Peripheral Organ Equivalent Dose Estimation Procedure in Proton Therapy.

The aim of this work is to present a reproducible methodology for the evaluation of total equivalent doses in organs during proton therapy facilities. The methodology is based on measuring the dose equivalent in representative locations inside an anthropomorphic phantom where photon and neutron dosimeters were inserted. The Monte Carlo simulation was needed for obtaining neutron energy distribution inside the phantom. The methodology was implemented for a head irradiation case in the passive proton beam of iThemba Labs (South Africa). Thermoluminescent dosimeter (TLD)-600 and TLD-700 pairs were used as dosimeters inside the phantom and GEANT code for simulations. In addition, Bonner sphere spectrometry was performed inside the treatment room to obtain the neutron spectra, some relevant neutron dosimetric quantities per treatment Gy, and a percentual distribution of neutron fluence and ambient dose equivalent in four energy groups, at two locations. The neutron spectrum at one of those locations was also simulated so that a reasonable agreement between simulation and measurement allowed a validation of the simulation. Results showed that the total out-of-field dose equivalent inside the phantom ranged from 1.4 to 0.28 mSv/Gy, mainly due to the neutron contribution and with a small contribution from photons, 10% on average. The order of magnitude of the equivalent dose in organs was similar, displaying a slow reduction in values as the organ is farther from the target volume. These values were in agreement with those found by other authors in other passive beam facilities under similar irradiation and measurement conditions.

Modified Geometry of 106Ru Asymmetric Eye Plaques to Improve Dosimetric Calculations in Ophthalmic Brachytherapy.

Ru/Rh asymmetric plaques for ophthalmic brachytherapy have special geometric designs with a cutout intended to prevent irradiation of critical ocular structures proximal to the tumor. In this work, we present new geometric models for PENELOPE+PenEasy Monte Carlo simulations of these applicators, differing from the vendor-reported geometry, that better match their real geometry to assess their dosimetric impact. Simulation results were benchmarked to experimental dosimetric data from radiochromic film measurements, data provided by the manufacturer in the calibration certificates, and other experimental results published in the literature, obtaining, in all cases, better agreement with the modified geometries. The clinical impact of the new geometric models was evaluated by simulating real clinical cases using patient-specific eye models. The cases calculated using the modified geometries presented higher doses to the critical structures proximal to the cutout region. The modified geometric models presented in this work provide a more accurate representation of the asymmetric plaques, greatly improving the agreement between Monte Carlo calculations and experimental measurements. Lack of consideration of accurate geometric models has been shown to be translated into notable increases in dose to organs at risk in clinical cases.

Clinical Outcomes after Surgical Resection Combined with Brachytherapy for Uveal Melanomas.

Currently, brachytherapy is the most commonly used therapeutic approach for uveal melanomas. Surgical resection by means of endoresection or exoresection is an alternative approach. The present report recounts our experience over 15 years in the treatment of uveal melanoma using a combined approach of resection surgery with brachytherapy. This is a single-center observational retrospective cohort study in which we describe clinical outcomes, complications and survival in 35 cases of melanoma of the iris or the ciliary body after a combination of surgery and brachytherapy or brachytherapy alone. Local treatment of the tumor was successful in all cases with surgery and brachytherapy. The most frequent complications were scleromalacia, bullous keratopathy, retinal toxicity, cataracts, hypotonia, and photophobia. There were three cases of recurrence, all of which were found in the group of patients who had received brachytherapy alone, and in one case we had to perform a secondary enucleation due to tumor growth after brachytherapy. At present, only one patient has died during follow-up due to liver metastases six years after the start of treatment. In carefully selected patients, this approach can be effective and safe, as long as a close follow-up is carried out after surgery.

Intensity-modulated radiation therapy and volumetric modulated arc therapy versus conventional conformal techniques at high energy: Dose assessment and impact on second primary cancer in the out-of-field region.

The aim of this work was to estimate peripheral neutron and photon doses associated with the conventional 3D conformal radiotherapy techniques in comparison to modern ones such as Intensity modulated radiation therapy and volumetric modulated arc therapy. Assessment in terms of second cancer incidence ought to peripheral doses was also considered. For that, a dosimetric methodology proposed by the authors has been applied beyond the region where there is no CT information and, thus, treatment planning systems do not calculate and where, nonetheless, about one third of second primary cancers occurs.

Monte Carlo verification of radiotherapy treatments with CloudMC.

BACKGROUND: A new implementation has been made on CloudMC, a cloud-based platform presented in a previous work, in order to provide services for radiotherapy treatment verification by means of Monte Carlo in a fast, easy and economical way. A description of the architecture of the application and the new developments implemented is presented together with the results of the tests carried out to validate its performance. METHODS: CloudMC has been developed over Microsoft Azure cloud. It is based on a map/reduce implementation for Monte Carlo calculations distribution over a dynamic cluster of virtual machines in order to reduce calculation time. CloudMC has been updated with new methods to read and process the information related to radiotherapy treatment verification: CT image set, treatment plan, structures and dose distribution files in DICOM format. Some tests have been designed in order to determine, for the different tasks, the most suitable type of virtual machines from those available in Azure. Finally, the performance of Monte Carlo verification in CloudMC is studied through three real cases that involve different treatment techniques, linac models and Monte Carlo codes. RESULTS: Considering computational and economic factors, D1_v2 and G1 virtual machines were selected as the default type for the Worker Roles and the Reducer Role respectively. Calculation times up to 33 min and costs of 16 € were achieved for the verification cases presented when a statistical uncertainty below 2% (2σ) was required. The costs were reduced to 3-6 € when uncertainty requirements are relaxed to 4%. CONCLUSIONS: Advantages like high computational power, scalability, easy access and pay-per-usage model, make Monte Carlo cloud-based solutions, like the one presented in this work, an important step forward to solve the long-lived problem of truly introducing the Monte Carlo algorithms in the daily routine of the radiotherapy planning process.

Analysis of the analgesic interactions between ketorolac and tramadol during arthritic nociception in rat.

The potential advantage of using combination therapy is that analgesia can be maximized while minimizing the incidence of adverse effects. In order to assess a possible synergistic antinociceptive interactions, the antinociceptive effects of ketorolac tromethamine, p.o., a nonsteroidal anti-inflammatory drug (NSAID), and tramadol hydrochloride, p.o., an atypical opioid analgesic, administered either separately or in combination, were determined using a rat model of arthritic pain. The data were interpreted using the surface of synergistic interaction (SSI) analysis and an isobolographic analysis to establish the nature of the interaction. The surface of synergistic interaction was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Female rats received orally ketorolac alone (0.18, 0.32, 0.56, 1.0, 1.78, 3.16, and 5.62 mg/kg), tramadol alone (3.16, 5.62, 10.0, 17.78, 31.62, 56.23, and 100.0 mg/kg), or 24 different combinations of ketorolac plus tramadol. Ten combinations exhibited various degrees of potentiation of antinociceptive effects (17.78 mg/kg tramadol with either 0.18, 0.32, or 0.56 mg/kg ketorolac; 10.0 mg/kg tramadol with either 0.18, 0.32, 0.56, or 1.8 mg/kg ketorolac; 5.6 mg/kg tramadol with either 0.32 or 0.56 mg/kg ketorolac; and 3.16 mg/kg tramadol with 0.32 mg/kg ketorolac), whereas the other 14 combinations showed additive antinociceptive effects. Three combinations of ketorolac+tramadol (1.0+17.78, 1.78+10, and 1.78+17.78, mg/kg respectively) produced the maximum antinociceptive effects, and two combinations (0.32+10.0 and 0.56+10.0 mg/kg, respectively) presented effects of high potentiation (P<0.001). This combination caused gastric injuries less severe than those observed with indomethacin. The synergistic antinociceptive effects of ketorolac and tramadol were important and suggest that combinations with these drugs may have clinical utility in pain therapy.

Involvement of peripheral cyclooxygenase-1 and cyclooxygenase-2 in inflammatory pain.

Pain-induced functional impairment in the rat (PIFIR) is a model of inflammatory and arthritic pain similar to that of clinical gout. Nociception is induced by the intra-articular injection of uric acid into the right hind limb, inducing its dysfunction. Animals then receive analgesic drugs and the recovery of functionality over time is assessed as an expression of antinociception. We have examined the role of peripheral prostaglandins synthesized by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in inflammatory pain using the PIFIR model. Rofecoxib (a selective COX-2 inhibitor) and SC-560 (a selective COX-1 inhibitor) both produced dose-dependent effects. When the inhibitors were administered before uric acid, they showed similar potency, but the antinociceptive efficacy of SC-560 was lower than rofecoxib; the best antinociceptive effects were obtained with the dose of 100 microg/articulation of each inhibitor (pre-treatment). In post-treatment (inhibitors administered after the uric acid), rofecoxib showed the least antinociceptive effect and SC-560 was more potent than rofecoxib. The inhibition of both COX-1 and COX-2 produced a more profound analgesic effect than the inhibition of either COX-1 or COX-2 alone. The present data support the idea that both COX isoforms contribute to the development and maintenance of local inflammatory nociception. Thus, it could be expected that inhibition of both COX-1 and COX-2 is required for non-steroidal anti-inflammatory drugs (NSAID)-induced antinociception in the rat. These findings suggest that the therapeutic effects of NSAIDs may involve, at least in part, inhibition of COX-1 and COX-2.

Characterization of calcitonin gene-related peptide (CGRP) receptors and their receptor-activity-modifying proteins (RAMPs) in human brain microvascular and astroglial cells in culture.

1. In the present study, we examined the expression of the CGRP receptor-activity-modifying proteins (RAMP1, RAMP2 and RAMP3) and receptor component protein (RCP) in human brain astrocytes (AST), cerebromicrovascular endothelial (EC) and smooth muscle (SMC) cells in culture. Further, we pharmacologically characterized CGRP receptors in these cells by assessing the potency of the CGRP receptor antagonists h-alpha CGRP(8-37) and the new non-peptide compound BIBN4096BS to block the production of cAMP elicited by CGRP(1) and CGRP(2) receptor agonists. 2. AST, EC and SMC all expressed mRNAs for RAMP1, RAMP2 and RCP. In contrast, message for RAMP3 was detected in AST, but not in SMC and in only one out of four preparations of EC. 3. h-alpha CGRP, h-beta CGRP and [Cys (Et)(2,7)]-h-alpha CGRP exerted concentration-dependent production of cAMP in all cultures, with a maximal effect at 25-50 nM (20-60-fold increase from basal levels). In contrast, 50 nM [Cys (Acm)(2,7)]-h-alpha CGRP only induced a weak stimulatory effect on cAMP formation, especially in SMC and AST (1.5- and 5-fold increase above baseline, respectively). 4. h-alpha CGRP(8-37) and BIBN4096BS concentration-dependently inhibited cAMP formation evoked by CGRP receptor agonists. Depending on the agonists used, h-alpha CGRP(8-37) distinguished two different CGRP receptors for which it exhibited low (pIC(50)< or =6.4) and high (pIC(50) approximately 7.3) affinity, respectively. BIBN4096BS was much more potent (>2.5 orders of magnitude) than h-alpha CGRP(8-37). Further, BIBN4096BS was able to discriminate three different CGRP receptor sites for which it exhibited low (pIC(50) approximately 9.3-9.9), intermediate (pIC(50) approximately 10.9), and a very high (pIC(50) approximately 13.7) affinity, respectively. Together, these results suggest the presence of CGRP(1) and/or CGRP(2) receptors in human brain AST, EC and SMC, and of an additional population of CGRP receptors in AST, possibly associated to the combined expression of RAMP3 and RCP in these cells, for which BIBN4096BS exhibits an exquisitely high affinity.