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.

MR Imaging-Based In Vivo Macrophage Imaging to Monitor Immune Response after Radiofrequency Ablation of the Liver.

PURPOSE: To establish molecular magnetic resonance (MR) imaging instruments for in vivo characterization of the immune response to hepatic radiofrequency (RF) ablation using cell-specific immunoprobes. MATERIALS AND METHODS: Seventy-two C57BL/6 wild-type mice underwent standardized hepatic RF ablation (70 °C for 5 minutes) to generate a coagulation area measuring 6-7 mm in diameter. CD68+ macrophage periablational infiltration was characterized with immunohistochemistry 24 hours, 72 hours, 7 days, and 14 days after ablation (n = 24). Twenty-one mice were subjected to a dose-escalation study with either 10, 15, 30, or 60 mg/kg of rhodamine-labeled superparamagnetic iron oxide nanoparticles (SPIONs) or 2.4, 1.2, or 0.6 mg/kg of gadolinium-160 (160Gd)-labeled CD68 antibody for assessment of the optimal in vivo dose of contrast agent. MR imaging experiments included 9 mice, each receiving 10-mg/kg SPIONs to visualize phagocytes using T2∗-weighted imaging in a horizontal-bore 9.4-T MR imaging scanner, 160Gd-CD68 for T1-weighted MR imaging of macrophages, or 0.1-mmol/kg intravenous gadoterate (control group). Radiological-pathological correlation included Prussian blue staining, rhodamine immunofluorescence, imaging mass cytometry, and immunohistochemistry. RESULTS: RF ablation-induced periablational infiltration (206.92 µm ± 12.2) of CD68+ macrophages peaked at 7 days after ablation (P < .01) compared with the untreated lobe. T2∗-weighted MR imaging with SPION contrast demonstrated curvilinear T2∗ signal in the transitional zone (TZ) (186 µm ± 16.9), corresponsing to Iron Prussian blue staining. T1-weighted MR imaging with 160Gd-CD68 antibody showed curvilinear signal in the TZ (164 µm ± 3.6) corresponding to imaging mass cytometry. CONCLUSIONS: Both SPION-enhanced T2∗-weighted and 160Gd-enhanced T1-weighted MR imaging allow for in vivo monitoring of macrophages after RF ablation, demonstrating the feasibility of this model to investigate local immune responses.

Machine Learning Models for Prediction of Posttreatment Recurrence in Early-Stage Hepatocellular Carcinoma Using Pretreatment Clinical and MRI Features: A Proof-of-Concept Study.

BACKGROUND. Posttreatment recurrence is an unpredictable complication after liver transplant for hepatocellular carcinoma (HCC) that is associated with poor survival. Biomarkers are needed to estimate recurrence risk before organ allocation. OBJECTIVE. This proof-of-concept study evaluated the use of machine learning (ML) to predict recurrence from pretreatment laboratory, clinical, and MRI data in patients with early-stage HCC initially eligible for liver transplant. METHODS. This retrospective study included 120 patients (88 men, 32 women; median age, 60.0 years) with early-stage HCC diagnosed who were initially eligible for liver transplant and underwent treatment by transplant, resection, or thermal ablation between June 2005 and March 2018. Patients underwent pretreatment MRI and posttreatment imaging surveillance. Imaging features were extracted from postcontrast phases of pretreatment MRI examinations using a pretrained convolutional neural network. Pretreatment clinical characteristics (including laboratory data) and extracted imaging features were integrated to develop three ML models (clinical model, imaging model, combined model) for predicting recurrence within six time frames ranging from 1 through 6 years after treatment. Kaplan-Meier analysis with time to recurrence as the endpoint was used to assess the clinical relevance of model predictions. RESULTS. Tumor recurred in 44 of 120 (36.7%) patients during follow-up. The three models predicted recurrence with AUCs across the six time frames of 0.60-0.78 (clinical model), 0.71-0.85 (imaging model), and 0.62-0.86 (combined model). The mean AUC was higher for the imaging model than the clinical model (0.76 vs 0.68, respectively; p = .03), but the mean AUC was not significantly different between the clinical and combined models or between the imaging and combined models (p > .05). Kaplan-Meier curves were significantly different between patients predicted to be at low risk and those predicted to be at high risk by all three models for the 2-, 3-, 4-, 5-, and 6-year time frames (p < .05). CONCLUSION. The findings suggest that ML-based models can predict recurrence before therapy allocation in patients with early-stage HCC initially eligible for liver transplant. Adding MRI data as model input improved predictive performance over clinical parameters alone. The combined model did not surpass the imaging model's performance. CLINICAL IMPACT. ML-based models applied to currently underutilized imaging features may help design more reliable criteria for organ allocation and liver transplant eligibility.

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.

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.

PET/CT radiomics signature of human papilloma virus association in oropharyngeal squamous cell carcinoma.

PURPOSE: To devise, validate, and externally test PET/CT radiomics signatures for human papillomavirus (HPV) association in primary tumors and metastatic cervical lymph nodes of oropharyngeal squamous cell carcinoma (OPSCC). METHODS: We analyzed 435 primary tumors (326 for training, 109 for validation) and 741 metastatic cervical lymph nodes (518 for training, 223 for validation) using FDG-PET and non-contrast CT from a multi-institutional and multi-national cohort. Utilizing 1037 radiomics features per imaging modality and per lesion, we trained, optimized, and independently validated machine-learning classifiers for prediction of HPV association in primary tumors, lymph nodes, and combined "virtual" volumes of interest (VOI). PET-based models were additionally validated in an external cohort. RESULTS: Single-modality PET and CT final models yielded similar classification performance without significant difference in independent validation; however, models combining PET and CT features outperformed single-modality PET- or CT-based models, with receiver operating characteristic area under the curve (AUC) of 0.78, and 0.77 for prediction of HPV association using primary tumor lesion features, in cross-validation and independent validation, respectively. In the external PET-only validation dataset, final models achieved an AUC of 0.83 for a virtual VOI combining primary tumor and lymph nodes, and an AUC of 0.73 for a virtual VOI combining all lymph nodes. CONCLUSION: We found that PET-based radiomics signatures yielded similar classification performance to CT-based models, with potential added value from combining PET- and CT-based radiomics for prediction of HPV status. While our results are promising, radiomics signatures may not yet substitute tissue sampling for clinical decision-making.

LiverHccSeg: A publicly available multiphasic MRI dataset with liver and HCC tumor segmentations and inter-rater agreement analysis.

Accurate segmentation of liver and tumor regions in medical imaging is crucial for the diagnosis, treatment, and monitoring of hepatocellular carcinoma (HCC) patients. However, manual segmentation is time-consuming and subject to inter- and intra-rater variability. Therefore, automated methods are necessary but require rigorous validation of high-quality segmentations based on a consensus of raters. To address the need for reliable and comprehensive data in this domain, we present LiverHccSeg, a dataset that provides liver and tumor segmentations on multiphasic contrast-enhanced magnetic resonance imaging from two board-approved abdominal radiologists, along with an analysis of inter-rater agreement. LiverHccSeg provides a curated resource for liver and HCC tumor segmentation tasks. The dataset includes a scientific reading and co-registered contrast-enhanced multiphasic magnetic resonance imaging (MRI) scans with corresponding manual segmentations by two board-approved abdominal radiologists and relevant metadata and offers researchers a comprehensive foundation for external validation, and benchmarking of liver and tumor segmentation algorithms. The dataset also provides an analysis of the agreement between the two sets of liver and tumor segmentations. Through the calculation of appropriate segmentation metrics, we provide insights into the consistency and variability in liver and tumor segmentations among the radiologists. A total of 17 cases were included for liver segmentation and 14 cases for HCC tumor segmentation. Liver segmentations demonstrates high segmentation agreement (mean Dice, 0.95 ± 0.01 [standard deviation]) and HCC tumor segmentations showed higher variation (mean Dice, 0.85 ± 0.16 [standard deviation]). The applications of LiverHccSeg can be manifold, ranging from testing machine learning algorithms on public external data to radiomic feature analyses. Leveraging the inter-rater agreement analysis within the dataset, researchers can investigate the impact of variability on segmentation performance and explore methods to enhance the accuracy and robustness of liver and tumor segmentation algorithms in HCC patients. By making this dataset publicly available, LiverHccSeg aims to foster collaborations, facilitate innovative solutions, and ultimately improve patient outcomes in the diagnosis and treatment of HCC.

Improved performance and consistency of deep learning 3D liver segmentation with heterogeneous cancer stages in magnetic resonance imaging.

PURPOSE: Accurate liver segmentation is key for volumetry assessment to guide treatment decisions. Moreover, it is an important pre-processing step for cancer detection algorithms. Liver segmentation can be especially challenging in patients with cancer-related tissue changes and shape deformation. The aim of this study was to assess the ability of state-of-the-art deep learning 3D liver segmentation algorithms to generalize across all different Barcelona Clinic Liver Cancer (BCLC) liver cancer stages. METHODS: This retrospective study, included patients from an institutional database that had arterial-phase T1-weighted magnetic resonance images with corresponding manual liver segmentations. The data was split into 70/15/15% for training/validation/testing each proportionally equal across BCLC stages. Two 3D convolutional neural networks were trained using identical U-net-derived architectures with equal sized training datasets: one spanning all BCLC stages ("All-Stage-Net": AS-Net), and one limited to early and intermediate BCLC stages ("Early-Intermediate-Stage-Net": EIS-Net). Segmentation accuracy was evaluated by the Dice Similarity Coefficient (DSC) on a dataset spanning all BCLC stages and a Wilcoxon signed-rank test was used for pairwise comparisons. RESULTS: 219 subjects met the inclusion criteria (170 males, 49 females, 62.8±9.1 years) from all BCLC stages. Both networks were trained using 129 subjects: AS-Net training comprised 19, 74, 18, 8, and 10 BCLC 0, A, B, C, and D patients, respectively; EIS-Net training comprised 21, 86, and 22 BCLC 0, A, and B patients, respectively. DSCs (mean±SD) were 0.954±0.018 and 0.946±0.032 for AS-Net and EIS-Net (p<0.001), respectively. The AS-Net 0.956±0.014 significantly outperformed the EIS-Net 0.941±0.038 on advanced BCLC stages (p<0.001) and yielded similarly good segmentation performance on early and intermediate stages (AS-Net: 0.952±0.021; EIS-Net: 0.949±0.027; p = 0.107). CONCLUSION: To ensure robust segmentation performance across cancer stages that is independent of liver shape deformation and tumor burden, it is critical to train deep learning models on heterogeneous imaging data spanning all BCLC stages.