Hepatoblastoma in the Nordic countries.

Little is known about the etiology of hepatoblastoma. Because of the young age at diagnosis, several studies have looked at various birth characteristics. The purpose of our study was to investigate the incidence of hepatoblastoma in the Nordic countries and the association between selected birth characteristics and hepatoblastoma. Data from national cancer registries and birth registries in Denmark, Sweden, Norway and Finland 1985-2006 was used. Overall, 155 children with hepatoblastoma aged 0-14 years were included and individually matched to five controls drawn randomly from national population registries. The incidence rate of hepatoblastoma was 1.7 per million person-years with a predominance of boys (1.5:1). Incidence rate was highest before the age of 1 year (8.3 per million person-years). A higher risk of hepatoblastoma was found in children with birth weight <1,500 g [odds ratio (OR) = 9.5; 95% confidence interval (CI): 2.3-38.2], born preterm in week 22-32 (OR = 4.5; CI: 1.8-11.5) and Apgar scores <7 after 1 min (OR = 3.1; CI: 1.3-7.1) and 5 min (OR = 7.5; CI: 1.8-32.4). A doubling in risk was found in children who were large for gestational age (OR = 2.3; CI: 1.0-5.3). No associations were found with birth order, maternal age or maternal smoking. Our study indicates that intrauterine and/or neonatal factors are associated with increased risk of hepatoblastoma. These may include low birth weight and asphyxia leading to neonatal intensive care. Alternatively, the factors may be a consequence of hepatoblastoma developing in utero.

Infectious exposure in the first years of life and risk of central nervous system tumours in children: analysis of birth order, childcare attendance and seasonality of birth.

BACKGROUND: An infective, mostly viral basis has been found in different human cancers. To test the hypothesis of a possible infectious aetiology for central nervous system (CNS) tumours in children, we investigated the associations with proxy measures of exposure to infectious disease. METHODS: In a large case-control study nested in the populations of Denmark, Norway, Sweden, and Finland of 4.4 million children, we studied the association of birth order and seasonal variation of birth with subsequent risk for CNS tumours. We identified 3983 children from the national cancer registries, and information on exposure was obtained from the high-quality national administrative health registries. We investigated the association between childcare attendance during the first 2 years of life and the risk for CNS tumours in a subset of Danish children with CNS tumours, using information from the Danish Childcare database. RESULTS: We observed no association between birth order and risk of CNS tumours overall (odds ratio (OR) for second born or later born vs first born, 1.03; 95% confidence interval (CI), 0.96-1.10) or by histological subgroup, and children with CNS tumours did not show a seasonal variation of birth that was distinct from that of the background population. Childcare attendance compared with homecare showed a slightly increased OR (1.29; 95% CI, 0.90-1.86) for CNS tumours, with the highest risk observed in children attending a crèche. The strongest association was observed for embryonal CNS tumours. We found no effect of age at enrolment or duration of enrolment in childcare. CONCLUSION: These results do not support the hypothesis that the burden of exposure to infectious disease in early childhood has an important role in the aetiology of paediatric CNS tumours.

[Adults treated as children for acute lymphocytic leukemia--methotrexate, late effects and quality of life]. / Voksne behandlet for akutt lymfatisk leukemi som barn--metotreksat, seneffekter og livskvalitet.

From 1975 to 1980, 153 Norwegian children were diagnosed with acute lymphocytic leukaemia. In 1995, all 98 survivors were studied and compared to matched family controls. 132 children were treated with the national protocol. Of these, 93 (70.5%) were survivors at the time of the study. The remaining five survivors were treated with different treatment schemes. The national protocol included methotrexate infusions combined with intrathecal methotrexate as prophylactics against neuroleukaemia, instead of the irradiation. Neither doxorubicin nor cyclophosphamide were included. In this study, a questionnaire was used that covered demographic data, quality of life, and medical information the response rates were 96% (94 persons) for survivors and 92% (90 persons) for family controls. Information was also obtained for the remaining four survivors. No significant differences were found between survivors and controls with regard to quality of life and demographics, with one exception, Somatisation on the GHQ-28. Hospital records of all patients were checked for possible late effects. One case of serious sequela (hemiparesis during therapy) was found, probably related to methotrexate therapy. Seven other serious, possible sequelae were recorded, but probably not related to methotrexate. There were no cases of secondary malignant neoplasm.

Long-term survival and quality of life in patients treated with a national all protocol 15-20 years earlier: IDM/HDM and late effects?

In a follow-up matched control study the 93 (70.5%) survivors of 132 children treated with a national protocol for acute lymphoblastic leukemia (ALL) and 5 survivors of the other 21 cases of ALL in childhood diagnosed in the same period were evaluated. Thus it was also a population-based study. The national treatment protocol was used in the period 1975-1980. Methotrexate (MTX) infusions combined with intrathecal MTX were used as prophylaxis against neuroleukemia instead of irradiation. Neither doxorubicin (Adriamycin) nor cyclophosphamide was used in the protocol. A questionnaire covering demographic data, number of offspring, learning problems, level of athletic performance, education, and work status as well as medical information was used. Forms were received from 94 (96%) of the 98 adult surviving cases and corresponding controls in the family. Interviews were performed in the remaining four cases (4%). There were no statistical differences between the two groups with respect to physical and mental health and quality of life. Hospital records of all patients were also checked for possible late effects. There was no definite case of secondary malignant neoplasm; however, there was one case of prolactinoma and only one case of serious sequelae (hemiparesis during therapy), probably due to intrathecal and intravenous MTX.

Mutation spectrum in patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia: identification of twelve different mutations in the WASP gene.

Twelve different mutations in the WASP gene were found in twelve unrelated families with Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT). Four frameshift, one splice, one nonsense mutation, and one 18-base-pair deletion were detected in seven patients with WAS. Only missense mutations were found in five patients diagnosed as having XLT. One of the nucleotide substitutions in exon 2 (codon 86) results in an Arg to Cys replacement. Two other nucleotide substitutions in this codon, R86L and R86H, have been reported previously, both giving rise to typical WAS symptoms, indicating a mutational hot spot in this codon. The finding of mutations in the WASP gene in both WAS and XLT gives further evidence of these syndromes being allelic. The relatively small size of the WASP gene facilitates the detection of mutations and a reliable diagnosis of both carriers and affected fetuses in families with WAS or XLT.

Tnk1: a novel intracellular tyrosine kinase gene isolated from human umbilical cord blood CD34+/Lin-/CD38- stem/progenitor cells.

Degenerate PCR was employed to identify novel tyrosine kinase genes from an enriched population of human umbilical cord blood hematopoietic stem/progenitor cells. One novel tyrosine kinase gene, designated Tnk1, was cloned. The sequence of the complete Tnk1 coding region predicts a 72 kD protein. Comparison of Tnk1 to available sequences in protein databases reveals that it is most homologous to Ack, an intracellular tyrosine kinase which associates with the GTP-bound form of p21cdc42Hs. Like Ack, Tnk1 consists of an N-terminal kinase domain, a putative SH3 domain immediately C-terminal to the kinase domain, and a proline-rich C-terminal region. Analysis of Tnk1 mRNA expression demonstrates that Tnk1 is expressed in all cord blood, bone marrow and adult blood sub-populations, as well as in most of the leukemia cell lines examined (16 of 20). Hybridization to fetal multi-tissue Northern blots detected several different Tnk1 transcripts in all fetal tissues examined. In contrast, a single Tnk1 transcript was detected in only five of 16 adult tissues examined (prostate, testis, ovary, small intestine and colon). Fluorescence in situ hybridization (FISH) analysis of metaphase chromosomes localized the Tnk1 gene to the short arm of chromosome 17 (17p13.1), near the p53 locus. Thus, Tnk1 is a novel tyrosine kinase that may be involved in signalling pathways utilized broadly during fetal development, more selectively in adult tissues and in cell of the lymphohematopoietic system.

Factors associated with fatal outcome in childhood meningococcal disease.

The purpose of this study was to identify factors associated with a fatal outcome in children with meningococcal disease and to design a new clinical scoring system. We reviewed the charts of all 137 children with meningococcal disease admitted alive to the University Hospital, Tromsø, during the years 1977-92. Twelve of the children died (8.7%). On admission the following clinical signs were significantly associated with poor outcome: peripheral vasoconstriction, cyanosis, extensive petechiae, hypotension, altered consciousness, hyperventilation and absence of neck rigidity. The laboratory parameters low pH, low base excess, thrombocytopenia, low Trombotest and leukopenia were also associated with later death. Multiple logistic regression was performed to examine the independent effect of each variable. Cyanosis, peripheral vasoconstriction and base excess < -10 mmol/l or pH < 7.35 were significantly associated with a fatal outcome. A clinical scoring system based on the extent of petechiae, the presence of peripheral vasoconstriction, hyperventilation and/or cyanosis, the absence of neck rigidity and impairment of consciousness is proposed. Twenty-nine patients received > or = 3.5 points, of whom 12 died and 12 survived. None of the patients who died had less than 3.5 points. The clinical scoring system is based solely on clinical signs. It can be done rapidly and performs well in identifying children who might benefit from early intensive care.

How much is too much? Folinic acid rescue dose in children with acute lymphoblastic leukaemia.

The effect of folinic acid rescue dose on the event-free survival of 71 children with acute lymphoblastic leukaemia was examined in a retrospective clinical study. All patients, diagnosed between 1 January 1980 and 1 January 1989, were treated according to the Norwegian Pilot protocol which included eight courses of high dose (6-8 g/m2/24 h intravenous infusion) methotrexate. Following the infusion, a uniform dose of 75 mg (at 36 h after the beginning of the drug infusion) and 15 mg (at 39-106 h) folinic acid rescue was administered to all patients, at predetermined intervals. The uniformity of the rescue dose resulted in distribution of dosages in the range of 38-140 mg/m2 and 7.5-28 mg/m2 for the different periods, respectively, when the dose was recalculated on the basis of the body surface area of the individual patients. The event-free survival of children receiving less or more than 15 mg/m2 (75 mg/m2) rescue dose was compared. Although no significant difference was found, a tendency was observed for a lower risk of relapse in patients receiving less folinic acid. No major methotrexate-related toxicity was observed in the group of patients receiving the lower dose of rescue. These observations suggest that the reduction of folinic acid rescue dose below the generally accepted 12-15 mg/m2 dose may increase the efficacy of high-dose methotrexate therapy while still remaining safe in preventing treatment-related toxicity. Prospective, randomised clinical trials are needed to examine the role of rescue as a determinant of effective exposure to methotrexate in patients receiving high-dose methotrexate treatment.

[Neurofibromatosis and development of cancer in childhood]. / Neurofibromatose og kreftutvikling i barnealderen.

Neurofibromatosis takes two major forms; classical or peripheral neurofibromatosis as described by von Recklinghausen, which accounts for more than 90% of the cases, and central or bilateral acoustic neurofibromatosis. The diagnosis is often postponed until adulthood, since the classical signs gradually appear during childhood and adolescence. It is a relatively common autosomal dominant disorder affecting about one in 3,000. At least 20% of patients will develop one or more complications associated with neurofibromatosis. One of the complications is the development of malignancies. Four children at our hospital developed different forms of malignant tumours arising from neurofibromatosis. We recommend that all patients suffering from this disease are evaluated in detail after the diagnosis has been confirmed and are followed up every six to 12 months. In this way complications may be discovered early and the necessary steps taken.

BK virus infection in children with cancer: serological response studied by haemagglutination inhibition, neutralization, and IgG- and IgM-class specific ELISA tests.

We recently developed enzyme-linked immunosorbent assays (ELISAs) for the detection of anti-BK virus IgG- and IgM-antibodies, and also a convenient and rapid serum neutralization test. Complemented by a traditional haemagglutination inhibition test (HAI) these methods were used to investigate the longitudinal response to BKV infection in sequentially taken sera from 29 children under treatment for cancer. In separate experiments it was shown that the results were not at any extent influenced by antibodies against other polyomaviruses. At the time of diagnosis the prevalence of specific IgG- and IgM-antibodies and the geometric mean IgG levels were not significantly different for the patients compared with a group of healthy children. The primary infections seemed to occur at the same age for the two groups of children. Seven of the patients had a primary infection with BKV. The results indicate that the host response in moderately immunosuppressed children during primary infection is the same as expected for healthy individuals with the development of specific IgG, HAI, and NT antibodies, and, usually, production of BKV-IgM for several months. The results indicated that whether specific IgM was demonstrated in the first sample or appeared later during a reactivation episode, this parameter was correlated with profound immunosuppression. Significant titre changes, detectable IgM antibodies and/or seroconversions were demonstrated in 69% (20/29) of the cancer patients. Such indications of recent viral activity was recorded in 42% (8/19) of children with meningococcal infections. The observation periods for the two groups of patients are, however, not directly comparable.