Neoadjuvant chemo-immunotherapy is improved with a novel pulsed electric field technology in an immune-cold murine model.

Chemo-immunotherapy uses combined systemic therapies for resectable and unresectable tumors. This approach is gaining clinical momentum, but survival increases leave considerable room for improvement. A novel form of Pulsed Electric Field (PEF) ablation combines focal tissue destruction with immune activation in preclinical settings. The PEFs induce lethal cell damage without requiring thermal processes, leaving cellular proteins intact. This affords PEF a favorable safety profile, improved antigenicity, and significant immunostimulatory damage-associated molecular pattern release compared to other focal therapies. Preclinical investigations demonstrate a combinatorial benefit of PEF with immunostimulation. This study evaluates whether this proprietary PEF therapy induces an immunostimulatory effect sufficient to augment systemic neoadjuvant chemotherapy and immunotherapy to reverse metastatic disease in an immune-cold murine tumor model. To determine whether PEF improves a neoadjuvant chemo-immunotherapy standard-of-care, partial PEF ablation was delivered to orthotopically inoculated 4T1 metastatic tumors in addition to combinations of cisplatin chemotherapy and/or αPD-1 immunotherapy, followed by resection. In addition, to determine whether PEF combined with chemo-immunotherapy improves local and metastatic response in unresectable populations, partial PEF ablation was added to chemo-immunotherapy in mice that did not receive resection. Blood cytokines and flow cytometry evaluated immune response. Partial PEF ablation generates an immunostimulatory tumor microenvironment, increases systemic immune cell populations, slows tumor growth, and prolongs survival relative to neoadjuvant systemic therapies-alone. These data suggest the addition of this proprietary PEF locoregional therapy may synergize with systemic standard-of-care paradigms to improve outcomes with potential or demonstrated metastatic disease in both resectable and unresectable patient cohorts.

Outcomes of Transarterial Embolization for Acute Nonvariceal Upper Gastrointestinal Bleeding: Correlation with Periprocedural Endoscopy.

PURPOSE: To evaluate gastric and intestinal mucosal changes on postembolic endoscopy and mortality after transarterial embolization (TAE) for upper gastrointestinal bleeding (UGIB). MATERIALS AND METHODS: An institutional review board-approved retrospective review of patients who underwent arteriography for refractory UGIB at a multicenter health system from December 2003 to August 2019 was performed. Two hundred sixty-nine patients underwent TAE for UGIB. Data on etiology of bleeding, embolization technique, pre-embolic and postembolic endoscopic results, blood product requirements, and mortality were collected from the medical record. Endoscopy results were compared at the site of the target lesion before and after TAE. Multivariable logistic regressions were performed to assess predictors of new adverse mucosal responses and mortality. RESULTS: The most common etiology of UGIB was peptic ulcer. Twenty-five percent (n = 68) of the patients had clinical evidence of rebleeding after TAE, and the 30-day mortality rate was 26% (n = 73). Eighty-eight (32%) patients underwent post-TAE endoscopy, with only 15% showing new adverse mucosal changes after embolization. Procedural characteristics, including vascular territory and embolic choice, were not significantly predictive of increased risk of development of adverse mucosal response after TAE or increased mortality risk. No patients in the study were found to have bowel lumen stenosis at the time of post-TAE endoscopy or at 6 year follow-up. CONCLUSIONS: TAE is a safe and effective intervention for patients with UGIB. Post-TAE endoscopy demonstrated that most patients had either stability or improvement in the target lesion after TAE, and only a minority of patients demonstrated adverse mucosal changes.

Role of Fluorodeoxyglucose-PET in Interventional Radiology.

Fluorodeoxyglucose (FDG)-PET has expanding applications in the field of interventional radiology. FDG-PET provides both qualitative and quantitative assessments of malignancy, infection, and inflammation. These assessments can assist interventional radiologists in selecting the most appropriate treatment options for their oncology patients. FDG-PET is also useful for evaluating the response to interventional treatments and in predicting the prognosis of oncology patients. Finally, FDG-PET can assist the interventional radiologist in diagnosing and monitoring response to treatment of infection and inflammation. Nevertheless, there is a need for additional prospective studies to further establish the role of FDG-PET in these applications.

Multicenter assessment of augmented reality registration methods for image-guided interventions.

PURPOSE: To evaluate manual and automatic registration times and registration accuracies on HoloLens 2 for aligning a 3D CT phantom model onto a CT grid, a crucial step for intuitive 3D navigation during CT-guided interventions; to compare registration times between HoloLens 1 and 2. METHODS: Eighteen participants in various stages of clinical training across two academic centers performed registration of a 3D CT phantom model onto a CT grid using HoloLens 2. Registration times and accuracies were compared among different registration methods, clinical experience levels, and consecutive attempts. Registration times were also compared retrospectively to prior HoloLens 1 results. RESULTS: Mean aggregate manual registration times were 27.7 s, 24.3 s, and 72.8 s for one-handed gesture, two-handed gesture, and Xbox controller, respectively; mean automatic registration time was 5.3 s (ANOVA p < 0.0001). No significant difference in registration times was found among attendings, residents and fellows, and medical students (p > 0.05). Significant improvements in registration times were detected across consecutive attempts using hand gestures (p < 0.01). Compared to prior HoloLens 1 data, hand gesture registration was 81.7% faster with HoloLens 2 (p < 0.05). Registration accuracies were not significantly different across manual registration methods, measuring at 5.9 mm, 9.5 mm, and 8.6 mm with one-handed gesture, two-handed gesture, and Xbox controller, respectively (p > 0.05). CONCLUSIONS: Manual registration times decreased significantly on HoloLens 2, approaching those of automatic registration and outperforming Xbox controller registration. Fast, adaptive, and accurate registration of holographic models of cross-sectional imaging is paramount for the implementation of augmented reality-assisted 3D navigation during CT-guided interventions.

Preintervention Computed Tomography Improves the Performance of Endovascular Intervention in Patients with Abdominopelvic Trauma.

PURPOSE: To evaluate the role of computed tomography (CT) and CT angiography in guiding endovascular arteriography (EA) and embolization in hemodynamically (HD) stable and unstable patients with abdominal and/or pelvic (AP) trauma. MATERIALS AND METHODS: A retrospective review was performed of patients with AP trauma who underwent EA with or without embolization (from January 2012 to August 2020) at an urban, level I trauma center. Patients aged <18 years or those undergoing EA outside of the abdomen and/or pelvis were excluded. Demographics, imaging findings, procedure length, contrast agent administration, laboratory values, and outcomes were compared on the basis of preprocedural imaging technique and hemodynamic status. RESULTS: A total of 190 patients with AP trauma underwent EA with or without embolization; among them, 123 were HD stable and underwent CT/CT angiography, whereas 67 were initially HD unstable and underwent operative management prior to EA. Of these patients, 38 underwent CT/CT angiography after hemodynamic stability was achieved prior to postoperative EA. The incidence of therapeutic embolization for arterial injury on EA was significantly higher in patients with preprocedural CT/CT angiography (65.8% vs 44.8%, P = .04). The positive and negative predictive values of CT angiography for arterial injury at the time of EA were 92.3% and 100%, respectively. Prior imaging was associated with a reduced contrast agent requirement at the time of EA and reduced transfusion requirement (P = .05 and P = .02). No significant differences were observed in adverse outcomes for patients undergoing preprocedural imaging. CONCLUSIONS: CT or CT angiography prior to EA for HD stable and unstable patients with AP trauma may improve the likelihood of therapeutic embolization and enable improved procedure metrics without increasing adverse outcomes.

Neurology and the histiocytoses: a case of Rosai-Dorfman-Destombes disease.

The histiocytoses are a group of rare disorders characterised by the accumulation of neoplastic or non-neoplastic activated histiocytes in various tissues. Phenotypes vary widely from cutaneous lesions or lymphadenopathy that regress spontaneously to disseminated disease with poor prognosis. Neurological symptoms can be a presenting feature or appear during the course of disease. We present a challenging diagnostic and management case of Rosai-Dorfman-Destombes disease in a 48-year-old woman with a relapsing, partially steroid-responsive syndrome comprising patchy, non-length-dependent radiculoneuropathy with diffuse pachymeningitis and widespread systemic disease, and recent dramatic response to novel mitogen-activated kinase pathway inhibition. We discuss the clinical characteristics, diagnosis, recent breakthroughs in pathogenesis and emerging treatment options for Rosai-Dorfman disease and for the histiocytoses with neurological sequelae, including Langerhans cell histiocytosis and Erdheim-Chester disease.

Transarterial Embolization Modulates the Immune Response within Target and Nontarget Hepatocellular Carcinomas in a Rat Model.

Background Transarterial embolization (TAE) is the most common treatment for hepatocellular carcinoma (HCC); however, there remain limited data describing the influence of TAE on the tumor immune microenvironment. Purpose To characterize TAE-induced modulation of the tumor immune microenvironment in a rat model of HCC and identify factors that modulate this response. Materials and Methods TAE was performed on autochthonous HCCs induced in rats with use of diethylnitrosamine. CD3, CD4, CD8, and FOXP3 lymphocytes, as well as programmed cell death protein ligand-1 (PD-L1) expression, were examined in three cohorts: tumors from rats that did not undergo embolization (control), embolized tumors (target), and nonembolized tumors from rats that had a different target tumor embolized (nontarget). Differences in immune cell recruitment associated with embolic agent type (tris-acryl gelatin microspheres [TAGM] vs hydrogel embolics) and vascular location were examined in rat and human tissues. A generalized estimating equation model and t, Mann-Whitney U, and χ2 tests were used to compare groups. Results Cirrhosis-induced alterations in CD8, CD4, and CD25/CD4 lymphocytes were partially normalized following TAE (CD8: 38.4%, CD4: 57.6%, and CD25/CD4: 21.1% in embolized liver vs 47.7% [P = .02], 47.0% [P = .01], and 34.9% [P = .03], respectively, in cirrhotic liver [36.1%, 59.6%, and 4.6% in normal liver]). Embolized tumors had a greater number of CD3, CD4, and CD8 tumor-infiltrating lymphocytes relative to controls (191.4 cells/mm2 vs 106.7 cells/mm2 [P = .03]; 127.8 cells/mm2 vs 53.8 cells/mm2 [P < .001]; and 131.4 cells/mm2 vs 78.3 cells/mm2 [P = .01]) as well as a higher PD-L1 expression score (4.1 au vs 1.9 au [P < .001]). A greater number of CD3, CD4, and CD8 lymphocytes were found near TAGM versus hydrogel embolics (4.1 vs 2.0 [P = .003]; 3.7 vs 2.0 [P = .01]; and 2.2 vs 1.1 [P = .03], respectively). The number of lymphocytes adjacent to embolics differed based on vascular location (17.9 extravascular CD68+ peri-TAGM cells vs 7.0 intravascular [P < .001]; 6.4 extravascular CD68+ peri-hydrogel embolic cells vs 3.4 intravascular [P < .001]). Conclusion Transarterial embolization-induced dynamic alterations of the tumor immune microenvironment are influenced by underlying liver disease, embolic agent type, and vascular location. © RSNA, 2022 Online supplemental material is available for this article. See also the editorials by Kennedy et al and by White in this issue.

Variability in biopsy quality informs translational research applications in hepatocellular carcinoma.

In the era of precision medicine, biopsies are playing an increasingly central role in cancer research and treatment paradigms; however, patient outcomes and analyses of biopsy quality, as well as impact on downstream clinical and research applications, remain underreported. Herein, we report biopsy safety and quality outcomes for percutaneous core biopsies of hepatocellular carcinoma (HCC) performed as part of a prospective clinical trial. Patients with a clinical diagnosis of HCC were enrolled in a prospective cohort study for the genetic, proteomic, and metabolomic profiling of HCC at two academic medical centers from April 2016 to July 2020. Under image guidance, 18G core biopsies were obtained using coaxial technique at the time of locoregional therapy. The primary outcome was biopsy quality, defined as tumor fraction in the core biopsy. 56 HCC lesions from 50 patients underwent 60 biopsy events with a median of 8 core biopsies per procedure (interquartile range, IQR, 7-10). Malignancy was identified in 45/56 (80.4%, 4 without pathology) biopsy events, including HCC (40/56, 71.4%) and cholangiocarcinoma (CCA) or combined HCC-CCA (5/56, 8.9%). Biopsy quality was highly variable with a median of 40% tumor in each biopsy core (IQR 10-75). Only 43/56 (76.8%) and 23/56 (41.1%) samples met quality thresholds for genomic or metabolomic/proteomic profiling, respectively, requiring expansion of the clinical trial. Overall and major complication rates were 5/60 (8.3%) and 3/60 (5.0%), respectively. Despite uniform biopsy protocol, biopsy quality varied widely with up to 59% of samples to be inadequate for intended purpose. This finding has important consequences for clinical trial design and highlights the need for quality control prior to applications in which the presence of benign cell types may substantially alter findings.

Hydralazine augmented ultrasound hyperthermia for the treatment of hepatocellular carcinoma.

This study investigates the use of hydralazine to enhance ultrasound hyperthermia for the treatment of hepatocellular carcinoma (HCC) by minimizing flow-mediated heat loss from the tumor. Murine HCC tumors were treated with a continuous mode ultrasound with or without an intravenous administration of hydralazine (5 mg/kg). Tumor blood flow and blood vessels were evaluated by contrast-enhanced ultrasound (CEUS) imaging and histology, respectively. Hydralazine markedly enhanced ultrasound hyperthermia through the disruption of tumor blood flow in HCC. Ultrasound treatment with hydralazine significantly reduced peak enhancement (PE), perfusion index (PI), and area under the curve (AUC) of the CEUS time-intensity curves by 91.9 ± 0.9%, 95.7 ± 0.7%, and 96.6 ± 0.5%, compared to 71.4 ± 1.9%, 84.7 ± 1.1%, and 85.6 ± 0.7% respectively without hydralazine. Tumor temperature measurements showed that the cumulative thermal dose delivered by ultrasound treatment with hydralazine (170.8 ± 11.8 min) was significantly higher than that without hydralazine (137.7 ± 10.7 min). Histological assessment of the ultrasound-treated tumors showed that hydralazine injection formed larger hemorrhagic pools and increased tumor vessel dilation consistent with CEUS observations illustrating the augmentation of hyperthermic effects by hydralazine. In conclusion, we demonstrated that ultrasound hyperthermia can be enhanced significantly by hydralazine in murine HCC tumors by modulating tumor blood flow. Future studies demonstrating the safety of the combined use of ultrasound and hydralazine would enable the clinical translation of the proposed technique.

Demographic Trends in Female Interventional Radiology Trainees With the Advent of the Integrated Interventional Radiology Residency.

OBJECTIVE: Examine changes in gender representation in the interventional radiology (IR) training pool since the advent of the integrated IR residency in 2015 to 2020. METHODS: Electronic Residency Application Service and ACGME Data Resource Book records from 2015 to 2020 were reviewed for integrated IR residency and vascular and interventional radiology (VIR) fellowship applicant data and active IR resident and VIR fellow data, respectively. The Society of Interventional Radiology (SIR) 2018 registry data were reviewed for SIR membership data. Two-tailed Fisher's exact tests and χ2 analyses were used to compare trainees between application cycles. RESULTS: In the 2017 application cycle, 23% (247 of 1,062) of integrated IR residency applicants were female, with similar interest in the 2018, 2019, and 2020 cycles (χ2[3, n = 2,863] = 5.1, P = .17). In comparison, female VIR fellowship applicants were 12% from 2017 to 2020. Female integrated IR residents represented 13% to 18% of all integrated IR residents in the 2016 to 2020 academic years compared with the period before the integrated IR residency when female IR trainees represented 8% (23 of 275) of all IR trainees in 2015 to 2016 (P = .0002). Although in 2018, the total active SIR female membership was 9% (319 of 3,622), the female resident membership was 17% (131 of 793), and the female medical student membership was 25% (389 of 1,573). DISCUSSION: With the advent of the integrated IR residency, there is an increasing female constituency, at the medical student, IR applicant, and IR resident levels, with more than a doubling of female IR trainees, portending a continued reduction in the IR gender disparity in the future.

Subsequent Ultrasound Vascular Targeting Therapy of Hepatocellular Carcinoma Improves the Treatment Efficacy.

The response of hepatocellular carcinoma (HCC) to anti-vascular ultrasound therapy (AVUS) can be affected by the inherent differences in tumor vascular structure, and the functionality of tumor vessels at the time of treatment. In this study, we evaluate the hypothesis that repeated subsequent AVUS therapies are a possible approach to overcome these factors and improve the therapeutic efficacy of AVUS. HCC was induced in 30 Wistar rats by oral ingestion of diethylnitrosamine (DEN) for 12 weeks. A total of 24 rats received treatment with low intensity, 2.8 MHz ultrasound with an intravenous injection of microbubbles. Treated rats were divided into three groups: single therapy group (ST), 2-days subsequent therapy group (2DST), and 7-days subsequent therapy group (7DST). A sham control group did not receive ultrasound therapy. Tumor perfusion was measured by quantitative contrast-enhanced ultrasound (CEUS) nonlinear and power-Doppler imaging. Tumors were harvested for histologic evaluation of ultrasound-induced vascular changes. ANOVA was used to compare the percent change of perfusion parameters between the four treatment arms. HCC tumors treated with 2DST showed the largest reduction in tumor perfusion, with 75.3% reduction on average for all perfusion parameters. The ST group showed an average decrease in perfusion of 54.3%. The difference between the two groups was significant p < 0.001. The 7DST group showed a reduction in tumor perfusion of 45.3%, which was significant compared to the 2DST group (p < 0.001) but not different from the ST group (p = 0.2). The use of subsequent targeted AVUS therapies applied shortly (two days) after the first treatment enhanced the anti-vascular effect of ultrasound. This gain, however, was lost for a longer interval (1 week) between the therapies, possibly due to tumor necrosis and loss of tumor viability. These findings suggest that complex interplay between neovascularization and tumor viability plays a critical role in treatment and, therefore, must be actively monitored following treatment by CEUS for optimizing sequential treatment.

Augmented reality improves procedural efficiency and reduces radiation dose for CT-guided lesion targeting: a phantom study using HoloLens 2.

Out-of-plane lesions pose challenges for CT-guided interventions. Augmented reality (AR) headsets are capable to provide holographic 3D guidance to assist CT-guided targeting. A prospective trial was performed assessing CT-guided lesion targeting on an abdominal phantom with and without AR guidance using HoloLens 2. Eight operators performed a cumulative total of 86 needle passes. Total needle redirections, radiation dose, procedure time, and puncture rates of nontargeted lesions were compared with and without AR. Mean number of needle passes to reach the target reduced from 7.4 passes without AR to 3.4 passes with AR (p = 0.011). Mean CT dose index decreased from 28.7 mGy without AR to 16.9 mGy with AR (p = 0.009). Mean procedure time reduced from 8.93 min without AR to 4.42 min with AR (p = 0.027). Puncture rate of a nontargeted lesion decreased from 11.9% without AR (7/59 passes) to 0% with AR (0/27 passes). First needle passes were closer to the ideal target trajectory with AR versus without AR (4.6° vs 8.0° offset, respectively, p = 0.018). AR reduced variability and elevated the performance of all operators to the same level irrespective of prior clinical experience. AR guidance can provide significant improvements in procedural efficiency and radiation dose savings for targeting out-of-plane lesions.

Three-Dimensional Augmented Reality Visualization Informs Locoregional Therapy in a Translational Model of Hepatocellular Carcinoma.

PURPOSE: To evaluate the utility of visualizing preprocedural MR images in 3-dimensional (3D) space using augmented reality (AR) before transarterial embolization of hepatocellular carcinoma (HCC) in a preclinical model. MATERIALS AND METHODS: A total of 28 rats with diethylnitrosamine-induced HCCs > 5 mm treated with embolization were included in a prospective study. In 12 rats, 3D AR visualization of preprocedural MR images was performed before embolization. Procedural metrics including catheterization time and radiation exposure were compared vs a prospective cohort of 16 rats in which embolization was performed without AR. An additional cohort of 15 retrospective cases was identified and combined with the prospective control cohort (n = 31) to improve statistical power. RESULTS: A 37% reduction in fluoroscopy time, from 11.7 min to 7.4 minutes, was observed with AR when compared prospectively, which did not reach statistical significance (P = .12); however, when compared with combined prospective and retrospective controls, the reduction in fluoroscopy time from 14.1 min to 7.4 minutes (48%) was significant (P = .01). A 27% reduction in total catheterization time, from 42.7 minutes to 31.0 minutes, was also observed with AR when compared prospectively, which did not reach statistical significance (P = .11). No significant differences were seen in dose-area product or air kerma prospectively. CONCLUSIONS: Three-dimensional AR visualization of preprocedural imaging may aid in the reduction of procedural metrics in a preclinical model of transarterial embolization. These data support the need for further studies to evaluate the potential of AR in endovascular oncologic interventions.

Assessing the feasibility of NaF-PET/CT versus FDG-PET/CT to detect abdominal aortic calcification or inflammation in rheumatoid arthritis patients.

OBJECTIVE: We aimed to determine whether NaF-PET/CT or FDG-PET/CT can detect abdominal aortic molecular calcification and inflammation in patients with rheumatoid arthritis (RA). METHODS: In this study, 18 RA patients (4 women, 14 men; mean age 56.0 ± 11.7) and 18 healthy controls (4 women, 14 men; mean age 55.8 ± 11.9) were included. The controls were matched to patients by sex and age (± 4 years). All subjects of this study underwent NaF-PET/CT scanning 90 min following the administration of NaF. FDG-PET/CT imaging was performed 180 min following intravenous FDG injection. Using OsiriX software, the global mean standardized uptake value (global SUVmean) in abdominal aorta was calculated for both FDG and NaF. The NaF SUVmean and FDG SUVmean were divided by the blood pool activity providing target-to-background ratios (TBR) namely, NaF-TBRmean and FDG-TBRmean. The CT calcium volume score was obtained using a growing region algorithm based on Hounsfield units. RESULTS: The average NaF-TBRmean score among RA patients was significantly greater than that of healthy controls (median 1.61; IQR 1.49-1.88 and median 1.40; IQR 1.23-1.52, P = 0.002). The average CT calcium volume score among RA patients was also significantly greater than that of healthy controls (median 1.96 cm3; IQR 0.57-5.48 and median 0.004 cm3; IQR 0.04-0.05, P < 0.001). There was no significant difference between the average FDG-TBRmean scores in the RA patients when compared to healthy controls (median 1.29; IQR 1.13-1.52 and median 1.29; IQR 1.13-1.52, respectively, P = 0.98). CONCLUSION: Quantitative assessment with NaF-PET/CT identifies increased molecular calcification in the wall of the abdominal aorta among patients with RA as compared with healthy controls, while quantitative assessment with FDG-PET/CT did not identify a difference in aortic vessel wall FDG uptake between the RA and healthy control groups.

Augmented and Mixed Reality: Technologies for Enhancing the Future of IR.

Augmented and mixed reality are emerging interactive and display technologies. These technologies are able to merge virtual objects, in either 2 or 3 dimensions, with the real world. Image guidance is the cornerstone of interventional radiology. With augmented or mixed reality, medical imaging can be more readily accessible or displayed in actual 3-dimensional space during procedures to enhance guidance, at times when this information is most needed. In this review, the current state of these technologies is addressed followed by a fundamental overview of their inner workings and challenges with 3-dimensional visualization. Finally, current and potential future applications in interventional radiology are highlighted.

Dose-dependent effects of ultrasound therapy on hepatocellular carcinoma.

Non-invasive ischemic cancer therapy requires reduced blood flow whereas drug delivery and radiation therapy require increased tumor perfusion for a better response. In this study we investigate the hypothesis that different dose models of antivascular ultrasound therapy (AVUS) can have opposite effects on hepatocellular carcinoma (HCC) tumor blood flow. HCC was induced in 22 Wistar rats by ingestion of diethylnitrosamine (DEN) for 12 weeks. Rats received AVUS treatment at low and high doses. Low dose group received 1 watt/cm2 ultrasound for 1 min with 0.2 mL microbubbles injected IV. High dose group received 2 watts/cm2 for 2 min with 0.7 mL microbubbles IV. A sham group did not receive any treatment. Tumor perfusion was measured before and after AVUS with contrast-enhanced ultrasound. Quantitative perfusion measures: perfusion index (PI) and peak enhancement (PE) were obtained from each AVUS dose. After high-dose AVUS, PE and PI decreased by an average of 58.1 ± 4.9% and 49.1 ± 6.5 % respectively. Conversely, following low dose AVUS, PE and PI increased from baseline by an average of 47.8 ± 4.5% % and 20.3 ± 2.4 %, respectively. The high-dose AVUS therapy decreased tumoral perfusion, an effect that could be used for noninvasive ischemic therapy. Conversely, low-dose therapy increased tumor perfusion, which may improve drug delivery or radiation therapy. These opposite therapy effects can support multiple roles for AVUS in cancer therapy by tunable modulation of blood flow in tumors.

Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy.

BACKGROUND AND AIMS: Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease-the principal causes of cancer mortality-have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are often not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE-induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence. APPROACH AND RESULTS: In this study, we characterized and leveraged the metabolic reprogramming demonstrated by latent HCC cells in response to TAE-induced ischemia to enable their detection in vivo using dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) of 13 carbon-labeled substrates. Under TAE-induced ischemia, latent HCC cells demonstrated reduced metabolism and developed a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP-MRSI of 1-13 C-pyruvate and its downstream metabolites, 1-13 C-lactate and 1-13 C-alanine, predicted histological viability. CONCLUSIONS: These studies provide a paradigm for imaging latent, treatment-refractory cancer cells, suggesting that DNP-MRSI provides a technology for this application.

MR Imaging Enables Real-Time Monitoring of In Vitro Electrolytic Ablation of Hepatocellular Carcinoma.

PURPOSE: To evaluate the capability of T2-weighted magnetic resonance (MR) imaging to monitor electrolytic ablation-induced cell death in real time. MATERIALS AND METHODS: Agarose phantoms arranged as an electrolytic cell were exposed to varying quantities of electric charge under constant current to create a pH series. The pH phantoms were subjected to T2-weighted imaging with region of interest quantitation of the acquired signal intensity. Subsequently, hepatocellular carcinoma (HCC) cells encapsulated in an agarose gel matrix were subjected to 10 V of electrolytic ablation for variable lengths of time with and without concurrent T2-weighted MR imaging. Cellular death was confirmed by a fluorescent reporter. Finally, to confirm that real-time MR images corresponded to ablation zones, 10 V electrolytic ablations were performed followed by the addition of pH-neutralizing 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer. RESULTS: Analysis of MR imaging from agarose gel pH phantoms demonstrated a relationship between signal intensity and pH at the anodes and cathodes. The steep negative phase of the anode model (pH < 3.55) and global minimum of the cathode model (pH ≈ 11.62) closely approximated established cytotoxic pH levels. T2-weighted MR imaging demonstrated a strong correlation of ablation zones with regions of HCC cell death (r = 0.986; R2 = 0.916; P < .0001). The addition of HEPES buffer to the hydrogel resulted in complete obliteration of MR imaging-observed ablation zones, confirming that change in pH directly caused the observed signal intensity attenuation of the ablation zone. CONCLUSIONS: T2-weighted MR imaging enabled the real-time detection of electrolytic ablation zones, demonstrating a strong correlation with histologic cell death.

Microbubble-enhanced ultrasound for the antivascular treatment and monitoring of hepatocellular carcinoma.

Background and Objective: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and its current management relies heavily on locoregional therapy for curative therapy, bridge to transplant, and palliative therapy. Locoregional therapies include ablation and hepatic artery therapies such as embolization and radioembolization. In this study we evaluate the feasibility of using novel antivascular ultrasound (AVUS) as a noninvasive locoregional therapy to reduce perfusion in HCC lesions in a rat model and, monitor the effect with contrast-enhanced ultrasound imaging. Methods: HCC was induced in 36 Wistar rats by the ingestion of 0.01% diethylnitrosamine (DEN) for 12 weeks. Two therapy regimens of AVUS were evaluated. A primary regimen (n = 19) utilized 2-W/cm2, 3-MHz ultrasound (US) for 6 minutes insonation with 0.7 ml of microbubbles administered as an intravenous bolus. An alternate dose at half the primary intensity, sonication time, and contrast concentration was evaluated in 11 rats to assess the efficacy of a reduced dose. A control group (n = 6) received a sham therapy. Tumor perfusion was measured before and after AVUS with nonlinear contrast ultrasound (NLC) and power Doppler (PD). The quantitative perfusion measures included perfusion index (PI), peak enhancement (PE), time to peak (TTP), and perfusion area from NLC and PD scans. Total tumor area perfused during the scan was measured by a postprocessing algorithm called delta projection. Tumor histology was evaluated for signs of tissue injury and for vascular changes using CD31 immunohistochemistry. Results: DEN exposure induced autochthonous hepatocellular carcinoma lesions in all rats. Across all groups prior to therapy, there were no significant differences in the nonlinear contrast observations of peak enhancement and perfusion index. In the control group, there were no significant differences in any of the parameters after sham treatment. After the primary AVUS regimen, there were significant changes in all parameters (p ≤ 0.05) indicating substantial decreases in tumor perfusion. Peak enhancement in nonlinear contrast scans showed a 37.9% ± 10.1% decrease in tumor perfusion. Following reduced-dose AVUS, there were no significant changes in perfusion parameters, although there was a trend for the nonlinear contrast observations of peak enhancement and perfusion index to increase. Conclusion: This study translated low-intensity AVUS therapy into a realistic in vivo model of HCC and evaluated its effects on the tumor vasculature. The primary dose of AVUS tested resulted in significant vascular disruption and a corresponding reduction in tumor perfusion. A reduced dose of AVUS, on the other hand, was ineffective at disrupting perfusion but demonstrated the potential for enhancing tumor blood flow. Theranostic ultrasound, where acoustic energy and microbubbles are used to monitor the tumor neovasculature as well as disrupt the vasculature and treat lesions, could serve as a potent tool for delivering noninvasive, locoregional therapy for hepatocellular carcinoma.