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.

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.

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.

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.

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.