Beyond Average: α-Particle Distribution and Dose Heterogeneity in Bone Metastatic Prostate Cancer.

α-particle emitters are emerging as a potent modality for disseminated cancer therapy because of their high linear energy transfer and localized absorbed dose profile. Despite great interest and pharmaceutical development, there is scant information on the distribution of these agents at the scale of the α-particle pathlength. We sought to determine the distribution of clinically approved [223Ra]RaCl2 in bone metastatic castration-resistant prostate cancer at this resolution, for the first time to our knowledge, to inform activity distribution and dose at the near-cell scale. Methods: Biopsy specimens and blood were collected from 7 patients 24 h after administration. 223Ra activity in each sample was recorded, and the microstructure of biopsy specimens was analyzed by micro-CT. Quantitative autoradiography and histopathology were segmented and registered with an automated procedure. Activity distributions by tissue compartment and dosimetry calculations based on the MIRD formalism were performed. Results: We revealed the activity distribution differences across and within patient samples at the macro- and microscopic scales. Microdistribution analysis confirmed localized high-activity regions in a background of low-activity tissue. We evaluated heterogeneous α-particle emission distribution concentrated at bone-tissue interfaces and calculated spatially nonuniform absorbed-dose profiles. Conclusion: Primary patient data of radiopharmaceutical therapy distribution at the small scale revealed that 223Ra uptake is nonuniform. Dose estimates present both opportunities and challenges to enhance patient outcomes and are a first step toward personalized treatment approaches and improved understanding of α-particle radiopharmaceutical therapies.

Activation of nano-photosensitizers by Y-90 microspheres to enhance oxidative stress and cell death in hepatocellular carcinoma.

While radioembolization with yttrium-90 (Y-90) microspheres is a promising treatment for hepatocellular carcinoma (HCC), lower responses in advanced and high-grade tumors present an urgent need to augment its tumoricidal efficacy. The purpose of this study was to determine whether clinically used Y-90 microspheres activate light-responsive nano-photosensitizers to enhance hepatocellular carcinoma (HCC) cell oxidative stress and cytotoxicity over Y-90 alone in vitro. Singlet oxygen and hydroxyl radical production was enhanced when Y-90 microspheres were in the presence of several nano-photosensitizers compared to either alone in cell-free conditions. Both the SNU-387 and HepG2 human HCC cells demonstrated significantly lower viability when treated with low activity Y-90 microspheres (0.1-0.2 MBq/0.2 mL) and a nano-photosensitizer consisting of both titanium dioxide (TiO2) and titanocene (TC) labelled with transferrin (TiO2-Tf-TC) compared to Y-90 microspheres alone or untreated cells. Cellular oxidative stress and cell death demonstrated a linear dependence on Y-90 at higher activities (up to 0.75 MBq/0.2 mL), but was significantly more accentuated in the presence of increasing TiO2-Tf-TC concentrations in the poorly differentiated SNU-387 HCC cell line (p < 0.0001 and p = 0.0002 respectively) but not the well-differentiated HepG2 cell line. Addition of TiO2-Tf-TC to normal human hepatocyte THLE-2 cells did not increase cellular oxidative stress or cell death in the presence of Y-90. The enhanced tumoricidal activity of nano-photosensitizers with Y-90 microspheres is a potentially promising adjunctive treatment strategy for certain patient subsets. Applications in clinically relevant in vivo HCC models are underway.

Imaging to intervention: Thoracic outlet syndrome.

Thoracic outlet syndrome (TOS) is a clinical disorder resulting from compression of the neurovascular bundle of the lower neck and upper chest. TOS can be categorized into neurogenic, venous, and arterial subtypes which result from anatomical compression of the brachial plexus, subclavian vein, and subclavian artery, respectively. This can lead to neurogenic pain as well as vascular injury with thrombosis and thromboembolism. Interventional and diagnostic radiologists play a critical role in the imaging diagnosis and treatment of vascular TOS. Prompt imaging and endovascular management with surgical collaboration has been shown to provide the most successful and long-lasting clinical outcomes, from vessel patency to symptom relief. In this article, we review the anatomy and clinical presentations of TOS as well as the initial imaging modalities used for diagnosis. Furthermore, we detail the role of the diagnostic and interventional radiologist in the management of TOS, including pre-procedure and endovascular interventions, along with medical and surgical treatments. PRECIS: Diagnostic and Interventional Radiologists play a key role in diagnosis and management of vascular thoracic outlet syndromes and are critical for timely and successful outcomes.

Adrenal vein sampling for ACTH-producing pheochromocytomas.

Adrenocorticotropic hormone (ACTH)-producing pheochromocytoma can cause a variety of clinical manifestations of excess catecholamine and corticosteroid. Anatomic localization of this source of ectopic ACTH is critical to facilitate unilateral adrenalectomy and prevent adrenal insufficiency due to bilateral adrenalectomy. Although nuclear scintigraphy remains the diagnostic gold standard, recent radiotracer supply shortages have necessitated alternative diagnostic paradigms to localize adrenal pheochromocytomas. We present a case where adrenal vein sampling (AVS) was utilized to lateralize an adrenal pheochromocytoma and discuss the approach and nuance as it differs from routine AVS for hyperaldosteronism or hypercortisolism.

Outcomes of Yttrium-90 Radioembolization for Unresectable Combined Biphenotypic Hepatocellular-Cholangiocarcinoma.

PURPOSE: To evaluate outcomes of yttrium-90 radioembolization in patients with combined biphenotypic hepatocellular-cholangiocarcinoma (cHCC-CC). MATERIALS AND METHODS: A retrospective review of patients with biopsy-confirmed cHCC-CC treated with yttrium-90 radioembolization between 2012 and 2018 was performed. Twenty-two patients with cHCC-CC (mean age 65.6 y, 17 men, 5 women) underwent 29 radioembolization treatments (5 resin, 24 glass microspheres). Survival data were available in 21 patients, and hepatic imaging response data were available in 20 patients. Hepatic imaging response to radioembolization was assessed on follow-up CT or MR imaging using modified Response Evaluation Criteria In Solid Tumours criteria. Univariate stepwise Cox regression analysis was used to evaluate the association between demographic and clinical factors and survival. Logistic regression evaluated associations between clinical factors and response to treatment, overall response, and disease control. RESULTS: Hepatic imaging response was as follows: 15% complete response, 40% partial response, 10% stable disease, and 35% progressive disease (55% response rate, 65% disease control rate). Two patients were downstaged or bridged to transplant, and 1 patient was downstaged to resection. Median overall survival was 9.3 mo (range, 2.5-31.0 mo) from time of radioembolization. Nonreponse to treatment, bilobar disease, presence of multiple tumors, and elevated carbohydrate antigen 19-9 before treatment were associated with reduced survival after radioembolization. CONCLUSIONS: Radioembolization is a viable option for locoregional control of cHCC-CC with good response and disease control rates.

Contrast-enhanced US for the Interventional Radiologist: Current and Emerging Applications.

US is a powerful and nearly ubiquitous tool in the practice of interventional radiology. Use of contrast-enhanced US (CEUS) has gained traction in diagnostic imaging given the recent approval by the U.S. Food and Drug Administration (FDA) of microbubble contrast agents for use in the liver, such as sulfur hexafluoride lipid-type A microspheres. Adoption of CEUS by interventional radiologists can enhance not only procedure guidance but also preprocedure patient evaluation and assessment of treatment response across a wide spectrum of oncologic, vascular, and nonvascular procedures. In addition, the unique physical properties of microbubble contrast agents make them amenable as therapeutic vehicles in themselves, which can lay a foundation for future therapeutic innovations in the field in drug delivery, thrombolysis, and vascular flow augmentation. The purpose of this article is to provide an introduction to and overview of CEUS aimed at the interventional radiologist, highlighting its role before, during, and after frequently practiced oncologic and vascular interventions such as biopsy, ablation, transarterial chemoembolization, detection and control of hemorrhage, evaluation of transjugular intrahepatic portosystemic shunts (TIPS), detection of aortic endograft endoleak, thrombus detection and evaluation, evaluation of vascular malformations, lymphangiography, and percutaneous drain placement. Basic physical principles of CEUS, injection and scanning protocols, and logistics for practice implementation are also discussed. Early adoption of CEUS by the interventional radiology community will ensure rapid innovation of the field and development of future novel procedures. Online supplemental material is available for this article. ©RSNA, 2020.

Propensity-matched comparison of transjugular intrahepatic portosystemic shunt placement techniques: Intracardiac echocardiography (ICE) versus fluoroscopic guidance.

PURPOSE: To compare procedure characteristics and outcomes when TIPS is performed under intracardiac echocardiography guidance (iTIPS) compared to conventional fluoroscopic guidance (cTIPS). MATERIALS AND METHODS: A retrospective propensity-matched study of 30 iTIPS and 30 cTIPS procedures from January 2014 to March 2017 at a single US high volume academic medical center was performed. iTIPS and cTIPS cases were propensity score matched using predictive variables: age, race, gender, etiology of liver disease, indication for TIPS, MELD score, and portal vein patency. Procedure characteristics and post- procedure outcomes were compared between propensity-matched groups including: total procedure time, technical success, radiation dose, contrast volume, complication rate, 30- day mortality, and revision rate within 3 months. RESULTS: Radiation dose (875.3 vs 457.4 mGY, p = 0.039) and contrast volume (141 vs 103 mL, p = 0.005) were significantly decreased in the iTIPS versus the cTIPS group. There was no significant difference in procedure time (81.5 cTIPS vs 84 min iTIPS) or rate of TIPS revisions within 3 months. Average operator experience in the iTIPs group was 4.2 years and cTIPS group 11.0 years (p = 0.0004). All procedures were technically successful with no mortalities within 30 days. CONCLUSION: iTIPS resulted in significantly reduced radiation dose and contrast volume. However, there was no difference in total procedure time or overall outcomes despite greater operator experience in the cTIPS group.

Catalase-Containing Silica Particles as Ultrasound-Based Hydrogen Peroxide Sensors to Determine Infected From Noninfected Fluid Collections in Humans.

OBJECTIVE. Hydrogen peroxide (H2O2) plays a key role in neutrophil oxidative defense against infection. Catalase-containing silica nanoshells are nanoparticles that generate O2 microbubbles imaged with ultrasound in the presence of elevated H2O2. We aimed to determine whether ultrasound-detectable O2 microbubbles produced by catalase-containing silica nanoshells can determine whether fluid collections drained from patients are infected. SUBJECTS AND METHODS. During this HIPAA-compliant, institutional review board-approved study, 52 human fluid samples were collected from clinically required image-guided percutaneous drainage procedures. Catalase-containing silica nanoshells were added to the fluid samples during imaging in real time using a Sequoia-512 15L8-S linear transducer (Siemens Healthcare). Production of detectable microbubbles was graded subjectively as negative (noninfected) or positive (infected) with low, moderate, or high confidence by a single observer blinded to all clinical data. The truth standard was microbiology laboratory culture results. Performance characteristics including ROC curves were calculated. RESULTS. Microbubble detection to distinguish infected from noninfected fluids was 84% sensitive and 72% specific and offered negative and positive predictive values of 89% and 64%, respectively. The AUC was 0.79. Six of nine false-positive samples were peritoneal fluid collections that were all collected from patients with decompensated cirrhosis. CONCLUSION. The presence of elevated H2O2 indicated by microbubble formation in the presence of catalase-containing silica nanoshells is sensitive in distinguishing infected from noninfected fluids and offers a relatively high negative predictive value. False-positive cases may result from noninfectious oxidative stress. Catalase-containing silica nanoshells may constitute a novel point-of-care test performed at time of percutaneous drainage, potentially obviating placement of drains into otherwise sterile collections and minimizing risk of secondary infection or other complication.

Pelvic Blood Flow Predicts Fibroid Volume and Embolic Required for Uterine Fibroid Embolization: A Pilot Study With 4D Flow MR Angiography.

OBJECTIVE: We report here an initial experience using 4D flow MRI in pelvic imaging-specifically, in imaging uterine fibroids. We hypothesized that blood flow might correlate with fibroid volume and that quantifying blood flow might help to predict the amount of embolic required to achieve stasis at subsequent uterine fibroid embolization (UFE). MATERIALS AND METHODS: Thirty-three patients with uterine fibroids and seven control subjects underwent pelvic MRI with 4D flow imaging. Of the patients with fibroids, 10 underwent 4D flow imaging before UFE and seven after UFE; in the remaining 16 patients with fibroids, UFE had yet to be performed. Four-dimensional flow measurements were performed using Arterys CV Flow. The flow fraction of the internal iliac artery was expressed as the ratio of internal iliac artery flow to external iliac artery flow and was compared between groups. The flow ratios between the internal iliac arteries on each side were calculated. Fibroid volume versus internal iliac flow fraction, embolic volume versus internal iliac flow fraction, and embolic volume ratio between sides versus the ratio of internal iliac artery flows between sides were compared. RESULTS: The mean internal iliac flow fraction was significantly higher in the 26 patients who underwent imaging before UFE (mean ± standard error, 0.78 ± 0.06) than in the seven patients who underwent imaging after UFE (0.48 ± 0.07, p < 0.01) and in the seven control patients without fibroids (0.48 ± 0.08, p < 0.0001). The internal iliac flow fraction correlated well with fibroid volumes before UFE (r = 0.7754, p < 0.0001) and did not correlate with fibroid volumes after UFE (r = -0.3051, p = 0.51). The ratio of embolic required to achieve stasis between sides showed a modest correlation with the ratio of internal iliac flow (r = 0.6776, p = 0.03). CONCLUSION: Internal iliac flow measured by 4D flow MRI correlates with fibroid volume and is predictive of the ratio of embolic required to achieve stasis on each side at subsequent UFE and may be useful for preprocedural evaluation of patients with uterine fibroids.

Effect of Different Meditation Types on Migraine Headache Medication Use.

Spiritual meditation has been found to reduce the frequency of migraines and physiological reactivity to stress. However, little is known about how introducing a spirituality component into a meditation intervention impacts analgesic medication usage. In this study, 92 meditation-naïve participants were randomly assigned to one of four groups: (1) Spiritual Meditation, (n = 25), (2) Internally Focused Secular Meditation (n = 23), (3) Externally Focused Secular Meditation (n = 22), or (4) Progressive Muscle Relaxation (n = 22); and practiced their technique for 20 min/day over 30 days while completing daily diaries. Headache frequency, headache severity, and pain medication use were assessed. Migraine frequency decreased in the Spiritual Meditation group compared to other groups (p < 0.05). Headache severity ratings did not differ across groups (p = ns). After adjusting for headache frequency, migraine medication usage decreased in the Spiritual Meditation group compared to other groups (p < 0.05). Spiritual Meditation was found to not affect pain sensitivity, but it does improve pain tolerance with reduced headache related analgesic medication usage.

Control of massive hemoptysis via a "back-door" approach through the pulmonary artery.

Bronchial artery embolization is an effective nonsurgical therapy for massive hemoptysis. Routine selection of the bronchial arteries from the aorta usually enables the interventionalist full interrogation and embolization of the culprit vascular abnormality. In problematic cases where bronchial artery access is difficult, a systemic-to-pulmonary arterial shunt can be exploited as a retrograde means of vascular intervention. A case is presented where inaccessibility of a tortuous left bronchial artery was circumvented by accessing the left pulmonary artery, leading to successful embolization and control of hemoptysis.

Tumor Detection at 3 Tesla with an Activatable Cell Penetrating Peptide Dendrimer (ACPPD-Gd), a T1 Magnetic Resonance (MR) Molecular Imaging Agent.

PURPOSE: The ability to detect small malignant lesions with magnetic resonance imaging (MRI) is limited by inadequate accumulations of Gd with standard chelate agents. To date, no T1-targeted agents have proven superiority to Gd chelates in their ability to detect small tumors at clinically relevant field strengths. Activatable cell-penetrating peptides and their Gd-loaded dendrimeric form (ACPPD-Gd) have been shown to selectively accumulate in tumors. In this study we compared the performance of ACPPD-Gd vs. untargeted Gd chelates to detect small tumors in rodent models using a clinical 3T-MR system. MATERIALS AND METHODS: This study was approved by the Institutional-Animal Care-and-Use Committee. 2 of 4 inguinal breast fat pads of 16 albino-C57BL/6 mice were inoculated with tumor Py8119 cells and the other 2 with saline at random. MRI at 3T was performed at 4, 9, and 14 days after inoculation on 8 mice 24-hours after injection of 0.036mmol Gd/kg (ACPPD-Gd), and before and 2-3 minutes after 0.1 mmol/kg gadobutrol on the other 8 mice. T1-weighted (T1w) tumor signal normalized to muscle, was compared among the non-contrast, gadobutrol, and ACPPD-Gd groups using ANOVA. Experienced and trainee readers blinded to experimental conditions assessed for the presence of tumor in each of the 4 breast regions. Receiver operator characteristic (ROC) curves and area-under-curve (AUC) values were constructed and analyzed. RESULTS: Tumors ≥1mm3 were iso-intense to muscle without contrast on T1w sequences. They enhanced diffusely and homogeneously by 57±20% (p<0.001) 24 hours after ACPPD-Gd and by 25±13% (p<0.001) immediately after gadobutrol. The nearly 2-fold difference was similar for small tumors (1-5mm3) (45±19% vs. 19±18%, p = 0.03). ACPPD-Gd tended to improve tumor detection by an experienced reader (AUC 0.98 vs 0.91) and significantly more for a trainee (0.93 vs. 0.82, p = 0.02) compared to gadobutrol. This improvement was more pronounced when obvious tumors (>5mm3) were removed from the ROC analysis for both the experienced observer (0.96 vs. 0.86) and more so for the trainee (0.86 vs. 0.69, p = 0.04). CONCLUSION: ACPPD-Gd enhances MMP-expressing tumors of any size at 3T 24 hours after administration, improving their detection by blinded observers when compared to non-contrast and contrast groups given commercial Gd-chelates and imaged during the equilibrium phase.

Migraine: treatments, comorbidities, and quality of life, in the USA.

This study sought to characterize the experience of stress, treatment patterns, and medical and disability profile in the migraineur population to better understand how the experience of migraines impacts the social and psychological functioning of this group. A 30-minute self-report survey was presented via a migraine-specific website with data collection occurring between May 15 and June 15, 2012. Recruitment for the study was done through online advertisements. In total, 2,907 individuals began the survey and 2,735 met the inclusion criteria for the study. The sample was predominantly female (92.8%). Migraine-associated stress was correlated with length of time since first onset of symptoms (P<0.01) and number of symptoms per month (P<0.01). Disorders related to stress, such as depression (P<0.01) and anxiety (P<0.01), were also positively correlated with the measured stress resulting from migraines. Migraine-associated stress must be understood as a multidimensional experience with broader impacts of stress on an individual correlating much more highly with negative mental and physical health profiles. Stress resulting from frequent migraine headaches may contribute to the development of medical and psychological comorbidities and may be a part of a cyclical relationship wherein stress is both a cause and effect of the social and medical impairments brought about by migraine.

Toward in vivo detection of hydrogen peroxide with ultrasound molecular imaging.

We present a new class of ultrasound molecular imaging agents that extend upon the design of micromotors that are designed to move through fluids by catalyzing hydrogen peroxide (H2O2) and propelling forward by escaping oxygen microbubbles. Micromotor converters require 62 mm of H2O2 to move - 1000-fold higher than is expected in vivo. Here, we aim to prove that ultrasound can detect the expelled microbubbles, to determine the minimum H2O2 concentration needed for microbubble detection, explore alternate designs to detect the H2O2 produced by activated neutrophils and perform preliminary in vivo testing. Oxygen microbubbles were detected by ultrasound at 2.5 mm H2O2. Best results were achieved with a 400-500 nm spherical design with alternating surface coatings of catalase and PSS over a silica core. The lowest detection limit of 10-100 µm was achieved when assays were done in plasma. Using this design, we detected the H2O2 produced by freshly isolated PMA-activated neutrophils allowing their distinction from naïve neutrophils. Finally, we were also able to show that direct injection of these nanospheres into an abscess in vivo enhanced ultrasound signal only when they contained catalase, and only when injected into an abscess, likely because of the elevated levels of H2O2 produced by inflammatory mediators.

Human mesenchymal stromal cells (MSCs) reduce neointimal hyperplasia in a mouse model of flow-restriction by transient suppression of anti-inflammatory cytokines.

AIM: Mesenchymal stromal cells from human bone marrow (hMSCs) were observed to produce therapeutic benefits in some models for cardiac and vascular injuries but their mode of action was not defined. We tested the effects of hMSCs in models for restricted vascular flow. METHODS: We made model for restricted vascular flow produced by permanent ligation of a carotid artery and injected hMSCs to clarify the effects of hMSCs to vascular lesions. RESULTS: Seven, 14, and 28 days after infusion of hMSCs into the cardiac left ventricle of the mice, there was a significant reduction in neointimal hyperplasia (p<0.05). Seven days after administration of the hMSCs, macrophages infiltration into the ligated artery and serum levels of monocyte chemoattractive protein-1 (MCP-1/CCL-2) (p<0.05) were reduced. However, no hMSCs were detected in the lesions by sensitive PCR assays. We then observed that the serum level of MCP-1 was a potential biomarker for the therapeutic effects of hMSCs in a mouse model for high-fat-diet. CONCLUSIONS: These results indicated the administration of hMSCs decreased the initial and excess inflammatory responses to carotid artery ligation. The decrease in inflammatory response apparently decreased the subsequent neointimal hyperplasia.