Oxidative imbalance and kidney damage in spontaneously hypertensive rats: activation of extrinsic apoptotic pathways.

In both humans and animals, essential hypertension acts as a risk factor for subclinical kidney damage and precedes renal dysfunction. Several lines of evidence indicate that hypertension and oxidative stress are closely related. The increase in vascular oxidative stress plays a key role in the pathophysiological consequences of hypertension, including kidney disease. Our study examined this issue in spontaneously hypertensive rat (SHR), a reliable model of essential hypertension. We used SHR 20 weeks old when hypertension is stably developed, vascular remodeling started, but kidney function is preserved. We examined plasmatic pro-oxidant and antioxidant status showing a significant alteration in oxidative balance in SHR. As index of oxidative damage, we evaluated lipid peroxidation in kidney, liver, and skeletal muscle, detecting a significant rise in lipid peroxidation levels in all SHR tissues, particularly relevant in kidney. In addition, we analyzed the expression of cytoplasmic antioxidant enzymes, superoxide dismutase 1 (SOD1) and glutatione S-tranferasi P1 (GSTP1). In SHR liver, SOD1 expression slight increased while we have not detected any variation in other tissues. Concerning GSTP1, SHR renal tissues did not display variations in enzyme expression, while in the other tissues, we observed a significant increase in both monomeric and pro-apoptotic dimeric form of the enzyme. By analyzing apoptotic signal, we founded c-Jun N-terminal kinase (JNK) activation in all SHR tissues, but only kidney presented extrinsic apoptotic pathway activation. Our results suggest that, in hypertensive animals with preserved renal function, despite the remarkable oxidative damage of renal tissues, only the extrinsic apoptotic pathway is activated.

Accuracy of Spencer-Attix cavity theory and calculations of fluence correction factors for the air kerma formalism.

EGSnrc calculations of ion chamber response and Spencer-Attix (SA) restricted stopping-power ratios are used to test the assumptions of the SA cavity theory and to assess the accuracy of this theory as it applies to the air kerma formalism for 60Co beams. Consistent with previous reports, the EGSnrc calculations show that the SA cavity theory, as it is normally applied, requires a correction for the perturbation of the charged particle fluence (K(fl)) by the presence of the cavity. The need for K(fl) corrections arises from the fact that the standard prescription for choosing the low-energy threshold delta in the SA restricted stopping-power ratio consistently underestimates the values of delta needed if no perturbation to the fluence is assumed. The use of fluence corrections can be avoided by appropriately choosing delta, but it is not clear how delta can be calculated from first principles. Values of delta required to avoid K(fl) corrections were found to be consistently higher than delta values obtained using the conventional approach and are also observed to be dependent on the composition of the wall in addition to the cavity size. Values of K(fl) have been calculated for many of the graphite-walled ion chambers used by the national metrology institutes around the world and found to be within 0.04% of unity in all cases, with an uncertainty of about 0.02%.

Systematic uncertainties in the Monte Carlo calculation of ion chamber replacement correction factors.

In a previous study [Med. Phys. 35, 1747-1755 (2008)], the authors proposed two direct methods of calculating the replacement correction factors (P(repl) or P(cav)P(dis)) for ion chambers by Monte Carlo calculation. By "direct" we meant the stopping-power ratio evaluation is not necessary. The two methods were named as the high-density air (HDA) and low-density water (LDW) methods. Although the accuracy of these methods was briefly discussed, it turns out that the assumption made regarding the dose in an HDA slab as a function of slab thickness is not correct. This issue is reinvestigated in the current study, and the accuracy of the LDW method applied to ion chambers in a 60Co photon beam is also studied. It is found that the two direct methods are in fact not completely independent of the stopping-power ratio of the two materials involved. There is an implicit dependence of the calculated P(repl) values upon the stopping-power ratio evaluation through the choice of an appropriate energy cutoff delta, which characterizes a cavity size in the Spencer-Attix cavity theory. Since the delta value is not accurately defined in the theory, this dependence on the stopping-power ratio results in a systematic uncertainty on the calculated P(repl) values. For phantom materials of similar effective atomic number to air, such as water and graphite, this systematic uncertainty is at most 0.2% for most commonly used chambers for either electron or photon beams. This uncertainty level is good enough for current ion chamber dosimetry, and the merits of the two direct methods of calculating P(repl) values are maintained, i.e., there is no need to do a separate stopping-power ratio calculation. For high-Z materials, the inherent uncertainty would make it practically impossible to calculate reliable P(repl) values using the two direct methods.

Impaired Oxidative Status Is Strongly Associated with Cardiovascular Risk Factors.

The main target of primary prevention is the identification of cardiovascular risk factors aimed at reducing of the adverse impact of modifiable factors, such as lifestyle and pharmacological treatments. In humans, an alteration of the oxidative status has been associated with several pathologies, including diabetes and cardiovascular diseases. However, the prognostic relevance of circulating oxidative stress biomarkers remains poorly understood. Our study explored, in a healthy population (n = 322), the relationship between oxidative status and cardiovascular risk factors. Here, we were successful in demonstrating that plasmatic oxidative status is significantly associated with traditional cardiovascular risk factors. We revealed a significant depletion in the efficacy of total plasma antioxidant barrier in high cardiovascular risk categories, and we confirmed an age-related alteration of oxidative status. The efficacy of total plasma antioxidant barrier is significantly depleted in relation to metabolic disorders. Interestingly, the cholesterol imbalance is the main factor in depleting the efficacy of total plasma antioxidant barrier. The oxidative status is also influenced by hypertension, and a slight increase in systolic blood pressure determines a highly significant effect. We showed that the first detectable event of a redox disturbance is the repairing intervention of the antioxidant barrier that is thus decreased as overutilized.

Poster - Thur Eve - 72: Conversion of helical tomotherapy plans into clinically favourable step-and-shoot IMRT plans deliverable on a c-arm linac.

The treatment planning software SharePlan is designed to convert dose distributions generated by the TomoTherapy planning station into step-and-shoot IMRT plans deliverable on a c-arm linear accelerator. Five anal canal patients who were planned for TomoTherapy treatments were exported into a SharePlan system and plans were generated for delivery on an Elekta Synergy unit. A total of 80 plans were generated for those five patients, with either seven, nine, eleven or twenty-one gantry angles and different priorities between focusing on matching either the target doses or healthy tissue sparing of the TomoTherapy plan. The plans generated by SharePlan, while often not matching target coverage at prescription, matched well the TomoTherapy coverage at 95% and 105% of the prescription dose. Organ at risk dose, when heavily emphazied in the SharePlan calculations matched or bettered the TomoTherapy dose due to the placement of the beams and the sharper sup-inf fall off of the dose distribution on a linac. For one of the patients, it was possible to produce a better DVH with SharePlan than the original TomoTherapy plan for those reasons. The TomoTherapy plans boasted significantly shorter delivery times than the plans generated with SharePlan.

Sci-Thur AM: Planning - 10: Improved dosimetric accuracy for patient specific quality assurance using a dual-detector measurement method for cyberknife output factors.

The measurement of output factors for small fields is challenging and can lead to large dose errors in patient treatments if corrections for detector size and scatter from high-Z material are not applied. Due to its high spatial resolution and near tissue equivalence, GAFCHROMIC® film potentially provides a correction free measure of output factors but it can be challenging to obtain high quality dosimetric results using this film. We propose minimizing errors in the clinical determination of small field output factors by employing diode measurements with Monte-Carlo generated corrections for small fields ≤10 mm diameter and using small volume ion chambers for apertures >10 mm diameter with independent validation using radiochromic film. We performed patient specific quality assurance (QA) measurements for 9 patients using GAFCHROMIC® film and an A16 small volume ion chamber in a head-shaped phantom, employing this hybrid dual detector method for relative output factor measurements within the Multiplan treatment planning system. Our results suggest that consistent output factors can be determined using this method with experimental verification using GAFCHROMIC® film dosimetry. For the patient specific QA using film, we achieve good dosimetric agreement (<2σ) of the measured and calculated average dose for pixels within the 80% isodose line. For patient specific QA using the micro-ion chamber, we get good agreement (<3%) for cone sizes greater than 5 mm. The differences observed for the 5 mm cone plans are consistent with a 1 mm radial setup uncertainty for patient positioning using the Cyberknife system.

Poster - Thur Eve - 19: Risk assessment of clinical radiation processes using failure modes and effect analysis.

The aim of this work was to apply failure modes and effect analysis (FMEA) to assess risk in two radiation planning and treatment processes; our on-call (out-of-clinical hours) process and our tomotherapy process. The motivation was provided by analysis of 2506 adverse incidents reported over a 5 year period, the on-call process for giving rise to a higher than expected number of incidents and our tomotherapy process for the reverse. For the on-call scenario, three separate processes were analysed: our current process, our current process incorporating a software upgrade eliminating several planning steps and a fully integrated process in which the patient is imaged, planned and treated on a single platform (TomoTherapy Hi Art, Accuray Incorporated, Sunnyvale, CA). After construction of a detailed process map for each case, a multidisciplinary group identified potential failure modes for each process step, the effects of each failure and existing controls. Risk probability numbers were determined from severity, frequency of occurrence and detectability scores assigned to each failure mode according to a standard scale. The results were analysed to identify and prioritise feasible and effective process improvements. For the on-call process, our current workflow was identified as incurring the highest risk of the three processes analysed, demonstrating quantitatively the value of the software upgrade and providing a clear rationale for the associated expense. In summary, we have found FMEA to be a feasible tool for assessing relative risk in a clinical process. However, operational and resource issues must be considered separately.

Sci-Fri PM: Planning-09: An EGSnrc investigation of ion chamber response to Co-60 beams.

The EGSnrc Monte Carlo code was evaluated for its ability to calculate the relative response of a variety of ion chambers to Co-60 beams as a means of justifying the use of this code in future investigations of cavity theory. EGSnrc calculations were compared to measurements with four separate ion chambers, which were each configured with several wall materials (ranging from plastic to lead) and cavity sizes (or cavity air pressures). The experimental results included measurements by Nilsson et al. in 1992, and experiments by Whyte, Attix et al. and Cormack and Johns in the mid-to-late 1950's designed to evaluate Spencer-Attix cavity theory. Experiments by Whyte involved measurements of the response per unit mass as a function of cavity air pressure for a large cylindrical chamber, whereas the other experiments consisted of measurements of the response per unit mass (or ionization current) as a function of the distance between the front and back wall (cavity height) of a plane-parallel chamber. EGSnrc calculations, which could account for the change in response associated with changes in wall material in most cases, were generally within 1-3% of experimental values, even for experimental data that required calculations of unreported wall corrections determined using experimental techniques. The ability of EGSnrc to accurately model these experiments, which showed variations up to 300%, confirms its suitability for detailed Monte Carlo studies of cavity theory.