contrast-enhanced-subharmonic-aided-pressure-estimation-shape-using

Contrast-Enhanced Subharmonic Aided Pressure Estimation (SHAPE) Using Ultrasound Imaging with a Focus on Identifying Portal Hypertension

Noninvasive, accurate measurement of pressures within the human body has long been an important but elusive clinical goal. Contrast agents for ultrasound ...

Thomas Jefferson University

The objective of this study was to evaluate and compare contrast-enhanced subharmonic and harmonic ultrasound as tools for characterizing solid renal masses and monitoring their response to cryoablation therapy.

Contrast-Enhanced Subharmonic and Harmonic Ultrasound of Renal Masses Undergoing Percutaneous Cryoablation.

To evaluate the accuracy and change over time of contrast-enhanced ultrasound (US) imaging for assessing residual blood flow after transarterial chemoembolization of hepatocellular carcinoma with drug-eluting beads at 2 different follow-up intervals.

Contrast-enhanced ultrasound evaluation of residual blood flow to hepatocellular carcinoma after treatment with transarterial chemoembolization using drug-eluting beads: a prospective study.

Pembrolizumab is a monoclonal antibody that is designed against programmed cell death protein 1 (PD-1). Pembrolizumab and other immunocheckpoint-blocking monoclonal antibodies work by modulating a patient's own immune system to increase anti-tumor activity. While immunocheckpoint blockade has shown promising results, only 20-40 % of patients experience objective clinical benefit. Differences in individual tumor biology and the presence multiple immune checkpoints present a challenge for treatment. Because radiotherapy has immunomodulatory effects on the tumor microenvironment, it has the potential to synergize with immunotherapy and augment tumor response. NCT02318771 is a phase 1 clinical trial designed to investigate the immunomodulatory effects of radiation therapy in combination with pembrolizumab.

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy.

Contrast-Enhanced Sonography and Fusion Technology for Assessment of an Embolized Renal Angiomyolipoma.

Mesenteric vascular insufficiency is a serious medical condition that may lead to bowel infarction, morbidity, and mortality that may approach 50%. Recommended therapy for acute mesenteric ischemia includes aspiration embolectomy, transcatheter thrombolysis, and angioplasty with or without stenting for the treatment of underlying arterial stenosis. Nonocclusive mesenteric ischemia may respond to transarterial infusion of vasodilators such as nitroglycerin, papaverine, glucagon, and prostaglandin E1. Recommended therapy for chronic mesenteric ischemia includes angioplasty with or without stent placement and, if an endovascular approach is not possible, surgical bypass or endarterectomy. The diagnosis of median arcuate ligament syndrome is controversial, but surgical release may be appropriate depending on the clinical situation. Venous mesenteric ischemia may respond to systemic anticoagulation alone. Transhepatic or transjugular superior mesenteric vein catheterization and thrombolytic infusion can be offered depending on the severity of symptoms, condition of the patient, and response to systemic anticoagulation. Adjunct transjugular intrahepatic portosystemic shunt creation can be considered for outflow improvement. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria Radiologic Management of Mesenteric Ischemia.

Metastatic liver disease is a major cause of cancer-related morbidity and mortality. Surgical resection is considered the only curative treatment, yet only a minority is eligible. Patients who present with unresectable disease are treated with systemic agents and/or locoregional therapies. The latter include thermal ablation and catheter-based transarterial interventions. Thermal ablation is reserved for those with limited tumor burden. It is used to downstage the disease to enable curative surgical resection, as an adjunct to surgery, or in select patients it is potentially curative. Transarterial therapies are indicated in those with more diffuse disease. The goals of care are to palliate symptoms and prolong survival. The indications and supporting data for thermal ablation and transarterial interventions are reviewed, technical and tumor factors that need to be considered prior to intervention are outlined, and finally several cases are presented.

Metastatic Liver Disease: Indications for Locoregional Therapy and Supporting Data.

Obtaining central venous access is one of the most commonly performed procedures in hospital settings. Multiple devices such as peripherally inserted central venous catheters, tunneled central venous catheters (eg, Hohn catheter, Hickman catheter, C. R. Bard, Inc, Salt Lake City UT), and implantable ports are available for this purpose. The device selected for central venous access depends on the clinical indication, duration of the treatment, and associated comorbidities. It is important for health care providers to familiarize themselves with the types of central venous catheters available, including information about their indications, contraindications, and potential complications, especially the management of catheters in the setting of catheter-related bloodstream infections. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria Radiologic Management of Central Venous Access.

Iliac artery occlusive disease can present as a sudden-onset acute thrombotic or thromboembolic event or as a chronic progressive atherosclerotic process that presents as claudication progressing to rest pain. Depending on the clinical presentation, the diagnosis is usually confirmed through Doppler vascular ultrasound, CT angiography, or MR angiography; the choice of imaging is usually based on modality availability and the presence of patient comorbidities such as chronic kidney disease. The Trans-Atlantic Inter-Society Consensus II classification system is commonly used to describe the extent of the peripheral vascular disease. Depending on the pathophysiology, clinical presentation, and radiologic extent of the disease process, therapeutic options for acute thrombotic cases can include supportive care, anticoagulation, thrombolytic therapy, surgical or catheter-directed mechanical thrombectomy, and surgical bypass. Therapeutic options for atherosclerotic disease include supportive measures such as behavior modification, a supervised exercise program, adjunctive treatment with anticoagulation and antiplatelet medications, angioplasty, stent placement, stent-graft placement, surgical or catheter-directed endarterectomy or plaque excision, and surgical bypass. This document describes the appropriateness of imaging in this patient population, treatment procedures for specific clinical scenarios, and the likely prognosis for these patients. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria Iliac Artery Occlusive Disease.

The mainstay of treatment for unresectable hepatocellular carcinoma is locoregional therapy including percutaneous ablation and transarterial chemo- and radioembolization. While monitoring for tumor response after transarterial chemoembolization is crucial, current imaging strategies are suboptimal. The standard of care is contrast-enhanced magnetic resonance imaging or computed tomography imaging performed at least 4 to 6 weeks after therapy. We present a case in which contrast-enhanced ultrasound identified a specific extra-hepatic collateral from the gastroduodenal artery supplying residual viable tumor and assisting with directed transarterial management.

Contrast-enhanced ultrasound identifies early extrahepatic collateral contributing to residual hepatocellular tumor viability after transarterial chemoembolization.

Quantitative 2D and 3D contrast-enhanced ultrasound (CEUS) was assessed to evaluate early transarterial chemoembolization (TACE) treatment response. Seventeen patients scheduled for TACE for the treatment of hepatocellular carcinoma participated in the study. 2D and 3D CEUS were performed for each patient at three time points: prior to TACE, 1-2 weeks post TACE, and 1 month post TACE. Peak-intensities of the tumor and surrounding liver tissue were calculated from 2D and 3D data before and after TACE and used to evaluate tumor treatment response. Residual tumor percentages were calculated from 2D and 3D CEUS acquired 1-2 weeks and 1 month post TACE and compared with results from MRI 1 month post TACE. Nine subjects had complete response while 8 had incomplete response. Peak-intensities of the tumor from 3D CEUS prior to TACE were similar between the complete and incomplete treatment groups (p=0.70), while 1-2 weeks (p<0.01) and 1 month post treatment (p<0.01) were significantly lower in the complete treatment group than in the incomplete treatment group. For 2D CEUS, only the peak-intensity values of the tumor from1 month post TACE were significantly different (p<0.01). The correlation coefficients between 2D and 3D residual tumor estimates 1-2 weeks post TACE and the estimates from MRI were 0.73 and 0.94, respectively, while those from 2D and 3D CEUS 1 month post TACE were 0.66 and 0.91, respectively. Quantitative analysis on 2D and 3D CEUS shows potential to differentiate patients with complete  incomplete response to TACE as early as 1-2 weeks post treatment.

Evaluation of Hepatocellular Carcinoma Transarterial Chemoembolization using Quantitative Analysis of 2D and 3D Real-time Contrast Enhanced Ultrasound.

AUTHOR REPLY.

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however  imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with "microbubble" ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation  are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors. : To monitor the therapeutic efficacy of sonopermeation  we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted  along with associated vascular changes. : In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment . Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid onset of doxorubicin-induced apoptosis of NB cells but without damage to blood vessels. : Our results suggest that significant L-DOX uptake can occur by increasing tumor vascular permeability with microbubble sonopermeation without otherwise damaging the vasculature, as confirmed by  qCEUS imaging and  analysis. The use of qCEUS imaging to monitor sonopermeation efficiency and predict drug uptake could potentially provide real-time feedback to clinicians for determining treatment efficacy in tumors, leading to better and more efficient personalized therapies. Finally, we demonstrate how the IGDD strategy outlined in this study could be implemented in human patients using a single case study.

Perfusion-guided sonopermeation of neuroblastoma: a novel strategy for monitoring and predicting liposomal doxorubicin uptake .

Transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) often requires retreatment and identification of feeding vessels supplying the residual/recurrent tumor is an important step in treatment planning. The objective of this study was to determine if contrast-enhanced ultrasound (CEUS) could correctly identify the vessel supplying the residual tumor. To date, 69 patients have undergone CEUS follow-up of HCC TACE therapy at our institution as part of an ongoing institutional review board approved trial (NCT02764801). The CEUS examinations were performed before HCC TACE as well as 1 to 2 weeks and 1 month after treatment using a Logiq E9 scanner with a C1-6 curved array transducer (GE Healthcare, Waukesha, WI). The CEUS images obtained 2 weeks after initial TACE treatment were reviewed, and any feeding vessels supplying the residual HCC were identified. Digital subtraction angiograms during the retreatment TACE were used as reference standard for feeding vessel identification. Thirteen patients with viable HCC post-TACE were included in this study. In these cases, the sonographer correctly identified 85% (11 of 13) of the feeding vessels later confirmed by angiography. Importantly, one of the false-negative cases involved a segment 8 tumor with parasitic blood supply from the medial left hepatic artery. In this case, CEUS identified a largely treated tumor with some residual internal flow, but was unable to visualize any major hepatic vascularity supplying the tumor. In conclusion, CEUS appears to be a valuable tool for planning retreatment of residual HCC post-TACE.

Contrast-enhanced Ultrasound Identifies Patent Feeding Vessels in Transarterial Chemoembolization Patients With Residual Tumor Vascularity.

Background The current standard for assessing the severity of portal hypertension is the invasive acquisition of hepatic venous pressure gradient (HVPG). A noninvasive US-based technique called subharmonic-aided pressure estimation (SHAPE) could reduce risk and enable routine acquisition of these pressure estimates. Purpose To compare quantitative SHAPE to HVPG measurements to diagnose portal hypertension in participants undergoing a transjugular liver biopsy. Materials and Methods This was a prospective cross-sectional trial conducted at two hospitals between April 2015 and March 2019 (ClinicalTrials.gov identifier, NCT02489045). This trial enrolled participants who were scheduled for transjugular liver biopsy. After standard-of-care transjugular liver biopsy and HVPG pressure measurements, participants received an infusion of a US contrast agent and saline. During infusion, SHAPE data were collected from a portal vein and a hepatic vein, and the difference was compared with HVPG measurements. Correlations between data sets were determined by using the Pearson correlation coefficient, and statistical significance between groups was determined by using the Student  test. Receiver operating characteristic analysis was performed to determine the sensitivity and specificity of SHAPE. Results A total of 125 participants (mean age ± standard deviation, 59 years ± 12; 80 men) with complete data were included. Participants at increased risk for variceal hemorrhage (HVPG ≥12 mm Hg) had a higher mean SHAPE gradient compared with participants with lower HVPGs (0.79 dB ± 2.53 vs -4.95 dB ± 3.44;  < .001), which is equivalent to a sensitivity of 90% (13 of 14; 95% CI: 88, 94) and a specificity of 80% (79 of 99; 95% CI: 76, 84). The SHAPE gradient between the portal and hepatic veins was in good overall agreement with the HVPG measurements ( = 0.68). Conclusion Subharmonic-aided pressure estimation is an accurate noninvasive technique for detecting clinically significant portal hypertension. © RSNA, 2020  See also the editorial by Kiessling in this issue.

Article	Year
Contrast-Enhanced Subharmonic and Harmonic Ultrasound of Renal Masses Undergoing Percutaneous Cryoablation. Academic radiology\| PubMed ID: 25882093	2015
Contrast-enhanced ultrasound evaluation of residual blood flow to hepatocellular carcinoma after treatment with transarterial chemoembolization using drug-eluting beads: a prospective study. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine\| PubMed ID: 25911704	2015
Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. Journal of hematology & oncology\| PubMed ID: 27663515	2016
Contrast-Enhanced Sonography and Fusion Technology for Assessment of an Embolized Renal Angiomyolipoma. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine\| PubMed ID: 27672234	2016
ACR Appropriateness Criteria Radiologic Management of Mesenteric Ischemia. Journal of the American College of Radiology : JACR\| PubMed ID: 28473083	2017
Metastatic Liver Disease: Indications for Locoregional Therapy and Supporting Data. Seminars in interventional radiology\| PubMed ID: 28579683	2017
ACR Appropriateness Criteria Radiologic Management of Central Venous Access. Journal of the American College of Radiology : JACR\| PubMed ID: 29101989	2017
ACR Appropriateness Criteria Iliac Artery Occlusive Disease. Journal of the American College of Radiology : JACR\| PubMed ID: 29101990	2017
Contrast-enhanced ultrasound identifies early extrahepatic collateral contributing to residual hepatocellular tumor viability after transarterial chemoembolization. Radiology case reports\| PubMed ID: 29721125	2018
Evaluation of Hepatocellular Carcinoma Transarterial Chemoembolization using Quantitative Analysis of 2D and 3D Real-time Contrast Enhanced Ultrasound. Biomedical physics & engineering express\| PubMed ID: 29887989	2018
AUTHOR REPLY. Urology\| PubMed ID: 30526907	2018
Perfusion-guided sonopermeation of neuroblastoma: a novel strategy for monitoring and predicting liposomal doxorubicin uptake . Theranostics\| PubMed ID: 32724463	2020
Contrast-enhanced Ultrasound Identifies Patent Feeding Vessels in Transarterial Chemoembolization Patients With Residual Tumor Vascularity. Ultrasound quarterly\| PubMed ID: 32890324	2020
Diagnosing Portal Hypertension with Noninvasive Subharmonic Pressure Estimates from a US Contrast Agent. Radiology\| PubMed ID: 33201789	2020

Colette M. Shaw

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