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Purpose: To show that hepatic tumor volume and enhancement pattern measurements can be obtained in a time-efficient and reproducible manner on a voxel-by-voxel basis to provide a true three-dimensional (3D) volumetric assessment.Materials and Methods: Magnetic resonance (MR) imaging data obtained from 20 patients recruited for a single-institution prospective study were retrospectively evaluated. All patients had a diagnosis of hepatocellular carcinoma (HCC) and underwent drug-eluting beads (DEB) transcatheter arterial chemoembolization for the first time. All patients had undergone contrast-enhanced MR imaging before and after DEB transcatheter arterial chemoembolization; poor image quality excluded 3 patients, resulting in a final count of 17 patients. Volumetric RECIST (vRECIST) and quantitative EASL (qEASL) were measured, and segmentation and processing times were recorded.Results: There were 34 scans analyzed. The time for semiautomatic segmentation was 65 seconds±33 (range, 40-200 seconds). vRECIST and qEASL of each tumor were computed<1 minute for each.Conclusions: Semiautomatic quantitative tumor enhancement (qEASL) and volume (vRECIST) assessment is feasible in a workflow-efficient time frame. Clinical correlation is necessary, but vRECIST and qEASL could become part of the assessment of intraarterial therapy for interventional radiologists. [ABSTRACT FROM AUTHOR]

Tranarterial chemoembolization (TACE) has been established by a meta-analysis of randomized controlled trials as the standard of care for nonsurgical patients with large or multinodular noninvasive hepatocellular carcinoma (HCC) isolated to the liver and with preserved liver function. Although conventional TACE with administration of an anticancer-in-oil emulsion followed by embolic agents has been the most popular technique, the introduction of embolic drug-eluting beads has provided an alternative to lipiodol-based regimens. Experimental studies have shown that TACE with drug-eluting beads has a safe pharmacokinetic profile and results in effective tumor killing in animal models. Early clinical experiences have confirmed that drug-eluting beads provide a combined ischemic and cytotoxic effect locally with low systemic toxic exposure. Recently, the clinical value of a TACE protocol performed by using the embolic microsphere DC Bead loaded with doxorubicin (DEBDOX; drug-eluting bead doxorubicin) has been shown by randomized controlled trials. An important limitation of conventional TACE has been the inconsistency in the technique and the treatment schedules. This limitation has hampered the acceptance of TACE as a standard oncology treatment. Doxorubicin-loaded DC Bead provides levels of consistency and repeatability not available with conventional TACE and offers the opportunity to implement a standardized approach to HCC treatment. With this in mind, a panel of physicians took part in a consensus meeting held during the European Conference on Interventional Oncology in Florence, Italy, to develop a set of technical recommendations for the use of DEBDOX in HCC treatment. The conclusions of the expert panel are summarized. [ABSTRACT FROM AUTHOR]

The Warburg hypothesis states that aggressive cancers obtain much of their adenosine triphosphate (ATP) by metabolizing glucose directly to lactic acid. As a result of its high tumor selectivity, 3-bromopyruvic acid (3-BrPA), a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. We investigated the effect of 3-BrPA in a mouse model of aggressive metastatic lymphoma. Epstein-Barr-virus-infected human Raji lymphoma cells with lentivirally transfected green fluorescent protein and luciferase were incubated with RPMI/fetal bovine serum, and various concentrations of 3-BrPA were used to determine the LD50 in vitro. In total, 18 severely combined immunodeficient mice were injected with 1 million human Raji lymphoma cells via the tail vein. Using bioluminescent imaging, tumor growth was measured daily for 12 days to determine the tumor burden. At day 0 (start of treatment), the mice were randomized. Six mice received 10 mg/kg 3-BrPA i.p. daily for 7 days, 6 mice received 1 treatment at day 0, and 6 mice received the control buffer. Tumor growth was assessed daily from day 0 until day 7 using bioluminescent imaging. All data were normalized to acquisition time (luminescence/second; L/s). Body weight was measured daily to determine the toxicity of 3-BrPA. The LD50 for Raji lymphoma cells exposed to 3-BrPA in vitro was 11 [mu]M with an extremely steep dose response curve. At day 0, tumor activity medians in the group with daily treatment was 2131 L/s (244-12,725), with a 1-day dose of 3095 L/s (523-9650) and in the nontreated control group, 2997 L/s (1521-6911). In mice treated with a daily dose of 10 mg/kg 3-BrPa for 7 days, a significant reduction in tumor activity was found during the whole treatment period compared with the control mice (P = 0.0043 at day 7). In mice with a single treatment at day 0, growth delay was only evident at day 2 (P = 0.0152 at day 2) but not for the rest of the observation period. The only manifestation of toxicity of the daily administration of 10 mg/kg 3-BrPA was a reduction in body weight. Body weight at day 0 was 17.22 g ± 0.84 g in the treatment group and 17.58 g ± 0.86 g in the control group. Body weight at day +6 was 15.02 g ± 2.04 g in the treated group and 19.4 g ± 0.63 g in the control group. 3-BrPA demonstrated a significant positive tumor response both in vitro and in vivo. This, to our knowledge, is the first report of the use of 3-BrPA in a systemic tumor model. Based on these data, 3-BrPA holds promise for treatment of systemic metastatic cancers. [ABSTRACT FROM AUTHOR]

Conventional transcatheter arterial chemoembolization and chemoembolization with drug-eluting beads are increasingly being performed interchangeably in many institutions throughout the world. As both therapies continue to being tested in many phase II and III studies and in combination with other therapies, especially targeted agents, for treatment of primary and metastatic liver cancer, it is imperative to review their current status and evaluate their impact on patient survival. This review critically assesses patient selection, indications, contraindications, techniques, materials, safety, and clinical outcomes of patients treated with conventional chemoembolization and chemoembolization with drug-eluting beads. [ABSTRACT FROM AUTHOR]

Acute nonvariceal upper gastrointestinal (UGI) hemorrhage is a frequent complication associated with significant morbidity and mortality. The most common cause of UGI bleeding is peptic ulcer disease, but the differential diagnosis is diverse and includes tumors; ischemia; gastritis; arteriovenous malformations, such as Dieulafoy lesions; Mallory-Weiss tears; trauma; and iatrogenic causes. Aggressive treatment with early endoscopic hemostasis is essential for a favorable outcome. However, severe bleeding despite conservative medical treatment or endoscopic intervention occurs in 5-10% of patients, requiring surgery or transcatheter arterial embolization. Surgical intervention is usually an expeditious and gratifying endeavor, but it can be associated with high operative mortality rates. Endovascular management using superselective catheterization of the culprit vessel, «sandwich» occlusion, or blind embolization has emerged as an alternative to emergent operative intervention for high-risk patients and is now considered the first-line therapy for massive UGI bleeding refractory to endoscopic treatment. Indeed, many published studies have confirmed the feasibility of this approach and its high technical and clinical success rates, which range from 69 to 100% and from 63 to 97%, respectively, even if the choice of the best embolic agent among coils, cyanaocrylate glue, gelatin sponge, or calibrated particles remains a matter of debate. However, factors influencing clinical outcome, especially predictors of early rebleeding, are poorly understood, and few studies have addressed this issue. This review of the literature will attempt to define the role of embolotherapy for acute nonvariceal UGI hemorrhage that fails to respond to endoscopic hemostasis and to summarize data on factors predicting angiographic and embolization failure. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer. [ABSTRACT FROM AUTHOR]

A bovine collagen matrix is sometimes used as a delivery medium during direct intratumoral injection of a chemo-therapeutic agent. The bovine collagen enhances the dose and duration of local drug delivery and limits systemic toxicity. Although this strategy is advocated as a means of easy and effective delivery of chemotherapeutic drugs, the associated risks are not well defined. We report the case of a 71-year-old man with hepatocellular carcinoma who underwent weekly intratumoral injections of cisplatin in a bovine collagen matrix. During the third injection, he suddenly and unexpectedly underwent cardiac arrest and died. An autopsy disclosed diffuse occlusion of the pulmonary microcirculation by bovine collagen. The collagen emboli were associated with an inflammatory infiltrate typical of bovine collagen-induced hypersensitivity. This case identifies a fatal complication of intratumoral chemotherapy injections using a bovine collagen matrix, which does not appear to have been previously reported. This case underscores the valuable role of the traditional autopsy examination as a means of identifying possible complications of novel oncologic strategies, which are being rapidly developed and implemented. [ABSTRACT FROM AUTHOR]

Purpose: To investigate toxicity, efficacy, and microenvironmental effects of idarubicin-loaded 40-μm and 100-μm drug-eluting embolic (DEE) transarterial chemoembolization in a rabbit liver tumor model., Materials and Methods: Twelve male New Zealand White rabbits with orthotopically implanted VX2 liver tumors were assigned to DEE chemoembolization with 40-μm (n = 5) or 100-μm (n = 4) ONCOZENE microspheres or no treatment (control; n = 3). At 24-72 hours postprocedurally, multiparametric magnetic resonance (MR) imaging including dynamic contrast-enhanced (DCE), diffusion-weighted imaging (DWI), and biosensor imaging of redundant deviation in shifts (BIRDS) was performed to assess extracellular pH (pHe), followed by immediate euthanasia. Laboratory parameters and histopathologic ex vivo analysis included fluorescence confocal microscopy and immunohistochemistry., Results: DCE MR imaging demonstrated a similar degree of devascularization of embolized tumors for both microsphere sizes (mean arterial enhancement, 8% ± 12 vs 36% ± 51 in controls; P = .07). Similarly, DWI showed postprocedural increases in diffusion across the entire lesion (apparent diffusion coefficient, 1.89 × 10 -3 mm 2 /s ± 0.18 vs 2.34 × 10 -3 mm 2 /s ± 0.18 in liver; P = .002). BIRDS demonstrated profound tumor acidosis at baseline (mean pHe, 6.79 ± 0.08 in tumor vs 7.13 ± 0.08 in liver; P = .02) and after chemoembolization (6.8 ± 0.06 in tumor vs 7.1 ± 0.04 in liver; P = .007). Laboratory and ex vivo analyses showed central tumor core penetration and greater increase in liver enzymes for 40-μm vs 100-μm microspheres. Inhibition of cell proliferation, intratumoral hypoxia, and limited idarubicin elution were equally observed with both sphere sizes., Conclusions: Noninvasive multiparametric MR imaging visualized chemoembolic effects in tumor and tumor microenvironment following DEE chemoembolization. Devascularization, increased hypoxia, coagulative necrosis, tumor acidosis, and limited idarubicin elution suggest ischemia as the predominant therapeutic mechanism. Substantial size-dependent differences indicate greater toxicity with the smaller microsphere diameter., (Copyright © 2020 SIR. Published by Elsevier Inc. All rights reserved.)

The goal of this study was to investigate the role of Lipiodol as a tumor-specific imaging biomarker to determine therapeutic efficacy of cTACE and investigate its inter-dependency with tumor perfusion using radiological-pathological correlation in an animal model of liver cancer., Methods: A total of N=36 rabbits were implanted in the left lobe of the liver with VX2 tumors, treated with cTACE using doxorubicin suspended in Lipiodol, and randomly sacrificed at 24 h, 7 days, or 20 days post-TACE. Unenhanced and contrast-enhanced CT scans including a perfusion protocol were obtained before cTACE and immediately before sacrifice. Tumor vascularity and Lipiodol deposition within tumors and hepatic tissue (non-target deposits) were quantified using 3D quantitative assessment tools and measurements of arterial flow, portal flow, and perfusion index (PI). After sacrifice histologic staining, including hematoxylin and eosin (H&E), CD31, and Oil Red O (ORO) were performed on tumor and liver samples to evaluate necrosis, microvascular density (MVD), and Lipiodol retention over time. Transmission electron microscopy (TEM) was performed to assess Lipiodol deposition and clearance over time., Results: All cTACE procedures were carried out successfully except for one, which was excluded from further analysis. Twenty-four hours post-TACE, tumor PI (p=0.04) was significantly decreased, which was maintained at 7 days (p=0.003), but not at 20 days (p=0.4). A strong correlation (R 2 = 0.894) was found between the volume of enhancing tumor tissue at baseline and Lipiodol-positive tumor volume post-TACE. Both ORO and TEM showed deposition of Lipiodol across all imaging time points within the VX2 tumors. However, gradual and ultimately near-complete Lipiodol washout was observed over time in the non-tumoral liver. MVD decreased between 24 h and 7 days post-TACE, and then increased 20 days post-TACE (both p<0.01)., Conclusions: Our data provide radiology-pathology evidence for the function of Lipiodol as a theranostic, tumor-specific drug delivery agent because it is both imageable and tumor-seeking, whereby it is preferentially taken up and retained by tumor cells. Those tumor-specific functions also enable Lipiodol to act as an imaging biomarker for the therapeutic efficacy of cTACE. Together with volumetric quantification of tumor vascularization on CT, Lipiodol could be used as a predictor of a patient's response to cTACE and contribute to the therapeutic management of patients with liver cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Purpose: The primary end point of this trial was to determine the feasibility and safety of transarterial chemoembolization with the use of 75-150-μm drug-eluting embolics loaded with irinotecan (DEE-IRI) for the treatment of metastatic colorectal cancer (CRC) refractory to systemic chemotherapy., Materials and Methods: Fourteen patients (mean age 57.9 years) with liver-dominant metastatic disease (14.3% unilobar, 85.7% bilobar), who had failed at least 1 line of chemotherapy, were enrolled and received up to 4 (mean 2.3) cycles of DEE-IRI lobar transarterial chemoembolization. Technical complications and adverse events were recorded, and response was assessed by means of imaging-based criteria. Levels of irinotecan and angiogenesis biomarkers in the serum were measured at multiple time points., Results: Thirty-two DEE-IRI transarterial chemoembolizations were successfully performed, and the full dose (100 mg) was delivered in all cases. The only grade 3-4 toxicity was abdominal pain (29%). One patient had objective response according to the Response Evaluation Criteria in Solid Tumors and World Health Organization, and 3 patients had objective response according to the European Association for the Study of the Liver. The median overall survival was 18.14 months, and the 1-year survival was 65%. The average plasma C max of the active metabolite was 41.5 ± 26.1 ng/mL, with average T max of 1.3 ± 0.5 hours. The treatment significantly reduced levels of vascular endothelial growth factor receptor 1 (VEGFR1) at 24 hours., Conclusions: Lobar transarterial chemoembolization with the use of DEE-IRI is a technically feasible and well tolerated palliative treatment for patients with refractory liver-predominant CRC metastatic disease and has acceptable pharmacokinetics. VEGFR1 is a potential biomarker for predicting treatment efficacy and risk of adverse events., (Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.)

Intra-arterial therapies are the standard of care for patients with hepatocellular carcinoma who cannot undergo surgical resection. The objective of this study was to develop a method to predict response to intra-arterial treatment prior to intervention. The method provides a general framework for predicting outcomes prior to intra-arterial therapy. It involves pooling clinical, demographic and imaging data across a cohort of patients and using these data to train a machine learning model. The trained model is applied to new patients in order to predict their likelihood of response to intra-arterial therapy. The method entails the acquisition and parsing of clinical, demographic and imaging data from N patients who have already undergone trans-arterial therapies. These data are parsed into discrete features (age, sex, cirrhosis, degree of tumor enhancement, etc.) and binarized into true/false values (e.g., age over 60, male gender, tumor enhancement beyond a set threshold, etc.). Low-variance features and features with low univariate associations with the outcome are removed. Each treated patient is labeled according to whether they responded or did not respond to treatment. Each training patient is thus represented by a set of binary features and an outcome label. Machine learning models are trained using N - 1 patients with testing on the left-out patient. This process is repeated for each of the N patients. The N models are averaged to arrive at a final model. The technique is extensible and enables inclusion of additional features in the future. It is also a generalizable process that may be applied to clinical research questions outside of interventional radiology. The main limitation is the need to derive features manually from each patient. A popular modern form of machine learning called deep learning does not suffer from this limitation, but requires larger datasets.

Purpose: To use magnetic resonance (MR) imaging and clinical patient data to create an artificial intelligence (AI) framework for the prediction of therapeutic outcomes of transarterial chemoembolization by applying machine learning (ML) techniques., Materials and Methods: This study included 36 patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization. The cohort (age 62 ± 8.9 years; 31 men; 13 white; 24 Eastern Cooperative Oncology Group performance status 0, 10 status 1, 2 status 2; 31 Child-Pugh stage A, 4 stage B, 1 stage C; 1 Barcelona Clinic Liver Cancer stage 0, 12 stage A, 10 stage B, 13 stage C; tumor size 5.2 ± 3.0 cm; number of tumors 2.6 ± 1.1; and 30 conventional transarterial chemoembolization, 6 with drug-eluting embolic agents). MR imaging was obtained before and 1 month after transarterial chemoembolization. Image-based tumor response to transarterial chemoembolization was assessed with the use of the 3D quantitative European Association for the Study of the Liver (qEASL) criterion. Clinical information, baseline imaging, and therapeutic features were used to train logistic regression (LR) and random forest (RF) models to predict patients as treatment responders or nonresponders under the qEASL response criterion. The performance of each model was validated using leave-one-out cross-validation., Results: Both LR and RF models predicted transarterial chemoembolization treatment response with an overall accuracy of 78% (sensitivity 62.5%, specificity 82.1%, positive predictive value 50.0%, negative predictive value 88.5%). The strongest predictors of treatment response included a clinical variable (presence of cirrhosis) and an imaging variable (relative tumor signal intensity >27.0)., Conclusions: Transarterial chemoembolization outcomes in patients with HCC may be predicted before procedures by combining clinical patient data and baseline MR imaging with the use of AI and ML techniques., (Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: Our study aimed to evaluate quantitative tumor response assessment (quantitative EASL-[qEASL]) on computed tomography (CT) images in patients with hepatocellular carcinoma (HCC) treated using conventional transarterial chemoembolization (cTACE), compared to existing 1-dimensional and 2-dimensional methods (RECIST, mRECIST, EASL)., Materials and Methods: In this IRB-approved, single-institution retrospective cohort study, 52 consecutive patients with intermediate-stage HCC were consecutively included. All patients underwent contrast-enhanced CT scan at baseline and 4 weeks after cTACE., Results: Median follow-up period was 13.5 months (range 1.2-54.1). RECIST, mRECIST and EASL identified progression in 2 (4%), 1 (2%) and 1 (2%) patients, respectively, whereas qEASL identified 10 (19%) patients. qEASL was the only tumor response method able to predict survival among different tumor response groups (P < 0.05), whereas RECIST, mRECIST and EASL did not (P > 0.05). Both EASL and qEASL were able to identify responders and non-responders and were predictive of survival (P < 0.05). Multivariate analysis showed that progression was an independent predictor of overall survival with hazard ratio of 1.9 (P = 0.025). Patients who demonstrated progression with qEASL had significantly shorter survival than those with non-progression (7.6 vs. 20.4 months, P = 0.012). Similar multivariate analysis using RECIST, mRECIST and EASL could not be performed because too few patients were categorized as progressive disease., Conclusion: qEASL could be applied on CT images to assess tumor response following cTACE and is a more sensitive biomarker to predict survival and identify tumor progression than RECIST, mRECIST and EASL at an early time point., Level of Evidence: Level 2a, retrospective cohort study.

As part of the ongoing effort to better understand and mitigate pro-oncogenic off-target effects of imaging-guided radiofrequency ablation (RFA), Kumar et al ( 1 ) used gene expression and network pathway analysis to examine the gene activation profiles in the peri-ablational zone after RFA in a breast adenocarcinoma liver metastasis animal model. Their analysis identified STAT3 (signal transducer and activator of transcription 3) as a key transcription factor upregulated in many signaling pathways in the peri-ablational zone after RFA. Consequently, the authors successfully used two STAT3 inhibitors to reduce distant tumor growth after treatment with RFA. By demonstrating that judicious and appropriate adjuvant therapy helped contain distant tumor growth caused by ablation, Kumar et al have managed to pave the road ahead for the definitive success of ablation.

Objectives: To compare efficacy, survival outcome and prognostic factors of conventional transarterial chemoembolisation (cTACE), drug-eluting beads TACE (DEB-TACE) and yttrium-90 radioembolisation (Y90) for the treatment of liver metastases from gastroenteropancreatic (GEP) neuroendocrine tumours (NELM)., Methods: This retrospective analysis included 192 patients (58.6 years mean age, 56% men) with NELM treated with cTACE (N = 122), DEB-TACE (N = 26) or Y90 (N = 44) between 2000 and 2014. Radiologic response to therapy was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) and World Health Organization (WHO) criteria using periprocedural MR imaging. Survival analysis included propensity score analysis (PSA), median overall survival (MOS), hepatic progression-free survival, Kaplan-Meier using log-rank test and the uni- and multivariate Cox proportional hazards model (MVA)., Results: MOS of the entire study population was 28.8 months. As for cTACE, DEB-TACE and Y90, MOS was 33.8 months, 21.7 months and 23.6 months, respectively. According to the MVA, cTACE demonstrated a significantly longer MOS as compared to DEB-TACE (p <.01) or Y90 (p = .02). The 5-year survival rate after initial cTACE, DEB-TACE and Y90 was 28.2%, 10.3% and 18.5%, respectively., Conclusions: Upon PSA, our study suggests significant survival benefits for patients treated with cTACE as compared to DEB-TACE and Y90. This data supports the therapeutic decision for cTACE as the primary intra-arterial therapy option in patients with unresectable NELM until proven otherwise., Key Points: • cTACE achieved a significantly longer overall survival in patients with unresectable NELM. • Patients treated with cTACE showed a prolonged hepatic progression-free survival. • cTACE, DEB-TACE and Y90 radioembolisation demonstrated comparable safety and toxicity profiles. • Age >70 years, extrahepatic metastases and tumour burden >50% were identified as negative predictors. • Propensity score analysis suggests the superiority of cTACE over DEB-TACE and Y90.

In an effort to improve the technical success rates and clinical outcomes of radiofrequency (RF) ablation, Yan et al validated the use of a tumor-penetrating peptide and thermosensitive doxorubicin (DOX)-loaded nanoparticles in combination with RF ablation in a hepatocellular carcinoma mouse model. By achieving higher chemotherapeutic drug concentrations in target lesions, fewer toxic effects, and improved survival end points in an animal tumor model, the authors conclude that superior tumor treatment with RF ablation is possible when combined with molecular-targeted drug delivery systems.

Purpose: To investigate whether bevacizumab compromises early response assessment after Transarterial Chemoembolization (TACE) in patients with hepatocellular carcinoma by 3D quantitative European Association for the Study of the Liver (qEASL) criteria in comparison to other imaging-based criteria., Materials and Methods: Each of 14 patients receiving TACE and bevacizumab was matched with two patients receiving TACE alone. Baseline and Follow-up MRI was retrospectively analyzed regarding qEASL and other imaging-based criteria., Results: Percentage-based qEASL achieved significant separation in both therapy arms (p=0.046 and p=0.015). Response and Overall Survival showed similar association among treatment groups (p=0.749)., Conclusions: Anti-angiogenic therapy with bevacizumab does not impede early response assessment by qEASL., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this issue of Radiology, Gade et al ( 1 ) describe a unique mechanism of hepatocellular carcinoma (HCC) cells for surviving ischemia induced by transarterial embolization (TAE)/transarterial chemoembolization (TACE) in a state of cell cycle arrest-a function that may serve as a defensive shield against conventional chemotherapeutic agents. This finding adds to our knowledge and establishes a previously poorly understood mechanism of chemoresistance in HCC. As the Achilles heel in terms of this process, a concurrent upregulation of autophagic flux as an adaptive response to TAE-like ischemia was found by the authors. This is a targetable mechanism that can potentially be exploited for combined therapeutic approaches of embolotherapy and autophagy inhibition in HCC.

Purpose To investigate whether whole-liver enhancing tumor burden [ETB] can serve as an imaging biomarker and help predict survival better than World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) methods in patients with multifocal, bilobar neuroendocrine liver metastases (NELM) after the first transarterial chemoembolization (TACE) procedure. Materials and Methods This HIPAA-compliant, institutional review board-approved retrospective study included 51 patients (mean age, 57.8 years ± 13.2; range, 13.5-85.8 years) with multifocal, bilobar NELM treated with TACE. The largest area (WHO), longest diameter (RECIST), longest enhancing diameter (mRECIST), largest enhancing area (EASL), and largest enhancing volume (ETB) were measured at baseline and after the first TACE on contrast material-enhanced magnetic resonance images. With three-dimensional software, ETB was measured as more than 2 standard deviations the signal intensity of a region of interest in normal liver. Response was assessed with WHO, RECIST, mRECIST, and EASL methods according to their respective criteria. For ETB response, a decrease in enhancement of at least 30%, 50%, and 65% was analyzed by using the Akaike information criterion. Survival analysis included Kaplan-Meier curves and Cox regressions. Results Treatment response occurred in 5.9% (WHO criteria), 2.0% (RECIST), 25.5% (mRECIST), and 23.5% (EASL criteria) of patients. With 30%, 50%, and 65% cutoffs, ETB response was seen in 60.8%, 39.2%, and 21.6% of patients, respectively, and was the only biomarker associated with a survival difference between responders and nonresponders (45.0 months vs 10.0 months, 84.3 months vs 16.7 months, and 85.2 months vs 21.2 months, respectively; P < .01 for all). The 50% cutoff provided the best survival model (hazard ratio [HR]: 0.2; 95% confidence interval [CI]: 0.1, 0.4). At multivariate analysis, ETB response was an independent predictor of survival (HR: 0.2; 95% CI: 0.1, 0.6). Conclusion Volumetric ETB is an early treatment response biomarker and surrogate for survival in patients with multifocal, bilobar NELM after the first TACE procedure. © RSNA, 2016.

Background & Aims: There is debate over the best way to stage hepatocellular carcinoma (HCC). We attempted to validate the prognostic and clinical utility of the recently developed Hong Kong Liver Cancer (HKLC) staging system, a hepatitis B-based model, and compared data with that from the Barcelona Clinic Liver Cancer (BCLC) staging system in a North American population that underwent intra-arterial therapy (IAT)., Methods: We performed a retrospective analysis of data from 1009 patients with HCC who underwent IAT from 2000 through 2014. Most patients had hepatitis C or unresectable tumors; all patients underwent IAT, with or without resection, transplantation, and/or systemic chemotherapy. We calculated HCC stage for each patient using 5-stage HKLC (HKLC-5) and 9-stage HKLC (HKLC-9) system classifications, and the BCLC system. Survival information was collected up until the end of 2014 at which point living or unconfirmed patients were censored. We compared performance of the BCLC, HKLC-5, and HKLC-9 systems in predicting patient outcomes using Kaplan-Meier estimates, calibration plots, C statistic, Akaike information criterion, and the likelihood ratio test., Results: Median overall survival time, calculated from first IAT until date of death or censorship, for the entire cohort (all stages) was 9.8 months. The BCLC and HKLC staging systems predicted patient survival times with significance (P < .001). HKLC-5 and HKLC-9 each demonstrated good calibration. The HKLC-5 system outperformed the BCLC system in predicting patient survival times (HKLC C = 0.71, Akaike information criterion = 6242; BCLC C = 0.64, Akaike information criterion = 6320), reducing error in predicting survival time (HKLC reduced error by 14%, BCLC reduced error by 12%), and homogeneity (HKLC chi-square = 201, P < .001; BCLC chi-square = 119, P < .001) and monotonicity (HKLC linear trend chi-square = 193, P < .001; BCLC linear trend chi-square = 111, P < .001). Small proportions of patients with HCC of stages IV or V, according to the HKLC system, survived for 6 months and 4 months, respectively., Conclusions: In a retrospective analysis of patients who underwent IAT for unresectable HCC, we found the HKLC-5 staging system to have the best combination of performances in survival separation, calibration, and discrimination; it consistently outperformed the BCLC system in predicting survival times of patients. The HKLC system identified patients with HCC of stages IV and V who are unlikely to benefit from IAT., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide with rapidly growing incidence rates in the USA and Europe. Despite improving surveillance programs, most patients are diagnosed at intermediate to advanced stages and are no longer amenable to curative therapies, such as ablation, surgical resection and liver transplantation. For such patients, catheter-based image-guided embolotherapies such as transarterial chemoembolization (TACE) represent the standard of care and mainstay therapy, as recommended and endorsed by a variety of national guidelines and staging systems. The main benefit of these therapies is explained by the preferentially arterial blood supply of liver tumors, which allows to deliver the anticancer therapy directly to the tumor-feeding artery while sparing the healthy hepatic tissue mainly supplied by the portal vein. The tool box of an interventional oncologist contains several different variants of transarterial treatment modalities. Ever since the first TACE more than 30 years ago, these techniques have been progressively refined, both with respect to drug delivery materials and with respect to angiographic micro-catheter and image-guidance technology, thus substantially improving therapeutic outcomes of HCC. This review will summarize the fundamental principles, technical and clinical data on the application of different embolotherapies, such as bland transarterial embolization, Lipiodol-based conventional transarterial chemoembolization as well as TACE with drug-eluting beads (DEB-TACE). Clinical data on 90 Yttrium radioembolization as an emerging alternative, mostly applied for niche indications such as HCC with portal vein invasion, will be discussed. Furthermore, we will summarize the principle of HCC staging, patient allocation and response assessment in the setting of HCC embolotherapy. In addition, we will evaluate the role of cone-beam computed tomography as a novel intra-procedural image-guidance technology. Finally, this review will touch on new technical developments such as radiopaque, imageable DEBs and the rationale and role of combined systemic and locoregional therapies, mostly in combination with Sorafenib.

Treatment of unresectable recurrent hepatocellular carcinoma (HCC) in patients who recur after resection or orthotopic liver transplantation (OLT) remains a clinical challenge. One option is sorafenib, although little is known about its safety and tolerance in this unique patient population; therefore, we analyzed patients who underwent prior surgical resection and/or OLT and were treated with sorafenib in US cohort of GIDEON registry. In US, 645 patients were enrolled; 553 for intent to treat and 563 for safety. Data were analyzed in the safety population of 479 patients no surgery and 56 for resection or OLT. Forty-one patients underwent resection prior to the initiation of sorafenib, 15 patients had previously received an OLT, and 6 patients had both resection and OLT. Initial low starting doses (400 mg/day) were observed for more patients with prior OLT (71%) than prior resection (36%), resection and OLT (50%), concomitant OLT (25%), and no surgery (36%). Most AEs occurred in the first 4 weeks of treatment. Drug-related AEs were higher in patients with prior resection (87%), prior OLT (100%), or both (100%) than in patients with concomitant OLT (63%) or no surgery (70%). However, incidence of AEs resulting in permanent discontinuation were similar in all groups (19-38%)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Our study sought to compare the overall survival in patients with hepatocellular carcinoma (HCC) and portal venous thrombosis (PVT), treated with either conventional trans-arterial chemoembolization (cTACE) or drug-eluting beads (DEB) TACE., Methods: This retrospective analysis included a total of 133 patients, treated without cross-over and compared head-to-head by means or propensity score weighting. Mortality was compared using survival analysis upon propensity score weighting. Adverse events and liver toxicity grade ≥3 were recorded and reported for each TACE. In order to compare with historical sorafenib studies, a sub-group analysis was performed and included patients who fulfilled the SHARP inclusion criteria., Results: The median overall survival (MOS) of the entire cohort was 4.53 months (95 % CI, 3.63-6.03). MOS was similar across treatment arms, no significant difference between cTACE (N = 95) and DEB-TACE (N = 38) was observed (MOS of 5.0 vs. 3.33 months, respectively; p = 0.157). The most common adverse events after cTACE and DEB- TACE, respectively, were as follows: post-embolization syndrome [N = 57 (30.0 %) and N = 38 (61.3 %)], diarrhea [N = 3 (1.6 %) and N = 3 (4.8 %)], and encephalopathy [N = 11 (5.8 %) and N = 2 (3.2 %)]., Conclusion: Our retrospective study could not reveal a difference in toxicity and efficiency between cTACE and DEB-TACE for treatment of advanced stage HCC with PVT., Key Points: • Conventional TACE (cTACE) and drug-eluting-beads TACE (DEB-TACE) demonstrated equal safety profiles. • Survival rates after TACE are similar to patients treated with sorafenib. • Child-Pugh class and tumor burden are reliable predictors of survival.

Introduction: Intra-arterial therapies (IATs) play an integral role in the management of unresectable hepatocellular carcinoma and liver metastases. The ability to accurately assess tumor response to intra-arterial therapies is crucial for clinical management. Several one- and two-dimensional manual imaging-based response assessment techniques, based both on tumor size or enhancement, have shown to be highly subjective and merely surrogate for the actual tumor as a whole. Areas covered: Given the currently existing literature, we will discuss all available tumor assessment techniques and criteria for liver cancer with a strong emphasis on 3D quantitative imaging biomarkers of tumor response in this review. Expert commentary: The growing role of information technology in medicine has brought about the advent of software-assisted, segmentation-based assessment techniques that address the outstanding issues of a subjective reader and provide for more accurate assessment techniques for the locally treated lesions. Three-dimensional quantitative tumor assessment techniques are superior to one- and two-dimensional measurements. This allows for treatment alterations and more precise targeting, potentially resulting in improved patient outcome.

Purpose: To evaluate safety and characterize anticancer efficacy of hepatic hypoxia-activated intra-arterial therapy (HAIAT) with evofosfamide in a rabbit model., Experimental Design: VX2-tumor-bearing rabbits were assigned to 4 intra-arterial therapy (IAT) groups (n = 7/group): (i) saline (control); (ii) evofosfamide (Evo); (iii) doxorubicin-lipiodol emulsion followed by embolization with 100-300 μm beads (conventional, cTACE); or (iv) cTACE and evofosfamide (cTACE + Evo). Blood samples were collected pre-IAT and 1, 2, 7, and 14 days post-IAT. A semiquantitative scoring system assessed hepatocellular damage. Tumor volumes were segmented on multidetector CT (baseline, 7/14 days post-IAT). Pathologic tumor necrosis was quantified using manual segmentation on whole-slide images. Hypoxic fraction (HF) and compartment (HC) were determined by pimonidazole staining. Tumor DNA damage, apoptosis, cell proliferation, endogenous hypoxia, and metabolism were quantified (γ-H2AX, Annexin V, caspase-3, Ki-67, HIF1α, VEGF, GAPDH, MCT4, and LDH)., Results: cTACE + Evo showed a similar profile of liver enzymes elevation and pathologic scores compared with cTACE. Neither hematologic nor renal toxicity were observed. Animals treated with cTACE + Evo demonstrated smaller tumor volumes, lower tumor growth rates, and higher necrotic fractions compared with cTACE. cTACE + Evo resulted in a marked reduction in the HF and HC. Correlation was observed between decreases in HF or HC and tumor necrosis. cTACE + Evo promoted antitumor effects as evidenced by increased expression of γ-H2AX, apoptotic biomarkers, and decreased cell proliferation. Increased HIF1α/VEGF expression and tumor glycolysis supported HAIAT., Conclusions: HAIAT achieved a promising step towards the locoregional targeting of tumor hypoxia. The favorable toxicity profile and enhanced anticancer effects of evofosfamide in combination with cTACE pave the way towards clinical trials in patients with liver cancer. Clin Cancer Res; 23(2); 536-48. ©2016 AACR., (©2016 American Association for Cancer Research.)

It remains controversial whether transarterial chemoembolization (TACE) should be performed in patients with advanced-stage hepatocellular carcinoma (HCC). The present large retrospective cohort study aimed to define the survival outcome following TACE of advanced HCC and to identify the prognostic factors. Five hundred eight patients with Barcelona Clinic Liver Cancer (BCLC) C-stage HCC, Child-Pugh A/B who were treated with TACE between November 1998 and December 2013 were identified. There was no significant difference in overall survival (OS) between patients with Eastern Cooperative Oncology Group (ECOG) 0 and those with ECOG ≥1 (10.5 months vs. 11.9 months, P = 0.87). The median OS of patients without portal vein tumor thrombosis (PVTT) was longer than that of patients with PVTT (16.9 vs. 6.1 months, P < 0.001). Child-Pugh B class, PVTT, extrahepatic metastasis, tumor size ≥5 cm, number of tumors ≥3, and alpha-fetoprotein ≥400 ng/dL were significantly associated with decreased survival and were used for determining the risk scores. All patients were divided into two groups (low-risk and high-risk groups) according to the cutoff value of 6.5 for risk scores. The patients with a value <6.5 (low-risk group) had significantly longer survival than those with >6.5 (high-risk group) (24.1 vs. 7.5 months, respectively; P < 0.001). TACE is an effective therapy for select patients with advanced stage HCC and may provide equal or improved survival as compared with reported outcomes with sorafenib. The results highlight the need for a differentiated approach to therapeutic recommendations for patients with BCLC C.

The clinical management of hepatocellular carcinoma has evolved greatly in the last decade mostly through recent technical innovations. In particular, the application of cutting-edge image guidance has led to minimally invasive solutions for complex clinical problems and rapid advances in the field of interventional oncology. Many image-guided therapies, such as transarterial chemoembolization and radiofrequency ablation, have meanwhile been fully integrated into interdisciplinary clinical practice, whereas others are currently being investigated. This review summarizes and evaluates the most relevant completed and ongoing clinical trials, provides a synopsis of recent innovations in the field of intraprocedural imaging and tumor response assessment, and offers an outlook on new technologies, such as radiopaque embolic materials. In addition, combination therapies consisting of locoregional therapies and systemic molecular targeted agents (e.g., sorafenib) remain of major interest to the field and are also discussed. Finally, we address the many substantial advances in immune response pathways that have been related to the systemic effects of locoregional therapies. Knowledge of these new developments is crucial as they continue to shape the future of cancer treatment, further establishing interventional oncology along with surgical, medical, and radiation oncology as the fourth pillar of cancer care.

Aim: To evaluate the pharmacokinetic profile (PK) and embolization effect of 70-150-μm doxorubicin eluting beads (DEBs) following intra-arterial injection (i.a.) in the rabbit liver VX2 tumour model., Materials and Methods: In this ACUC-approved study, 25 white New Zealand rabbits were randomly assigned into a small DEB group (SDB, n = 7, 70-150-μm DEBs), large DEB group (LDB, n = 7, 100-300-μm DEBs), untreated controls (n = 7), and doxorubicin controls (n = 4, without tumour, received i.a. 12.5 mg doxorubicin). Plasma PK was assessed up to 180 min post-injection. Drug tissue and liver enzyme levels, radiologic tumor response and histopathologic tumour necrosis were assessed at 7 days., Results: Mean tumour doxorubicin concentrations were 922.83 nM (SD = 722.05) and 361.48 nM (SD = 473.23) for the SDB and LDB, respectively (p = 0.005). There was no statistically significant difference in tumour doxorubicinol, plasma doxorubicin and doxorubicinol PK values. More beads were observed in the SDB tumours (p = 0.01). Liver enzymes increased and gradually declined over the observation period, with significantly higher values in the SDB., Conclusion: In this preclinical study, plasma PK of i.a.-injected 70-150-μm DEBs was not different than that of 100-300-μm DEBs. More beads and higher tissue doxorubicin levels were observed in the SDB tumours., Key Points: • Small and large doxorubicin-eluting beads show similar plasma pharmacokinetic profiles. • Higher tissue doxorubicin levels were observed in the small bead group. • Liver enzymes were overall significantly higher in the small bead group.

Purpose: Liver metastases from renal cell carcinoma (RCC) are not uncommon in the course of disease. However, data about tumor response to intraarterial therapy (IAT) are scarce. This study assessed whether changes of enhancing tumor volume using quantitative European Association for the Study of the Liver (qEASL) on magnetic resonance imaging (MRI) and computed tomography (CT) can evaluate tumor response and predict overall survival (OS) early after therapy., Methods and Materials: Fourteen patients with liver metastatic RCC treated with IAT (transarterial chemoembolization: n= 9 and yttrium-90: n= 5) were retrospectively included. All patients underwent contrast-enhanced imaging (MRI: n= 10 and CT: n= 4) 3 to 4 weeks pre- and posttreatment. Response to treatment was evaluated on the arterial phase using Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization, modified RECIST, EASL, tumor volume, and qEASL. Paired t test was used to compare measurements pre- and post-IAT. Patients were stratified into responders (≥65% decrease in qEASL) and nonresponders (<65% decrease in qEASL). OS was evaluated using Kaplan-Meier curves with log-rank test and the Cox proportional hazard model., Results: Mean qEASL (cm 3 ) decreased from 93.5 to 67.2 cm 3 (P= .004) and mean qEASL (%) from 63.1% to 35.6% (P= .001). No significant changes were observed using other response criteria. qEASL was the only significant predictor of OS when used to stratify patients into responders and nonresponders with median OS of 31.9 versus 11.1 months (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.19-0.97; P= .042) for qEASL (cm 3 ) and 29.9 versus 10.2 months (HR, 0.09; 95% CI, 0.01-0.74; P= .025) for qEASL (%)., Conclusion: Three-dimensional (3D) quantitative tumor analysis is a reliable predictor of OS when assessing treatment response after IAT in patients with RCC metastatic to the liver. qEASL outperforms conventional non-3D methods and can be used as a surrogate marker for OS early after therapy., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare the visibility of liver metastases on dual-phase cone-beam CT (DP-CBCT) and digital subtraction angiography (DSA), with reference to preinterventional contrast-enhanced magnetic resonance imaging (CE-MRI) of the liver., Methods: This IRB-approved, retrospective study included 28 patients with neuroendocrine (NELM), colorectal (CRCLM), or sarcoma (SLM) liver metastases who underwent DP-CBCT during intra-arterial therapy (IAT) between 01/2010 and 10/2014. DP-CBCT was acquired after a single contrast agent injection in the tumor-feeding arteries at early and delayed arterial phases (EAP and DAP). The visibility of each lesion was graded by two radiologists in consensus on a three-rank scale (complete, partial, none) on DP-CBCT and DSA images using CE-MRI as reference., Results: 47 NELM, 43 CRCLM, and 16 SLM were included. On DSA 85.1, 44.1, and 37.5 % of NELM, CRCLM, and SLM, were at least partially depicted, respectively. EAP-CBCT yielded significantly higher sensitivities of 88.3 and 87.5 % for CRCLM and SLM, respectively (p < 0.01), but not for NELM (89.4 %; p = 1.0). On DAP-CBCT all NELM, CRCLM, and SLM were visible (p < 0.001). Complete depiction was achieved on DSA for 59.6, 16.3, and 18.8 % of NELM, CRCLM, and SLM, respectively. The complete depiction rate on EAP-CBCT was significantly higher for CRCLM (46.5 %; p < 0.001), lower for NELM (40.4 %; p = 0.592), and similar for SLM (25 %, p = 0.399). On DAP-CBCT however, the highest rates of complete depiction were found-NELM (97.8 %; p = 0.008), CRCLM (95.3 %; p = 0.008), and SLM (100 %; p < 0.001)., Conclusion: DAP-CBCT substantially improved the visibility of liver metastases during IAT. Future studies need to evaluate the clinical impact., Competing Interests: Compliance with Ethical Standards Ethical Approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Objectives: To compare the ability of single- vs. multi-lesion assessment on baseline MRI using 1D- and 3D-based measurements to predict overall survival (OS) in patients with hepatocellular carcinoma (HCC) before transarterial chemoembolization (TACE)., Methods: This retrospective analysis included 122 patients. A quantitative 3D analysis was performed on baseline MRI to calculate enhancing tumour volume (ETV [cm(3)]) and enhancing tumour burden (ETB [%]) (ratio between ETV [cm(3)] and liver volume). Furthermore, enhancing and overall tumour diameters were measured. Patients were stratified into two groups using thresholds derived from the BCLC staging system. Statistical analysis included Kaplan-Meier plots, uni- and multivariate cox proportional hazard ratios (HR) and concordances., Results: All methods achieved good separation of the survival curves (p < 0.05). Multivariate analysis showed an HR of 5.2 (95 % CI 3.1-8.8, p < 0.001) for ETV [cm(3)] and HR 6.6 (95 % CI 3.7-11.5, p < 0.001) for ETB [%] vs. HR 2.6 (95 % CI 1.2-5.6, p = 0.012) for overall diameter and HR 3.0 (95 % CI 1.5-6.3, p = 0.003) for enhancing diameter. Concordances were highest for ETB [%], with no added predictive power for multi-lesion assessment (difference between concordances not significant)., Conclusion: 3D quantitative assessment is a stronger predictor of survival as compared to diameter-based measurements. Assessing multiple lesions provides no substantial improvement in predicting OS than evaluating the dominant lesion alone., Key Points: • 3D quantitative tumour assessment on baseline MRI predicts survival in HCC patients. • 3D quantitative tumour assessment predicts survival better than any current radiological method. • Multiple lesion assessment provides no improvement than evaluating the dominant lesion alone. • Measuring enhancing tumour volume in proportion to liver volume reflects tumour burden.

Objective: Yttrium-90 (Y-90) radioembolization is an emerging treatment option for unresectable neuroendocrine liver metastases (NELM). However, the data regarding this treatment are currently limited. This study evaluates the efficacy and tolerability of Y-90 radioembolization and identifies prognostic factors for radiographic response and survival., Methods and Materials: Thirty-eight patients underwent Y-90 radioembolization for NELM at our institution between April 2004 and February 2012. Patients were assessed radiographically (RECIST criteria, enhancement), serologically, and clinically at 1month, and then at every 3months after treatment for tumor response, toxicity, and survival outcomes., Results: Median length of follow-up was 17.0months (IQR, 9.0-37.0). Median survival was 29.2months. Three patients (9%) had a radiographic complete response to treatment, 6 (17%) had a partial response, 21 (60%) had stable disease, and 5 (14%) developed progressive disease. Two factors were significantly associated with a good radiographic response (complete/partial response): islet cell histological subtype (p=0.043) and hepatic tumor burden ≥33% (p=0.031). Multivariate analysis revealed that patients requiring multiple Y-90 treatments (HR 2.9, p=0.035) and patients who had previously failed systemic therapy with octreotide/chemotherapy (HR 4.4, p=0.012) had worse survival. Grade 3 serologic toxicity was observed in 2 patients (5%; hyperbilirubinemia, elevated alkaline phosphatase) after treatment. Grade 3 non-serologic toxicities included abdominal pain (11%), fatigue (11%), nausea/vomiting (5%), ascites (5%), dyspnea (3%), diarrhea (3%), and peripheral edema (3%). No grade 4 or 5 toxicity was reported., Conclusions: Y-90 radioembolization is a promising treatment option for inoperable NELM and is associated with low rates of grade≥3 toxicity., (Copyright © 2016. Published by Elsevier Inc.)

In their effort to characterize the systemic "off-target" effects of radiofrequency (RF) ablation and irreversible electroporation (IRE), Bulvik et al demonstrated substantial differences in physiologic, tumorigenic, and immunologic responses between the two ablative modalities. By establishing that IRE may in fact stimulate more robust inflammatory and systemic reactions than RF at liver ablation, the authors conclude that the selection of a given ablation energy source may alter the clinical outcome depending on the circumstance-both favorably and unfavorably.

Purpose: To describe first clinical experience with a directly image-able, inherently radio-opaque microspherical embolic agent for transarterial embolization of liver tumors., Methodology: LC Bead LUMI™ is a new product based upon sulfonate-modified polyvinyl alcohol hydrogel microbeads with covalently bound iodine (~260 mg I/ml). 70-150 μ LC Bead LUMI™ iodinated microbeads were injected selectively via a 2.8 Fr microcatheter to near complete flow stasis into hepatic arteries in three patients with hepatocellular carcinoma, carcinoid, or neuroendocrine tumor. A custom imaging platform tuned for LC LUMI™ microbead conspicuity using a cone beam CT (CBCT)/angiographic C-arm system (Allura Clarity FD20, Philips) was used along with CBCT embolization treatment planning software (EmboGuide, Philips)., Results: LC Bead LUMI™ image-able microbeads were easily delivered and monitored during the procedure using fluoroscopy, single-shot radiography (SSD), digital subtraction angiography (DSA), dual-phase enhanced and unenhanced CBCT, and unenhanced conventional CT obtained 48 h after the procedure. Intra-procedural imaging demonstrated tumor at risk for potential under-treatment, defined as paucity of image-able microbeads within a portion of the tumor which was confirmed at 48 h CT imaging. Fusion of pre- and post-embolization CBCT identified vessels without beads that corresponded to enhancing tumor tissue in the same location on follow-up imaging (48 h post)., Conclusion: LC Bead LUMI™ image-able microbeads provide real-time feedback and geographic localization of treatment in real time during treatment. The distribution and density of image-able beads within a tumor need further evaluation as an additional endpoint for embolization.

Background & Aims: Treatment approaches for hepatocellular carcinoma (HCC) vary across countries, but these differences and their potential impact on outcomes have not been comprehensively assessed. Data from the multinational GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) registry evaluated differences in patient characteristics, practice patterns and outcomes in HCC across geographical regions in patients who received sorafenib., Methods: GIDEON is a non-randomised, observational registry study conducted in 39 countries across five global regions. HCC patients in whom a decision to treat with sorafenib was made in clinical practice and according to local practices were included., Results: 3202 patients were evaluable for safety analysis: Asia-Pacific (n = 928), Japan (n = 508), Europe (n = 1113), USA (n = 563) and Latin America (n = 90). Patients in Japan had earlier-stage disease at initial diagnosis compared with patients in other regions (Barcelona Clinic Liver Cancer stage A; 43.7% vs 9.1-24.3%). Use of locoregional therapies before sorafenib, including transarterial chemoembolisation, was more common in Japan (84.4%) and Asia-Pacific (67.2%) compared with the USA (49.4%) and Europe (43.5%). Treatment patterns with respect to sorafenib also differed, with a shorter duration of treatment reported in the USA and Asia-Pacific. Time from initial diagnosis to death was longer in Japan compared with other regions (median, 79.6 months vs 14.8-25.0 months)., Conclusions: Data from GIDEON highlight regional variations in the management of HCC and patient outcomes. Greater standardisation of management may help optimise outcomes for HCC patients., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The dependence of tumor cells, particularly those originating in the brain, on glucose is the target of the ketogenic diet, which creates a plasma nutrient profile similar to fasting: increased levels of ketone bodies and reduced plasma glucose concentrations. The use of ketogenic diets has been of particular interest for therapy in brain tumors, which reportedly lack the ability to oxidize ketone bodies and therefore would be starved during ketosis. Because studies assessing the tumors' ability to oxidize ketone bodies are lacking, we investigated in vivo the extent of ketone body oxidation in 2 rodent glioma models., Methods: Ketone body oxidation was studied using (13)C MR spectroscopy in combination with infusion of a (13)C-labeled ketone body (beta-hydroxybutyrate) in RG2 and 9L glioma models. The level of ketone body oxidation was compared with nontumorous cortical brain tissue., Results: The level of (13)C-beta-hydroxybutyrate oxidation in 2 rat glioma models was similar to that of contralateral brain. In addition, when glioma-bearing animals were fed a ketogenic diet, the ketone body monocarboxylate transporter was upregulated, facilitating uptake and oxidation of ketone bodies in the gliomas., Conclusions: These results demonstrate that rat gliomas can oxidize ketone bodies and indicate upregulation of ketone body transport when fed a ketogenic diet. Our findings contradict the hypothesis that brain tumors are metabolically inflexible and show the need for additional research on the use of ketogenic diets as therapy targeting brain tumor metabolism., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Unlabelled: Transarterial chemoembolization (TACE) using lipiodol-based regimens, including the administration of an anticancer-in-oil emulsion followed by embolic agents, is widely used in the treatment of hepatocellular carcinoma (HCC). This approach has been supported by meta-analyses of randomized, controlled trials (RCTs) performed more than a decade ago. We performed a systematic review to understand current efficacy and safety data of lipiodol TACE in treatment of HCC. A search of the literature published between January 1, 1980 and June 30, 2013 was performed using MEDLINE and EMBASE databases. All potentially relevant publications were reviewed and articles were selected based on predefined inclusion and exclusion criteria. Of a total of 1,564 articles reviewed, 101 articles, including a total of 10,108 patients treated with lipiodol TACE, were selected for the efficacy analysis. Objective response rate was 52.5% (95% confidence interval [CI]: 43.6-61.5). Overall survival (OS) was 70.3% at 1 year, 51.8% at 2 years, 40.4% at 3 years, and 32.4% at 5 years. Median OS was 19.4 months (95% CI: 16.2-22.6). A total of 217 articles presenting precise description on numbers of adverse events (AEs) were selected for the safety review: In these studies, a total of 21,461 AEs were reported in 15,351 patients. Liver enzyme abnormalities were the most commonly observed AE, followed by the symptoms associated with postembolization syndrome. Overall mortality rate was 0.6% and the most common cause of death was related to acute liver insufficiency., Conclusions: In a systematic literature review, survival figures of HCC patients undergoing lipiodol TACE appear to be in line with those reported in previous RCTs, and no new or unexpected safety concerns were identified. (Hepatology 2016;64:106-116)., (© 2016 by the American Association for the Study of Liver Diseases.)

Objective: To review the current management, outline recent advances and address controversies in the management of hepatocellular carcinoma (HCC)., Summary of Background Data: The treatment of HCC is multidisciplinary involving hepatologists, surgeons, medical oncologists, radiation oncologists, radiologists, interventional radiologists, and other disciplines. Each of these disciplines brings its unique perspective and differing opinions that add to controversies in the management of HCC., Methods: A focused literature review was performed to identify recent studies on the management of HCC and thereby summarize relevant information on the various therapeutic modalities and controversies involved in the treatment of HCC., Results: The main treatment algorithms continue to rely on hepatic resection or transplantation with controversies involving patients harboring early stage disease and borderline hepatic function. The other treatment strategies include locoregional therapies, radiation, and systemic therapy used alone or in combination with other treatment modalities. Recent advances in locoregional therapies, radiation, and systemic therapies have provided better therapeutic options with curative intent potential for some locoregional therapies. Further refinements in combination therapies such as algorithms consisting of locoregional therapies and systemic or radiation therapies are likely to add additional options and improve survival., Conclusions: The management of HCC has witnessed significant strides with advances in existing options and introduction of several new treatment modalities of various combinations. Further refinements in these treatment options combined with enrollment in clinical trials are essential to improve the management and outcomes of patients with HCC.

Purpose To assess the visibility of radiopaque microspheres during transarterial embolization (TAE) in the VX2 rabbit liver tumor model by using multimodality imaging, including single-snapshot radiography, cone-beam computed tomography (CT), multidetector CT, and micro-CT. Materials and Methods The study was approved by the institutional animal care and use committee. Fifteen VX2-tumor-bearing rabbits were assigned to three groups depending on the type of embolic agent injected: 70-150-μm radiopaque microspheres in saline (radiopaque microsphere group), 70-150-μm radiopaque microspheres in contrast material (radiopaque microsphere plus contrast material group), and 70-150-μm radiolucent microspheres in contrast material (nonradiopaque microsphere plus contrast material group). Rabbits were imaged with single-snapshot radiography, cone-beam CT, and multidetector CT. Three to 5 weeks after sacrifice, excised livers were imaged with micro-CT and histologic analysis was performed. The visibility of the embolic agent was assessed with all modalities before and after embolization by using a qualitative three-point scale score reading study and a quantitative assessment of the signal-to-noise ratio (SNR) change in various regions of interest, including the tumor and its feeding arteries. The Kruskal-Wallis test was used to compare the rabbit characteristics across groups, and the Wilcoxon signed rank test was used to compare SNR measurements before and after embolization. Results Radiopaque microspheres were qualitatively visualized within tumor feeding arteries and targeted tissue with all imaging modalities (P < .05), and their presence was confirmed with histologic examination. SNRs of radiopaque microsphere deposition increased after TAE on multidetector CT, cone-beam CT, and micro-CT images (P < .05). Similar results were obtained when contrast material was added to radiopaque microspheres, except for additional image attenuation due to tumor enhancement. For the group with nonradiopaque microspheres and contrast material, retained tumoral contrast remained qualitatively visible with all modalities except for micro-CT, which demonstrated soluble contrast material washout over time. Conclusion Radiopaque microspheres were visible with all imaging modalities and helped increase conspicuity of the tumor as well as its feeding arteries after TAE in a rabbit VX2 liver tumor model. (©) RSNA, 2015.

Unlabelled: Hepatic metastases of colorectal carcinoma are a leading cause of cancer-related mortality. Most colorectal liver metastases become refractory to chemotherapy and biologic agents, at which point the median overall survival declines to 4-5 mo. Radioembolization with (90)Y has been used in the salvage setting with favorable outcomes. This study reports the survival and safety outcomes of 531 patients treated with glass-based (90)Y microspheres at 8 institutions, making it the largest (90)Y study for patients with colorectal liver metastases., Methods: Data were retrospectively compiled from 8 institutions for all (90)Y glass microsphere treatments for colorectal liver metastases. Exposure to chemotherapeutic or biologic agents, prior liver therapies, biochemical parameters before and after treatment, radiation dosimetry, and complications were recorded. Uni- and multivariate analyses for predictors of survival were performed. Survival outcomes and clinical or biochemical adverse events were recorded., Results: In total, 531 patients received (90)Y radioembolization for colorectal liver metastases. The most common clinical adverse events were fatigue (55%), abdominal pain (34%), and nausea (19%). Grade 3 or 4 hyperbilirubinemia occurred in 13% of patients at any time. The median overall survival from the first (90)Y treatment was 10.6 mo (95% confidence interval, 8.8-12.4). Performance status, no more than 25% tumor burden, no extrahepatic metastases, albumin greater than 3 g/dL, and receipt of no more than 2 chemotherapeutic agents independently predicted better survival outcomes., Conclusion: This multiinstitutional review of a large cohort of patients with colorectal liver metastases treated with (90)Y radioembolization using glass microspheres has demonstrated promising survival outcomes with low toxicity and low side effects. The outcomes were reproducible and consistent with prior reports of radioembolization., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: To evaluate transarterial chemoembolization (TACE) use prior to and concomitantly with sorafenib in patients with unresectable hepatocellular carcinoma (HCC) across different global regions., Materials and Methods: GIDEON is an observational registry study of more than 3000 HCC patients. Patients with histologically, cytologically, or radiographically diagnosed HCC, and for whom a decision had been made to treat with sorafenib, were eligible. Patients were enrolled into the registry from 39 countries beginning in January 2009, with the last patient follow-up in April 2012. Detailed data on treatment history, treatment patterns, adverse events, and outcomes were collected. All treatment decisions were at the discretion of the treating physicians. Documented approval from local ethics committees was obtained, and all patients provided signed informed consent. Descriptive statistics, including minimum, median, and maximum, were calculated for metric data, and frequency tables for categorical data. Kaplan-Meier estimates with 95% confidence intervals were calculated for survival end points., Results: A total of 3202 patients were eligible for safety analysis, of whom 2631 (82.2%) were male. Median age was 62 years (range, 15-98 years). A total of 1511 (47.2%) patients underwent TACE prior to sorafenib; 325 (10.1%) underwent TACE concomitantly. TACE prior to sorafenib was more common in Japan and Asia-Pacific compared with all other regions (362 [71.3%] and 560 [60.3%] vs 12-209 [13.3%-37.1%]). Adverse events were reported in 2732 (85.3%) patients overall, with no notable differences in the incidence of adverse events, regardless of TACE treatment history. Overall survival was 12.7 months in prior-TACE patients, 9.2 months in non-prior-TACE patients, 21.6 months in concomitant-TACE patients, and 9.7 months in non-concomitant-TACE patients., Conclusion: Global variation exists in TACE use in sorafenib-treated HCC patients. The combination of TACE with sorafenib appears to be a well-tolerated and viable therapeutic approach., ((©) RSNA, 2016 Online supplemental material is available for this article.)