Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: phase 1 trial in adults with malignant glioma.

We determined the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of imatinib mesylate, an inhibitor of the receptor tyrosine kinases platelet-derived growth factor receptor (PDGFR), the proto-oncogene product c-kit, and the fusion protein Bcr-Abl, when administered for 8 days in combination with temozolomide (TMZ) to malignant glioma (MG) patients. MG patients who had not failed prior TMZ were eligible to receive TMZ at a dose of 150-200 mg/m(2) per day on days 4-8 plus imatinib mesylate administered orally on days 1-8 of each 4-week cycle. Patients were stratified based on concurrent administration of CYP3A4-inducing antiepileptic drugs (EIAEDs).

Glioblastoma multiforme: an emerging paradigm of anti-VEGF therapy.

Background: Adults with malignant glioma, especially the most common subtype, glioblastoma multiforme, have an unacceptably poor outcome with current therapies. Malignant gliomas are amongst the most angiogenic of cancers, and VEGF is the dominant angiogenic mediator in these tumors.

Objective: To summarize the clinical experience of VEGF-directed treatment for malignant glioma.

Preliminary evaluation of noninvasive microscopic imaging techniques for the study of vocal fold development.

Understanding pediatric voice development and laryngeal pathology is predicated on a detailed knowledge of the microanatomy of the layered structure of the vocal fold. Our current knowledge of this microanatomy and its temporal evolution is limited by the lack of pediatric specimen availability. By providing the capability to image pediatric vocal folds in vivo, a noninvasive microscopy technique could greatly expand the existing database of pediatric laryngeal microanatomy and could furthermore make longitudinal studies possible.

A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost.

The purpose of this study was to determine the feasibility and assess the efficacy and toxicity, among newly diagnosed malignant glioma patients, of administering (131)I-labeled murine antitenascin monoclonal antibody 81C6 ((131)I-81C6) into a surgically created resection cavity (SCRC) to achieve a patient-specific, 44-Gy boost to the 2-cm SCRC margin. A radioactivity dose of (131)I-81C6 calculated to achieve a 44-Gy boost to the SCRC was administered, followed by conventional external beam radiotherapy (XRT) and chemotherapy. Twenty-one patients were enrolled in the study: 16 with glioblastoma multiforme (GBM) and 5 with anaplastic astrocytoma.

The emerging role of anti-angiogenic therapy for malignant glioma.

Adults with glioblastoma multiforme (GBM), the most common primary brain tumor, have an unacceptably poor outcome with conventional cytotoxic therapies. Malignant gliomas are remarkably angiogenic, and vascular endothelial growth factor (VEGF) is the dominant pro-angiogenic factor. Recent clinical trials targeting VEGF signaling have achieved unprecedented rates of durable radiographic and clinical response, while also confirming adequate safety among recurrent malignant glioma patients.

Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan.

Purpose: The combination of a vascular endothelial growth factor (VEGF) -neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy.

Patients And Methods: In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan.

Backscattering spectroscopic contrast with angle-resolved optical coherence tomography.

Backscattering spectroscopic contrast using angle-resolved optical coherence tomography is demonstrated as a powerful method for determining scatterer diameter with subwavelength resolution. By applying spectroscopic digital processing algorithms to interferograms acquired in the frequency domain with a wavelength-swept laser centered at 1295 nm, it was shown that differences in wavelength-dependent backscattering from 0.3 and 1 microm diameter microspheres can be clearly resolved.

Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.

Purpose: The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan.

Patients And Methods: This phase II trial included two cohorts of patients.

Increased ranging depth in optical frequency domain imaging by frequency encoding.

A technique for increasing the ranging depth in optical frequency domain imaging utilizing frequency encoding is presented. Ranging depth is enhanced by using two interferometer reference arms with different path lengths and independent modulation frequencies (25 and 50 MHz). With this configuration, the sensitivity decreases by 6 dB over a depth range of 7 mm, approximately a threefold improvement over the conventional optical frequency domain imaging technique.

Evolutionary conservation of drug action on lipoprotein metabolism-related targets.

Genetic analysis has shown that the slower than normal rhythmic defecation behavior of the clk-1 mutants of Caenorhabditis elegans is the result of altered lipoprotein metabolism. We show here that this phenotype can be suppressed by drugs that affect lipoprotein metabolism, including drugs that affect HMG-CoA reductase activity, reverse cholesterol transport, or HDL levels. These pharmacological effects are highly specific, as these drugs affect defecation only in clk-1 mutants and not in the wild-type and do not affect other behaviors of the mutants.

Wheat kernel black point and fumonisin contamination by Fusarium proliferatum.

Fusarium proliferatum is a major cause of maize ear rot and fumonisin contamination and also can cause wheat kernel black point disease. The primary objective of this study was to determine whether nine F. proliferatum strains from wheat from Nepal can cause black point and fumonisin contamination in wheat kernels.

Molecular biology of Fusarium mycotoxins.

As the 20th century ended, Fusarium mycotoxicology entered the age of genomics. With complete genomes of Fusarium graminearum and F. verticillioides and several Fusarium gene expression sequence databases on hand, researchers worldwide are working at a rapid pace to identify mycotoxin biosynthetic and regulatory genes.

Evidence for recombination and segregation of virulence to pine in a hybrid cross between Gibberella circinata and G. subglutinans.

Two species associated with the Gibberella fujikuroi species complex, G. circinata (the cause of pitch canker in pines) and G. subglutinans (avirulent on pine), were found to have limited interfertility in hybrid crosses.

Structure-activity relationships of trichothecene toxins in an Arabidopsis thaliana leaf assay.

Many Fusarium species produce trichothecenes, sesquiterpene epoxides that differ in patterns of oxygenation and esterification at carbon positions C-3, C-4, C-7, C-8, and C-15. For the first comprehensive and quantitative comparison of the effects of oxygenation and esterification on trichothecene phytotoxicity, we tested 24 precursors, intermediates, and end products of the trichothecene biosynthetic pathway in an Arabidopsis thaliana detached leaf assay. At 100 microM, the highest concentration tested, only the trichothecene precursor trichodiene was nontoxic.

Estimation of the scattering coefficients of turbid media using angle-resolved optical frequency-domain imaging.

Noninvasive measurements of the scattering coefficients of optically turbid media using angle-resolved optical frequency-domain imaging (OFDI) are demonstrated. It is shown that, by incoherently averaging OFDI reflectance signals acquired at different backscattering angles, speckle noise is reduced, allowing scattering coefficients to be extracted from a single A-line with much higher accuracy than with measurements from conventional OFDI and optical coherence tomography systems. Modeling speckle as a random phasor sum, the relationship between the measurement accuracy and the number of compounded angles is derived.

Molecularly targeted therapy for malignant glioma.

Malignant gliomas are relatively uncommon but lethal cancers. Despite recent research efforts in cancer therapy, the prognosis of patients with malignant gliomas has remained dismal. Understanding the molecular pathogenesis of glioma may lead to a rational development of new therapies.

Angle-resolved optical coherence tomography with sequential angular selectivity for speckle reduction.

We present a novel method for rapidly acquiring optical coherence tomography (OCT) images at multiple backscattering angles. By angularly compounding these images, high levels of speckle reduction were achieved. Signal-to-noise ratio (SNR) improvements of 3.

Complete genetic linkage maps from an interspecific cross between Fusarium circinatum and Fusarium subglutinans.

The Gibberella fujikuroi complex includes many plant pathogens of agricultural crops and trees, all of which have anamorphs assigned to the genus Fusarium. In this study, an interspecific hybrid cross between Gibberella circinata and Gibberella subglutinans was used to compile a genetic linkage map. A framework map was constructed using a total of 578 AFLP markers together with the mating type (MAT-1 and MAT-2) genes and the histone (H3) gene.

Comprehensive esophageal microscopy by using optical frequency-domain imaging (with video).

Background: Optical coherence tomography (OCT) has been used for high-resolution endoscopic imaging and diagnosis of specialized intestinal metaplasia, dysplasia, and intramucosal carcinoma of the esophagus. However, the relatively slow image-acquisition rate of the present OCT systems inhibits wide-field imaging and limits the clinical utility of OCT for diagnostic imaging in patients with Barrett's esophagus.

Objective: This study describes a new optical imaging technology, optical frequency-domain imaging (OFDI), derived from OCT, that enables comprehensive imaging of large esophageal segments with microscopic resolution.

Temozolomide in children with progressive low-grade glioma.

We conducted a phase II study to assess the efficacy of oral temozolomide (TMZ) in children with progressive low-grade glioma. Thirty eligible patients were enrolled on this study. Median age at enrollment was 10 years (range, 4-18 years).

Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma.

Purpose: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available salvage therapy. This study was conducted to determine if the combination of a novel antiangiogenic therapy, bevacizumab, and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma.

Experimental Design: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma.

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas.

Purpose: Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG).

Patients And Method: Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule.

A novel gene cluster in Fusarium graminearum contains a gene that contributes to butenolide synthesis.

The development of expressed sequence tag (EST) databases, directed transformation and a sequenced genome has facilitated the functional analysis of Fusarium graminearum genes. Extensive analysis of 10,397 ESTs, derived from thirteen cDNA libraries of F. graminearum grown under diverse conditions, identified a novel cluster of eight genes (gene loci fg08077-fg08084) located within a 17kb region of genomic sequence contig 1.