Long-term evolution of LI-RADS observations in HCV-related cirrhosis treated with direct-acting antivirals.

BACKGROUND & AIMS: The risk of progression of indeterminate observations to hepatocellular carcinoma (HCC) after direct-acting antivirals (DAA) is still undetermined. To assess whether DAA therapy changes the risk of progression of observations with low (LR-2), intermediate (LR-3) and high (LR-4) probability for HCC in cirrhotic patients and to identify predictors of progression. METHODS: This retrospective study included cirrhotic patients treated with DAA who achieved sustained virological response between 2015 and 2019. A total of 68 patients had pre-DAA indeterminate observations and at least six months CT/MRI follow-up before and after DAA. Two radiologists reviewed CT/MRI studies to categorize observations according to the LI-RADSv2018 and assess the evolution on subsequent follow-ups. Predictors of evolutions were evaluated by using the Cox proportional hazard model, Kaplan-Meier method and log-rank test. RESULTS: A total of 109 untreated observations were evaluated, including 31 (28.4%) LR-2, 67 (61.5%) LR-3 and 11 (10.1%) LR-4. During a median follow-up of 41 months, 17.4% and 13.3% of observations evolved to LR-5 or LR-M and LR-5, before and after DAA respectively (P = .428). There was no difference in rate of progression of neither LR-2 (P = 1.000), LR-3 (P = .833) or LR-4 (P = .505). At multivariate analysis, only initial LI-RADS category was an independent predictor of progression to LR-5 or LR-M for all observations (hazard ratio 6.75, P < .001), and of progression to LR-5 after DAA (hazard ratio 4.34, P = .047). CONCLUSIONS: DAA therapy does not increase progression of indeterminate observations to malignant categories. The initial LI-RADS category is an independent predictor of observations upgrade.

Patient-Informed Organ Dose Estimation in Clinical CT: Implementation and Effective Dose Assessment in 1048 Clinical Patients.

OBJECTIVE. The purpose of this study is to comprehensively implement a patient-informed organ dose monitoring framework for clinical CT and compare the effective dose (ED) according to the patient-informed organ dose with ED according to the dose-length product (DLP) in 1048 patients. MATERIALS AND METHODS. Organ doses for a given examination are computed by matching the topogram to a computational phantom from a library of anthropomorphic phantoms and scaling the fixed tube current dose coefficients by the examination volume CT dose index (CTDIvol) and the tube-current modulation using a previously validated convolution-based technique. In this study, the library was expanded to 58 adult, 56 pediatric, five pregnant, and 12 International Commission on Radiological Protection (ICRP) reference models, and the technique was extended to include multiple protocols, a bias correction, and uncertainty estimates. The method was implemented in a clinical monitoring system to estimate organ dose and organ dose-based ED for 647 abdomen-pelvis and 401 chest examinations, which were compared with DLP-based ED using a t test. RESULTS. For the majority of the organs, the maximum errors in organ dose estimation were 18% and 8%, averaged across all protocols, without and with bias correction, respectively. For the patient examinations, DLP-based ED was significantly different from organ dose-based ED by as much as 190.9% and 234.7% for chest and abdomen-pelvis scans, respectively (mean, 9.0% and 24.3%). The differences were statistically significant (p < .001) and exhibited overestimation for larger-sized patients and underestimation for smaller-sized patients. CONCLUSION. A patient-informed organ dose estimation framework was comprehensively implemented applicable to clinical imaging of adult, pediatric, and pregnant patients. Compared with organ dose-based ED, DLP-based ED may overestimate effective dose for larger-sized patients and underestimate it for smaller-sized patients.

Risk of erectile dysfunction after modern radiotherapy for intact prostate cancer.

BACKGROUND: Erectile dysfunction (ED) is a prevalent side effect of prostate cancer treatment. We hypothesized that the previously reported rates of ED may have improved with the advent of modern technology. The purpose of this project was to evaluate modern external beam radiotherapy and brachytherapy techniques to determine the incidence of radiotherapy (RT) induced ED. METHODS: A systematic review of the literature published between January 2002 and December 2018 was performed to obtain patient reported rates of ED after definitive external beam radiotherapy, ultrafractionated stereotactic radiotherapy, and brachytherapy (BT) to the prostate in men who were potent prior to RT. Univariate and multivariate analyses of radiation dose, treatment strategy, and length of follow-up were analyzed to ascertain their relationship with RT-induced ED. RESULTS: Of 890 articles reviewed, 24 met inclusion criteria, providing data from 2714 patients. Diminished erectile function status post RT was common and similar across all studies. The median increase in men reporting ED was 17%, 26%, 23%, and 23%, 3DCRT, IMRT, low dose rate BT, and SBRT, respectively, at 2-year median follow-up. CONCLUSION: ED is a common side effect of RT. Risk of post-RT ED is similar for both LDR brachytherapy and external beam RT with advanced prostate targeting and penile-bulb sparing techniques utilized in modern RT techniques.

Early 18F-FDG-PET Response During Radiation Therapy for HPV-Related Oropharyngeal Cancer May Predict Disease Recurrence.

PURPOSE: Early indication of treatment outcome may guide therapeutic de-escalation strategies in patients with human papillomavirus (HPV)-related oropharyngeal cancer (OPC). This study investigated the relationships between tumor volume and 18F-fluorodeoxyglucose positron emission tomography (PET) parameters before and during definitive radiation therapy with treatment outcomes. METHODS AND MATERIALS: Patients undergoing definitive (chemo)radiation for HPV-related/p16-positive OPC were prospectively enrolled on an institutional review board-approved study. 18F-fluorodeoxyglucose PET/computed tomography scans were performed at simulation and after 2 weeks at a dose of ∼20 Gy. Tumor volume and standardized uptake value (SUV) characteristics were measured. SUV was normalized to blood pool uptake. Tumor volume and PET parameters associated with recurrence were identified through recursive partitioning (RPART). Recurrence-free survival (RFS) and overall survival (OS) curves between RPART-identified cohorts were estimated using the Kaplan-Meier method, and Cox models were used to estimate the hazard ratios (HRs). RESULTS: From 2012 to 2016, 62 patients with HPV-related OPC were enrolled. Median follow-up was 4.4 years. RPART identified patients with intratreatment SUVmax (normalized to blood pool SUVmean) <6.7 or SUVmax (normalized to blood pool SUVmean) ≥6.7 with intratreatment SUV40% ≥2.75 as less likely to recur. For identified subgroups, results of Cox models showed unadjusted HRs for RFS and OS (more likely to recur vs less likely) of 7.33 (90% confidence interval [CI], 2.97-18.12) and 6.09 (90% CI, 2.22-16.71), respectively, and adjusted HRs of 6.57 (90% CI, 2.53-17.05) and 5.61 (90% CI, 1.90-16.54) for RFS and OS, respectively. CONCLUSIONS: PET parameters after 2 weeks of definitive radiation therapy for HPV-related OPC are associated with RFS and OS, thus potentially informing an adaptive treatment approach.

Utilization of Lung Cancer Screening in the Medicare Fee-for-Service Population.

BACKGROUND: A number of organizations, including the US Preventive Services Task Force (USPSTF), recommend lung cancer screening (LCS) with low-dose CT (LDCT) imaging for high-risk current and former smokers. In 2015, Medicare issued a decision to cover LCS as a preventive health benefit; however, utilization by the Medicare population has not been thoroughly examined. RESEARCH QUESTION: Our objective was to evaluate the early use of LCS in the Medicare fee-for-service (FFS) population and determine the relationship(s) among beneficiary sociodemographic characteristics, geographic location, and use. STUDY DESIGN AND METHODS: This cross-sectional observational study used 100% Medicare FFS claims files for Medicare beneficiaries receiving LCS between January 1, 2016 and December 31, 2016. We estimated the LCS-eligible Medicare population using population and smoking data from the US Census Bureau and Centers for Disease Control and Prevention. We assessed variation in LCS rates by beneficiary characteristics and geography, using univariate and multivariate regression, the latter also including how interactions between geographic location and race/ethnicity influence screening. RESULTS: A total of 103,892 Medicare FFS beneficiaries received LCS in 2016, comprising 4.1% (95% CI, 3.9%-4.3%) of the estimated LCS-eligible Medicare population. Accounting for the interactions between race/ethnicity and US region, nonwhite (black, Hispanic) beneficiaries in all US regions were screened with lower frequency than white beneficiaries (P < .001). Screening rates in the Northeast were significantly higher than in other regions (adjusted rate ratio [95% CI] of Northeast relative to South: 1.83 [1.36-2.46]). INTERPRETATION: The early adoption of LCS among Medicare beneficiaries was low. Our results suggest geographic and racial disparities in screening use, with populations in the South and those of nonwhite race/ethnicity being screened with lower frequency. Further work is needed to improve LCS uptake and ensure consistent use by all at-risk populations.

Hepatobiliary phase hypointensity predicts progression to hepatocellular carcinoma for intermediate-high risk observations, but not time to progression.

PURPOSE: To determine whether hepatobiliary phase hypointensity, enhancing "capsule" and size provide prognostic information regarding the risk of progression to hepatocellular carcinoma (HCC), as well as the time to progression, of intermediate to high risk observations ≥ 10 mm with arterial phase hyperenhancement (APHE). METHOD: This retrospective dual-institution study included 160 LR-3 and 26 LR-4 observations measuring more than 10 mm and having APHE in 136 patients (mean age [SD], 57 [11] years old). A composite reference standard of pathologic analysis and imaging follow-up was used. The prognostic performance of hepatobiliary phase hypointensity, enhancing "capsule" and size (cut-off: 20 mm) for the prediction of probability of progression to HCC and median time to progression to HCC was assessed and compared by means of Log-rank test, Cox-regression and Kaplan-Meier curves. RESULTS: 110 (59%) of 186 of observations progressed to HCC, 29.1% (32) progressed within 6 months, 60% (66) within 1 year and 84.5% (93) within 2 years. Hepatobiliary phase hypointensity was a significant predictor of progression to HCC (p < 0.0001, odds ratio: 20.62) but not of time to progression (p = 0.17). Median time to progression to HCC was 284 days [IQR: 266-363] and was shorter - though not significantly - for observations with enhancing "capsule" (118 days vs 301 days; p = 0.19). CONCLUSIONS: Hepatobiliary phase hypointensity is an independent predictor of progression to HCC in intermediate to high risk APHE observations ≥ 10 mm.

Liver Imaging Reporting and Data System (LI-RADS) v2018: diagnostic value of ancillary features favoring malignancy in hypervascular observations ≥ 10 mm at intermediate (LR-3) and high probability (LR-4) for hepatocellular carcinoma.

OBJECTIVE: This study was conducted in order to assess the diagnostic accuracy of LI-RADS v2018 ancillary features (AFs) favoring malignancy applied to LR-3 and LR-4 observations on gadoxetate-enhanced MRI. METHODS: In this retrospective dual-institution study, we included consecutive patients at high risk for hepatocellular carcinoma (HCC) imaged with gadoxetate disodium-enhanced MRI between 2009 and 2014 fulfilling the following criteria: (i) at least one LR-3 or LR-4 observation ≥ 10 mm; (ii) nonrim arterial phase hyperenhancement; and (iii) confirmation of benignity or malignancy by pathology or imaging follow-up. We compared the distribution of AFs between HCCs and benign observations and the diagnostic performance for the diagnosis of HCC using univariate and multivariate analyses. Significance was set at p value < 0.05. RESULTS: Two hundred five observations were selected in 155 patients (108 M, 47 F) including 167 (81.5%) LR-3 and 38 (18.5%) LR-4. There were 126 (61.5%) HCCs and 79 (28.5%) benign lesions. A significantly larger number of AFs favoring malignancy were found in LR-3 and LR-4 lesions that progressed to HCC compared to benign lesions (p < 0.001 and p = 0.003, respectively). The most common AFs favoring malignancy in HCCs were hepatobiliary phase (HBP) hypointensity (p < 0.001), transitional phase hypointensity (p < 0.001), and mild-moderate T2 hyperintensity (p < 0.001). Sensitivity and specificity of AFs for the diagnosis of HCC ranged 0.8-76.2% and 86.1-100%, respectively. HBP hypointensity yielded the highest sensitivity but also the lowest specificity and was the only AF remaining independently associated with the diagnosis of HCC at multivariate logistic regression analysis (OR 14.83, 95% CI 5.81-42.76, p < 0.001). CONCLUSIONS: Among all AFs, HBP hypointensity yields the highest sensitivity for the diagnosis of HCC. KEY POINTS: • LR-3 and LR-4 observations diagnosed as HCC have a significantly higher number of ancillary features favoring malignancy compared to observations proven to be benign. • The presence of three or more ancillary features favoring malignancy has a high specificity (96.2%) for the diagnosis of HCC. • Among all ancillary features favoring malignancy, hepatobiliary phase hypointensity yields the highest sensitivity, but also the lowest specificity for the diagnosis of HCC.

Assessing heterogeneity of treatment effect analyses in health-related cluster randomized trials: A systematic review.

BACKGROUND: Cluster-randomized trials (CRTs) are being increasingly used to test a range of interventions, including medical interventions commonly used in clinical practice. Policies created by the NIH and the Food and Drug Administration (FDA) require the reporting of demographics and the examination of demographic heterogeneity of treatment effect (HTE) for individually randomized trials. Little is known about how frequent demographics are reported and HTE analyses are conducted in CRTs. OBJECTIVES: We sought to understand the prevalence of HTE analyses and the statistical methods used to conduct them in CRTs focused on treating cardiovascular disease, cancer, and chronic lower respiratory diseases. Additionally, we also report on the proportion of CRTs that reported on baseline demographics of its populations and conducted demographic HTE analyses. DATA SOURCES: We searched PubMed and Embase for CRTs published between 1/1/2010 and 3/29/2016 that focused on treating the top 3 Center for Disease Control causes of death (cardiovascular disease, chronic lower respiratory disease, and cancer). Evidence Screening And Review: Of 1,682 unique titles, 117 abstracts were screened. After excluding 53 articles, we included 64 CRT publications and abstracted information on study characteristics and demographic information, statistical analysis, HTE analysis, and study quality. RESULTS: Age and sex were reported in greater than 95.3% of CRTs, while race and ethnicity were reported in only 20.3% of CRTs. HTE analyses were conducted in 28.1% (n = 18) of included CRTs and 77.8% (n = 12) were prespecified analyses. Four CRTs conducted a demographic subgroup analysis. Only 6/18 CRTs used interaction testing to determine whether HTE existed. CONCLUSIONS: Baseline demographic reporting was high for age and sex in CRTs, but was uncommon for race and ethnicity. HTE analyses were uncommon and was rare for demographic subgroups, which limits the ability to examine the extent of benefits or risks for treatments tested with CRT designs.

A Geospatial Analysis of Factors Affecting Access to CT Facilities: Implications for Lung Cancer Screening.

OBJECTIVE: The association between access to CT facilities for lung cancer screening and population characteristics is understudied. We aimed to determine the relationship between census tract-level socioeconomic characteristics (SEC) and driving distance to an ACR-accredited CT facility. METHODS: Census tract-level SEC were determined from the US Census Bureau. Distance to nearest ACR-accredited CT facility was derived at the census tract level. Census tract-level multivariable regression modeling was used to determine the relationship between driving distance to a CT facility and census tract SEC, including population density (a marker of rural versus urban), gender, race, insurance status or type, and education level. RESULTS: In an adjusted multivariable model, census tract-level population density was the greatest relative determinant of distance to a CT facility. Namely, rural census tracts had relatively longer distances to CT facilities than urban census tracts (P < .001). Census tracts with higher uninsured, Medicaid, undereducated (less

Development and Preliminary Evaluation of a Murine Model of Chronic Radiation-Induced Proctitis.

PURPOSE: Radiotherapy (RT) is commonly used to treat most pelvic malignancies. While treatment is often effective, curative radiation doses to the rectum can result in chronic radiation-induced proctitis, which is characterized by diarrhea, tenesmus, and/or rectal bleeding, recently termed pelvic radiation disease. An animal model of chronic radiation-induced proctitis would be useful to test both preventative and therapeutic strategies to limit this morbidity but has been elusive because of the high rodent mortality associated with acute bowel RT injury. The objective of this research was to develop a novel mouse model of chronic radiation-induced proctitis using advanced technology. METHODS AND MATERIALS: Using an X-RAD 225-Cx (Precision X-Ray) small animal irradiator, multiple plan configurations were evaluated for planning treatment volume and organ-at-risk avoidance to deliver a 15 Gy 3D conformal treatment plan. The final plan was verified by high resolution 3D dosimetry (PRESAGE/optical-CT), and delivered using a single arc. Mice were monitored for mortality for 250 days, followed by histopathological correlates including mucicarmine, Masson's trichrome, and fecal pellet length. RESULTS: Six beam arrangements were considered: single and parallel-opposed fields with whole-pelvis coverage, and collimated fields in parallel-opposed, 3-field, 4-field, and arc geometries. A collimated arc plan offered superior planning treatment volume coverage and organ-at-risk avoidance compared to whole-pelvis irradiation. Treatment verification with PRESAGE 3D dosimetry (Heuris Inc) showed >99% of voxels passing gamma analysis with 2%/2 mm criteria. Our treatment resulted in no acute mortality and 40% mortality at 250 days. Histopathological analysis showed increased mucous production and fibrosis of the irradiated colon, but no change in fecal pellet length. CONCLUSIONS: Our model was able to target successfully lower colon and rectum with lower mortality than other published models. This permitted measurement of late effects that recapitulate some features of rectal damage in humans.

Effectiveness of informational decision aids and a live donor financial assistance program on pursuit of live kidney transplants in African American hemodialysis patients.

BACKGROUND: African Americans have persistently poor access to living donor kidney transplants (LDKT). We conducted a small randomized trial to provide preliminary evidence of the effect of informational decision support and donor financial assistance interventions on African American hemodialysis patients' pursuit of LDKT. METHODS: Study participants were randomly assigned to receive (1) Usual Care; (2) the Providing Resources to Enhance African American Patients' Readiness to Make Decisions about Kidney Disease (PREPARED); or (3) PREPARED plus a living kidney donor financial assistance program. Our primary outcome was patients' actions to pursue LDKT (discussions with family, friends, or doctor; initiation or completion of the recipient LDKT medical evaluation; or identification of a donor). We also measured participants' attitudes, concerns, and perceptions of interventions' usefulness. RESULTS: Of 329 screened, 92 patients were eligible and randomized to Usual Care (n = 31), PREPARED (n = 30), or PREPARED plus financial assistance (n = 31). Most participants reported interventions helped their decision making about renal replacement treatments (62%). However there were no statistically significant improvements in LDKT actions among groups over 6 months. Further, no participants utilized the living donor financial assistance benefit. CONCLUSIONS: Findings suggest these interventions may need to be paired with personal support or navigation services to overcome key communication, logistical, and financial barriers to LDKT. TRIAL REGISTRATION: ClinicalTrials.gov [ NCT01439516 ] [August 31, 2011].

Application of a Novel Murine Ear Vein Model to Evaluate the Effects of a Vascular Radioprotectant on Radiation-Induced Vascular Permeability and Leukocyte Adhesion.

Vascular injury after radiation exposure contributes to multiple types of tissue injury through a cascade of events. Some of the earliest consequences of radiation damage include increased vascular permeability and promotion of inflammation, which is partially manifested by increased leukocyte-endothelial (L/E) interactions. We describe herein a novel intravital imaging method to evaluate L/E interactions, as a function of shear stress, and vascular permeability at multiple time points after local irradiation to the ear. This model permitted analysis of quiescent vasculature that was not perturbed by any surgical manipulation prior to imaging. To evaluate the effects of radiation on vascular integrity, fluorescent dextran was injected intravenously and its extravasation in the extravascular space surrounding the ear vasculature was measured at days 3 and 7 after 6 Gy irradiation. The vascular permeability rate increased approximately twofold at both days 3 and 7 postirradiation ( P < 0.05). Leukocyte rolling, which is indicative of L/E interactions, was significantly increased in mice at 24 h postirradiation compared to that of nonirradiated mice. To assess our model, as a means for assessing vascular radioprotectants, we treated additional cohorts of mice with a thrombopoietin mimetic, TPOm (RWJ-800088). In addition to stimulating platelet formation, thrombopoietin can protect vasculature after several forms of injury. Thus, we hypothesized that TPOm would reduce vascular permeability and L/E adhesion after localized irradiation to the ear vasculature of mice. If TPOm reduced these consequences of radiation, it would validate the utility of our intravital imaging method. TPOm reduced radiation-induced vascular leakage to control levels at day 7. Furthermore, L/E cell interactions were also reduced in irradiated mice treated with TPOm, compared with mice receiving irradiation alone, particularly at high shear stress ( P = 0.03, Kruskal-Wallis). We conclude that the ear model is useful for monitoring quiescent normal tissue vascular injury after radiation exposure. Furthermore, the application of TPOm, for preventing early inflammatory response created by damage to vascular endothelium, suggests that this drug may prove useful in reducing toxicities from radiotherapy, which damage microvasculature that critically important to tissue function.

Clinical Utility of Fetal Short-Lag Spatial Coherence Imaging.

In this study, we evaluate the clinical utility of fetal short-lag spatial coherence (SLSC) imaging. Previous work has documented significant improvements in image quality with fetal SLSC imaging as quantified by measurements of contrast and contrast-to-noise ratio (CNR). The objective of this study was to examine whether this improved technical efficacy is indicative of the clinical utility of SLSC imaging. Eighteen healthy volunteers in their first and second trimesters of pregnancy were scanned using a modified Siemens SC2000 clinical scanner. Raw channel data were acquired for routinely examined fetal organs and used to generate fully matched raw and post-processed harmonic B-mode and SLSC image sequences, which were subsequently optimized for dynamic range and other imaging parameters by a blinded sonographer. Optimized videos were reviewed in matched B-mode and SLSC pairs by three blinded clinicians who scored each video based on overall quality, target conspicuity and border definition. SLSC imaging was highly favored over conventional imaging with SLSC scoring equal to (28.2 ± 10.5%) or higher than (63.9 ± 12.9%) B-mode for video pairs across all examined structures and processing conditions. Multivariate modeling revealed that SLSC imaging is a significant predictor of improved image quality with p ≤ 0.002. Expert-user scores for image quality support the application of SLSC in fetal ultrasound imaging.

Interchangeability between real and three-dimensional simulated lung tumors in computed tomography: an interalgorithm volumetry study.

Using hybrid datasets consisting of patient-derived computed tomography (CT) images with digitally inserted computational tumors, we establish volumetric interchangeability between real and computational lung tumors in CT. Pathologically-confirmed malignancies from 30 thoracic patient cases from the RIDER database were modeled. Tumors were either isolated or attached to lung structures. Patient images were acquired on one of two CT scanner models (Lightspeed 16 or VCT; GE Healthcare) using standard chest protocol. Real tumors were segmented and used to inform the size and shape of simulated tumors. Simulated tumors developed in Duke Lesion Tool (Duke University) were inserted using a validated image-domain insertion program. Four readers performed volume measurements using three commercial segmentation tools. We compared the volume estimation performance of segmentation tools between real tumors in actual patient CT images and corresponding simulated tumors virtually inserted into the same patient images (i.e., hybrid datasets). Comparisons involved (1) direct assessment of measured volumes and the standard deviation between simulated and real tumors across readers and tools, respectively, (2) multivariate analysis, involving segmentation tools, readers, tumor shape, and attachment, and (3) effect of local tumor environment on volume measurement. Volume comparison showed consistent trends (9% volumetric difference) between real and simulated tumors across all segmentation tools, readers, shapes, and attachments. Across all cases, readers, and segmentation tools, an intraclass correlation coefficient = 0.99 indicates that simulated tumors correlated strongly with real tumors ( p = 0.95 ). In addition, the impact of the local tumor environment on tumor volume measurement was found to have a segmentation tool-related influence. Strong agreement between simulated tumors modeled in this study compared to their real counterparts suggests a high degree of similarity. This indicates that, volumetrically, simulated tumors embedded into patient CT data can serve as reasonable surrogates to real patient data.

Local complexity metrics to quantify the effect of anatomical noise on detectability of lung nodules in chest CT imaging.

The purpose of this study is to (1) develop metrics to characterize the regional anatomical complexity of the lungs, and (2) relate these metrics with lung nodule detection in chest CT. A free-scrolling reader-study with virtually inserted nodules (13 radiologists × 157 total nodules = 2041 responses) is used to characterize human detection performance. Metrics of complexity based on the local density and orientation of distracting vasculature are developed for two-dimensional (2-D) and three-dimensional (3-D) considerations of the image volume. Assessed characteristics included the distribution of 2-D/3-D vessel structures of differing orientation (dubbed "2-D/3-D and dot-like/line-like distractor indices"), contiguity of inserted nodules with local vasculature, mean local gray-level surrounding each nodule, the proportion of lung voxels to total voxels in each section, and 3-D distance of each nodule from the trachea bifurcation. A generalized linear mixed-effects statistical model is used to determine the influence of each these metrics on nodule detectability. In order of decreasing effect size: 3-D line-like distractor index, 2-D line-like distractor index, 2-D dot-like distractor index, local mean gray-level, contiguity with 2-D dots, lung area, and contiguity with 3-D lines all significantly affect detectability ( P < 0.05 ). These data demonstrate that local lung complexity degrades detection of lung nodules.

Differential response to exercise in claudin-low breast cancer.

Exposure to exercise following a breast cancer diagnosis is associated with reductions in the risk of recurrence. However, it is not known whether breast cancers within the same molecular-intrinsic subtype respond differently to exercise. Syngeneic mouse models of claudin-low breast cancer (i.e., EO771, 4TO7, and C3(1)SV40Tag-p16-luc) were allocated to a uniform endurance exercise treatment dose (forced treadmill exercise) or sham-exercise (stationary treadmill). Compared to sham-controls, endurance exercise treatment differentially affected tumor growth rate: 1- slowed (EO771), 2- accelerated (C3(1)SV40Tag-p16-luc), or 3- was not affected (4TO7). Differential sensitivity of the three tumor lines to exercise was paralleled by effects on intratumoral Ki-67, Hif1-α, and metabolic programming. Inhibition of Hif1-α synthesis by the cardiac glycoside, digoxin, completely abrogated exercise-accelerated tumor growth in C3(1)SV40Tag-p16-luc. These results suggest that intratumoral Hif1-α expression is an important determinant of claudin-low breast cancer adaptation to exercise treatment.

Optimizing window settings for improved presentation of virtual monoenergetic images in dual-energy computed tomography.

PURPOSE: Dual-energy computed tomography virtual monoenergetic imaging (VMI) at 40 keV exhibits superior contrast-to-noise ratio (CNR), although practicing radiologists do not consistently prefer it over VMI at 70 keV due to high perceivable noise. We hypothesize that the presentation of 40 keV VMI may be compromised using window settings (i.e., window-and-level values [W-L values]) designed for conventional single-energy CT. This study aimed to devise optimum window settings that reduce the apparent noise and utilize the high CNR of 40 keV VMI, in order to improve the conspicuity of hypervascular liver lesions. MATERIALS AND METHODS: Three W-L value adjustment methods were investigated to alter the presentation of 40 keV VMI. To harness the high CNR of 40 keV VMI, the methods were designed to achieve (a) liver histogram distribution, (b) lesion-to-liver contrast, or (c) liver background noise comparable to those perceived in 70 keV VMI. This IRB-approved study included 18 patient abdominal datasets reconstructed at 40 and 70 keV. For each patient, the W-L values were determined using the three methods. For each of the images with default or adjusted W-L values, the noise, contrast, and CNR were calculated in terms of both display space and native CT number (referred to as HU) space. An observer study was performed to compare the 40 keV images with the three adjusted W-L values, and 40 and 70 keV images with default W-L values in terms of noise, contrast, and diagnostic preference. A comparison was also made in terms of the applicability of using patient-specific or patient-averaged W-L values. RESULTS: Using the default W-L values, 40 keV VMI exhibited higher HU CNR than 70 keV VMI by 24.6 ± 14.9% (P < 0.001) but lower display CNR by 38.0 ± 16.4% (P < 0.001). Using adjusted W-L values, 40 keV images showed increased display CNR as compared to 70 keV images, by 21.2 ± 13.1%, 17.4 ± 13.6%, and 24.2 ± 15.9% (P < 0.001) for histogram-, noise-, and contrast equalization methods, respectively. The 40 keV images with all three W-L value adjustment methods showed improved perceived conspicuity (CNR) of liver presentation by 103-120% (P < 0.001), as compared to default W-L values. The qualitative observer study revealed that 40 keV images with noise- and histogram-equalized W-L values were the most preferred, followed by 40 keV images with contrast-equalized W-L values and 70 keV images with default W-L values. The 40 keV images with default W-L values were the least preferred. Patient-specific W-L values offered similar results to those of patient-averaged W-L values. CONCLUSION: The adjusted W-L values can significantly improve the perception of VMI dataset image quality by improving the actual display CNR.

Inhibition of the Continuum of Radiation-Induced Normal Tissue Injury by a Redox-Active Mn Porphyrin.

Normal tissue damage after head and neck radiotherapy involves a continuum of pathologic events to the mucosa, tongue and salivary glands. We examined the radioprotective effects of MnBuOE, a redox-active manganese porphyrin, at three stages of normal tissue damage: immediate (leukocyte endothelial cell [L/E] interactions), early (mucositis) and late (xerostomia and fibrosis) after treatment. In this study, mice received 0 or 9 Gy irradiation to the oral cavity and salivary glands ± MnBuOE treatment. Changes in leukocyte-endothelial cell interactions were measured 24 h postirradiation. At 11 days postirradiation, mucositis was assessed with a cathepsin-sensitive near-infrared optical probe. Stimulated saliva production was quantified at 11 weeks postirradiation. Finally, histological analyses were conducted to assess the extent of long-term effects in salivary glands at 12 weeks postirradiation. MnBuOE reduced oral mucositis, xerostomia and salivary gland fibrosis after irradiation. Additionally, although we have previously shown that MnBuOE does not interfere with tumor control at high doses when administered with radiation alone, most head and neck cancer patients will be treated with the combinations of radiotherapy and cisplatin. Therefore, we also evaluated whether MnBuOE would protect tumors against radiation and cisplatin using tumor growth delay as an endpoint. Using a range of radiation doses, we saw no evidence that MnBuOE protected tumors from radiation and cisplatin. We conclude that MnBuOE radioprotects normal tissue at both early and late time points, without compromising anti-tumor effects of radiation and cisplatin.

Variations in the functional visual field for detection of lung nodules on chest computed tomography: Impact of nodule size, distance, and local lung complexity.

PURPOSE: To explore the characteristics that impact lung nodule detection by peripheral vision when searching for lung nodules on chest CT-scans. METHODS: This study was approved by the local IRB and is HIPAA compliant. A simulated primary (1°) target mass (2 × 2 × 5 cm) was embedded into 5 cm thick subvolumes (SV) extracted from three unenhanced lung MDCT scans (64 row, 1.25 mm thickness, 0.7 mm increment). One of 30 solid, secondary nodules with either 3-4 mm and 5-8 mm diameters were embedded into 192 of 207 SVs. The secondary nodule was placed at a random depth within each SV, a transverse distance of 2.5, 5, 7.5, or 10 mm, and along one of eight rays cast every 45° from the center of the 1° mass. Video recordings of transverse paging in cranio-caudal direction were created for each SV (frame rate three sections/sec). Six radiologists observed each cine-loop once while gaze-tracking hardware assured that gaze was centered on the 1° mass. Each radiologist assigned a confidence rating (0-5) to the detection of a secondary nodule and indicated its location. Detection sensitivity was analyzed relative to secondary nodule size, transverse distance, radial orientation, and lung complexity. Lung complexity was characterized by the number of particles (connected pixels) and the sum of the area of all particles above a -500 HU threshold within regions of interest around the 1° mass and secondary nodule. RESULTS: Using a proportional odds logistic regression model and eliminating redundant predictors, models fit individually to each reader resulted in the following decreasing order of association based on greatest reduction in Akaike Information Criterion: secondary nodule diameter (6/6 readers, P < 0.001), distance from central mass (6/6 readers, P < 0.001), lung complexity particle count (5/6 readers, P = 0.05), and lung complexity particle area (3/6 readers, P = 0.03). Substantial inter-reader differences in sensitivity to decreasing nodule diameter, distance, and complexity characteristics were observed. CONCLUSIONS: Of the investigated parameters, secondary nodule size, distance from the gaze center and lung complexity (particle number and area) significantly impact nodule detection with peripheral vision.