Martin Lepage

Polymer gel dosimetry

Polymer gel dosimeters are fabricated from radiation sensitive chemicals which, upon irradiation, polymerize as a function of the absorbed radiation dose. These gel dosimeters, with the capacity to uniquely record the radiation dose distribution in three-dimensions (3D), have specific advantages when compared to one-dimensional dosimeters, such as ion chambers, and two-dimensional dosimeters, such as film. These advantages are particularly significant in dosimetry situations where steep dose gradients exist such as in intensity-modulated radiation therapy (IMRT) and stereotactic radiosurgery. Polymer gel dosimeters also have specific advantages for brachytherapy dosimetry. Potential dosimetry applications include those for low-energy x-rays, high-linear energy transfer (LET) and proton therapy, radionuclide and boron capture neutron therapy dosimetries. These 3D dosimeters are radiologically soft-tissue equivalent with properties that may be modified depending on the application. The 3D radiation dose distribution in polymer gel dosimeters may be imaged using magnetic resonance imaging (MRI), optical-computerized tomography (optical-CT), x-ray CT or ultrasound. The fundamental science underpinning polymer gel dosimetry is reviewed along with the various evaluation techniques. Clinical dosimetry applications of polymer gel dosimetry are also presented.

Dose resolution in radiotherapy polymer gel dosimetry: effect of echo spacing in MRI pulse sequence

In polymer gel dosimetry using magnetic resonance imaging, the uncertainty in absorbed dose is dependent on the experimental determination of T2. The concept of dose resolution (Dpdelta) of polymer gel dosimeters is developed and applied to the uncertainty in dose related to the uncertainty in T2 from a range of T4 encountered in polymer gel dosimetry. Dpdelta is defined as the minimal separation between two absorbed doses such that they may be distinguished with a given level of confidence, p. The minimum detectable dose (MDD) is Dpdelta as the dose approaches zero. Dpdelta and the minimum detectable dose both give a quantifiable indication of the likely practical limitations and usefulness of the dosimeter. Dpdelta of a polyacrylamide polymer gel dosimeter is presented for customized 32-echo and standard multiple-spin-echo sequences on a clinical MRI scanner. In evaluating uncertainties in T2, a parameter of particular significance in the pulse sequence is the echo spacing (ES). For optimal results, ES should be selected to minimize Dpdelta over a range of doses of interest in polymer gel dosimetry.

Modelling of post-irradiation events in polymer gel dosimeters

The nuclear magnetic resonance (NMR) spin-spin relaxation time (T2) is related to the radiation-dependent concentration of polymer formed in polymer gel dosimeters manufactured from monomers in an aqueous gelatin matrix. Changes in T2 with time post-irradiation have been reported in the literature but their nature is not fully understood. We investigated those changes with time after irradiation using FT-Raman spectroscopy and the precise determination of T2 at high magnetic field in a polymer gel dosimeter. A model of fast exchange of magnetization taking into account ongoing gelation and strengthening of the gelatin matrix as well as the polymerization of the monomers with time is presented. Published data on the changes of T2 in gelatin gels as a function of post-manufacture time are used and fitted closely by the model presented. The same set of parameters characterizing the variations of T2 in gelatin gels and the increasing concentration of polymer determined from FT-Raman spectroscopy are used successfully in the modelling of irradiated polymer gel dosimeters. Minimal variations in T2 in an irradiated PAG dosimeter are observed after 13 h.

Brain glucose and acetoacetate metabolism: a comparison of young and older adults

The extent to which the age-related decline in regional brain glucose uptake also applies to other important brain fuels is presently unknown. Ketones are the brains major alternative fuel to glucose, so we developed a dual tracer positron emission tomography protocol to quantify and compare regional cerebral metabolic rates for glucose and the ketone, acetoacetate. Twenty healthy young adults (mean age, 26 years) and 24 healthy older adults (mean age, 74 years) were studied. In comparison with younger adults, older adults had 8 ± 6% (mean ± SD) lower cerebral metabolic rates for glucose in gray matter as a whole (p = 0.035), specifically in several frontal, temporal, and subcortical regions, as well as in the cingulate and insula (p ≤ 0.01, false discovery rate correction). The effect of age on cerebral metabolic rates for acetoacetate in gray matter did not reach significance (p = 0.11). Rate constants (min(-1)) of glucose (Kg) and acetoacetate (Ka) were significantly lower (-11 ± 6%; [p = 0.005], and -19 ± 5%; [p = 0.006], respectively) in older adults compared with younger adults. There were differential effects of age on Kg and Ka as seen by significant interaction effects in the caudate (p = 0.030) and post-central gyrus (p = 0.023). The acetoacetate index, which expresses the scaled residuals of the voxel-wise linear regression of glucose on ketone uptake, identifies regions taking up higher or lower amounts of acetoacetate relative to glucose. The acetoacetate index was higher in the caudate of young adults when compared with older adults (p ≤ 0.05 false discovery rate correction). This study provides new information about glucose and ketone metabolism in the human brain and a comparison of the extent to which their regional use changes during normal aging.

Radiation Dose Distribution in Polymer Gels by Raman Spectroscopy

The Raman spectroscopy of polymer gel dosimeters has been investigated with a view to developing a novel dosimetry technique that is capable of determining radiation dose within a micrometer of spatial resolution. The polymer gel dosimeter, known as the PAG dosimeter, is typically made up of acrylamide, N,N′-methylene-bis-acrylamide, gelatin, and water. A polyacrylamide network within the gelatin matrix forms in response to an absorbed dose. The loss of monomers may be monitored by corresponding changes to the Raman spectrum. Principal component analysis offers a simple method of quantifying the absorbed radiation dose from the Raman spectrum of the polymer gel. The background luminescence in the spectrum increased significantly with dose and is shown to originate in the glass of the sample vial. The competing effects of elastic scatter, which increases with dose due to the formation of polymer, and sample absorption were quantified and found to introduce errors of up to 5% under certain conditions. Raman spectra as a function of distance from the air–surface interface have been measured for samples that were subjected to doses delivered by a clinical linear accelerator. The depth dose profile thus obtained compared favorably with “gold standard” ion-chamber measurements.

Long-term consequences of a prolonged febrile seizure in a dual pathology model

Clinical evidence suggests that febrile status epilepticus (SE) in children can lead to acute hippocampal injury and subsequent temporal lobe epilepsy. The contribution of febrile SE to the mechanisms underlying temporal lobe epilepsy are however poorly understood. A rat model of temporal lobe epilepsy following hyperthermic SE was previously established in our laboratory, wherein a focal cortical lesion induced at postnatal day 1 (P1), followed by a hyperthermic SE (more than 30 min) at P10, leads to hippocampal atrophy at P22 (dual pathology model) and spontaneous recurrent seizures (SRS) with mild visuospatial memory deficits in adult rats. The goal of this study was to identify the long term electrophysiological, anatomical and molecular changes in this model. Following hyperthermic SE, all cortically lesioned pups developed progressive SRS as adults, characterized by the onset of highly rhythmic activity in the hippocampus. A reduction of hippocampal volume on the side of the lesion preceded the SRS and was associated with a loss of hippocampal neurons, a marked decrease in pyramidal cell spine density, an increase in the hippocampal levels of NMDA receptor NR2A subunit, but no significant change in GABA receptors. These findings suggest that febrile SE in the abnormal brain leads to hippocampal injury that is followed by progressive network reorganization and molecular changes that contribute to the epileptogenesis as well as the observed memory deficits.

White Matter Injury and Autistic-Like Behavior Predominantly Affecting Male Rat Offspring Exposed to Group B Streptococcal Maternal Inflammation

The impact of the group B streptococcus (GBS)-induced maternal inflammation on offsprings brain has not yet been investigated despite GBS being one of the most frequent bacteria colonizing or infecting pregnant women. According to our hypothesis GBS-induced maternal immune activation plays a role in offspring perinatal brain damage and subsequent neurodisabilities such as autism. Using a new preclinical rat model of maternal inflammation triggered by inactivated GBS, we demonstrated placental, neuropathological and behavioral impacts on offspring. GBS-exposed placentas presented cystic lesions and polymorphonuclear infiltration located within the decidual/maternal side of the placenta, contrasting with macrophagic infiltration and necrotic areas located in the labyrinth/fetal compartment of the placenta after lipopolysaccharide-induced maternal inflammation. Brain damage featured lateral ventricles widening, predominately in the male, reduction of periventricular external capsules thickness, oligodendrocyte loss, and disorganization of frontoparietal subcortical tissue with no glial proliferation. Autistic hallmarks were found in offspring exposed to GBS, namely deficits in motor behavior, social and communicative impairments, i.e. profound defects in the integration and response to both acoustic and chemical signals that are predominant modes of communication in rats. Surprisingly, only male offspring were affected by these combined autistic-like traits. Our results show for the first time that materno-fetal inflammatory response to GBS plays a role in the induction of placental and cerebral insults, remarkably recapitulating cardinal features of human autism such as gender dichotomy and neurobehavioral traits. Unlike other models of prenatal inflammatory brain damage (induced by viral/toll-like receptor 3 (TLR3) or Gram-negative/TLR4), maternal inflammation resulting from GBS/TLR2 interactions induced a distinctive pattern of chorioamnionitis and cerebral injuries. These results also provide important evidence that beyond genetic influences, modifiable environmental factors play a role in both the occurrence of autism and its gender imbalance.

Irradiation of normal mouse tissue increases the invasiveness of mammary cancer cells

Purpose: Treatment of breast tumours frequently involves irradiating the whole breast to reach malignant microfoci scattered throughout the breast. In this study, we determined whether irradiation of normal tissues could increase the invasiveness of breast cancer cells in a mouse model. Materials and methods: Non-irradiated MC7-L1 mouse mammary carcinoma cells were injected subcutaneously in irradiated and non-irradiated thighs of Balb/c mice. The invasion volume, tumour volume, blood vessel permeability and interstitial volumes were monitored by magnetic resonance imaging (MRI). Slices of normal tissue invaded by cancer cells were examined by histology. Activity of matrix metalloproteinase -2 and -9 (MMP -2 and -9) in healthy and irradiated tissues was determined, and the proliferation index of the invading cancer cells was evaluated. Results: Three weeks after irradiation, enhancement of MC7-L1 cells invasiveness in irradiated thighs was already detected by MRI. The tumour invasion volume continued to extend 28- to 37-fold compared to the non-irradiated implantation site for the following three weeks, and it was associated with an increase of MMP-2 and -9 activities in healthy tissues. The interstitial volume associated with invading cancer cells was significantly larger in the pre–irradiated sites; while the blood vessels permeability was not altered. Cancer cells invading the healthy tissues were proliferating at a lower rate compared to non-invading cancer cells. Conclusion: Implantation of non-irradiated mammary cancer cells in previously irradiated normal tissue enhances the invasive capacity of the mammary cancer cells and is associated with an increased activity of MMP-2 and -9 in the irradiated normal tissue.

Induction of Selective Blood-Tumor Barrier Permeability and Macromolecular Transport by a Biostable Kinin B1 Receptor Agonist in a Glioma Rat Model

Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg9BK (LDBK) and SarLys[dPhe8]desArg9BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T 1-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites.

Investigation and analysis of ferrous sulfate polyvinyl alcohol (PVA) gel dosimeter

Ferrous sulfate (Fe(SO4)2) PVA gels were investigated for a range of absorbed doses up to 20 Gy using both magnetic resonance imaging (MRI) and spectrophotometry to determine R1 and optical density (OD) dose responses and G values. It was found that R1- and OD-dose sensitivities increased with O2 saturation or by the introduction of a freeze-thaw cycle during preparation of the PVA gel. The storage temperature of the Fe(SO4)2 PVA gel at -18 degrees C increased R1-dose sensitivity above that of gels stored at 5 degrees C. The addition of sucrose to the formulation was found to result in the largest increase in both R1- and OD-dose sensitivities. Fe(SO4)2 PVA gel with and without the addition of xylenol orange was demonstrated to have a G value of approximately 20 ions/100 eV and with sucrose approximately 24 ions/100 eV.