Effect of Transmit Beamforming on Clutter Levels in Transthoracic Echocardiography.

Transmit beamforming has a strong impact on several factors that govern image quality, field-of-view, and frame-rate in ultrasound imaging. For cardiac applications, the visualization of fine structures and the ability to track their motion is equally important. Consequently, beamforming choices for echocardiography aim to optimize these trade-offs. Acoustic clutter can dramatically impact image quality and degrade the diagnostic value of cardiac ultrasound imaging. Clutter levels, however, are closely tied to the choice of beamforming configuration. This study aims to quantify the impact of transmit beamforming on clutter levels under in vivo conditions. The performance of focused as well as plane wave transmit configurations in fundamental and harmonic modes is evaluated under matched conditions. Contrast between the cardiac chambers and the interventricular septum is used as a surrogate for the level of clutter in a given imaging scenario. Under in vivo conditions, contrast was found to improve incrementally across the four beamforming configurations in the following order: fundamental-plane, fundamental-focused, harmonic-plane, and harmonic-focused. Using the fundamental-focused configuration as a reference, the harmonic-plane and harmonic-focused cases showed improvements in median contrast of 2.97 dB and 6.1 dB, respectively, while the fundamental-plane case showed a contrast deterioration of 1.23 dB. Contrast was also found to vary systematically as a function of imaging depth. Median contrast for the right ventricle (shallow chamber) was measured to be 2.96 dB lower than that in the left ventricle (deep chamber).

Effect of Radiation Dose Reduction and Reconstruction Algorithm on Image Noise, Contrast, Resolution, and Detectability of Subtle Hypoattenuating Liver Lesions at Multidetector CT: Filtered Back Projection versus a Commercial Model-based Iterative Reconstruction Algorithm.

Purpose To determine the effect of radiation dose and iterative reconstruction (IR) on noise, contrast, resolution, and observer-based detectability of subtle hypoattenuating liver lesions and to estimate the dose reduction potential of the IR algorithm in question. Materials and Methods This prospective, single-center, HIPAA-compliant study was approved by the institutional review board. A dual-source computed tomography (CT) system was used to reconstruct CT projection data from 21 patients into six radiation dose levels (12.5%, 25%, 37.5%, 50%, 75%, and 100%) on the basis of two CT acquisitions. A series of virtual liver lesions (five per patient, 105 total, lesion-to-liver prereconstruction contrast of -15 HU, 12-mm diameter) were inserted into the raw CT projection data and images were reconstructed with filtered back projection (FBP) (B31f kernel) and sinogram-affirmed IR (SAFIRE) (I31f-5 kernel). Image noise (pixel standard deviation), lesion contrast (after reconstruction), lesion boundary sharpness (average normalized gradient at lesion boundary), and contrast-to-noise ratio (CNR) were compared. Next, a two-alternative forced choice perception experiment was performed (16 readers [six radiologists, 10 medical physicists]). A linear mixed-effects statistical model was used to compare detection accuracy between FBP and SAFIRE and to estimate the radiation dose reduction potential of SAFIRE. Results Compared with FBP, SAFIRE reduced noise by a mean of 53% ± 5, lesion contrast by 12% ± 4, and lesion sharpness by 13% ± 10 but increased CNR by 89% ± 19. Detection accuracy was 2% higher on average with SAFIRE than with FBP (P = .03), which translated into an estimated radiation dose reduction potential (±95% confidence interval) of 16% ± 13. Conclusion SAFIRE increases detectability at a given radiation dose (approximately 2% increase in detection accuracy) and allows for imaging at reduced radiation dose (16% ± 13), while maintaining low-contrast detectability of subtle hypoattenuating focal liver lesions. This estimated dose reduction is somewhat smaller than that suggested by past studies. © RSNA, 2017 Online supplemental material is available for this article.

Characterization of Small Focal Renal Lesions: Diagnostic Accuracy with Single-Phase Contrast-enhanced Dual-Energy CT with Material Attenuation Analysis Compared with Conventional Attenuation Measurements.

Purpose To determine whether single-phase contrast material-enhanced dual-energy material attenuation analysis improves the characterization of small (1-4 cm) renal lesions compared with conventional attenuation measurements by using histopathologic analysis and follow-up imaging as the clinical reference standards. Materials and Methods In this retrospective, HIPAA-compliant, institutional review board-approved study, 136 consecutive patients (95 men and 41 women; mean age, 54 years) with 144 renal lesions (111 benign, 33 malignant) measuring 1-4 cm underwent single-energy unenhanced and contrast-enhanced dual-energy computed tomography (CT) of the abdomen. For each renal lesion, attenuation measurements were obtained; attenuation change of greater than or equal to 15 HU was considered evidence of enhancement. Dual-energy attenuation measurements were also obtained by using iodine-water, water-iodine, calcium-water, and water-calcium material basis pairs. Mean lesion attenuation values and material densities were compared between benign and malignant renal lesions by using the two-sample t test. Diagnostic accuracy of attenuation measurements and dual-energy material densities was assessed and validated by using 10-fold cross-validation to limit the effect of optimistic bias. Results By using cross-validated optimal thresholds at 100% sensitivity, iodine-water material attenuation images significantly improved specificity for differentiating between benign and malignant renal lesions compared with conventional enhancement measurements (93% [103 of 111]; 95% confidence interval: 86%, 97%; vs 81% [90 of 111]; 95% confidence interval: 73%, 88%) (P = .02). Sensitivity with iodine-water and calcium-water material attenuation images was also higher than that with conventional enhancement measurements, although the difference was not statistically significant. Conclusion Contrast-enhanced dual-energy CT with material attenuation analysis improves specificity for characterization of small (1-4 cm) renal lesions compared with conventional attenuation measurements. © RSNA, 2017 Online supplemental material is available for this article.

Classification of polyhedral shapes from individual anisotropically resolved cryo-electron tomography reconstructions.

BACKGROUND: Cryo-electron tomography (cryo-ET) enables 3D imaging of macromolecular structures. Reconstructed cryo-ET images have a "missing wedge" of data loss due to limitations in rotation of the mounting stage. Most current approaches for structure determination improve cryo-ET resolution either by some form of sub-tomogram averaging or template matching, respectively precluding detection of shapes that vary across objects or are a priori unknown. Various macromolecular structures possess polyhedral structure. We propose a classification method for polyhedral shapes from incomplete individual cryo-ET reconstructions, based on topological features of an extracted polyhedral graph (PG). RESULTS: We outline a pipeline for extracting PG from 3-D cryo-ET reconstructions. For classification, we construct a reference library of regular polyhedra. Using geometric simulation, we construct a non-parametric estimate of the distribution of possible incomplete PGs. In studies with simulated data, a Bayes classifier constructed using these distributions has an average test set misclassification error of < 5 % with upto 30 % of the object missing, suggesting accurate polyhedral shape classification is possible from individual incomplete cryo-ET reconstructions. We also demonstrate how the method can be made robust to mis-specification of the PG using an SVM based classifier. The methodology is applied to cryo-ET reconstructions of 30 micro-compartments isolated from E. coli bacteria. CONCLUSIONS: The predicted shapes aren't unique, but all belong to the non-symmetric Johnson solid family, illustrating the potential of this approach to study variation in polyhedral macromolecular structures.

Quantitative Features of Liver Lesions, Lung Nodules, and Renal Stones at Multi-Detector Row CT Examinations: Dependency on Radiation Dose and Reconstruction Algorithm.

PURPOSE: To determine if radiation dose and reconstruction algorithm affect the computer-based extraction and analysis of quantitative imaging features in lung nodules, liver lesions, and renal stones at multi-detector row computed tomography (CT). MATERIALS AND METHODS: Retrospective analysis of data from a prospective, multicenter, HIPAA-compliant, institutional review board-approved clinical trial was performed by extracting 23 quantitative imaging features (size, shape, attenuation, edge sharpness, pixel value distribution, and texture) of lesions on multi-detector row CT images of 20 adult patients (14 men, six women; mean age, 63 years; range, 38-72 years) referred for known or suspected focal liver lesions, lung nodules, or kidney stones. Data were acquired between September 2011 and April 2012. All multi-detector row CT scans were performed at two different radiation dose levels; images were reconstructed with filtered back projection, adaptive statistical iterative reconstruction, and model-based iterative reconstruction (MBIR) algorithms. A linear mixed-effects model was used to assess the effect of radiation dose and reconstruction algorithm on extracted features. RESULTS: Among the 23 imaging features assessed, radiation dose had a significant effect on five, three, and four of the features for liver lesions, lung nodules, and renal stones, respectively (P < .002 for all comparisons). Adaptive statistical iterative reconstruction had a significant effect on three, one, and one of the features for liver lesions, lung nodules, and renal stones, respectively (P < .002 for all comparisons). MBIR reconstruction had a significant effect on nine, 11, and 15 of the features for liver lesions, lung nodules, and renal stones, respectively (P < .002 for all comparisons). Of note, the measured size of lung nodules and renal stones with MBIR was significantly different than those for the other two algorithms (P < .002 for all comparisons). Although lesion texture was significantly affected by the reconstruction algorithm used (average of 3.33 features affected by MBIR throughout lesion types; P < .002, for all comparisons), no significant effect of the radiation dose setting was observed for all but one of the texture features (P = .002-.998). CONCLUSION: Radiation dose settings and reconstruction algorithms affect the extraction and analysis of quantitative imaging features in lesions at multi-detector row CT.

Virtual Monochromatic Images from Dual-Energy Multidetector CT: Variance in CT Numbers from the Same Lesion between Single-Source Projection-based and Dual-Source Image-based Implementations.

PURPOSE: To determine the variance in virtual monochromatic computed tomography (CT) numbers from the same lesion, comparing the two clinically available dual-energy multidetector CT hardware implementations (single-source projection-based and dual-source image-based), in a phantom-based simulated abdominal environment. MATERIALS AND METHODS: This phantom-based study was exempt from institutional review board oversight. Polyethylene terephthalate spheres (15 and 18 mm) with two iodine-to-saline dilutions (0.8 and 1.2 mg of iodine per millilliter) were serially suspended in a cylindrical polypropylene bottle filled with diluted iodinated contrast material. The bottle was placed into a 36-cm-wide torso-shaped water phantom simulating the abdomen of a medium-sized patient. Dual-energy (80/140 kVp) and single-energy (100 and 120 kVp) scans were obtained with single-source and dual-source multidetector CT implementations. Virtual monochromatic images were reconstructed at energy levels of 40-140 keV (in 10-keV increments) in either the projection-space or image-space domain. A multivariate regression analysis approach was used to investigate the effect of energy level, lesion size, lesion iodine content, and implementation type on measured CT numbers. RESULTS: There were significant differences in the attenuation values measured in the simulated lesions with the single-source projection-based platform and the dual-source image-based implementation (P < .001 for all comparisons). The magnitude of these differences was greatest at lower monochromatic energy levels and at lower iodine concentrations (average difference at 40 keV: 25.7 HU; average difference at 140 keV: 7 HU). The monochromatic energy level and the lesion iodine concentration had a significant effect on the difference in the measured attenuation values between the two implementations, which indicates that the two imaging platforms respond differently to changes in investigated variables (P < .001 for all comparisons). CONCLUSION: There is a statistically significant variance in virtual monochromatic CT numbers from the same lesion examined with single-source projection-based and dual-source image-based implementations. The magnitude of the variance is a function of the selected energy level and the lesion iodine content.

Dual-energy multidetector CT for the characterization of incidental adrenal nodules: diagnostic performance of contrast-enhanced material density analysis.

PURPOSE: To determine whether contrast material-enhanced dual-energy multidetector computed tomography (CT) with material decomposition analysis allows differentiation of adrenal adenomas from nonadenomatous lesions and to compare findings with those of nonenhanced multidetector CT. MATERIALS AND METHODS: This retrospective HIPAA-compliant study was approved by the institutional review board of Duke University, with waiver of informed consent. Thirty-eight nonconsecutive patients (22 men and 16 women; mean age, 65 years) with 47 adrenal nodules underwent nonenhanced and contrast-enhanced dual-energy multidetector CT of the abdomen. For each adrenal nodule, nonenhanced attenuation values were recorded; dual-energy density measurements were obtained by using fat-iodine and fat-water material density basis pairs. Mean and median values of nonenhanced attenuation and material densities were compared between adenomas and nonadenomas by using the two-sample t test and Wilcoxon rank sum test, respectively. The diagnostic performance of nonenhanced multidetector CT and dual-energy material densities was assessed by setting the specificity for diagnosis of adenomas at 100%. RESULTS: Adenomas (lipid rich and lipid poor) displayed significantly different mean density values (in milligrams per cubic centimeter) than those of nonadenomas on fat-iodine (970.4 ± 17.2 vs 1012.3 ± 9.3), iodine-fat (2.5 ± 0.3 vs 4.5 ± 1.5), fat-water (-666.7 ± 154.8 vs -2141.8 ± 953.2), and water-fat (1628.4 ± 177.3 vs 3225 ± 986.1) images, respectively (P < .0001). For diagnosis of adenomas, dual-energy material density analysis showed a sensitivity of 96% (23 of 24 lesions) at a specificity of 100% (23 of 23 lesions), yielding significantly improved diagnostic performance compared with nonenhanced multidetector CT attenuation (sensitivity of 67% [16 of 24 lesions] at a specificity of 100% [23 of 23 lesions]) (P = .035). CONCLUSION: Contrast-enhanced dual-energy multidetector CT with material density analysis allows differentiation between adrenal adenomas and nonadenomas, reflecting an improved ability over nonenhanced multidetector CT for diagnosis of lipid-poor adenoma.

Characterizing search, recognition, and decision in the detection of lung nodules on CT scans: elucidation with eye tracking.

PURPOSE: To determine the effectiveness of radiologists' search, recognition, and acceptance of lung nodules on computed tomographic (CT) images by using eye tracking. MATERIALS AND METHODS: This study was performed with a protocol approved by the institutional review board. All study subjects provided informed consent, and all private health information was protected in accordance with HIPAA. A remote eye tracker was used to record time-varying gaze paths while 13 radiologists interpreted 40 lung CT images with an average of 3.9 synthetic nodules (5-mm diameter) embedded randomly in the lung parenchyma. The radiologists' gaze volumes ( GV gaze volume s) were defined as the portion of the lung parenchyma within 50 pixels (approximately 3 cm) of all gaze points. The fraction of the total lung volume encompassed within the GV gaze volume s, the fraction of lung nodules encompassed within each GV gaze volume (search effectiveness), the fraction of lung nodules within the GV gaze volume detected by the reader (recognition-acceptance effectiveness), and overall sensitivity of lung nodule detection were measured. RESULTS: Detected nodules were within 50 pixels of the nearest gaze point for 990 of 992 correct detections. On average, radiologists searched 26.7% of the lung parenchyma in 3 minutes and 16 seconds and encompassed between 86 and 143 of 157 nodules within their GV gaze volume s. Once encompassed within their GV gaze volume , the average sensitivity of nodule recognition and acceptance ranged from 47 of 100 nodules to 103 of 124 nodules (sensitivity, 0.47-0.82). Overall sensitivity ranged from 47 to 114 of 157 nodules (sensitivity, 0.30-0.73) and showed moderate correlation (r = 0.62, P = .02) with the fraction of lung volume searched. CONCLUSION: Relationships between reader search, recognition and acceptance, and overall lung nodule detection rate can be studied with eye tracking. Radiologists appear to actively search less than half of the lung parenchyma, with substantial interreader variation in volume searched, fraction of nodules included within the search volume, sensitivity for nodules within the search volume, and overall detection rate.

The Alzheimer structural connectome: changes in cortical network topology with increased amyloid plaque burden.

PURPOSE: To evaluate differences in the structural connectome among patients with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer disease (AD) and to determine associations between the structural connectome and cortical amyloid deposition. MATERIALS AND METHODS: Patients enrolled in a multicenter biomarker study (Alzheimer's Disease Neuroimaging Initiative [ADNI] 2) who had both baseline diffusion-tensor (DT) and florbetapir positron emission tomography (PET) data at the time of data analyses in November 2012 were studied. All institutions received institutional review board approval. There were 102 patients in ADNI 2 who met criteria for analysis. Patients' T1-weighted images were automatically parcellated into cortical regions of interest. Standardized uptake value ratio (SUVr) was calculated from florbetapir PET images for composite cortical regions (frontal, cingulate, parietal, and temporal). Structural connectome graphs were created from DT images, and connectome topology was analyzed in each region by using graph theoretical metrics. Analysis of variance of structural connectome metrics and florbetapir SUVr across diagnostic group was performed. Linear mixed-effects models were fit to analyze the effect of florbetapir SUVr on structural connectome metrics. RESULTS: Diagnostic group (NC, MCI, or AD) was associated with changes in weighted structural connectome metrics, with decreases from the NC group to the MCI group to the AD group shown for (a) strength in the bilateral frontal, right parietal, and bilateral temporal regions (P < .05); (b) weighted local efficiency in the left temporal region (P < .05); and (c) weighted clustering coefficient in the bilateral frontal and left temporal regions (P < .05). Increased cortical florbetapir SUVr was associated with decreases in weighted structural connectome metrics; namely, strength (P = .00001), weighted local efficiency (P = .00001), and weighted clustering coefficient (P = .0006), independent of brain region. For every 0.1-unit increase in florbetapir SUVr, there was a 14% decrease in strength, an 11% decrease in weighted local efficiency, and a 9% decrease in weighted clustering coefficient, regardless of the analyzed cortical region or, in the case of weighted local efficiency and clustering coefficient, diagnostic group. CONCLUSION: Increased amyloid burden, as measured with florbetapir PET imaging, is related to changes in the topology of the large-scale cortical network architecture of the brain, as measured with graph theoretical metrics of DTI tractography, even in the preclinical stages of AD. Online supplemental material is available for this article.

Bone marrow biopsy: RNA isolation with expression profiling in men with metastatic castration-resistant prostate cancer--factors affecting diagnostic success.

PURPOSE: To determine the rate at which computed tomographically guided pelvic percutaneous bone biopsy in men with metastatic castration-resistant prostate cancer (mCRPC) yields adequate tissue for genomic profiling and to identify issues likely to affect diagnostic yields. MATERIALS AND METHODS: This study was institutional review board approved, and written informed consent was obtained. In a phase II trial assessing response to everolimus, 31 men with mCRPC underwent 54 biopsy procedures (eight men before and 23 men both before and during treatment). Variables assessed were lesion location (iliac wing adjacent to sacroiliac joint, iliac wing anterior and/or superior to sacroiliac joint, sacrum, and remainder of pelvis), mean lesion attenuation, subjective lesion attenuation (purely sclerotic vs mixed), central versus peripheral lesion sampling, lesion size, core number, and use of zoledronic acid for more than 1 year. RESULTS: Of 54 biopsy procedures, 21 (39%) yielded adequate tissue for RNA isolation and genomic profiling. Three of four sacral biopsies were adequate. Biopsies of the ilium adjacent to the sacroiliac joints were more likely adequate than those from elsewhere in the ilium (48% vs 28%, respectively). All five biopsies performed in other pelvic locations yielded inadequate tissue for RNA isolation. Mean attenuation of lesions with inadequate tissue was 172 HU greater than those with adequate tissue (621.1 HU ± 166 vs 449 HU ± 221, respectively; P = .002). Use of zoledronic acid, peripheral sampling, core number, and lesion size affected yields, but the differences were not statistically significant. Histologic examination with hematoxylin-eosin staining showed that results of 36 (67%) biopsies were positive for cancer; only mean attenuation differences were significant (707 HU ± 144 vs 473 HU ± 191, negative vs positive, respectively; P < .001). CONCLUSION: In men with mCRPC, percutaneous sampling of osseous metastases for genomic profiling is possible, but use of zoledronic acid for more than 1 year may reduce the yield of adequate tissue for RNA isolation. Sampling large low-attenuating lesions at their periphery maximizes yield.

A comparison of least squares and conditional maximum likelihood estimators under volume endpoint censoring in tumor growth experiments.

Measurements in tumor growth experiments are stopped once the tumor volume exceeds a preset threshold: a mechanism we term volume endpoint censoring. We argue that this type of censoring is informative. Further, least squares (LS) parameter estimates are shown to suffer a bias in a general parametric model for tumor growth with an independent and identically distributed measurement error, both theoretically and in simulation experiments. In a linear growth model, the magnitude of bias in the LS growth rate estimate increases with the growth rate and the standard deviation of measurement error. We propose a conditional maximum likelihood estimation procedure, which is shown both theoretically and in simulation experiments to yield approximately unbiased parameter estimates in linear and quadratic growth models. Both LS and maximum likelihood estimators have similar variance characteristics. In simulation studies, these properties appear to extend to the case of moderately dependent measurement error. The methodology is illustrated by application to a tumor growth study for an ovarian cancer cell line.

Analysis of multi-arm tumor growth trials in xenograft animals using phase change adaptive piecewise quadratic models.

Xenograft trials allow tumor growth in human cell lines to be monitored over time in a mouse model. We consider the problem of inferring the effect of treatment combinations on tumor growth. A piecewise quadratic model with flexible phase change locations is proposed to model the effect of change in therapy over time. Each piece represents a growth phase, with phase changes in response to change in treatment. Piecewise slopes represent phase-specific (log) linear growth rates and curvature parameters represent departure from linear growth. Trial data are analyzed in two stages: (i) subject-specific curve fitting (ii) analysis of slope and curvature estimates across subjects. A least-squares approach with penalty for phase change point location is proposed for curve fitting. In simulation studies, the method is shown to give consistent estimates of slope and curvature parameters under independent and AR (1) measurement error. The piecewise quadratic model is shown to give excellent fit (median R(2)=0.98) to growth data from a six armed xenograft trial on a lung carcinoma cell line.

Impact of Colorized Display of Mammograms on Lesion Detection.

OBJECTIVE: To assess the effect of the colorized display of digital mammograms on observer detection of subtle breast lesions. METHODS: Three separate observer studies compared detection performance using grayscale versus color display of 1) low-contrast mass-like objects in a standardized mammography phantom; 2) simulated microcalcifications in a background of normal breast parenchyma; and 3) standard-of-care clinical digital mammograms with subtle calcifications and masses. Colorization of the images was done by displaying each image pixel in blue, green, and red hues, or gray, maintaining DICOM-calibrated luminance scale and consistent luminance range. For the simulated calcifications and clinical mammogram studies, comparison of detection rates was computed using McNemar's test for paired differences. RESULTS: For the phantom study, mass-like object detection was significantly better using a green colormap than grayscale (73.3% vs 70.8%, P = .009), with no significant improvement using blue or red colormaps (72.6% and 72.5%, respectively). For simulated microcalcifications, no significant difference was noted in detection using the green colormap, as compared with grayscale. For clinical digital screening mammograms, no significant difference was noted between gray and green colormaps for detection of microcalcifications. Green color display, however, resulted in decreased sensitivity for detection of subtle masses (63% vs 69%, P = .03). CONCLUSION: Although modest improvement was demonstrated for a detection task using colorized display of a standard mammography phantom, no significant improvement was demonstrated using a color display for a simulated clinical detection task, and actual clinical performance was worse for colorized display of mammograms in comparison to standard grayscale display.

Impact of baseline covariate imbalance on bias in treatment effect estimation in cluster randomized trials: Race as an example.

Individual-level baseline covariate imbalance could happen more frequently in cluster randomized trials, and may influence the observed treatment effect. Using computer and real-data simulations, this paper quantifies the extent and impact of covariate imbalance on the estimated treatment effect for both continuous and binary outcomes, and relates it to the degree of imbalance for different numbers of clusters, cluster sizes, and covariate intraclass correlation coefficients. We focused on the impact of race as a covariate, given the emphasis of regulatory and funding bodies on understanding the influence of demographic characteristics on treatment effectiveness. We found that bias in the treatment effect is proportional to both the degree of baseline covariate imbalance and the covariate effect size. Larger numbers of clusters result in lower covariate imbalance, and increasing cluster size is less effective in reducing imbalance compared to increasing the number of clusters. Models adjusted for important baseline confounders are superior to unadjusted models for minimizing bias in both model-based simulations and an innovative simulation based on real clinical trial data. Higher outcome intraclass correlation coefficients did not affect bias but resulted in greater variance in treatment estimates.

Retrospective analysis of safety and efficacy of anti-PD-1 therapy and radiation therapy in advanced melanoma: A bi-institutional study.

BACKGROUND AND PURPOSE: Antibodies against programmed cell death protein 1 (PD-1) are standard treatments for advanced melanoma. Palliative radiation therapy (RT) is commonly administered for this disease. Safety and optimal timing for this combination for melanoma has not been established. MATERIALS AND METHODS: In this retrospective cohort study, records for melanoma patients who received anti-PD-1 therapy at Duke University or Emory University (1/1/2013-12/30/2015) were reviewed. Patients were categorized by receipt of RT and RT timing relative to anti-PD-1. RESULTS: 151 patients received anti-PD-1 therapy. Median follow-up was 12.9 months. Patients receiving RT (n = 85) had worse baseline prognostic factors than patients without RT (n = 66). One-year overall survival (OS) was lower for RT patients than patients without RT (66%, 95% CI: 55-77% vs 83%, 95% CI: 73-92%). One-year OS was 61% for patients receiving RT before anti-PD-1 (95% CI: 46-76%), 78% for RT during anti-PD-1 (95% CI: 60-95%), and 58% for RT after anti-PD-1 (95% CI: 26-89%). On Cox regression, OS for patients without RT did not differ significantly from patients receiving RT during anti-PD-1 (HR 1.07, 95% CI: 0.41-2.84) or RT before anti-PD-1 (HR 0.56, 95% CI: 0.21-1.45). RT and anti-PD-1 therapy administered within 6 weeks of each other was well tolerated. CONCLUSION: RT can be safely administered with anti-PD-1 therapy. Despite worse baseline prognostic characteristics for patients receiving RT, OS was similar for patients receiving concurrent RT with anti-PD-1 therapy compared to patients receiving anti-PD-1 therapy alone.

Branch order regression for modeling brain vasculature.

PURPOSE: Many biological objects, including neuronal dendrites, blood vasculature, airways, phylogenetic trees, produce tree structured data. Current methods of analysis either ignore the complex structure of trees or use distance-based methods which limit the scope of multivariate modeling. METHODS: We propose a branching process model which enables analysis of both the branching structure and associated properties. Our novel parametrization preserves an important aspect of tree structure, namely its branch order. The model is amenable to standard methods of analysis, like generalized linear/additive models. RESULTS: The model fit the distribution of the observed data quite well when applied to a collection of 98 brain artery systems. The estimated probability of branching decreases log linearly with branch order. Likewise, the average diameter of arteries decreases, while average length increases with branch order. Frontal arterial branches are on average longer and thinner than those in the back at equivalent branch orders. A mechanistic arterial branching model based on Poiseuille's blood flow law, which uses vessel length and diameter information, fit the observed branching structure significantly better. This model is further improved by including branch order, suggesting viscoelastic flow impacts branching in narrower vessels. CONCLUSION: After adjustment for branch order, brain arterial branching probabilities decreased significantly with age and length, but increased with diameter. Arteries become thicker and branch less frequently with increasing age, but the age effect decreases with branch order.

Effect of Tumor Size on Risk of Metastatic Disease and Survival for Thyroid Cancer: Implications for Biopsy Guidelines.

BACKGROUND: In many risk-stratification systems, the decision to biopsy thyroid nodules is determined by their sonographic features and size. Nevertheless, even low-suspicion nodules are often biopsied at small size thresholds because it is assumed that larger malignant nodules are associated with poorer outcomes. The aim of this study was to quantify the effect of thyroid cancer tumor size on survival and risk of T4 stage, nodal disease, and distant metastases. METHODS: The Surveillance, Epidemiology, and End Results 18 database was queried to obtain tumor size, staging information, and survival data for cases of differentiated thyroid cancer (DTC) and non-DTC reported between 2004 and 2014. Observed probabilities of tumor extent at diagnosis, including regional nodal disease and distant metastases, as a function of size and tumor histology were estimated for thyroid cancers measuring between 1 and 150 mm. A multivariate Cox regression model was used to describe all-cause mortality as a function of patient and tumor characteristics, and the functional dependence of mortality on size was computed. RESULTS: A total of 112,128 patients were analyzed, with 67% having thyroid cancers ≥1 cm, and 29% ≥ 2.5 cm. For DTC tumors <4 cm, the risk of local invasion, nodal metastases, or distant metastases was low, and there was no size threshold associated with a sharp rise in adverse outcomes. For DTC tumors <4 cm, the probability of distant metastases was <3%. Older age, male sex, non-DTC histology, T4 stage, and regional and distant metastatic disease increased the all-cause mortality rate. Tumor size did not increase the mortality rate above baseline until tumors were >2.5 cm. CONCLUSION: Increasing tumor size does not affect survival until a threshold of 2.5 cm. Since the dimension of nodules on ultrasound has been shown to be larger than their size at gross pathology, these findings suggest that recommended size thresholds to biopsy low-suspicion thyroid nodules can be increased.

A Lamina-Associated Domain Border Governs Nuclear Lamina Interactions, Transcription, and Recombination of the Tcrb Locus.

Tcrb locus V(D)J recombination is regulated by positioning at the nuclear periphery. Here, we used DamID to profile Tcrb locus interactions with the nuclear lamina at high resolution. We identified a lamina-associated domain (LAD) border composed of several CTCF-binding elements that segregates active non-LAD from inactive LAD regions of the locus. Deletion of the LAD border causes an enhancer-dependent spread of histone H3 lysine 27 acetylation from the active recombination center into recombination center-proximal LAD chromatin. This is associated with a disruption to nuclear lamina association, increased chromatin looping to the recombination center, and increased transcription and recombination of recombination center-proximal gene segments. Our results show that a LAD and LAD border are critical components of Tcrb locus gene regulation and suggest that LAD borders may generally function to constrain the activity of nearby enhancers.

Techniques for virtual lung nodule insertion: volumetric and morphometric comparison of projection-based and image-based methods for quantitative CT.

Virtual nodule insertion paves the way towards the development of standardized databases of hybrid CT images with known lesions. The purpose of this study was to assess three methods (an established and two newly developed techniques) for inserting virtual lung nodules into CT images. Assessment was done by comparing virtual nodule volume and shape to the CT-derived volume and shape of synthetic nodules. 24 synthetic nodules (three sizes, four morphologies, two repeats) were physically inserted into the lung cavity of an anthropomorphic chest phantom (KYOTO KAGAKU). The phantom was imaged with and without nodules on a commercial CT scanner (SOMATOM Definition Flash, Siemens) using a standard thoracic CT protocol at two dose levels (1.4 and 22 mGy CTDIvol). Raw projection data were saved and reconstructed with filtered back-projection and sinogram affirmed iterative reconstruction (SAFIRE, strength 5) at 0.6 mm slice thickness. Corresponding 3D idealized, virtual nodule models were co-registered with the CT images to determine each nodule's location and orientation. Virtual nodules were voxelized, partial volume corrected, and inserted into nodule-free CT data (accounting for system imaging physics) using two methods: projection-based Technique A, and image-based Technique B. Also a third Technique C based on cropping a region of interest from the acquired image of the real nodule and blending it into the nodule-free image was tested. Nodule volumes were measured using a commercial segmentation tool (iNtuition, TeraRecon, Inc.) and deformation was assessed using the Hausdorff distance. Nodule volumes and deformations were compared between the idealized, CT-derived and virtual nodules using a linear mixed effects regression model which utilized the mean, standard deviation, and coefficient of variation ([Formula: see text], [Formula: see text] and [Formula: see text] of the regional Hausdorff distance. Overall, there was a close concordance between the volumes of the CT-derived and virtual nodules. Percent differences between them were less than 3% for all insertion techniques and were not statistically significant in most cases. Correlation coefficient values were greater than 0.97. The deformation according to the Hausdorff distance was also similar between the CT-derived and virtual nodules with minimal statistical significance in the ([Formula: see text]) for Techniques A, B, and C. This study shows that both projection-based and image-based nodule insertion techniques yield realistic nodule renderings with statistical similarity to the synthetic nodules with respect to nodule volume and deformation. These techniques could be used to create a database of hybrid CT images containing nodules of known size, location and morphology.

Tcrd Rearrangement Redirects a Processive Tcra Recombination Program to Expand the Tcra Repertoire.

Adaptive immunity depends on diverse T cell receptor repertoires generated by variable, diversity, and joining (V[D]J) recombination. Here, we define the principles by which combinatorial diversity is generated in the murine Tcra repertoire. Tcra and Tcrd gene segments share the Tcra-Tcrd locus, with interspersed Vα and Vδ segments undergoing Vδ-Dδ-Jδ rearrangement in CD4-CD8- thymocytes and then multiple rounds of Vα-Jα rearrangement in CD4+CD8+ thymocytes. We document stepwise, highly coordinated proximal-to-distal progressions of Vα and Jα use on individual Tcra alleles, limiting combinatorial diversity. This behavior is supported by an extended chromatin conformation in CD4+CD8+ thymocytes, with only nearby Vα and Jα segments contacting each other. Tcrd rearrangements can use distal Vδ segments due to a contracted Tcra-Tcrd conformation in CD4-CD8- thymocytes. These rearrangements expand the Tcra repertoire by truncating the Vα array to permit otherwise disfavored Vα-Jα combinations. Therefore, recombination events at two developmental stages with distinct chromatin conformations synergize to promote Tcra repertoire diversity.