Per Nilsson

Endothelial basement membrane laminin |[alpha]|5 selectively inhibits T lymphocyte extravasation into the brain

Specific inhibition of the entry of encephalitogenic T lymphocytes into the central nervous system in multiple sclerosis would provide a means of inhibiting disease without compromising innate immune responses. We show here that targeting lymphocyte interactions with endothelial basement membrane laminins provides such a possibility. In mouse experimental autoimmune encephalomyelitis, T lymphocyte extravasation correlates with sites expressing laminin α4 and small amounts of laminin α5. In mice lacking laminin α4, laminin α5 is ubiquitously expressed along the vascular tree, resulting in marked and selective reduction of T lymphocyte infiltration into the brain and reduced disease susceptibility and severity. Vessel phenotype and immune response were not affected in these mice. Rather, laminin α5 directly inhibited integrin α6β1–mediated migration of T lymphocytes through laminin α4. The data indicate that T lymphocytes use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier, permitting specific targeting of this immune cell population.

Volumetric and dosimetric evaluation of radiation treatment plans: radiation conformity index

PURPOSE The use of conformal radiation therapy has grown substantially during the last years since three-dimensional (3D) treatment planning systems with beams-eye-view planning has become commercially available. We studied the degree of conformity reached in clinical routines for some common diagnoses treated at our department by calculating a radiation conformity index (RCI). METHODS AND MATERIALS The radiation conformity index, determined as the ratio between the target volume (PTV) and the irradiated volume, has been evaluated for 57 patients treated with 3D treatment plans. RESULTS AND CONCLUSION The RCI was found to vary from 0.3 to 0.6 (average 0.4), a surprisingly low figure. The higher RCI is typical for pelvic treatments (e.g., prostate) and stereotactic treatments. The lower RCI is found for extended tumors, such as mammary carcinomas where the adjacent nodes are included. The latter is also valid for most lung cancer patients studied. The RCI gives a consistent method for quantifying the degree of conformity based on isodose surfaces and volumes. Care during interpretation of RCI must always be taken, since small changes in the minimum dose can dramatically change the treated volume.

Limitations of a pencil beam approach to photon dose calculations in lung tissue

A common limitation in treatment planning systems for photon dose calculation is to ignore the impact on electron transport and photon scatter from patient heterogeneities. The heterogeneity correlation is often based on scaling operations along beam rays as for the method according to Batho or the more novel approach of 1D convolutions along beam paths applied in pencil-beam-based systems. The effects of the limitation have been studied in a mediastinum geometry for a wide range of beam qualities by comparing the results from a pencil-beam-based treatment planning system with the results from Monte Carlo calculations. As expected, the deviations within unit-density volumes are small while deviations in low-density volumes increase with increasing beam energy from approximately 3% for 4 MV to 14% for 18 MV x-rays as a result of increased electron disequilibrium.

Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma.

Abstract Introduction. The aim of this model study was to estimate and compare the risk of radiation-induced adverse late effects in pediatric patients with medulloblastoma (MB) treated with either three-dimensional conformal radiotherapy (3D CRT), inversely-optimized arc therapy (RapidArc® (RA)) or spot-scanned intensity-modulated proton therapy (IMPT). The aim was also to find dose-volume toxicity parameters relevant to children undergoing RT to be used in the inverse planning of RA and IMPT, and to use in the risk estimations. Material and methods. Treatment plans were created for all three techniques on 10 pediatric patients that have been treated with craniospinal irradiation (CSI) at our institution in 2007–2009. Plans were generated for two prescription CSI doses, 23.4 Gy and 36 Gy. Risk estimates were based on childhood cancer survivor data when available and secondary cancer (SC) risks were estimated as a function of age at exposure and attained age according to the organ-equivalent dose (OED) concept. Results. Estimates of SC risk was higher for the RA plans and differentiable from the estimates for 3D CRT at attained ages above 40 years. The risk of developing heart failure, hearing loss, hypothyroidism and xerostomia was highest for the 3D CRT plans. The risks of all adverse effects were estimated as lowest for the IMPT plans, even when including secondary neutron (SN) irradiation with high values of the neutron radiation weighting factors (WRneutron). Conclusions. When comparing RA and 3D CRT treatment for pediatric MB it is a matter of comparing higher SC risk against higher risks of non-cancer adverse events. Considering time until onset of the different complications is necessary to fully assess patient benefit in such a comparison. The IMPT plans, including SN dose contribution, compared favorably to the photon techniques in terms of all radiobiological risk estimates.

Underdosage of the upper-airway mucosa for small fields as used in intensity-modulated radiation therapy: A comparison between radiochromic film measurements, Monte Carlo simulations, and collapsed cone convolution calculations

Head-and-neck tumors are often situated at an air-tissue interface what may result in an underdosage of part of the tumor in radiotherapy treatments using megavoltage photons, especially for small fields. In addition to effects of transient electronic disequilibrium, for these small fields, an increased lateral electron range in air will result in an important extra reduction of the central axis dose beyond the cavity. Therefore dose calculation algorithms need to model electron transport accurately. We simulated the trachea by a 2 cm diameter cylindrical air cavity with the rim situated 2 cm beneath the phantom surface. A 6 MV photon beam from an Elekta SLiplus linear accelerator, equipped with the standard multileaf collimator (MLC), was assessed. A 10 x 2 cm2 and a 10 x 1 cm2 field, both widthwise collimated by the MLC, were applied with their long side parallel to the cylinder axis. Central axis dose rebuild-up was studied. Radiochromic film measurements were performed in an in-house manufactured polystyrene phantom with the films oriented either along or perpendicular to the beam axis. Monte Carlo simulations were performed with BEAM and EGSnrc. Calculations were also performed using the pencil beam (PB) algorithm and the collapsed cone convolution (CCC) algorithm of Helax-TMS (MDS Nordion, Kanata, Cahada) version 6.0.2 and using the CCC algorithm of Pinnacle (ADAC Laboratories, Milpitas, CA, USA) version 4.2. A very good agreement between the film measurements and the Monte Carlo simulations was found. The CCC algorithms were not able to predict the interface dose accurately when lateral electronic disequilibrium occurs, but were shown to be a considerable improvement compared to the PB algorithm. The CCC algorithms overestimate the dose in the rebuild-up region. The interface dose was overestimated by a maximum of 31% or 54%, depending on the implementation of the CCC algorithm. At a depth of 1 mm, the maximum dose overestimation was 14% or 24%.

Dose-volume relationships between enteritis and irradiated bowel volumes during 5-fluorouracil and oxaliplatin based chemoradiotherapy in locally advanced rectal cancer.

Purpose. Radiation enteritis is the main acute side-effect during pelvic irradiation. The aim of this study was to quantify the dose-volume relationship between irradiated bowel volumes and acute enteritis during combined chemoradiotherapy for rectal cancer. Material and methods. Twenty-eight patients with locally advanced rectal cancer received chemoradiotherapy. The radiation therapy was given with a traditional multi-field technique to a total dose of 50 Gy, with concurrent 5-Fluorouracil (5-FU) and oxaliplatin (OXA) based chemotherapy. All patients underwent three-dimensional CT-based treatment planning. Individual loops of small and large bowel as well as a volume defined as “whole abdomen” were systematically contoured on each CT slice, and dose-volume histograms were generated. Diarrhea during treatment was scored retrospectively according to the NCI Common Toxicity Criteria scale. Results. There was a strong correlation between the occurrence of grade 2+diarrhea and irradiated small bowel volume, most notably at doses >15 Gy. Neither irradiated large bowel volume, nor irradiated “whole abdomen” volume correlated significantly with diarrhea. Clinical or treatment related factors such as age, gender, hypertension, previous surgery, enterostomy, or dose fractionation (1.8 vs. 2.0 Gy/fraction) did not correlate with grade 2+diarrhea. Discussion. This study indicates a strong dose-volume relationship between small bowel volume and radiation enteritis during 5-FU-OXA-based chemoradiotherapy. These findings support the application of maneuvers to minimize small bowel irradiation, such as using a “belly board” or the use of IMRT technique aiming at keeping the small bowel volume receiving more than 15 Gy under 150 cc.

The dosimetric verification of a pencil beam based treatment planning system.

A new three-dimensional treatment planning system (TPS) based on convolution/superposition algorithms (TMS-Radix from HELAX AB, Uppsala, Sweden) was recently installed at the University Hospital in Lund. The purpose of the present study was to design a quality assurance and acceptance testing programme to meet the specific characteristics of this convolution model. The model is based on parametrization of a non-measurable quantity-the polyenergetic pencil beam. However, the verification of the treatment planning model is still dependent on numerous comparisons of measured depth-doses and dose profiles. The test programme was divided in two basic parts: (i) model implementation and beam data consistency and (ii) model performance and limitations in special situations. The first part was scheduled for all photon beam qualities available before they could be used for clinical treatment planning. The second part was performed for selected energies only. The results indicate clearly that the model is well suited for clinical three-dimensional dose planning and that the TPS handles data as expected. For example, calculated depth-doses for open and wedge beams at depths larger than the depth of dose maximum and profiles for open beams shows a very good agreement with measurements. However, depth-dose deviations at shallow depths, especially for high energies, were found. Monitor units calculated by the system were accurate for most fields except for very large fields, where deviations of several per cent were found.

Verification of a pencil beam based treatment planning system: output factors for open photon beams shaped with MLC or blocks

The accuracy of monitor unit calculations from a pencil beam based, three-dimensional treatment planning system (3D TPS) has been evaluated for open irregularly shaped photon fields. The dose per monitor unit was measured in water and in air for x-ray beam qualities from 6 to 15 MV. The fields were shaped either with a multileaf collimator (MLC) or with customized alloy blocks. Calculations from the 3D TPS were compared with measurements. The agreement between calculated and measured dose per monitor unit depended on field size and the amount of blocking and was within 3% for the MLC-shaped fields. The deviation could be traced to limitations in head scatter modelling for the MLC. For fields shaped with alloy blocks, the dose per monitor unit was calculated to be within 1.6% of measured values for all fields studied. The measured and calculated relative phantom scatter for fields with the same equivalent field size were identical for MLC and alloy shaped fields. These results indicate that the accuracy in the TPS calculations for open irregular fields, shaped with MLC or blocks, is satisfactory for clinical situations.

Microwave-induced hyperthermia and radiotherapy in human superficial tumours: Clinical results with a comparative study of combined treatment versus radiotherapy alone

Eighty-five evaluable superficial recurrent malignant tumours, mainly adenocarcinomas (78 per cent), in 38 patients were treated with either combined local hyperthermia (41-45 degrees C for four sessions) and low dose radiotherapy (30.0 Gy) or the same low dose radiotherapy alone. The treatment was given for two weeks. Hyperthermia was induced externally with 2450 MHz or 915 MHz microwaves. Totally 57 tumours were given combined treatment with a complete and partial response rate of 46 and 30 per cent, respectively (duration 1-38 months). In 18 patients with 2-10 superficial tumours each, 56 tumours were used in a comparative study, comparing the effect of combined hyperthermia and low dose radiotherapy versus the same low dose radiotherapy alone, the patients acting as their own controls. The total response rates were 89 and 50 per cent, respectively, in the two treatment modality groups. The difference in response rates is significant (p = 0.0039) in favour of the combined treatment, and this is also found when comparing complete remissions only (p = 0.0027). Local pain and normal tissue reactions presented problems during and after 2450 MHz microwave-induced hyperthermia treatment, performed without a coupling water bag system. Introduction of 915 MHz microwave-induced hyperthermia with a coupling deionized water bag system and refinement of microwave applicators, as well as the temperature control system considerably reduced these problems.

Modeling transmission and scatter for photon beam attenuators.

The development of treatment planning methods in radiation therapy requires dose calculation methods that are both accurate and general enough to provide a dose per unit monitor setting for a broad variety of fields and beam modifiers. The purpose of this work was to develop models for calculation of scatter and transmission for photon beam attenuators such as compensating filters, wedges, and block trays. The attenuation of the beam is calculated using a spectrum of the beam, and a correction factor based on attenuation measurements. Small angle coherent scatter and electron binding effects on scattering cross sections are considered by use of a correction factor. Quality changes in beam penetrability and energy fluence to dose conversion are modeled by use of the calculated primary beam spectrum after passage through the attenuator. The beam spectra are derived by the depth dose effective method, i.e., by minimizing the difference between measured and calculated depth dose distributions, where the calculated distributions are derived by superposing data from a database for monoenergetic photons. The attenuator scatter is integrated over the area viewed from the calculation point of view using first scatter theory. Calculations are simplified by replacing the energy and angular-dependent cross-section formulas with the forward scatter constant r2(0) and a set of parametrized correction functions. The set of corrections include functions for the Compton energy loss, scatter attenuation, and secondary bremsstrahlung production. The effect of charged particle contamination is bypassed by avoiding use of dmax for absolute dose calibrations. The results of the model are compared with scatter measurements in air for copper and lead filters and with dose to a water phantom for lead filters for 4 and 18 MV. For attenuated beams, downstream of the buildup region, the calculated results agree with measurements on the 1.5% level. The accuracy was slightly less in situations where the scatter component is very large, as for very large fields with very short filter to detector distances. The implementation of the model into treatment planning systems is discussed.