Assessing perfusion changes during whole brain irradiation for patients with cerebral metastases

Purpose: To assess perfusion changes within brain and correlate these with clinical symptoms during whole brain radiotherapy (WBRT) for cerebral metastases. Materials and methods: Fourteen patients with cerebral metastases underwent dynamic CT perfusion scans during palliative whole brain irradiation. Perfusion scans were performed on Day 1 prior to initial radiotherapy treatment, then on Day 2, and on Day 5 immediately after completion of radiotherapy. Measurements of cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and capillary surface area permeability product (PS) were performed for each perfusion scan, and daily symptom assessment was taken prior to initial perfusion scan and thereafter prior to each daily radiation treatment. Results: Utilizing Day 1 as baseline, a 19% increase (P=0.033) was noted in PS at Day 2, (median 1.47 ml/100 g/min), which returned to Day 1 range at Day 5 (median 1.31 ml/100 g/min). When symptoms were correlated with perfusion parameters, a statistically significant association between change in MTT with change in headache scores was observed, baseline to Day 2 (P=0.019), and a trend between change in nausea scores with change in CBV (P=0.059) as well as change in MTT (P=0.098), baseline to Day 5. Conclusion: This study has demonstrated the feasibility of a non-invasive technique to assess changes occurring within the human brain during a course of radiation treatment. Dynamic perfusion tomography provides insight into the pathophysiological processes taking place and allows correlation with patient symptomatology.     

Error in the delivery of radiation therapy: results of a quality assurance review

PURPOSE: To examine error rates in the delivery of radiation therapy (RT), technical factors associated with RT errors, and the influence of a quality improvement intervention on the RT error rate. METHODS AND MATERIALS: We undertook a review of all RT errors that occurred at the Princess Margaret Hospital (Toronto) from January 1, 1997, to December 31, 2002. Errors were identified according to incident report forms that were completed at the time the error occurred. Error rates were calculated per patient, per treated volume (>/=1 volume per patient), and per fraction delivered. The association between tumor site and error was analyzed. Logistic regression was used to examine the association between technical factors and the risk of error. RESULTS: Over the study interval, there were 555 errors among 28,136 patient treatments delivered (error rate per patient = 1.97%, 95% confidence interval [CI], 1.81-2.14%) and among 43,302 treated volumes (error rate per volume = 1.28%, 95% CI, 1.18-1.39%). The proportion of fractions with errors from July 1, 2000, to December 31, 2002, was 0.29% (95% CI, 0.27-0.32%). Patients with sarcoma or head-and-neck tumors experienced error rates significantly higher than average (5.54% and 4.58%, respectively); however, when the number of treated volumes was taken into account, the head-and-neck error rate was no longer higher than average (1.43%). The use of accessories was associated with an increased risk of error, and internal wedges were more likely to be associated with an error than external wedges (relative risk = 2.04; 95% CI, 1.11-3.77%). Eighty-seven errors (15.6%) were directly attributed to incorrect programming of the "record and verify" system. Changes to planning and treatment processes aimed at reducing errors within the head-and-neck site group produced a substantial reduction in the error rate. CONCLUSIONS: Errors in the delivery of RT are uncommon and usually of little clinical significance. Patient subgroups and technical factors associated with errors can be identified. The introduction of new technology can produce new ways for errors to occur, necessitating ongoing evaluation of RT errors for quality assurance. Modifications to processes of care can produce important reductions in error rates.     

Inhibition of calpain prevents NMDA-induced cell death and β-amyloid-induced synaptic dysfunction in hippocampal slice cultures

Background and purpose:

Alzheimer''s disease (AD) is a multifactorial, neurodegenerative disease, which is in part caused by an impairment of synaptic function, probably mediated by oligomeric forms of amyloid-β (Aβ). While the Aβ pathology mainly affects the physiology of neurotransmission, neuronal decline is caused by excitotoxic cell death, which is mediated by the NMDA receptor. A comprehensive therapeutic approach should address both Aβ-induced synaptic deficits, as well as NMDA receptor-mediated neurodegeneration, via one molecular target. This study was designed to test whether calpain could be involved in both pathological pathways, which would offer a promising avenue for new treatments.

Experimental approach:

Application of the specific, water-soluble calpain inhibitor A-705253 was used to inhibit calpain in hippocampal slice cultures. We examined whether inhibition of calpain would prevent Aβ-induced deficits in neurotransmission in CA1, as well as NMDA-induced neuronal cell death.

Key results:

A-705253 dose-dependently prevented excitotoxicity-induced neurodegeneration at low nanomolar concentrations, determined by propidium iodide histochemistry. Inhibition of the NMDA receptor similarly protected from neuronal damage. Caspase staining indicated that calpain inhibition was protective by reducing apoptosis. Electrophysiological analysis revealed that inhibition of calpain by A-705253 also fully prevented Aβ oligomer-induced deficits in neurotransmission. The protective effect of calpain was compared to the clinically available NMDA receptor antagonist memantine, which was also effective in this model.

Conclusions and implications:

We suggest that inhibition of calpain exhibits a promising strategy to address several aspects of the pathology of AD that may go beyond the available therapeutic intervention by memantine.     

Elucidation of stannin function using microarray analysis: implications for cell cycle control

Stannin (Snn) is a highly conserved, vertebrate protein whose cellular function is unclear. We have recently demonstrated in human umbilical vein endothelial cells (HUVECs) that Snn gene expression is significantly induced by tumor necrosis factor-alpha (TNF-alpha) in a protein kinase C-epsilon (PKC-epsilon)-dependent manner. In HUVEC, TNF-alpha stimulation of HUVECs results in altered gene expression, and a slowing or halting of cell growth. An initial set of experiments established that Snn knockdown via siRNA, prior to TNF-alpha treatment, resulted in a significant inhibition of HUVEC growth compared to TNF-alpha treatment alone. In order to assess how Snn may be involved in TNF-alpha signaling in HUVEC growth arrest, we performed microarray analysis of TNF-alpha-stimulated HUVECs with and without Snn knockdown via siRNA. The primary comparison made was between TNF-alpha-stimulated HUVECs and TNF-alpha-exposed HUVECs that had Snn knocked down via Snn-specific siRNAs. Ninety-six genes were differentially expressed between these two conditions. Of particular interest was the significant upregulation of several genes associated with control of cell growth and/or the cell cycle, including interleukin-4, p29, WT1/PRKC, HRas-like suppressor, and MDM4. These genes act upon cyclin D1 and/or p53, both of which are key regulators of the G1 phase of the cell cycle. Functional studies further supported the role of Snn in cell growth, as cell cycle analysis using flow cytometry shows a significant increase of G1 cell cycle arrest in HUVECs with Snn knockdown in response to TNF-alpha treatment. Together these studies suggest a functional role of Snn in regulation of TNF-alpha-induced signaling associated with HUVEC growth arrest.     

Immune interactions between mosquitoes and their hosts

The intimate contact between mosquitoes and the immune system of their hosts is generally not considered important because of the transient nature of mosquito feeding. However, when hosts are exposed to many feeding mosquitoes, they develop immune responses against a range of salivary antigens. Understanding the importance of these responses will provide new tools for monitoring vector populations and identifying individuals at risk of mosquito-borne diseases, and allow the development of novel methods for monitoring control and mosquito-release programmes. Antibodies targeting the mosquito midgut are also important in the development of mosquito vaccines. The feasibility of this approach has been demonstrated and future research opportunities are considered in this review. The potential impact of mosquito vaccines is also discussed. Our understanding of the interplay between mosquitoes and the immune system of their hosts is still in its infancy, but it is clear that there is great potential for exploiting this interplay in the control of mosquito-borne diseases.