Increased uptake of social security benefits among long-term survivors of cancer in childhood, adolescence and young adulthood: a Norwegian population-based cohort study.

BACKGROUND: As the number of cancer survivors increases, their health and welfare have come into focus. Thus, long-term medical consequences of cancer at a young age (<25 years), obtained from social security benefit records, were studied. METHODS: Standardised incidence ratios (SIRs) of long-term medical consequences for 5-year cancer survivors, born during 1965-1985, were explored by linking population-based registries in Norway. RESULTS: Among the 5-year cancer survivors (4031 individuals), 29.7% received social security benefits. The survivors had an overall 4.4 times (95% confidence interval (95% CI): 4.1-4.6) higher risk of social security benefit uptake than the cancer-free population. Survivors of malignancies of bone and connective tissues (SIR: 10.8; 95% CI: 9.1-12.9), CNS tumours (SIR: 7.7; 95% CI: 6.9-8.6) and malignancies of the haematopoietic system (SIR: 6.1; 95% CI: 5.3-7.0) had the highest risks of social security benefits uptake. The most notified causes of social security benefit uptake were diseases of the nervous system, and injury and poisoning. CONCLUSION: The uptake of social security benefits among 5-year cancer survivors increased substantially and it may represent a solid outcome measure for the burden of the most severe late effects, especially in countries with comparable social welfare systems.

Plasma homocysteine in children with acute lymphoblastic leukemia: changes during a chemotherapeutic regimen including methotrexate.

Plasma homocysteine was determined in 12 children with acute lymphoblastic leukemia. The patients were investigated prior to chemotherapy (stage I), during seven weeks of induction chemotherapy (stage II), and thereafter during intermittent high-dose methotrexate (HD-MTX) therapy (stage III). The patients were followed for a period of three to 15 months, and the study included a total of 80 HD-MTX courses. Before start of chemotherapy (stage I), the average plasma homocysteine level in the children with leukemia was 13.18 +/- 6.23 (SD) mumol/liter, which is significantly (P less than 0.001) higher than the level in control children (6.52 +/- 1.21 mumol/liter). The plasma homocysteine level in the patients was positively correlated with the peripheral white blood cell count (P less than 0.01) and negatively correlated with serum folate (P less than 0.02). The serum folate was normal or subnormal in these patients. During induction therapy with cytotoxic drugs such as vincristine, asparaginase, and intrathecal MTX (stage II), there was a drastic change in plasma homocysteine as a function of time. A reciprocal alteration in serum folate was observed, suggesting fluctuating intracellular folate status at this stage of therapy. At the end of stage II (about seven weeks), there was a significant (P less than 0.01) reduction in total homocysteine (to 7.08 +/- 3.84 mumol/liter). HD-MTX (8 g/m2) therapy with 5-formyltetrahydrofolate "rescue" (stage III) was usually begun about seven weeks after start of chemotherapy, and the patients were followed for two to eight courses separated by three to eight weeks. Plasma homocysteine showed a transient increase (26-64%) following each MTX infusion. After three MTX infusions, basal total plasma homocysteine was reduced to 5.56 +/- 1.12 mumol/liter. During most MTX infusions, there was a variable reduction (17-56%) in plasma methionine followed by a rebound increase. It is concluded that plasma homocysteine in children with acute lymphoblastic leukemia is elevated prior to therapy, probably because of occasional folate deficiency and increased burden of proliferating cells. During induction therapy, monitoring plasma homocysteine and serum folate both suggest a labile folate homeostasis, usually a deficiency state. HD-MTX induced a temporary intracellular folate depletion before 5-formyl-tetrahydrofolate was administered, as judged by a transient homocysteinemia. The methionine depletion may interfere with the antileukemic effect of MTX.

Deletion of the Ink4-locus (the p16ink4a, p14ARF and p15ink4b genes) predicts relapse in children with ALL treated according to the Nordic protocols NOPHO-86 and NOPHO-92.

Inactivation of the Ink4 gene locus locus on 9p comprising the tumour suppressor gene p16ink4a and its neighbours p14ARF and p15ink4b is common in childhood acute lymphoblastic leukaemia (ALL), but the prognostic significance is controversial. DNA from 230 patients was retrospectively analysed by Southern blotting, single strand conformation polymorphism (SSCP) and sequencing techniques. The results were correlated with clinical characteristics and outcome. One hundred and ninety-four fully analysed patients, similarly treated using the Nordic NOPHO-86 or the current NOPHO-92 protocols, were included in the outcome analysis. Deletions approached a minimally deleted region between the p16ink4a and p15ink4b genes, making the p14ARF gene the most commonly deleted coding sequence. Bi-allelic deletion was associated with high white blood cell count (WBC) (P < 0.001), T cell phenotype (P < 0.001) and mediastinal mass (P < 0.001). Patients with Ink4 locus bi-allelic deletions had an inferior pEFS (P < 0.01) and multivariate analysis indicated that bi-allelic deletion of the p16ink4a and the p14ARF genes was an independent prognostic risk factor (P < 0.05). Sub-group analysis revealed a pronounced impact of deletion status for high-risk patients, ie with high WBC. Deletion-status and clinical risk criteria (WBC) could thus be combined to further differentiate risk within the high-risk group. The analysis of the Ink4 locus adds independent prognostic information in childhood ALL treated by Nordic protocols and may help in selection of patients for alternative treatment.

Rational use of blood products.

Blood product transfusions can be life saving and must be considered in the supportive care of children of any age with underlying oncological or haematological problems, as well as after major surgery or after serious trauma. Paediatric transfusions are particularly challenging because life-long effects of transfusion complications are more durable and serious in children than in adults, in whom the median age at transfusion is >70 years (Tynell E, Norda R, Shanwell A, Björkman A. Long-term survival in transfusion recipients in Sweden, 1993. Transfusion 2001, 41, 251-255). While the general indications for transfusions in paediatric patients are similar to adults, the threshold, volumes and infusion rates for transfusions vary with age. In this Update, we discuss current blood products, then suggest transfusion "triggers" in major surgery and haematological and oncologic practice. Finally, future developments and new possibilities are considered.

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.

A simplified method for the preparation of EAC14.

Sheep erythrocytes (E), sensitized with unheated rabbit antiserum containing IgG antibodies (EA), bound human C4 when heat-inactivated serum was used as the source of complement (EAC). The EA were not agglutinated by antiserum to rabbit C3 and were not lysed in the presence of C4-deficient guinea pig serum. The EAC were agglutinated by antiserum to human C4, lysed by the addition of C4-deficient serum and were reactive in immune adherence. They were not agglutinated by antiserum to human C3. Accordingly, the cells could be designated as EAC14. They were stable and could be stored at 4 degrees C for at least 1 week without haemolysis occurring, and with no loss of reactivity in immune adherence test. E sensitized in the presence of EDTA or with heat-inactivated rabbit serum did not bind C4.

Competitive PCR for quantification of minimal residual disease in acute lymphoblastic leukaemia.

A very precise and reproducible polymerase chain reaction (PCR) method was developed in order to quantify minimal residual disease (MRD) in children with acute lymphoblastic leukaemia (ALL). A clone-specific competitor was constructed by introducing a restriction site in a PCR product identical to parts of the highly specific rearranged T-cell receptor delta (TCR-delta), T-cell receptor gamma (TCR-gamma), or immunoglobulin heavy chain (IgH) genes of the malignant clone. Using primers located externally to the restriction site the competitor and the DNA from the malignant clone will be amplified under identical conditions. After restriction enzyme cleavage, the PCR products originating from the competitor and the malignant clone can be distinguished by size in a gel electrophoresis step and the amount of residual disease can be determined. The method is very sensitive with a detection limit of at least one malignant cell in 10(5) normal cells. This method may be used for treatment stratification based on the early response to antileukaemic therapy.

The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse.

Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (>or=10 years) and 176 non-adolescents (<10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) <50 x 10(9)/l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS(12y):0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r(S)=0.36, P=0.02), which became nonsignificant for those who relapsed (r(S)=0.05, P=0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P=0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient=0.65, P=0.003) than for non-adolescents (coefficient=0.42, P=0.04). Adolescents had higher mean neutrophil counts (P=0.002) than non-adolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r(S)=0.38, P=0.02), which was not the case for those who developed a relapse (r(S)=0.15, P=0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.

Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study.

Myelotoxicity during thiopurine therapy is enhanced in patients, who because of single nucleotide polymorphisms have decreased activity of the enzyme thiopurine methyltransferase (TPMT) and thus more thiopurine converted into 6-thioguanine nucleotides. Of 601 children with acute lymphoblastic leukemia (ALL) who were treated by the NOPHO ALL-92 protocol, 117 had TPMT genotype determined, whereas for 484 patients only erythrocyte TPMT activity was available. The latter were classified as heterozygous, if TPMT activity was <14 IU/ml, or deficient (<1.0 IU/ml). 526 patients had TPMT wild type, 73 were presumed heterozygous, and two were TPMT deficient. Risk of relapse was higher for the 526 TPMT wild type patients than for the remaining 75 patients (18 vs 7%, P=0.03). In Cox multivariate regression analysis, sex (male worse; P=0.06), age (higher age worse, P=0.02), and TPMT activity (wild type worse; P=0.02) were related to risk of relapse. Despite a lower probability of relapse, patients in the low TPMT activity group did not have superior survival (P=0.82), possibly because of an excess of secondary cancers among these 75 patients (P=0.07). These data suggest that children with ALL and TPMT wild type might have their cure rate improved, if the pharmacokinetics/-dynamics of TPMT low-activity patients could be mimicked without a concurrent excessive risk of second cancers.

Prevalence of Norwegian patients diagnosed with childhood cancer, their working ability and need of health insurance benefits.

The object of this study was in a population-based material to investigate the prevalence of patients diagnosed with childhood cancer, and compared to the general population to assess working ability, yearly income and need for health insurance benefits in patients surviving at least five years after treatment for childhood CNS tumours or hematological malignancies. During the period January 1, 1970 to December 31, 2002 the prevalence in the Norwegian population of patients diagnosed with any childhood cancer increased from 12.2 (473/3 888 305) to 65.1 (2944/4 524 066) per 100 000 population. The proportion of survivors in need of any health insurance benefit was for CNS tumours 47.1% and for hematological malignancies 21.0%. The proportion in the age group 16-67 receiving disability pension for CNS tumours was 94/454 (20.7%) compared to 21/575 (3.7%) for patients treated for hematological malignancies (p < 0.001). Of patients given radiotherapy 25/70 (35.7%) received disability pension, compared to 90/959 (9.4%) in unirradiated patients, p < 0.001. Yearly income and working ability was particularly low for CNS tumour survivors. This study illustrates loss of working capability associated with pediatric cancer and treatment and long-term requirement of health insurance benefits.

Children with acute lymphoblastic leukaemia have high plasma levels of total homocysteine at time of diagnosis.

OBJECTIVE: Cancer can induce venous thromboembolic complications for various reasons. As part of a greater study, acquired and congenital prothrombotic risk factors were investigated in children with leukaemia or non-Hodgkin's lymphoma and compared with similar investigations in children with congenital heart defects. MATERIAL AND METHODS: Blood samples were taken from 60 children with newly diagnosed leukaemia or lymphoma and 133 children with congenital heart defects in the course of a scheduled cardiac catheterization. When children with cancer were in remission, analyses of acquired prothrombotic risk factors were repeated. Children with cancer were observed for symptoms of thromboembolism throughout their treatment period. RESULTS: Total homocysteine levels were significantly raised in children with cancer (median value 10.0 micromol/L) as compared with the levels in children with congenital heart diseases (5.0 micromol/L) (p<0.001), while children with acute lymphoblastic leukaemia had the highest values. The median level of lipoprotein(a) was slightly increased in children with newly diagnosed leukaemia or lymphoma (105 mg/L versus 100 mg/L, p<0.001), and levels of coagulation inhibitors were higher (p<0.001). Total homocysteine levels normalized when children attained remission of cancer disease. Two children had symptoms of acute thrombosis. CONCLUSIONS: Raised concentrations of total homocysteine were frequent in children with newly diagnosed cancer, but this normalized when the children were in remission. The clinical significance of our observations and the impact on venous thromboembolism have yet to be defined.

Characterization of heat eluates of human malignant tissues.

Eluates of 13 malignant and 17 normal tissues were prepared at 56 degrees C using the continuous flow technique. Albumin was detected in all the eluates. IgG, IgA, C3 or haptoglobin were detected in most of the malignant and some of the normal tissues. Carcinoembryonic antigen, beta 2-microglobulin, alpha 1-antitrypsin or alpha 1-antichymotrypsin were detected in some of the eluates of the malignant tissues only. IgM, IgD, C1q, C4, Cl-INH, alpha 1-macroglobulin, beta 2-lipoprotein, fibrinogen and alpha 1-foetoprotein were not detected in any of the eluates. The ratio of the concentration of albumin to the concentration of IgG was similar in extracts and eluates of all the normal tissue and in 3 of the malignant tissues indicating non-specific binding of IgG.

Fragments and subclasses of IgG in eluates of human malignant tissues.

Eluates of 13 malignant tumours were prepared at 56 degrees C using the continuous flow technique. By using immunodiffusion techniques, 50--80 per cent of the IgG detected was found to be of the IgG1 subclass. The ratio of Ig/kappa to Ig/lambda was similar in eluates and in the corresponding extracts, and this ratio was similar to that obtained using pooled human serum. This indicates a normal distribution of IgG subclasses in the eluates. Besides whole IgG, the eluates and corresponding extracts contained fragments of IgG. This was revealed by using sodium dodecyl sulphate electrophoresis (SDS-PAGE). However, since parts of the IgG associated with human malignant tumours can be non-specifically bound, and since fragments of IgG was found in extracts and eluates of normal tissues, although to a lesser degree than in those of malignant tissue, no conclusive evidence was obtained that the malignant tissue could degrade Ig. SDS-PAGE of extracts and eluates of malignant tissues showed 2--3 constant bands not detected in isolated IgG or in extracts and eluates of most of the normal tissues. These bands were not identified.

Tissue reactivity of IgG eluted from human carcinomas.

Mixed haemagglutination with tissue sections was used to study the tissue reactivity of IgG eluted from human carcinomas. IgG eluted from 21 of 29 tumours, bound to the autologous tissue. The binding was mediated through the Fab-portion, and the bound IgG had an intact Fc-portion. Most eluted IgG bound to the autologous tissue, but binding was also seen to other carcinomas of the same type as well as to other types. In addition, the IgG bound to several cancer-free tissues. Accordingly, the eluates of the 21 tumours contained IgG with a broad tissue reactivity. The eluates of a) the remaining 8 tumours, b)normal tissue, and c) liver tissue from patients with non-malignant diseases, contained IgG which did not bind to any tissue. The IgG associated with these tissues was probably non-specifically bound or bound to receptors in vivo.

Non-specifically bound IgG and Fc gamma receptors in human malignant tissues.

Similar amounts of non-specifically bound IgG were found in the eluates of the same tissues both after the Fc gamma receptor activity (FcRA) had been abolished by disrupting the tissue and when FcRA was intact. This indicates that the non-specifically bound IgG is either not attached to the FcR, or that only the free FcR were abolished. No FcRA was detected in the supernatant of the tissue from which the FcRA was abolished, thus indicating that the FcRA was destroyed.

Fc gamma receptors and IgG associated with human malignant tumours.

Thirteen solid tumours were tested for Fc gamma receptors (FcR) using tissue sections and sheep erythrocytes sensitized with rabbit antibodies as indicator cells. No alteration was found in FcR activity (FcRA) between untreated tissue and tissue homogenized for 2 min or less. More extensive homogenization abolished the FcRA. Tissues homogenized for 1 min were washed at 4C and eluted at 37, 45 and 56C. The FcRA was not altered after elution at 37 and 45C. However, elution at 56C abolished the activity indicating that the FcR were either eluted or destroyed. Tumours which showed a diffuse pattern of FcRA and no non-specifically bound IgG displayed an inverse relationship between the FcRA and the eluted IgG. Such relationship was not found with tumours containing non-specifically bound IgG.

Microcephalus, medulloblastoma and excessive toxicity from chemotherapy: an unusual presentation of Fanconi anaemia.

UNLABELLED: Fanconi anaemia is a genetically and phenotypically heterogeneous disorder with different forms of clinical presentation. In this case the patient had suffered from microcephalus and delayed motor development from birth, but extensive investigation did not disclose any aetiology. At 3.5 y she developed a cerebellar medulloblastoma which was treated with surgery and chemotherapy. Following chemotherapy with alkylating agents she suffered from severe bone marrow aplasia which caused life-threatening infections, feeding problems and impaired kidney function. Fanconi anaemia was suspected, but it took 2 mo before the chromosome fragility test came out positive. From the moment diagnosis of Fanconi anaemia was made, no further active treatment was given. The patient's condition improved for some time, but she relapsed and died exactly 1 y after the first diagnosis of brain tumour. CONCLUSION: Fanconi anaemia must always be suspected in patients who experience excessive toxicity from chemotherapy regardless of the type of malignancy and congenital malformations.

Evidence for non-specifically bound IgG in human tumours.

Heat eluates of homogenized human malignant and normal tissues were prepared using the continuous flow elution technique. IgG antibodies to rabbit erythrocytes served as marker antibodies for non-specifically bound IgG. Eluates of all of the 13 malignant tumours tested contained IgG. Most were eluted at 56C, but considerable amounts also at 37C and 45C. Marker antibodies were present in eluates of 4 of the tumours, indicating that at least parts of the IgG associated with malignant human tumours are non-specifically bound. Eight tumours contained too little IgG to detect marker antibodies, and one contained high amounts of IgG without marker antibodies. Eluates of normal organs contained either no or only small amounts of IgG, although apparently normal kidneys from older individuals contained some more IgG. Marker antibodies were detected in some of the eluates indicating non-specific binding.

IgG and other proteins associated with human carcinomas and cancer-free tissue from the same organs.

Eluates of different were prepared at 56 degrees C using a continuous flow technique. More IgG and other serum proteins were found in liver from patients with non-malignant diseases than in liver tissue from healthy control individuals. Cancer-free liver tissue from patients with carcinomas was similar to that of patients with non-malignant diseases, but liver metastases contained twice the amount of IgG. No differences were found between non-perfused carcinomas of the kidney and cancer-free renal tissue, whereas more IgG was present in perfused carcinomas of the kidney than in cancer-free renal tissue. Most eluates of the malignant tissues and of the cancer-free renal tissue showed a reduced ratio of albumin IgG compared to that of serum or extracts, indicating a binding of IgG to antigens and/or receptors.

Agglutinins to rabbit erythrocytes in extracts of human malignant tissues.

Agglutinins to rabbit erythrocytes in extracts from human malignant tissues were identified as the naturally occurring IgG antibodies in human serum to rabbit erythrocytes. This was revealed by agglutination, absorption, antiglobulin and inhibition tests, immunization of rabbits and immunochemical analyses. The agglutinins can therefore be used as convenient markers for both extracellular immunoglobulin and unspecifically bound immunoglobulin in tumour tissues. Apparently the extracts also contained small amounts of IgA antibodies to rabbit erythrocytes.