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.

Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes.

Podocytes are terminally differentiated epithelial cells that reside along the glomerular filtration barrier. Evidence suggests that after podocyte injury, endoplasmic reticulum stress response is activated, but the molecular mechanisms involved are incompletely defined. In a mouse model, we confirmed that podocyte injury induces endoplasmic reticulum stress response and upregulated unfolded protein response pathways, which have been shown to mitigate damage by preventing the accumulation of misfolded proteins in the endoplasmic reticulum. Furthermore, simultaneous podocyte-specific genetic inactivation of X-box binding protein-1 (Xbp1), a transcription factor activated during endoplasmic reticulum stress and critically involved in the untranslated protein response, and Sec63, a heat shock protein-40 chaperone required for protein folding in the endoplasmic reticulum, resulted in progressive albuminuria, foot process effacement, and histology consistent with ESRD. Finally, loss of both Sec63 and Xbp1 induced apoptosis in podocytes, which associated with activation of the JNK pathway. Collectively, our results indicate that an intact Xbp1 pathway operating to mitigate stress in the endoplasmic reticulum is essential for the maintenance of a normal glomerular filtration barrier.

Predicting tumor recurrence on baseline MR imaging in patients with early-stage hepatocellular carcinoma using deep machine learning.

Tumor recurrence affects up to 70% of early-stage hepatocellular carcinoma (HCC) patients, depending on treatment option. Deep learning algorithms allow in-depth exploration of imaging data to discover imaging features that may be predictive of recurrence. This study explored the use of convolutional neural networks (CNN) to predict HCC recurrence in patients with early-stage HCC from pre-treatment magnetic resonance (MR) images. This retrospective study included 120 patients with early-stage HCC. Pre-treatment MR images were fed into a machine learning pipeline (VGG16 and XGBoost) to predict recurrence within six different time frames (range 1-6 years). Model performance was evaluated with the area under the receiver operating characteristic curves (AUC-ROC). After prediction, the model's clinical relevance was evaluated using Kaplan-Meier analysis with recurrence-free survival (RFS) as the endpoint. Of 120 patients, 44 had disease recurrence after therapy. Six different models performed with AUC values between 0.71 to 0.85. In Kaplan-Meier analysis, five of six models obtained statistical significance when predicting RFS (log-rank p < 0.05). Our proof-of-concept study indicates that deep learning algorithms can be utilized to predict early-stage HCC recurrence. Successful identification of high-risk recurrence candidates may help optimize follow-up imaging and improve long-term outcomes post-treatment.

Thermal ablation alone vs thermal ablation combined with transarterial chemoembolization for patients with small (<3 cm) hepatocellular carcinoma.

PURPOSE: Thermal ablation (TA) and transarterial chemoembolization (TACE) may be used alone or in combination (TACE+TA) for the treatment of hepatocellular carcinoma (HCC). The aim of our study was to compare the time to tumor progression (TTP) and overall survival (OS) for patients who received TA alone or TACE+TA for HCC tumors under 3 cm. MATERIALS AND METHODS: This HIPAA-compliant IRB-approved retrospective analysis included 85 therapy-naïve patients from 2010 to 2018 (63 males, 22 females, mean age 62.4 ± 8.5 years) who underwent either TA alone (n = 64) or TA in combination with drug-eluting beads (DEB)-TACE (n = 18) or Lipiodol-TACE (n = 3) for locoregional therapy of early stage HCC with maximum tumor diameter under 3 cm. Kaplan-Meier analysis was performed using the log-rank test to assess TTP and OS. RESULTS: All TA and TACE+TA treatments included were technically successful. TTP was 23.0 months in the TA group and 22.0 months in the TACE+TA group. There was no statistically significant difference in TTP (p = 0.64). Median OS was 69.7 months in the TA group and 64.6 months in the TACE+TA group. There was no statistically significant difference in OS (p = 0.14). The treatment cohorts had differences in AFP levels (p = 0.03) and BCLC stage (p = 0.047). Complication rates between patient groups were similar (p = 0.61). CONCLUSION: For patients with HCC under 3 cm, TA alone and TACE+TA have similar outcomes in terms of TTP and OS, suggesting that TACE+TA may not be needed for these tumors unless warranted by tumor location or other technical consideration.

Therapy of Intermediate-Stage Hepatocellular Carcinoma: Current Evidence and Clinical Practice.

Intermediate-stage Hepatocellular Carcinoma (HCC) represents a wide range of disease burden. Patients with different levels of liver function, tumor size, and number of lesions may all have intermediate-stage disease according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Several minimally invasive image-guided locoregional therapies are available for the treatment of intermediate-stage HCC, including conventional transarterial chemoembolization (cTACE), drug-eluting bead TACE (DEB-TACE), yttrium-90 radioembolization (Y-90 RE), thermal ablation, bland embolization, and combination therapy. Available clinical evidence points to cTACE as the current gold standard for the locoregional treatment of intermediate-stage HCC. DEB-TACE is at best non-inferior to cTACE in terms of survival benefit. Y-90 RE is a maturing therapy, and some institutions have adopted it as first-line therapy for intermediate-stage HCC. Thermal ablation combined with TACE may be used in select patients, while bland embolization has only limited evidence for its use. The combination of locoregional therapy with VEGF inhibitors or immune checkpoint inhibitors has also been explored. This article will examine in detail the clinical evidence supporting available locoregional treatment options for intermediate-stage HCC.

Podocyte histone deacetylase activity regulates murine and human glomerular diseases.

We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, the leading cause of end-stage kidney disease. mRNA expression profiling from proteinuric mouse glomeruli was linked to Connectivity Map databases, identifying HDAC1 and HDAC2 with the differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment with valproic acid (a class I HDAC inhibitor) or SAHA (a pan-HDAC inhibitor) mitigated the degree of proteinuria and glomerulosclerosis, leading to a striking increase in survival. Podocyte HDAC1 and HDAC2 activities were increased in mice podocytopathy models, and podocyte-associated Hdac1 and Hdac2 genetic ablation improved proteinuria and glomerulosclerosis. Podocyte early growth response 1 (EGR1) was increased in proteinuric patients and mice in an HDAC1- and HDAC2-dependent manner. Loss of EGR1 in mice reduced proteinuria and glomerulosclerosis. Longitudinal analysis of the multicenter Veterans Aging Cohort Study demonstrated a 30% reduction in mean annual loss of estimated glomerular filtration rate, and this effect was more pronounced in proteinuric patients receiving valproic acid. These results strongly suggest that inhibition of HDAC1 and HDAC2 activities may suppress the progression of human proteinuric kidney diseases through the regulation of EGR1.