CT-guided High-Dose-Rate Brachytherapy versus Transarterial Chemoembolization in Patients with Unresectable Hepatocellular Carcinoma.

Background CT-guided high-dose-rate (HDR) brachytherapy (hereafter, HDR brachytherapy) has been shown to be safe and effective for patients with unresectable hepatocellular carcinoma (HCC), but studies comparing this therapy with other local-regional therapies are scarce. Purpose To compare patient outcomes of HDR brachytherapy and transarterial chemoembolization (TACE) in patients with unresectable HCC. Materials and Methods This multi-institutional retrospective study included consecutive treatment-naive adult patients with unresectable HCC who underwent either HDR brachytherapy or TACE between January 2010 and December 2022. Overall survival (OS) and progression-free survival (PFS) were compared between patients matched for clinical and tumor characteristics by propensity score matching. Not all patients who underwent TACE had PFS available; thus, a different set of patients was used for PFS and OS analysis for this treatment. Hazard ratios (HRs) were calculated from Kaplan-Meier survival curves. Results After propensity matching, 150 patients who underwent HDR brachytherapy (median age, 71 years [IQR, 63-77 years]; 117 males) and 150 patients who underwent TACE (OS analysis median age, 70 years [IQR, 63-77 years]; 119 male; PFS analysis median age, 68 years [IQR: 63-76 years]; 119 male) were analyzed. Hazard of death was higher in the TACE versus HDR brachytherapy group (HR, 4.04; P < .001). Median estimated PFS was 32.8 months (95% CI: 12.5, 58.7) in the HDR brachytherapy group and 11.6 months (95% CI: 4.9, 22.7) in the TACE group. Hazard of disease progression was higher in the TACE versus HDR brachytherapy group (HR, 2.23; P < .001). Conclusion In selected treatment-naive patients with unresectable HCC, treatment with CT-guided HDR brachytherapy led to improved OS and PFS compared with TACE. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Chapiro in this issue.

Automated graded prognostic assessment for patients with hepatocellular carcinoma using machine learning.

BACKGROUND: Accurate mortality risk quantification is crucial for the management of hepatocellular carcinoma (HCC); however, most scoring systems are subjective. PURPOSE: To develop and independently validate a machine learning mortality risk quantification method for HCC patients using standard-of-care clinical data and liver radiomics on baseline magnetic resonance imaging (MRI). METHODS: This retrospective study included all patients with multiphasic contrast-enhanced MRI at the time of diagnosis treated at our institution. Patients were censored at their last date of follow-up, end-of-observation, or liver transplantation date. The data were randomly sampled into independent cohorts, with 85% for development and 15% for independent validation. An automated liver segmentation framework was adopted for radiomic feature extraction. A random survival forest combined clinical and radiomic variables to predict overall survival (OS), and performance was evaluated using Harrell's C-index. RESULTS: A total of 555 treatment-naïve HCC patients (mean age, 63.8 years ± 8.9 [standard deviation]; 118 females) with MRI at the time of diagnosis were included, of which 287 (51.7%) died after a median time of 14.40 (interquartile range, 22.23) months, and had median followed up of 32.47 (interquartile range, 61.5) months. The developed risk prediction framework required 1.11 min on average and yielded C-indices of 0.8503 and 0.8234 in the development and independent validation cohorts, respectively, outperforming conventional clinical staging systems. Predicted risk scores were significantly associated with OS (p < .00001 in both cohorts). CONCLUSIONS: Machine learning reliably, rapidly, and reproducibly predicts mortality risk in patients with hepatocellular carcinoma from data routinely acquired in clinical practice. CLINICAL RELEVANCE STATEMENT: Precision mortality risk prediction using routinely available standard-of-care clinical data and automated MRI radiomic features could enable personalized follow-up strategies, guide management decisions, and improve clinical workflow efficiency in tumor boards. KEY POINTS: • Machine learning enables hepatocellular carcinoma mortality risk prediction using standard-of-care clinical data and automated radiomic features from multiphasic contrast-enhanced MRI. • Automated mortality risk prediction achieved state-of-the-art performances for mortality risk quantification and outperformed conventional clinical staging systems. • Patients were stratified into low, intermediate, and high-risk groups with significantly different survival times, generalizable to an independent evaluation cohort.

Automated MRI liver segmentation for anatomical segmentation, liver volumetry, and the extraction of radiomics.

OBJECTIVES: To develop and evaluate a deep convolutional neural network (DCNN) for automated liver segmentation, volumetry, and radiomic feature extraction on contrast-enhanced portal venous phase magnetic resonance imaging (MRI). MATERIALS AND METHODS: This retrospective study included hepatocellular carcinoma patients from an institutional database with portal venous MRI. After manual segmentation, the data was randomly split into independent training, validation, and internal testing sets. From a collaborating institution, de-identified scans were used for external testing. The public LiverHccSeg dataset was used for further external validation. A 3D DCNN was trained to automatically segment the liver. Segmentation accuracy was quantified by the Dice similarity coefficient (DSC) with respect to manual segmentation. A Mann-Whitney U test was used to compare the internal and external test sets. Agreement of volumetry and radiomic features was assessed using the intraclass correlation coefficient (ICC). RESULTS: In total, 470 patients met the inclusion criteria (63.9±8.2 years; 376 males) and 20 patients were used for external validation (41±12 years; 13 males). DSC segmentation accuracy of the DCNN was similarly high between the internal (0.97±0.01) and external (0.96±0.03) test sets (p=0.28) and demonstrated robust segmentation performance on public testing (0.93±0.03). Agreement of liver volumetry was satisfactory in the internal (ICC, 0.99), external (ICC, 0.97), and public (ICC, 0.85) test sets. Radiomic features demonstrated excellent agreement in the internal (mean ICC, 0.98±0.04), external (mean ICC, 0.94±0.10), and public (mean ICC, 0.91±0.09) datasets. CONCLUSION: Automated liver segmentation yields robust and generalizable segmentation performance on MRI data and can be used for volumetry and radiomic feature extraction. CLINICAL RELEVANCE STATEMENT: Liver volumetry, anatomic localization, and extraction of quantitative imaging biomarkers require accurate segmentation, but manual segmentation is time-consuming. A deep convolutional neural network demonstrates fast and accurate segmentation performance on T1-weighted portal venous MRI. KEY POINTS: • This deep convolutional neural network yields robust and generalizable liver segmentation performance on internal, external, and public testing data. • Automated liver volumetry demonstrated excellent agreement with manual volumetry. • Automated liver segmentations can be used for robust and reproducible radiomic feature extraction.

Gd-EOB-DTPA-MRCP to localize bile leakage after liver trauma and surgery: impact on treatment and outcome.

OBJECTIVES: Bile leakage (BL) is a challenging complication after hepatobiliary surgery and liver trauma. Gadolinium ethoxybenzyl (Gd-EOB-DTPA)-enhanced magnetic resonance cholangiopancreatography (MRCP) is used to diagnose BL non-invasively. We assessed the value of Gd-EOB-DTPA-MRCP in the detection of postoperative and post-traumatic BL hypothesizing that exact identification of the leakage site is pivotal for treatment planning and outcome. METHODS: We retrospectively enrolled 39 trauma and postoperative patients who underwent Gd-EOB-DTPA-MRCP for suspected BL. Three readers rated the presence of BL and leakage site (intraparenchymal, central, peripheral ± aberrant or disconnected ducts). Imaging findings were compared to subsequent interventional procedures and their complexity and outcome. RESULTS: BL was detected in Gd-EOB-DTPA-MRCP in 25 of patients and was subsequently confirmed. Sites of BL differed significantly between postoperative (central [58%] and peripheral [42%]) and trauma patients (intraparenchymal [100%]; p < 0.001). Aberrant or disconnected ducts were diagnosed in 8%/26% of cases in the postoperative subgroup. Inter-rater agreement for the detection and localization of BL was almost perfect (Κ = 0.85 and 0.88; p < 0.001). Intraparenchymal BL required significantly less complex interventional procedures (p = 0.002), whereas hospitalization and mortality did not differ between the subgroups (p > 0.05). CONCLUSIONS: Gd-EOB-DTPA-MRCP reliably detects and exactly locates BL in postoperative and trauma patients. Exact localization of biliary injuries enables specific treatment planning, as intraparenchymal leakages, which occur more frequently after trauma, require less complex interventions than central or peripheral leaks in the postoperative setting. As a result of specific treatment based on exact BL localization, there was no difference in the duration of hospitalization or mortality. CLINICAL RELEVANCE STATEMENT: Gd-EOB-DTPA-MRCP is a reliable diagnostic tool for exactly localizing iatrogenic and post-traumatic biliary leakage. Its precise localization helps tailor local therapies for different injury patterns, resulting in comparable clinical outcomes despite varying treatments. KEY POINTS: • Gd-EOB-DTPA-MRCP enables adequate detection and localization of bile leakages in both postoperative and post-traumatic patients. • The site of bile leakage significantly impacts the complexity of required additional interventions. • Intraparenchymal bile leakage is commonly seen in patients with a history of liver trauma and requires less complex interventions than postoperative central or peripheral bile leakages, while hospitalization and mortality are similar.

Non-hypervascular hepatobiliary phase hypointense lesions detected in patients with hepatocellular carcinoma: a post hoc analysis of SORAMIC trial to identify risk factors for progression.

OBJECTIVES: To identify clinical and imaging parameters associated with progression of non-hypervascular hepatobiliary phase hypointense lesions during follow-up in patients who received treatment for hepatocellular carcinoma. METHODS: A total of 67 patients with 106 lesions were identified after screening 538 patients who underwent gadoxetic acid-enhanced MRI within the SORAMIC trial. All patients were allocated to the trial treatment according to the trial scheme, and 61 of 67 patients received systemic treatment with sorafenib (either alone or combined with locoregional therapies) during the trial period. Follow-up images after treatment according to trial scheme were reviewed for subsequent hypervascularization or > 1 cm size increase. The correlation between progression and several imaging and clinical parameters was assessed using univariable and multivariable analyses. RESULTS: On a median 178 (range, 48-1072) days follow-up period, progression was encountered in 18 (16.9%) lesions in 12 (17.9%) patients. In univariable analysis size > 12.6 mm (p = 0.070), ECOG-PS (p = 0.025), hypointensity at T1-weighted imaging (p = 0.028), hyperintensity at T2-weighted imaging (p < 0.001), hyperintensity at DWI images (p = 0.007), and cirrhosis (p = 0.065) were correlated with progression during follow-up. Hyperintensity at T2 images (p = 0.011) was an independent risk factor for progression in multivariable analysis, as well as cirrhosis (p = 0.033) and ECOG-PS (p = 0.030). CONCLUSIONS: Non-hypervascular hepatobiliary phase hypointense lesions are associated with subsequent progression after treatment in patients with HCC. T2 hyperintensity, diffusion restriction, cirrhosis, and higher ECOG-PS could identify lesions with increased risk. These factors should be considered for further diagnostic evaluation or treatment of such lesions. KEY POINTS: • Non-hypervascular hepatobiliary phase hypointense lesions have considerable risk of progression in patients with hepatocellular carcinoma receiving treatment. • T2 hyperintensity, cirrhosis, ECOG-PS, and hyperintensity at DWI are associated with increased risk of progression. • Non-hypervascular hepatobiliary phase hypointense lesions should be considered in the decision-making process of locoregional therapies, especially in the presence of these risk factors.

Low bone mineral density is a prognostic factor for elderly patients with HCC undergoing TACE: results from a multicenter study.

OBJECTIVES: Low bone mineral density (BMD) was recently identified as a novel risk factor for patients with hepatocellular carcinoma (HCC). In this multicenter study, we aimed to validate the role of BMD as a prognostic factor for patients with HCC undergoing transarterial chemoembolization (TACE). METHODS: This retrospective multicenter trial included 908 treatment-naïve patients with HCC who were undergoing TACE as a first-line treatment, at six tertiary care centers, between 2010 and 2020. BMD was assessed by measuring the mean Hounsfield units (HUs) in the midvertebral core of the 11th thoracic vertebra, on contrast-enhanced computer tomography performed before treatment. We assessed the influence of BMD on median overall survival (OS) and performed multivariate analysis including established estimates for survival. RESULTS: The median BMD was 145 HU (IQR, 115-175 HU). Patients with a high BMD (≥ 114 HU) had a median OS of 22.2 months, while patients with a low BMD (< 114 HU) had a lower median OS of only 16.2 months (p < .001). Besides albumin, bilirubin, tumor number, and tumor diameter, BMD remained an independent prognostic factor in multivariate analysis. CONCLUSIONS: BMD is an independent predictive factor for survival in elderly patients with HCC undergoing TACE. The integration of BMD into novel scoring systems could potentially improve survival prediction and clinical decision-making. KEY POINTS: • Bone mineral density can be easily assessed in routinely acquired pre-interventional computed tomography scans. • Bone mineral density is an independent predictive factor for survival in elderly patients with HCC undergoing TACE. • Thus, bone mineral density is a novel imaging biomarker for prognosis prediction in elderly patients with HCC undergoing TACE.

MR Imaging Volumetric Response after Yttrium-90 Radioembolization for Colorectal Liver Metastases: Predictability at Baseline and Correlation with Survival.

PURPOSE: To prove the utility of magnetic resonance (MR) imaging response as a surrogate end point of treatment efficacy and survival after yttrium-90 transarterial radioembolization (TARE) for colorectal liver metastases (CRLMs), and to investigate whether outcomes can be predicted at baseline using MR imaging or clinical variables. MATERIALS AND METHODS: A total of 50 (135) patients with TARE for CRLMs between August 2008 and January 2020 and peri-interventional MR imaging within defined timeframes were included for tumor segmentation. Pretreatment and posttreatment target tumor volumes were measured according to the volumetric Response Evaluation Criteria In Solid Tumors (vRECIST) and the quantitative European Association for the Study of the Liver (qEASL) criteria. Cox regression models were used to analyze the impact of MR morphologic response, vascularity at baseline, and clinical variables on patient survival. Logistic regression analyses were used to evaluate the predictors of MR morphologic response at baseline. RESULTS: The median survival was 337 days (95% confidence interval [CI], 243-431). As opposed to the vRECIST, the application of the qEASL criteria 3 months after the treatment allowed for a significant (P < .05) separation of the survival curves for partial response, stable disease, and progressive disease with a median survival of 412 days (95% CI, 57-767) in responders. High tumor burden and technetium-99m lung shunt significantly decreased the probability of survival. MR morphologic response was not predictable at baseline using imaging or clinical data. CONCLUSIONS: MR response according to the qEASL criteria outperformed the vRECIST in measuring the biologic impact of TARE and predicting patient survival. Baseline contrast enhancement did not predict MR response to treatment, which may reflect elevated dose requirements in tumors with a high proportion of viable tumor volume.

Prognostic value of baseline imaging and clinical features in patients with advanced hepatocellular carcinoma.

AIMS: To investigate the prognostic value of baseline imaging features for overall survival (OS) and liver decompensation (LD) in patients with hepatocellular carcinoma (HCC). DESIGN: Patients with advanced HCC from the SORAMIC trial were evaluated in this post hoc analysis. Several radiological imaging features were collected from baseline computed tomography (CT) and magnetic resonance imaging (MRI) imaging, besides clinical values. The prognostic value of these features for OS and LD (grade 2 bilirubin increase) was quantified with univariate Cox proportional hazard models and multivariate Least Absolute Shrinkage and Selection Operator (LASSO) regression. RESULTS: Three hundred and seventy-six patients were included in this study. The treatment arm was not correlated with OS. LASSO showed satellite lesions, atypical HCC, peritumoral arterial enhancement, larger tumour size, higher albumin-bilirubin (ALBI) score, liver-spleen ratio <1.5, ascites, pleural effusion and higher bilirubin values were predictors of worse OS, and higher relative liver enhancement, smooth margin and capsule were associated with better OS. LASSO analysis for LD showed satellite lesions, peritumoral hypointensity in hepatobiliary phase, high ALBI score, higher bilirubin values and ascites were predictors of LD, while randomisation to sorafenib arm was associated with lower LD. CONCLUSIONS: Imaging features showing aggressive tumour biology and poor liver function, in addition to clinical parameters, can serve as imaging biomarkers for OS and LD in patients receiving sorafenib and selective internal radiation therapy for HCC.

Addition of Y-90 radioembolization increases tumor response and local disease control in hepatocellular carcinoma patients receiving sorafenib.

PURPOSE: To compare the treatment response and progression-free survival (PFS) in advanced hepatocellular carcinoma (HCC) patients who received sorafenib treatment either alone or combined with radioembolization (RE). METHODS: Follow-up images of the patients treated within a multicenter phase II trial (SORAMIC) were assessed by mRECIST. A total of 177 patients (73 combination arm [RE + sorafenib] and 104 sorafenib arm) were included in this post-hoc analysis. Response and progression characteristics were compared between treatment arms. Survival analyses were done to compare PFS and post-progression survival between treatment arms. Multivariate Cox regression analysis was used to compare survival with factors known to influence PFS in patients with HCC. RESULTS: The combination arm had significantly higher objective response rate (61.6% vs. 29.8%, p < 0.001), complete response rate (13.7% vs. 3.8%, p = 0.022), and a trend for higher disease control rate (79.2% vs. 72.1%, p = 0.075). Progression was encountered in 116 (65.5%) patients and was more common in the sorafenib arm (75% vs. 52.0%, p = 0.001). PFS (median 8.9 vs. 5.4 months, p = 0.022) and hepatic PFS were significantly better in the combination arm (9.0 vs. 5.7 months, p = 0.014). Multivariate analysis confirmed the treatment arm as an independent predictor of PFS. CONCLUSION: In advanced HCC patients receiving sorafenib, combination with RE has an additive anticancer effect on sorafenib treatment resulting in a higher and longer tumor response. However, the enhanced response did not translate into prolonged survival. Better patient selection and superselective treatment could improve outcomes after combination therapy.

FIRE-9 - PORT / AIO-KRK-0418: a prospective, randomized, open, multicenter Phase III trial to investigate the efficacy of adjuvant/additive chemotherapy in patients with definitely-treated metastatic colorectal cancer.

BACKGROUND: Additive/adjuvant chemotherapy as concept after local treatment of colorectal metastases has not been proven to be successful by phase III trials. Accordingly, a standard of care to improve relapse rates and long-term survival is not established and adjuvant chemotherapy cannot be recommended as a standard therapy due to limited evidence in literature. The PORT trial aims to generate evidence that post-resection/ablation/radiation chemotherapy improves the survival in patients with metastatic colorectal cancer. METHODS: Patients to be included into this trial must have synchronous or metachronous metastases of colorectal cancer-either resected (R0 or R1) and/or effectively treated by ablation or radiation within 3-10 weeks before randomization-and have the primary tumor resected, without radiographic evidence of active metastatic disease at study entry. The primary endpoint of the trial is progression-free survival after 24 months, secondary endpoints include overall survival, safety, quality of life, treatments (including efficacy) beyond study participation, translational endpoints, and others. One arm of the study comprising 2/3 of the population will be treated for 6 months with modified FOLFOXIRI or modified FOLFOX6 (investigator´s choice, depending on the performance status of the patients but determined before randomization), while the other arm (1/3 of the population) will be observed and undergo scheduled follow-up computed tomography scans according to the interventional arm. DISCUSSION: Optimal oncological management after removal of colorectal metastases is unclear. The PORT trial aims to generate evidence that additive/adjuvant chemotherapy after definitive treatment of colorectal metastases improves progression free and overall survival in patients with colorectal cancer. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov ( NCT05008809 ) and EudraCT (2020-006,144-18).

Yttrium-90 radioembolization for unresectable hepatocellular carcinoma: predictive modeling strategies to anticipate tumor response and improve patient selection.

OBJECTIVES: This study aims to better characterize potential responders of Y-90-radioembolization at baseline through analysis of clinical variables and contrast enhanced (CE) MRI tumor volumetry in order to adjust therapeutic regimens early on and to improve treatment outcomes. METHODS: Fifty-eight HCC patients who underwent Y-90-radioembolization at our center between 10/2008 and 02/2017 were retrospectively included. Pre- and post-treatment target lesion volumes were measured as total tumor volume (TTV) and enhancing tumor volume (ETV). Survival analysis was performed with Cox regression models to evaluate 65% ETV reduction as surrogate endpoint for treatment efficacy. Univariable and multivariable logistic regression analyses were used to evaluate the combination of baseline clinical variables and tumor volumetry as predictors of ≥ 65% ETV reduction. RESULTS: Mean patients' age was 66 (SD 8.7) years, and 12 were female (21%). Sixty-seven percent of patients suffered from liver cirrhosis. Median survival was 11 months. A threshold of ≥ 65% in ETV reduction allowed for a significant (p = 0.04) separation of the survival curves with a median survival of 11 months in non-responders and 17 months in responders. Administered activity per tumor volume did predict neither survival nor ETV reduction. A baseline ETV/TTV ratio greater than 50% was the most important predictor of arterial devascularization (odds ratio 6.3) in a statistically significant (p = 0.001) multivariable logistic regression model. The effect size was strong with a Cohen's f of 0.89. CONCLUSION: We present a novel approach to identify promising candidates for Y-90 radioembolization at pre-treatment baseline MRI using tumor volumetry and clinical baseline variables. KEY POINTS: • A decrease of 65% enhancing tumor volume (ETV) on follow-up imaging 2-3 months after Y-90 radioembolization of HCC enables the early prediction of significantly improved median overall survival (11 months vs. 17 months, p = 0.04). • Said decrease in vascularization is predictable at baseline: an ETV greater than 50% is the most important variable in a multivariable logistic regression model that predicts responders at a high level of significance (p = 0.001) with an area under the curve of 87%.

Correlation of liver enhancement in gadoxetic acid-enhanced MRI with liver functions: a multicenter-multivendor analysis of hepatocellular carcinoma patients from SORAMIC trial.

OBJECTIVES: To evaluate the correlation between liver enhancement on hepatobiliary phase and liver function parameters in a multicenter, multivendor study. METHODS: A total of 359 patients who underwent gadoxetic acid-enhanced MRI using a standardized protocol with various scanners within a prospective multicenter phase II trial (SORAMIC) were evaluated. The correlation between liver enhancement on hepatobiliary phase normalized to the spleen (liver-to-spleen ratio, LSR) and biochemical laboratory parameters, clinical findings related to liver functions, liver function grading systems (Child-Pugh and Albumin-Bilirubin [ALBI]), and scanner characteristics were analyzed using uni- and multivariate analyses. RESULTS: There was a significant positive correlation between LSR and albumin (rho = 0.193; p < 0.001), platelet counts (rho = 0.148; p = 0.004), and sodium (rho = 0.161; p = 0.002); and a negative correlation between LSR and total bilirubin (rho = -0.215; p < 0.001) and AST (rho = -0.191; p < 0.001). Multivariate analysis confirmed independent significance for each of albumin (p = 0.022), total bilirubin (p = 0.045), AST (p = 0.031), platelet counts (p = 0.012), and sodium (p = 0.006). The presence of ascites (1.47 vs. 1.69, p < 0.001) and varices (1.55 vs. 1.69, p = 0.006) was related to significantly lower LSR. Similarly, patients with ALBI grade 1 had significantly higher LSR than patients with grade 2 (1.74 ± 0.447 vs. 1.56 ± 0.408, p < 0.001); and Child-Pugh A patients had a significantly higher LSR than Child-Pugh B (1.67 ± 0.44 vs. 1.49 ± 0.33, p = 0.021). Also, LSR was negatively correlated with MELD-Na scores (rho = -0.137; p = 0.013). However, one scanner brand was significantly associated with lower LSR (p < 0.001). CONCLUSIONS: The liver enhancement on the hepatobiliary phase of gadoxetic acid-enhanced MRI is correlated with biomarkers of liver functions in a multicenter cohort. However, this correlation shows variations between scanner brands. KEY POINTS: • The correlation between liver enhancement on the hepatobiliary phase of gadoxetic acid-enhanced MRI and liver function is consistent in a multicenter-multivendor cohort. • Signal intensity-based indices (liver-to-spleen ratio) can be used as an imaging biomarker of liver function. • However, absolute values might change between vendors.

Comparison of metabolic and immunologic responses to transarterial chemoembolization with different chemoembolic regimens in a rabbit VX2 liver tumor model.

OBJECTIVES: The goal of this study was to investigate the effects of TACE using Lipiodol, Oncozene™ drug-eluting embolics (DEEs), or LUMI™-DEEs alone, or combined with bicarbonate on the metabolic and immunological tumor microenvironment in a rabbit VX2 tumor model. METHODS: VX2 liver tumor-bearing rabbits were assigned to five groups. MRI and extracellular pH (pHe) mapping using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) were performed before and after intra-arterial therapy with conventional TACE (cTACE), DEE-TACE with Idarubicin-eluting Oncozene™-DEEs, or Doxorubicin-eluting LUMI™-DEEs, each with or without prior bicarbonate infusion, and in untreated rabbits or treated with intra-arterial bicarbonate only. Imaging results were validated with immunohistochemistry (IHC) staining of cell viability (PCNA, TUNEL) and immune response (HLA-DR, CD3). Statistical analysis was performed using Mann-Whitney U test. RESULTS: pHe mapping revealed that combining cTACE with prior bicarbonate infusion significantly increased tumor pHe compared to control (p = 0.0175) and cTACE alone (p = 0.0025). IHC staining revealed peritumoral accumulation of HLA-DR+ antigen-presenting cells and CD3 + T-lymphocytes in controls. cTACE-treated tumors showed reduced immune infiltration, which was restored through combination with bicarbonate. DEE-TACE with Oncozene™-DEEs induced moderate intratumoral and marked peritumoral infiltration, which was slightly reduced with bicarbonate. Addition of bicarbonate prior to LUMI™-beads enhanced peritumoral immune cell infiltration compared to LUMI™-beads alone and resulted in the strongest intratumoral immune cell infiltration across all treated groups. CONCLUSIONS: The choice of chemoembolic regimen for TACE strongly affects post-treatment TME pHe and the ability of immune cells to accumulate and infiltrate the tumor tissue. KEY POINTS: • Combining conventional transarterial chemotherapy with prior bicarbonate infusion increases the pHe towards a more physiological value (p = 0.0025). • Peritumoral infiltration and intratumoral accumulation patterns of antigen-presenting cells and T-lymphocytes after transarterial chemotherapy were dependent on the choice of the chemoembolic regimen. • Combination of intra-arterial treatment with Doxorubicin-eluting LUMI™-beads and bicarbonate infusion resulted in the strongest intratumoral presence of immune cells (positivity index of 0.47 for HLADR+-cells and 0.62 for CD3+-cells).

MR Imaging Biomarkers for the Prediction of Outcome after Radiofrequency Ablation of Hepatocellular Carcinoma: Qualitative and Quantitative Assessments of the Liver Imaging Reporting and Data System and Radiomic Features.

PURPOSE: To assess the Liver Imaging Reporting and Data System (LI-RADS) and radiomic features in pretreatment magnetic resonance (MR) imaging for predicting progression-free survival (PFS) in patients with nodular hepatocellular carcinoma (HCC) treated with radiofrequency (RF) ablation. MATERIAL AND METHODS: Sixty-five therapy-naïve patients with 85 nodular HCC tumors <5 cm in size were included in this Health Insurance Portability and Accountability Act-compliant, institutional review board-approved, retrospective study. All patients underwent RF ablation as first-line treatment and demonstrated complete response on the first follow-up imaging. Gadolinium-enhanced MR imaging biomarkers were analyzed for LI-RADS features by 2 board-certified radiologists or by analysis of nodular and perinodular radiomic features from 3-dimensional segmentations. A radiomic signature was calculated with the most informative features of a least absolute shrinkage and selection operator Cox regression model using leave-one-out cross-validation. The association between both LI-RADS features and radiomic signatures with PFS was assessed via the Kaplan-Meier analysis and a weighted log-rank test. RESULTS: The median PFS was 19 months (95% confidence interval, 16.1-19.4) for a follow-up period of 24 months. Multifocality (P = .033); the appearance of capsular continuity, compared with an absent or discontinuous capsule (P = .012); and a higher radiomic signature based on nodular and perinodular features (P = .030) were associated with poorer PFS in early-stage HCC. The observation size, presence of arterial hyperenhancement, nonperipheral washout, and appearance of an enhancing "capsule" were not associated with PFS (P > .05). CONCLUSIONS: Although multifocal HCC clearly indicates a more aggressive phenotype even in early-stage disease, the continuity of an enhancing capsule and a higher radiomic signature may add value as MR imaging biomarkers for poor PFS in HCC treated with RF ablation.

Impact of Chemoembolic Regimen on Immune Cell Recruitment and Immune Checkpoint Marker Expression following Transcatheter Arterial Chemoembolization in a VX2 Rabbit Liver Tumor Model.

PURPOSE: To characterize the effects of commonly used transcatheter arterial chemoembolization (TACE) regimens on the immune response and immune checkpoint marker expression using a VX2 rabbit liver tumor model. MATERIALS AND METHODS: Twenty-four VX2 liver tumor-bearing New Zealand white rabbits were assigned to 7 groups (n = 3 per group) undergoing locoregional therapy as follows: (a) bicarbonate infusion without embolization, (b) conventional TACE (cTACE) using a water-in-oil emulsion containing doxorubicin mixed 1:2 with Lipiodol, drug-eluting embolic-TACE with either (c) idarubicin-eluting Oncozene microspheres (40 µm) or (d) doxorubicin-eluting Lumi beads (40-90 µm). For each therapy arm (b-d), a tandem set of 3 animals with additional bicarbonate infusion before TACE was added, to evaluate the effect of pH modification on the immune response. Three untreated rabbits served as controls. Tissue was harvested 24 hours after treatment, followed by digital immunohistochemistry quantification (counts/µm2 ± SEM) of tumor-infiltrating cluster of differentiation 3+ T-lymphocytes, human leukocyte antigen DR type antigen-presenting cells (APCs), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and programmed cell death protein-1 (PD-1)/PD-1 ligand (PD-L1) pathway axis expression. RESULTS: Lumi-bead TACE induced significantly more intratumoral T-cell and APC infiltration than cTACE and Oncozene-microsphere TACE. Additionally, tumors treated with Lumi-bead TACE expressed significantly higher intratumoral immune checkpoint markers compared with cTACE and Oncozene-microsphere TACE. Neoadjuvant bicarbonate demonstrated the most pronounced effect on cTACE and resulted in a significant increase in intratumoral cluster of differentiation 3+ T-cell infiltration compared with cTACE alone. CONCLUSIONS: This preclinical study revealed significant differences in evoked tumor immunogenicity depending on the choice of chemoembolic regimen for TACE.

[Differentiated Strategies for the Therapy of Liver Metastases in Gastro-entero-pancreatic Neuroendocrine Neoplasia]. / Differenzierte Therapiestrategie bei Lebermetastasen gastro-entero-pankreatischer Neuroendokriner Neoplasien.

Neuroendocrine neoplasias comprise a heterogenous group of malignant tumours, mostly arising from the gastro-entero-pancreatic system (GEP). Most of these tumours develop from the small intestine and pancreas and the liver is the predominant site for distant metastases. Patients may be asymptomatic for a long time and liver metastases are frequently diagnosed by chance or during operations for bowel obstruction, for example, during emergency surgery. The only curative therapy consists in complete removal of primary and metastases. In case of metastatic disease, various treatment modalities need to be discussed in interdisciplinary tumour boards comprised of specialists from gastroenterology, (liver-)surgery, radiology, nuclear medicine, radiotherapy, pathology and endocrinology. By combining different therapies, even patients with progressive disease may reach long-term overall survival with good quality of life. The most important factors for decisions on therapy are individual factors like tumour grading, hormonal functionality, type of metastases and evolution of the disease. Adequate treatment of liver metastases comprises various surgical strategies as well as locally ablative radiological interventions and nuclear medical therapies, in complement to systemic treatments.

Impact of interventionalist's experience and gender on radiation dose and procedural time in CT-guided interventions-a retrospective analysis of 4380 cases over 10 years.

OBJECTIVES: To investigate the impact of the interventionalist's experience and gender on radiation dose and procedural time in CT-guided interventions. METHODS: We retrospectively analyzed 4380 CT-guided interventions performed at our institution with the same CT scanner from 2009 until 2018, 1287 (29%) by female and 3093 (71%) by male interventionalists. Radiation dose, number of CT fluoroscopy images taken per intervention, total procedural time, type of intervention, and degree of difficulty were derived from the saved dose reports and images. All 16 interventionalists included in this analysis performed their first CT-guided interventions during the study period, and interventions performed by each interventionalist were counted to assess the level of experience for each intervention in terms of the number of prior interventions performed by her or him. The Mann-Whitney U test (MWU test), multivariate regression, and linear mixed model analysis were performed. RESULTS: Assessment of the impact of gender with the MWU test revealed that female interventionalists took a significantly smaller number of images (p < 0.0001) and achieved a lower dose-length product per intervention (p < 0.0001) while taking more time per intervention (p = 0.0001). This finding was confirmed for most types of interventions when additionally accounting for other possible impact factors in multivariate regression analysis. In linear mixed model analysis, we found that radiation dose, number of images taken per intervention, and procedural time decreased statistically significantly with interventionalist's experience. CONCLUSIONS: Radiation doses of CT-guided interventions are reduced by interventionalist's experience and, for most types of interventions, when performed by female interventionalists. KEY POINTS: • Radiation doses in CT-guided interventions are lower when performed by female interventionalists. • Procedural times of CT-guided interventions are longer when performed by female interventionalists. • Radiation doses of CT-guided interventions decrease with the interventionalist's experience.

Deep learning-assisted differentiation of pathologically proven atypical and typical hepatocellular carcinoma (HCC) versus non-HCC on contrast-enhanced MRI of the liver.

OBJECTIVES: To train a deep learning model to differentiate between pathologically proven hepatocellular carcinoma (HCC) and non-HCC lesions including lesions with atypical imaging features on MRI. METHODS: This IRB-approved retrospective study included 118 patients with 150 lesions (93 (62%) HCC and 57 (38%) non-HCC) pathologically confirmed through biopsies (n = 72), resections (n = 29), liver transplants (n = 46), and autopsies (n = 3). Forty-seven percent of HCC lesions showed atypical imaging features (not meeting Liver Imaging Reporting and Data System [LI-RADS] criteria for definitive HCC/LR5). A 3D convolutional neural network (CNN) was trained on 140 lesions and tested for its ability to classify the 10 remaining lesions (5 HCC/5 non-HCC). Performance of the model was averaged over 150 runs with random sub-sampling to provide class-balanced test sets. A lesion grading system was developed to demonstrate the similarity between atypical HCC and non-HCC lesions prone to misclassification by the CNN. RESULTS: The CNN demonstrated an overall accuracy of 87.3%. Sensitivities/specificities for HCC and non-HCC lesions were 92.7%/82.0% and 82.0%/92.7%, respectively. The area under the receiver operating curve was 0.912. CNN's performance was correlated with the lesion grading system, becoming less accurate the more atypical imaging features the lesions showed. CONCLUSION: This study provides proof-of-concept for CNN-based classification of both typical- and atypical-appearing HCC lesions on multi-phasic MRI, utilizing pathologically confirmed lesions as "ground truth." KEY POINTS: • A CNN trained on atypical appearing pathologically proven HCC lesions not meeting LI-RADS criteria for definitive HCC (LR5) can correctly differentiate HCC lesions from other liver malignancies, potentially expanding the role of image-based diagnosis in primary liver cancer with atypical features. • The trained CNN demonstrated an overall accuracy of 87.3% and a computational time of < 3 ms which paves the way for clinical application as a decision support instrument.

CT fluoroscopy-guided pancreas transplant biopsies: a retrospective evaluation of predictors of complications and success rates.

To identify predictors of biopsy success and complications in CT-guided pancreas transplant (PTX) core biopsy. We retrospectively identified all CT fluoroscopy-guided PTX biopsies performed at our institution (2000-2017) and included 187 biopsies in 99 patients. Potential predictors related to patient characteristics (age, gender, body mass index (BMI), PTX age, PTX volume) and procedure characteristics (biopsy depth, needle size, access path, number of samples, interventionalist's experience) were correlated with biopsy success (sufficient tissue for histologic diagnosis) and the occurrence of complications. Biopsy success (72.2%) was more likely to be obtained in men [+25.3% (10.9, 39.7)] and when the intervention was performed by an experienced interventionalist [+27.2% (8.1, 46.2)]. Complications (5.9%) occurred more frequently in patients with higher PTX age [OR: 1.014 (1.002, 1.026)] and when many (3-4) tissue samples were obtained [+8.7% (-2.3, 19.7)]. Multivariable regression analysis confirmed male gender [OR: 3.741 (1.736, 8.059)] and high experience [OR: 2.923 (1.255, 6.808)] (biopsy success) as well as older PTX age [OR: 1.019 (1.002, 1.035)] and obtaining many samples [OR: 4.880 (1.240, 19.203)] (complications) as independent predictors. Our results suggest that CT-guided PTX biopsy should be performed by an experienced interventionalist to achieve higher success rates, and not more than two tissue samples should be obtained to reduce complications. Caution is in order in patients with older transplants because of higher complication rates.

Trans-arterial chemoembolization with degradable starch microspheres (DSM-TACE) versus selective internal radiation therapy (SIRT) in multifocal hepatocellular carcinoma.

BACKGROUND: To date there is no therapy consensus in patients with multifocal hepatocellular carcinoma (mHCC). PURPOSE: To compare outcome of trans-arterial chemoembolization (TACE) with degradable starch microspheres (DSM-TACE) versus selective internal radiation therapy (SIRT) in mHCC. MATERIAL AND METHODS: In this single-center study, 36 patients without portal vein invasion, treated between May 2014 and May 2018, were enrolled retrospectively. Eighteen consecutive patients received DSM-TACE and were matched by age, gender, BCLC stage, Child-Pugh status, and tumor volume and 18 patients underwent SIRT. Overall survival (OS), progression-free survival (PFS), and local tumor control (LTC) were evaluated. Toxicity profiles for both therapies were also evaluated and compared. RESULTS: In the entire collective, median OS was 9.5, PFS 5.0, and LTC 5.5 months. Subgroup analysis revealed an OS of 9.5 months in both groups (P = 0.621). PFS was 6 months for the SIRT and 4 months for the DSM-TACE cohort (P = 0.065). Although not significantly, LTC was lower (4 months) in the SIRT compared to the DSM-TACE cohort (7 months; P = 0.391). When DSM-TACE was performed ≥3 times (n = 11), OS increased, however without statistical difference compared to SIRT, to 11 months, PFS to 7 months, and LTC to 7 months. When DSM-TACE was performed <3 times (n = 7), OS, PFS, and LTC decreased (5 months, P = 0.333; 2 months, P = 0.047; 2 months, P = 0.47). Toxicity profiles and adverse event analysis only revealed a significant difference for nausea and vomiting (more frequent in the SIRT cohort, P = 0.015), while no other parameter showed a significant difference (P > 0.05). CONCLUSION: DSM-TACE might be an alternative to SIRT in multifocal HCC patients as OS, PFS, and LTC did not differ significantly and toxicity profiles seem to be comparable.