Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.     

Inhibitory effect of phospholipase A2 isolated from Crotalus durissus terrificus venom on macrophage function

Recent work demonstrated that crotoxin, the main toxin of Crotalus durissus terrificus venom, inhibits macrophage spreading and phagocytic activities. The crotoxin molecule is composed of two subunits, an acidic non-toxic and non-enzymatic polypeptide named crotapotin and a weakly toxic basic phospholipase A₂ (PLA₂). In the present work, the active subunit responsible for the inhibitory effect of crotoxin on macrophage function was investigated. Peritoneal macrophages harvested from naive rats were used. Crotapotin (2.12, 3.75, or 8.37 nM/ml), added for 2 h to the medium of peritoneal cell incubation, did not modify the spreading and phagocytic activities of these cells. On the other hand, the PLA₂ (1.43, 2.86, or 6.43 nM/ml) subunit caused a significant reduction (30, 33, and 35%, respectively) of the spreading activity. The PLA₂ also inhibited the phagocytosis of opsonised zymosan, opsonised sheep erythrocytes, and Candida albicans, indicating that this inhibitory effect is not dependent on the type of receptor involved in the phagocytosis process. The inhibitory effect of PLA₂ was not due to loss of cell membrane integrity, since macrophage viability was higher than 95%. These findings indicate that the inhibitory effect of crotoxin on macrophage spreading and phagocytic activities is caused by the phospholipase A₂ subunit.     

The effect of chronic inflammation on gingival connective tissue proteoglycans and hyaluronic acid

Proteoglycans have been isolated and analysed from extracts of normal and chronically inflamed human gingiva in order to determine the effects of chronic inflammation on these important soft connective tissue extracellular macromolecules. The uronic acid content of glycosaminoglycans isolated by papain digestion of normal and inflamed gingiva did not differ significantly. Likewise, electrophoretic analysis revealed that the content of hyaluronic acid, heparan sulfate, dermatan sulfate and chondroitin sulfute was similar. The sulfated glycosaminoglycans from both sources eluted from a Sepharose C1-6B column with a Kav of 0.45 (approximate M_r 25,000). However, hyaluronic acid from normal gingiva was predominantly of a large size eluting in the void volume of a Sepharose. CL-6B column, while that isolated from inflamed tissue was mostly a small molecular weight species which elutccl in the included volume of a Sepharose CL-6B column. Using dissociative conditions, intact proteoglycans could be more readily extracted from inflamed tissues (90% of the total tissue uronic acid) than from normal tissues where only 80% of the total tissue uronic acid was extractable. Even though DEAE-Sephacel ion-exchange chromatography revealed no differences in charge between normal and inflamed gingival proteoglycans, Sepharose CL-4B chromatography revealed more molecular size polydispersity in samples from inflamed tissue than from normal tissue. Taken together, these results indicate that while hyaluronic acid is depolymerized in inflamed tissue, no evidence of sulfated glycosaminoglycan degradation was found. Therefore, the most likely cause for disruption to the molecular integrity of the proteoglycans is via proteolytic alteration to the proteoglycan core protein.     

Quantitative relationship between global left ventricular thallium uptake and blood flow: effects of propranolol, ouabain, dipyridamole, and coronary artery occlusion

The quantitative relationship between fractional myocardial thallium uptake and radioactive microsphere-determined flow was studied in 33 open chest dogs under baseline conditions during increased coronary flow (dipyridamole), decreased coronary flow (propranolol and coronary artery stenosis), inhibition of Na-K ATPase (ouabain), and regional infarction. Myocardial contents of thallium and microspheres were compared in left ventricular (LV) biopsies taken 5, 10, 15, 30, and 60 min after thallium injection, expressed as fractions of injected dose. Maximal LV thallium uptake occurred 10 min after injection and the 10-min values were therefore used for subsequent comparisons. Combining all dogs, fractional LV thallium content (% injected dose) correlated well with fractional LV blood flow (% cardiac output) (r = 0.95). However, for fractional LV flows in the low, normal, or moderately elevated range (LV flow/cardiac output less than 9%), thallium content consistently exceeded flow by about 15%. This relationship was not altered by ouabain or regional ischemia or infarction. For greatly elevated fractional LV flows (greater than 9%), thallium content was not significantly different from flow. To explain these differences, myocardial and systemic extraction fractions for thallium were determined in eight dogs with a dual tracer method. At baseline, myocardial extraction fraction was significantly greater than systemic (88 +/- 0.4% compared with 75 +/- 1%, p less than 0.001). During dipyridamole, myocardial extraction fraction decreased and myocardial and systemic values were no longer significantly different (82 +/- 1% compared with 79 +/- 1%). These results show that the fraction of injected thallium dose taken up by the LV myocardium exceeds the delivered fraction of cardiac output over a wide range of LV flows, and is not altered by ouabain-induced inhibition of sodium-potassium ATPase or regional myocardial infarction. This difference is explained by a greater myocardial than systemic extraction fraction for thallium. During high LV flows produced by dipyridamole, fractional LV thallium uptake and flow become similar as myocardial and systemic extraction fractions equalize.     

Adrenergic and dopaminergic control of the canine paw microcirculation

Basal isolated canine paw blood flow was equally distributed between arteriovenous anastomosis (AVA) and capillary circulations. Norepinephrine decreased AVA flow by 92% and capillary flow by 41%. Dopamine significantly reduced AVA flow by 94% compared to baseline with a 37% reduction in capillary flow. However, with alpha-adrenergic blockade dopamine decreased AVA flow 66% while capillary flow increased 42%. Isoproterenol increased capillary flow almost twofold and appeared to decrease AVA flow, although the latter was statistically insignificant. Differential effects of adrenergic and dopaminergic agonists on canine paw AVA and capillary blood flow suggest the existence of independent regulation of these components of the microcirculation.     

Scar sign of renal oncocytoma: Magnetic resonance imaging appearance and lack of specificity

This case report illustrates the magnetic resonance imaging (MRI) appearance of a typically asymptomatic renal oncocytoma as a homogeneous mass of medium signal with a stellate central region of decreased signal, representing the central scar. The MRI was correlated with computed tomography (CT), ultrasound (US), and gross pathologic appearance. The appearance of a central scar is not specific for oncocytoma and does not exclude renal cell carcinoma, as illustrated by a second case.     

Mitogen responsiveness of lymphocytes from the BB/W rat

The response of BB diabetes-prone (DP) and W-line non-diabetes-prone rats to the T-cell mitogen concanavalin A (ConA) was measured. The W line was a good responder to ConA, whereas the DP was relatively unresponsive. This unresponsiveness could not be reversed with exogenous interleukin 2 (IL-2). The response of DP rats was enhanced by removing adherent cells. To directly test the response of BB T-cells, they were isolated by flow sorting. These experiments demonstrated that BB T-cells could mount a normal ConA response. The normal function of isolated BB T-cells suggested that they were under suppression. Suppressor activity could not be found in the OX8+ population but was found in the DP-adherent cell population. Adherent cells from the W line were not suppressive at the concentrations used. These results showed that the decreased mitogen responsiveness of BB T-cells was not due to an intrinsic T-cell abnormality but was due, in part, to suppression by adherent cells.     

Cryptococcal meningoencephalitis. Case report and review of Italian literature

A case of cryptococcal meningoencephalitis, as presented by a hypertensive hydrocephalus, is described. To our knowledge, this is the 24th case described in Italy since 1953. The diagnosis was made with ventricular fluid examination: the patient was successfully treated with amphotericin B and 5-fluorocytosine, thus avoiding the risks of surgical treatment of hydrocephalus. Early diagnosis and proper therapy are necessary in order to decrease the high lethality of cryptococcosis.