Isolation and genome sequence annotation of SallyK, a newly discovered cluster EG bacteriophage infecting Microbacterium.

Discovered from soil in a flower planter in Pocatello, Idaho and using Microbacterium foliorum, SallyK is a lytic bacteriophage with a siphovirus morphology. It has a 62,883 bp-long genome with 103 putative genes. Based on gene content similarity to actinobacteriophages, SallyK is assigned to cluster EG.

Isolation and genome sequence annotation of KillerTomato, a newly discovered cluster EE bacteriophage infecting Microbacterium.

Discovered in Pocatello, Idaho, soil near a tomato garden, siphovirus KillerTomato infects Microbacterium foliorum NRRL B-24224. KillerTomato is a lytic cluster EE phage with a 17,442-bp genome and 68.6% GC content. Of 25 genes, 20 were assigned putative functions, including a putative tail assembly chaperone protein with a programmed frameshift and an endolysin.

Methodology for computed tomography characterization of commercially available 3D printing materials for use in radiology/radiation oncology.

3D printing in medical physics provides opportunities for creating patient-specific treatment devices and in-house fabrication of imaging/dosimetry phantoms. This study characterizes several commercial fused deposition 3D printing materials with some containing nonstandard compositions. It is important to explore their similarities to human tissues and other materials encountered in patients. Uniform cylinders with infill from 50 to 100% at six evenly distributed intervals were printed using 13 different filaments. A novel approach rotating infill angle 10o between each layer avoids unwanted patterns. Five materials contained high-Z/metallic components. A clinical CT scanner with a range of tube potentials (70, 80, 100, 120, 140 kVp) was used. Density and average Hounsfield unit (HU) were measured. A commercial GAMMEX phantom mimicking various human tissues provides a comparison. Utility of the lookup tables produced is demonstrated. A methodology for calibrating print materials/parameters for a desired HU is presented. Density and HU were determined for all materials as a function of tube voltage (kVp) and infill percentage. The range of HU (-732.0-10047.4 HU) and physical densities (0.36-3.52 g/cm3 ) encompassed most tissues/materials encountered in radiology/radiotherapy applications with many overlapping those of human tissues. Printing filaments doped with high-Z materials demonstrated increased attenuation due to the photoelectric effect with decreased kVp, as found in certain endogenous materials (e.g., bone). HU was faithfully reproduced (within one standard deviation) in a 3D-printed mimic of a commercial anthropomorphic phantom section. Characterization of commercially available 3D print materials facilitates custom object fabrication for use in radiology and radiation oncology, including human tissue and common exogenous implant mimics. This allows for cost reduction and increased flexibility to fabricate novel phantoms or patient-specific devices imaging and dosimetry purposes. A formalism for calibrating to specific CT scanner, printer, and filament type/batch is presented. Utility is demonstrated by printing a commercial anthropomorphic phantom copy.

Proof-of-principle Phase I results of combining nivolumab with brachytherapy and external beam radiation therapy for Grade Group 5 prostate cancer: safety, feasibility, and exploratory analysis.

BACKGROUND: To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa. METHODS: Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189). RESULTS: Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post-HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders. CONCLUSION: Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.

High-dose intensity-modulated chemoradiotherapy in vulvar squamous cell carcinoma: Outcome and toxicity.

INTRODUCTION: To evaluate clinical outcomes, pattern of failure, and toxicity after high-dose intensity-modulated radiation therapy (IMRT) for advanced vulvar cancer. METHODS: In this IRB approved retrospective study, the charts of women with histologically confirmed, non-metastatic vulvar cancer consecutively treated at our institution from 2012 to 2018 were reviewed to identify patients that received high-dose IMRT with curative intent. The treatment compliance, toxicities, and patterns of failure were investigated. Actuarial local, regional and distant recurrence and survival were estimated using Kaplan-Meier method and compared using log rank test. RESULTS: Twenty-six patients were identified, 23 were unresectable, and 3 refused surgery. Fifteen patients (58%) had inguinal node metastases; 10(38%) had pelvic node metastases. Elective surgical staging of groins was performed in 9-patients. Median tumor dose was 65.4Gy. Concurrent platinum-based chemotherapy was administered in 22(84.6%) patients. Complete response (CR) was achieved in 21/26 (80.7%) patients. Five patients had persistent disease following treatment and one sustained recurrence 5-months following radiotherapy. All persistent or recurrent disease occurred inside the irradiated volume. Median follow-up was 19 months (3-52 months). Actuarial 1-year local, regional and distant controls were 72.4%, 85.4%, and 86%, respectively. One and 2-year overall survivals were 91% and 62%, respectively. Complete response at 3-months was a strong predictor for overall survival (1-yr OS 73% vs 27%, HR 7.1 (95% CI 1.2-44); p = 0.01). Lymph node metastases adversely affected overall survival (2-yr OS 49% vs. 83%, p = 0.09). Grade 3-4 late urinary and soft-tissue toxicity was seen in 5 patients. Tumor doses >66 Gy (p = 0.03) and prior pelvic radiotherapy (p = 0.002) predicted grade 3-4 toxicity. CONCLUSION: High-dose IMRT for vulvar cancer achieves high rates of local control with acceptable dose dependent long-term toxicity.

Practical quantification of image registration accuracy following the AAPM TG-132 report framework.

The AAPM TG 132 Report enumerates important steps for validation of the medical image registration process. While the Report outlines the general goals and criteria for the tests, specific implementation may be obscure to the wider clinical audience. We endeavored to provide a detailed step-by-step description of the quantitative tests' execution, applied as an example to a commercial software package (Mirada Medical, Oxford, UK), while striving for simplicity and utilization of readily available software. We demonstrated how the rigid registration data could be easily extracted from the DICOM registration object and used, following some simple matrix math, to quantify accuracy of rigid translations and rotations. The options for validating deformable image registration (DIR) were enumerated, and it was shown that the most practically viable ones are comparison of propagated internal landmark points on the published datasets, or of segmented contours that can be generated locally. The multimodal rigid registration in our example did not always result in the desired registration error below ½ voxel size, but was considered acceptable with the maximum errors under 1.3 mm and 1°. The DIR target registration errors in the thorax based on internal landmarks were far in excess of the Report recommendations of 2 mm average and 5 mm maximum. On the other hand, evaluation of the DIR major organs' contours propagation demonstrated good agreement for lung and abdomen (Dice Similarity Coefficients, DSC, averaged over all cases and structures of 0.92 ± 0.05 and 0.91 ± 0.06, respectively), and fair agreement for Head and Neck (average DSC = 0.73 ± 0.14). The average for head and neck is reduced by small volume structures such as pharyngeal constrictor muscles. Even these relatively simple tests show that commercial registration algorithms cannot be automatically assumed sufficiently accurate for all applications. Formalized task-specific accuracy quantification should be expected from the vendors.

Investigating multi-radiomic models for enhancing prediction power of cervical cancer treatment outcomes.

Quantitative image features, also known as radiomic features, have shown potential for predicting treatment outcomes in several body sites. We quantitatively analyzed 18Fluorine-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET) uptake heterogeneity in the Metabolic Tumor Volume (MTV) of eighty cervical cancer patients to investigate the predictive performance of radiomic features for two treatment outcomes: the development of distant metastases (DM) and loco-regional recurrent disease (LRR). We aimed to fit the highest predictive features in multiple logistic regression models (MLRs). To generate such models, we applied backward feature selection method as part of Leave-One-Out Cross Validation (LOOCV) within a training set consisting of 70% of the original patient cohort. The trained MLRs were tested on an independent set consisted of 30% of the original cohort. We evaluated the performance of the final models using the Area under the Receiver Operator Characteristic Curve (AUC). Accordingly, six models demonstrated superior predictive performance for both outcomes (four for DM and two for LRR) when compared to both univariate-radiomic feature models and Standard Uptake Value (SUV) measurements. This demonstrated approach suggests that the ability of the pre-radiochemotherapy PET radiomics to stratify patient risk for DM and LRR could potentially guide management decisions such as adjuvant systemic therapy or radiation dose escalation.

Accounting for reconstruction kernel-induced variability in CT radiomic features using noise power spectra.

Large variability in computed tomography (CT) radiomics feature values due to CT imaging parameters can have subsequent implications on the prognostic or predictive significance of these features. Here, we investigated the impact of pitch, dose, and reconstruction kernel on CT radiomic features. Moreover, we introduced correction factors to reduce feature variability introduced by reconstruction kernels. The credence cartridge radiomics and American College of Radiology (ACR) phantoms were scanned on five different scanners. ACR phantom was used for 3-D noise power spectrum (NPS) measurements to quantify correlated noise. The coefficient of variation (COV) was used as the variability assessment metric. The variability in texture features due to different kernels was reduced by applying the NPS peak frequency and region of interest (ROI) maximum intensity as correction factors. Most texture features were dose independent but were strongly kernel dependent, which is demonstrated by a significant shift in NPS peak frequency among kernels. Percentage improvement in robustness was calculated for each feature from original and corrected %COV values. Percentage improvements in robustness of 19 features were in the range of 30% to 78% after corrections. We show that NPS peak frequency and ROI maximum intensity can be used as correction factors to reduce variability in CT texture feature values due to reconstruction kernels.

Reproducibility of F18-FDG PET radiomic features for different cervical tumor segmentation methods, gray-level discretization, and reconstruction algorithms.

Site-specific investigations of the role of radiomics in cancer diagnosis and therapy are emerging. We evaluated the reproducibility of radiomic features extracted from 18 Flourine-fluorodeoxyglucose (18 F-FDG) PET images for three parameters: manual versus computer-aided segmentation methods, gray-level discretization, and PET image reconstruction algorithms. Our cohort consisted of pretreatment PET/CT scans from 88 cervical cancer patients. Two board-certified radiation oncologists manually segmented the metabolic tumor volume (MTV1 and MTV2 ) for each patient. For comparison, we used a graphical-based method to generate semiautomated segmented volumes (GBSV). To address any perturbations in radiomic feature values, we down-sampled the tumor volumes into three gray-levels: 32, 64, and 128 from the original gray-level of 256. Finally, we analyzed the effect on radiomic features on PET images of eight patients due to four PET 3D-reconstruction algorithms: maximum likelihood-ordered subset expectation maximization (OSEM) iterative reconstruction (IR) method, fourier rebinning-ML-OSEM (FOREIR), FORE-filtered back projection (FOREFBP), and 3D-Reprojection (3DRP) analytical method. We extracted 79 features from all segmentation method, gray-levels of down-sampled volumes, and PET reconstruction algorithms. The features were extracted using gray-level co-occurrence matrices (GLCM), gray-level size zone matrices (GLSZM), gray-level run-length matrices (GLRLM), neighborhood gray-tone difference matrices (NGTDM), shape-based features (SF), and intensity histogram features (IHF). We computed the Dice coefficient between each MTV and GBSV to measure segmentation accuracy. Coefficient values close to one indicate high agreement, and values close to zero indicate low agreement. We evaluated the effect on radiomic features by calculating the mean percentage differences (d¯) between feature values measured from each pair of parameter elements (i.e. segmentation methods: MTV1 -MTV2 , MTV1 -GBSV, MTV2 -GBSV; gray-levels: 64-32, 64-128, and 64-256; reconstruction algorithms: OSEM-FORE-OSEM, OSEM-FOREFBP, and OSEM-3DRP). We used |d¯| as a measure of radiomic feature reproducibility level, where any feature scored |d¯| ±SD ≤ |25|% ± 35% was considered reproducible. We used Bland-Altman analysis to evaluate the mean, standard deviation (SD), and upper/lower reproducibility limits (U/LRL) for radiomic features in response to variation in each testing parameter. Furthermore, we proposed U/LRL as a method to classify the level of reproducibility: High- ±1% ≤ U/LRL ≤ ±30%; Intermediate- ±30% < U/LRL ≤ ±45%; Low- ±45 < U/LRL ≤ ±50%. We considered any feature below the low level as nonreproducible (NR). Finally, we calculated the interclass correlation coefficient (ICC) to evaluate the reliability of radiomic feature measurements for each parameter. The segmented volumes of 65 patients (81.3%) scored Dice coefficient >0.75 for all three volumes. The result outcomes revealed a tendency of higher radiomic feature reproducibility among segmentation pair MTV1 -GBSV than MTV2 -GBSV, gray-level pairs of 64-32 and 64-128 than 64-256, and reconstruction algorithm pairs of OSEM-FOREIR and OSEM-FOREFBP than OSEM-3DRP. Although the choice of cervical tumor segmentation method, gray-level value, and reconstruction algorithm may affect radiomic features, some features were characterized by high reproducibility through all testing parameters. The number of radiomic features that showed insensitivity to variations in segmentation methods, gray-level discretization, and reconstruction algorithms was 10 (13%), 4 (5%), and 1 (1%), respectively. These results suggest that a careful analysis of the effects of these parameters is essential prior to any radiomics clinical application.

Validation of a GPU-Based 3D dose calculator for modulated beams.

A superposition/convolution GPU-accelerated dose computation algorithm (the Calculator) has been recently incorporated into commercial software. The algorithm requires validation prior to clinical use. Three photon energies were examined: conventional 6 MV and 15 MV, and 10 MV flattening filter free (10 MVFFF). For a set of IMRT and VMAT plans based on four of the five AAPM Practice Guideline 5a downloadable datasets, ion chamber (IC) measurements were performed on the water-equivalent phantoms. The average difference between the Calculator and IC was -0.3 ± 0.8% (1SD). The same plans were projected on a phantom containing a biplanar diode array. We used the forthcoming criteria for routine gamma analysis, 3% dose-error (global (G) normalization, 2 mm distance to agreement, and 10% low dose cutoff). The γ (3%G/2 mm) average passing rate was 98.9 ± 2.1%. Measurement-guided three-dimensional dose reconstruction on the patient CT dataset (excluding the Lung) resulted in a similar average agreement rate with the Calculator: 98.2 ± 2.0%. The mean γ (3%G/2 mm) passing rate comparing the Calculator to the TPS (again excluding the Lung) was 99.0 ± 1.0%. Because of the significant inhomogeneity, the Lung case was investigated separately. The calculator has an alternate heterogeneity correction mode that can change the results in the thorax for higher-energy beams (15 MV). As this correction is nonphysical and was optimized for simple slab geometries, its application leads to mixed results when compared to the TPS and independent Monte Carlo calculations, depending on the CT dataset and the plan. The Calculator vs. TPS 15 MV Guideline 5a IMRT and VMAT plans demonstrate 96.3% and 93.4% γ (3%G/2 mm) passing rates respectively. For the lower energies, which should be predominantly used in the thoracic region, the passing rates for the same plans and criteria range from 98.6 to 100%. Overall, the Calculator accuracy is sufficient for the intended use.

Intrinsic dependencies of CT radiomic features on voxel size and number of gray levels.

PURPOSE: Many radiomics features were originally developed for non-medical imaging applications and therefore original assumptions may need to be reexamined. In this study, we investigated the impact of slice thickness and pixel spacing (or pixel size) on radiomics features extracted from Computed Tomography (CT) phantom images acquired with different scanners as well as different acquisition and reconstruction parameters. The dependence of CT texture features on gray-level discretization was also evaluated. METHODS AND MATERIALS: A texture phantom composed of 10 different cartridges of different materials was scanned on eight different CT scanners from three different manufacturers. The images were reconstructed for various slice thicknesses. For each slice thickness, the reconstruction Field Of View (FOV) was varied to render pixel sizes ranging from 0.39 to 0.98 mm. A fixed spherical region of interest (ROI) was contoured on the images of the shredded rubber cartridge and the 3D printed, 20% fill, acrylonitrile butadiene styrene plastic cartridge (ABS20) for all phantom imaging sets. Radiomic features were extracted from the ROIs using an in-house program. Features categories were: shape (10), intensity (16), GLCM (24), GLZSM (11), GLRLM (11), and NGTDM (5), fractal dimensions (8) and first-order wavelets (128), for a total of 213 features. Voxel-size resampling was performed to investigate the usefulness of extracting features using a suitably chosen voxel size. Acquired phantom image sets were resampled to a voxel size of 1 × 1 × 2 mm3 using linear interpolation. Image features were therefore extracted from resampled and original datasets and the absolute value of the percent coefficient of variation (%COV) for each feature was calculated. Based on the %COV values, features were classified in 3 groups: (1) features with large variations before and after resampling (%COV >50); (2) features with diminished variation (%COV <30) after resampling; and (3) features that had originally moderate variation (%COV <50%) and were negligibly affected by resampling. Group 2 features were further studied by modifying feature definitions to include voxel size. Original and voxel-size normalized features were used for interscanner comparisons. A subsequent analysis investigated feature dependency on gray-level discretization by extracting 51 texture features from ROIs from each of the 10 different phantom cartridges using 16, 32, 64, 128, and 256 gray levels. RESULTS: Out of the 213 features extracted, 150 were reproducible across voxel sizes, 42 improved significantly (%COV <30, Group 2) after resampling, and 21 had large variations before and after resampling (Group 1). Ten features improved significantly after definition modification effectively removed their voxel-size dependency. Interscanner comparison indicated that feature variability among scanners nearly vanished for 8 of these 10 features. Furthermore, 17 out of 51 texture features were found to be dependent on the number of gray levels. These features were redefined to include the number of gray levels which greatly reduced this dependency. CONCLUSION: Voxel-size resampling is an appropriate pre-processing step for image datasets acquired with variable voxel sizes to obtain more reproducible CT features. We found that some of the radiomics features were voxel size and gray-level discretization-dependent. The introduction of normalizing factors in their definitions greatly reduced or removed these dependencies.

Sensitivity of Image Features to Noise in Conventional and Respiratory-Gated PET/CT Images of Lung Cancer: Uncorrelated Noise Effects.

The effect of noise on image features has yet to be studied in depth. Our objective was to explore how significantly image features are affected by the addition of uncorrelated noise to an image. The signal-to-noise ratio and noise power spectrum were calculated for a positron emission tomography/computed tomography scanner using a Ge-68 phantom. The conventional and respiratory-gated positron emission tomography/computed tomography images of 31 patients with lung cancer were retrospectively examined. Multiple sets of noise images were created for each original image by adding Gaussian noise of varying standard deviation equal to 2.5%, 4.0%, and 6.0% of the maximum intensity for positron emission tomography images and 10, 20, 50, 80, and 120 Hounsfield units for computed tomography images. Image features were extracted from all images, and percentage differences between the original image and the noise image feature values were calculated. These features were then categorized according to the noise sensitivity. The contour-dependent shape descriptors averaged below 4% difference in positron emission tomography and below 13% difference in computed tomography between noise and original images. Gray level size zone matrix features were the most sensitive to uncorrelated noise exhibiting average differences >200% for conventional and respiratory-gated images in computed tomography and 90% in positron emission tomography. Image feature differences increased as the noise level increased for shape, intensity, and gray-level co-occurrence matrix features in positron emission tomography and for gray-level co-occurrence matrix and gray-level size zone matrix features in conventional computed tomography. Investigators should be aware of the noise effects on image features.

Technical Note: Motion-perturbation method applied to dosimetry of dynamic MLC target tracking--A proof-of-concept.

PURPOSE: Previous studies show that dose to a moving target can be estimated using 4D measurement-guided dose reconstruction based on a process called virtual motion simulation, or VMS. A potential extension of VMS is to estimate dose during dynamic multileaf collimator (MLC)-tracking treatments. The authors introduce a modified VMS method and quantify its performance as proof-of-concept for tracking applications. METHODS: Direct measurements with a moving biplanar diode array were used to verify accuracy of the VMS dose estimates. A tracking environment for variably sized circular MLC apertures was simulated by sending preprogrammed control points to the MLC while simultaneously moving the accelerator treatment table. Sensitivity of the method to simulated tracking latency (0-700 ms) was also studied. Potential applicability of VMS to fast changing beam apertures was evaluated by modeling, based on the demonstrated dependence of the cumulative dose on the temporal dose gradient. RESULTS: When physical and virtual latencies were matched, the agreement rates (2% global/2 mm gamma) between the VMS and the biplanar dosimeter were above 96%. When compared to their own reference dose (0 induced latency), the agreement rates for VMS and biplanar array track closely up to 200 ms of induced latency with 10% low-dose cutoff threshold and 300 ms with 50% cutoff. Time-resolved measurements suggest that even in the modulated beams, the error in the cumulative dose introduced by the 200 ms VMS time resolution is not likely to exceed 0.5%. CONCLUSIONS: Based on current results and prior benchmarks of VMS accuracy, the authors postulate that this approach should be applicable to any MLC-tracking treatments where leaf speeds do not exceed those of the current Varian accelerators.

Health-related quality-of-life changes due to high-dose-rate brachytherapy, low-dose-rate brachytherapy, or intensity-modulated radiation therapy for prostate cancer.

PURPOSE: To compare urinary, bowel, and sexual health-related quality-of-life (HRQOL) changes due to high-dose-rate (HDR) brachytherapy, low-dose-rate (LDR) brachytherapy, or intensity-modulated radiation therapy (IMRT) monotherapy for prostate cancer. METHODS AND MATERIALS: Between January 2002 and September 2013, 413 low-risk or favorable intermediate-risk prostate cancer patients were treated with HDR brachytherapy monotherapy to 2700-2800 cGy in two fractions (n = 85), iodine-125 LDR brachytherapy monotherapy to 14,500 cGy in one fraction (n = 249), or IMRT monotherapy to 7400-8100 cGy in 37-45 fractions (n = 79) without pelvic lymph node irradiation. No androgen deprivation therapy was given. Patients used an international prostate symptoms score questionnaire, an expanded prostate cancer index composite-26 bowel questionnaire, and a sexual health inventory for men questionnaire to assess their urinary, bowel, and sexual HRQOL, respectively, pretreatment and at 1, 3, 6, 9, 12, and 18 months posttreatment. RESULTS: Median follow-up was 32 months. HDR brachytherapy and IMRT patients had significantly less deterioration in their urinary HRQOL than LDR brachytherapy patients at 1 and 3 months after irradiation. The only significant decrease in bowel HRQOL between the groups was seen 18 months after treatment, at which point IMRT patients had a slight, but significant, deterioration in their bowel HRQOL compared with HDR and LDR brachytherapy patients. HDR brachytherapy patients had worse sexual HRQOL than both LDR brachytherapy and IMRT patients after treatment. CONCLUSIONS: IMRT and HDR brachytherapy cause less severe acute worsening of urinary HRQOL than LDR brachytherapy. However, IMRT causes a slight, but significant, worsening of bowel HRQOL compared with HDR and LDR brachytherapy.

Methods, software and datasets to verify DVH calculations against analytical values: Twenty years late(r).

PURPOSE: The authors designed data, methods, and metrics that can serve as a standard, independent of any software package, to evaluate dose-volume histogram (DVH) calculation accuracy and detect limitations. The authors use simple geometrical objects at different orientations combined with dose grids of varying spatial resolution with linear 1D dose gradients; when combined, ground truth DVH curves can be calculated analytically in closed form to serve as the absolute standards. METHODS: dicom RT structure sets containing a small sphere, cylinder, and cone were created programmatically with axial plane spacing varying from 0.2 to 3 mm. Cylinders and cones were modeled in two different orientations with respect to the IEC 1217 Y axis. The contours were designed to stringently but methodically test voxelation methods required for DVH. Synthetic RT dose files were generated with 1D linear dose gradient and with grid resolution varying from 0.4 to 3 mm. Two commercial DVH algorithms-pinnacle (Philips Radiation Oncology Systems) and PlanIQ (Sun Nuclear Corp.)-were tested against analytical values using custom, noncommercial analysis software. In Test 1, axial contour spacing was constant at 0.2 mm while dose grid resolution varied. In Tests 2 and 3, the dose grid resolution was matched to varying subsampled axial contours with spacing of 1, 2, and 3 mm, and difference analysis and metrics were employed: (1) histograms of the accuracy of various DVH parameters (total volume, Dmax, Dmin, and doses to % volume: D99, D95, D5, D1, D0.03 cm(3)) and (2) volume errors extracted along the DVH curves were generated and summarized in tabular and graphical forms. RESULTS: In Test 1, pinnacle produced 52 deviations (15%) while PlanIQ produced 5 (1.5%). In Test 2, pinnacle and PlanIQ differed from analytical by >3% in 93 (36%) and 18 (7%) times, respectively. Excluding Dmin and Dmax as least clinically relevant would result in 32 (15%) vs 5 (2%) scored deviations for pinnacle vs PlanIQ in Test 1, while Test 2 would yield 53 (25%) vs 17 (8%). In Test 3, statistical analyses of volume errors extracted continuously along the curves show pinnacle to have more errors and higher variability (relative to PlanIQ), primarily due to pinnacle's lack of sufficient 3D grid supersampling. Another major driver for pinnacle errors is an inconsistency in implementation of the "end-capping"; the additional volume resulting from expanding superior and inferior contours halfway to the next slice is included in the total volume calculation, but dose voxels in this expanded volume are excluded from the DVH. PlanIQ had fewer deviations, and most were associated with a rotated cylinder modeled by rectangular axial contours; for coarser axial spacing, the limited number of cross-sectional rectangles hinders the ability to render the true structure volume. CONCLUSIONS: The method is applicable to any DVH-calculating software capable of importing dicom RT structure set and dose objects (the authors' examples are available for download). It includes a collection of tests that probe the design of the DVH algorithm, measure its accuracy, and identify failure modes. Merits and applicability of each test are discussed.

Lipiodol as a fiducial marker for image-guided radiation therapy for bladder cancer.

PURPOSE: To evaluate Lipiodol as a liquid, radio-opaque fiducial marker for image-guided radiation therapy (IGRT) for bladder cancer. MATERIALS AND METHODS: Between 2011 and 2012, 5 clinical T2a-T3b N0 M0 stage II-III bladder cancer patients were treated with maximal transurethral resection of a bladder tumor (TURBT) and image-guided radiation therapy (IGRT) to 64.8 Gy in 36 fractions ± concurrent weekly cisplatin-based or gemcitabine chemotherapy. Ten to 15mL Lipiodol, using 0.5mL per injection, was injected into bladder submucosa circumferentially around the entire periphery of the tumor bed immediately following maximal TURBT. The authors looked at inter-observer variability regarding the size and location of the tumor bed (CTVboost) on computed tomography scans with versus without Lipiodol. RESULTS: Median follow-up was 18 months. Lipiodol was visible on every orthogonal two-dimensional kV portal image throughout the entire, 7-week course of IGRT. There was a trend towards improved inter-observer agreement on the CTVboost with Lipiodol (p = 0.06). In 2 of 5 patients, the tumor bed based upon Lipiodol extended outside a planning target volume that would have been treated with a radiation boost based upon a cystoscopy report and an enhanced computed tomography (CT) scan for staging. There was no toxicity attributable to Lipiodol. CONCLUSIONS: Lipiodol constitutes a safe and effective fiducial marker that an urologist can use to demarcate a tumor bed immediately following maximal TURBT. Lipiodol decreases inter-observer variability in the definition of the extent and location of a tumor bed on a treatment planning CT scan for a radiation boost.

A dosimetric study of polyethylene glycol hydrogel in 200 prostate cancer patients treated with high-dose rate brachytherapy±intensity modulated radiation therapy.

BACKGROUND AND PURPOSE: We sought to analyze the effect of polyethylene glycol (PEG) hydrogel on rectal doses in prostate cancer patients undergoing radiotherapy. MATERIALS AND METHODS: Between July 2009 and April 2013, we treated 200 clinically localized prostate cancer patients with high-dose rate (HDR) brachytherapy±intensity modulated radiation therapy. Half of the patients received a transrectal ultrasound (TRUS)-guided transperineal injection of 10mL PEG hydrogel (DuraSeal™ Spinal Sealant System; Covidien, Mansfield, MA) in their anterior perirectal fat immediately prior to the first HDR brachytherapy treatment and 5mL PEG hydrogel prior to the second HDR brachytherapy treatment. Prostate, rectal, and bladder doses and prostate-rectal distances were calculated based upon treatment planning CT scans. RESULTS: There was a success rate of 100% (100/100) with PEG hydrogel implantation. PEG hydrogel significantly increased the prostate-rectal separation (mean±SD, 12±4mm with gel vs. 4±2mm without gel, p<0.001) and significantly decreased the mean rectal D2 mL (47±9% with gel vs. 60±8% without gel, p<0.001). Gel decreased rectal doses regardless of body mass index (BMI). CONCLUSIONS: PEG hydrogel temporarily displaced the rectum away from the prostate by an average of 12mm and led to a significant reduction in rectal radiation doses, regardless of BMI.

Lipiodol as a Fiducial Marker for Image-Guided Radiation Therapy for Bladder Cancer

Purpose To evaluate Lipiodol as a liquid, radio-opaque fiducial marker for image-guided radiation therapy (IGRT) for bladder cancer.Materials and Methods Between 2011 and 2012, 5 clinical T2a-T3b N0 M0 stage II-III bladder cancer patients were treated with maximal transurethral resection of a bladder tumor (TURBT) and image-guided radiation therapy (IGRT) to 64.8 Gy in 36 fractions ± concurrent weekly cisplatin-based or gemcitabine chemotherapy. Ten to 15mL Lipiodol, using 0.5mL per injection, was injected into bladder submucosa circumferentially around the entire periphery of the tumor bed immediately following maximal TURBT. The authors looked at inter-observer variability regarding the size and location of the tumor bed (CTVboost) on computed tomography scans with versus without Lipiodol.Results Median follow-up was 18 months. Lipiodol was visible on every orthogonal two-dimensional kV portal image throughout the entire, 7-week course of IGRT. There was a trend towards improved inter-observer agreement on the CTVboost with Lipiodol (p = 0.06). In 2 of 5 patients, the tumor bed based upon Lipiodol extended outside a planning target volume that would have been treated with a radiation boost based upon a cystoscopy report and an enhanced computed tomography (CT) scan for staging. There was no toxicity attributable to Lipiodol.Conclusions Lipiodol constitutes a safe and effective fiducial marker that an urologist can use to demarcate a tumor bed immediately following maximal TURBT. Lipiodol decreases inter-observer variability in the definition of the extent and location of a tumor bed on a treatment planning CT scan for a radiation boost.

High-dose-rate brachytherapy with or without intensity modulated radiation therapy as salvage treatment for an isolated, gross local recurrence of prostate cancer post-prostatectomy.

PURPOSE: To evaluate the use of high-dose-rate (HDR) brachytherapy ± intensity modulated radiation therapy (IMRT) as salvage therapy for patients with an isolated, gross local recurrence of prostate cancer after radical prostatectomy. METHODS AND MATERIALS: Between October 2009 and May 2013, the authors treated six patients with salvage iridium-192 HDR brachytherapy ± IMRT for biopsy-proven, recurrent prostate cancer post-prostatectomy. In each patient, a pelvic MRI scan or CT scan demonstrated a nodule (range 1.6, 4.7 cm) in the prostate bed. Although prostate-specific antigen values were 0.2-9.5 ng/mL at the time of salvage brachytherapy, there was no pelvic adenopathy on CT or MRI scan, and a bone scan was negative in all cases. Five patients were treated with IMRT to 4500-5040 cGy in 25-28 fractions to the prostate bed followed by two 950 cGy HDR brachytherapy fractions separated by 1-2 weeks. A sixth patient underwent HDR brachytherapy monotherapy consisting of 3800 cGy in four fractions over 3 days. Toxicities were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Median followup was 9 months (range 3, 40 months). All six patients have been free of androgen deprivation therapy and have an undetectable prostate-specific antigen. One patient developed late Grade 2 urinary incontinence. There was no late grade ≥2 gastrointestinal toxicity. CONCLUSIONS: HDR brachytherapy ± IMRT is a safe and effective salvage therapy option for an isolated, gross local recurrence of prostate cancer after radical prostatectomy and merits further study.

High-dose-rate endorectal brachytherapy for locally advanced rectal cancer in previously irradiated patients.

PURPOSE: Preoperative high-dose-rate (HDR) endorectal brachytherapy is well tolerated among patients with locally advanced rectal cancer. However, these studies excluded patients who previously received pelvic radiation therapy (RT). Because a favorable toxicity profile has been published for HDR endorectal brachytherapy, we evaluated this technique in patients who have previously received pelvic irradiation. METHODS AND MATERIALS: We included patients who had received pelvic irradiation for a previous pelvic malignancy and later received preoperative HDR endorectal brachytherapy for rectal cancer. Brachytherapy was delivered to a total dose of 26 Gy in 4 consecutive daily 6.5 Gy fractions. RESULTS: We evaluated 10 patients who previously received pelvic external beam radiation therapy (EBRT) alone (n=6), EBRT and brachytherapy (n=2), or brachytherapy alone (n=2). The median interval between the initial course of RT and endorectal brachytherapy was approximately 11 years (range, 1-19 years). Two patients experienced a complete pathologic response while 1 patient had a near complete pathologic response. No acute grade ≥3 toxicity was observed. No intraoperative or postoperative surgical complications were observed. CONCLUSIONS: Preoperative HDR endorectal brachytherapy is an alternative to EBRT for patients with locally advanced rectal cancer who have previously received pelvic RT.