Comparative Study of Histotripsy Pulse Parameters Used to Inactivate Escherichia coli in Suspension.

OBJECTIVE: Bacterial loads can be effectively reduced using cavitation-mediated focused ultrasound, or histotripsy. In this study, gram-negative bacteria (Escherichia coli) in suspension were used as model bacteria to evaluate the effectiveness of two regimens of histotripsy treatments: cavitation histotripsy (CH) and boiling histotripsy (BH). METHODS: Ten-milliliter volumes of Escherichia coli were treated at different negative focal pressure amplitudes and over time periods up to 40 min. Cavitation activity was characterized with coaxial passive cavitation detection (PCD) and synchronized plane wave B-mode imaging. RESULTS: CH treatments exhibited a threshold behavior that was consistent with PCD metrics of cavitation. Above the threshold, bacterial inactivation followed a monotonically increasing log-linear relationship that indicated an exponential inactivation rate. BH exhibited no threshold, but instead followed a different monotonically increasing inactivation rate. Inactivation rates were larger for BH at or below the CH threshold, and larger for CH substantially above the threshold. CH studies performed at different pulse lengths at the same duty cycle had similar inactivation rates, suggesting that at any given pressure amplitude, the "on time" was the most important variable for inactivating E. coli. The maximum inactivation was produced by CH at the highest pressure amplitudes used, leading to a log reduction >4.2 for a 40 min treatment. CONCLUSION: The results of this study suggest that both CH and BH can be used to inactivate E. coli in suspension, with the optimal regimen depending on the attainable peak negative focal pressure at the target.

Enhanced efficacy of direct immunochemotherapy for hepatic cancer with image-guided intratumoral radiofrequency hyperthermia.

BACKGROUND: It is still a challenge to prevent tumor recurrence post radiofrequency ablation (RFA) of medium-to-large hepatocellular carcinomas (HCC). Immunochemotherapy, a combination of immunotherapy with chemotherapy, has demonstrated a great potential in augmenting the treatment efficacy for some malignancies. In this study, we validated the feasibility of using radiofrequency hyperthermia (RFH)-enhanced intratumoral immunochemotherapy of LTX-315 with liposomal doxorubicin for rat orthotopic HCC. METHODS: Different groups of luciferase-labeled rat HCC cells and rat orthotopic HCC models were treated by: (1) phosphate buffered saline; (2) RFH; (3) LTX-315; (4) RFH+LTX-315; (5) liposomal doxorubicin; (6) RFH+liposomal doxorubicin; (7) LTX-315+liposomal doxorubicin; and (8) RFH+LTX-315+liposomal doxorubicin. Cell viabilities and apoptosis of different treatment groups were compared. Changes in tumor sizes were quantified by optical and ultrasound imaging, which were confirmed by subsequent histopathology. The potential underlying biological mechanisms of the triple combination treatment (RFH+LTX-315+liposomal doxorubicin) were explored. RESULTS: Flow cytometry and MTS assay showed the highest percentage of apoptotic cells and lowest cell viability in the triple combination treatment group compared with other seven groups (p<0.001). Tumors in this group also presented the most profound decrease in bioluminescence signal intensities and the smallest tumor volumes compared with other seven groups (p<0.001). A significant increase of CD8+ T cells, CD8+/interferon (IFN)-γ+ T cells, CD8+/tumor necrosis factor (TNF)-α+ T cells, and natural killer cells, and a significant decrease of regulatory T cells were observed in the tumors (p<0.001). Meanwhile, a significantly higher level of Th1-type cytokines in both plasma (interleukin (IL)-2, IL-12, IL-18, IFN-γ) and tumors (IL-2, IL-18, IFN-γ, TNF-α), as well as a significantly lower Th2-type cytokines of IL-4 and IL-10 in plasma and tumor were detected. CONCLUSIONS: Intratumoral RFA-associated RFH could enhance the efficacy of immunochemotherapy of LTX-315 with liposomal doxorubicin for HCC, which may provide a new strategy to increase the curative efficacy of thermal ablation for medium-to-large HCC.

Development of a Three-Dimensional Multi-Modal Perfusion-Thermal Electrode System for Complete Tumor Eradication.

Background: Residual viable tumor cells after ablation at the tumor periphery serve as the source for tumor recurrence, leading to treatment failure. Purpose: To develop a novel three-dimensional (3D) multi-modal perfusion-thermal electrode system completely eradicating medium-to-large malignancies. Materials and Methods: This study included five steps: (i) design of the new system; (ii) production of the new system; (iii) ex vivo evaluation of its perfusion-thermal functions; (iv) mathematic modeling and computer simulation to confirm the optimal temperature profiles during the thermal ablation process, and; (v) in vivo technical validation using five living rabbits with orthotopic liver tumors. Results: In ex vivo experiments, gross pathology and optical imaging demonstrated the successful spherical distribution/deposition of motexafin gadolinium administered through the new electrode, with a temperature gradient from the electrode core at 80 °C to its periphery at 42 °C. An excellent repeatable correlation of temperature profiles at varying spots, from the center to periphery of the liver tumor, was found between the mathematic simulation and actual animal tumor models (Pearson coefficient ≥0.977). For in vivo validation, indocyanine green (ICG) was directly delivered into the peritumoral zones during simultaneous generation of central tumoral lethal radiofrequency (RF) heat (>60 °C) and peritumoral sublethal RF hyperthermia (<60 °C). Both optical imaging and fluorescent microscopy confirmed successful peritumoral ICG distribution/deposition with increased heat shock protein 70 expression. Conclusion: This new 3D, perfusion-thermal electrode system provided the evidence on the potential to enable simultaneous delivery of therapeutic agents and RF hyperthermia into the difficult-to-treat peritumoral zones, creating a new strategy to address the critical limitation, i.e., the high incidence of residual and recurrent tumor following thermal ablation of unresectable medium-to-large and irregular tumors.

Exploring telerobotic cardiac catheter ablation in a rural community hospital: A pilot study.

Background: Telerobotic surgery could improve access to specialty procedures such as cardiac catheter ablation in rural and underserved regions in the United States and worldwide. Advancements in telecommunications, internet infrastructure, and surgical robotics are lowering the technical hurdles for this future healthcare delivery paradigm. Nonetheless, important questions remain regarding the safe implementation of telerobotic surgery in rural community hospital settings. Objective: The purpose of this study was to pilot test a system and methods to explore telerobotic cardiac catheter ablation in a rural community hospital setting. Methods: We assembled a portable preclinical telerobotic catheter ablation system from commercial-grade components using third-party vendors. We then carried out 4 telerobotic surgery simulations with an urban surgeon and a rural community hospital operating room (OR) team spanning a distance of more than 2000 miles. Two challenge scenarios were incorporated into the simulations, including loss of network connection and cardiac perforation with subsequent life-threatening tamponade physiology. An ethnographic analysis was then performed. Results: Interviews and observations suggested that rural OR teams readily adapt to the telesurgery context. However, participant perceptions of team trust, communication, and emergency management were significantly altered by the remote location of the surgeon. In addition, most participants believed the OR team would have been better equipped for the challenges had they received formal training or had prior experience with the procedure being simulated. Conclusion: We demonstrate the utility and feasibility of a system and methods for studying specialty telerobotic surgery in a rural hospital OR setting.

Opportunities and Barriers to Rural Telerobotic Surgical Health Care in 2021: Report and Research Agenda from a Stakeholder Workshop.

Background: There are well-recognized challenges to delivering specialty health care in rural settings. These challenges are particularly evident for specialized surgical health care due to the lack of trained operators in rural communities. Telerobotic surgery could have a significant impact on the rural-urban health care gap, but thus far, the promise of this method of health care delivery has gone unrealized. With the increasing adoption of telehealth over the past year, along with the maturation of telecommunication and robotic technologies over the past 2 decades, a reappraisal of the opportunities and barriers to widespread implementation of telerobotic surgery is warranted. Here we report the outcome of a rural telerobotic stakeholder workshop to explore modern-day issues critical to the advancement of telerobotic surgical health care. Materials and Methods: We assembled a multidisciplinary stakeholder panel to participate in a 2-day Rural Telerobotic Surgery Stakeholder Workshop. Participants had diverse expertise, including specialty surgeons, technology experts, and representatives of the broader telerobotic health care ecosystem, including economists, lawyers, regulatory consultants, public health advocates, rural hospital administrators, nurses, and payers. The research team reviewed transcripts from the workshop with themes identified and research questions generated based on stakeholder comments and feedback. Results: Stakeholder discussions fell into four general themes, including (1) operating room team interactions, (2) education and training, (3) network and security, and (4) economic issues. The research team then identified several research questions within each of these themes and provided specific research strategies to address these questions. Conclusions: There are still important unanswered questions regarding the implementation and adoption of rural telerobotic surgery. Based on stakeholder feedback, we have developed a research agenda along with suggested strategies to address outstanding research questions. The successful execution of these research opportunities will fill critical gaps in our understanding of how to advance the widespread adoption of rural telerobotic health care.

Interventional real-time optical imaging guidance for complete tumor ablation.

The aim of this study was to develop an interventional optical imaging (OI) technique for intraprocedural guidance of complete tumor ablation. Our study employed four strategies: 1) optimizing experimental protocol of various indocyanine green (ICG) concentrations/detection time windows for ICG-based OI of tumor cells (ICG cells); 2) using the optimized OI to evaluate ablation-heat effect on ICG cells; 3) building the interventional OI system and investigating its sensitivity for differentiating residual viable tumors from nonviable tumors; and 4) preclinically validating its technical feasibility for intraprocedural monitoring of radiofrequency ablations (RFAs) using animal models with orthotopic hepatic tumors. OI signal-to-background ratios (SBRs) among preablation tumors, residual, and ablated tumors were statistically compared and confirmed by subsequent pathology. The optimal dose and detection time window for ICG-based OI were 100 µg/mL at 24 h. Interventional OI displayed significantly higher fluorescence signals of viable ICG cells compared with nonviable ICG cells (189.3 ± 7.6 versus 63.7 ± 5.7 au, P < 0.001). The interventional OI could differentiate three definitive zones of tumor, tumor margin, and normal surrounding liver, demonstrating significantly higher average SBR of residual viable tumors compared to ablated nonviable tumors (2.54 ± 0.31 versus 0.57 ± 0.05, P < 0.001). The innovative interventional OI technique permitted operators to instantly detect residual tumors and thereby guide repeated RFAs, ensuring complete tumor eradication, which was confirmed by ex vivo OI and pathology. In conclusion, we present an interventional oncologic technique, which should revolutionize the current ablation technology, leading to a significant advancement in complete treatment of larger or irregular malignancies.

Sonographic Features of Abscess Maturation in a Porcine Model.

Abscesses are walled-off collections of infected fluids that often develop as complications in the setting of surgery and trauma. Treatment is usually limited to percutaneous catheterization with a course of antibiotics. As an alternative to current treatment strategies, a histotripsy approach was developed and tested in a novel porcine animal model. The goal of this article is to use advanced ultrasound imaging modes to extract sonographic features associated with the progression of abscess development in a porcine model. Intramuscular or subcutaneous injections of a bi-microbial bacteria mixture plus dextran particles as an irritant led to identifiable abscesses over a 2 to 3 wk period. Selected abscesses were imaged at least weekly with B-mode, 3-D B-mode, shear-wave elastography and plane-wave Doppler imaging. Mature abscesses were characterized by a well-defined core of varying echogenicity surrounded by a hypoechoic capsule that was highly vascularized on Doppler imaging. 3-D imaging demonstrated the natural history of abscess morphology, with the abscess becoming less complex in shape and increasing in volume. Furthermore, shear-wave elastography demonstrated variations in stiffness as phlegmon becomes abscess and then liquefies, over time. These ultrasound features potentially provide biomarkers to aid in selection of treatment strategies for abscesses.

Interventional Optical Imaging-Monitored Synergistic Effect of Radio-Frequency Hyperthermia and Oncolytic Immunotherapy.

PURPOSE: To develop a new interventional oncology technique using indocyanine green (ICG)-based interventional optical imaging (OI) to monitor the synergistic effect of radiofrequency hyperthermia (RFH)-enhanced oncolytic immunotherapy. MATERIALS AND METHODS: This study included (1) optimization of ICG dose and detection time-window for intracellular uptake by VX2 tumor cells; (2) in-vitro confirmation of capability of using ICG-based OI to assess efficacy of RFH-enhanced oncolytic therapy (LTX-401) for VX2 cells; and (3) in-vivo validation of the interventional OI-monitored, intratumoral RFH-enhanced oncolytic immunotherapy using rabbit models with orthotopic liver VX2 tumors. Both in-vitro and in-vivo experiments were divided into four study groups (n=6/group) with different treatments: (1) combination therapy of RFH+LTX-401; (2) RFH alone at 42°C for 30 min; (3) oncolytic therapy with LTX-401; and (4) control with saline. For in-vivo validation, orthotopic hepatic VX2 tumors were treated using a new multi-functional perfusion-thermal radiofrequency ablation electrode, which enabled simultaneous delivery of both LTX-401 and RFH within the tumor and at the tumor margins. RESULTS: In in-vitro experiments, taking up of ICG by VX2 cells was linearly increased from 0 µg/mL to 100 µg/mL, while ICG-signal intensity (SI) reached the peak at 24 hours. MTS assay and apoptosis analysis demonstrated the lowest cell viability and highest apoptosis in combination therapy, compared to three monotherapies (P<0.005). In in-vivo experiments, ultrasound imaging detected the smallest relative tumor volume for the combination therapy, compared to other monotherapies (P<0.005). In both in-vitro and in-vivo experiments, ICG-based interventional optical imaging detected a significantly decreased SI in combination therapy (P<0.005), which was confirmed by the "gold standard" optical/X-ray imaging (P<0.05). Pathologic/laboratory examinations further confirmed the significantly decreased cell proliferation with Ki-67 staining, significantly increased apoptotic index with TUNEL assay, and significantly increased quantities of CD8 and CD80 positive cells with immunostaining in the combination therapy group, compared to other three control groups (P<0.005). CONCLUSIONS: We present a new interventional oncology technique, interventional optical imaging-monitored RFH-enhanced oncolytic immunotherapy, which may open new avenues to effectively manage those patients with larger, irregular and unresectable malignancies, not only in liver but also the possibility in other organs.

Treating Porcine Abscesses with Histotripsy: A Pilot Study.

Infected abscesses are walled-off collections of pus and bacteria. They are a common sequela of complications in the setting of surgery, trauma, systemic infections and other disease states. Current treatment is typically limited to antibiotics with long-term catheter drainage, or surgical washout when inaccessible to percutaneous drainage or unresponsive to initial care efforts. Antibiotic resistance is also a growing concern. Although bacteria can develop drug resistance, they remain susceptible to thermal and mechanical damage. In particular, short pulses of focused ultrasound (i.e., histotripsy) generate mechanical damage through localized cavitation, representing a potential new paradigm for treating abscesses non-invasively, without the need for long-term catheterization and antibiotics. In this pilot study, boiling and cavitation histotripsy treatments were applied to subcutaneous and intramuscular abscesses developed in a novel porcine model. Ultrasound imaging was used to evaluate abscess maturity for treatment monitoring and assessment of post-treatment outcomes. Disinfection was quantified by counting bacteria colonies from samples aspirated before and after treatment. Histopathological evaluation of the abscesses was performed to identify changes resulting from histotripsy treatment and potential collateral damage. Cavitation histotripsy was more successful in reducing the bacterial load while having a smaller treatment volume compared with boiling histotripsy. The results of this pilot study suggest focused ultrasound may lead to a technology for in situ treatment of acoustically accessible abscesses.

Percutaneous Extra-Anatomic Lymphovenous Bypass Creation: Toward Treatment of Central Conducting Lymphatic Obstructions.

INTRODUCTION: Protein-losing enteropathy manifests as a loss of serum proteins through the gastrointestinal tract, resulting in hypoproteinemia, extravascular fluid retention, and edema. Management consists of nutritional maintenance in conjunction with interventions targeted at treating the underlying etiology. MATERIALS AND METHODS: This report describes a patient with protein-losing enteropathy from a central conducting lymphatic obstruction who was treated with percutaneous extra-anatomic lymphovenous bypass creation. RESULTS: A modified gun-sight technique was used to create a lymphovenous bypass between an occluded terminal thoracic duct and the left internal jugular vein. CONCLUSION: A percutaneous technique to reconstruct the terminal thoracic duct via lymphovenous bypass creation was feasible.

Effect of Stiffness of Large Extravascular Hematomas on Their Susceptibility to Boiling Histotripsy Liquefaction in Vitro.

Large intra-abdominal, retroperitoneal and intramuscular hematomas are common consequences of sharp and blunt trauma and post-surgical bleeds, and often threaten organ failure, compartment syndrome or spontaneous infection. Current therapy options include surgical evacuation and placement of indwelling drains that are not effective because of the viscosity of the organized hematoma. We have previously reported the feasibility of using boiling histotripsy (BH)-a pulsed high-intensity focused ultrasound method-for liquefaction of large volumes of freshly coagulated blood and subsequent fine-needle aspiration. The goal of this work was to evaluate the changes in stiffness of large coagulated blood volumes with aging and retraction in vitro, and to correlate these changes with the size of the BH void and, therefore, the susceptibility of the material to BH liquefaction. Large-volume (55-200 mL) whole-blood clots were fabricated in plastic molds from human and bovine blood, either by natural clotting or by recalcification of anticoagulated blood, with or without addition of thrombin. Retraction of the clots was achieved by incubation for 3 h, 3 d or 8 d. The shear modulus of the samples was measured with a custom-built indentometer and shear wave elasticity (SWE) imaging. Sizes of single liquefied lesions produced with a 1.5-MHz high-intensity focused ultrasound transducer within a 30-s standard BH exposure served as the metric for susceptibility of clot material to this treatment. Neither the shear moduli of naturally clotted human samples (0.52 ± 0.08 kPa), nor their degree of retraction (ratio of expelled fluid to original volume 50%-58%) depended on the length of incubation within 0-8 d, and were significantly lower than those of bovine samples (2.85 ± 0.17 kPa, retraction 5%-38%). In clots made from anticoagulated bovine blood, the variation of calcium chloride concentration within 5-40 mmol/L did not change the stiffness, whereas lower concentrations and the addition of thrombin resulted in significantly softer clots, similar to naturally clotted human samples. Within the achievable shear modulus range (0.4-1.6 kPa), the width of the BH-liquefied lesion was more affected by the changes in stiffness than the length of the lesion. In all cases, however, the lesions were larger compared with any soft tissue liquefied with the same BH parameters, indicating higher susceptibility of hematomas to BH damage. These results suggest that clotted bovine blood with added thrombin is an acceptable in vitro model of both acute and chronic human hematomas for assessing the efficiency of BH liquefaction strategies.

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.

Virtual-Reality Guided Versus Fluoroscopy-Guided Transseptal Puncture in a Cardiac Phantom.

OBJECTIVES: We compared virtual-reality guided versus fluoroscopy-guided transseptal puncture by novice and experienced operators in a cardiac phantom. Outcome measures included accuracy, time, transseptal path distance, and a survey of the operator experience. METHODS: A transseptal simulator was created using a Plexiglas case and a 3D-printed cardiac phantom with a replaceable fossa ovalis, a customized support, and an electromagnetic tracking system. A precisely registered virtual-reality rendering was constructed. To display the transseptal instruments in virtual reality, we attached electromagnetic sensors to standard transseptal instruments, including the needle, dilator, and sheath. Each subject completed 6 simulated transseptal punctures (3 fluoroscopy-guided and 3 virtual-reality guided). We measured the distance traversed by the transseptal needle, accuracy, and time for each simulated transseptal puncture. Operators were then surveyed regarding their experience. RESULTS: A total of 8 subjects (6 faculty, 2 fellows) completed the trial. We found that virtual-reality guidance resulted in significantly more accurate puncture site selection and, subjectively, was more intuitive for the operator, particularly for novices. None of the participants experienced negative symptoms in virtual reality that required cessation of the procedure. CONCLUSIONS: Virtual reality compared with fluoroscopic guidance for transseptal puncture shows considerable promise, particularly for novice trainees, where it could lessen the learning curve. Current barriers to widespread implementation are discussed.

Contrast-enhanced ultrasound to ultrasound fusion during microwave ablation: feasibility study in a perfused porcine liver model.

PURPOSE: To obtain a complete response with thermal ablation, the margin and entire tumor volume must be treated. Real-time ultrasound visualization is limited during ablation due to gas production. This study assesses the feasibility of fusing volumetric contrast-enhanced ultrasound (CEUS), obtained immediately prior to microwave ablation, with real-time CEUS during and following ablation in a machine-perfused porcine liver. METHODS: Ten, 3-4 cm microwave ablations were performed in five explanted perfused livers. Prior to ablation, microbubbles were injected into the vasculature while an ultrasound sweep across the liver captured a volumetric image during maximum enhancement. This volumetric image was then fused to overlay the real-time ultrasound imaging. Since the perfused livers did not have tumors, a spherical marker circumscribing a target volume was placed on the images. Approximatively, 75% of the total intended circumscribed spherical volume was ablated. Following ablation, a second bolus injection of ultrasound contrast was administered demonstrating continued enhancement of the intentionally non-ablated 25%. A second volumetric image of the post-ablation CEUS was then fused to overlay the real-time ultrasound images for guidance during ablation of the remaining enhancing volume. RESULTS: Technical success was achieved in 100% of the cases. The pre- and then the post-ablation CEUS volume was fused with real-time imaging during antenna placement for initial and subsequent ablation. CONCLUSION: CEUS-CEUS fusion during thermal ablation is feasible and greatly improves the workflow. The approach may augment the use of dynamic CEUS for guidance, improving antenna placement, and aiding in the identification and ablation of initial and residual enhancing tissue.

Inactivation of Planktonic Escherichia coli by Focused 1-MHz Ultrasound Pulses with Shocks: Efficacy and Kinetics Upon Volume Scale-Up.

This study addresses inactivation of E. coli in either 5- or 10-mL volumes, which were 50- to 100-fold greater than used in an earlier study (Brayman et al. 2017). Cells were treated with 1-MHz pulsed high-intensity focused ultrasound (10 cycles, 2-kHz repetition frequency, +65/-12.8 MPa focal pressures). The surviving fraction was assessed by coliform assay, and inactivation demonstrated curvilinear kinetics. The reduction of surviving fraction to 50% required 2.5 or 6 min in 5- or 10-mL samples, respectively. Exposure of 5 mL for 20 min reduced the surviving fraction to ∼1%; a similar exposure of 10-mL samples reduced the surviving fraction to ∼10%. Surviving cells from 5-min exposures appeared normal under light microscopy, with minimal debris; after 20 min, debris dominated. Transmission electron microscopy images of insonated samples showed some undamaged cells, a few damaged but largely intact cells and comminuted debris. Cellular damage associated with substantive but incomplete levels of inactivation can be variable, ranging from membrane holes tens of nanometers in diameter to nearly complete comminution.

Hepatotoxic Dose Thresholds by Positron-Emission Tomography After Yttrium-90 Radioembolization of Liver Tumors: A Prospective Single-Arm Observational Study.

PURPOSE: To define a threshold radiation dose to non-tumoral liver from 90Y radioembolization that results in hepatic toxicity using pair-production PET. MATERIALS AND METHODS: This prospective single-arm study enrolled 35 patients undergoing radioembolization. A total of 34 patients (27 with HCC and 7 with liver metastases) were included in the final analysis. Of 27 patients with underlying cirrhosis, 22 and 5 patients were Child-Pugh A and B, respectively. Glass and resin microspheres were used in 32 (94%) and 2 (6%) patients, respectively. Lobar and segmental treatment was done in 26 (76%) and 8 (24%) patients, respectively. Volumetric analysis was performed on post-radioembolization time-of-flight PET imaging to determine non-tumoral parenchymal dose. Hepatic toxicity was evaluated up to 120 days post-treatment, with CTCAE grade ≤ 1 compared to grade ≥ 2. RESULTS: The median dose delivered to the non-tumoral liver in the treated lobe was 49 Gy (range 0-133). A total of 15 patients had grade ≤ 1 hepatic toxicity, and 19 patients had grade ≥ 2 toxicity. Patients with a grade ≥ 2 change in composite toxicity (70.7 vs. 43.8 Gy), bilirubin (74.1 vs. 43.3 Gy), albumin (84.2 vs. 43.8 Gy), and AST (94.5 vs. 47.1 Gy) have significantly higher non-tumoral parenchymal doses than those with grade ≤ 1. Liver parenchymal dose and Child-Pugh status predicted grade ≥ 2 toxicity, observed above a dose threshold of 54 Gy. CONCLUSION: Increasing delivered 90Y dose to non-tumoral liver measured by internal pair-production PET correlates with post-treatment hepatic toxicity. The likelihood of toxicity exceeds 50% at a dose threshold of 54 Gy. ClinicalTrials.gov identifier: NCT02848638.

Prospective Trial Using Internal Pair-Production Positron Emission Tomography to Establish the Yttrium-90 Radioembolization Dose Required for Response of Hepatocellular Carcinoma.

PURPOSE: To prospectively assess the threshold dose for objective response of hepatocellular carcinoma (HCC), using 90Y internal pair-production positron emission tomography (PET) to quantify the radiation dose delivered to hepatic tumors after radioembolization. METHODS AND MATERIALS: A prospective study was performed under institutional review board approval from 2012 to 2014. Thirty-five patients with primary and secondary liver tumors undergoing 90Y treatment were recruited. Eight patients did not meet inclusion criteria, and 27 patients with HCC were included for analysis. Time-of-flight PET imaging was performed immediately after radioembolization and voxel values converted into 90Y activity. The radioembolization dose was calculated from PET images, and image segmentation was performed with volumetric analysis of dose deposition within tumors. Radiographic response was assessed on follow-up imaging. RESULTS: Treated HCC showed 84% objective response, 11% stable disease, and 5% progressive disease according to modified RECIST 1.1 response criteria. Responders had a higher median 90Y tumor dose than nonresponders (225 Gy vs 83 Gy, P < .01). Logistic regression models show tumor dose (P = .002) strongly predicted objective response. All nonresponders had tumor dose <200 Gy. No statistical difference for patient age, tumor volume, multifocal or extrahepatic disease, portal vein invasion, or injected 90Y activity was found between responders and nonresponders. CONCLUSIONS: Hepatocellular carcinoma that resulted in objective response after radioembolization had a greater median tumor dose of 225 Gy, compared with 83 Gy in nonresponders. Delivered tumor dose can be assessed by PET and significantly impacts treatment response in HCC.

Dual-balloon infusion microcatheter for selective drug-eluting bead transarterial chemoembolization: initial feasibility study.

PURPOSE: We aimed to demonstrate feasibility of the use of a dual-balloon infusion microcatheter for segmental/subsegmental drug-eluting bead transarterial chemoembolization (DEB-TACE). METHODS: Over a 16-month period, 15 segmental and 21 subsegmental DEB-TACE procedures were attempted using a dual-balloon anti-reflux microcatheter (IsoFlow™ microcatheter, Vascular Designs Inc.) in 21 patients (15 males; median age, 61 years; range, 49-82 years) with hepatocellular carcinoma (Barcelona clinic liver cancer stage A [n=4]; B [n=12]; C [n=5]) with one to three tumors, median size of 3.4 cm (1.2-9 cm). Follow-up enhanced computed tomography or magnetic resonance imaging was obtained at one month then subsequently every three months for one year. Technical success was evaluated. Modified RECIST criteria was used for target tumor response assessment. Safety was evaluated by assessing for arterial injury and hepatic injury at the time of the procedure and subsequent evidence of complications and liver toxicity. RESULTS: In 26 of the procedures, the segmental/subsegmental arteries were thought not to be easily selected with standard microcatheters due to the arterial branches being severely tortuous/angulated or atretic from prior TACE or anti-angiogenic therapy or could not be catheterized. Radiologic response assessment of treated tumors demonstrated 32% complete response, 19% partial response, 34% stable disease, and 15% progressive disease. No complications occurred. The median time to progression for the targeted tumors was 7 months (range, 3-12 months). CONCLUSION: DEB-TACE, using this dual-balloon anti-reflux infusion microcatheter is feasible and safe.

Segmental Yttrium-90 Radioembolization versus Segmental Chemoembolization for Localized Hepatocellular Carcinoma: Results of a Single-Center, Retrospective, Propensity Score-Matched Study.

PURPOSE: To compare segmental radioembolization with segmental chemoembolization for localized, unresectable hepatocellular carcinoma (HCC) not amenable to ablation. MATERIALS AND METHODS: In a single-center, retrospective study (2010-2015), 101 patients with 132 tumors underwent segmental radioembolization, and 77 patients with 103 tumors underwent segmental doxorubicin-based drug-eluting embolic or conventional chemoembolization. Patients receiving chemoembolization had worse performance status (Eastern Cooperative Oncology Group 0, 76% vs 56%; P = .003) and Child-Pugh class (class A, 65% vs 52%; P = .053); patients receiving radioembolization had larger tumors (32 mm vs 26 mm; P < .001), more infiltrative tumors (23% vs 9%; P = .01), and more vascular invasion (18% vs 1%; P < .001). Toxicity, tumor response, tumor progression, and survival were compared. Analyses were weighted using a propensity score (PS). RESULTS: Toxicity rates were low, without significant differences. Index and overall complete response rates were 92% and 84% for radioembolization and 74% and 58% for chemoembolization (P = .001 and P < .001). Index tumor progression at 1 and 2 years was 8% and 15% in the radioembolization group and 30% and 42% in the chemoembolization group (P < .001). Median progression-free and overall survival were 564 days and 1,198 days in the radioembolization group and 271 days and 1,043 days in the chemoembolization group (PS-adjusted P = .002 and P = .35; censored by transplant PS-adjusted P < .001 and P = .064). CONCLUSIONS: Segmental radioembolization demonstrates higher complete response rates and local tumor control compared with segmental chemoembolization for HCC, with similar toxicity profiles. Superior progression-free survival was achieved.

Inactivation of Planktonic Escherichia coli by Focused 2-MHz Ultrasound.

This study was motivated by the desire to develop a non-invasive means to treat abscesses, and represents the first steps toward that goal. Non-thermal, high-intensity focused ultrasound (HIFU) was used to inactivate Escherichia coli (∼1 × 109 cells/mL) in suspension. Cells were treated in 96-well culture plate wells using 1.95-MHz ultrasound and incident focal acoustic pressures as high as 16 MPa peak positive and 9.9 MPa peak negative (free field measurements). The surviving fraction was assessed by coliform culture and the alamarBlue assay. No biologically significant heating was associated with ultrasound exposure. Bacterial inactivation kinetics were well described by a half-life model, with a half-time of 1.2 min. At the highest exposure levels, a 2log inactivation was typically achieved within 10 min. The free field-equivalent peak negative acoustic pressure threshold for inactivation was ∼7 MPa. At the highest acoustic pressures used, inactivation efficacy was insensitive to reciprocal changes in pulse length and pulse repetition frequency at constant duty factor. Although treated volumes were very small, proof of principle was provided by these experiments.