Consensus Guidelines of Irreversible Electroporation for Pancreatic Tumors: Protocol Standardization Using the Modified Delphi Technique.

Since no uniform treatment protocol for pancreatic irreversible electroporation (IRE) exists, the heterogeneity throughout literature complicates the comparison of results. To reach agreement among experts, a consensus study was performed. Eleven experts, recruited according to predefined criteria regarding previous IRE publications, participated anonymously in three rounds of questionnaires according to a modified Delphi technique. Consensus was defined as having reached ≥80% agreement. Response rates were 100, 64, and 64% in rounds 1 to 3, respectively; consensus was reached in 93%. Pancreatic IRE should be considered for stage III pancreatic cancer and inoperable recurrent disease after previous local treatment. Absolute contraindications are ventricular arrhythmias, implantable stimulation devices, congestive heart failure NYHA class 4, and severe ascites. The inter-electrode distance should be 10 to 20 mm and the exposure length should be 15 mm. After 10 test pulses, 90 treatment pulses of 1,500 V/cm should be delivered continuously, with a 90-µs pulse length. The first postprocedural contrast-enhanced computed tomography should take place 1 month post-IRE, and then every 3 months. This article provides expert recommendations regarding patient selection, procedure, and follow-up for IRE treatment in pancreatic malignancies through a modified Delphi consensus study. Future studies should define the maximum tumor diameter, response evaluation criteria, and the optimal number of preoperative FOLFIRINOX cycles.

Emerging Potential of Microwave Ablation for Primary Aldosteronism Resulting From Unilateral Aldosterone-producing Adenoma.

Primary aldosteronism (PA) is the most prevalent form of secondary hypertension and is most commonly caused by an adrenal adenoma or bilateral adrenal hyperplasia. Minimally invasive adrenalectomy is the treatment of choice for unilateral disease. Here, we report the case of a 57-year-old man with previous bladder cancer who was referred for evaluation of resistant hypertension and hypokalemia. Diagnostic workup indicated PA with computed tomography imaging revealing a left adrenal adenoma and adrenal venous sampling lateralizing to the left adrenal. He was therefore referred for a left adrenalectomy using a retroperitoneoscopic approach. However, surgery was complicated by significant perinephritis related to previous bladder cancer immunotherapy and, in view of an identifiable adrenal adenoma, a partial adrenalectomy was performed. Despite histology confirming removal of an adrenal adenoma, he remained hypertensive and hypokalemic with persistent PA. He underwent a computed tomography-guided percutaneous thermal (microwave) ablation of the residual adrenal nodule with immediate biochemical reversal of PA. Six years postprocedure, he remains biochemically and clinically cured from PA. This article presents the details of the case and reviews the literature on long-term outcomes for patients undergoing thermal ablation and adrenalectomy, suggesting that thermal ablation may be a viable alternative for selected patients.

Irreversible Electroporation for Hepatic Tumors: Protocol Standardization Using the Modified Delphi Technique.

PURPOSE: A consensus study of panelists was performed to provide a uniform protocol regarding (contra) indications, procedural parameters, perioperative care, and follow-up of irreversible electroporation (IRE) for the treatment of hepatic malignancies. MATERIALS AND METHODS: Interventional radiologists who had 2 or more publications on IRE, reporting at least 1 patient cohort in the field of hepatobiliary IRE, were recruited. The 8 panelists were asked to anonymously complete 3 iterative rounds of IRE-focused questionnaires to collect data according to a modified Delphi technique. Consensus was defined as having reached 80% or greater agreement. RESULTS: Panel members' response rates were 88%, 75%, and 88% in rounds 1, 2, and 3, respectively; consensus was reached on 124 of 136 items (91%). Percutaneous or intraoperative hepatic IRE should be considered for unresectable primary and secondary malignancies that are truly unsuitable for thermal ablation because of proximity to critical structures. Absolute contraindications are ventricular arrhythmias, cardiac stimulation devices, and congestive heart failure of New York Heart Association class 3 or higher. A metal stent outside the ablation zone should not be considered a contraindication. For the only commercially available IRE device, the recommended settings are an inter-electrode distance of 10-20 mm and an exposure length of 20 mm. After 10 test pulses, 90 treatment pulses of 1500 V/cm should be delivered continuously, with a pulse length of 70-90 µs. The first post-procedural follow-up should take place 1 month after IRE and thereafter every 3 months, using cross-sectional imaging plus tumor marker assessment. CONCLUSIONS: This article provides recommendations, created by a modified Delphi consensus study, regarding patient selection, workup, procedure, and follow-up of IRE treatment for hepatic malignancies.

Percutaneous irreversible electroporation with systemic treatment for locally advanced pancreatic adenocarcinoma.

BACKGROUND: The prognosis for unresectable locally advanced pancreatic adenocarcinoma (LAPC) remains poor. There is increasing interest in modern ablative techniques to improve outcomes. We report on the potential value of integrating percutaneous irreversible electroporation (IRE) in patients undergoing systemic chemotherapy. METHODS: Seventy-five patients with unresectable pancreatic carcinoma underwent percutaneous IRE after chemotherapy using computerised tomography guidance under general anaesthesia. Postoperative immediate and 30-day morbidity and mortality, progression-free (PFS) and overall survival (OS) were evaluated. RESULTS: Post-procedural immediate and 30-day mortality rates were both zero. All-grade adverse events were 25%. Median in-patient stay was 1 day (range, 1-5 days). Median OS and PFS post-IRE for LAPC were 27 and 15 months respectively. Four patients with LAPC down-staged post-IRE ablation to be surgically resectable, with R0 resections in 3 cases. CONCLUSIONS: These results suggest that percutaneous IRE ablation of unresectable LAPC is safe to integrate with standard-of-care chemotherapy and may improve survival, which provides a template for further evaluation in prospective randomized clinical trials.

The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Long Version).

The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.

The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Short Version).

The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.

Evaluation of Perfusion Quantification Methods with Ultrasound Contrast Agents in a Machine-Perfused Pig Liver.

PURPOSE: To evaluate dynamic contrast-enhanced ultrasound (DCEUS) as a tool for measuring blood flow in the macro- and microcirculation of an ex-vivo machine-perfused pig liver and to confirm the ability of DCEUS to accurately detect induced flow rate changes so that it could then be used clinically for monitoring flow changes in liver tumors. MATERIALS AND METHODS: Bolus injections of contrast agents in the hepatic artery (HA) and portal vein (PV) were administered to 3 machine-perfused pig livers. Flow changes were induced by the pump of the machine perfusion system. The induced flow rates were of clinical relevance (150 - 400 ml/min for HA and 400 - 1400 ml/min for PV). Quantification parameters from time-intensity curves [rise time (RT), mean transit time (MTT), area under the curve (AUC) and peak intensity (PI)] were extracted in order to evaluate whether the induced flow changes were reflected in these parameters. RESULTS: A linear relationship between the image intensity and the microbubble concentration was confirmed first, while time parameters (RT and MMT) were found to be independent of concentration. The induced flow changes which propagated from the larger vessels to the parenchyma were reflected in the quantification parameters. Specifically, RT, MTT and AUC correlated with flow rate changes. CONCLUSION: Machine-perfused pig liver is an excellent test bed for DCEUS quantification approaches for the study of the hepatic vascular networks. DCEUS quantification parameters (RT, MTT, and AUC) can measure relative flow changes of about 20 % and above in the liver vasculature. DCEUS quantification is a promising tool for real-time monitoring of the vascular network of tumors.

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

Evaluation of the Accuracy of Liver Lesion DCEUS Quantification With Respiratory Gating.

Confidence in the accuracy of dynamic contrast enhanced ultrasound (DCEUS) quantification parameters is imperative for the correct diagnosis of liver lesion perfusion characteristics. An important source of uncertainty in liver DCEUS acquisitions is artifacts introduced by respiratory motion. The objective of this study is to construct a respiratory motion simulation model (RMSM) of dual contrast imaging mode acquisitions of liver lesions in order to evaluate an algorithm for automatic respiratory gating (ARG). The respiratory kinetics as well as the perfusion models of the liver lesion and parenchyma used by the RMSM were solely derived from clinical data. The quality of fit (of the DCEUS data onto the bolus kinetics model) depends on the respiration amplitude. Similar trends in terms of quality of fit as a function of respiration amplitude were observed from RMSM and clinical data. The errors introduced on the DCEUS quantification under the influence of respiration were evaluated. The RMSM revealed that the error in the liver lesion DCEUS quantification parameters significantly decreased (p < 0.001) from a maximum of 32.3% to 6.2% when ARG was used. The use of RMSM clearly demonstrates the capability of the ARG algorithm in significantly reducing errors introduced from both in-plane and out-of-plane respiratory motion.

Improvement of the accuracy of liver lesion DCEUS quantification with the use of automatic respiratory gating.

OBJECTIVES: To evaluate the efficiency of automatic respiratory gating (ARG) in reducing respiratory motion-induced artefacts from dynamic contrast-enhanced ultrasound (DCEUS) acquisitions and to assess the impact of ARG on DCEUS quantification parameters in patients with liver malignancies. METHODS: Twenty-five patients with liver metastasis were imaged with DCEUS. The lognormal indicator dilution model was fitted on time-intensity curves extracted from hepatic lesions with and without the use of ARG and DCEUS quantification parameters were extracted. The goodness of fit was assessed using the coefficient of determination (R (2) LN ). The effect respiration had on the data was assessed using the respiration amplitude (RA) metric. Pearson's correlation coefficient (r) was used to assess the correlation between R (2) LN and RA with and without the use of ARG. RESULTS: The RA parameter was strongly correlated with R (2) LN (r = -0.96, P = 7.412 × 10(-15)) and this correlation became weaker with ARG (r = -0.64, P = 5.449 × 10(-4)). ARG significantly influenced the values of the quantification parameters extracted (P ≤ 0.05). The RA was significantly decreased when ARG was used (P = 1.172 × 10(-6)). CONCLUSIONS: ARG has a significant impact on the quantification parameters extracted and it has been shown to improve the accuracy of liver lesion DCEUS. KEY POINTS: • ARG has a significant impact on DCEUS quantification parameters. • ARG can improve the modelling of liver lesion haemodynamics using DCEUS quantification. • ARG significantly reduces the respiration amplitude of DCEUS lesion time-intensity curves.

Early Diagnosis of Intrahepatic Pseudoaneurysm during Radiofrequency Ablation using Contrast-Enhanced Ultrasound.

Radiofrequency ablation is one of the more established forms of local treatment in patients with unresectable tumours, including colorectal hepatic metastases. Complications associated with this method of intervention include thermal and mechanical injuries, including vascular insults resulting in haemorrhage or pseudoaneurysm formation. This is the first case demonstrating the detection of post-ablation acute pseudoaneurysm formation identified on the table using contrast-enhanced ultrasound (CEUS) and the subsequent successful management.

Image-guided tumor ablation: standardization of terminology and reporting criteria--a 10-year update.

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes.

Dynamic contrast-enhanced ultrasound of slaughterhouse porcine livers in machine perfusion.

The aim of this study was to enable investigations into novel imaging and surgical techniques by developing a readily accessible, versatile liver machine perfusion system. Slaughterhouse pig livers were used, and dynamic contrast-enhanced ultrasound was introduced to optimize the procurement process and provide real-time perfusion monitoring. The system comprised a single pump, oxygenator, bubble trap and two flowmeters for pressure-controlled perfusion of the vessels using an off-the-shelf perfusate at room temperature. Successful livers exhibited homogeneous perfusion in both the portal vein and hepatic artery with dynamic contrast-enhanced ultrasound, which correlated with stable oxygen uptake, bile production and hepatic resistance and normal histology at the end of 3 h of perfusion. Dynamic contrast-enhanced ultrasound revealed perfusion abnormalities invisible to the naked eye, thereby providing context to the otherwise systemic biochemical/hemodynamic measurements and focal biopsy findings. The model developed here is a simple, cost-effective approach for stable ex vivo whole-organ machine perfusion.

Introduction of genes via sonoporation and electroporation.

Gene therapy delivery using viral vectors has demonstrated efficient transfection but has safety issues. The need for safer yet effective delivery systems has led to the active development of non-viral techniques. In this chapter, we will discuss two evolving techniques - sonoporation with microbubble contrast agents and electroporation with focus on their basic principle, parameters affecting delivery efficiency, current evolving techniques and future prospects.

Image-guided tumor ablation: standardization of terminology and reporting criteria--a 10-year update.

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. Online supplemental material is available for this article .

Automatic respiratory gating for contrast ultrasound evaluation of liver lesions.

Dynamic contrast-enhanced ultrasound (DCEUS) has been used in radiology for many years for lesion detection and characterization. In recent years, more emphasis has been placed on tumor perfusion quantification with DCEUS. To ensure accuracy in both quantitative and qualitative evaluation of liver tumors with DCEUS, sources of noise in clinical data must be identified and, if possible, removed. One of the major sources of such noise is respiratory motion. A new automatic respiratory gating (ARG) algorithm is presented and evaluated with clinical data. The results of the evaluation demonstrate the potential of the ARG algorithm for clinical use as a fast and easy-to-implement method for removing respiratory motion from DCEUS loops.

Guidelines and good clinical practice recommendations for Contrast Enhanced Ultrasound (CEUS) in the liver - update 2012: A WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

Reproducibility of quantitative assessment of altered hepatic hemodynamics with dynamic contrast-enhanced ultrasound.

OBJECTIVES: The aim of this clinical study was to evaluate the reproducibility of quantitative assessment of altered hepatic hemodynamics with dynamic contrast-enhanced ultrasound. METHODS: Fifteen patients with colorectal liver metastases and 5 volunteers were studied. The hepatic artery proper and the portal vein were imaged simultaneously with dynamic contrast-enhanced ultrasound. The examination was repeated with 2 different contrast bolus volumes (1.2 and 2.4 mL), and time-intensity curves were formed from dynamic contrast-enhanced ultrasound image loops. The rise time, peak intensity, and wash-in slope were derived from hepatic artery and portal vein time-intensity curves. Inter-reader, intra-reader, and inter-scan agreement was assessed by 2 independent readers. Quantitative (intraclass correlation coefficients and coefficients of variation [CVs]) and qualitative (Landis and Koch classification) analyses were performed. RESULTS: Intra-reader and inter-reader agreement was "almost perfect" for the hepatic artery (CV, 10%-15% and 8%-9%, respectively), portal vein (CV, 5%-8% and 6%-12%), and hepatic artery/portal vein ratio (CV, 8%-14% and 10%-15%) measurements of 3 all studied parameters. In contrast, inter-scan agreement was only "slight" to "moderate" (CV, 25%-27%) and "fair" to "moderate" (CV, 19%-24%) for rise time and peak intensity measurements in the hepatic artery and portal vein, respectively. CONCLUSIONS: Quantitative assessment of altered hepatic hemodynamics with dynamic contrast-enhanced ultrasound is reproducible provided that measurements in the hepatic artery are normalized by those in the portal vein.

Irreversible electroporation for focal ablation at the porta hepatis.

Patients with chemotherapy-refractory liver metastases who are not candidates for surgery may be treated with focal ablation techniques with established survival benefits. Irreversible electroporation is the newest of these and has the putative advantages of a nonthermal action, preventing damage to adjacent biliary structures and bowel. This report describes the use of irreversible electroporation in a 61-year-old man with a solitary chemoresistant liver metastasis unsuitable for radiofrequency ablation as a result of its proximity to the porta hepatis. At 3 months, tumor size was decreased on computed tomography from 28 × 19 to 20 × 17 mm, representing stable disease according to the response evaluation criteria in solid tumors. This corresponded to a decrease in tumor volume size from 5.25 to 3.16 cm(3). There were no early or late complications. Chemoresistant liver metastases in the proximity of the porta hepatis that are considered to be too high a risk for conventional surgery or thermal ablation may be considered for treatment by the novel ablation technique of irreversible electroporation.

Dynamic contrast enhanced ultrasound assessment of the vascular effects of novel therapeutics in early stage trials.

Imaging is key in the accurate monitoring of response to cancer therapies targeting tumour vascularity to inhibit its growth and dissemination. Dynamic contrast enhanced ultrasound (DCE ultrasound) is a quantitative method with the advantage of being non-invasive, widely available, portable, cost effective, highly sensitive and reproducible using agents that are truly intravascular. Under the auspices of the initiative of the Experimental Cancer Medicine Centre Imaging Network, bringing together experts from the UK, Europe and North America for a 2-day workshop in May 2010, this consensus paper aims to provide guidance on the use of DCE ultrasound in the measurement of tumour vascular support in clinical trials. Key Points • DCE ultrasound can quantify and extract specific blood flow parameters, such as flow velocity, relative vascular volume and relative blood flow rate. • DCE ultrasound can be performed repeatedly and is therefore ideally suited for pharmacokinetic and pharmacodynamic studies evaluating vascular-targeted drugs. • DCE ultrasound provides a reproducible method of assessing the vascular effects of therapy in pre-clinical and early clinical trials, which is easily translatable into routine clinical practice.