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OBJECTIVE: The objective of this study is to compare detection rates of extracapsular extension (ECE) of prostate cancer (PCa) using artificial intelligence (AI)-generated cancer maps versus MRI and conventional nomograms. MATERIALS AND METHODS: We retrospectively analysed data from 147 patients who received MRI-targeted biopsy and subsequent radical prostatectomy between September 2016 and May 2022. AI-based software cleared by the United States Food and Drug Administration (Unfold AI, Avenda Health) was used to map 3D cancer probability and estimate ECE risk. Conventional ECE predictors including MRI Likert scores, capsular contact length of MRI-visible lesions, PSMA T stage, Partin tables, and the PRedicting ExtraCapsular Extension nomogram were used for comparison.Postsurgical specimens were processed using whole-mount histopathology sectioning, and a genitourinary pathologist assessed each quadrant for ECE presence. ECE predictors were then evaluated on the patient (Unfold AI versus all comparators) and quadrant level (Unfold AI versus MRI Likert score). Receiver operator characteristic curves were generated and compared using DeLongs test. RESULTS: Unfold AI had a significantly higher area under the curve (AUC = 0.81) than other predictors for patient-level ECE prediction. Unfold AI achieved 68% sensitivity, 78% specificity, 71% positive predictive value, and 75% negative predictive value. At the quadrant level, Unfold AI exceeded the AUC of MRI Likert scores for posterior (0.89 versus 0.82, p = 0.003), anterior (0.84 versus 0.80, p = 0.34), and all quadrants (0.89 versus 0.82, p = 0.002). The false negative rate of Unfold AI was lower than MRI in both the anterior (-60%) and posterior prostate (-40%). CONCLUSIONS: Unfold AI accurately predicted ECE risk, outperforming conventional methodologies. It notably improved ECE prediction over MRI in posterior quadrants, with the potential to inform nerve-spare technique and prevent positive margins. By enhancing PCa staging and risk stratification, AI-based cancer mapping may lead to better oncological and functional outcomes for patients.

PURPOSE: Defining prostate cancer contours is a complex task, undermining the efficacy of interventions such as focal therapy. A multireader multicase study compared physicians' performance using artificial intelligence (AI) vs standard-of-care methods for tumor delineation. MATERIALS AND METHODS: Cases were interpreted by 7 urologists and 3 radiologists from 5 institutions with 2 to 23 years of experience. Each reader evaluated 50 prostatectomy cases retrospectively eligible for focal therapy. Each case included a T2-weighted MRI, contours of the prostate and region(s) of interest suspicious for cancer, and a biopsy report. First, readers defined cancer contours cognitively, manually delineating tumor boundaries to encapsulate all clinically significant disease. Then, after ≥ 4 weeks, readers contoured the same cases using AI software. Using tumor boundaries on whole-mount histopathology slides as ground truth, AI-assisted, cognitively-defined, and hemigland cancer contours were evaluated. Primary outcome measures were the accuracy and negative margin rate of cancer contours. All statistical analyses were performed using generalized estimating equations. RESULTS: The balanced accuracy (mean of voxel-wise sensitivity and specificity) of AI-assisted cancer contours (84.7%) was superior to cognitively-defined (67.2%) and hemigland contours (75.9%; P < .0001). Cognitively-defined cancer contours systematically underestimated cancer extent, with a negative margin rate of 1.6% compared to 72.8% for AI-assisted cancer contours (P < .0001). CONCLUSIONS: AI-assisted cancer contours reduce underestimation of prostate cancer extent, significantly improving contouring accuracy and negative margin rate achieved by physicians. This technology can potentially improve outcomes, as accurate contouring informs patient management strategy and underpins the oncologic efficacy of treatment.

PURPOSE: To evaluate the efficacy of combination therapy using transarterial chemoembolization with microwave ablation (MWA) therapy vs. MWA monotherapy for hepatocellular carcinomas (HCCs) >3 cm in size. METHODS: This two-arm retrospective observational study included patients with HCCs >3 cm who underwent either combination therapy (29 patients) or MWA monotherapy (35 patients) between 2014 and 2020. The treatment outcomes related to primary treatment efficacy, local tumor progression (LTP), tumor control rate, and overall survival were compared between each cohort. RESULTS: The technical success and primary efficacy were 96.56% and 100.00% in the combination therapy cohort, and 91.42% and 100.00% in the MWA cohort, respectively, over a mean follow-up period of 27.6 months. The 1- and 3-year rates of LTP-free survival were 78.57% and 69.56% in the combination therapy cohort, vs. 72.45% and 35.44% in the MWA cohort, respectively (P = 0.001). The overall progression-free survival was longer in the combination therapy cohort compared with the MWA cohort (median: 56.0 vs. 13.0 months; P = 0.017). With the incorporation of additional locoregional therapy, the overall survival rates were not significantly different, with 1- and 3-year overall survival rates of 100.00% and 88.71% in the combination therapy cohort and rates of 90.15% and 82.76% in the MWA cohort, respectively (P = 0.235). CONCLUSION: The combination therapy provided significantly longer upfront LTP-free survival in HCCs >3 cm when compared with the MWA treatment alone, albeit with similar local tumor control and overall survival rates when accounting for additional locoregional therapies.

Ionizing radiation (IR) can reprogram proteasome structure and function in cells and tissues. In this article, we show that IR can promote immunoproteasome synthesis with important implications for Ag processing and presentation and tumor immunity. Irradiation of a murine fibrosarcoma (FSA) induced dose-dependent de novo biosynthesis of the immunoproteasome subunits LMP7, LMP2, and Mecl-1, in concert with other changes in the Ag-presentation machinery (APM) essential for CD8+ T cell-mediated immunity, including enhanced expression of MHC class I (MHC-I), β2-microglobulin, transporters associated with Ag processing molecules, and their key transcriptional activator NOD-like receptor family CARD domain containing 5. In contrast, in another less immunogenic, murine fibrosarcoma (NFSA), LMP7 transcripts and expression of components of the immunoproteasome and the APM were muted after IR, which affected MHC-I expression and CD8+ T lymphocyte infiltration into NFSA tumors in vivo. Introduction of LMP7 into NFSA largely corrected these deficiencies, enhancing MHC-I expression and in vivo tumor immunogenicity. The immune adaptation in response to IR mirrored many aspects of the response to IFN-γ in coordinating the transcriptional MHC-I program, albeit with notable differences. Further investigations showed divergent upstream pathways in that, unlike IFN-γ, IR failed to activate STAT-1 in either FSA or NFSA cells while heavily relying on NF-κB activation. The IR-induced shift toward immunoproteasome production within a tumor indicates that proteasomal reprogramming is part of an integrated and dynamic tumor-host response that is specific to the stressor and the tumor and therefore is of clinical relevance for radiation oncology.

BACKGROUND: While image-derived predictors of intracranial aneurysm (IA) rupture have been well-explored, current understanding of IA growth is limited. Pulsatility index (PI) and wall shear stress pulsatility index (WSSPI) are important metrics measuring temporal hemodynamic instability. However, they have not been investigated in IA growth research. The present study seeks to verify reliable predictors of IA growth with comparative analyses of several important morphological and hemodynamic metrics between stable and growing cases among a group of unruptured IAs. METHODS: Using 3D images, vascular models of 16 stable and 20 growing cases were constructed and verified using Geodesic techniques. With an overall mean follow-up period of 25 months, cases exhibiting a 10% or higher increase in diameter were considered growing. Patient-specific, pulsatile simulations were performed, and hemodynamic calculations were computed at 5 important regions of each aneurysm (inflow artery, aneurysm neck, body, dome, and outflow artery). Index values were compared between growing and stable IAs using ANCOVA controlling for aneurysm diameter. Stepwise multiple logistic regression and ROC analyses were conducted to investigate predictive models of IA growth. RESULTS: Compared to stable IAs, growing IAs exhibited significantly higher intrasaccular PI, intrasaccular WSSPI, intrasaccular spatial flow rate deviation, and intrasaccular spatial wall shear stress (WSS) deviation. Stepwise logistic regression analysis revealed a significant predictive model involving PI at aneurysm body, WSSPI at inflow artery, and WSSPI at aneurysm body. CONCLUSIONS: Our results showed that high degree of hemodynamic variations within IAs is linked to growth, even after controlling for morphological parameters. Further, evaluation of PI in conjunction with WSSPI yielded a highly accurate predictive model of IA growth. Upon validation in future cohorts, these metrics may aid in early identification of IA growth and current understanding of IA remodeling mechanism.

ObjectivesTo investigate the usefulness of minimal ablative margin (MAM) control by intra-procedural contrast-enhanced CT (CECT) in microwave ablation (MWA) of liver tumors.MethodsA total of 334 consecutive liver tumors (240 hepatocellular carcinomas [HCCs] and 94 colorectal liver metastases [CRLMs]) in 172 patients treated with percutaneous MWA were retrospectively included. MAM of each tumor was assessed after expected ablation completion using intra-procedural CECT, allowing within-session additional ablation to any potentially insufficient margin. On immediate post-MWA MRI, complete ablation coverage of tumor and final MAM status were determined. The cumulative local tumor progression (LTP) rate was estimated by using the Kaplan-Meier method. To identify predictors of LTP, Cox regression analysis with a shared frailty model was performed.ResultsIntra-procedural CECT findings prompted additional ablation in 18.9% (63/334) of tumors. Final complete ablation coverage of tumor and sufficient MAM were determined by MRI to be achieved in 99.4% (332/334) and 77.5% (259/334), and their estimated 6-month, 1-year, and 2-year LTP rates were 3.2%, 7.5%, and 12.9%; and 1.0%, 2.1%, and 6.9%, respectively. Insufficient MAM on post-MWA MRI, perivascular tumor location, and tumor size (cm) were independent risk factors for LTP (hazard ratio = 14.4, 6.0, and 1.1, p < 0.001, p = 0.003, and p = 0.011, respectively), while subcapsular location and histology (HCC vs CRLM) were not.ConclusionsIn MWA of liver tumors, intra-procedural CECT monitoring of minimal ablative margin facilitates identification of potentially suboptimal margins and guides immediate additional intra-session ablation to maximize rates of margin-sufficient ablations, the latter being a highly predictive marker for excellent long-term local tumor control.Key points• In MWA of liver tumors, intra-procedural CECT can identify potentially suboptimal minimal ablative margin, leading to immediate additional ablation in a single treatment session. • Achieving a finally sufficient ablative margin through the MWA with intra-procedural CECT monitoring of minimal ablative margin results in excellent local tumor control.

OBJECTIVE: We aimed to investigate if the use of read-out segmented echoplanar imaging with additional two-dimensional navigator correction (Readout Segmentation of Long Variable Echo, RESOLVE) for acquiring prostate diffusion-weighted imaging (DWI) improves image quality, compared to single-shot echoplanar imaging (ss-EPI). METHODS: This single-center prospective study cohort included 162 males with suspected prostate cancer, who underwent 3 Tesla multiparametric MRI (3T-mpMRI). Two abdominal radiologists, blinded to the clinical information, separately reviewed each 3T-mpMRI study to rank geometrical distortion, degree of rectal distention, lesion conspicuity, and anatomic details delineation first on ss-EPI-DWI and later on RESOLVE-DWI using 5-point scales (1 = excellent, 5 = poor). The average of the ranking scores given by two readers was generated and used as the final score. RESULTS: There was good-to-excellent interreader agreement for scoring image quality parameters on both ss-EPI and RESOLVE. Geometrical distortion scores > 3 was seen in 12.3% (20/162) of ss-EPI images, with all having geometrical distortion score

BackgroundComputerized methodologies standardize the myocardial perfusion imaging (MPI) interpretation process.MethodsTo develop an automated relative perfusion quantitation approach for 18F-flurpiridaz, PET MPI studies from all phase III trial participants of 18F-flurpiridaz were divided into 3 groups. Count distributions were obtained in N = 40 normal patients undergoing pharmacological or exercise stress. Then, N = 90 additional studies were selected in a derivation group. Following receiver operating characteristic curve analysis, various standard deviations below the mean normal were used as cutoffs for significant CAD, and interobserver variability determined. Finally, diagnostic performance was compared between blinded visual readers and blinded derivations of automated relative quantitation in the remaining N = 548 validation patients.ResultsBoth approaches yielded comparable accuracies for the detection of global CAD, reaching 71% and 72% by visual reads, and 72% and 68% by automated relative quantitation, when using CAD ≥ 70% or ≥ 50% stenosis for significance, respectively. Similar results were observed when analyzing individual coronary territories. In both pharmacological and exercise stress, automated relative quantitation demonstrated significantly more interobserver agreement than visual reads.ConclusionsOur automated method of 18F-flurpiridaz relative perfusion analysis provides a quantitative, objective, and highly reproducible assessment of PET MPI in normal and CAD subjects undergoing either pharmacological or exercise stress.

ObjectivesThe main objective of this work was to detect novel biomarkers in breast cancer by spreading the MR spectra over two dimensions in multiple spatial locations using an accelerated 5D EP-COSI technology.MethodsThe 5D EP-COSI data were non-uniformly undersampled with an acceleration factor of 8 and reconstructed using group sparsity-based compressed sensing reconstruction. Different metabolite and lipid ratios were then quantified and statistically analyzed for significance. Linear discriminant models based on the quantified metabolite and lipid ratios were generated. Spectroscopic images of the quantified metabolite and lipid ratios were also reconstructed.ResultsThe 2D COSY spectra generated using the 5D EP-COSI technique showed differences among healthy, benign, and malignant tissues in terms of their mean values of metabolite and lipid ratios, especially the ratios of potential novel biomarkers based on unsaturated fatty acids, myo-inositol, and glycine. It is further shown the potential of choline and unsaturated lipid ratio maps, generated from the quantified COSY signals across multiple locations in the breast, to serve as complementary markers of malignancy that can be added to the multiparametric MR protocol. Discriminant models using metabolite and lipid ratios were found to be statistically significant for classifying benign and malignant tumor from healthy tissues.ConclusionsAccelerated 5D EP-COSI technique demonstrates the potential to detect novel biomarkers such as glycine, myo-inositol, and unsaturated fatty acids in addition to commonly reported choline in breast cancer, and facilitates metabolite and lipid ratio maps which have the potential to play a significant role in breast cancer detection.Advances in knowledgeThis study presents the first evaluation of a multidimensional MR spectroscopic imaging technique for the detection of potentially novel biomarkers based on glycine, myo-inositol, and unsaturated fatty acids, in addition to commonly reported choline. Spatial mapping of choline and unsaturated fatty acid ratios with respect to water in malignant and benign breast masses are also shown. These metabolic characteristics may serve as additional biomarkers for improving the diagnostic and therapeutic evaluation of breast cancer.

Background: Prostatic artery embolization (PAE) is an emerging treatment for benign prostatic hyperplasia (BPH). However, changes in public interest in PAE over time, especially relative to interest in alternative BPH treatments, are difficult to assess. The online tool for analysis of the popularity of top search queries (Google Trends; Alphabet Inc) provides a relative search volume (RSV) of specified keywords and insight about patterns of user searches.Purpose: The purpose of this study is to assess changes in public interest in PAE over time and compare them with changes in public interest in alternative BPH treatments as indicated by search queries.Material and Methods: Using Google Trends, we identified the RSV of specified keywords within search queries submitted between 2010 and 2019 in the United States. The RSVs of keywords with high search volume were identified and normalized on a scale of values from 0 to 100. Interest in PAE was assessed by comparing RSVs and trends of the keyword PAE as well as of other prostate-treatment-related keywords. Prostate embolization was a PAE-related, BPH-treatment-specific keyword with the highest average RSV. A linear regression analysis was performed to characterize annual search trends of the use of these keywords. Subsequently, the annual search trend of prostate embolization was compared with that of keywords related to transurethral resection of the prostate (TURP) and minimally invasive surgical treatments (MISTs).Results: The mean annual RSV of prostate embolization increased by 8.6 fold between 2010 and 2019. However, during this period, the mean RSV of the keywords transurethral resection of the prostate and TURP were 3.6 and 49.3 times higher, respectively (P

BackgroundHepatic arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT) patients are most commonly hepatic artery to hepatic venous shunts which can result in high-output heart failure. This condition can be debilitating and is a leading cause of liver transplantation in HHT patients. However, it is not known what characteristics can discriminate between asymptomatic patients and those who will develop heart failure symptoms.Results176 patients with HHT were evaluated with computed tomography angiography (CTA) between April 2004 and February 2019 at our HHT Center of Excellence. 63/176 (35.8%) patients were found to have hepatic AVMs on CTA. 18 of these patients were excluded because of the presence of another condition which could confound evaluation of heart failure symptoms. In the remaining 45 patients included in our cohort, 25/45 (55.6%) patients were classified as asymptomatic and 20/45 (44.4%) were classified as symptomatic, and these groups were compared. In symptomatic patients, mean common hepatic artery (CHA) diameter was significantly higher (11.1 versus 8.4 mm) and mean hemoglobin levels were significantly lower (10.7 vs 12.6 g/dL). A stepwise multiple logistic regression analysis demonstrated that both CHA diameter and hemoglobin level were independent predictors of heart failure symptoms with ORs of 2.554 (95% CI 1.372-4.754) and 0.489 (95% CI 0.299-0.799), respectively. The receiver operator characteristic (ROC) curve of our analysis demonstrated an AUC of 0.906 (95% CI 0.816-0.996), sensitivity 80.0% (95% CI 55.7-93.4%), and specificity 75.0% (95% CI 52.9-89.4%).ConclusionsCTA is an effective and easily reproducible method to evaluate hepatic involvement of HHT. Utilizing CTA, clinical, and laboratory data we determined CHA diameter and hemoglobin level were independent predictors of heart failure symptoms.

We previously reported several vignettes on types and classes of drugs able to mitigate acute and, in at least one case, late radiation syndromes in mice. Most of these had emerged from high throughput screening (HTS) of bioactive and chemical drug libraries using ionizing radiation-induced lymphocytic apoptosis as a readout. Here we report the full analysis of the HTS screen of libraries with 85,000 small molecule chemicals that identified 220 "hits." Most of these hits could be allocated by maximal common substructure analysis to one of 11 clusters each containing at least three active compounds. Further screening validated 23 compounds as being most active; 15 of these were cherry-picked based on drug availability and tested for their ability to mitigate acute hematopoietic radiation syndrome (H-ARS) in mice. Of these, five bore a 4-nitrophenylsulfonamide motif while 4 had a quinoline scaffold. All but two of the 15 significantly (p < 0.05) mitigated H-ARS in mice. We had previously reported that the lead 4-(nitrophenylsulfonyl)-4-phenylpiperazine compound (NPSP512), was active in mitigating multiple acute and late radiation syndromes in mice of more than one sex and strain. Unfortunately, the formulation of this drug had to be changed for regulatory reasons and we report here on the synthesis and testing of active analogs of NPSP512 (QS1 and 52A1) that have increased solubility in water and in vivo bioavailability while retaining mitigator activity against H-ARS (p < 0.0001) and other radiation syndromes. The lead quinoline 057 was also active in multiple murine models of radiation damage. Taken together, HTS of a total of 150,000 bioactive or chemical substances, combined with maximal common substructure analysis has resulted in the discovery of diverse groups of compounds that can mitigate H-ARS and at least some of which can mitigate multiple radiation syndromes when given starting 24 h after exposure. We discuss what is known about how these agents might work, and the importance of formulation and bioavailability.

OBJECTIVE. The objective of our study was to determine the performance of 3-T multiparametric MRI (mpMRI) for prostate cancer (PCa) detection and localization, stratified by anatomic zone and level, using Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) and whole-mount histopathology (WMHP) as reference. MATERIALS AND METHODS. Multiparametric MRI examinations of 415 consecutive men were compared with thin-section WMHP results. A genitourinary radiologist and pathologist collectively determined concordance. Two radiologists assigned PI-RADSv2 scores and sector location to all detected foci by consensus. Tumor detection rates were calculated for clinical and pathologic (tumor location and zone) variables. Both rigid and adjusted sector-matching models were used to account for fixation-related issues. RESULTS. Of 863 PCa foci in 16,185 prostate sectors, the detection of overall and index PCa lesions in the midgland, base, and apex was 54.9% and 83.1%, 42.1% and 64.0% (p = 0.04, p = 0.02), and 41.9% and 71.4% (p = 0.001, p = 0.006), respectively. Tumor localization sensitivity was highest in the midgland compared with the base and apex using an adjusted match compared with a rigid match (index lesions, 71.3% vs 43.7%; all lesions, 70.8% vs 36.0%) and was greater in the peripheral zone (PZ) than in the transition zone. Three-Tesla mpMRI had similarly high specificity (range, 93.8-98.3%) for overall and index tumor localization when using both rigid and adjusted sector-matching approaches. CONCLUSION. For 3-T mpMRI, the highest sensitivity (83.1%) for detection of index PCa lesions was in the midgland, with 98.3% specificity. Multiparametric MRI performance for sectoral localization of PCa within the prostate was moderate and was best for index lesions in the PZ using an adjusted model.

The purpose of this study was to determine the dynamic contributions of different immune cell subsets to primary and abscopal tumor regression after hypofractionated radiation therapy (hRT) and the impact of anti-PD-1 therapy. A bilateral syngeneic FSA1 fibrosarcoma model was used in immunocompetent C3H mice, with delayed inoculation to mimic primary and microscopic disease. The effect of tumor burden on intratumoral and splenic immune cell content was delineated as a prelude to hRT on macroscopic T1 tumors with 3 fractions of 8 Gy while microscopic T2 tumors were left untreated. This was performed with and without systemic anti-PD-1. Immune profiles within T1 and T2 tumors and in spleen changed drastically with tumor burden in untreated mice with infiltrating CD4+ content declining, while the proportion of CD4+ Tregs rose. Myeloid cell representation escalated in larger tumors, resulting in major decreases in the lymphoid:myeloid ratios. In general, activation of Tregs and myeloid-derived suppressor cells allow immunogenic tumors to grow, although their relative contributions change with time. The evidence suggests that primary T1 tumors self-regulate their immune content depending on their size and this can influence the lymphoid compartment of T2 tumors, especially with respect to Tregs. Tumor burden is a major confounding factor in immune analysis that has to be taken into consideration in experimental models and in the clinic. hRT caused complete local regression of primary tumors, which was accompanied by heavy infiltration of CD8+ T cells activated to express IFN-γ and PD-1; while certain myeloid populations diminished. In spite of this active infiltrate, primary hRT failed to generate the systemic conditions required to cause abscopal regression of unirradiated microscopic tumors unless PD-1 blockade, which on its own was ineffective, was added to the RT regimen. The combination further increased local and systemically activated CD8+ T cells, but few other changes. This study emphasizes the subtle interplay between the immune system and tumors as they grow and how difficult it is for local RT, which can generate a local immune response that may help with primary tumor regression, to overcome the systemic barriers that are generated so as to effect immune regression of even small abscopal lesions.

OBJECTIVE. The purpose of this study was to compare in a multireader manner the diagnostic accuracies of 3-T multiparametric MRI interpretation and serial prostate-specific antigen (PSA) measurement in predicting the presence of residual clinically significant prostate cancer after focal laser ablation. MATERIALS AND METHODS. Eighteen men had undergone focal laser ablation for low- or intermediate-risk prostate cancer as part of two National Cancer Institute-funded phase 1 clinical trials. Multiparametric MRI was performed immediately after and 6 and 12 months after focal laser ablation. Serial PSA measurements after focal laser ablation were recorded, and MRI-ultrasound fusion biopsy was performed 6 and 12 months after ablation and served as the reference standard. Multiparametric MRI was performed at 3 T with pelvic phased-array coils. T2-weighted, DW, and dynamic contrast-enhanced MR images were retrospectively assessed by two blinded radiologists using a 3-point Likert scale (0-2). Inter-reader agreement was assessed with the Cohen kappa statistic. The diagnostic accuracies of multiparametric MRI and PSA measurement were compared. RESULTS. Residual clinically significant prostate cancer was identified in 11 of 18 (61%) men. Logistic regression analysis of serial PSA measurements yielded a correct classification rate of 61.1% (p > 0.05). Using a multiparametric MRI threshold score of 4 or greater, both radiologists made correct classifications for 16 of 18 men (89%) at 6 months and 15 of 17 men (88%) at 12 months. Interreader agreement was substantial to excellent for T2-weighted imaging, DWI, and dynamic contrast-enhanced MRI and improved uniformly from 6 to 12 months. Logistic regression analysis of the retrospectively reviewed multiparametric MR images yielded AUCs greater than 0.90 for each radiologist 6 and 12 months after focal laser ablation (p < 0.001). CONCLUSION. Multiparametric MRI 6 and 12 months after focal laser ablation significantly outperformed serial PSA measurements for predicting the presence of residual clinically significant prostate cancer.

Intensive research is underway to find new agents that can successfully mitigate the acute effects of radiation exposure. This is primarily in response to potential counterthreats of radiological terrorism and nuclear accidents but there is some hope that they might also be of value for cancer patients treated with radiation therapy. Research into mitigation countermeasures typically employs classic animal models of acute radiation syndromes (ARS) that develop after whole-body irradiation (WBI). While agents are available that successfully mitigate ARS when given after radiation exposure, their success raises questions as to whether they simply delay lethality or unmask potentially lethal radiation pathologies that may appear later in time. Life shortening is a well-known consequence of WBI in humans and experimental animals, but it is not often examined in a mitigation setting and its causes, other than cancer, are not well-defined. This is in large part because delayed effects of acute radiation exposure (DEARE) do not follow the strict time-dose phenomena associated with ARS and present as a diverse range of symptoms and pathologies with low mortality rates that can be evaluated only with the use of large cohorts of subjects, as in this study. Here, we describe chronically increased mortality rates up to 660 days in large numbers of mice given LD70/30 doses of WBI. Systemic myeloid cell activation after WBI persists in some mice and is associated with late immunophenotypic changes and hematopoietic imbalance. Histopathological changes are largely of a chronic inflammatory nature and variable incidence, as are the clinical symptoms, including late diarrhea that correlates temporally with changes in the content of the microbiome. We also describe the acute and long-term consequences of mitigating hematopoietic ARS (H-ARS) lethality after LD70/30 doses of WBI in multiple cohorts of mice treated uniformly with radiation mitigators that have a common 4-nitro-phenylsulfonamide (NPS) pharmacophore. Effective NPS mitigators dramatically decrease ARS mortality. There is slightly increased subacute mortality, but the rate of late mortalities is slowed, allowing some mice to live a normal life span, which is not the case for WBI controls. The study has broad relevance to radiation late effects and their potential mitigation and epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis.

PurposeWe present a method for generating a T2 MR-based probabilistic model of tumor occurrence in the prostate to guide the selection of anatomical sites for targeted biopsies and serve as a diagnostic tool to aid radiological evaluation of prostate cancer.Materials and methodsIn our study, the prostate and any radiological findings within were segmented retrospectively on 3D T2-weighted MR images of 266 subjects who underwent radical prostatectomy. Subsequent histopathological analysis determined both the ground truth and the Gleason grade of the tumors. A randomly chosen subset of 19 subjects was used to generate a multi-subject-derived prostate template. Subsequently, a cascading registration algorithm involving both affine and non-rigid B-spline transforms was used to register the prostate of every subject to the template. Corresponding transformation of radiological findings yielded a population-based probabilistic model of tumor occurrence. The quality of our probabilistic model building approach was statistically evaluated by measuring the proportion of correct placements of tumors in the prostate template, i.e., the number of tumors that maintained their anatomical location within the prostate after their transformation into the prostate template space.ResultsProbabilistic model built with tumors deemed clinically significant demonstrated a heterogeneous distribution of tumors, with higher likelihood of tumor occurrence at the mid-gland anterior transition zone and the base-to-mid-gland posterior peripheral zones. Of 250 MR lesions analyzed, 248 maintained their original anatomical location with respect to the prostate zones after transformation to the prostate.ConclusionWe present a robust method for generating a probabilistic model of tumor occurrence in the prostate that could aid clinical decision making, such as selection of anatomical sites for MR-guided prostate biopsies.

Purpose: This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients.Experimental Design: Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for five cycles, with focal radiotherapy to a metastatic site at week 1 (three doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5, and 15 to isolate PBMCs, plasma, and serum.Results: Twenty-three patients were randomized, median age 57 (range 35-77). Seven grade 3/4 adverse events occurred in 5 of 11 patients in the 1 mg/kg arm and in 2 of 12 patients in the 10 mg/kg arm, respectively. Response was limited to three stable disease. At a median follow up of 12 months, 20 of 23 patients are deceased. Patients receiving the 10 mg/kg had a significantly higher median overall survival than those receiving 1 mg/kg fresolimumab dose [hazard ratio: 2.73 with 95% confidence interval (CI), 1.02-7.30; P = 0.039]. The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool.Conclusions: TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group. Clin Cancer Res; 24(11); 2493-504. ©2018 AACR.

Our ability to use ionizing radiation as an energy source, as a therapeutic agent, and, unfortunately, as a weapon, has evolved tremendously over the past 120 years, yet our tool box to handle the consequences of accidental and unwanted radiation exposure remains very limited. We have identified a novel group of small molecule compounds with a 4-nitrophenylsulfonamide (NPS) backbone in common that dramatically decrease mortality from the hematopoietic acute radiation syndrome (hARS). The group emerged from an in vitro high throughput screen (HTS) for inhibitors of radiation-induced apoptosis. The lead compound also mitigates against death after local abdominal irradiation and after local thoracic irradiation (LTI) in models of subacute radiation pneumonitis and late radiation fibrosis. Mitigation of hARS is through activation of radiation-induced CD11b+Ly6G+Ly6C+ immature myeloid cells. This is consistent with the notion that myeloerythroid-restricted progenitors protect against WBI-induced lethality and extends the possible involvement of the myeloid lineage in radiation effects. The lead compound was active if given to mice before or after WBI and had some anti-tumor action, suggesting that these compounds may find broader applications to cancer radiation therapy.

Four-point electrode systems are commonly used for electric impedance measurements of biomaterials and tissues. We introduce a 2-point system to reduce electrode polarization for heterogeneous measurements of vascular wall. Presence of endoluminal oxidized low density lipoprotein (oxLDL) and lipids alters the electrochemical impedance that can be measured by electrochemical impedance spectroscopy (EIS). We developed a catheter-based 2-point micro-electrode configuration for intravascular deployment in New Zealand White rabbits. An array of 2 flexible round electrodes, 240 µm in diameter and separated by 400 µm was microfabricated and mounted on an inflatable balloon catheter for EIS measurement of the oxLDL-rich lesions developed as a result of high-fat diet-induced hyperlipidemia. Upon balloon inflation, the 2-point electrode array conformed to the arterial wall to allow deep intraplaque penetration via alternating current (AC). The frequency sweep from 10 to 300 kHz generated an increase in capacitance, providing distinct changes in both impedance (Ω) and phase (ϕ) in relation to varying degrees of intraplaque lipid burden in the aorta. Aortic endoluminal EIS measurements were compared with epicardial fat tissue and validated by intravascular ultrasound and immunohistochemistry for plaque lipids and foam cells. Thus, we demonstrate a new approach to quantify endoluminal EIS via a 2-point stretchable electrode strategy.

PurposeTo identify potential biomarkers of the renal impairment in lupus nephritis using a multi-parametric renal quantitative MRI (qMRI) protocol including diffusion weighted imaging (DWI), blood oxygen level dependent (BOLD), arterial spin labeling (ASL) and T1rho MRI between a cohort of healthy volunteers and lupus nephritis (LN) patients.Materials and methodsThe renal qMRI protocol was performed twice with repositioning in between on 10 LN patients and 10 matched controls at 1.5 T. Navigator-gated and breath-hold acquisitions followed by non-rigid image registration were used to control respiratory motion. The repeatability of the 4 MRI modalities was evaluated with the intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Unpaired t-test and stepwise logistic regression were carried out to evaluate qMRI parameters between the LN and control groups.ResultsThe reproducibility of the 4 qMRI modalities ranged from moderate to good (ICC=0.4-0.91, wsCV≤12%) with a few exceptions. T1rho MRI and ASL renal blood flow (RBF) demonstrated significant differences between the LN and control groups. Stepwise logistic regression yielded only one significant parameter (medullar T1rho) in differentiating LN from control groups with 95% accuracy.ConclusionA reasonable degree of test-retest repeatability and accuracy of a multi-parametric renal qMRI protocol has been demonstrated in healthy volunteers and LN subjects. T1rho and ASL RBF are promising imaging biomarkers of LN.

Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier γδ T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 μg/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. γδ T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated γδ T cell null (Tcrd(-/-) ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd(-/-) ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd(-/-) ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of γδ T cells from human peripheral blood (h-γδ T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-γδ T cells exhibited rapid expansion and robust IFN-γ secretion. When h-γδ T cells were injected into ZOL-treated immunodeficient (Rag2(-/-) ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2(-/-) ZOL mice did not develop osteonecrosis. The results indicate that γδ T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ.

A pulsed terahertz (THz) imaging system and millimeter-wave reflectometer were used to acquire images and point measurements, respectively, of five rabbit cornea in vivo. These imaging results are the first ever produced of in vivo cornea. A modified version of a standard protocol using a gentle stream of air and a Mylar window was employed to slightly dehydrate healthy cornea. The sensor data and companion central corneal thickness (CCT) measurements were acquired every 10-15 min over the course of two hours using ultrasound pachymmetry.. Statistically significant positive correlations were established between CCT measurements and millimeter wave reflectivity. Local shifts in reflectivity contrast were observed in the THz imagery; however, the THz reflectivity did not display a significant correlation with thickness in the region probed by the 100 GHz and CCT measurements. This is explained in part by a thickness sensitivity at least 10× higher in the mm-wave than the THz systems. Stratified media and effective media modeling suggest that the protocol perturbed the thickness and not the corneal tissue water content (CTWC). To further explore possible etalon effects, an additional rabbit was euthanized and millimeter wave measurements were obtained during death induced edema. These observations represent the first time that the uncoupled sensing of CTWC and CCT have been achieved in vivo.

Terahertz (THz) spectral properties of human cornea are explored as a function of central corneal thickness (CCT) and corneal water content, and the clinical utility of THz-based corneal water content sensing is discussed. Three candidate corneal tissue water content (CTWC) perturbations, based on corneal physiology, are investigated that affect the axial water distribution and total thickness. The THz frequency reflectivity properties of the three CTWC perturbations were simulated and explored with varying system center frequency and bandwidths (Q-factors). The modeling showed that at effective optical path lengths on the order of a wavelength the cornea presents a lossy etalon bordered by air at the anterior and the aqueous humor at the posterior. The simulated standing wave peak-to-valley ratio is pronounced at lower frequencies and its effect on acquired data can be modulated by adjusting the bandwidth of the sensing system. These observations are supported with experimental spectroscopic data. The results suggest that a priori knowledge of corneal thickness can be utilized for accurate assessments of corneal tissue water content. The physiologic variation of corneal thickness with respect to the wavelengths spanned by the THz band is extremely limited compared to all other structures in the body making CTWC sensing unique amongst all proposed applications of THz medical imaging.

This study demonstrates the feasibility and performance of the point‐resolved spectroscopy (PRESS)‐based, single‐shot diffusion trace‐weighted sequence in quantifying the trace apparent diffusion coefficient (ADC) in phantom and in vivo using a 3‐T MRI/MRS scanner. The single‐shot diffusion trace‐weighted PRESS sequence was implemented and compared with conventional diffusion‐weighted (DW)‐PRESS variants using bipolar and unipolar diffusion‐sensitizing gradients. Nine phantom datasets were acquired using each sequence, and seven volunteers were scanned in three different brain regions to determine the range and variability of trace ADC values, and to allow a comparison of trace ADCs among the sequences. This sequence results in a comparatively stable range of trace ADC values that are statistically significantly higher than those produced from unipolar and bipolar DW‐PRESS sequences. Only total n‐acetylaspartate, total creatine, and total choline were reliably estimated in all sequences with Cramér–Rao lower bounds of, at most, 20%. The larger trace ADCs from the single‐shot sequences are probably attributable to the shorter diffusion time relative to the other sequences. Overall, this study presents the first demonstration of the single‐shot diffusion trace‐weighted sequence in a clinical scanner at 3 T. The results show excellent agreement of phantom trace ADCs computed with all sequences, and in vivo ADCs agree well with the expected differences between gray and white matter. The diffusion trace‐weighted sequence could provide an estimate of the trace ADC in a shorter scan time (by nearly a factor of 3) compared with conventional DW‐PRESS approaches that require three separate orthogonal directions. [ABSTRACT FROM AUTHOR]

PurposeTo characterize the relationship between aneurysm size and epidemiologic risk factors with growth and rupture by using computed tomographic (CT) angiography.Materials and methodsIn this HIPAA-compliant, institutional review board approved study, patients with known asymptomatic unruptured intracerebral aneurysms were followed up longitudinally with CT angiographic examinations. Growth was defined as an increase in one or more dimensions above the measurement error, and at least 5% volume by using the ABC/2 method. Associations of epidemiologic factors with aneurysm growth and rupture were analyzed by using logistic regression analysis. Intra- and interobserver agreement coefficients for dimension, volume, and growth were evaluated by using the Pearson correlation coefficient and difference of means with 95% confidence intervals, the agreement statistic, and the McNemar χ(2).ResultsPatients (n = 165) with aneurysms (n = 258) had a mean follow-up time of 2.24 years from time of diagnosis. Forty-six of 258 (18%) aneurysms in 38 patients grew larger. Spontaneous rupture occurred in four of 228 (1.8%) intradural aneurysms of average size (6.2 mm). Risk of aneurysm rupture per patient-year was 2.4% (95% CI: 0.5%, 7.12%) with growth and 0.2% (95% CI: 0.006%, 1.22%) without growth (P = .034). There was a 12-fold higher risk of rupture for growing aneurysms (P < .002), with high intra- and interobserver correlation coefficients for size, volume, and growth. Tobacco smoking (3.806, one degree of freedom; P < .015,) and initial size (5.895, two degrees of freedom; P < .051) were independent covariates, predicting 78.4% of growing aneurysms.ConclusionThese results support imaging follow-up of all patients with aneurysms, including those whose aneurysms are smaller than the current 7-mm treatment threshold. Aneurysm growth, size, and smoking were associated with increased rupture risk.

IntroductionStudies have reported a correlation between blood flow dynamics in the cardiac cycle and vascular diseases, but research to analyze the dynamic changes of flow in cerebral aneurysms is limited. This quantitative study investigates the temporal changes in flow during a cardiac cycle (flow waveform) in different regions of aneurysms and their association with aneurysm rupture.MethodsTwelve ruptured and 29 unruptured aneurysms from the internal carotid artery-ophthalmic artery segment were studied. Patient-specific aneurysm data were implemented to simulate blood flow. The temporal flow changes at different regions of the aneurysm were recorded to compare the flow waveforms.ResultsIn more than 60 % of the cases, peak flow in the aneurysm sac occurred after peak flow in the artery. Flow rate varied among cases and no correlation with rupture, aneurysm flow rate, and aneurysm size was found. Higher pulsatility within aneurysm sacs was found when comparing with the parent artery (P < 0.001). Pulsatility was high throughout ruptured aneurysms, but increased from neck to dome in unruptured ones (P = 0.021). Significant changes between inflow and outflow flow profile were found in unruptured aneurysms (P = 0.023), but not in ruptured aneurysms.ConclusionQuantitative analysis which considers temporal blood flow changes appears to provide additional information which is not apparent from aneurysmal flow at a single time point (i.e., peak of systole). By considering the flow waveform throughout the cardiac cycle, statistically significant differences were found between ruptured and unruptured cases - for flow profile, pulsatility and timing of peak flow.

As immune defects in amyloid-β (Aβ) phagocytosis and degradation underlie Aβ deposition and inflammation in Alzheimer's disease (AD) brain, better understanding of the relation between Aβ phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD patients and controls: 1α,25(OH)2-vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-Aβ by AD macrophages and inhibited fibrillar Aβ-induced apoptosis. The action of 1,25D3 depended on the nuclear vitamin D and the protein disulfide isomerase A3 receptors, whereas RvD1 required the chemokine receptor, GPR32. The activities of 1,25D3 and RvD1 commonly required intracellular calcium, MEK1/2, PKA, and PI3K signaling; however, the effect of RvD1 was more sensitive to pertussis toxin. In this case study, the AD patients: a) showed significant transcriptional up regulation of IL1RN, ITGB2, and NFκB; and b) revealed two distinct groups when compared to controls: group 1 decreased and group 2 increased transcription of TLRs, IL-1, IL1R1 and chemokines. In the PBMCs/macrophages of both groups, soluble Aβ (sAβ) increased the transcription/secretion of cytokines (e.g., IL1 and IL6) and chemokines (e.g., CCLs and CXCLs) and 1,25D3/RvD1 reversed most of the sAβ effects. However, they both further increased the expression of IL1 in the group 1, sβ-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote Aβ phagocytosis, and suggest that low vitamin D3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/RvD1 in PBMCs could contribute to AD onset/pathology.

As immune defects in amyloid-β (Aβ) phagocytosis and degradation underlie Aβ deposition and inflammation in Alzheimer's disease (AD) brain, better understanding of the relation between Aβ phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD patients and controls: 1α,25(OH)2-vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-Aβ by AD macrophages and inhibited fibrillar Aβ-induced apoptosis. The action of 1,25D3 depended on the nuclear vitamin D and the protein disulfide isomerase A3 receptors, whereas RvD1 required the chemokine receptor, GPR32. The activities of 1,25D3 and RvD1 commonly required intracellular calcium, MEK1/2, PKA, and PI3K signaling; however, the effect of RvD1 was more sensitive to pertussis toxin. In this case study, the AD patients: a) showed significant transcriptional up regulation of IL1RN, ITGB2, and NFκB; and b) revealed two distinct groups when compared to controls: group 1 decreased and group 2 increased transcription of TLRs, IL-1, IL1R1 and chemokines. In the PBMCs/macrophages of both groups, soluble Aβ (sAβ) increased the transcription/secretion of cytokines (e.g., IL1 and IL6) and chemokines (e.g., CCLs and CXCLs) and 1,25D3/RvD1 reversed most of the sAβ effects. However, they both further increased the expression of IL1 in the group 1, sβ-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote Aβ phagocytosis, and suggest that low vitamin D3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/RvD1 in PBMCs could contribute to AD onset/pathology.