Carboplatin for the treatment of children with newly diagnosed optic chiasm gliomas: a phase II study.

Management of low grade optic glioma in children and adolescents remains controversial. Treatment with chemotherapy may delay or eliminate the need for radiation therapy. Children with newly diagnosed optic chiasm glioma were eligible for enrollment in this phase II trial and received intravenous carboplatin (CBDCA) (560 mg/m2) every four weeks. Patients were monitored closely for toxicity and tumor status. Twelve children were enrolled. Six patients had stable disease, four a partial response and two progressed on therapy. Overall progression free survival was 83 +/- 11%. The median duration of follow-up was 38.6 months (range 18-63 months). No deaths were noted in our series. Thrombocytopenia was the major toxicity, and two patients required platelet transfusions. One child developed an urticarial reaction requiring discontinuation of therapy. Another child developed unilateral high frequency hearing loss. No renal toxicity was encountered. We have demonstrated that carboplatin can eliminate or delay radiation therapy in children and adolescents with low grade optic glioma. CBDCA deserves further investigation in larger clinical trials as a treatment for children with optic chiasm glioma.

Unilateral laterothoracic exanthem in a child with acute lymphoblastic leukemia.

Unilateral laterothoracic exanthem (ULE) is a rare childhood condition of unknown etiology characterized by a morbilliform rash that usually begins in the axilla and spreads centrifugally. The condition is usually self-limited, does not require specific treatment, and disappears within 4 to 6 weeks. Pruritus may be relieved by oral antihistamines and topical emollients and/or bath oils. We describe ULE in a 6-year-old girl with acute lymphoblastic leukemia, the first report of ULE in a patient with malignancy.

Congenital central nervous system tumors.

Congenital central nervous system (CNS) tumors are a rare and diverse group of tumors with variable biological behavior depending on location and histology. This review summarizes the published literature and describes the definition, epidemiology, diagnosis and evaluation, and treatment of congenital central nervous system tumors.

Aminophylline for methotrexate-induced neurotoxicity.

Methotrexate, a mainstay treatment for children with acute lymphoblastic leukaemia, can cause neurotoxicity, with paralysis, seizures, somnolence, anorexia, and headaches. The pathophysiology of this reaction is unknown. It has been suggested that the anti-inflammatory effect of methotrexate in patients with arthritis is due to adenosine release brought on by inhibition of purine synthesis. Since adenosine is a central nervous system depressant, we wondered whether adenosine release in the central nervous system could account for some of the neurotoxicity due to methotrexate, and whether that toxicity could be lessened by displacement of adenosine from its receptor by aminophylline. 6 patients (age 3-16 years) who had methotrexate-induced neurotoxicity unresponsive to standard treatment received 2.5 mg/kg aminophylline. In addition, the concentration of adenosine in the cerebrospinal fluid (CSF) from 11 children completing a 24-h systemic methotrexate protocol was compared with that in 8 newly diagnosed patients and 12 who had not received any treatment for at least a week. 4 of 6 patients with toxic signs and symptoms attributed to methotrexate and unrelieved by steroids, epidural blood patch, promethazine, 5-hydroytryptamine antagonists, paracetamol, and narcotics, had complete resolution of neurotoxicity after or during a 1-h infusion of aminophylline; 2 others had a pronounced improvement but persistent nausea. CSF adenosine concentrations of patients receiving methotrexate, even when there was very slight or no toxicity, were greatly increased compared with control subjects (mean values of 217 and 51 nmol/L, median 175 and 52 nmol/L). Subacute methotrexate neurotoxicity may be mediated by adenosine and relieved by aminophylline.

Rhabdoid tumor of the kidney with primitive neuroectodermal tumor of the central nervous system: associated tumors with different histologic, cytogenetic, and molecular findings.

Rhabdoid tumor of the kidney (RTK) is associated with tumors of the central nervous system (CNS) in approximately 15% of cases. We describe the clinical features, histologic and cytogenetic findings, and molecular analysis of renal and CNS tumors from the same patient. The histology of the renal tumor was consistent with rhabdoid tumor. The CNS tumor was a primitive neuroectodermal tumor (PNET). The karyotype of the RTK was normal male. The PNET of the brain demonstrated monosomy 22 as the only cytogenetic abnormality, similar to reported cases of malignant rhabdoid tumor of the brain, but dissimilar to nonrandom cytogenetic findings in other CNS PNETs. Molecular cytogenetic and DNA marker studies confirmed loss of chromosome 22 in this patient's brain tumor. DNA allelotyping showed retention of both parental chromosome 22 alleles in the RTK and loss of the maternal allele in the PNET. Evaluation of additional RTKs and brain tumors occurring in the same patient may provide insight into the origins and relationships of these enigmatic tumors.

Adjuvant chemotherapy for treatment of unresectable and metastatic angiomatoid malignant fibrous histiocytoma.

Angiomatoid malignant fibrous histiocytoma (AMFH) is a low grade soft tissue sarcoma usually treated with surgery alone. Only one adult patient has been treated with systemic chemotherapy. The authors report a case of unresectable, metastatic AMFH treated initially with vincristine, doxorubicin, dactinomycin, and cyclophosphamide. A complete response at the metastatic site and a marked reduction in the size of the primary tumor allowed complete surgical excision 7 months after treatment was initiated. The patient remains disease free 19 months after being diagnosed. It was concluded that systemic chemotherapy may be effective in patients with AMFH.

Splenic rupture in hemophilia.

PURPOSE: Little information is available regarding splenic injury in patients with hemophilia. We describe here the management of splenic rupture in five of our patients with hemophilia and summarize the literature describing this complication. PATIENTS AND METHODS: Two human immunodeficiency virus-seropositive patients were managed medically and did not require splenectomy. A third patient had a high titer inhibitor to both porcine and human factor VIII and required emergency splenectomy. Two boys had not been previously diagnosed with hemophilia until they underwent splenectomy after abdominal trauma. RESULTS: All five patients survived. CONCLUSIONS: These cases demonstrate that nonsurgical management of splenic injury in patients with hemophilia can be performed safely and that splenectomy can be successfully performed despite a high titer of factor VIII inhibitor.

Accumulation of 5-methyltetrahydrofolic acid and folylpolyglutamate synthetase expression by mitogen stimulated human lymphocytes.

The accumulation of 5-methyl[3H]tetrahydrofolic acid (5CH3[3H]FH4) by phytohaemagglutinin stimulated lymphocytes (PHA-L) cultured in folate free media was investigated to determine the mechanism of uptake of 5CH3FH4 and the requirement of the cells for this vitamin as assessed by monitoring de novo thymidine synthesis. When grown in 20 nM 5CH3[3H]FH4 PHA-L accumulate radiolabel at a rate of 0.04 pmol/h/10(6) cells. This doubles the endogenous folate pool of unstimulated cells (0.6 +/- 0.16 pmol/10(6) cells) in about 15 h. Uptake proceeded via a saturable process, independent of a high affinity folate receptor as assessed by ligand binding and by Northern and Western blot analysis. However, transport was blocked by probenecid, which is consistent with an anion carrier mechanism. Unstimulated cells lacked folypolyglutamate synthetase (FPGS) activity and did not express significant amounts of FPGS mRNA. After 48 h of mitogen stimulation there was a 4-10-fold increase in FPGS mRNA and folypolyglutamate formation (Glu > or = 5) was essentially simultaneous with 5CH3[3H]FH4 transport. Increasing extracellular folate to 2 microM only increased intracellular folate 8-fold, but the length of the folylpolyglutamates decreased. The increased folate did not increase de novo thymidine synthesis compared to cells grown in physiological folate. We conclude that mitogen stimulation activates the process(es) for folate accumulation, especially FPGS, and that physiological uptake (0.04 pmol/h/10(6) cells) is adequate for meeting the cells' need for the vitamin.

Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues.

In some epithelial cells studied in vitro a membrane-bound folate receptor initiates the process for cell accumulation of 5-methyltetrahydrofolic acid. This receptor was found to be GP38, an overexpressed, glycosyl-phosphatidylinositol anchored glycoprotein, recognized by two monoclonal antibodies, designated MOv18 and MOv19. Using immunoblotting with MOv19, radioimmunoassay with MOv18 and 19, Northern blot analysis, and radioligand binding when possible, we describe the limited expression of the folate receptor in a large number of normal tissues from four autopsies. The immunoblot technique detected as little as 40 pg (approximately 1 fmol) of receptor protein. Choroid plexus consistently had the largest amount of folate receptor. Other tissues containing substantial amounts of receptor included lung, thyroid, and kidney. The liver, intestines, muscle, cerebellum, cerebrum, and spinal cord were immunologically nonreactive. Folate receptor gene expression determined by Northern blot analysis confirmed these observations. We also show that several malignant cell lines express significantly more receptor than normal epithelial cells or fibroblasts. Specifically, malignant cells bound greater than or equal to 20 pmol [3H]folate/10(6) cells, while normal epithelial cells and fibroblasts bound less than or equal to 1 pmol radioligand/10(6) cells. We also demonstrate that 4 of 6 brain tumors overexpress the folate receptor. These studies reveal the limited normal tissue distribution of the folate receptor, a cell surface protein which may be a useful immunological or pharmacological target for the development of selective cancer therapy.