Decision-Tree Models Indicative of Microvascular Invasion on MRI Predict Survival in Patients with Hepatocellular Carcinoma Following Tumor Ablation.

Purpose: Histological microvascular invasion (MVI) is a risk factor for poor survival and early recurrence in hepatocellular carcinoma (HCC) after surgery. Its prognostic value in the setting of locoregional therapies (LRT), where no tissue samples are obtained, remains unknown. This study aims to establish CT-derived indices indicative of MVI on liver MRI with superior soft tissue contrast and evaluate their association with patient survival after ablation via interstitial brachytherapy (iBT) versus iBT combined with prior conventional transarterial chemoembolization (cTACE). Patients and Methods: Ninety-five consecutive patients, who underwent ablation via iBT alone (n = 47) or combined with cTACE (n = 48), were retrospectively included between 01/2016 and 12/2017. All patients received contrast-enhanced MRI prior to LRT. Overall (OS), progression-free survival (PFS), and time-to-progression (TTP) were assessed. Decision-tree models to determine Radiogenomic Venous Invasion (RVI) and Two-Trait Predictor of Venous Invasion (TTPVI) on baseline MRI were established, validated on an external test set (TCGA-LIHC), and applied in the study cohorts to investigate their prognostic value for patient survival. Statistics included Fisher's exact and t-test, Kaplan-Meier and cox-regression analysis, area under the receiver operating characteristic curve (AUC-ROC) and Pearson's correlation. Results: OS, PFS, and TTP were similar in both treatment groups. In the external dataset, RVI showed low sensitivity but relatively high specificity (AUC-ROC = 0.53), and TTPVI high sensitivity but only low specificity (AUC-ROC = 0.61) for histological MVI. In patients following iBT alone, positive RVI and TTPVI traits were associated with poorer OS (RVI: p < 0.01; TTPVI: p = 0.08), PFS (p = 0.04; p = 0.04), and TTP (p = 0.14; p = 0.03), respectively. However, when patients with combined cTACE and iBT were stratified by RVI or TTPVI, no differences in OS (p = 0.75; p = 0.55), PFS (p = 0.70; p = 0.43), or TTP (p = 0.33; p = 0.27) were observed. Conclusion: The study underscores the role of non-invasive imaging biomarkers indicative of MVI to identify patients, who would potentially benefit from embolotherapy via cTACE prior to ablation rather than ablation alone.

MR Elastography in Cancer.

ABSTRACT: The mechanical traits of cancer include abnormally high solid stress as well as drastic and spatially heterogeneous changes in intrinsic mechanical tissue properties. Whereas solid stress elicits mechanosensory signals promoting tumor progression, mechanical heterogeneity is conducive to cell unjamming and metastatic spread. This reductionist view of tumorigenesis and malignant transformation provides a generalized framework for understanding the physical principles of tumor aggressiveness and harnessing them as novel in vivo imaging markers. Magnetic resonance elastography is an emerging imaging technology for depicting the viscoelastic properties of biological soft tissues and clinically characterizing tumors in terms of their biomechanical properties. This review article presents recent technical developments, basic results, and clinical applications of magnetic resonance elastography in patients with malignant tumors.

Non-Invasive Imaging Biomarkers to Predict the Hepatopulmonary Shunt Fraction Before Transarterial Radioembolization in Patients with Hepatocellular Carcinoma.

Purpose: To identify disease-specific profiles comprising patient characteristics and imaging biomarkers on contrast-enhanced (CE)-computed tomography (CT) that enable the non-invasive prediction of the hepatopulmonary shunt fraction (HPSF) in patients with hepatocellular carcinoma (HCC) before resin-based transarterial radioembolization (TARE). Patients and Methods: This institutional review board-approved (EA2/071/19) retrospective study included 56 patients with HCC recommended for TARE. All patients received tri-phasic CE-CT within 6 weeks prior to an angiographic TARE evaluation study using technetium-99m macroaggregated albumin. Imaging biomarkers representative of tumor extent, morphology, and perfusion, as well as disease-specific clinical parameters, were used to perform data-driven variable selection with backward elimination to generate multivariable linear regression models predictive of HPSF. Results were used to create clinically applicable risk scores for patients scheduled for TARE. Additionally, Cox regression was used to identify independent risk factors for poor overall survival (OS). Results: Mean HPSF was 13.11% ± 7.6% (range: 2.8- 35.97%). Index tumor diameter (p = 0.014) or volume (p = 0.034) in combination with index tumor non-rim arterial phase enhancement (APHE) (p < 0.001) and washout (p < 0.001) were identified as significant non-invasive predictors of HPSF on CE-CT. Specifically, the prediction models revealed that the HPSF increased with index lesion diameter or volume and showed higher HPSF if non-rim APHE was present. In contrast, index tumor washout was associated with decreased HPSF levels. Independent risk factors of poorer OS were radiogenomic venous invasion and ascites at baseline. Conclusion: The featured prediction models can be used for the initial non-invasive estimation of HPSF in patients with HCC before TARE to assist in clinical treatment evaluation while potentially sparing ineligible patients from the angiographic shunt evaluation study.

Conventional vs. Drug-Eluting Beads Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma-A Propensity Score Weighted Comparison of Efficacy and Safety.

This study compared the efficacy and safety of conventional transarterial chemoembolization (cTACE) with drug-eluting beads (DEB)-TACE in patients with unresectable hepatocellular carcinoma (HCC). This retrospective analysis included 370 patients with HCC treated with cTACE (n = 248) or DEB-TACE (n = 122) (January 2000-July 2014). Overall survival (OS) was assessed using uni- and multivariate Cox proportional hazards models and Kaplan-Meier analysis. Additionally, baseline imaging was assessed, and clinical and laboratory toxicities were recorded. Propensity score weighting via a generalized boosted model was applied to account for group heterogeneity. There was no significant difference in OS between cTACE (20 months) and DEB-TACE patients (24.3 months, ratio 1.271, 95% confidence interval 0.876-1.69; p = 0.392). However, in patients with infiltrative disease, cTACE achieved longer OS (25.1 months) compared to DEB-TACE (9.2 months, ratio 0.366, 0.191-0.702; p = 0.003), whereas DEB-TACE proved more effective in nodular disease (39.4 months) than cTACE (18 months, ratio 0.458, 0.308-0681; p = 0.007). Adverse events occurred with similar frequency, except for abdominal pain, which was observed more frequently after DEB-TACE (101/116; 87.1%) than cTACE (119/157; 75.8%; p = 0.02). In conclusion, these findings suggest that tumor morphology and distribution should be used as parameters to inform decisions on the selection of embolic materials for TACE for a more personalized treatment planning in patients with unresectable HCC.

Analysis of Tumor Burden as a Biomarker for Patient Survival with Neuroendocrine Tumor Liver Metastases Undergoing Intra-Arterial Therapies: A Single-Center Retrospective Analysis.

PURPOSE: To assess the value of quantitative analysis of tumor burden on baseline MRI for prediction of survival in patients with neuroendocrine tumor liver metastases (NELM) undergoing intra-arterial therapies. MATERIALS AND METHODS: This retrospective single-center analysis included 122 patients with NELM who received conventional (n = 74) or drug-eluting beads, (n = 20) chemoembolization and radioembolization (n = 28) from 2000 to 2014. Overall tumor diameter (1D) and area (2D) of up to 3 largest liver lesions were measured on baseline arterially contrast enhanced MR images. Three-dimensional quantitative analysis was performed using the qEASL tool (IntelliSpace Portal Version 8, Philips) to calculate enhancing tumor burden (the ratio between enhancing tumor volume and total liver volume). Based on Q-statistics, patients were stratified into low tumor burden (TB) or high TB. RESULTS: The survival curves were significantly separated between low TB and high TB groups for 1D (p < 0.001), 2D (p < 0.001) and enhancing TB (p = 0.008) measurements, with, respectively, 2.7, 2.6 and 2.2 times longer median overall survival (MOS) in the low TB group (p < 0.001, p < 0.001 and p = 0.008). Multivariate analysis showed that 1D, 2D, and enhancing TB were independent prognostic factors for MOS, with respective hazard ratios of 0.4 (95%CI: 0.2-0.6, p < 0.001), 0.4 (95%CI: 0.3-0.7, p < 0.001) and 0.5 (95%CI: 0.3-0.8, p = 0.003). CONCLUSION: The overall tumor diameter, overall tumor area, and enhancing tumor burden are strong prognostic factors of overall survival in patients with neuroendocrine tumor liver metastases undergoing intra-arterial therapies.

Optimization of the BCLC Staging System for Locoregional Therapy for Hepatocellular Carcinoma by Using Quantitative Tumor Burden Imaging Biomarkers at MRI.

Background Patients with intermediate- and advanced-stage hepatocellular carcinoma (HCC) represent a highly heterogeneous patient collective with substantial differences in overall survival. Purpose To evaluate enhancing tumor volume (ETV) and enhancing tumor burden (ETB) as new criteria within the Barcelona Clinic Liver Cancer (BCLC) staging system for optimized allocation of patients with intermediate- and advanced-stage HCC to undergo transarterial chemoembolization (TACE). Materials and Methods In this retrospective study, 682 patients with HCC who underwent conventional TACE or TACE with drug-eluting beads from January 2000 to December 2014 were evaluated. Quantitative three-dimensional analysis of contrast-enhanced MRI was performed to determine thresholds of ETV and ETB (ratio of ETV to normal liver volume). Patients with ETV below 65 cm3 or ETB below 4% were reassigned to BCLC Bn, whereas patients with ETV or ETB above the determined cutoffs were restratified or remained in BCLC Cn by means of stepwise verification of the median overall survival (mOS). Results This study included 494 patients (median age, 62 years [IQR, 56-71 years]; 401 men). Originally, 123 patients were classified as BCLC B with mOS of 24.3 months (95% CI: 21.4, 32.9) and 371 patients as BCLC C with mOS of 11.9 months (95% CI: 10.5, 14.8). The mOS of all included patients (including the BCLC B and C groups) was 15 months (95% CI: 12.3, 17.2). A total of 152 patients with BCLC C tumors were restratified into a new BCLC Bn class, in which the mOS was then 25.1 months (95% CI: 21.8, 29.7; P < .001). The mOS of the remaining patients (ie, BCLC Cn group) (n = 222; ETV ≥65 cm3 or ETB ≥4%) was 8.4 months (95% CI: 6.1, 11.2). Conclusion Substratification of patients with intermediate- and advanced-stage hepatocellular carcinoma according to three-dimensional quantitative tumor burden identified patients with a survival benefit from transarterial chemoembolization before therapy. © RSNA, 2022 Online supplemental material is available for this article.

Lipiodol Deposition and Washout in Primary and Metastatic Liver Tumors After Chemoembolization.

BACKGROUND/AIM: Lipiodol is the key component of conventional trans-arterial chemoembolization. Our aim was to evaluate lipiodol deposition and washout rate after conventional trans-arterial chemoembolization in intrahepatic cholangiocarcinoma and hepatic metastases originating from neuroendocrine tumors and colorectal carcinoma. PATIENTS AND METHODS: This was a retrospective analysis of 44 patients with intrahepatic cholangiocarcinoma and liver metastasis from neuroendocrine tumors or colorectal carcinoma who underwent conventional trans-arterial chemoembolization. Lipiodol volume (cm3) was analyzed on non-contrast computed tomography imaging obtained within 24 h post conventional trans-arterial chemoembolization, and 40-220 days after conventional trans-arterial chemoembolization using volumetric image analysis software. Tumor response was assessed on contrast-enhanced magnetic resonance imaging 1 month after conventional trans-arterial chemoembolization. RESULTS: The washout rate was longer for neuroendocrine tumors compared to colorectal carcinoma, with half-lives of 54.61 days (p<0.00001) and 19.39 days (p<0.001), respectively, with no exponential washout among intrahepatic cholangiocarcinomas (p=0.83). The half-life for lipiodol washout was longer in tumors larger than 300 cm3 compared to smaller tumors (25.43 vs. 22.71 days). Lipiodol wash out half-life was 54.76 days (p<0.01) and 29.45 days (p<0.00001) for tumors with a contrast enhancement burden of 60% or more and less than 60%, respectively. A negative exponential relationship for lipiodol washout was observed in non-responders (p<0.00001). CONCLUSION: Lipiodol washout is a time-dependent process, and occurs faster in colorectal carcinoma tumors, tumors smaller than 300 cm3, tumors with baseline contrast enhancement burden of less than 60%, and non-responding target lesions.

Comparison of intrahepatic progression patterns of hepatocellular carcinoma and colorectal liver metastases following CT-guided high dose-rate brachytherapy.

INTRODUCTION: Given the metachronous and multifocal occurrence of hepatocellular carcinoma (HCC) and colorectal cancer metastases in the liver (CRLM), this study aimed to compare intrahepatic progression patterns after computed tomography (CT)-guided high dose-rate brachytherapy. PATIENTS AND METHODS: This retrospective analysis included 164 patients (114 HCC, 50 CRLM) treated with brachytherapy between January 2016 and January 2018. Patients received multiparametric magnetic resonance imaging (MRI) before, and about 8 weeks after brachytherapy, then every 3 months for the first, and every 6 months for the following years, until progression or death. MRI scans were assessed for local or distant intrahepatic tumor progression according to RECIST 1.1 and electronic medical records were reviewed prior to therapy. The primary endpoint was progression-free survival (PFS). Specifically, local and distant intra-hepatic PFS were assessed to determine differences between the intrahepatic progression patterns of HCC and CRLM. Secondary endpoints included the identification of predictors of PFS, time to progression (TTP), and overall survival (OS). Statistics included Kaplan-Meier analysis and univariate and multivariate Cox regression modeling. RESULTS: PFS was longer in HCC [11.30 (1.33-35.37) months] than in CRLM patients [8.03 (0.73-19.80) months, p = 0.048], respectively. Specifically, local recurrence occurred later in HCC [PFS: 36.83 (1.33-40.27) months] than CRLM patients [PFS: 12.43 (0.73-21.90) months, p = 0.001]. In contrast, distant intrahepatic progression occurred earlier in HCC [PFS: 13.50 (1.33-27.80) months] than in CRLM patients [PFS: 19.80 (1.43-19.80) months, p = 0.456] but without statistical significance. Multivariate Cox regression confirmed tumor type and patient age as independent predictors for PFS. CONCLUSION: Brachytherapy proved to achieve better local tumor control and overall PFS in patients with unresectable HCC as compared to those with CRLM. However, distant progression preceded local recurrence in HCC. As a result, these findings may help design disease-specific surveillance strategies and personalized treatment planning that highlights the strengths of brachytherapy. They may also help elucidate the potential benefits of combinations with other loco-regional or systemic therapies.

Current Trends in Non-Invasive Imaging of Interactions in the Liver Tumor Microenvironment Mediated by Tumor Metabolism.

With the increasing understanding of resistance mechanisms mediated by the metabolic reprogramming in cancer cells, there is a growing clinical interest in imaging technologies that allow for the non-invasive characterization of tumor metabolism and the interactions of cancer cells with the tumor microenvironment (TME) mediated through tumor metabolism. Specifically, tumor glycolysis and subsequent tissue acidosis in the realms of the Warburg effect may promote an immunosuppressive TME, causing a substantial barrier to the clinical efficacy of numerous immuno-oncologic treatments. Thus, imaging the varying individual compositions of the TME may provide a more accurate characterization of the individual tumor. This approach can help to identify the most suitable therapy for each individual patient and design new targeted treatment strategies that disable resistance mechanisms in liver cancer. This review article focuses on non-invasive positron-emission tomography (PET)- and MR-based imaging techniques that aim to visualize the crosstalk between tumor cells and their microenvironment in liver cancer mediated by tumor metabolism.

Atezolizumab and bevacizumab-induced encephalitis in advanced hepatocellular carcinoma: Case report and literature review.

INTRODUCTION: On the basis of the results of the IMBRAVE-150 trial, the combination of atezolizumab, a programmed cell death ligand 1 (PD-L1) antibody, as well as bevacizumab, a vascular endothelial growth factor (VEGF) antibody, represents a promising novel first-line therapy in patients with advanced hepatocellular carcinoma (HCC). Despite favorable safety data, serious adverse events have been described. However, central nervous system complications such as encephalitis have rarely been reported. We present the case of a 70-year-old woman with hepatitis C virus (HCV)-related liver cirrhosis and advanced HCC who developed severe encephalitis after only one cycle of atezolizumab/bevacizumab. PATIENT CONCERNS: Ten days after administration, the patient presented with confusion, somnolence, and emesis. Within a few days, the patient's condition deteriorated, and mechanical ventilation became necessary. DIAGNOSIS: Cerebrospinal fluid (CSF) analysis showed increased cell count and elevated protein values. Further work-up revealed no signs of an infectious, paraneoplastic, or other autoimmune cause. INTERVENTION: Suspecting an atezolizumab/bevacizumab-related encephalitis, we initiated a high-dose steroid pulse therapy as well as repeated plasmapheresis, which resulted in clinical improvement and remission of CSF abnormalities. OUTCOME: Despite successful weaning and transfer to a rehabilitation ward, the patient died of progressive liver cancer 76 days after initial treatment with atezolizumab/bevacizumab, showing no response. CONCLUSION: This case illustrates that rapid immunosuppressive treatment with prednisolone can result in remission even of severe encephalitis. We discuss this case in the context of available literature and previously reported cases of atezolizumab-induced encephalitis in different tumor entities, highlighting the diagnostic challenges in oncologic patients treated with immune checkpoint-inhibitors.

Hepatic Radiofrequency Ablation: Monitoring of Ablation-Induced Macrophage Recruitment in the Periablational Rim Using SPION-Enhanced Macrophage-Specific Magnetic Resonance Imaging.

OBJECTIVES: Macrophages accumulating in the periablational rim play a pivotal role in initiating and sustaining the perifocal inflammatory reaction, which has been shown to be at least 1 of the mechanisms responsible for the systemic pro-oncogenic effects of focal hepatic radiofrequency ablation (RFA). Herein, we tested the hypothesis to use superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI) for noninvasive quantification of iron-loaded macrophages in the periablational rim of VX2 tumor-bearing rabbits. MATERIALS AND METHODS: Twelve VX2 tumor-bearing rabbits underwent MRI immediately after and up to 3 weeks after focal hepatic RFA. For noninvasive quantification of macrophage accumulation in the periablational rim, animals were scanned before and 24 hours after SPION injection. T2*-weighted images were analyzed and correlated with histopathological and immunohistochemical findings. Furthermore, correlations with quantitative measurements (ICP-MS [inductively coupled plasma-mass spectrometry] and LA-ICP-MS [laser ablation-ICP-MS]) were performed. RESULTS: SPION-enhanced T2*-weighted MRI scans displayed a progressive increase in the areas of signal intensity (SI) loss within the periablational rim peaking 3 weeks after RFA. Accordingly, quantitative analysis of SI changes demonstrated a significant decline in the relative SI ratio reflecting a growing accumulation of iron-loaded macrophages in the rim. Histological analyses confirmed a progressive accumulation of iron-loaded macrophages in the periablational rim. The ICP-MS and LA-ICP-MS confirmed a progressive increase of iron concentration in the periablational rim. CONCLUSIONS: SPION-enhanced MRI enables noninvasive monitoring and quantification of ablation-induced macrophage recruitment in the periablational rim. Given the close interplay between ablation-induced perifocal inflammation and potential unwanted tumorigenic effects of RFA, SPION-enhanced MRI may serve as a valuable tool to guide and modulate adjuvant therapies after hepatic RFA.

Elastin-specific MRI of extracellular matrix-remodelling following hepatic radiofrequency-ablation in a VX2 liver tumor model.

Hepatic radiofrequency ablation (RFA) induces a drastic alteration of the biomechanical environment in the peritumoral liver tissue. The resulting increase in matrix stiffness has been shown to significantly influence carcinogenesis and cancer progression after focal RF ablation. To investigate the potential of an elastin-specific MR agent (ESMA) for the assessment of extracellular matrix (ECM) remodeling in the periablational rim following RFA in a VX2 rabbit liver tumor-model, twelve New-Zealand-White-rabbits were implanted in the left liver lobe with VX2 tumor chunks from donor animals. RFA of tumors was performed using a perfused RF needle-applicator with a mean tip temperature of 70 °C. Animals were randomized into four groups for MR imaging and scanned at four different time points following RFA (week 0 [baseline], week 1, week 2 and week 3 after RFA), followed by sacrifice and histopathological analysis. ESMA-enhanced MR imaging was used to assess ECM remodeling. Gadobutrol was used as a third-space control agent. Molecular MR imaging using an elastin-specific probe demonstrated a progressive increase in contrast-to-noise ratio (CNR) (week 3: ESMA: 28.1 ± 6.0; gadobutrol: 3.5 ± 2.0), enabling non-invasive imaging of the peritumoral zone with high spatial-resolution, and accurate assessment of elastin deposition in the periablational rim. In vivo CNR correlated with ex vivo histomorphometry (ElasticaVanGiesson-stain, y = 1.2x - 1.8, R2 = 0.89, p < 0.05) and gadolinium concentrations at inductively coupled mass spectroscopy (ICP-MS, y = 0.04x + 1.2, R2 = 0.95, p < 0.05). Laser-ICP-MS confirmed colocalization of elastin-specific probe with elastic fibers. Following thermal ablation, molecular imaging using an elastin-specific MR probe is feasible and provides a quantifiable biomarker for the assessment of the ablation-induced remodeling of the ECM in the periablational rim.

A high-throughput imaging platform to characterize extracellular pH in organotypic three-dimensional in vitro models of liver cancer.

Given the extraordinary nature of tumor metabolism in hepatocellular carcinoma and its impact on oncologic treatment response, this study introduces a novel high-throughput extracellular pH (pHe ) mapping platform using magnetic resonance spectroscopic imaging in a three-dimensional (3D) in vitro model of liver cancer. pHe mapping was performed using biosensor imaging of redundant deviation in shifts (BIRDS) on 9.4 T and 11.7 T MR scanners for validation purposes. 3D cultures of four liver cancer (HepG2, Huh7, SNU475, VX2) and one hepatocyte (THLE2) cell line were simultaneously analyzed (a) without treatment, (b) supplemented with 4.5 g/L d-glucose, and (c) treated with anti-glycolytic 3-bromopyruvate (6.25, 25, 50, 75, and 100 µM). The MR results were correlated with immunohistochemistry (GLUT-1, LAMP-2) and luminescence-based viability assays. Statistics included the unpaired t-test and ANOVA test. High-throughput pHe imaging with BIRDS for in vitro 3D liver cancer models proved feasible. Compared with non-tumorous hepatocytes (pHe = 7.1 ± 0.1), acidic pHe was revealed in liver cancer (VX2, pHe = 6.7 ± 0.1; HuH7, pHe = 6.8 ± 0.1; HepG2, pHe = 6.9 ± 0.1; SNU475, pHe = 6.9 ± 0.1), in agreement with GLUT-1 upregulation. Glucose addition significantly further decreased pHe in hyperglycolytic cell lines (VX2, HepG2, and Huh7, by 0.28, 0.06, and 0.11, respectively, all p < 0.001), whereas 3-bromopyruvate normalized tumor pHe in a dose-dependent manner without affecting viability. In summary, this study introduces a non-invasive pHe imaging platform for high-yield screening using a translational 3D liver cancer model, which may help reveal and target mechanisms of therapy resistance and inform personalized treatment of patients with hepatocellular carcinoma.

Fibronodular hepatocellular carcinoma-a new variant of liver cancer: clinical, pathological and radiological correlation.

AIMS: To establish and define a new, not previously reported hepatocellular carcinoma (HCC) variant, termed fibronodular HCC (FN-HCC). METHODS: We retrospectively reviewed 290 HCC cases and identified 29 FN-HCC and 24 scirrhous HCC (SCHCC). Clinical, pathological and radiological features of FN-HCC were reviewed and compared with 30 conventional HCCs (CV-HCC) and SC-HCC. RESULTS: FN-HCCs were more likely to arise in non-advanced fibrotic livers with lower advanced Barcelona Clinic Liver Cancer (BCLC) stage, had lower rates of progression and longer time to progression and were more likely to be surgically resected compared with CV-HCCs and SC-HCCs. Imaging analysis of FN-HCCs demonstrated higher rates of non-peripheral washout and a new distinct pattern of enhancement which is characterised by the presence of multiple rounded nodules within a lesion embedded in fibrotic-appearing parenchyma. CONCLUSIONS: FN-HCC may represent a specific variant of HCC with distinct pathological, radiological and clinical features with potential ramifications for outcome.

Reliable prediction of survival in advanced-stage hepatocellular carcinoma treated with sorafenib: comparing 1D and 3D quantitative tumor response criteria on MRI.

OBJECTIVES: To compare 1D and 3D quantitative tumor response criteria applied to DCE-MRI in patients with advanced-stage HCC undergoing sorafenib therapy to predict overall survival (OS) early during treatment. METHODS: This retrospective analysis included 29 patients with advanced-stage HCC who received sorafenib for at least 60 days. All patients underwent baseline and follow-up DCE-MRI at 81.5 ± 29.3 days (range 35-140 days). Response to sorafenib was assessed in 46 target lesions using 1D criteria RECIST1.1 and mRECIST. In addition, a segmentation-based 3D quantification of absolute enhancing lesion volume (vqEASL) was performed on the arterial phase MRI, and the enhancement fraction of total tumor volume (%qEASL) was calculated. Accordingly, patients were stratified into groups of disease control (DC) and disease progression (DP). OS was evaluated using Kaplan-Meier curves with log-rank test and Cox proportional hazards regression model. RESULTS: The Kaplan-Meier analysis revealed that stratification of patients in DC vs. DP according to mRECIST (p = 0.0371) and vqEASL (p = 0.0118) successfully captured response and stratified OS, while stratification according to RECIST and %qEASL did not correlate with OS (p = 0.6273 and p = 0.7474, respectively). Multivariable Cox regression identified tumor progression according to mRECIST and qEASL as independent risk factors of decreased OS (p = 0.039 and p = 0.006, respectively). CONCLUSIONS: The study identified enhancement-based vqEASL and mRECIST as reliable predictors of patient survival early after initiation of treatment with sorafenib. This data provides evidence for potential advantages 3D quantitative, enhancement-based tumor response analysis over conventional techniques regarding early identification of treatment success or failure. KEY POINTS: • Tumor response criteria on MRI can be used to predict survival benefit of sorafenib therapy in patients with advanced HCC. • Stratification into DC and DP using mRECIST and vqEASL significantly correlates with OS (p = 0.0371 and p = 0.0118, respectively) early after initiation of sorafenib, while stratification according to RECIST and %qEASL did not correlate with OS (p = 0.6273 and p = 0.7474, respectively). • mRECIST (HR = 0.325, p = 0.039. 95%CI 0.112-0.946) and qEASL (HR = 0.183, p = 0.006, 95%CI 0.055-0.613) are independent prognostic factors of survival in HCC patients undergoing sorafenib therapy.

Automated feature quantification of Lipiodol as imaging biomarker to predict therapeutic efficacy of conventional transarterial chemoembolization of liver cancer.

Conventional transarterial chemoembolization (cTACE) is a guideline-approved image-guided therapy option for liver cancer using the radiopaque drug-carrier and micro-embolic agent Lipiodol, which has been previously established as an imaging biomarker for tumor response. To establish automated quantitative and pattern-based image analysis techniques of Lipiodol deposition on 24 h post-cTACE CT as biomarker for treatment response. The density of Lipiodol deposits in 65 liver lesions was automatically quantified using Hounsfield Unit thresholds. Lipiodol deposition within the tumor was automatically assessed for patterns including homogeneity, sparsity, rim, and peripheral deposition. Lipiodol deposition was correlated with enhancing tumor volume (ETV) on baseline and follow-up MRI. ETV on baseline MRI strongly correlated with Lipiodol deposition on 24 h CT (p < 0.0001), with 8.22% ± 14.59 more Lipiodol in viable than necrotic tumor areas. On follow-up, tumor regions with Lipiodol showed higher rates of ETV reduction than areas without Lipiodol (p = 0.0475) and increasing densities of Lipiodol enhanced this effect. Also, homogeneous (p = 0.0006), non-sparse (p < 0.0001), rim deposition within sparse tumors (p = 0.045), and peripheral deposition (p < 0.0001) of Lipiodol showed improved response. This technical innovation study showed that an automated threshold-based volumetric feature characterization of Lipiodol deposits is feasible and enables practical use of Lipiodol as imaging biomarker for therapeutic efficacy after cTACE.

Molecular MRI of the Immuno-Metabolic Interplay in a Rabbit Liver Tumor Model: A Biomarker for Resistance Mechanisms in Tumor-targeted Therapy?

Background The immuno-metabolic interplay has gained interest for determining and targeting immunosuppressive tumor micro-environments that remain a barrier to current immuno-oncologic therapies in hepatocellular carcinoma. Purpose To develop molecular MRI tools to reveal resistance mechanisms to immuno-oncologic therapies caused by the immuno-metabolic interplay in a translational liver cancer model. Materials and Methods A total of 21 VX2 liver tumor-bearing New Zealand white rabbits were used between October 2018 and February 2020. Rabbits were divided into three groups. Group A (n = 3) underwent intra-arterial infusion of gadolinium 160 (160Gd)-labeled anti-human leukocyte antigen-DR isotope (HLA-DR) antibodies to detect antigen-presenting immune cells. Group B (n = 3) received rhodamine-conjugated superparamagnetic iron oxide nanoparticles (SPIONs) intravenously to detect macrophages. These six rabbits underwent 3-T MRI, including T1- and T2-weighted imaging, before and 24 hours after contrast material administration. Group C (n = 15) underwent extracellular pH mapping with use of MR spectroscopy. Of those 15 rabbits, six underwent conventional transarterial chemoembolization (TACE), four underwent conventional TACE with extracellular pH-buffering bicarbonate, and five served as untreated controls. MRI signal intensity distribution was validated by using immunohistochemistry staining of HLA-DR and CD11b, Prussian blue iron staining, fluorescence microscopy of rhodamine, and imaging mass cytometry (IMC) of gadolinium. Statistical analysis included Mann-Whitney U and Kruskal-Wallis tests. Results T1-weighted MRI with 160Gd-labeled antibodies revealed localized peritumoral ring enhancement, which corresponded to gadolinium distribution detected with IMC. T2-weighted MRI with SPIONs showed curvilinear signal intensity representing selective peritumoral deposition in macrophages. Extracellular pH-specific MR spectroscopy of untreated liver tumors showed acidosis (mean extracellular pH, 6.78 ± 0.09) compared with liver parenchyma (mean extracellular pH, 7.18 ± 0.03) (P = .008) and peritumoral immune cell exclusion. Normalization of tumor extracellular pH (mean, 6.96 ± 0.05; P = .02) using bicarbonate during TACE increased peri- and intratumoral immune cell infiltration (P = .002). Conclusion MRI in a rabbit liver tumor model was used to visualize resistance mechanisms mediated by the immuno-metabolic interplay that inform susceptibility and response to immuno-oncologic therapies, providing a therapeutic strategy to restore immune permissiveness in liver cancer. © RSNA, 2020 Online supplemental material is available for this article.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictors of tumor response in hepatocellular carcinoma after DEB-TACE.

OBJECTIVES: To investigate the predictive value of quantifiable imaging and inflammatory biomarkers in patients with hepatocellular carcinoma (HCC) for the clinical outcome after drug-eluting bead transarterial chemoembolization (DEB-TACE) measured as volumetric tumor response and progression-free survival (PFS). METHODS: This retrospective study included 46 patients with treatment-naïve HCC who received DEB-TACE. Laboratory work-up prior to treatment included complete and differential blood count, liver function, and alpha-fetoprotein levels. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were correlated with radiomic features extracted from pretreatment contrast-enhanced magnetic resonance imaging (MRI) and with tumor response according to quantitative European Association for the Study of the Liver (qEASL) criteria and progression-free survival (PFS) after DEB-TACE. Radiomic features included single nodular tumor growth measured as sphericity, dynamic contrast uptake behavior, arterial hyperenhancement, and homogeneity of contrast uptake. Statistics included univariate and multivariate linear regression, Cox regression, and Kaplan-Meier analysis. RESULTS: Accounting for laboratory and clinical parameters, high baseline NLR and PLR were predictive of poorer tumor response (p = 0.014 and p = 0.004) and shorter PFS (p = 0.002 and p < 0.001). When compared to baseline imaging, high NLR and PLR correlated with non-spherical tumor growth (p = 0.001 and p < 0.001). CONCLUSIONS: This study establishes the prognostic value of quantitative inflammatory biomarkers associated with aggressive non-spherical tumor growth and predictive of poorer tumor response and shorter PFS after DEB-TACE. KEY POINTS: • In treatment-naïve hepatocellular carcinoma (HCC), high baseline platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) are associated with non-nodular tumor growth measured as low tumor sphericity. • High PLR and NLR are predictive of poorer volumetric enhancement-based tumor response and PFS after DEB-TACE in HCC. • This set of readily available, quantitative immunologic biomarkers can easily be implemented in clinical guidelines providing a paradigm to guide and monitor the personalized application of loco-regional therapies in HCC.

Molecular Imaging of Extracellular Tumor pH to Reveal Effects of Locoregional Therapy on Liver Cancer Microenvironment.

PURPOSE: To establish magnetic resonance (MR)-based molecular imaging paradigms for the noninvasive monitoring of extracellular pH (pHe) as a functional surrogate biomarker for metabolic changes induced by locoregional therapy of liver cancer. EXPERIMENTAL DESIGN: Thirty-two VX2 tumor-bearing New Zealand white rabbits underwent longitudinal imaging on clinical 3T-MRI and CT scanners before and up to 2 weeks after complete conventional transarterial chemoembolization (cTACE) using ethiodized oil (lipiodol) and doxorubicin. MR-spectroscopic imaging (MRSI) was employed for pHe mapping. Multiparametric MRI and CT were performed to quantify tumor enhancement, diffusion, and lipiodol coverage of the tumor posttherapy. In addition, incomplete cTACE with reduced chemoembolic doses was applied to mimic undertreatment and exploit pHe mapping to detect viable tumor residuals. Imaging findings were correlated with histopathologic markers indicative of metabolic state (HIF-1α, GLUT-1, and LAMP-2) and viability (proliferating cell nuclear antigen and terminal deoxynucleotidyl-transferase dUTP nick-end labeling). RESULTS: Untreated VX2 tumors demonstrated a significantly lower pHe (6.80 ± 0.09) than liver parenchyma (7.19 ± 0.03, P < 0.001). Upregulation of HIF-1α, GLUT-1, and LAMP-2 confirmed a hyperglycolytic tumor phenotype and acidosis. A gradual tumor pHe increase toward normalization similar to parenchyma was revealed within 2 weeks after complete cTACE, which correlated with decreasing detectability of metabolic markers. In contrast, pHe mapping after incomplete cTACE indicated both acidic viable residuals and increased tumor pHe of treated regions. Multimodal imaging revealed durable tumor devascularization immediately after complete cTACE, gradually increasing necrosis, and sustained lipiodol coverage of the tumor. CONCLUSIONS: MRSI-based pHe mapping can serve as a longitudinal monitoring tool for viable tumors. As most liver tumors are hyperglycolytic creating microenvironmental acidosis, therapy-induced normalization of tumor pHe may be used as a functional biomarker for positive therapeutic outcome.