat less densely populated. Although other interpretations are possible, these results may assist in the identification of characteristics which infectious agents must possess if direct or indirect causes of CL.

Electronic telephone directory listings: preferred sampling frame for a population-based study of childhood cancer in Australia.

PURPOSE: We report our telephone-based system for selecting community control series appropriate for a complete Australia-wide series of Ewing's sarcoma cases. METHODS: We used electronic directory random sampling to select age-matched controls. The sampling has all listed telephone numbers on an up-dated CD-Rom. RESULTS: 95% of 2245 telephone numbers selected were successfully contacted. The mean number of attempts needed was 1.94, 58% answering at the first attempt. On average, we needed 4.5 contacts per control selected. Calls were more likely to be successful (reach a respondent) when made in the evening (except Saturdays). The overall response rate among contacted telephone numbers was 92.8%. Participation rates among female and male respondents were practically the same. The exclusion of unlisted numbers (13.5% of connected households) and unconnected households (3.7%) led to potential selection bias. However, restricting the case series to listed cases only, plus having external information on the direction of potential bias allow meaningful interpretation of our data. CONCLUSION: Sampling from an electronic directory is convenient, economical and simple, and gives a very good yield of eligible subjects compared to other methods.

Postoperative chemotherapy without radiation in young children with malignant non-astrocytic brain tumours. A report from the Australia and New Zealand Childhood Cancer Study Group (ANZCCSG).

Young children with malignant brain tumours have particularly poor survival and manifest severe sequelae of radiation therapy. A multi-institutional pilot study of post-operative primary chemotherapy for children under 3 years with primitive neuroectodermal tumours (PNET) or ependymoma was initiated in 1987. The chemotherapy protocol comprised carboplatin, vincristine and the "eight drugs in 1 day" regimen. Radiation was recommended only if tumour progression or recurrence was documented. A total of 14 patients between 5 and 36 months of age were enrolled. Seven had supratentorial tumours (PNET, pinealoblastoma, intracranial retinoblastoma) with multiple predictors of adverse outcome. Four of these responded to initial chemotherapy but subsequently progressed and all had died by 16 months from diagnosis. The seven patients with infratentorial tumours (three medulloblastomas, four ependymomas) had more favourable predictors of outcome: no meningeal dissemination and gross macroscopic resection in six of the seven cases. One patient progressed rapidly and died within 5 months. The other six are alive at 37-57 months from diagnosis. Four are in continuous complete remission at 57, 51, 41 and 37 months, respectively from the time of their tumour resection. One is described as having stable disease with a persistent radiographic lesion at 41 months from diagnosis. One has relapsed on two occasions and is the only surviving patient to have been irradiated. Intelligence scores for the six long-term survivors have thus for remained within the normal range. It is suggested that some infants with standard-risk ependymoma and, possibly, medulloblastoma may be cured without radiation therapy.

The relationship of incidence of childhood lymphoblastic leukaemia to social class.

A study has been made of the relationship between socio-economic factors and the incidence of acute lymphoblastic leukaemia (ALL) of childhood. It was found that the incidence of childhood ALL in 12 areas of Queensland. Australia, correlated well with some indicators of above-average socio-economic status for these areas. A similar result was found when Brisbane City was studied separately. Social class was determined from the fathers' occupations at the time of diagnosis. There was found to be a higher than expected number of ALL cases in each of the upper 5 social classes and a lower than expected number in the remaining 2 lower classes. Factors associated with differences in lifestyle amongst the various social classes may increase or decrease the risk of development of ALL.

Plasma tocopherol in infants and children.

A study has been made of plasma tocopherol concentrations in normal children and in children with intestinal abnormalities. A positive correlation between plasma tocopherol and age is shown between the ages of 4 months and 10 years. Most patients with cystic fibrosis or coeliac disease were found to have markedly reduced plasma tocopherol concentrations in comparison with the normal children of similar age.

Incidence trends in childhood cancer in Queensland, 1973-1988.

OBJECTIVE: To determine whether there are any secular trends in the incidence of childhood cancer in Queensland. DESIGN: A retrospective epidemiological study of the incidence of cancer in children, aged 0-12 years, in Queensland during the 16-year period 1973-1988 inclusive. SETTING: Cases were found from the records of the Queensland Childhood Malignancy Registry. Ascertainment is believed to be virtually complete for children aged 0-12 years. PARTICIPANTS: All children who were resident in Queensland and less than 13 years of age at the time of diagnosis of cancer. The cases included all malignant neoplasms and also all intracranial neoplasms in children but excluded Langerhans' cell histiocytosis. MAIN OUTCOME MEASUREMENTS: The incidence by year of diagnosis was calculated for each of a number of standard diagnostic groups of neoplasms. These data were analysed by the chi 2, for trend test. RESULTS: Cancer incidence was found to be increasing at a rate of about 0.9% per year. The rise was almost entirely accounted for by a rise in incidence among boys, whereas there was virtually no change in the incidence in girls. Statistically significant increases in incidence were found in acute non-lymphocytic leukaemia and also in non-Hodgkin's lymphoma in boys; Hodgkin's disease was found to be decreasing in incidence. CONCLUSIONS: The results of this study emphasise the importance of childhood cancer incidence surveillance in Australia to determine whether these trends will continue in the future. The findings also indicate a need for continuing research in childhood cancer epidemiology.

What causes childhood leukaemia? Some beliefs of parents of affected children.

The theories of parents about the cause of their children's leukaemia have been documented in the course of a case-control study. From a sample of 175 children who were diagnosed as having acute lymphoblastic leukaemia, 91.4% of their parents put forward their theories. Some of these theories were related clearly to material that had been published and therefore had some scientific validity. Other theories often had no apparent scientific basis. Persons who are involved in the care of children with leukaemia should be aware of the wide variety of theories that are held by their parents so that they may provide counselling which could be of help in the relief of feelings of anxiety or guilt among the parents. Parents should always be afforded the opportunity to put forward their own theories so that they may be discussed on a rational basis. It is conceivable that some parents might put forward new hypotheses about leukaemogenesis that could be tested scientifically.

Childhood melanoma in Australia.

Data from a population-based registry, the Australian Paediatric Cancer Registry, were used to determine the incidence of malignant melanoma in children under 15 years of age in Australia. Over a 17-year period, 217 cases were identified. For the period 1977-89 inclusive, the annual age incidence was 0.34 per 100,000. There was some variation in incidence between the different states with Queensland recording the highest incidence at 0.97 per 100,000, the highest reported incidence in the world for childhood melanoma. Most of the cases occurred in children aged 13 or 14 years old with girls affected slightly more often, the sex ratio being 0.92. There was a statistically significant seasonal variation with fewer cases being diagnosed during the winter months. The commonest site was the trunk. Two of the cases were second neoplasms. This series demonstrates the need for increased education of children living in tropical and subtropical regions about the dangers of sun exposure and of methods of reducing exposure. Children who have undergone chemotherapy appear to be at particular risk.

Epidemiology of acute lymphoblastic leukaemia of childhood in Brisbane.

The incidence of acute lymphoblastic leukaemia of childhood in the Brisbane Statistical Division has been studied. Sixty-four cases occurred during a five-year period. A significant difference between the two subdivisions of the Statistical Division was found, with a higher incidence in Brisbane City than in the surrounding area. The average age at presentation of the leukaemic children within Brisbane City was significantly higher than in the rest of the Brisbane Statistical Division. Various socioeconomic and demographic differences exist between the two populations, and these may be responsible for the variation in leukaemia incidence. The findings indicate the need for further, more detailed, epidemiological studies.

Childhood cancer survival trends in Queensland 1956-80.

The true survival rates for the various forms of childhood cancer are best determined from a population-based study rather than from the results of clinical trials. Population-based survival rates have been calculated for four periods between 1956 and 1980 in Queensland. There was a significant improvement in survival for children who developed cancer after 1973 compared with those diagnosed before this date. There has however been no significant improvement in the survival rate for childhood cancer overall, or for acute lymphoblastic leukaemia since 1973. Over the 25 year period significant trends in survival rates were seen in acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin's disease, Wilms' tumour, medulloblastoma, and retinoblastoma. No such trend was seen for acute non-lymphoblastic leukaemia, neuroblastoma, rhabdomyosarcoma, juvenile or anaplastic astrocytoma, brain stem glioma, histiocytosis X, or bone tumours. There is a need for continuing research into better methods of treatment of childhood cancer.

Incidence of childhood tumours in Queensland.

The incidence of childhood cancer in Queensland has been studied using the data of the population-based Queensland Childhood Malignancy Registry. During the 7-year period 1973-1979, 454 cases were registered, giving an annual age-specific incidence of 11.34/10(5) for the age group 0-14 years inclusive. There was a male/female ratio of 1.36. The commonest group of diseases was that of the leukaemias, followed by that of CNS tumours. The incidences of the various types of tumour in Queensland have been compared with those from other reported series. The incidence of leukaemia was midway between that of U.S. whites and that of Manchester, while the incidences of lymphoma and Wilms' tumour were much closer to those of the United States. Ewing's tumour was considerably commoner than osteosarcoma.

Childhood cancer incidence in Queensland, 1979-88.

Data on the incidence of childhood cancer in Queensland during the 10-year period 1979-88 are presented. During this period, 786 cases were registered. The average annual crude and age-standardized (to the world population) incidence rates for both sexes were 12.63 and 13.30 per 100,000 respectively. The incidence of cancer in males is unusually high, as is the sex ratio of 1.57. ALL accounted for 78% of all leukaemias. There appears to have been a decline in the incidence of Hodgkin's disease, especially in older children, compared with an earlier Queensland series. Ewing's tumour remains commoner than osteosarcoma. Some modifications to the classification scheme for childhood cancer are proposed. The most important of these is the omission of Langerhans-cell histiocytosis, which is not now regarded as a neoplasm.

Incidence of cutaneous childhood melanoma in Queensland, Australia.

The incidence of cutaneous melanoma in children aged 0-14 years was examined in Queensland, Australia. Details of notifications were collected from the population-based Australian Paediatric Cancer Registry. Between 1987 and 1994, the age-adjusted incidence rates of invasive cutaneous melanoma occurring in Queensland children were estimated at 8.5/million for males and 7.1/million for females. Incidence rates rose steeply in both sexes with increasing age, from less than 1/million in the 0-4 age group, to nearly 30/million in the 10-14 age group. To assess the uniformity of the anatomical distribution of lesions, relative tumour densities (RTDs) were calculated compared with the body as a whole. In both sexes, melanomas were most common on the trunk (RTD > 3), while lower limb lesions were less common (RTD < 0.6) and no melanomas were reported on the buttocks or external genitalia. Although not statistically significant, there was a tendency for truncal lesions in males to occur on the back, while in females, truncal melanomas were more evenly distributed across the chest, back and shoulders. No consistent relationship between latitude and melanoma incidence was observed, with higher rates reported in the subtropical than the tropical regions of Queensland. These are the first reported incidence rates of cutaneous melanoma in Australian children and are the highest ever reported in the world in this age group. Our findings provide baseline data from which to monitor changes in the occurrence of cutaneous melanoma in children.

Childhood cancer incidence in Australia, 1982-1991.

The data of the Australian Paediatric Cancer Registry on childhood cancer incidence in Australia for the 10-year period 1982-1991 are presented. The crude average annual incidence of cancer in children under the age of 15 years was 13.8 per 100,000. The incidence of childhood cancer in Australia is rising. Significant increases were seen in acute non-lymphoblastic leukaemia, astrocytoma and melanoma. The age-standardised incidence of 14.4 per 100,000 is about 34% higher than in the UK. Most types of cancer had a higher incidence in Australia than in the UK, and the difference was significant for acute lymphoblastic leukaemia, astrocytoma and melanoma. Of particular interest is malignant melanoma, whose incidence in Australia is more than 5 times that in the UK, as a result of excessive UV exposure. Australia has a higher incidence of Ewing's tumour than osteosarcoma, nearly twice that of the UK. International comparative studies may help to elucidate the aetiology of these tumours.

Social class as a prognostic variable in acute lymphoblastic leukaemia.

We studied the relationship between social class and prognosis in children with acute lymphoblastic leukaemia. Seventy children who were commencing on curative therapy, and who received central nervous system prophylaxis, were included in the study. Children from social classes 1 to 5 had a significantly better five-year survival rate and duration of first remission than children from social classes 6 and 7. There was no apparent difference either in the treatment given to the two groups or in the clinical and haematological parameters studied. A study of the causes of this difference in survival could lead to better over-all results in the treatment of childhood leukaemia.

Carcinomas in childhood. A registry-based study of incidence and survival.

During a 10 year period, 1971-80, there were 234 children in Great Britain younger than 15 years with a diagnosis of carcinoma registered in Great Britain. These cases represented approximately 2% of all childhood malignant disease. The most common primary site was the thyroid, followed by the nasopharynx and the adrenal cortex. With the exception of adrenocortical tumors, most of the carcinomas occurred in children older than 10 years. In some patients there was a genetic predisposition to neoplasia. Children with carcinomas of the thyroid and female genital tract have an excellent prognosis with 5-year survival rates of over 90%. The prognosis for other sites was generally less favorable; 60% of children with nasopharyngeal tumors were alive at 5 years from diagnosis but less than 20% of those with carcinomas of the gastrointestinal tract or the adrenal cortex.

Cerebral astrocytoma as a complication of acute lymphoblastic leukaemia.

A boy who developed acute lymphoblastic leukaemia at the age of two years and 10 months had several central nervous system relapses, and received two courses of cranial irradiation, each of 24 Gy, in addition to systemic and intrathecal chemotherapy. Nearly 10 years after the onset of his leukaemia he developed a brain stem astrocytoma from which he died. This appears to be a rare occurrence, and the role of the treatment in the induction of his second tumour is discussed. The need for the long-term follow-up of cancer patients after apparent cure is emphasized.

Risk factors for childhood melanoma in Queensland, Australia.

The causes of cutaneous melanoma among children under 15 years are largely unknown. We report the findings of an epidemiological study of childhood melanoma in Queensland, Australia, which has the highest incidence rates in the world. All 61 cases of melanoma in children less than 15 years notified to the Queensland Cancer Registry 1987-1994 were eligible to participate in a population-based, case-control study. Data were collected through structured, face-to-face interviews with parents and skin examinations of the 52 participating cases and 156 age- and sex-matched controls. The strongest determinants of melanoma risk found among Queensland children were constitutional factors, including the presence of more than 10 naevi greater than 5 mm in diameter (RR 9.9, 95% CI 2.5-38.9), heavy facial freckling (RR 6.4, 95% CI 1.9-21.6), an inability to tan on exposure to the sun (RR 8.8, 95% CI 2.1-36.2) and a family history of melanoma (RR 4.2, 95% CI 1.9-9.3). These factors remained significantly associated with melanoma after adjusting for other risk factors. No measures of acute or chronic exposure to solar UV radiation were associated with childhood melanoma in our study. Established risk factors, including giant congenital naevi and xeroderma pigmentosum, were not present among any of the children in the study. Melanoma in childhood appears to have similar epidemiologic characteristics to the adult form of the disease, being associated with a cluster of phenotypic attributes indicating cutaneous sensitivity to the effects of sun exposure. Our findings support the contention that childhood melanoma occurs in susceptible individuals with a low threshold for pigment cell tumorigenesis. From a public-health perspective, children at elevated risk for melanoma can be identified on the basis of phenotype and family history.

Melanocytic naevi and melanoma in survivors of childhood cancer.

There is evidence from previous studies of small numbers of children who received cytotoxic therapy for cancer, that they may develop increased numbers of melanocytic naevi (moles), the strongest known risk factors for melanoma. Our aim was to investigate a large number of survivors of childhood cancer in order to test the hypothesis that they have more melanocytic naevi than matched controls. Total-body naevus counts were obtained from 263 oncology patients ascertained in paediatric oncology departments in Queensland, Australia, and from 263 hospital controls matched for age and sex. Additional information was gathered from children's parents about concurrent factors influencing naevus development such as type of complexion and history of sun exposure. Matched analyses, both crude and adjusted for possible confounding factors, revealed no significant difference in overall density of naevi among oncology patients and control subjects, according to diagnosis or to duration or type of chemotherapy. However significantly more oncology patients had atypical naevi (P < 0.05) and acral naevi (P < 0.0001) than controls. One patient developed a malignant melanoma 13 years after chemotherapy and radiotherapy for rhabdomyosarcoma. These findings support an association between treatment for childhood cancer and acral naevi and suggest that atypical naevi may also be associated with chemotherapy in childhood.

Cross-reactivity to porcine factor VIII of factor VIII inhibitors in patients with haemophilia in Australia and New Zealand.

BACKGROUND: Inhibitory antibodies which neutralise factor VIII develop in 10-20% of individuals with inherited haemophilia A and rarely as autoantibodies in normal individuals to cause acquired haemophilia. The antibodies are directed against human factor VIII but cross-react to varying degrees with porcine factor VIII. Porcine factor VIII can be used for treatment in individuals with low cross-reactivity. AIMS: To determine the cross-reactivity of factor VIII inhibitors between human factor VIII and porcine factor VIII, in a population of patients with inherited and acquired haemophilia A. Also, to determine whether patients with inherited haemophilia and inhibitors have a higher incidence of factor VIII gene inversion in intron 22. METHODS: Samples and data sheets from 43 patients with inherited and ten with acquired haemophilia were submitted from hospitals in Australia and New Zealand. Inhibitor levels to human and porcine factor VIII were measured by the Bethesda method in 39 with inherited and nine with acquired haemophilia A. RESULTS: Of 39 patients with inherited haemophilia A, cross-reactivity was 0% in 17 patients, 1-19% in six, 20-39% in 11 and 40-80% in five. In six of nine patients with acquired haemophilia cross-reactivity was < or = 7%. In inherited severe haemophilia A, the frequency of the intron 22 inversion was not greater in 37 study patients than in 28 patients without an inhibitor. CONCLUSIONS: Many patients in Australia and New Zealand with inhibitors to human factor VIII presently show a low or absent level of cross-reactivity to porcine factor VIII. These may respond to treatment with this concentrate at least in the short term. There remains a group of patients with high cross-reactivity who will respond only to recombinant factor VIIa or prothrombin complex concentrates.