Glial progenitor cell recruitment drives aggressive glioma growth: mathematical and experimental modelling.

Currently available glioma treatments remain unsuccessful at prolonging disease-free remission. Recent evidence suggests that tumour recruitment of glial progenitor cells by platelet-derived growth factor (PDGF) may play a role in the development and progression of these tumours. Building upon our recent experimental results and previous proliferation-invasion (PI) reaction-diffusion model, in this study, we created a proliferation-invasion-recruitment (PIR) model that includes a mechanism for progenitor cell recruitment, wherein paracrine PDGF signalling stimulates migration and proliferation of progenitors derived from the local brain environment. Parametrizing this mathematical model with data obtained from the PDGF-driven rat glioma model, we explored the consequences of recruitment, using the PIR model to compare the effects of high versus low PDGF secretion rates on tumour growth and invasion dynamics. The mathematical model predicts correlation between high levels of recruitment and both increased radial velocity of expansion on magnetic resonance imaging and less diffusely invasive edges. Thus, the PIR model predicts that PDGF levels correlate with tumour aggressiveness, and results are consistent with both human and experimental data, demonstrating that the effects of progenitor cell recruitment provide a novel mechanism to explain the variability in the rates of proliferation and dispersion observed in human gliomas.

Convection-enhanced delivery of topotecan into a PDGF-driven model of glioblastoma prolongs survival and ablates both tumor-initiating cells and recruited glial progenitors.

The contribution of microenvironment to tumor growth has important implications for optimizing chemotherapeutic response and understanding the biology of recurrent tumors. In this study, we tested the effects of locally administered topotecan on a rat model of glioblastoma that is induced by intracerebral injection of PDGF (platelet-derived growth factor)-IRES (internal ribosome entry site)-GFP (green fluorescent protein)-expressing retrovirus, treated the tumors by convection-enhanced delivery (CED) of topotecan (136 µmol/L) for 1, 4, or 7 days, and then characterized the effects on both the retrovirus-transformed tumor cells (GFP(+) cells) as well as the uninfected glial progenitor cells (GFP(-) cells) that are recruited to the tumor. Topotecan treatment reduced GFP(+) cells about 10-fold and recruited progenitors by about 80-fold while providing a significant survival advantage that improved with greater treatment duration. Regions of glial progenitor ablation occurred corresponding to the anatomic distribution of topotecan as predicted by MRI of a surrogate tracer. Histopathologic changes in recurrent tumors point to a decrease in recruitment, most likely due to the chemotherapeutic ablation of the recruitable progenitor pool.

Clinical usefulness and safety of routine intraoperative angiography for patients and personnel.

OBJECTIVE: The routine use of intraoperative angiography (IA) is still surrounded by controversy. We prospectively performed IAs in consecutive patients undergoing surgery for aneurysms, arteriovenous malformations, and dural arteriovenous fistulae. We calculated the percentage of identified residual pathologies, the cases requiring further surgical intervention, and the complication rates associated with the procedure. We also recorded radiation dose received by personnel during IA for comparison with elective procedures. If our review supported the routine use of IA, recommendations should be tempered by radiation dose to personnel regarding whether or not annual exposure would go beyond recommended limits and whether or not radiation doses indicate a need for specialized operating rooms. METHODS: Two hundred and four consecutive IAs were performed on 191 patients over a 2-year period. Angiographic findings were reviewed retrospectively and noted for additional interventions. Complications related to IA were recorded. Radiation doses received by personnel and fluoroscopy times were compiled from 18 IAs. Mean dose/minutes in intraoperative procedures was compared with mean dose/minutes of a separate cohort of 15 elective angiograms (Student's t test). RESULTS: Twenty-three percent of IAs revealed relevant findings. Clip repositioning or additional clip placement was performed in 8% of the patients. Resection of residual arteriovenous malformations or additional surgery for residual arteriovenous shunting in dural arteriovenous fistulae was performed in 2% of the patients. Fewer than 1% of the patients received intra-arterial verapamil or topical papaverine. The complication rate was less than 1%. The mean dose per procedure for physicians was 1.018 microsieverts (uSv) versus 0.988 uSv for technicians (P = 0.94). The mean effective dose/minutes in the angiogram suite was 0.9209 uSv/minute versus 1.213 uSv/minute in the operating room (P = 0.33). CONCLUSION: IA identifies a significant number of pertinent findings during open neurovascular surgery, half of which require additional intervention. It is associated with a low complication rate. Radiation dose received by personnel per procedure is negligible. IA radiation dose is not different from dose in the angiogram suite; thus, specialized operating rooms may not be necessary. These data support routine intraoperative angiography in open surgeries for neurovascular disorders.

Convection-enhanced delivery in the treatment of malignant glioma.

Despite advancements in glioma therapy, median survival remains low because of rapid post-resection recurrence. A regional method of drug delivery to address local invasion may improve clinical outcomes. Convection-enhanced delivery (CED) is a novel therapy that allows distribution of substances throughout the interstitium via positive-pressure infusion. Studies using various agents have investigated the parameters that affect CED including infusion rate, cannula size, infusion volume, extracellular space, particle characteristics and tumor tissue structure. We review models of small animal glioma that have been successfully treated using different substances administered through CED, particularly our favorable results using topotecan in a C6 rat glioma model. We also review Phase I/II trials utilizing CED which have shown promising response rates and acceptable safety profiles. Future studies should include prospective clinical trials and investigation of novel antitumor agents that are ineffective with systemic delivery. Development of a large animal glioma model would enhance pre-clinical investigation of CED. Clinically, methods to monitor distribution of therapeutic agents and real-time patient response should likewise be explored.