Neuroimaging findings in acute ethylene glycol poisoning

The CT and MR findings of a patient with acute ethylene glycol poisoning are presented. Basal ganglia hemorrhagic infarction especially involving the putamen was detected. The differential diagnosis includes other toxic and hypoxic encephalopathies.     

The unique aspects of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) accounts for approximately 10% of cases of acute myeloid leukemia (AML). Distinctive features of this disorder at the time of diagnosis include leukopenia coexisting with a marrow replaced with granulated dysplastic promyelocytes, disseminated intravascular coagulopathy, lack of Ia (HLA-DR) antigen expression, and translocation between the long arms of chromosomes 15 and 17 (t[15;17]). Heparin is widely but not universally used to interfere with the coagulopathy during the initial phases of treatment. Serial bone marrow examinations during the induction period demonstrate the achievement of remission despite the persistence of malignant-appearing promyelocytes. Patients with APL are generally younger than those with other subtypes of AML, have a 70% to 80% likelihood of entering remission, and are thought to have a more favorable prognosis than other individuals with AML. Remission may be achieved with a conventional anthracycline-cytarabine combination, anthracycline alone, or, apparently, all-trans retinoic acid. Genes potentially important in myeloid differentiation such as granulocyte colony-stimulating factor (G-CSF) and myeloperoxidase are located close to the breakpoint in the t(15;17) but have not been conclusively shown to be rearranged in the translocation. A better understanding of the unique aspects of APL may well shed light on the pathogenetic processes of AML.     

Basic and clinical aspects of IL-6]

Interleukin-6 (IL-6) is a pleiotropic cytokine regulating immune response, production of acute phase reactants in hepatocytes, growth of hematopoietic stem cells and other cellular functions in many cell lineages. The increased production of IL-6 is often seen in infections diseases, chronic inflammatory diseases, and certain tumors which accompany polyclonal B cell activation and increased level of CRP. Recent progress in the study of the basic aspects on IL-6 will be discussed, which includes the regulation mechanisms of IL-6 gene, the structure of IL-6 receptor complex (IL-6, 80 KDa IL-6 receptor and signal transducing gp130) and IL-6 signal transduction pathways.     

Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia?

The cytotoxic activity of 6-mercaptopurine (6-MP) is affected by thiopurine methyltransferase (TPMT), a genetically regulated and variable intracellular enzyme. 6-Thioguanine (6-TG), a closely related thiopurine, is less affected by that enzyme and so it may be a more reliable drug-at least for patients with constitutionally high TPMT activity. We attempted to assess its suitability as an alternative by comparing the pharmacokinetics of both drugs in a small group of children with lymphoblastic leukaemia (ALL). Patients were included who were in their second or subsequent remission, who would otherwise have received 6-MP, and on whom pharmacokinetic data concerning 6-MP metabolism had been collected in a previous remission. Plasma 6-TG concentrations were assayed following an oral dose of 40 mg m-2, and the accumulation and fluctuation of intracellular (erythrocyte, RBC) 6-TG nucleotides (6-TGNs) were measured at regular intervals during daily oral therapy. Seven children were studied. Plasma 6-TG concentrations were low and cleared within 6 h of oral dosing. At 7 days, 6-TGN concentrations ranged from 959 to 2361 pmol 8 x 10(-8) RBCs, in all cases significantly higher (P = 0.002) than those produced by the same patients on 6-MP. After a total therapy time of 35 patient months, a modest rise of alanine aminotransferase was seen on one occasion, otherwise no toxicity apart from myelosuppression was encountered. In the context used, 6-TG appears well tolerated and produces higher concentrations of intracellular cytotoxic metabolites than 6-MP. For children constitutionally ''resistant'' to the traditional drug, if not all, it may be a preferable alternative.     

Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine

Mercaptopurine (6MP) has been the standard drug for maintenance therapy of acute lymphoblastic leukemia. In a multicenter study we investigated whether thioguanine (6TG), which is converted more directly to the cytotoxic thioguanine nucleotides (TGN), offers a therapeutic advantage over 6MP. In this study (COALL-92), 6TG was randomized versus 6MP in maintenance therapy, whereby the doses of both drugs had to be adjusted to a white blood cell (WBC) count of between 2 and 3/nl. In 19 children the plasma levels of both drugs and/or the accumulation of their metabolites in red blood cells (RBC) were measured during intensive treatment in two consecutive chemotherapy blocks, and in 54 children the metabolites in RBC were measured every 3 months during daily treatment in maintenance therapy. There was a marked interindividual difference in the plasma kinetics of the two drugs; after identical doses of 100 mg/m² an about 4-fold higher peak concentration of the parent drug was reached with 6MP. The main metabolites of 6TG were thioguanine nucleotides (TGN), whereas during 6MP treatment, methylated thioinosine nucleotides (TIN) predominated in erythrocytes. In patients receiving 6TG during maintenance therapy (22 patients) the concentration of methylated TGN reached about 40% of that of unmethylated TGN; after 6MP administration (32 patients) the methylated TIN were concentrated about 26-fold higher in RBC than were TGN. In contrast to 6TG, for 6MP the pattern of metabolites shifted toward the methylated ones with increasing dose. The median TGN concentration was about 7-fold higher in the TG branch, although the median dose was only about 70% of that of 6MP. The WBC values were equivalent in the two treatment groups. Our results suggest that the cytotoxic effect of 6MP is not based solely on the formation of TGN. Received: 23 June 1997 / Accepted: 4 February 1998     

Effects of an anti-interleuktn-6 (IL-6) murine monoclonal antibody in a patient with acute monoblastic leukemia

Because IL-6 has been involved in the pathogenesis of acute monoblastic leukemia, we investigated thein vitro anti-proliferative effect and thein vivo anti-tumoral effect of an anti-IL-6 murine monoclonal antibody (mAb) in a patient with MSB type acute leukemia. In the current study, we clearly show the IL-6 dependence of monoblastic cell viability and proliferationin vitro in short-term cultures of malignant cells and the clinical activity of the anti-IL-6 murine mAb. The complete neutralization of IL-6in vivo was associated with a transient but complete disappearance of malignant monoblastic cells in the peripheral blood, with improvement or even normalization of several other biological parameters of disease activity, No immunization against the anti-IL-6 murine mAb was observed.     

Variability of 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with acute leukemia

The effects of some environmental and genetic factors on the inter- and intraindividual variations of 6-mercaptopurine (6-MP) pharmacokinetics were studied in children on oral remission maintenance therapy for acute lymphoblastic leukemia or non-Hodgkin’s lymphoma. Blood samples were obtained 0–4 h after drug intake. 6-MP concentrations were determined in plasma and in erythrocyte concentrates. The influence of food on the pharmacokinetics was examined in a prospective study of 15 children. Each child was examined four times, twice in the fasted state and twice after intake of a standardized, milky, breakfast. There were pronounced inter- and intraindividual variations. Food intake seemed to reduce these variations but there were no significant changes in peak concentrations and area under the plasma concentration vs time curves (AUC) between the fasted and fed states. Food intake reduced the time to peak concentration both in plasma, from 1.8 h to 1.1 h (P < 0.01) and in red blood cells, from 1.8 h to 1.3 h (P < 0.01). Retrospective subdivision of the patients indicated a tendency for different pharmacokinetic patterns according to dose; five out of seven patients receiving > 70 mg m⁻² had a higher AUC in the fasting state, while five out of eight patients receiving <70 mg m⁻² had a higher AUC in the fed state. The cytochrome P-450-dependent hydroxylation capacity was evaluated with debrisoquine but no correlation was found to the pharmacokinetics of 6-MP.     

Variability of 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with acute leukemia

The effects of some environmental and genetic factors on the inter- and intraindividual variations of 6-mercaptopurine (6-MP) pharmacokinetics were studied in children on oral remission maintenance therapy for acute lymphoblastic leukemia or non-Hodgkin's lymphoma. Blood samples were obtained 0-4 h after drug intake. 6-MP concentrations were determined in plasma and in erythrocyte concentrates. The influence of food on the pharmacokinetics was examined in a prospective study of 15 children. Each child was examined four times, twice in the fasted state and twice after intake of a standardized, milky, breakfast. There were pronounced inter- and intraindividual variations. Food intake seemed to reduce these variations but there were no significant changes in peak concentrations and area under the plasma concentration vs time curves (AUC) between the fasted and fed states. Food intake reduced the time to peak concentration both in plasma, from 1.8 h to 1.1 h (P less than 0.01) and in red blood cells, from 1.8 h to 1.3 h (P less than 0.01). Retrospective subdivision of the patients indicated a tendency for different pharmacokinetic patterns according to dose; five out of seven patients receiving greater than 70 mg m-2 had a higher AUC in the fasting state, while five out of eight patients receiving less than 70 mg m-2 had a higher AUC in the fed state. The cytochrome P-450-dependent hydroxylation capacity was evaluated with debrisoquine but no correlation was found to the pharmacokinetics of 6-MP.     

Cellular and pharmacologic aspects of drug resistance in acute myeloid leukemia.

Modern treatments and supportive care regimens for acute myeloid leukemia have produced some cures of what was once a uniformly fatal disease. To enhance the cure rate, intense efforts are now being put forth to understand the mechanisms of resistance to chemotherapeutic regimens that actually arise in clinical cases of acute myeloid leukemia, and to develop ways and means to circumvent such resistance. This review focuses on such efforts involving daunorubicin and cytarabine, the two most effective agents currently available for treatment of the disease. Most current published studies of daunorubicin have focused on detecting the classic form of multidrug resistance. For cytarabine, pharmacologically directed treatment approaches and enhancement of cytarabine leukemic cell kill by increasing the distribution of cells in S-phase and manipulating cellular cytarabine transport are currently under investigation.     

Treatment of acute myelocytic leukemia with a daunorubicin-cytarabine-6 thioguanine regimen without maintenance therapy

The present study reports on the treatment of 44 patients with AML. 17 patients were male, 27 female. Mean age was 50.1 years. Treatment-regimen consisted of induction-therapy with daunorubicin 45 mg/m2 i.v. d 1-3, cytarabine 100 mg/m2 X 24 h continuous intravenous infusion (c.i.v.i.) d 1-7, 6 thioguanine 100 mg/m2 twice orally d 1-7. There were only two consolidation therapies with daunorubicin and cytarabine and no maintenance therapy. 30 patients (68%) achieved CR, 1 patient (2%) PR, 3 were non-responders (7%). There were 10 (23%) early deaths during or following induction therapy. Median disease-free survival was 6 months, median overall survival 7.5 months. We conclude, that the reported induction therapy is efficient though toxic. To improve long term results, consolidation and intensification therapy should be escalated.     

Association of CYP2B6 G15631T polymorphism with acute leukemia susceptibility

The Cytochrome P450 (CYP) enzymes constitute one of the biggest gene families and play a vital role in the metabolism of endogenous biomolecules, drugs and xenobiotics. One of the members of this family, CYP2B6, plays a very important role in metabolizing carcinogens and medications. CYP2B6G15631T gene polymorphism reduces CYP2B6 enzyme activity. In this study, we aimed to determine whether any association exists between genetic polymorphism in CYP2B6G15631T and individual susceptibility to acute leukemia. Our study group consisted of 80 acute leukemia patients and 100 unrelated healthy volunteers as a control group. 44 of the acute leukemia patients were diagnosed with acute lymphoblastic leukemia (ALL) and 36 patients with acute myeloid leukemia (AML). Genomic DNA was isolated from peripheral blood and genomic DNA samples were assayed for restriction fragment length polymorphism in the CYP2B6 loci by PCR amplification followed by digestion with BsrI. The data were analyzed statistically employing chi-square and logistic regression analyses. The frequencies of GG genotype (wild type) were 40.9%, 50% and 67% in ALL, AML and control groups, respectively. The frequencies of polymorphic GT genotype (heterozygous variant) were found to be 59.1% in ALL patients, 50% in AML patients and 33% in controls. The TT genotype (homozygous variant) was not observed in either control or leukemia cases. Logistic regression analyses showed a significant correlation between the CYP2B6 G15631T polymorphism (GT) and acute leukemia patients (OR = 2.481, 95% CI = 1.353–4.551, p = 0.003). Our findings indicate that GT genotype may be an important genetic determinant for acute leukemias. According to our knowledge, this is the first report of an association between acute leukemia cases and the CYP2B6 G15631T polymorphism.     

Cranial irradiation and cerebrospinal fluid levels of 6-mercaptopurine in children with acute leukemia

We measured 6-mercaptopurine levels in the cerebrospinal fluid and plasma of 15 children undergoing treatment for acute leukemia. Plasma and cerebrospinal fluid samples obtained by lumbar puncture were collected before, during, and after cranial irradiation in order to evaluate a possible change in blood-brain barrier permeability to orally administered 6-mercaptopurine. Considerable interpatient variability has been observed in both plasma and cerebrospinal fluid 6-mercaptopurine levels. No statistical differences in the 6-mercaptopurine cerebrospinal fluid levels under the three different conditions could be detected. Our data suggest that cranial irradiation does not significantly influence the cerebrospinal fluid levels.     

X;6 translocation in a child with congenital acute lymphocytic leukemia.

A case of congenital acute lymphoblastic leukemia (ALL) displayed an X;6 translocation. This is the third reported case of ALL with an X;6 translocation. In addition, two of the three ALL cases occurred during infancy, at ages 2 months and newborn, and both translocations involved the band q15-16 region of chromosome 6. Anomalies of the long arm of chromosome 6, mainly interstitial and terminal deletions, have been reported as a recurrent karyotypic event in a significant number of ALL cases. The molecular basis and propensity of an X;6 rearrangement in this case of congenital ALL is unclear and merits further investigation. The similarities in this case and the other infant ALL case cited suggest that an X;6 rearrangement with a breakpoint in bands q15-16 of chromosome 6 is characteristic of a form of congenital ALL.