Targeting Accuracy Considerations for Simultaneous Tumor Treating Fields Antimitotic Therapy During Robotic Hypofractionated Radiation Therapy.

Purpose: Tumor treating fields (TTFields) is a novel antimitotic treatment that was first proven effective for glioblastoma multiforme, now with trials for several extracranial indications underway. Several studies focused on concurrent TTFields therapy with radiation in the same time period, but were not given simultaneously. This study evaluates the targeting accuracy of simultaneous radiation therapy while TTFields arrays are in place and powered on, ensuring that radiation does not interfere with TTFields and TTFields does not interfere with radiation. This is one of several options to enable TTFields to begin several weeks sooner, and opens potential for synergistic effects of combined therapy. Methods: TTFields arrays were attached to a warm saline water bath and salt was added until the TTFields generator reached the maximal 2000 mA peak-to-peak current. A ball cube phantom containing 2 orthogonal films surrounded by fiducials was placed in the water phantom, CT scanned, and a radiation treatment plan with 58 isocentric beams was created using a 3 cm circular collimator. Fiducial tracking was used to deliver radiation, the films were scanned, and end-to-end targeting error was measured with vendor-supplied software. In addition, radiation effects on electric fields generated by the TTFields system were assessed by examining logfiles generated from the field generator. Results: With TTFields arrays in place and powered on, the robotic radiosurgery system achieved a final targeting result of 0.47 mm, which was well within the submillimeter specification. No discernible effects on TTFields current output beyond 0.3% were observed in the logfiles when the radiation beam pulsed on and off. Conclusion: A robotic radiosurgery system was used to verify that radiation targeting was not adversely affected when the TTFields arrays were in place and the TTFields delivery device was powered on. In addition, this study verified that radiation delivered simultaneously with TTFields did not interfere with the generation of the electric fields.

Estimating the tolerance of brachial plexus to hypofractionated stereotactic body radiotherapy: a modelling-based approach from clinical experience.

BACKGROUND: Brachial plexopathy is a potentially serious complication from stereotactic body radiation therapy (SBRT) that has not been widely studied. Therefore, we compared datasets from two different institutions and generated a brachial plexus dose-response model, to quantify what dose constraints would be needed to minimize the effect on normal tissue while still enabling potent therapy for the tumor. METHODS: Two published SBRT datasets were pooled and modeled from patients at Indiana University and the Richard L. Roudebush Veterans Administration Medical Center from 1998 to 2007, as well as the Karolinska Institute from 2008 to 2013. All patients in both studies were treated with SBRT for apically located lung tumors localized superior to the aortic arch. Toxicities were graded according to Common Terminology Criteria for Adverse Events, and a probit dose response model was created with maximum likelihood parameter fitting. RESULTS: This analysis includes a total of 89 brachial plexus maximum point dose (Dmax) values from both institutions. Among the 14 patients who developed brachial plexopathy, the most common complications were grade 2, comprising 7 patients. The median follow-up was 30 months (range 6.1-72.2) in the Karolinska dataset, and the Indiana dataset had a median of 13 months (range 1-71). Both studies had a median range of 3 fractions, but in the Indiana dataset, 9 patients were treated in 4 fractions, and the paper did not differentiate between the two, so our analysis is considered to be in 3-4 fractions, one of the main limitations. The probit model showed that the risk of brachial plexopathy with Dmax of 26 Gy in 3-4 fractions is 10%, and 50% with Dmax of 70 Gy in 3-4 fractions. CONCLUSIONS: This analysis is only a preliminary result because more details are needed as well as additional comprehensive datasets from a much broader cross-section of clinical practices. When more institutions join the QUANTEC and HyTEC methodology of reporting sufficient details to enable data pooling, our field will finally reach an improved understanding of human dose tolerance.

Characterizing spoken responses in masked-onset priming of reading aloud using articulography.

A key method for studying articulatory planning at different levels of phonological organization is masked-onset priming. In previous work using that paradigm the dependent variable has been acoustic response time (RT). We used electromagnetic articulography to measure articulatory RTs and the articulatory properties of speech gestures in non-word production in a masked-onset priming experiment. Initiation of articulation preceded acoustic response onset by 199 ms, but the acoustic lag varied by up to 63 ms, depending on the phonological structure of the target. Onset priming affected articulatory response latency, but had no effect on gestural duration, inter-gestural coordination, or articulatory velocity. This is consistent with an account of the masked-onset priming effect in which the computation from orthography of an abstract phonological representation of the target is initiated earlier in the primed than in the unprimed condition. We discuss the implications of these findings for models of speech production and the scope of articulatory planning and execution.

Maximizing Tumor Control and Limiting Complications With Stereotactic Body Radiation Therapy for Pancreatic Cancer.

PURPOSE: Stereotactic body radiation therapy (SBRT) and stereotactic ablative body radiation therapy is being increasingly used for pancreatic cancer (PCa), particularly in patients with locally advanced and borderline resectable disease. A wide variety of dose fractionation schemes have been reported in the literature. This HyTEC review uses tumor control probability models to evaluate the comparative effectiveness of the various SBRT treatment regimens used in the treatment of patients with localized PCa. METHODS AND MATERIALS: A PubMed search was performed to review the published literature on the use of hypofractionated SBRT (usually in 1-5 fractions) for PCa in various clinical scenarios (eg, preoperative [neoadjuvant], borderline resectable, and locally advanced PCa). The linear quadratic model with α/ß= 10 Gy was used to address differences in fractionation. Logistic tumor control probability models were generated using maximum likelihood parameter fitting. RESULTS: After converting to 3-fraction equivalent doses, the pooled reported data and associated models suggests that 1-year local control (LC) without surgery is ≈79% to 86% after the equivalent of 30 to 36 Gy in 3 fractions, showing a dose response in the range of 25 to 36 Gy, and decreasing to less than 70% 1-year LC at doses below 24 Gy in 3 fractions. The 33 Gy in 5 fraction regimen (Alliance A021501) corresponds to 28.2 Gy in 3 fractions, for which the HyTEC pooled model had 77% 1-year LC without surgery. Above an equivalent dose of 28 Gy in 3 fractions, with margin-negative resection the 1-year LC exceeded 90%. CONCLUSIONS: Pooled analyses of reported tumor control probabilities for commonly used SBRT dose-fractionation schedules for PCa suggests a dose response. These findings should be viewed with caution given the challenges and limitations of this review. Additional data are needed to better understand the dose or fractionation-response of SBRT for PCa.

Examining speech motor planning difficulties in apraxia of speech and aphasia via the sequential production of phonetically similar words.

This study investigated the underlying nature of apraxia of speech (AOS) by testing two competing hypotheses. The Reduced Buffer Capacity Hypothesis argues that people with AOS can plan speech only one syllable at a time Rogers and Storkel [1999. Planning speech one syllable at a time: The reduced buffer capacity hypothesis in apraxia of speech. Aphasiology, 13(9-11), 793-805. https://doi.org/10.1080/026870399401885]. The Program Retrieval Deficit Hypothesis states that selecting a motor programme is difficult in face of competition from other simultaneously activated programmes Mailend and Maas [2013. Speech motor programming in apraxia of speech: Evidence from a delayed picture-word interference task. American Journal of Speech-Language Pathology, 22(2), S380-S396. https://doi.org/10.1044/1058-0360(2013/12-0101)]. Speakers with AOS and aphasia, aphasia without AOS, and unimpaired controls were asked to prepare and hold a two-word utterance until a go-signal prompted a spoken response. Phonetic similarity between target words was manipulated. Speakers with AOS had longer reaction times in conditions with two similar words compared to two identical words. The Control and the Aphasia group did not show this effect. These results suggest that speakers with AOS need additional processing time to retrieve target words when multiple motor programmes are simultaneously activated.

Dose-Volume Predictors of Radiation Pneumonitis After Lung Stereotactic Body Radiation Therapy (SBRT): Implications for Practice and Trial Design.

Background and purpose Recently published HyTEC report summarized lung toxicity data and proposed guidelines of mean lung dose (MLD) <8 Gy and normal lung receiving at least 20 Gy, V20Gy<10-15% to avoid lung toxicity. Support for preferred use of a particular dosimetric parameter has been limited. We performed a detailed dose-volume analysis of data on radiation pneumonitis (RP) following lung stereotactic body radiation therapy (SBRT) to search for parameters showing the strongest correlation with RP. Materials and methods Two patient cohorts (primary and metastatic lung tumor patients) from previously reported studies were analyzed. Total number of patients was 96, and incidence of grade ≥2 RP was 13.5% (13/96). Fitting to the logistic function was performed to investigate correlation between incidence of RP and reported dosimetric and volumetric parameters. Another independent cohort was used to explore correlation between dosimetric parameters. Results Among normal lung parameters (MLD and reported Vx), only MLD consistently showed significant correlation with incidence of RP. Gross tumor volume (GTV), internal target volume, planning target volume (PTV), and minimum dose covering 95% of GTV or PTV did not show statistical significance. A significant correlation between reported Vx and MLD was observed in all cohorts. Conclusions In considering tumor- and target-specific (e.g., GTV, PTV) and normal lung-specific (e.g., MLD, Vx) metrics, MLD was the only parameter that consistently correlated with incidence of RP across both cohorts. Because SBRT planning constraints allow small normal lung volumes to receive high doses, utility of MLD is not obvious. The parallel structure of lung is one possible explanation, but correlation between dosimetric parameters obscures elucidation of the preferred or mechanistically based parameter to guide radiotherapy planning.

Potential Clinical Significance of Overall Targeting Accuracy and Motion Management in the Treatment of Tumors That Move With Respiration: Lessons Learnt From a Quarter Century of Stereotactic Body Radiotherapy From Dose Response Models.

OBJECTIVE: To determine the long-term normal tissue complication probability with stereotactic body radiation therapy (SBRT) treatments for targets that move with respiration and its relation with the type of respiratory motion management (tracking vs. compression or gating). METHODS: A PubMed search was performed for identifying literature regarding dose, volume, fractionation, and toxicity (grade 3 or higher) for SBRT treatments for tumors which move with respiration. From the identified papers logistic or probit dose-response models were fitted to the data using the maximum-likelihood technique and confidence intervals were based on the profile-likelihood method in the dose-volume histogram (DVH) Evaluator. RESULTS: Pooled logistic and probit models for grade 3 or higher toxicity for aorta, chest wall, duodenum, and small bowel suggest a significant difference when live motion tracking was used for targeting tumors with move with respiration which was on the average 10 times lower, in the high dose range. CONCLUSION: Live respiratory motion management appears to have a better toxicity outcome when treating targets which move with respiration with very steep peripheral dose gradients. This analysis is however limited by sparsity of rigorous data due to poor reporting in the literature.

Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer.

PURPOSE: RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non-small-cell lung cancer (NSCLC). METHODS: The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS). RESULTS: Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm v 12.1% and 17.4% in the HD arm, respectively (P = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months (P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% (P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms. CONCLUSION: A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.

Speech motor planning in the context of phonetically similar words: Evidence from apraxia of speech and aphasia.

The purpose of this study was to test two competing hypotheses about the nature of the impairment in apraxia of speech (AOS). The Reduced Buffer Capacity Hypothesis argues that people with AOS can hold only one syllable at a time in the speech motor planning buffer. The Program Retrieval Deficit Hypothesis, states that people with AOS have difficulty accessing the intended motor program in the context where several motor programs are activated simultaneously. The participants included eight speakers with AOS, most of whom also had aphasia, nine speakers with aphasia without AOS, and 25 age-matched control speakers. The experimental paradigm prompted single word production following three types of primes. In most trials, prime and target were the same (e.g., bill-bill). On some trials, the initial consonant differed in one phonetic feature (e.g., bill-dill; Similar) or in all phonetic features (fill-bill; Different). The dependent measures were accuracy and reaction time. The results revealed a switch cost - longer reaction times in trials where the prime and target differed compared to trials where they were the same words - in all groups; however, the switch cost was significantly larger in the AOS group compared to the other two groups. These findings are in line with the prediction of the Program Retrieval Deficit Hypothesis and suggest that speakers with AOS have difficulty with selecting one program over another when several programs compete for selection.

Is the L2 lexicon different from the L1 lexicon? Evidence from novel word lexicalization.

Studies on the representation of newly learned words in the native language show that after repeated sessions of learning, novel words produce less form priming than nonwords when they are used as primes in a masked priming experiment. This suggests that the newly learned words have established lexical representations, and therefore start to behave more like real words than nonwords (Qiao & Forster, 2013). Since adult language learning normally happens in a foreign language context rather than in the native language context, it is important to see whether similar results could be obtained if bilingual subjects were taught novel words in their second language (L2) rather than their first language (L1). The current experiment explores this issue using the same procedure and materials as used in the L1 experiment. Results show that in contrast to the nonsignificant priming observed with the L1 speakers, L2 speakers show enhanced facilitatory priming after the same training process. In addition, a significant facilitatory priming effect is also obtained with real words as primes, suggesting that the L1 and L2 lexicons might work in rather different ways. One possibility is that the L2 lexicon is not represented in the same type of memory system as the L1 lexicon, rather it is represented in a system where competitive effects are not observed.

Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.

BACKGROUND: We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer. METHODS: In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949. FINDINGS: Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001). INTERPRETATION: 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients. FUNDING: National Cancer Institute and Bristol-Myers Squibb.

A behavioral database for masked form priming.

Reading involves a process of matching an orthographic input with stored representations in lexical memory. The masked priming paradigm has become a standard tool for investigating this process. Use of existing results from this paradigm can be limited by the precision of the data and the need for cross-experiment comparisons that lack normal experimental controls. Here, we present a single, large, high-precision, multicondition experiment to address these problems. Over 1,000 participants from 14 sites responded to 840 trials involving 28 different types of orthographically related primes (e.g., castfe-CASTLE) in a lexical decision task, as well as completing measures of spelling and vocabulary. The data were indeed highly sensitive to differences between conditions: After correction for multiple comparisons, prime type condition differences of 2.90 ms and above reached significance at the 5% level. This article presents the method of data collection and preliminary findings from these data, which included replications of the most widely agreed-upon differences between prime types, further evidence for systematic individual differences in susceptibility to priming, and new evidence regarding lexical properties associated with a target word's susceptibility to priming. These analyses will form a basis for the use of these data in quantitative model fitting and evaluation and for future exploration of these data that will inform and motivate new experiments.

Evaluation of bolus electron conformal therapy compared with conventional techniques for the treatment of left chest wall postmastectomy in patients with breast cancer.

Postmastectomy radiation (PMRT) lowers local-regional recurrence risk and improves survival in selected patients with breast cancer. The chest wall and lower axilla are technically challenging areas to treat with homogenous doses and normal tissue sparing. This study compares several techniques for PMRT to provide data to guide selection of optimal treatment techniques. Twenty-five consecutive left-sided patients treated postmastectomy were contoured using Radiation Therapy Oncology Group (RTOG) atlas guidelines then planned using 4 different PMRT techniques: opposed tangents with wedges (3-dimensional [3D] wedges), opposed tangents with field-in-field (FiF) modulation, 8-field intensity modulation radiotherapy (IMRT), and custom bolus electron conformal therapy (BolusECT, .decimal, Inc., Sanford, FL). Required planning target volume (PTV) coverage was held constant, and then dose homogeneity and normal tissue dose parameters were compared among the 4 techniques. BolusECT achieved clincally acceptable PTV coverage for 22 out of 25 cases. Compared with either tangential technique, IMRT and BolusECT provided the lowest heart V25 doses (3.3% ± 0.9% and 6.6% ± 3.2%, respectively with p < 0.0001). FiF had the lowest mean total lung dose (7.3 ± 1.1Gy, with p = 0.0013), IMRT had the lowest total lung V20 (10.3% ± 1.6%, p < 0.0001), and BolusECT had the lowest mean heart dose (7.3 ± 2.0Gy, p = 0.0002). IMRT provided the optimal dose homogeneity and normal tissue sparing compared with all other techniques for the cases in which BolusECT could not achieve acceptable PTV coverage. IMRT generally exposes contralateral breast and lung to slightly higher doses. Optimal PMRT technique depends upon patient anatomy. Patients whose maximal target volume depth is about 5.7cm or less can be treated with BolusECT-assisted 12 or 15MeV electron beams. At these energies, BolusECT has comparable dose-volume statistics as IMRT and lower heart V25 than opposed tangential beams. Patients with larger depths are best treated with IMRT, which provides significant advantages in both dose homogeneity and normal tissue sparing compared with all other techniques.

Dependence of ventilation image derived from 4D CT on deformable image registration and ventilation algorithms.

Ventilation imaging using 4D CT is a convenient and low-cost functional imaging methodology which might be of value in radiotherapy treatment planning to spare functional lung volumes. Deformable image registration (DIR) is needed to calculate ventilation imaging from 4D CT. This study investigates the dependence of calculated ventilation on DIR methods and ventilation algorithms. DIR of the normal end expiration and normal end inspiration phases of the 4D CT images was used to correlate the voxels between the two respiratory phases. Three different DIR algorithms, optical flow (OF), diffeomorphic demons (DD), and diffeomorphic morphons (DM) were retrospectively applied to ten esophagus and ten lung cancer cases with 4D CT image sets that encompassed the entire lung volume. The three ventilation extraction methods were used based on either the Jacobian, the change in volume of the voxel, or directly calculated from Hounsfield units. The ventilation calculation algorithms used are the Jacobian, ΔV, and HU method. They were compared using the Dice similarity coefficient (DSC) index and Bland-Altman plots. Dependence of ventilation images on the DIR was greater for the ΔV and the Jacobian methods than for the HU method. The DSC index for 20% of low-ventilation volume for ΔV was 0.33 ± 0.03 (1 SD) between OF and DM, 0.44 ± 0.05 between OF and DD, and 0.51 ± 0.04 between DM and DD. The similarity comparisons for Jacobian were 0.32 ± 0.03, 0.44 ± 0.05, and 0.51 ± 0.04, respectively, and for HU they were 0.53 ± 0.03, 0.56 ± 0.03, and 0.76 ± 0.04, respectively. Dependence of extracted ventilation on the ventilation algorithm used showed good agreement between the ΔV and Jacobian methods, but differed significantly for the HU method. DSC index for using OF as DIR was 0.86 ± 0.01 between ΔV and Jacobian, 0.28 ± 0.04 between ΔV and HU, and 0.28 ± 0.04 between Jacobian and HU, respectively. When using DM or DD as DIR, similar values were obtained when comparing the different ventilation calculation methods. The similarity values for the 20% high-ventilation volume were close to those found for the 20% low-ventilation volume. The results obtained with DSC index were confirmed when using the Bland-Altman plots for comparing the ventilation images. Our data suggest that ventilation calculated from 4D CT depends on the DIR algorithm employed. Similarities between ΔV and Jacobian are higher than between ΔV and HU, and Jacobian and HU.

Validation of three deformable image registration algorithms for the thorax.

Deformable image registration (DIR) has been proposed for lung ventilation calculation using 4D CT. Spatial accuracy of DIR can be evaluated using expert landmark correspondences. Additionally, image differences between the deformed and the target images give a degree of accuracy of DIR algorithms for the same image modality registration. DIR of the normal end-expiration (50%), end-inspiration (0%), midexpiration (30%), and midinspiration image (70%) phases of the 4D CT images was used to correlate the voxels between the respiratory phases. Three DIR algorithms, optical flow (OF), diffeomorphic morphons (DM), and diffeomorphic demons (DD) were validated using a 4D thorax model, consisting of a 4D CT image dataset, along with associated landmarks delineated by a radiologist. Image differences between the deformed and the target images were used to evaluate the degree of registration accuracy of the three DIR algorithms. In the validation of the DIR algorithms, the average target registration error (TRE) for normal end-expiration-to-end-inspiration registration with one standard deviation (SD) for the DIR algorithms was 1.6 ± 0.9 mm (maximum 3.1 mm) for OF, 1.4 ± 0.6 mm (maximum 3.3 mm) for DM, and 1.4 ± 0.7 mm (maximum 3.3 mm) for DD, indicating registration errors were within two voxels. As a reference, the median value of TRE between 0 and 50% phases with rigid registration only was 5.0 mm with one SD of 2.5 mm and the maximum value of 12.0 mm. For the OF algorithm, 81% of voxels were within a difference of 50 HU, and 93% of the voxels were within 100 HU. For the DM algorithm, 69% of voxels were within 50 HU, and 87% within 100 HU. For the DD algorithm, 71% of the voxels were within 50 HU, and 87% within a difference of 100 HU. These data suggest that the three DIR methods perform accurate registrations in the thorax region. The mean TRE for all three DIR methods was less than two voxels suggesting that the registration performed by all methods are equally accurate in the thorax.

Novel word lexicalization and the prime lexicality effect.

This study investigates how newly learned words are integrated into the first-language lexicon using masked priming. Two lexical decision experiments are reported, with the aim of establishing whether newly learned words behave like real words in a masked form priming experiment. If they do, they should show a prime lexicality effect (PLE), in which less priming is obtained due to form similarity when the prime is a word. In the first experiment, subjects were taught the meanings of novel words that were neighbors of real words, but no PLE was observed; that is, equally strong form priming was obtained for both trained and untrained novel primes. In the second experiment, 4 training sessions were spread over 4 weeks, and under these conditions, a clear PLE was obtained in the final session. It is concluded that lexicalization requires multiple training sessions. Possible explanations of the PLE are discussed.

Comparing dose in the build-up region between compensator- and MLC-based IMRT.

The build-up dose in the megavoltage photon beams can be a limiting factor in intensity-modulated radiation therapy (IMRT) treatments. Excessive surface dose can cause patient discomfort and treatment interruptions, while underdosing may lead to tumor repopulation and local failure. Dose in the build-up region was investigated for IMRT delivery with solid brass compensator technique(compensator-based IMRT) and compared with that of multileaf collimator (MLC)-based IMRT. A Varian Trilogy linear accelerator equipped with an MLC was used for beam delivery. A special solid brass step-wise compensator was designed and built for testing purposes. Two step-and-shoot MLC fields were programmed to produce a similar modulated step-wise dose profile. The MLC and compensator dose profiles were measured and adjusted to match at the isocenter depth of 10 cm. Build-up dose in the 1-5 mm depth range was measured with an ultrathin window, fixed volume parallel plate ionization chamber. Monte Carlo simulations were used to model the brass compensator and step-and-shoot MLC fields. The measured and simulated profiles for the two IMRT techniques were matched at the isocenter depth of 10 cm. Different component contributions to the shallow dose, including the MLC scatter, were quantified. Mean spectral energies for the open and filtered beams were calculated. The compensator and MLC profiles at 10 cm depth were matched better than ± 1.5%. The build-up dose was up to 7% lower for compensator IMRT compared to MLC IMRT due to beam hardening in the brass. Low-energy electrons contribute 22% and 15% dose at 1 mm depth for compensator and MLC modalities, respectively. Compensator-based IMRT delivers less dose in the build-up region than MLC-based IMRT does, even though a compensator is closer to the skin than the MLC.

Providing a fast conversion of total dose to biological effective dose (BED) for hybrid seed brachytherapy.

Optimization of permanent seed implant brachytherapy plans for treatment of prostate cancer should be based on biological effective dose (BED) distributions, since dose does not accurately represent biological effects between different types of sources. Currently, biological optimization for these plans is not feasible due to the amount of time necessary to calculate the BED distribution. This study provides a fast calculation method, based on the total dose, to calculate the BED distribution. Distributions of various numbers of hybrid seeds were used to calculate total dose distributions, as well as BED distributions. Hybrid seeds are a mixture of different isotopes (in this study (125)I and (103)Pd). Three ratios of hybrid seeds were investigated: 25/75, 50/50, and 75/25. The total dose and BED value from each voxel were coupled together to produce graphs of total dose vs. BED. Equations were then derived from these graphs. The study investigated four types of tissue: bladder, rectum, prostate, and other normal tissue. Equations were derived from the total dose - BED correspondence. Accuracy of conversion from total dose to BED was within 2 Gy; however, accuracy of conversion was found to be better for high total dose regions as compared to lower dose regions. The method introduced in this paper allows one to perform fast conversion of total dose to BED for brachytherapy using hybrid seeds, which makes the BED-based plan optimization practical. The method defined here can be extended to other ratios, as well as other tissues that are affected by permanent seed implant brachytherapy (i.e., breast).

Promise and pitfalls of quantitative imaging in oncology clinical trials.

Quantitative imaging using computed tomography, magnetic resonance imaging and positron emission tomography modalities will play an increasingly important role in the design of oncology trials addressing molecularly targeted, personalized therapies. The advent of molecularly targeted therapies, exemplified by antiangiogenic drugs, creates new complexities in the assessment of response. The Quantitative Imaging Network addresses the need for imaging modalities which can accurately and reproducibly measure not just change in tumor size but changes in relevant metabolic parameters, modulation of relevant signaling pathways, drug delivery to tumor and differentiation of apoptotic cell death from other changes in tumor volume. This article provides an overview of the applications of quantitative imaging to phase 0 through phase 3 oncology trials. We describe the use of a range of quantitative imaging modalities in specific tumor types including malignant gliomas, lung cancer, head and neck cancer, lymphoma, breast cancer, prostate cancer and sarcoma. In the concluding section, we discuss potential constraints on clinical trials using quantitative imaging, including complexity of trial conduct, impact on subject recruitment, incremental costs and institutional barriers. Strategies for overcoming these constraints are presented.