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.

Health and persistent functional late effects in adult survivors of childhood CNS tumours: a population-based cohort study.

Survivors of central nervous system (CNS) tumours are particularly vulnerable to tumour- and treatment-related disability. We present the incidence of specific and overall functional and health-related late effects in a national adult survivor cohort. Diagnostic subgroups at particular risk for persistent sequels are identified. Data collection targeted 708 eligible >18 years old survivors, 708 parent proxies and 1000 general population controls. Functional disability including sensory and cognitive impairment, emotional status and pain was assessed using the Health Utilities Index Mark 2/3 (HUI2/3). Survivors and controls, and diagnostic subgroups were contrasted to identify the general and relative risk for late effects by sub-diagnosis. Survivors had persistent late effects in sensation, mobility, self-care and cognition. Deficits in these domains indicated clinically important disability in overall health, although indices of emotion and pain were unaffected compared to controls. Late effects tended to aggravate with time, and female survivors had poorer health. Oligodendroglioma, mixed/unspecified glioma, intracranial germ cell tumour and medulloblastoma survivors had poorest overall health. Least late effects were found for other specified/unspecified CNS tumours (including meningeoma and nerve sheath tumours), and for astrocytoma. An impact on educational, vocational and family-related outcomes, and higher utilisation of social insurance or government subsidies validated health-related sequelae in adulthood. Comparisons with controls confirm persistent disability in multiple functional domains in adult CNS tumour survivors. The heightened proportion of survivors presenting severe disability is a factor that specifically differentiates survivors from controls, although diagnostic subgroups differ significantly regarding the amount and severity of late effects.

Acute lymphoblastic leukemia in adolescents between 10 and 19 years of age in Denmark--secondary publication.

INTRODUCTION: Data seem to indicate that young adults with acute lymphoblastic leukemia (ALL) have a better survival when treated with pediatric protocols compared with adult ALL protocols. The purpose of the study was to report the clinical characteristics and outcome of all children and young adults 10-19 years of age diagnosed with ALL in Denmark between 1992 and 2001. MATERIAL: The study includes 99 patients 10-19 years of age with ALL in Denmark during a ten year period found in the complete NOPHO (Nordic Society of Pediatric Hematology and Oncology) registry and through the Danish Cancer Registry and local pathology databases. Data were retrieved by reviewing medical charts of the patients. A total of 61 children (10-14 years) treated on pediatric protocols and 38 young adults (15-19 years) were diagnosed with ALL. Data were reported as of January 1st 2005. RESULTS: There were no difference with respect to the distribution of T-ALL, CNS-leukemia, total white blood count and high risk chromosomal abnormalities between the two groups. There was a statistical significant lower event free survival (p<0.01) and lower overall survival (p<0.01) in young adults compared with 10-14 year-old children (0.38 vs 0.60 and 0.47 vs 0.67). There were more transplant-related deaths in the young adults. Higher treatment intensity in children may be an additional explanatory factor. Children received more prednisone, vincristine and high-dose methotrexate than young adults. CONCLUSION: Young adult patients with ALL might benefit from therapy with pediatric NOPHO ALL protocols.

Long-term results in children with AML: NOPHO-AML Study Group--report of three consecutive trials.

In all, 447 children with acute myeloid leukaemia (AML) have been treated on three consecutive NOPHO studies from July 1984 to December 2001. NOPHO-AML 84 was of moderate intensity with an induction of three courses of cytarabine, 6-thioguanine and doxorubicin followed by four consolidation courses with high-dose cytarabine. The 5-year event-free survival (EFS), disease free survival (DFS) and overall survival (OS) were 29, 37 and 38%. NOPHO-AML 88 was of high intensity with the addition of etoposide and mitoxantrone in selected courses during induction and consolidation. The interval between the induction courses should be as short as possible, that is, time intensity was introduced. The 5-year EFS, DFS and OS were 41, 48 and 46%. In NOPHO-AML 93, the treatment was stratified according to response to first induction course. The protocol utilised the same induction blocks as NOPHO-AML 88, but after the first block, children with a hypoplastic, nonleukaemic bone marrow were allowed to recover before the second block. Consolidation was identical with NOPHO-AML 88. The 5-year EFS, DFS and OS in NOPHO-AML 93 were 48, 52 and 65%. The new NOPHO-AML protocol has been based on experiences from previous protocols with stratification of patients with regard to in vivo response and specific cytogenetic aberrations.

Cassini measurements of cold plasma in the ionosphere of Titan.

The Cassini Radio and Plasma Wave Science (RPWS) Langmuir probe (LP) sensor observed the cold plasma environment around Titan during the first two flybys. The data show that conditions in Saturn's magnetosphere affect the structure and dynamics deep in the ionosphere of Titan. The maximum measured ionospheric electron number density reached 3800 per cubic centimeter near closest approach, and a complex chemistry was indicated. The electron temperature profiles are consistent with electron heat conduction from the hotter Titan wake. The ionospheric escape flux was estimated to be 10(25) ions per second.

Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage.

Rearrangements in the 11q23 region, the site of the mixed lineage leukaemia (MLL) gene, are found in both childhood acute myeloid (AML) and lymphoblastic (ALL) leukaemia. We studied the in vitro drug resistance by the fluorometric microculture cytotoxicity assay (FMCA) in 132 children with AML and 178 children with ALL (aged 0-17 years). In AML, children with t(9;11) (n = 10) were significantly more sensitive to cytarabine (P < 0.001) and doxorubicin (P = 0.005) than non-11q23 rearranged patients (n = 108). Children with other 11q23 rearrangements (n = 14) differed less from non-rearranged children. The 'AML-profile' common to all three groups included relative resistance to glucocorticoids and vincristine. In ALL, children with 11q23 rearrangement (n = 22) were significantly more sensitive to cytarabine (P = 0.026) than children without 11q23 rearrangement (n = 156), also after stratification for white blood cell count. In conclusion, the findings indicate that the cellular drug resistance is correlated to both the cell lineage and the type of 11q23 rearrangement. High cellular sensitivity to cytarabine and doxorubicin might explain the excellent treatment results in children with AML and t(9;11). The present study supports the strategy of contemporary protocols to include high-dose cytarabine in the treatment of 11q23-positive patients both in AML and ALL.

Radio and plasma wave observations at Saturn from Cassini's approach and first orbit.

We report data from the Cassini radio and plasma wave instrument during the approach and first orbit at Saturn. During the approach, radio emissions from Saturn showed that the radio rotation period is now 10 hours 45 minutes 45 +/- 36 seconds, about 6 minutes longer than measured by Voyager in 1980 to 1981. In addition, many intense impulsive radio signals were detected from Saturn lightning during the approach and first orbit. Some of these have been linked to storm systems observed by the Cassini imaging instrument. Within the magnetosphere, whistler-mode auroral hiss emissions were observed near the rings, suggesting that a strong electrodynamic interaction is occurring in or near the rings.

Outcome of children with high-risk acute lymphoblastic leukemia (HR-ALL): Nordic results on an intensive regimen with restricted central nervous system irradiation.

BACKGROUND: Improvement in outcome of childhood high-risk (HR) ALL was sought with a very intensive Nordic protocol leaving most patients without CNS-RT. METHODS: A total of 426 consecutive children entered the NOPHO-92 HR-ALL program. HR criteria included WBC > or =50 x 10(9)/L, CNS or testicular involvement, T-cell, lymphomatous features, t(9;22), t(4;11), or slow response. Of these, 152 children had very high risk (VHR) with special definitions. CNS consolidation was based on high-dose MTX (8 g/m2) and ARA-C (12 g/m2) alternating. VHR patients also received cranial RT. RESULTS: The 9-year EFS was 61 +/- 3%, OS 74 +/- 2%, and EFS for T-ALL 62 +/- 4%. Cumulative incidence of isolated CNS relapse was 4.7 +/- 1%, and CNS relapse in total 9.9 +/- 2%. Poor prognostic factors were WBC > or =200 x 10(9)/L and a very slow response. CONCLUSIONS: HR-ALL was successfully treated on the NOPHO-92 regimen, with a relatively low CNS relapse rate for non-irradiated children. WBC > or =200 x 10(9)/L and very slow response emerged as strong poor prognostic factors.

Slow magnetosonic solitons detected by the cluster spacecraft.

Experimental evidence is provided for the existence of slow-mode magnetosonic solitons in the col-lisionless plasma at the magnetopause boundary layer. The solitons were detected by the fleet of Cluster spacecraft at the dusk flank of the magnetosphere as magnetic field depressions (up to 85%) accom-panied with enhancement of the plasma density and temperature by a factor of 2. The solitons propagate 250 km/s with respect to the satellites and have perpendicular size of 1000-2000 km, which is a few ion inertial scale lengths. The comparison with numerical solutions of a theoretical model shows quantitative agreement between the model and observations.

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.

Real-time quantitative PCR assays for deoxycytidine kinase, deoxyguanosine kinase and 5'-nucleotidase mRNA measurement in cell lines and in patients with leukemia.

The relative levels of the deoxycytidine kinase (dCK), deoxyguanosine kinase (dGK), and the 5'-nucleotidase (5'-NT) are of importance for the effect of many nucleoside analogues used in the treatment of hematological malignancies. To elucidate dCK, dGK and 5'-NT gene expressions in cell lines and in samples from patients with leukemia, we have established a real-time quantitative PCR (RQ-PCR) method. From the available dCK, dGK and 5'-NT cDNA sequences we designed specific primers and fluorogenic probes for the respective genes. The mRNA of dCK, dGK and 5'-NT was also measured by semi-quantitative RT-PCR, the enzyme activities by a radioactive substrate-based technique and Western blot was used to measure the amount of dCK and dGK protein. A MOLT-4 wild-type and its 9-beta-D-arabinofuranosylguanine (Ara-G)-resistant subline was used for the methods comparisons and the RQ-PCR assay was used in 35 samples from pediatric patients with ALL and AML. The results from RQ-PCR for the cell lines were in agreement with the semi-quantitative RT-PCR. The mRNA expression for dCK, dGK and 5'-NT (expressed as the ratio of the respective gene and the reference gene) in pediatric ALL and AML patients showed a large interindividual variability from 0.06 to 2.34, non-detectable to 0.06 and 0.04 to 0.30, respectively. These results show that the quantitative evaluation by RQ-PCR is a valuable tool in the determination of dCK, dGK and 5'-NT mRNA levels in cell lines and in clinical samples which were expressed at various levels. This rapid, convenient and specific method is suitable for further studies of these genes in clinical samples.

A Swedish study of chemoradiation in squamous cell carcinoma of the esophagus.

This multicenter study describes the development of a chemoradiation protocol for the treatment of non-metastatic squamous cell carcinoma of the esophagus. Eighty patients were treated with three courses of chemotherapy (cisplatinum and 5-fluorouracil) with concomitant radiotherapy (40 Gy) during the last two courses of chemotherapy. Esophagectomy was performed, when feasible. If no operation was performed, patients were planned to receive a target dose of 64 Gy. Toxicity was mainly attributable to hematological impairment and led to two adjustments of the treatment protocol (addition of filgrastim and lowering of the 5-fluorouracil dose). These changes made it possible to administer the planned treatment in a gradually higher proportion of patients (13/23 [57%] before changes of treatment compared with 30/36 [83%] after changes). Treatment-related mortality was 3.75% (3 patients, associated with leucopenic septicemia after chemotherapy). Fifty-four patients were resected. No per- or postoperative mortality was encountered. The complete response (pathological CR) rate in operated patients was 46% (27/59 patients) after chemoradiation. In the whole series the CR rate (including clinical CR for non-resected patients) was 44%. With a minimum follow-up of 37 months, the 3-year survival for the whole group was 31% compared with 57% for the CR patients. Total 5-year survival thus far (July 1999) is 26%.

Outcome after lung cancer surgery. Factors predicting early mortality and major morbidity.

OBJECTIVE: This study was undertaken to assess mortality, complications and major morbidity during the first 30 days after lung cancer surgery and to estimate the significance of presurgical risk factors. METHODS: The study was based on all patients referred for surgery for primary lung cancer from 1 January 1987 to 1 September 1999. There were in total 616 patients with primary lung cancer. Three-hundred and ninety-four were men and 222 women. Postoperative events studied were divided into major and minor complications or death during the first 30 days after surgery. The significance of risk factors for an adverse outcome (defined as death or major complication in the first 30 days postoperatively) was assessed by uni- and multivariate logistic regression analyses. RESULTS: During the study period an increasing number of women and of patients older than 70 years underwent surgery. Overall 30-day mortality was 2.9, 0.6% after single lobectomy and 5.7% after pneumonectomy. Major complications occurred in 54 patients (8.8%). Fifty-eight patients (9.5%) had an adverse outcome during the first 30 days. Male gender, smoker, FEV(1)< or =70% of expected value, squamous cell carcinoma and pneumonectomy were risk factors predicting adverse outcome in the univariate model. Pneumonectomy and FEV(1)< or =70%, were the only independently significant factors for adverse outcome. Only pneumonectomy was independently associated with an increased risk for early death. CONCLUSION: Our results show low mortality and morbidity after lung cancer surgery. However, patients with reduced lung capacity and those undergoing pneumonectomy should be treated with great care, as they run a considerable risk of major complications or death during the first 30 days postoperatively. Older age (>70 years) does not appear to be a contraindication to lung cancer surgery, but patients in this group should undergo careful preoperative evaluation.

No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission.

PURPOSE: We evaluated the outcome of children with acute lymphoblastic leukemia (ALL) in second remission (2CR), comparing bone marrow transplantation (BMT) using either matched sibling donors or unrelated donors (URDs). PATIENTS AND METHODS: A total of 65 patients, aged 2 months to 20 years at BMT, with ALL in 2CR underwent allogeneic BMT at seven Nordic centers during 1990 to 1997. Of the first relapses, 85% were in bone marrow; 46% occurred on therapy, and 54%, off therapy. The preparative regimens were cyclophosphamide plus total-body irradiation +/- antithymocyte/antilymphocyte globulin, busulfan plus cyclophosphamide +/- antithymocyte/antilymphocyte globulin, or cytarabine plus total-body irradiation. Of the allografts, 37 were from HLA-matched siblings and 28 were from URDs. RESULTS: In the sibling versus URD graft recipient groups, the posttransplantation 5-year event-free survival was 39% versus 54% (P =.4), the estimated posttransplantation relapse rate was 76% versus 40% (P = not significant [NS]), and the toxic death rate was 19% versus 11% (P = NS). The incidence of significant (grade 2 to 4) acute graft-versus-host disease (GVHD) was 38% versus 64% (P <.05) and was 14% versus 32% (P <.10) for severe (grade 3 to 4) acute GVHD; the incidence of chronic GVHD was 26% versus 57% (P <.05) and was 13% versus 22% (P = NS) for extensive chronic GVHD in the sibling and URD groups. CONCLUSION: BMT with matched URD allografts offers at least equal survival for children with ALL in 2CR, as compared with allografts from matched sibling donors. URD allografts were not associated with a higher toxic mortality rate, although both acute and chronic GVHD were more frequent with URD. Indications for using matched URD allografts in ALL 2CR can be considered the same as for using matched sibling donors.

Release of heat, moisture and carbon dioxide in an aviary system for laying hens.

1. Production of total heat, divided into sensible and latent heat, together with carbon dioxide and animal activity were determined at different ambient temperatures under full-scale conditions in an aviary system with loose-housed laying hens. 2. Sensible heat production decreased approximately linearly with increasing ambient temperature and was lower during the day than at night. One explanation may be that some sensible heat produced by the hens was converted to latent heat by evaporation of moisture due to increased activity of the hens during the day (scratching in the bedding and drinking/waste water). 3. Latent heat production increased with increasing ambient temperature and was higher during the day than at night. This confirms that the hens, by agitating the bedding during the day and by spilling drinking water, transferred some sensible heat to latent heat by evaporation. 4. Total heat production decreased with increasing temperature because the hens by thermoregulation decreased their metabolism in order to maintain a constant body temperature. The difference between day and night values of total heat production was less pronounced than in the case of sensible and latent heat. In comparison with current guidelines the measurements showed a higher total heat production (22% higher at 20 degrees C). 5. There was a large diurnal variation in carbon dioxide production, closely correlated to measured animal activity; on average carbon dioxide production during the 12-h dark period was only 66% of the production during the day.

Possible reasons for the prognostic value of troponin-T on admission in patients with ST-elevation myocardial infarction.

BACKGROUND: In patients with acute myocardial infarction and ST-segment elevation, increased troponin-T (TnT) on admission implies an increased mortality. OBJECTIVE: To elucidate the underlying mechanisms of the prognostic value of TnT. METHODS AND RESULTS: One hundred and one patients were included and all received thrombolytic treatment. The patients were compared according to TnT level on admission (cut-off 0.1 microg/l). Elevation of TnT was associated with long-term mortality and also with longer delay, more episodes of chest pain during the last 24 h and fewer noninvasive signs of reperfusion at 90 min. In the group with elevated TnT, the coronary angiography at 24 h showed a strong trend towards lower patency in the infarct-related artery. TnT was also associated with increased infarct size if a higher cut-off level (0.43 microg/l) was used. In univariate analysis, elevated TnT, longer delay, repeated chest pain, Q-waves on admission and reduced left ventricular (LV) function were significantly associated with long-term mortality. In multivariate models, only reduced LV function and less than TIMI (thrombolysis in myocardial infarction) grade 3 flow turned out to be significant independent risk factors. CONCLUSIONS: The prognostic value of TnT level on admission regarding long-term mortality was confirmed and seems mainly to be explained by its association with longer delay and recent myocardial damage, but its association with reduced effect of thrombolytic treatment, larger infarct size and impaired LV function might also be of importance.

Prognostic impact of karyotypic findings in childhood acute lymphoblastic leukaemia: a Nordic series comparing two treatment periods. For the Nordic Society of Paediatric Haematology and Oncology (NOPHO) Leukaemia Cytogenetic Study Group.

The prognostic impact of acquired chromosome abnormalities was evaluated in a population-based consecutive series of 768 children (< 15 years of age) with acute lymphoblastic leukaemia (ALL). The study cohort included all cases of cytogenetically abnormal childhood ALL diagnosed between 1986 and 1997 in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). The probability of event-free survival (pEFS) for the total cohort was 0. 72 +/- 0.02. When comparing the two treatment periods of July 1986 to December 1991 and January 1992 to December 1997, a better survival was seen for the latter time period (pEFS of 0.69 +/- 0.02 vs. 0.76 +/- 0.02, P = 0.05). Hypodiploidy with less than 45 chromosomes, t(9;22)(q34;q11) and 11q23 translocations were associated with a dismal outcome during the whole study period (pEFS of 0.57 +/- 0.12, 0.41 +/- 0.14 and 0.37 +/- 0.10 respectively). The poor prognostic influence of 11q23 rearrangements seemed to be restricted to infants and older children (> 10 years), who differed significantly from children aged 1-10 years in this regard (P < 0. 01). Patients with t(9;22)-positive ALL seemed to benefit from allogeneic bone marrow transplantation in first remission (P = 0.05). The pEFS for children with t(1;19)(q23;p13)-positive ALL was intermediate (0.63 +/- 0.17), with a tendency to a better outcome for patients with the unbalanced variant der(19)t(1;19). Hyperdiploid ALL patients, subdivided into moderate hyperdiploidy (47-51 chromosomes), massive hyperdiploidy (52-60 chromosomes) and cases in the tri-/tetraploid range (> 60 chromosomes) had the best outcome in the last treatment period (pEFS of 0.81 +/- 0.06, 0.80 +/- 0.04 and 0.88 +/- 0.07 respectively), unless t(1;19), t(8;14), t(9;22) or 11q23 translocations were present. In a multivariate analysis including white blood cell (WBC) count, immunophenotype, age, mediastinal mass, central nervous system involvement and leukaemia karyotype, only WBC and modal chromosome number were shown to be significant independent risk factors (P < 0.01).

Early diagnosis and exclusion of acute myocardial infarction by two hours' vector-ECG and determination of either myoglobin or CK-mb. BIOMACS-study. BIOchemical Markers in Acute Coronary Syndromes.

This retrospective study assesses the early diagnostic potential of a combination of multilead continuous vectorcardiography (VCG) and biochemical markers (myoglobin, troponin-t and CK-mb mass) in patients with chest pain who present with suspected acute myocardial infarction (AMI), but without ST-elevation on resting 12-lead ECG on admission. Within a multicenter study 56 patients admitted for chest pain (< 12 h) and with a non-diagnostic 12-lead ECG on admission and a VCG recording were included. Venous blood samples were drawn on admission and the continuous VCG was monitored for 2 h. The results were related to the clinical diagnosis of AMI. Neither the biochemical markers nor VCG alone permitted the diagnosis or exclusion of AMI at admission. However, if either analysis of myoglobin on admission or 2 h of VCG recording were positive, they would have a sensitivity for detection of AMI of 100% and specificity of 69%. In a subset of patients with more than 4 h delay since start of chest pain, CK-mb could replace myoglobin and give a sensitivity of 100% and a specificity of 81%. Determination of myoglobin or CK-mb at admission and VCG monitoring for 2 h can reliably confirm or exclude AMI within 2 h. This combination seems useful for early stratifications of patients in chest pain or coronary care units.