Association of Diffusion and Anatomic Imaging Parameters with Survival for Patients with Newly Diagnosed Glioblastoma Participating in Two Different Clinical Trials

PURPOSE: To evaluate the time course and association with survival of anatomic lesion volumes and diffusion imaging parameters for patients with newly diagnosed glioblastoma who were treated with radiation and concurrently with either temozolomide and enzastaurin (TMZ+enza cohort) or temozolomide, erlotonib, and bevaciumab (TMZ+erl+bev cohort). MATERIALS AND METHODS: Regions of interest corresponding to the contrast-enhancing and hyperintense lesions on T2-weighted images were generated. Diffusion-weighted images were processed to provide maps of apparent diffusion coefficient, fractional anisotropy, and longitudinal and radial eigenvalues. Histograms of diffusion values were generated and summary statistics calculated. Cox proportional hazards models were employed to assess the association of representative imaging parameters with survival with adjustments for age, Karnofsky performance status, and extent of resection. RESULTS: Although progression-free survival was significantly longer for the TMZ+erl+bev cohort (12.8 vs 7.3 months), there was no significant difference in overall survival between the two populations (17.0 vs 17.8 months). The median contrast-enhancing lesion volumes decreased from 6.3 to 1.9 cm³ from baseline to the postradiotherapy scan for patients in the TMZ+enza cohort and from 2.8 to 0.9cm³ for the TMZ+erl+bev cohort. Changes in the T2 lesion volumes were only significant for the latter cohort (26.5 to 11.9 cm³). The median apparent diffusion coefficient and related diffusion parameters were significantly increased for the TMZ+enza cohort (1054 to 1225 μm²/s). More of the anatomic parameters were associated with survival for the TMZ+enza cohort, whereas more diffusion parameters were associated with survival for the TMZ+erl+bev cohort. CONCLUSION: The early changes in anatomic and diffusion imaging parameters and their association with survival reflected differences in the mechanisms of action of the treatments that were being given. This suggests that integrating diffusion metrics and anatomic lesion volumes into the Response Assessment in Neuro-Oncology criteria would assist in interpreting treatment-induced changes and predicting outcome in patients with newly diagnosed glioblastoma who are receiving such combination treatments.     

Tissue distribution of a plasmid DNA encoding Hsp65 gene is dependent on the dose administered through intramuscular delivery

In order to assess a new strategy of DNA vaccine for a more complete understanding of its action in immune response, it is important to determine the in vivo biodistribution fate and antigen expression. In previous studies, our group focused on the prophylactic and therapeutic use of a plasmid DNA encoding the Mycobacterium leprae 65-kDa heat shock protein (Hsp65) and achieved an efficient immune response induction as well as protection against virulent M. tuberculosis challenge. In the present study, we examined in vivo tissue distribution of naked DNA-Hsp65 vaccine, the Hsp65 message, genome integration and methylation status of plasmid DNA. The DNA-Hsp65 was detectable in several tissue types, indicating that DNA-Hsp65 disseminates widely throughout the body. The biodistribution was dose-dependent. In contrast, RT-PCR detected the Hsp65 message for at least 15 days in muscle or liver tissue from immunized mice. We also analyzed the methylation status and integration of the injected plasmid DNA into the host cellular genome. The bacterial methylation pattern persisted for at least 6 months, indicating that the plasmid DNA-Hsp65 does not replicate in mammalian tissue, and Southern blot analysis showed that plasmid DNA was not integrated. These results have important implications for the use of DNA-Hsp65 vaccine in a clinical setting and open new perspectives for DNA vaccines and new considerations about the inoculation site and delivery system.     

Influence of dimethyl sulphoxide on intermediate filament proteins in human rhabdomyosarcoma cell lines: modulation at subcellular level

Summary The effects of dimethyl sulphoxide have been investigated on differentiation in human rhabdomyosarcoma cell lines obtained from typically malignant, poorly differentiated tumours. The expression of cell differentiation marker proteins (desmin and vimentin) was assessed in cell lines A-204, A-673 and RD, and the modifications in expression after 3, 8 and 24 h of induction with 1.25% dimethyl sulphoxide were recorded. Protein expression in both the cytoplasm and cytoskeleton was significantly altered by treatments lasting 8 and 24 h, the most noteworthy changes being increased desmin and decreased vimentin expression. The results clearly indicate that dimethyl sulphoxide induced changes typical of differentiation in rhabdomyosarcoma cell lines A-673 and RD; less marked changes were observed in line A-204.     

Analysis of binding properties and specificity through identification of the interface forming residues (IFR) for serine proteases <Emphasis Type="Italic">in silico</Emphasis> docked to different inhibitors

Background  

Enzymes belonging to the same super family of proteins in general operate on variety of substrates and are inhibited by wide selection of inhibitors. In this work our main objective was to expand the scope of studies that consider only the catalytic and binding pocket amino acids while analyzing enzyme specificity and instead, include a wider category which we have named the Interface Forming Residues (IFR). We were motivated to identify those amino acids with decreased accessibility to solvent after docking of different types of inhibitors to sub classes of serine proteases and then create a table (matrix) of all amino acid positions at the interface as well as their respective occupancies. Our goal is to establish a platform for analysis of the relationship between IFR characteristics and binding properties/specificity for bi-molecular complexes.     

Accuracy of noninvasive estimates of respiratory muscle effort during spontaneous breathing in restrictive diseases.

Mean inspiratory pressure (Pi), estimated from the occlusion pressure at the mouth and the inspiratory time, is useful as a noninvasive estimate of respiratory muscle effort during spontaneous breathing in normal subjects and patients with chronic obstructive pulmonary disease. The aim of this study was to compare the Pi with respect to mean esophageal pressure (Pes) in patients with restrictive disorders. Eleven healthy volunteers, 12 patients with chest wall disease, 14 patients with usual interstitial pneumonia, and 17 patients with neuromuscular diseases were studied. Pi, Pes, and mean transdiaphragmatic pressure were simultaneously measured. Tension-time indexes of diaphragm (TTdi) and inspiratory muscles (TTmu) were also determined. In neuromuscular patients, significant correlations were found between Pi and Pes, Pi and transdiaphragmatic pressure, and TTmu and TTdi. A moderate agreement between Pi and Pes and between TTmu and TTdi was found. No significant correlation between these parameters was found in the other patient groups. These findings suggest that Pi is a good surrogate for the invasive measurement of respiratory muscle effort during spontaneous breathing in neuromuscular patients.