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.     

Bactericidal/permeability-increasing protein in host defense and its efficacy in the treatment of bacterial sepsis

The 55-kD bactericidal/permeability-increasing protein (BPI) is a neutrophil-derived polypeptide belonging to a family of lipid and endotoxin binding proteins. BPI is composed of two functionally distinct structural domains: a potently antibacterial and antiendotoxin ∼ 20-kD aminoterminal half, and an opsonic carboxy-terminal portion. In multiple animal models, a recombinant amino-terminal fragment of BPI (rBPI₂₁) is nontoxic and protects against gram-negative bacteria and endotoxin. In humans, rBPI₂₁ is also nontoxic and nonimmunogenic and has undergone phase II/III clinical trials with apparent therapeutic benefit.     

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.     

Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy.

PURPOSE: A postoperative nomogram for prostate cancer recurrence after radical prostatectomy (RP) has been independently validated as accurate and discriminating. We have updated the nomogram by extending the predictions to 10 years after RP and have enabled the nomogram predictions to be adjusted for the disease-free interval that a patient has maintained after RP. METHODS: Cox regression analysis was used to model the clinical information for 1,881 patients who underwent RP for clinically-localized prostate cancer by two high-volume surgeons. The model was externally validated separately on two independent cohorts of 1,782 patients and 1,357 patients, respectively. Disease progression was defined as a rising prostate-specific antigen (PSA) level, clinical progression, radiotherapy more than 12 months postoperatively, or initiation of systemic therapy. RESULTS: The 10-year progression-free probability for the modeling set was 79% (95% CI, 75% to 82%). Significant variables in the multivariable model included PSA (P = .002), primary (P < .0001) and secondary Gleason grade (P = .0006), extracapsular extension (P < .0001), positive surgical margins (P = .028), seminal vesicle invasion (P < .0001), lymph node involvement (P = .030), treatment year (P = .008), and adjuvant radiotherapy (P = .046). The concordance index of the nomogram when applied to the independent validation sets was 0.81 and 0.79. CONCLUSION: We have developed and validated as a robust predictive model an enhanced postoperative nomogram for prostate cancer recurrence after RP. Unique to predictive models, the nomogram predictions can be adjusted for the disease-free interval that a patient has achieved after RP.