A phase II study of ifosfamide in children with recurrent solid tumours

Summary Twenty children with recurrent or unresponsive tumours (10 Wilms', 3 rhabdomyosarcoma, 4 Ewings's, 1 osteosarcoma, 1 hepatoblastoma, 1 hepatoma) and one untreated patient with renal carcinoma were given ifosfamide as a 24-h infusion (5 mg/m²), with mesna as uroprotective. The number of courses ranged from 1 to 13 (median 3), and the interval between them was 2–3 weeks. Sixteen of these patients had previously received cyclophosphamide. Complete clinical responses were seen in 3 cases (2 Wilms' and 1 Ewing's) and lasted 5, 7, and 9 months. Partial responses were seen in 3 instances, mixed response or stable disease in 4, and progressive disease in 11. Treatment was well tolerated in most patients, with no cystitis or severe myelosuppression, but 2 children developed transient neurological symptoms and 1 became hypertensive. Nausea and vomiting were controlled by high-dose dexamethasone in most children.Plasma ifosfamide levels were estimated by means of gas-liquid chromatography in 10 patients. Peak concentrations ranged from 38 to 125 g/ml (median 80). The elimination half-life, at 2.5–5.2 h (median 3.2) was shorter than previously reported in adults.Future studies should test the possibility that ifosfamide-containing combination chemotherapy may be more effective than the regimens, usually including cyclophosphamide, that are currently used as front-line treatment of embryonal and Ewing's sarcoma.     

Paramagnetic macrocyclic complexes as contrast agents for MR imaging: proton nuclear relaxation rate enhancement in aqueous solution and in rat tissues

Paramagnetic macrocyclic chelates show promise as magnetic resonance (MR) imaging contrast agents due to stability and relaxivity comparable to those of DTPA-type chelates. For the three copper and manganese macrocyclic complexes studied in aqueous solution, T1 and T2 relaxivities ranged from 0.14 to 5.88 mM-1sec-1 at 6.25 MHz. In rats, the intravenous administration of 16 mumol/kg of Mn(cyclam) caused the liver T1 relaxation rate to double at 15 minutes after injection. T1 measurements by pulsed MR imaging and manganese analyses on excised tissue showed that both relaxation rate (1/T1) and manganese content of liver and kidney increase linearly with the dosage of Mn(cyclam). The linear relationship between 1/T1 and manganese content can be considered an "in tissue" relaxivity plot for the agent. The resulting relaxivity is 54 mM-1sec-1 in liver, compared with 3.1 mM-1sec-1 in aqueous solution. Although this work is preliminary, the implication for medical MR imaging applications is that macrocyclic contrast agents can be effective at approximately one-tenth the current typical dose used for gadolinium DTPA.     

Chronic dermal sinuses as a manifestation of histiocytosis X

Two young patients presented with generalised lymphadenopathy, otorrhoea, otitis, and rash. Over the next few years chronically discharging sinuses began to form over enlarged nodes and histological appearances were typical of histiocytosis X. In neither case were micro-organisms isolated from the lesions, and in both patients healing occurred with immunosuppressive agents. Chronic dermal sinus formation secondary to lymph node disease has never before been recorded as a manifestation of histiocytosis X. Histiocytosis X should therefore be considered in the differential diagnosis of "suppurative" lymphadenopathy so that appropriate treatment may be given without delay.     

Flexible effects of quantified cigarette-smoke delivery on EEG dimensional complexity

A quantified smoke delivery system (QSDS) was used to experimentally control the administration of inhaled cigarette smoke to 28 male smokers. One puff (2 s, 35 cc) was taken every 30 s on a cigarette (nicotine yield 1.0 mg) until the char line reached 3 mm from the filter wrap. The smoke was inhaled for 5 s. Resting eyes-closed and eyes-open EEG was recorded from F3, F4, P3, and P4 before and after quantified smoke delivery (QSD). EEG dimensional complexity (DC _x, a measure derived from chaos theory) was computed using the Takens-Ellner method. QSD appeared to have a flexible effect on EEGDC _x, primarily lowering it in subjects whose pre-smoking level was high, not affecting it in subjects whose pre-smoking level was intermediate, and tending to raise it in subjects whose pre-smoking level was low. This replicates previous results obtained with ad libitum smoking, suggesting the hypothesis that smoking may have an optimizing effect on the complexity of brain dynamics.     

Mechanism of Intestinal Absorption of Ranitidine and Ondansetron: Transport Across Caco-2 Cell Monolayers

We have investigated the transport of ranitidine and ondansetron across the Caco-2 cell monolayers. The apparent permeability coefficients (P _app) were unchanged throughout the concentration range studied, indicating a passive diffusion pathway across intestinal mucosa. No metabolism was observed for ranitidine and ondansetron during the incubation with Caco-2 cell monolayers. P _app values for ranitidine and ondansetron (bioavailability of 50 and 100% in humans, respectively) were 1.03 ± 0.17 × 10^–7 and 1.83 ± 0.055 × 10^–5 cm/sec, respectively. The P _app value for ranitidine was increased by 15- to 20-fold in a calcium-free medium or in the transport medium containing EDTA, whereas no significant change occurred with ondansetron, indicating that paracellular passive diffusion is not rate determining for ondansetron. Uptake of ondansetron by Caco-2 cell monolayers was 20- and 5-fold higher than that of ranitidine when the uptake study was carried out under sink conditions and at steady state. These results suggest that ranitidine and ondansetron are transported across Caco-2 cell monolayers predominantly via paracellular and transcellular pathways, respectively.     

Undifferentiated embryonal sarcoma of the liver: results of clinical management in one center

PURPOSE: This study was undertaken to review the authors' clinical experience with undifferentiated embryonal sarcoma of the liver (UES) in children, focusing on the clinical presentation and results of treatment. METHODS: A retrospective analysis of all children who have undergone treatment for UES during the 15-year period from 1984 through 1998 was performed. RESULTS: Seven patients (4 boys and 3 girls) ranging in age from 20 months to 12 years at the time of diagnosis were identified. All presented with large abdominal masses and normal liver function test results. All underwent complete tumor resection; trisegmentectomy was required in 4 of these cases. All patients received postoperative chemotherapy. Two patients suffered tumor recurrence at 12 and 29 months; both of these patients died of their disease. Another patient died of complications related to chemotherapy. The other 4 patients are alive with no evidence of disease after 19 to 150 months' follow-up. CONCLUSIONS: Undifferentiated embryonal sarcoma of the liver presents as a large hepatic tumor. Operative resection is difficult, but combined with adjuvant chemotherapy offers the best hope for cure.