Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine.

Methotrexate is widely administered with mercaptopurine, a prodrug requiring activation into thioguanine nucleotides (TGN) to exert antileukemic effects. In vitro, methotrexate enhances TGN formation, but in vivo, such enhancement has yet to be demonstrated. We investigated whether TGN concentrations were related to methotrexate concentrations in children with acute lymphoblastic leukemia who received a weekly intravenous methotrexate (40 mg/m(2)) dose combined with daily mercaptopurine (75 mg/m(2)). A total of 141 erythrocyte TGN concentrations were measured with erythrocyte methotrexate polyglutamates (MTX-PG) concentrations in 87 patients. Average TGN concentrations ranged from 137 to 958 pmol/8 x 10(8) cells (median 389), average total MTX-PG concentrations (MTX- PG(1-7)) from 0.60 to 97.7 pmol/10(9)cells (median 29), and average long chain polyglutamate concentrations (MTX-PG(5-7)) from 0 to 8.35 pmol/10(9) cells (median 2.43). Higher TGN concentrations correlated with higher MTX-PG(5-7) concentrations (P = 0.002). These data support the practice of administering methotrexate with mercaptopurine during continuation therapy of acute lymphoblastic leukemia.     

Factor V Leiden and other hypercoagulable state mutations are not associated with osteonecrosis during or after treatment for pediatric malignancy

OBJECTIVE: Osteonecrosis (ON) is a debilitating complication of cancer treatment in children and is usually associated with systemic steroid therapy. Defects of coagulation may be important in the pathogenesis of ON. This study evaluated the prevalence of factor V Leiden (FVL, 1691G-->A), the most common inherited thrombophilic state, the prothrombin 20210G-->A polymorphism, and the thermolabile methylene tetrahydrofolate reductase (MTHFR, 677C-->T) variant in a group of children in whom ON developed during or after treatment for cancer. STUDY DESIGN: Children in whom ON developed during cancer treatment at St Jude Children's Research Hospital were studied (n = 24). Genomic DNA was isolated, and polymerase chain reaction was performed to identify the FVL, prothrombin 20210, and thermolabile MTHFR mutations. RESULTS: Sixteen of 24 patients had acute lymphoblastic leukemia. The mean age at ON diagnosis was 14.4 +/- 3. 7 years. The mean interval between cancer diagnosis and ON diagnosis was 27 +/- 21 months. Twenty-two patients had received steroids for a mean duration of 24 +/- 15 weeks before having development of ON. No patient had a history of thrombosis. Five (21%) patients had a family history of thrombosis. Genetic analysis revealed 0 (0%) of 24 FVL, 1 (4.5%) of 22 prothrombin 20210, and 3 (13.6%) of 22 thermolabile MTHFR. None of these mutation frequencies was significantly different from our control frequencies or published values. CONCLUSIONS: Although procoagulant abnormalities in general and FVL in particular have been detected in a significant number of patients with ON of the jaw and Legg-Perthes disease, we did not identify an increased prevalence of FVL or other hypercoagulable state mutations in a cohort of children with ON that developed during or after treatment for a variety of cancers.     

Elephantiasis nostras verrucosa: beneficial effect of oral etretinate therapy

Elephantiasis nostras verrucosa is characterized by chronic secondary, non-filarial lymphoedema due to recurrent lymphangitis, dermal fibrosis, and epidermal changes consisting of hyperkeratotic, verrucous and papillomatous lesions. Histologically, there is pseudoepitheliomatous hyperplasia. Therapeutic efforts should aim to reduce lymph stasis, which will also lead to improvement of the cutaneous changes. In this study, rapid disappearance of the hyperkeratotic and verrucous lesions, remarkable flattening of the papillomatous nodules and improvement of lymphoedema occurred in three obese patients treated with etretinate in an initial dose of 0.6-0.75 mg/kg/day for 4-6 weeks. Monitoring of plasma concentrations of etretinate, acitretin and 13-cis-acitretin by HPLC revealed sufficient short-time absorption (4 h) and bioavailability of the drug (30 days; two out of three patients). Long-term maintenance therapy in one patient produced a remarkable improvement in the lymphoedema; another patient relapsed after discontinuation of the etretinate and responded again after this was reintroduced. In the third patient treatment was withdrawn because of an increase in triglycerides, but improvement persisted 6 months later. The clinical side-effects of oral retinoid therapy were moderate and well tolerated.     

Impact of treatment efficacy on the prognostic value of glucocorticoid receptor levels in childhood acute lymphoblastic leukemia

Glucocorticoid receptor (GR) levels were quantitated in leukemic blasts from bone marrow aspirates of 249 children with acute lymphoblastic leukemia (ALL) who were entered on two St. Jude Total Therapy Studies. Of these, 235 were evaluable for analysis of the relation of GR levels to clinical outcome. For the 42 patients in the earlier Total Therapy Study IX, lower GR levels (<16,000 sites/cell) were associated with both induction failure and more frequent relapse (p <0.01) [Cancer Research, Vol. 42, p. 4801 (1982)]. When patients with ‘high-risk’ features (leukocyte count >100 × 10³/mm³, positive erythrocyte rosette test, central nervous system involvement, and mediastinal mass) were excluded, lower receptor levels were still associated with early and more frequent relapse (p <0.02). The other 193 evaluable patients were consecutively admitted to Total Therapy Study X, in which patients with ‘standard-risk’ or ‘high-risk’ features were assigned to separate protocols — XS and XH, respectively. Induction chemotherapy in both protocols consisted of prednisone, vincristine and l-asparaginase; patients in the XH protocol received additional epipodophyllotoxin (VM-26) and cytosine arabinoside twice a week for 2 weeks preceding the conventional induction therapy. To compare the prognostic value of GR level in Study X with that of Study IX (which included both ‘high-risk’ and ‘standard-risk’ patients but did not separate them into different protocol groups), children in the XH and XS protocols were analysed together. The proportion of patients with ‘standard-risk’ features was the same in the two studies: 69% in Study IX and 73% in Study X. In Study X, which had a significantly better treatment result (p <0.001), lower receptor levels were not associated with induction failure, but were correlated with more frequent relapse (p <0.05). When patients in XH and XS protocols were analysed separately, however, receptor levels were no longer related to treatment outcome. Thus, GR level in childhood ALL has prognostic value, but it is not an independent factor and its importance is related to the efficacy of treatment.     

Musculoskeletal melioidosis: clinical and imaging features

Objective. Melioidosis is a tropical infection caused by a gram-negative bacillus, Pseudomonas pseudomallei. The disease manifests initially as localized suppurative lesions and can progress to acute disseminated septicemia with 65–90% mortality if inadequately treated. Musculoskeletal involvement is common. The purpose of this study was to describe the clinical features and imaging appearances of musculoskeletal melioidosis. Design. We retrospectively analyzed the clinical profiles and images of 26 patients diagnosed over a 6-year period as suffering from melioidosis.Patients. The study group comprised 11 patients with musculoskeletal melioidosis and 15 patients with nonmusculoskeletal melioidosis. Results and Conclusions. We found that musculoskeletal melioidosis mimicks other infections both clinically and radiologically. Clinical awareness is therefore crucial, as diagnosis can only be established by bacteriological and immunological studies. Prompt treatment with long-term combination antibiotics in high dosages and surgical drainage of abscesses improves survival.     

Effect of chronic intoxication with (+)-amphetamine on its concentration in liver and brain and on (14C) leucine incorporation into microsomal and cytoplasmic proteins of rat liver

Rats were treated with increasing concentrations of (+)-amphetamine sulphate in drinking water for 90 days. The ingested dose of amphetamine was found to increase from 16 mg kg^?1 on the first day up to 90 mg kg^?1 on the 32nd day of treatment. The rats were maintained on the highest dose regime for a further 58 days without any deaths, which showed that tolerance to the overall toxicity of the drug developed. The concentrations of [³H]amphetamine in liver and brain of chronically treated rats were significantly higher than those of controls. Chronic treatment with amphetamine significantly reduced body and liver weight of rats, but did not influence the relative liver to body weight. A marked inhibition of [¹⁴C]leucine incorporation into liver microsomal and cytoplasmic proteins was observed after 90 days of treatment with amphetamine. The relation between inhibition of microsomal protein synthesis and the increase of amphetamine concentrations in liver and brain is discussed.     

The role of gluten, milk, and other dietary proteins in chronic or intermittent dyspepsia

In twenty-seven patients with chronic or intermittent dyspepsia raised levels of the gamma-M-globulin and of the α₁- and of the α₂-globulin were encountered. Malabsorption, present in about three-quarters of the cases, was usually mild. Various degrees of villous abnormalities were seen but no flat mucosa. Eight patients also had dermatitis. During dietary treatment with the elimination of gluten, milk, or other food elements the dyspepsia and the malabsorption subsided in all but two, and the dermatitis in all but one. In nearly all the investigated cases the raised levels of the gamma-M-globulin and of the α₁- and of the α₂-globulin decreased. During challenge feeding with the offending food the dyspepsia and the dermatitis reappeared. Also the faecal fat excretion increased again, and a rise was noticed in the α₁- and in the α₂-globulins and in the gamma-M-globulins. The findings suggest that gluten, milk and other dietary proteins may play a role in some chronic dyspepsias by exerting an antigenic stimulus on the small intestinal mucosa, and thus inducing a state of hypersensitivity towards these foods. The clinical and laboratory findings favour the view that the condition is different from coeliac disease