Cardiac autonomic dysfunction in survivors of acute lymphoblastic leukemia in childhood

Lower levels of baseline ventilatory function have consistently been associated with increased risk of cardiovascular mortality in prospective studies, but the underlying mechanisms are not known. Increased risk of coronary heart disease is associated with higher serum insulin levels. This report examines the relationship between ventilatory function and indirect measures of insulin resistance. Cross-sectional data from 922 nondiabetic participants in the Normative Aging Study were analysed using multiple linear regression models with adjustment for potential confounders. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were examined in relation to indicators of insulin resistance, i.e. fasting insulin and the fasting insulin resistance index (FIRI). Diabetics were excluded because impaired insulin secretion interferes with the validity of these as measures of insulin resistance. Fasting insulin and FIRI were negatively correlated with FVC and FEV1 (all p< 0.001). These associations persisted after adjusting for potential confounders including age, height, body mass index, waist to hip circumference ratio, physical activity, alcohol intake and smoking in separate multiple linear regression models, for both insulin (all p< or =0.0008) and FIRI (all p< or =0.0001). Negative cross-sectional associations between ventilatory function and indirect measures of insulin resistance were found in nondiabetic males. Insulin resistance may contribute to the previously unexplained association between ventilatory function impairment and cardiovascular mortality. Mechanisms underlying the relationship between insulin resistance and decreased ventilatory function remain to be elucidated.     

Late sequelae of CNS recurrence of acute lymphoblastic leukemia in childhood]

The inheritance complex chromosome translocation is a rare. A familial complex chromosome rearrangement t(1;4;10)(q21.3;q27;q26.1) involving three chromosomes ascertained due to four spontaneous abortions in phenotypically normal childless woman there is presented. Cytogenetic analysis according to classic banding techniques were verified by fluorescent in situ hybridization (FISH) technique.     

Long-term sequelae of therapy for childhood acute lymphoblastic leukaemia

Childhood ALL has provided the model for basic therapeutic principles in the past and now provides the model for late effects studies. Common threads which run throughout the literature in this area of clinical research are the importance of young age with increased vulnerability to long-term treatment induced sequelae and the relatively large contribution of radiation as compared with chemotherapy in the pathogenesis of adverse sequelae. Previous retrospective studies of long-term childhood ALL survivors focused on neuropsychologic changes and anatomic changes in the CNS after cranial irradiation. More recent retrospective studies have made the following new observations: (i) the high frequency of significant short adult stature in those less than 6 years of age at diagnosis who received 24 Gy cranial irradiation; (ii) actuarial risk of 2.5% of developing a second malignancy with approximately one-half of secondary malignancies occurring in the CNS in children 5 years of age or less who received cranial irradiation; (iii) the association of secondary ANLL with epipodophyllo-toxin use, and (iv) delayed cardiac toxicity despite anthracycline dosage reduction. Current therapy regimens, especially in high-risk patients, are both more successful and more intensive than those used in the past. While it will be another decade before many of the long-term sequelae begin to emerge, one can anticipate, based on current experience, some of the problems that will occur.     

Comparative genomic hybridization in childhood acute lymphoblastic leukemia

DNA copy number changes were studied by comparative genomic hybridization (CGH) on bone marrow samples obtained from 72 patients with childhood acute lymphoblastic leukemia (ALL) at diagnosis. The patients had been admitted to the Helsinki University Central Hospital (Finland) between 1982 and 1997. CGH showed DNA copy number changes in 45 patients (62.5%) with a mean of 4.6 aberrations per patient (range, 1 to 22). The results of CGH and chromosome banding analysis were generally concordant, but CGH facilitated specific karyotyping in 34 cases. DNA copy number gains were more frequent than losses (gains:losses, 6:1). Gains of DNA sequences affected almost exclusively whole chromosomes and were most commonly observed in chromosomes 21 (25%), 18 (22.2%), X (19.4%), 10 (19.4%) and 17 (19.4%). The most common partial gain was 1q31-q32 (8.3%). The most common gains of chromosomes 21, 18, X, 10, 17, 14, 4, 6 and 8 appeared concurrently. High-level amplifications of small chromosome regions were sporadic, detected only in two patients (2.8%). Chromosome 21 was involved in both cases. The most common losses were 9p22-pter (12.5%) and 12p13-pter (11.1%). No statistically significant association between the CGH findings and the diagnostic white blood cell count was observed.     

Methotrexate pharmacology and resistance in childhood acute lymphoblastic leukemia

Impressive gains have been made in the therapy of childhood acute lymphoblastic leukemia (ALL) in recent years such that remissions today are commonly achieved in up to 95% of patients and long term disease-free survival rates approach 70%. Methotrexate is a key component in ALL consolidation and maintenance therapies and is administered intrathecally in the prophylaxis and treatment of central nervous system leukemia. Critical determinants of methotrexate sensitivity and resistance (dihydrofolate reductase levels, methotrexate membrane transport, methotrexate polyglutamylation) previously described in cultured cells have recently been identified in lymphoblasts from children with ALL. Heterogenous expressions of increased dihydrofolate reductase or impaired methotrexate transport can be detected in both diagnostic and relapsed ALL specimens by flow cytometry with fluorescent methotrexate analogues. Lymphoblasts from children with ALL synthesize long chain polyglutamates and correlations have been established between the accumulation of methotrexate polyglutamates in ALL blasts and characteristic patient prognostic features. Variations in methotrexate polyglutamate accumulation may reflect changes in polyglutamate synthetic or degradative enzymes, or may be secondary to changes in methotrexate influx or dihydrofolate reductase levels. Other critical elements in treatment response to methotrexate include the dose and route of methotrexate administration, its catabolism to 7-hydroxymethotrexate, and the rate of methotrexate plasma clearance. A unique relationship exists between chromosome 21 and ALL leukemogenesis, and response to treatment including methotrexate. A better understanding of the molecular bases of methotrexate response and the development of methotrexate resistance in childhood ALL should facilitate further improvements in the effectiveness of methotrexate-based chemotherapy for this disease.     

Nature of HLA-associated predisposition to childhood acute lymphoblastic leukemia

A molecular analysis was carried out in 63 sequentially diagnosed childhood acute lymphoblastic leukemia (ALL) patients and 1011 controls to investigate the homozygosity rate for HLA-DR53. HLA-DR53 is associated with acute myeloblastic leukemia at the protein level, and our previous study has shown its association with early-onset chronic myeloid leukemia only in homozygous form at the DNA level. In the present study, the homozygosity rates for DR53 were 17.5 and 13.6% in patients and controls, respectively. Ten of the 11 homozygous patients were boys. In the common ALL group (n = 40), all seven DR53 homozygous patients were boys, and among 19 girls this genotype was not observed (P = 0.006). For males, homozygosity for DR53 revealed a relative risk (RR) of 3.29 (P = 0.008) for common ALL. Five of the 11 relapsed patients were homozygous for DR53. Heterozygous frequencies for HLA-DR53 were not different between patients and controls. Homozygosity for DR53 was associated with a very high relapse rate (45.5 vs 7.7%, P = 0.002, RR = 9.1). These results extended our findings in chronic myeloid leukemia and showed the recessive nature and the male predominance of the interactive HLA influence on the development of childhood leukemia. Molecular mimicry of an HLA-DR53 epitope by oncogenic (retro)viruses or putative susceptibility genes in linkage disequilibrium with HLA-DR53 may be responsible for this association.     

Physical development in patients with acute lymphoblastic leukemia in childhood

Acute lymphoblastic leukaemia (ALL) is one of the readily treatable neoplastic diseases of childhood. One of the late sequelae of treatment can be impaired growth. The authors followed up therefore a group of 63 patients where during childhood a diagnosis of ALL was made. The investigated group was treated according to two fundamental protocols--according to Pinkel's protocol and according to BMF protocols. All patients treated according to Pinkel's protocol had, as part of prevention of leukaemia of the CNS, radiotherapy of the skull, patients treated according to the BMF protocol only when the risk factor was higher than 0.8. The authors investigated in their patients the height and proportionality after termination of all antileukaemic therapy. They found that the height of children, adolescents and adults who suffered from ALL during childhood is average or less. A tendency towards obesity is typical. The authors did not observe a correlation with the total cumulative doses of cytostatics nor a marked correlation with radiotherapy. Impaired growth was more frequent when ALL was diagnosed before the age of 3 years and where the interval after completed therapy was shorter.     

Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia

The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute leukemia. Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in acute lymphoblastic leukemia (ALL). Several large clinical trials of the Berlin-Frankfurt-Münster (BFM) Study Group with more than 3500 patients since 1981 have demonstrated that intensive systemic and intrathecal chemotherapy without or with limited CRT can efficiently prevent central nervous system (CNS) relapses in a large percentage of patients. However, only in low-risk patients prophylactic radiotherapy can be completely and safely replaced by conventional doses of methotrexate. In addition, reduction of chemotherapy in low-risk ALL increased the rate of relapses with CNS involvement. Thus, only a combination of multidrug induction, high-dose methotrexate (HD-MTX) consolidation, and reintensification allowed safe elimination of CRT in low-risk ALL. This approach combined with CRT with 12Gy and 18 Gy in medium and high risk ALL, respectively, reduced the incidence of relapses with CNS involvement to less than 5% (trial ALL-BFM 86). Patients with inadequate response to therapy, or with T-cell ALL, or with overt CNS disease are at particularly high risk for relapse with CNS involvement, and require more systemic and intrathecal chemotherapy combined with cranial irradiation. In B-cell ALL, short intensive chemotherapy pulses including HD-MTX could completely replace radiotherapy. In AML, post-consolidation CRT appears to be advantageous with regard to control of extramedullary as well as systemic relapses.     

L-asparaginase (Leunase) induced pancreatitis in childhood acute lymphoblastic leukemia

PURPOSE: To evaluate the pharmacokinetics of furosemide and torsemide before and after diuresis in patients presenting with marked fluid overload. SUBJECTS AND METHODS: We studied 44 patients with New York Heart Association class III or IV heart failure, ejection fraction < or =40%, and an estimated excess fluid body weight > or =6.8 kg. Oral furosemide or torsemide was administered before and after diuresis. Pharmacokinetic parameters were assessed before and after diuresis. RESULTS: Following diuresis, maximum plasma concentration increased from 11.0+/-5.0 microg/mL to 13.9+/-6.8 with torsemide (P <0.05) and from 3.1< or =1.5 to 3.9+/-1.9 with furosemide (P=0.16). Maximum concentration increased by more than 30% in only one third of the patients. Total absorption (by area under the curve method) increased 6% among patients on torsemide (P=0.38) and 7% among patients on furosemide (P=0.63) and increased >30% in only 1 torsemide and 2 furosemide patients. The time to maximum concentration decreased from 1.40+/-.82 h to 0.81+/-0.36 with torsemide (P <0.01). There were no differences between furosemide and torsemide in the effects of edema on absorption. CONCLUSION: Marked diuresis altered the pharmacokinetics of both furosemide and torsemide in only a small percentage of patients. The use of adequate doses of oral diuretics in edematous patients may be successful, thereby permitting home treatment with oral diuretics and avoiding the cost of hospitalizations or home intravenous administration services.     

Recent advances in B cell acute lymphoblastic leukemia (Burkitt leukemia) therapy in childhood

Acute lymphoblastic leukemia with Burkitt type cells has been described in 1975. Until the mid-1980, with conventional treatments, the prognosis was very poor with very few long-term survivors. Failures were mainly due to central nervous system involvement at diagnosis or relapse. After that period a dramatic improvement has been observed with intensified treatments based on Burkitt's lymphoma therapy regimens. High-dose cyclophosphamide, high-dose methotrexate, high-dose ara-C in compact protocols completed in 6-7 months have been proven useful. 75% of the patients can be cured.     

Thrombotic and hemorrhagic strokes complicating early therapy for childhood acute lymphoblastic leukemia

Sudden cerebrovascular insults occurred during or immediately following remission induction therapy in 4 children with acute lymphoblastic leukemia. In 3, cerebral infarction was due to thrombosis. In the fourth, an intracerebral hematoma developed representing either frank hemorrhaging or a hemorrhagic infarction. None of the patients had central nervous system leukemia or extreme leukocytosis at the time of diagnosis. Symptoms were obtundation, hemiparesis, seizures, and headache. The induction chemotherapy included L-asparaginase which causes deficiencies of antithrombin, plasminogen, fibrinogen, and factors IX and XI. These hemostatic abnormalities may explain the thromboses and bleeding observed in these children.     

Primary central nervous system lymphoma in a child with acute B-cell lymphoblastic leukaemia: consecutive Epstein-Barr virus-related malignancies

OBJECTIVE: The aim of the study was to evaluate the optimization of injection rates with an automatic power injector versus manual injection for contrast-enhanced breath-hold three-dimensional (3D) MR angiography of the abdominal aorta and its branches. SUBJECTS AND METHODS: In a prospective study, 50 patients underwent breath-hold 3D MR angiography (5/2 [TR/TE]; flip angle, 30 degrees) of the abdominal vessels on a 1.5-T system. Each patient received 0.15 mmol/kg of gadopentetate dimeglumine. All patients were randomly assigned to one of five equally sized groups. The contrast bolus was injected manually in group 1, always by the same investigator, who tried to perform a steady injection rate of 2 ml/sec. An automatic injector was used in groups 2-5 with injection flow rates of 0.5 ml/sec, 2 ml/sec, 4 ml/sec, and 6 ml/sec. The start of the MR sequence was tailored individually to the applied volume of contrast material after determination of circulation times by a test bolus. We measured the signal-to-noise and contrast-to-noise ratios as well as the relative vascular enhancement. The visualization of different abdominal vessel segments was independently ranked on a scale of 1-5 (1 = not visible; 5 = excellent visualization) by three reviewers who were unaware of the applied contrast material injection rate. RESULTS: The signal-to-noise and contrast-to-noise ratios of groups 3 and 4 (2 ml/sec and 4 ml/sec, respectively) were significantly (p < .05) higher than the ratios of groups 1, 2, and 5. The average relative vascular enhancement of groups 3 and 4 was significantly higher (p < .05) than the enhancement of all other groups. The contrast bolus applied with a faster injection rate (group 5) did not cover large parts of the K-space, resulting in increased blurring of the vessel contours. The subjective evaluation of large and small diameter vessels showed significantly better results in groups 3 and 4 than in groups 1, 2, and 5. CONCLUSION: The use of an automatic MR power injector proved superior to manual injection of contrast material. The optimal injection rate was 2 ml/sec for 3D breath-hold MR angiography of the abdominal vessels.     

非霍奇金淋巴瘤中枢神经系统累及的诊断和预防

非霍奇金淋巴瘤(NHL)患者中枢神经系统(CNS)累及预后不良,其中位生存期2～6个月.与NHLCNS累及相关参数是年轻、进展期、累及结外部位数、乳酸脱氢酶(LDH)增高和国际预后指标(IPI)积分.最有希望的治疗为自体造血于细胞移植,可延长中数生存期10～26个月.处于CNS侵袭高危状态的某些NHL亚型患者需要早期进行CNS预防,如伯基特淋巴瘤(BL)和淋巴母细胞淋巴瘤(LBL).弥漫性大B细胞淋巴瘤(DLBCL)初期治疗时是否需应用CNS预防久有争议,因为它属于CNS累及(≈5%)的低危群体.危险模式的确定有助于预示NHL的CNS复发.     

Exon 5 mutations in the p53 gene in relapsed childhood acute lymphoblastic leukemia

Thirty seven children with relapsed acute lymphoblastic leukemia (ALL), 25 B-lineage and 12 T-lineage, were analyzed for p53 alterations at different stages of the disease. Loss of heterozygosity (LOH) was detected in the relapse phase in three patients. p53 mutations were identified by single strand conformation polymorphism (SSCP) and sequencing analyzes in seven of the 37 ALL patients (19%); three B-lineage (12%) and four T-lineage (33%). Most of the mutations were identified in the relapse phase. In two exceptional cases, one of the mutations was indicated as a germ line and the other was already present at diagnosis. No p53 mutation was identified in any of the other 20 available bone marrow samples obtained at diagnosis. No correlation between the p53 status and clinical outcome could be determined. The majority of the mutations (four out of seven, 57%) were clustered at exon 5. Our data implicate that p53 exon 5 is a frequent site of mutations in relapsed childhood ALL.     

Toxicity of CNS prophylaxis for childhood leukemia

Long-term neurotoxicity associated with central nervous system (CNS) prophylaxis for childhood acute lymphoblastic leukemia (ALL), primarily involving physical growth and cognitive development, is an ongoing concern. Although contemporary treatment protocols are associated with less severe toxicity than was commonly observed with earlier protocols, there continue to be late effects. When treatment includes cranial radiation therapy (CRT), linear growth is likely to be impaired. Female patients are more vulnerable to late cognitive effects than male patients, particularly when treated with CRT and high doses of methotrexate. Young age at treatment is a risk factor as well, particularly for girls. In order to treat medical and psychological problems early, a commitment to long-term follow-up is essential.     

Asymptomatic sequelae to acute sarin poisoning in the central and autonomic nervous system 6 months after the Tokyo subway attack

Six to eight months after the Tokyo subway attack in March 1995, the neurophysiological effects of acute sarin poisoning were investigated in 18 passengers exposed to sarin (sarin cases) in the subways to ascertain the focal or functional brain deficits induced by sarin. The event-related and visual evoked potentials (P300 and VEP), brainstem auditory evoked potential, and electrocardiographic R-R interval variability (CVRR), together with the score on the posttraumatic stress disorder (PTSD) checklist, were measured in the sarin cases and the same number of control subjects matched for sex and age. None of the sarin cases had any obvious clinical abnormalities at the time of testing. The P300 and VEP (P100) latencies in the sarin cases were significantly prolonged compared with the matched controls. In the sarin cases, the CVRR was significantly related to serum cholinesterase (ChE) levels determined immediately after exposure; the PTSD score was not significantly associated with any neurophysiological data despite the high PTSD score in the sarin cases. These findings suggest that asymptomatic sequelae to sarin exposure, rather than PTSD, persist in the higher and visual nervous systems beyond the turnover period of ChE; sarin may have neurotoxic actions in addition to the inhibitory action on brain ChE.