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.     

Further evidence of dopamine transporter dysregulation in ADHD: a controlled PET imaging study using altropane.

BACKGROUND: The dopamine transporter (DAT) is known to be a key regulator of dopamine, and recent studies of genetics, treatment, and imaging have highlighted the role of DAT in attention-deficit/hyperactivity disorder (ADHD). The findings of in vivo neuroimaging of DAT in ADHD have been somewhat discrepant, however. METHOD: Dopamine transporter binding was measured using a highly selective ligand (C-11 altropane) and positron emission tomography (PET). The sample consisted of 47 well-characterized, treatment-na?ve, nonsmoking, non-comorbid adults with and without ADHD. Additionally, control subjects had few symptoms of ADHD. RESULTS: Results showed significantly increased DAT binding in the right caudate in adults with ADHD compared with matched control subjects without this disorder. CONCLUSIONS: These results confirm abnormal DAT binding in the striatum of adults with ADHD and provide further support that dysregulation of DAT may be an important component of the pathophysiology of ADHD.     

Body mass index and age affect Three-Factor Eating Questionnaire scores in male subjects

This cross-sectional analysis evaluated the effect of age and body mass index (BMI) on Three-Factor Eating Questionnaire scores in males. Subjects (n = 60) were recruited according to BMI status. Each completed the 51-item Three-Factor Eating Questionnaire. The group was split at the median age to produce a “younger” and “older” group for statistical analysis. A 2-way between-groups analysis of variance revealed a significant main effect of BMI on disinhibition (P = .003) and hunger (P = .041) with higher levels found in overweight males compared to healthy-weight counterparts. A significant main effect of age on hunger (P = .046) demonstrated older males were less susceptible to hunger than younger males. These insights provide a better understanding of eating behavior across the male life cycle and may assist health professionals to better guide men in weight management in the light of rising overweight/obesity.     

Detection of extrapulmonary lesions with integrated PET/CT in the staging of lung cancer.

The aim of the present study was to assess retrospectively the additional value of positron emission tomography (PET)/computed tomography (CT) in the detection of unexpected extrapulmonary lesions in the staging of patients with a malignant pulmonary lesion in comparison with CT and PET used alone. A total of 217 patients with a pathologically proven lung tumour underwent PET/CT. CT, PET and PET/CT were evaluated in the detection of extrapulmonary lesions. These abnormalities were compared with the final diagnosis obtained from the medical records and statistical analysis was carried out. In total, 108 lesions were clinically detected. PET/CT showed a sensitivity, specificity, positive and negative predictive values and accuracy of 100, 81, 71, 100 and 87%, respectively, for the detection of extrapulmonary lesions and 92, 98, 89, 98 and 97%, respectively, for the detection of malignant extrapulmonary lesions. PET/CT was significantly better than CT and PET used alone. Conventional staging work-up has a poor sensitivity in detecting second primary cancers or unexpected metastases. The detection of malignant extrapulmonary lesions is necessary for correct tumour staging. By combining both metabolic and anatomical information, positron emission tomography/computed tomography is able to depict more unexpected extrapulmonary lesions than computed tomography and positron emission tomography used alone, and positron emission tomography/computed tomography provides more additional information of malignancy or benignancy of lesions detected with one of the two imaging modalities alone.     

Scalp electrical recording during paralysis: quantitative evidence that EEG frequencies above 20 Hz are contaminated by EMG.

OBJECTIVE: To identify the possible contribution of electromyogram (EMG) to scalp electroencephalogram (EEG) rhythms at rest and induced or evoked by cognitive tasks. METHODS: Scalp EEG recordings were made on two subjects in presence and absence of complete neuromuscular blockade, sparing the dominant arm. The subjects undertook cognitive tasks in both states to allow direct comparison of electrical recordings. RESULTS: EEG rhythms in the paralysed state differed significantly compared with the unparalysed state, with 10- to 200-fold differences in the power of frequencies above 20 Hz during paralysis. CONCLUSIONS: Most of the scalp EEG recording above 20 Hz is of EMG origin. Previous studies measuring gamma EEG need to be re-evaluated. SIGNIFICANCE: This has a significant impact on measurements of gamma rhythms from the scalp EEG in unparalysed humans. It is to be hoped that signal separation methods will be able to rectify this situation.     

Modified cervical laminoforaminotomy based on anatomic landmarks reduces need for bony removal.

We describe a modified keyhole laminoforaminotomy (LF) using anatomic landmarks on the posterior aspect of the cervical vertebral body to decompress the intervertebral foramen with minimal bone removal. Twenty-four procedures were performed at C3-4, C4-5, and C5-6; 12 at C6-7; and 3 at C7-Tl. Facets and laminae structures were identified based on relative surgical perspectives. Bony resection was limited as follows: 1) inferior limit; inferior border of the superior facet; 2) superior limit, superior border of the superior facet; 3) lateral limit, a vertical line linking the junction of the lamina-facet to the lateral end of the superior limit; and 4) lateral aspect of the dural sac. Fluoroscopy was used to confirm that the intervertebral space was reached. The amount of bony removal was quantified for the superior and inferior laminae and facets. The length of the exposed nerve root was measured. The intervertebral foramen was exposed and the intervertebral disc reached in all specimens. Fluoroscopy showed that the center of the exposure remained at the same height with the intervertebral space. The mean length of the nerve root was 4.6 mm; the mean percentage of bony resection was 21.8%, 7.5%, 11.3%, and 11.5% for the superior and inferior laminae and facets, respectively. Opening the intervertebral foramen posteriorly consistently exposed sufficient nerve root length and allowed access to the intervertebral disc. The technique offers the most direct and safest method of decompressing the intervertebral foramen while minimizing bony resection. This simple surgical procedure may help reduce postoperative morbidity.     

Differential effects of within-day continuous vs. transient dopamine D2 receptor occupancy in the development of vacuous chewing movements (VCMs) in rats.

Accumulating evidence suggests that antipsychotics (APs) that lead to sustained blockade of dopamine D(2) receptors are more likely to induce acute extrapyramidal side effects (EPS) compared to APs that only occupy D(2) receptors transiently. It is unclear, however, whether a similar relationship exists for long-term AP-induced motoric side effects like tardive dyskinesia (TD). The objective of this study was to ascertain whether transient (via daily subcutaneous (s.c.) injections) vs continuous (via osmotic minipump) AP-induced D(2) receptor occupancy differentially affects the development of haloperidol-induced vacuous chewing movements (VCMs), an animal model of TD. Six groups of 12 rats received 0.1, 0.25, or 1 mg/kg of haloperidol or vehicle (n=36) via osmotic minipump (to provide within-day sustained) or daily s.c. injection (within-day transient) for 8 weeks. VCMs were measured on a weekly basis and D(2) occupancy levels were measured in vivo using [(3)H]-raclopride at the end of the experiment. Minipump-treated rats developed HAL dose-dependent D(2) occupancies of 0.1 mg/kg/day (57%), 0.25 mg/kg/day (70%), and 1 mg/kg/day (88%). S.C.-treated rats also developed HAL dose-dependent D(2) occupancies of 0.1 mg/kg/day (83% peak, 3% trough), 0.25 mg/kg/day (89% peak, 0% trough), and 1 mg/kg/day (94% peak, 17% trough). A total of 43% of rats given 0.25 and 1 mg/kg/day of HAL via minipump developed high VCMs compared to only 8% of the rats given the same doses via daily s.c. injections. The 0.1 mg/kg dose did not give rise to VCMs beyond vehicle levels regardless of the route of administration. These findings support the contention that D(2) occupancy levels induced by chronic HAL must be high and sustained through the day before significant risk of VCMs, and perhaps also TD, emerges.