Feasibility of using a transmission ion chamber for QA tests of medical linear accelerators.

PURPOSE: To study the feasibility of using the Integral Quality Monitoring (IQM) system for routine quality assurance (QA) of photon beams. METHODS: The IQM system is a commercially available dose delivery verification tool, which consists of a spatially sensitive large area transmission ion chamber, mounted on the Linac collimator, and a calculation algorithm to predict the signals in response to radiation beams. By comparing the measured and predicted signals the system verifies the accuracy of beam delivery. The ion chamber unit is a battery powered system including a dual-electrometer, temperature and pressure sensors, and inclinometers. The feasibility of using the IQM system for routine QA tests was investigated by measuring constancy values of beam parameters, with specially designed tests fields, and comparing them with those determined by a conventional system. RESULTS: The sensitivity of the beam output constancy measurements by the IQM system was found to agree with those measured by a Farmer type ion chamber placed in water phantoms to within 0.1% for typical daily output variation of ± 0.5% and ± 1%. The beam symmetry was measured with a 4 cm × 4 cm aperture at multiple off-axis distances and was found to have a highly linear relationship with those measured in a water phantom scan for intentionally introduced asymmetry between -3% and +3%. The beam flatness was measured with a two-field ratio method and was found to be linearly correlated with those measured by water phantom scan. The dosimetric equivalent of a picket fence test performed by the IQM system can serve as a constancy check of the multileaf collimator (MLC) bank positioning test. CONCLUSIONS: The IQM system has been investigated for constancy measurements of various beam parameters for photon beams. The results suggest that the system can be used for most of the routine QA tests effectively and efficiently.

Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies.

Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.

Recent advances in targeting the telomeric G-quadruplex DNA sequence with small molecules as a strategy for anticancer therapies.

Human telomeric DNA (hTelo), present at the ends of chromosomes to protect their integrity during cell division, comprises tandem repeats of the sequence d(TTAGGG) which is known to form a G-quadruplex secondary structure. This unique structural formation of DNA is distinct from the well-known helical structure that most genomic DNA is thought to adopt, and has recently gained prominence as a molecular target for new types of anticancer agents. In particular, compounds that can stabilize the intramolecular G-quadruplex formed within the human telomeric DNA sequence can inhibit the activity of the enzyme telomerase which is known to be upregulated in tumor cells and is a major contributor to their immortality. This provides the basis for the discovery and development of small molecules with the potential for selective toxicity toward tumor cells. This review summarizes the various families of small molecules reported in the literature that have telomeric quadruplex stabilizing properties, and assesses the potential for compounds of this type to be developed as novel anticancer therapies. A future perspective is also presented, emphasizing the need for researchers to adopt approaches that will allow the discovery of molecules with more drug-like properties in order to improve the chances of lead molecules reaching the clinic in the next decade.

Potential hazard due to induced radioactivity secondary to radiotherapy: the report of task group 136 of the American Association of Physicists in Medicine.

External-beam radiation therapy mostly uses high-energy photons (x-rays) produced by medical accelerators, but many facilities now use proton beams, and a few use fast-neutron beams. High-energy photons offer several advantages over lower-energy photons in terms of better dose distributions for deep-seated tumors, lower skin dose, less sensitivity to tissue heterogeneities, etc. However, for beams operating at or above 10 MV, some of the materials in the accelerator room and the radiotherapy patient become radioactive due primarily to photonuclear reactions and neutron capture, exposing therapy staff and patients to unwanted radiation dose. Some recent advances in radiotherapy technology require treatments using a higher number of monitor units and monitor-unit rates for the same delivered dose, and compared to the conventional treatment techniques and fractionation schemes, the activation dose to personnel can be substantially higher. Radiotherapy treatments with proton and neutron beams all result in activated materials in the treatment room. In this report, the authors review critically the published literature on radiation exposures from induced radioactivity in radiotherapy. They conclude that the additional exposure to the patient due to induced radioactivity is negligible compared to the overall radiation exposure as a part of the treatment. The additional exposure to the staff due to induced activity from photon beams is small at an estimated level of about 1 to 2 mSv y. This is well below the allowed occupational exposure limits. Therefore, the potential hazard to staff from induced radioactivity in the use of high-energy x-rays is considered to be low, and no specific actions are considered necessary or mandatory. However, in the spirit of the "As Low as Reasonably Achievable (ALARA)" program, some reasonable steps are recommended that can be taken to reduce this small exposure to an even lower level. The dose reduction strategies suggested should be followed only if these actions are considered reasonable and practical in the individual clinics. Therapists working with proton beam and neutron beam units handle treatment devices that do become radioactive, and they should wear extremity monitors and make handling apertures and boluses their last task upon entering the room following treatment. Personnel doses from neutron-beam units can approach regulatory limits depending on the number of patients and beams, and strategies to reduce doses should be followed.

A stochastic model for tumor geometry evolution during radiation therapy in cervical cancer.

PURPOSE: To develop mathematical models to predict the evolution of tumor geometry in cervical cancer undergoing radiation therapy. METHODS: The authors develop two mathematical models to estimate tumor geometry change: a Markov model and an isomorphic shrinkage model. The Markov model describes tumor evolution by investigating the change in state (either tumor or nontumor) of voxels on the tumor surface. It assumes that the evolution follows a Markov process. Transition probabilities are obtained using maximum likelihood estimation and depend on the states of neighboring voxels. The isomorphic shrinkage model describes tumor shrinkage or growth in terms of layers of voxels on the tumor surface, instead of modeling individual voxels. The two proposed models were applied to data from 29 cervical cancer patients treated at Princess Margaret Cancer Centre and then compared to a constant volume approach. Model performance was measured using sensitivity and specificity. RESULTS: The Markov model outperformed both the isomorphic shrinkage and constant volume models in terms of the trade-off between sensitivity (target coverage) and specificity (normal tissue sparing). Generally, the Markov model achieved a few percentage points in improvement in either sensitivity or specificity compared to the other models. The isomorphic shrinkage model was comparable to the Markov approach under certain parameter settings. Convex tumor shapes were easier to predict. CONCLUSIONS: By modeling tumor geometry change at the voxel level using a probabilistic model, improvements in target coverage and normal tissue sparing are possible. Our Markov model is flexible and has tunable parameters to adjust model performance to meet a range of criteria. Such a model may support the development of an adaptive paradigm for radiation therapy of cervical cancer.

A method for online verification of adapted fields using an independent dose monitor.

PURPOSE: Clinical implementation of online adaptive radiotherapy requires generation of modified fields and a method of dosimetric verification in a short time. We present a method of treatment field modification to account for patient setup error, and an online method of verification using an independent monitoring system. METHODS: The fields are modified by translating each multileaf collimator (MLC) defined aperture in the direction of the patient setup error, and magnifying to account for distance variation to the marked isocentre. A modified version of a previously reported online beam monitoring system, the integral quality monitoring (IQM) system, was investigated for validation of adapted fields. The system consists of a large area ion-chamber with a spatial gradient in electrode separation to provide a spatially sensitive signal for each beam segment, mounted below the MLC, and a calculation algorithm to predict the signal. IMRT plans of ten prostate patients have been modified in response to six randomly chosen setup errors in three orthogonal directions. RESULTS: A total of approximately 49 beams for the modified fields were verified by the IQM system, of which 97% of measured IQM signal agree with the predicted value to within 2%. CONCLUSIONS: The modified IQM system was found to be suitable for online verification of adapted treatment fields.

Applying usability heuristics to radiotherapy systems.

BACKGROUND AND PURPOSE: Heuristic evaluations have been used to evaluate safety of medical devices by identifying and assessing usability issues. Since radiotherapy treatment delivery systems often consist of multiple complex user-interfaces, a heuristic evaluation was conducted to assess the potential safety issues of such a system. MATERIAL AND METHODS: A heuristic evaluation was conducted to evaluate the treatment delivery system at Princess Margaret Hospital (Toronto, Canada). Two independent evaluators identified usability issues with the user-interfaces and rated the severity of each issue. RESULTS: The evaluators identified 75 usability issues in total. Eighteen of them were rated as high severity, indicating the potential to have a major impact on patient safety. A majority of issues were found on the record and verify system, and many were associated with the patient setup process. While the hospital has processes in place to ensure patient safety, recommendations were developed to further mitigate the risks of potential consequences. CONCLUSIONS: Heuristic evaluation is an efficient and inexpensive method that can be successfully applied to radiotherapy delivery systems to identify usability issues and improve patient safety. Although this study was conducted only at one site, the findings may have broad implications for the design of these systems.

The use of human factors methods to identify and mitigate safety issues in radiation therapy.

BACKGROUND AND PURPOSE: New radiation therapy technologies can enhance the quality of treatment and reduce error. However, the treatment process has become more complex, and radiation dose is not always delivered as intended. Using human factors methods, a radiotherapy treatment delivery process was evaluated, and a redesign was undertaken to determine the effect on system safety. MATERIAL AND METHODS: An ethnographic field study and workflow analysis was conducted to identify human factors issues of the treatment delivery process. To address specific issues, components of the user interface were redesigned through a user-centered approach. Sixteen radiation therapy students were then used to experimentally evaluate the redesigned system through a usability test to determine the effectiveness in mitigating use errors. RESULTS: According to findings from the usability test, the redesigned system successfully reduced the error rates of two common errors (p<.04 and p<.01). It also improved the mean task completion time by 5.5% (p<.02) and achieved a higher level of user satisfaction. CONCLUSIONS: These findings demonstrated the importance and benefits of applying human factors methods in the design of radiation therapy systems. Many other opportunities still exist to improve patient safety in this area using human factors methods.

Assessment and management of radiotherapy beam intersections with the treatment couch.

The impact of the treatment couch on a radiotherapy plan is rarely fully assessed during the treatment planning process. Incorporating a couch model into the treatment planning system (TPS) enables the planner to avoid or dosimetrically evaluate beam-couch intersections. In this work, we demonstrate how existing TPS tools can be used to establish this capability and assess the accuracy and effectiveness of the system through dose measurements and planning studies. Such capabilities may be particularly relevant for the planning of arc therapies.Treatment couch top models were introduced into a TPS by fusing their CT image sets with the patient CT dataset. Regions of interest characterizing couch elements were then imported and assigned appropriate densities in the TPS. Measurements in phantom agreed with TPS calculations to within 2% dose and 1 degrees gantry rotation. To clinically validate the model, a retrospective study was performed on patient plans that posed difficulties in beam-couch intersection during setup. Beam-couch intersection caused up to a 3% reduction in PTV coverage, defined by the 95% of the prescribed dose, and up to a 1% reduction in mean CTV coverage. Dose compensation strategies for IMRT treatments with beams passing through couch elements were investigated using a four-field IMRT plan with three beams passing through couch elements. In this study, ignoring couch effects resulted in point dose reductions of 8 +/- 3%.A methodology for incorporating detailed couch characteristics into a TPS has been established and explored. The method can be used to predict beam-couch intersections during planning, potentially eliminating the need for pretreatment appointments. Alternatively, if a beam-couch intersection problem arises, the impact of the couch can be assessed on a case-by-case basis and a clinical decision made based on full dosimetric information.

Verification of source and collimator configuration for Gamma Knife Perfexion using panoramic imaging.

PURPOSE: The new model of stereotactic radiosurgery system, Gamma Knife Perfexion, allows automatic selection of built-in collimation, eliminating the need for the time consuming manual collimator installation required with previous models. However, the configuration of sources and collimators inside the system does not permit easy access for the verification of the selected collimation. While the conventional method of exposing a film at the isocenter is useful for obtaining composite dose information, it is difficult to interpret the data in terms of the integrity of each individual source and corresponding collimation. The primary aim of this study was to develop a method of verifying the geometric configuration of the sources and collimator modules of the Gamma Knife Perfexion. In addition, the method was extended to make dose measurements and verify the accuracy of dose distributions calculated by the mathematical formalism used in the treatment planning system, Leksell Gamma Plan. METHODS: A panoramic view of all of 192 cobalt sources was simultaneously acquired by exposing a radiochromic film wrapped around the surface of a cylindrical phantom. The center of the phantom was mounted at the isocenter with its axis aligned along the longitudinal axis of the couch. The sizes and shapes of the source images projected on the phantom surface were compared to those calculated based on the manufacturer's design specifications. The measured dose at various points on the film was also compared to calculations using the algorithm of the planning system. RESULTS: The panoramic images allowed clear identification of each of the 192 sources, verifying source integrity and selected collimator sizes. Dose on the film surface is due to the primary beam as well as phantom scatter and leakage contributions. Therefore, the dose at a point away from the isocenter cannot be determined simply based on the proportionality of collimator output factors; the use of a dose computation algorithm is required. Scatter and leakage dose contributions from neighboring sources were calculated and found to be 6.3% (ranging from 4.5% to 7.4%), 16.7% (12.5%-19.3%), and 66.6% (38%-78%) for the 4, 8, and 16 mm collimators, respectively, at the centers of the source images. The measured average dose on films with 16 mm collimators agrees with the dose model of the treatment planning system to within 1.0%. The average doses on the film were 24.0, 60.8, and 186.2 cGy for 4, 8, and 16 mm diameter collimators, respectively, when the machine was set to deliver a reference dose of 100 Gy to the center of an 80 mm radius spherical dosimetry phantom. CONCLUSIONS: A method of simultaneously capturing and analyzing the panoramic images of 192 cobalt sources has been developed to verify the source and collimator configuration of GK systems. The method was extended to verify the dose calculation model of the treatment planning system by comparing the measured doses on the panoramic film images and the corresponding calculated doses. The method presented can play a significant role in comprehensive commissioning and routine quality assurance testing of the Gamma Knife systems.

Small field electron beam dosimetry using MOSFET detector.

The dosimetry of very small electron fields can be challenging due to relative shifts in percent depth-dose curves, including the location of dmax, and lack of lateral electronic equilibrium in an ion chamber when placed in the beam. Conventionally a small parallel plate chamber or film is utilized to perform small field electron beam dosimetry. Since modern radiotherapy departments are becoming filmless in favor of electronic imaging, an alternate and readily available clinical dosimeter needs to be explored. We have studied the performance of MOSFET as a relative dosimeter in small field electron beams. The reproducibility, linearity and sensitivity of a high-sensitivity microMOSFET were investigated for clinical electron beams. In addition, the percent depth doses, output factors and profiles have been measured in a water tank with MOSFET and compared with those measured by an ion chamber for a range of field sizes from 1 cm diameter to 10 cm × 10 cm for 6, 12, 16 and 20 MeV beams. Similar comparative measurements were also per-formed with MOSFET and films in solid water phantom. The MOSFET sensitivity was found to be practically constant over the range of field sizes investigated. The dose response was found to be linear and reproducible (within ± 1% for 100 cGy). An excellent agreement was observed among the central axis depth dose curves measured using MOSFET, film and ion chamber. The output factors measured with MOSFET for small fields agreed to within 3% with those measured by film dosimetry. Overall results indicate that MOSFET can be utilized to perform dosimetry for small field electron beam.

An integral quality monitoring system for real-time verification of intensity modulated radiation therapy.

PURPOSE: To develop an independent and on-line beam monitoring system, which can validate the accuracy of segment-by-segment energy fluence delivery for each treatment field. The system is also intended to be utilized for pretreatment dosimetric quality assurance of intensity modulated radiation therapy (IMRT), on-line image-guided adaptive radiation therapy, and volumetric modulated arc therapy. METHODS: The system, referred to as the integral quality monitor (IQM), utilizes an area integrating energy fluence monitoring sensor (AIMS) positioned between the final beam shaping device [i.e., multileaf collimator (MLC)] and the patient. The prototype AIMS consists of a novel spatially sensitive large area ionization chamber with a gradient along the direction of the MLC motion. The signal from the AIMS provides a simple output for each beam segment, which is compared in real time to the expected value. The prototype ionization chamber, with a physical area of 22 x 22 cm2, has been constructed out of aluminum with the electrode separations varying linearly from 2 to 20 mm. A calculation method has been developed to predict AIMS signals based on an elementwise integration technique, which takes into account various predetermined factors, including the spatial response function of the chamber, MLC characteristics, beam transmission through the secondary jaws, and field size factors. The influence of the ionization chamber on the beam has been evaluated in terms of transmission, surface dose, beam profiles, and depth dose. The sensitivity of the system was tested by introducing small deviations in leaf positions. A small set of IMRT fields for prostate and head and neck plans was used to evaluate the system. The ionization chamber and the data acquisition software systems were interfaced to two different types of linear accelerators: Elekta Synergy and Varian iX. RESULTS: For a 10 x 10 cm2 field, the chamber attenuates the beam intensity by 7% and 5% for 6 and 18 MV beams, respectively, without significantly changing the depth dose, surface dose, and dose profile characteristics. An MLC bank calibration error of 1 mm causes the IQM signal of a 3 x 3 cm2 aperture to change by 3%. A positioning error in a single 5 mm wide leaf by 3 mm in 3 X 3 cm2 aperture causes a signal difference of 2%. Initial results for prostate and head and neck IMRT fields show an average agreement between calculation and measurement to within 1%, with a maximum deviation for each of the smallest beam segments to within 5%. When the beam segments of a prostate IMRT field were shifted by 3 mm from their original position, along the direction of the MLC motion, the IQM signals varied, on average, by 2.5%. CONCLUSIONS: The prototype IQM system can validate the accuracy of beam delivery in real time by comparing precalculated and measured AIMS signals. The system is capable of capturing errors in MLC leaf calibration or malfunctions in the positioning of an individual leaf. The AIMS does not significantly alter the beam quality and therefore could be implemented without requiring recommissioning measurements.

Evaluation of the effect of patient dose from cone beam computed tomography on prostate IMRT using Monte Carlo simulation.

The aim of this study is to evaluate the impact of the patient dose due to the kilovoltage cone beam computed tomography (kV-CBCT) in a prostate intensity-modulated radiation therapy (IMRT). The dose distributions for the five prostate IMRTs were calculated using the Pinnacle treatment planning system. To calculate the patient dose from CBCT, phase-space beams of a CBCT head based on the ELEKTA x-ray volume imaging system were generated using the Monte Carlo BEAMnr code for 100, 120, 130, and 140 kVp energies. An in-house graphical user interface called DOSCTP (DOSXYZnrc-based) developed using MATLAB was used to calculate the dose distributions due to a 360 degrees photon arc from the CBCT beam with the same patient CT image sets as used in Pinnacle. The two calculated dose distributions were added together by setting the CBCT doses equal to 1%, 1.5%, 2%, and 2.5% of the prescription dose of the prostate IMRT. The prostate plan and the summed dose distributions were then processed in the CERR platform to determine the dose-volume histograms (DVHs) of the regions of interest. Moreover, dose profiles along the x- and y-axes crossing the isocenter with and without addition of the CBCT dose were determined. It was found that the added doses due to CBCT are most significant at the femur heads. Higher doses were found at the bones for a relatively low energy CBCT beam such as 100 kVp. Apart from the bones, the CBCT dose was observed to be most concentrated on the anterior and posterior side of the patient anatomy. Analysis of the DVHs for the prostate and other critical tissues showed that they vary only slightly with the added CBCT dose at different beam energies. On the other hand, the changes of the DVHs for the femur heads due to the CBCT dose and beam energy were more significant than those of rectal and bladder wall. By analyzing the vertical and horizontal dose profiles crossing the femur heads and isocenter, with and without the CBCT dose equal to 2% of the prescribed dose, it was found that there is about a 5% increase of dose at the femur head. Still, such an increase in the femur head dose is well below the dose limit of the bone in our IMRT plans. Therefore, under these dose fractionation conditions, it is concluded that, though CBCT causes a higher dose deposited at the bones, there may be no significant effect in the DVHs of critical tissues in the prostate IMRT.

Reduction of vanadium(V) to vanadium(IV) by NADPH, and vanadium(IV) to vanadium(III) by cysteine methyl ester in the presence of biologically relevant ligands.

To better understand the mechanism of vanadium reduction in ascidians, we examined the reduction of vanadium(V) to vanadium(IV) by NADPH and the reduction of vanadium(IV) to vanadium(III) by L-cysteine methyl ester (CysME). UV-vis and electron paramagnetic resonance spectroscopic studies indicated that in the presence of several biologically relevant ligands vanadium(V) and vanadium(IV) were reduced by NADPH and CysME, respectively. Specifically, NADPH directly reduced vanadium(V) to vanadium(IV) with the assistance of ligands that have a formation constant with vanadium(IV) of greater than 7. Also, glycylhistidine and glycylaspartic acid were found to assist the reduction of vanadium(IV) to vanadium(III) by CysME.

Patient dose from kilovoltage cone beam computed tomography imaging in radiation therapy.

Kilovoltage cone-beam computerized tomography (kV-CBCT) systems integrated into the gantry of linear accelerators can be used to acquire high-resolution volumetric images of the patient in the treatment position. Using on-line software and hardware, patient position can be determined accurately with a high degree of precision and, subsequently, set-up parameters can be adjusted to deliver the intended treatment. While the patient dose due to a single volumetric imaging acquisition is small compared to the therapy dose, repeated and daily image guidance procedures can lead to substantial dose to normal tissue. The dosimetric properties of a clinical CBCT system have been studied on an Elekta linear accelerator (Synergy RP, XVI system) and additional measurements performed on a laboratory system with identical geometry. Dose measurements were performed with an ion chamber and MOSFET detectors at the center, periphery, and surface of 30 and 16-cm-diam cylindrical shaped water phantoms, as a function of x-ray energy and longitudinal field-of-view (FOV) settings of 5,10,15, and 26 cm. The measurements were performed for full 360 degrees CBCT acquisition as well as for half-rotation scans for 120 kVp beams using the 30-cm-diam phantom. The dose at the center and surface of the body phantom were determined to be 1.6 and 2.3 cGy for a typical imaging protocol, using full rotation scan, with a technique setting of 120 kVp and 660 mAs. The results of our measurements have been presented in terms of a dose conversion factor fCBCT, expressed in cGy/R. These factors depend on beam quality and phantom size as well as on scan geometry and can be utilized to estimate dose for any arbitrary mAs setting and reference exposure rate of the x-ray tube at standard distance. The results demonstrate the opportunity to manipulate the scanning parameters to reduce the dose to the patient by employing lower energy (kVp) beams, smaller FOV, or by using half-rotation scan.

Dose to radiation therapists from activation at high-energy accelerators used for conventional and intensity-modulated radiation therapy.

The increased beam-on times which characterize intensity-modulated radiation therapy (IMRT) could lead to an increase in the dose received by radiation therapists due to induced activity. To examine this, gamma ray spectrometry was used to identify the major isotopes responsible for activation at a representative location in the treatment room of an 18 MV accelerator (Varian Clinac 21EX). These were found to be 28Al, 56Mn, and 24Na. The decay of the dose rate measured at this location following irradiation was analyzed in terms of the known half-lives to yield saturation dose rates of 9.6, 12.4, and 6.2 microSv/h, respectively. A formalism was developed to estimate activation dose (microSv/week) due to successive patient irradiation cycles, characterized by the number of 18 MV fractions per week, F, the number of MU per fraction, M, the in-room time between fractions, td (min), and the treatment delivery time t'r (min). The results are represented by the sum of two formulas, one for the dose from 28Al 1.8 x 10(-3) F M (1-e(-03t'(r))/t'r and one for the dose from the other isotopes approximately 1.1 x 10(-6) F(1.7) Mt(d). For conventional therapy doses are about 60 microSv/week for an 18 MV workload of 60,000 MU/week. Irradiation for QA purposes can significantly increase the dose. For IMRT as currently practiced, lengthy treatment delivery times limit the number of fractions that can be delivered per week and hence limit the dose to values similar to those in conventional therapy. However for an IMRT regime designed to maximize patient throughput, doses up to 330 microSv/week could be expected. To reduce dose it is recommended that IMRT treatments should be delivered at energies lower than 18 MV, that in multienergy IMRT, high-energy treatments should be scheduled in the latter part of the day, and that equipment manufacturers should strive to minimize activation in the design of high-energy accelerators.