A selective LC/RIA for dexamethasone and its prodrug dexamethasone-21-isonicotinate in biological fluids.

A combined LC/RIA procedure is described for the selective determination of dexamethasone (DEX) and its prodrug dexamethasone-21-isonicotinate (DIN) in plasma. The low affinity of the employed dexamethasone antiserum for DIN (cross-reactivity less than 0.5%) allowed the direct determination of DEX in plasma extracts. For the determination of DIN, both substances of interest were separated by LC, the DIN containing fraction was collected, hydrolysed and the generated DEX was consequently assayed by radioimmunoassay. The assay detection limits were 0.1 ng ml-1 for DEX and 0.75 ng ml-1 for DIN. For both substances, inter- and intra-day variabilities (RSDs) were 6 and 12%, respectively.     

Prostate thermal therapy with high intensity transurethral ultrasound: the impact of pelvic bone heating on treatment delivery.

PURPOSE: This study was designed to assess pelvic bone temperature during typical treatment regimens of transurethral ultrasound thermal ablation of the prostate to establish guidelines for limiting bone heating. METHODS: Treatment with transurethral planar, curvilinear, and sectored tubular applicators was simulated using an acoustic and biothermal pelvic model that accommodates applicator sweeping, boundary temperature control, and changes in perfusion and attenuation with thermal dose to more accurately model ultrasound energy penetration. The effects of various parameters including power and frequency (5-10 MHz) on bone heating were assessed for a range of prostate cross-sections (3-5 cm) and bone distances (1-3 cm). RESULTS: All devices can produce significant bone heating (temperatures >50 degrees C, thermal dose >240 EM(43 degrees C)) without optimization of applied frequency or power for bone <3 cm from the prostate boundary. In small glands ( approximately 3 cm) increasing operating frequency of curvilinear and planar devices can increase bone temperatures, whereas the tubular applicator can be used at 10 MHz to avoid likely bone damage. In larger prostates (4-5 cm wide) increasing frequency reduces bone heating but can substantially increase treatment time. Lowering power can reduce bone temperature but may increase thermal dose by increasing treatment duration. All applicators can be used to treat glands 4-5 cm with limited bone heating by selecting appropriate power and frequency. CONCLUSIONS: Pubic bone heating during ultrasound thermal therapy of the prostate can be substantial in certain situations. Successful realization of this therapy will require patient-specific treatment planning to optimally determine power and frequency in order to minimize bone heating.     

Molecular determinants of cetuximab efficacy.

PURPOSE: To investigate whether mRNA expression levels of cyclin D1 (CCND1), cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF), all members of the EGFR signaling pathway, are associated with clinical outcome in patients with EGFR-expressing metastatic colorectal cancer (CRC) treated with cetuximab. PATIENTS AND METHODS: Thirty-nine patients with metastatic CRC, refractory to both irinotecan and oxaliplatin, were enrolled on IMCL-0144 and treated with single-agent cetuximab. The intratumoral mRNA levels of CCND1, Cox-2, EGFR, IL-8, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture microdissection and quantitative real-time polymerase chain reaction. RESULTS: There were 21 women and 18 men with a median age of 64 years (range, 35 to 83 years). Higher gene expression levels of VEGF were associated with resistance to cetuximab (P = .038; Kruskal-Wallis test). The combination of low gene expression levels of Cox-2, EGFR, and IL-8 was significantly associated with overall survival (13.5 v 2.3 months; P = .028; log-rank test). Both findings were independent of skin toxicity that was itself significantly correlated to survival. Patients with a lower mRNA amount of EGFR had a longer overall survival compared with patients that had a higher mRNA amount (7.3 v 2.2 months; P = .09; log-rank test). Patients with lower expression of Cox-2 had a significantly higher rate of grade 2 to 3 skin reactions under cetuximab treatment. CONCLUSION: This pilot study suggests that gene expression levels of Cox-2, EGFR, IL-8, and VEGF in patients with metastatic CRC may be useful markers of clinical outcome in single-agent cetuximab treatment.     

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.     

Olfactory neuroblastoma mimicking primary intracranial neoplasm

A case of esthesioneuroblastoma with an unusual clinical and radiographic presentation is reported. The presenting symptoms as well as the computed tomographic examination were compatible with a primary intracranial mass.     

Radiographic appearance of artificially prepared periapical lesions confined to cancellous bone

Summary. Twenty artificial periapical lesions confined to cancellous bone were prepared at the apices of first and second mandibular molars of human cadavers. The lesions emphasized removal of the lamina dura and preparation of a 'halo' lesion surrounding the root apex, plus the addition of a simulated sclerotic border. Radiographs taken before and after creation of the lesions were scored by three examiners for detectable lesions Cross-sections of the lesions were assessed for the extent of bone destruction. Periapical lesions confined to cancellous bone were detected in 80 per cent of cases, and the presence of a sclerotic border tended to enhance visualization, although not in all cases. Intentional cortical involvement also improved detection of lesions. The anatomical features of the periapical area appear to promote the visualization of lesions which might not be detected in other locations.     

Disorders of language, communication, and behavior in mentally retarded children. Some ideas on their co-occurrence

The thesis of this article is that deficits in language and communication contribute to behavior problems in childhood. Mentally retarded children show a range of deficits in language and communication compared with normals; they are also at increased risk for behavior problems. The evidence suggests that these deficits are quantitative rather than qualitative. In addition, these linguistic deficits may contribute independently to the development of behavior disorders insofar as the linguistic deficit interferes with the child's ability to make himself understood or to understand others.     

Magnetic resonance imaging in planning limb-salvage surgery for primary malignant tumors of bone

In defining the linear extent of a malignant tumor in a long bone, radiographs, computerized tomography, and scintigraphy are routinely employed, especially when non-ablative surgery is being considered. The drawbacks of these modalities in defining the true intracompartmental extent of disease within a bone can largely be overcome with the use of magnetic resonance imaging. We did a prospective analysis of magnetic resonance imaging in sixteen consecutive patients with a primary malignant tumor of a long bone, and it showed that this modality has clinical promise of being more precise than the other modalities in defining the true proximal and distal extent of a tumor in a long bone. Coronal images permit easier planning of surgical techniques for salvage of a limb using an allograft than do a multiplicity of transverse images.