Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques.

In this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show that the administration of cyclosporin A or tacrolimus without radiotherapy did not result in lymphopenia. The addition of TBI to the regimen resulted in lymphopenia as well as alterations in the memory/naive ratio following reconstitution of lymphocyte populations. Dendritic cell (DC) numbers in whole blood were largely unaffected, while the monocyte population was altered by immunosuppressive treatment. Irradiation also resulted in increased levels of circulating cytokines and chemokines that correlated with T cell proliferative bursts and with the shift towards memory T cells. We also report that anti-thymocyte globulin (ATG) treatment and CD3 immunotoxin administration resulted in a selective and rapid depletion of naive CD4 and CD8 T cells and increased frequency of memory T cells. We also examined the impact of these treatments on reactivation of latent simian varicella virus (SVV) infection as a model of varicella zoster virus (VZV) infection of humans. None of the treatments resulted in overt SVV reactivation; however, select animals had transient increases in SVV-specific T cell responses following immunosuppression, suggestive of subclinical reactivation. Overall, we provide detailed observations into immune modulation by TBI and chemotherapeutic agents in rhesus macaques, an important research model of human disease.

Rat mammary tumor classification: notes on comparative aspects.

Mammary tumors (170 spontaneous and 1,613 induced with 7,12-dimethylbenz[a]anthracene) in inbred SD rats were classified histologically. The neoplasms were divided into three main categories: fibroepithelial, epithelial, and connective tissue. In the fibroepithelial category, compound tumors showing a wide range of histologic structures with variation in the arrangement of both epithelial and connective tissue elements that differ among lobules occurred in 44 (25.9%) spontaneous and 1,027 (63.7%) induced neoplasms, whereas fibroadenomas occurred in 41 (24.1%) untreated and 175 (10.9%) treated rats. Uncommon fissured tumors were found in 1 (0.7%) untreated and 6 (0.4%) treated animals, whereas carcinosarcomas were found in only 10 untreated animals. In the epithelial category, tubular adenomas occurred in 48 (28.2%) untreated and 164 (10.2%) treated animals. Cystadenomas, duct papillomas, intraductal carcinomas, and anaplastic carcinomas were found less frequently. Adenoacanthomas occurred in only 12 (0.8%) of the treated animals. Among tumors with a fibrous component only, fibromas occurred in 22 (13%) untreated and 97 (6.0%) treated animals, Fibrosarcomas were less frequent, occurring in 4 untreated (2.4%) and 54 (3.4%) treated animals.

Monte Carlo dose computation for IMRT optimization.

A method which combines the accuracy of Monte Carlo dose calculation with a finite size pencil-beam based intensity modulation optimization is presented. The pencil-beam algorithm is employed to compute the fluence element updates for a converging sequence of Monte Carlo dose distributions. The combination is shown to improve results over the pencil-beam based optimization in a lung tumour case and a head and neck case. Inhomogeneity effects like a broader penumbra and dose build-up regions can be compensated for by intensity modulation.

A diamond detector in the dosimetry of high-energy electron and photon beams.

A diamond detector type 60003 (PTW Freiburg) was examined for the purpose of dosimetry with 4-20 MeV electron beams and 4-25 MV photon beams. Results were compared with those obtained by using a Markus chamber for electron beams and an ionization chamber for photon beams. Dose distributions were measured in a water phantom with the detector connected to a Unidos electrometer (PTW Freiburg). After a pre-irradiation of about 5 Gy the diamond detector shows a stability in response which is better than that of an ionization chamber. The current of the diamond detector was measured under variation of photon beam dose rate between 0.1 and 7 Gy min(-1). Different FSDs were chosen. Furthermore the pulse repetition frequency and the depth of the detector were changed. The electron beam dose rate was varied between 0.23 and 4.6 Gy min(-1) by changing the pulse-repetition frequency. The response shows no energy dependence within the covered photon-beam energy range. Between 4 MeV and 18 MeV electron beam energy it shows only a small energy dependence of about 2%, as expected from theory. For smaller electron energies the response increases significantly and an influence of the contact material used for the diamond detector can be surmised. A slight sublinearity of the current and dose rate was found. Detector current and dose rate are related by the expression i alpha Ddelta, where i is the detector current, D is the dose rate and delta is a correction factor of approximately 0.963. Depth-dose curves of photon beams, measured with the diamond detector, show a slight overestimation compared with measurements with the ionization chamber. This overestimation is compensated for by the above correction term. The superior spatial resolution of the diamond detector leads to minor deviations between depth-dose curves of electron beams measured with a Markus chamber and a diamond detector.

Experimental investigation of a fast Monte Carlo photon beam dose calculation algorithm.

An experimental verification of the recently developed XVMC code, a fast Monte Carlo algorithm to calculate dose distributions of photon beams in treatment planning, is presented. The treatment head is modelled by a point source with energy distribution (primary photons) and an additional head scatter contribution. Utility software is presented, allowing the determination of the parameters for this model using a single measured depth dose curve in water. The simple beam model is considered to be a starting point for more complex models being planned for future versions of the code. This paper is mainly focused on the influence of the different techniques on variance reduction and material property determination for dose distributions. It is demonstrated that XVMC and the simple beam model reproduce measured (by a diamond detector) relative dose distributions with an accuracy of better than +/-2% in various homogeneous and inhomogeneous phantoms. Furthermore, relative dose distributions in solid state phantoms have been measured by film. Also for these cases, measured and calculated dose distributions agree within experimental uncertainty. The short calculation time (depending on voxel resolution, statistical accuracy, field size and energy, a span of 1 min to 1 h using a present-day personal computer) and an interface to a commercial planning system will allow the implementation of the code for routine treatment planning of clinical electron and photon beams.

Intensity modulated irradiation of a thorax phantom: comparisons between measurements, Monte Carlo calculations and pencil beam calculations.

The present study investigates the application of compensators for the intensity modulated irradiation of a thorax phantom. Measurements are compared with Monte Carlo and standard pencil beam algorithm dose calculations. Compensators were manufactured to produce the intensity profiles that were generated from the scientific version of the KonRad IMRT treatment-planning system for a given treatment plan. The comparison of dose distributions calculated with a pencil beam algorithm, with the Monte Carlo code EGS4 and with measurements is presented. By measurements in a water phantom it is demonstrated that the method used to manufacture the compensators reproduces the intensity profiles in a suitable manner. Monte Carlo simulations in a water phantom show that the accelerator head model used for simulations is sufficient. No significant overestimations of dose values inside the target volume by the pencil beam algorithm are found in the thorax phantom. An overestimation of dose values in lung by the pencil beam algorithm is also not found. Expected dose calculation errors of the pencil beam algorithm are suppressed, because the dose to the low density region lung is reduced by the use of a non-coplanar beam arrangement and by intensity modulation.

Investigation of photon beam output factors for conformal radiation therapy--Monte Carlo simulations and measurements.

The purpose of this study was to investigate beam output factors (OFs) for conformal radiation therapy and to compare the OFs measured with different detectors with those simulated with Monte Carlo methods. Four different detectors (diode, diamond, pinpoint and ionization chamber) were used to measure photon beam OFs in a water phantom at a depth of 10 cm with a source-surface distance (SSD) of 100 cm. Square fields with widths ranging from 1 cm to 15 cm were observed; the OF for the different field sizes was normalized to that measured at a 5 cm x 5 cm field size at a depth of 10 cm. The BEAM/EGS4 program was used to simulate the exact geometry of a 6 MV photon beam generated by the linear accelerator, and the DOSXYZ-code was implemented to calculate the OFs for all field sizes. Two resolutions (0.1 cm and 0.5 cm voxel size) were chosen here. In addition, to model the detector four kinds of material, water, air, graphite or silicon, were placed in the corresponding voxels. Profiles and depth dose distributions resulting from the simulation show good agreement with the measurements. Deviations of less than 2% can be observed. The OF measured with different detectors in water vary by more than 35% for 1 cm x 1 cm fields. This result can also be found for the simulated OF with different voxel sizes and materials. For field sizes of at least 2 cm x 2 cm the deviations between all measurements and simulations are below 3%. This demonstrates that very small fields have a bad effect on dosimetric accuracy and precision. Finally, Monte Carlo methods can be significant in determining the OF for small fields.

Compensators for IMRT--an investigation in quality assurance.

Intensity modulated radiotherapy (IMRT) allows dose distributions which adequately consider organs at risk (OAR) and dose homogeneity to the target volume. This is practically reached by conforming the beam profiles to the shape of the planning target volume (PTV), by shaping the fluence with multileaf collimators (MLC) or compensators. Though compensator production is time consuming and seems less convenient than the use of MLC, compensators offer much easier quality assurance. In this study the effects of certain simplifications of compensator production were studied. Compensators were produced and ionization chamber measurements in a water phantom and film measurements in a solid phantom were performed to verify the compensators. The results of the measurements were compared to the fluence distributions given by the planning system. The measurements were meant to show how realistic the investigated simplifications were, and to reveal a suitable and reliable testing method for compensators. Monte-Carlo calculations employing the EGS 4 Code were further performed to support the measurements.

[Monte Carlo simulation of a dynamic multileaf collimator:implementation and applications]. / Monte-Carlo-Simulation von Multileafkollimatoren mit gekrümmten Lamellenenden.

A model for the simulation of the accelerator heads of two identical linear accelerators was designed at the University Hospital of Tübingen, using the BEAM program developed at the National Research Council of Canada. Both linear accelerators are equipped with multileaf collimators (MLCs) and backup jaws (y-direction) with curved leaf-ends. The accelerator models were divided into two parts. The first part consisted of target, primary collimator, flattening filter, monitor chamber, and mirror. After the Monte Carlo simulation of these parts, the phase-space characteristics below the mirror were stored in a file and used as source for the second part of the accelerator head (jaw, MLC). The electron source was assumed to deliver a gaussian energy spectrum, with parallel direction to the beam axis. With this electron source, there was good agreement between the measured and simulated depth dose curves in water, with difference < 2%. A new module was created for the BEAM program to simulate backup jaws, while the standard MLCQ module from BEAM was used to simulate a MLC with curved leaf-ends. As a result, MLCs and backup jaws with curved leaf-ends make the shoulder of the y-profile higher than the straight-end MLCs.

[Long-term follow up of patients with pernicious anemia]. / Anaemia perniciosás betegek hosszan tartó megfigyelésével szerzett tapasztalataink.

The authors give several data of 357 patients with megaloblastic anaemia diagnosed, treated and controlled between 1958-1988. 334 of the patients had anaemia perniciosa and 23 of them had postresectional megaloblastic anaemia. After listing the criteria of the diagnosis the authors detail the mean age of the patients at the time of diagnosis, the distribution of sexes, age and blood groups among the patients, the number of new cases per year, the frequency of relapsus of the disease and its association with other autoimmune diseases. They also deal with the characteristic seasonal fluctuation and the accumulated cases in families. Its association with malignant tumours, especially with stomach carcinoma was examined.

On the sensitivity of common gamma-index evaluation methods to MLC misalignments in Rapidarc quality assurance.

PURPOSE: In this study the effects of small systematic MLC misalignments and gravitational errors on the quality of Rapidarc treatment plan delivery are investigated with respect to verification measurements with two detector arrays and the evaluation of clinical significance of the error-induced deviations. METHODS: Five prostate and six head and neck plans were modified by means of three error types: (1) both MLC banks are opened, respectively, in opposing directions, resulting in larger fields; (2) both MLC banks are closed, resulting in smaller fields; and (3) both MLC banks are shifted for lateral gantry angles, respectively, in the same direction to simulate the effects of gravity on the leaves. Measurements were evaluated with respect to a gamma-index of 3%/3 mm and 2%/2 mm. Dose in the modified plans was recalculated and the resulting dose volume histograms for target and critical structures were compared to those of the unaltered plans. RESULTS: The smallest introduced leaf position deviations which fail the >90% criterion for a gamma-index of 2%/2 mm are: (1) 1 mm; (2) 0.5 mm for prostate and 1.0 mm for head and neck cases; and (3) 3 mm corresponding to the error types, respectively. These errors would lead to significant changes in mean PTV dose and would not be detected with the more commonly used 3%/3 mm gamma-index criterion. CONCLUSIONS: A stricter gamma-index (2%/2 mm) is necessary in order to detect positional errors of the MLC. Nevertheless, the quality assurance procedure of Rapidarc treatment plans must include a thorough examination of where dose discrepancies occur, and professional judgment is needed when interpreting the gamma-index analysis, since even a >90% passing rate using the 2%/2 mm gamma-index criterion does not guarantee the absence of clinically significance dose deviation.

SU-E-T-490: Comparison of XVMC Monte Carlo Dose Calculations with Eclipse AAA Calculations for RapidArc Plans.

PURPOSE: The consistency between the AAA and XVMC algorithm in the treatment planning for RapidArc is investigated. While the majority of the radiation field is blocked by the MLC system, multiple small dose islands with MLC opened only slightly can be observed in one control point. This raises questions on how accurate the clinically used AAA algorithm in Eclipse is able to calculate RapidArc dose distributions. The fast Monte Carlo Code XVMC was used as a benchmark to test the AAA algorithm. METHODS: RadpidArc plans of 25 patients were calculated with AAA and XVMC. The patient cohort consisted of 4 different cancer sites (H&N, upper abdominal, lung, prostate). Dose distributions, PTV and OAR coverage were compared looking at the PTV mean dose Dmean, the volume V95% of the PTV receiving 95% of the prescribed dose, the dose D95% delivered to 95% of the PTV Volume, the percentage PTV mean dose with respect to the prescribed dose Dmean/prescr and OAR mean dose. RESULTS: The recalculation of RapidArc plans yielded good agreement of both calculation algorithms for treatment plans of all four cancer sites. PTV mean dose differences of AAA and XVMC were found to be in between -0.11% and 4.89% of the prescribed dose. The mean dose difference found was 0.48±0.77 Gy. Local dose differences were found when comparing dose distributions in regions of big mass density differences and in high dose regions. One head and neck plan and one prostate plan revealed significant differences in PTV coverage (ΔDmean=3.25 Gy) and OAR mean dose (prostate mean dose -13.71 Gy) respectively. CONCLUSIONS: The vast majority of treatment plans calculated with the AAA algorithm were found to agree within the expected and acceptable tolerances compared to XVMC results. Nevertheless in some cases dose differences were observed that could be of clinical significance. This work was funded by a Varian grant. Wolfram Laub is working in the physics group of CMS.

SU-E-J-27: Effects of Metal Artifacts of KV and MV CT Images on Structure Delineation and Tissue Electron/Mass Density Calculation.

PURPOSE: To quantitatively evaluate effects of image artifacts of hip prostheses on the accuracy of structure delineation and tissue density calculation on kV and MV CT images. METHODS: Five hip prostheses made of stainless steel, titanium and cobalt chrome alloys were positioned inside a water tank and scanned respectively on a Philips CT and a Tomotherapy Hi-Art unit. Prostheses were positioned to mimic single and bilateral implantations. Rods of tissue materials of lung, water and bone were placed at locations next and distal to metal implants near femoral head, neck and stem of prostheses. kV and MV CT scans were repeated for each placement. On CT images, cross-sectional outlines of metal implants and tissue rods were delineated. Densities of rod materials were determined and compared to the true values. RESULTS: Metal artifacts were severe on kV CTs and minimal on MV CTs. Cross-sectional outlines of metal implants and tissue rods on kV CTs were severely distorted by artifacts while those on MV CTs remained clearly identifiable. For kV CTs, deviations of measured tissue density from true value were up to 51.3%, 30.6% and 40.9% respectively for lung, bone and solid water. The magnitude of deviation was generally larger at locations closer to metal implants and greater with bilateral implants than single implant. For MV CTs, deviations of measured density from true value were less than 6% for all three tissue materials either with single or bilateral implants. Magnitude of deviation appeared to be uniform and independent of locations relative to metal implants. CONCLUSIONS: High Z metal artifacts on kV CTs can have severe impact on the accuracy of structure delineation and tissue density calculation, while on MV CTs, the impact is substantially less and insignificant. MV CTs should be considered for treatment planning on patients with high Z metal implants.