Hepatocellular Carcinoma Treatment Response Research Articles

Imaging After Locoregional Therapy for Hepatocellular Carcinoma with Emphasis on LIRADS Treatment Response Assessment Criteria

Radiologists play an essential role in assessing hepatocellular carcinoma treatment response and help guide further clinical management of patients. Interpretation of treatment response after locoregional therapy is challenging. The post-treatment imaging findings vary and depend on the type of treatment, the degree of treatment response, time interval after treatment and several other factors. Given the widespread use of local-regional therapies, understanding the appearance of treated lesions has become crucial to allow for a more accurate interpretation of post-treatment imaging. Several response criteria including the recently introduced Liver Imaging Reporting and Data System (LI-RADS) treatment response algorithm (TRA) are currently used to assess treatment response. This review article describes the imaging assessment of HCC treatment response after several locoregional therapies using various response assessment criteria, emphasizing the LI-RADS treatment algorithm.

Artificial intelligence in assessment of hepatocellular carcinoma treatment response.

Artificial Intelligence (AI) continues to shape the practice of radiology, with imaging of hepatocellular carcinoma (HCC) being of no exception. This article prepared by members of the LI-RADS Treatment Response (TR LI-RADS) work group and associates, presents recent trends in the utility of AI applications for the volumetric evaluation and assessment of HCC treatment response. Various topics including radiomics, prognostic imaging findings, and locoregional therapy (LRT) specific issues will be discussed in the framework of HCC treatment response classification systems with focus on the Liver Reporting and Data System treatment response algorithm (LI-RADS TRA).

Early evaluation of treatment response to transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The role of dynamic three-dimensional contrast-enhanced ultrasound.

Dynamic three-dimensional contrast-enhanced ultrasound (3D-CEUS) with quantitative analysis is available in recent years. It can reduce the quantitative sampling error caused by the inconsistency of different sections in order to evaluate local treatment response of hepatocellular carcinoma (HCC) accurately. To investigate the value of dynamic 3D-CEUS in evaluating the early response to transarterial chemoembolization (TACE) treatment in patients with advanced HCC lesions. In this prospective study, both two-dimensional (2D) CEUS and dynamic 3D-CEUS were performed on 40 HCC patients who scheduled for TACE at baseline (T0) and 1-3 days (T1) after treatment. Tumor microvascular perfusion changes were assessed by CEUS time-intensity curve (TIC) and quantitative parameters. According to contrast-enhanced computed tomography (CT) and magnetic resonance (MR) imaging 1 month after treatment results, patients were divided into responders and non-responders groups. The changes of perfusion parameters of both 2D-CEUS and 3D-CEUS were compared between responders and non-responders groups before and after TACE treatment. Before and after TACE treatment, no significant difference in maximum diameter of HCC lesions between the two groups could be found. There were more significant differences and ratios of perfusion parameters in 3D-CEUS quantitative analysis than in 2D-CEUS. The mutual significant differences and ratios of 2D-CEUS and 3D-CEUS included peak intensity (PI) difference, PI ratio, ratio of area under the curve (A), ratio of area under the wash-out part (AWO) and slope (S) difference. The former 4 corresponding parameters were better on 3D-CEUS than on 2D-CEUS. Dynamic 3D-CEUS can be used as a potential imaging method to evaluate early treatment response to TACE in advanced HCC patients.

Elevated AFP in the Absence of Hepatic Malignancy in a Patient with Acute Hepatitis

Alpha-fetoprotein is a tumor marker used in the clinical diagnosis and monitoring of treatment response in hepatocellular carcinoma (HCC). However, elevated levels are not specific for malignancy as it has been reported in other chronic liver diseases. This paper aims to describe such a case of elevated AFP in a case of acute hepatitis and its pathophysiology. Herein presents a 26-year-old Asian male with jaundice; who had no personal or family history of liver disease, drug or supplement use. The reported alcohol intake was not significant. The laboratory workup revealed hepatocellular type of liver injury (total bilirubin of 478 umol/L, direct bilirubin 401 umol/L, indirect bilirubin 77 umol/L, AST 1135 U/L, ALT 1592 U/L, LDH 53 U/L, ALP 139 u/L), elevated AFP (3337 IU/mL), elevated INR, positive autoimmune panel (ANA, Anti-Sm, Anti-TPO, Anti-TG). The serological examinations revealed a past infection with EBV and CMV, while imaging tests did not show ductal obstruction or the presence of mass lesions. A subsequent liver biopsy demonstrated interface hepatitis. The patient was then treated as a case of autoimmune hepatitis and was started on glucocorticoids with clinical and biochemical improvement including normalization of AFP levels.

US-triggered Microbubble Destruction for Augmenting Hepatocellular Carcinoma Response to Transarterial Radioembolization: A Randomized Pilot Clinical Trial.

Background US contrast agents are gas-filled microbubbles (MBs) that can be locally destroyed by using external US. Among other bioeffects, US-triggered MB destruction, also known as UTMD, has been shown to sensitize solid tumors to radiation in preclinical models through localized insult to the vascular endothelial cells. Purpose To evaluate the safety and preliminary efficacy of combining US-triggered MB destruction and transarterial radioembolization (TARE) in participants with hepatocellular carcinoma (HCC). Materials and Methods In this pilot clinical trial, participants with HCC scheduled for sublobar TARE were randomized to undergo either TARE or TARE with US-triggered MB destruction 1-4 hours and approximately 1 and 2 weeks after TARE. Enrollment took place between July 2017 and February 2020. Safety of US-triggered MB destruction was evaluated by physiologic monitoring, changes in liver function tests, adverse events, and radiopharmaceutical distribution. Treatment efficacy was evaluated by using modified Response Evaluation Criteria in Solid Tumors (mRECIST) on cross-sectional images, time to required next treatment, transplant rates, and overall survival. Differences across mRECIST reads were compared by using a Mann-Whitney U test, and the difference in prevalence of tumor response was evaluated by Fisher exact test, whereas differences in time to required next treatment and overall survival curves were compared by using a log-rank (Mantel-Cox) test. Results Safety results from 28 participants (mean age, 70 years ± 10 [standard deviation]; 17 men) demonstrated no significant changes in temperature (P = .31), heart rate (P = .92), diastolic pressure (P = .31), or systolic pressure (P = .06) before and after US-triggered MB destruction. No changes in liver function tests between treatment arms were observed 1 month after TARE (P > .15). Preliminary efficacy results showed a greater prevalence of tumor response (14 of 15 [93%; 95% CI: 68, 100] vs five of 10 [50%; 95% CI: 19, 81]; P = .02) in participants who underwent both US-triggered MB destruction and TARE (P = .02). Conclusion The combination of US-triggered microbubble destruction and transarterial radioembolization is feasible with an excellent safety profile in this patient population and appears to result in improved hepatocellular carcinoma treatment response. © RSNA, 2020.

Hepatocellular carcinoma Liver Imaging Reporting and Data Systems treatment response assessment: Lessons learned and future directions.

Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality worldwide, with rising clinical and economic burden as incidence increases. There are a multitude of evolving treatment options, including locoregional therapies which can be used alone, in combination with each other, or in combination with systemic therapy. These treatment options have shown to be effective in achieving remission, controlling tumor progression, improving disease free and overall survival in patients who cannot undergo resection and providing a bridge to transplant by debulking tumor burden to downstage patients. Following locoregional therapy (LRT), it is crucial to provide treatment response assessment to guide management and liver transplant candidacy. Therefore, Liver Imaging Reporting and Data Systems (LI-RADS) Treatment Response Algorithm (TRA) was created to provide a standardized assessment of HCC following LRT. LI-RADS TRA provides a step by step approach to evaluate each lesion independently for accurate tumor assessment. In this review, we provide an overview of different locoregional therapies for HCC, describe the expected post treatment imaging appearance following treatment, and review the LI-RADS TRA with guidance for its application in clinical practice. Unique to other publications, we will also review emerging literature supporting the use of LI-RADS for assessment of HCC treatment response after LRT.

Assessment of the Treatment Response of Hepatocellular Carcinoma to Radiofrequency Ablation Using Dynamic and Diffusion MR Imaging according to LI-RADS v2018 Treatment Response Algorithm

Abstract Background: Hepatocellular carcinoma is the most com-mon primary liver malignancy and considered as the fifth most common cancer worldwide. Resection and liver trans-plantation have a high survival in adequately selected patients, however locoregional ablative therapeutic techniques has several advantages over surgery like hepatic parenchymal preservation and overall have less morbidity and mortality. Aim of Study: The aim of this study was to evaluate the role of diffusion and dynamic MR imaging in the assessment of the treatment response of hepatocellular carcinoma after radiofrequency ablation according to the LI-RADS treatment response v2018. Patients and Methods: A retrospective study included 40 patients with 45 HCC lesions underwent radiofrequency ablation and followed-up by dynamic and diffusion MR imaging. The data were collected from the PACS of Radiology Department, Cairo University Hospitals. The MR images were assessed according to LI-RADS 2018 treatment response algorithm. Results: According to LI-RADS treatment response cri-teria, dynamic MRI has sensitivity of 100%, specificity 95.8%, Positive Predictive Value (PPV) 94.1% and Negative Predictive Value (NPV) 100% compared to sensitivity of 64.3%, specif-icity 95.8%, PPV 90% and NPV 82.1% for the diffusion weighted images in the detection of tumoural viability. Arterial Phase Hyperenhancement (APHE) was found in 87.5% of viable lesions while delayed wash out was found in 100% of the viable lesions. Conclusion: Dynamic MRI is the cornerstone in the assessment of treatment response of hepatocellular carcinoma to radiofrequency ablation. Arterial phase hyperenhancement and delayed wash out are the main criteria for diagnosis of tumoural viability according to LI-RADS treatment response algorithm. Diffusion imaging and ADC measurement are good negative techniques for exclusion of tumoural activity and also can confirm the dynamic findings in viable cases.

Comparison of response using mRECIST versus RECIST 1.1 Criteria in advanced hepatocellular carcinoma: A retrospective analysis of multicenter clinical trials.

4595 Background: mRECIST 2010 criteria for Hepatocellular Carcinoma (HCC) response assessment were focused on a concept of measuring viable tumor tissue showing enhancement in arterial phase of contrast enhanced CT/MRI, whereas RECIST 1.1 focuses mainly on the morphological measurements quantifying the tumor size irrespective of viability of the tumor and associated response to therapy. RECIST 1.1 does not address measures of antitumor activity other than tumor shrinkage, underestimating responses in HCC. Methods: We retrospectively analyzed multiple, phase III, multi-center clinical trials using both mRECIST and RECIST 1.1 criteria, read separately. The intent was to compare the overall responses at post-baseline assessments read independently by the two criteria. A total of 1682 subjects with 6159 post-baseline imaging timepoints were included in the analysis. The Overall response rate (ORR) as measured by sum of complete response (CR) and partial response(PR) and the Complete response rate (CRR) were evaluated. In addition, we also assessed the number of not evaluable (NE) time points by each criteria separately. We tested the following hypotheses 1. mRECIST may have better ORR and CRR compared to RECIST 1.1. 2. RECIST 1.1 may have more timepoints with Stable disease (SD) compared to mRECIST. 3. mRECIST may have more Not evaluable (NE) timepoints due to stringent imaging specifications. Results: The results are tabulated in the table below: Conclusions: The results above suggest that mRECIST shows more than double the CRR than RECIST 1.1, and the ORR is 62% higher using mRECIST than RECIST 1.1. Stable disease as expected was more commonly observed in RECIST 1.1 analysis. A NE response was 60% more common in mRECIST criteria evaluation. Our analysis confirms that reduction in viable tumor/enhancing area using contrast-enhanced radiologic imaging is the more optimal method to assess treatment response in HCC, and using RECIST 1.1 tumor measurement of a longest diameter as the sole measure of response, may not be adequate in response assessment for HCC. Our analysis validates and supports more widespread adoption of mRECIST in HCC tumor response assessment. Our results also indicate the need for uniform image acquisition and rigorous image quality control for a valid response in mRECIST criteria. [Table: see text]

Nanotheranostics: Their role in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most prevalent malignancy worldwide. Despite advances in imaging techniques, early diagnosis and management remain very poor. The early diagnosis of HCC requires diagnostic and imaging technologies with high sensitivity and precise quantification ability and with no tissue penetration limit. Nanotechnology-based cancer imaging is a rapidly emerging research area with significant applications in the diagnosis and treatment of cancer, which we review here with application to HCC. Furthermore, we discuss the combination of functional nanotheranostics and magnetic resonance imaging (MRI) for targeted delivery of phytochemical therapeutics, chemotherapeutic drugs, RNAi-based therapeutics, and vaccinations. Finally, this review presents the importance of MRI biomarkers for monitoring HCC treatment response. The use of advanced nanotheranostics as MRI contrast agents for imaging, diagnosis and drug delivery may enhance HCC management and provide a new area of research in tumor imaging technology.

Serum STIP1, a Novel Indicator for Microvascular Invasion, Predicts Outcomes and Treatment Response in Hepatocellular Carcinoma.

Background: Previous studies reported that stress-induced phosphoprotein 1 (STIP1) can be secreted by hepatocellular carcinoma (HCC) cells and is increased in the serum of HCC patients. However, the therapy-monitoring and prognostic value of serum STIP1 in HCC remains unclear. Here, we aimed to systemically explore the prognostic significance of serum STIP1 in HCC.Methods: A total of 340 HCC patients were recruited to this study; 161 underwent curative resection and 179 underwent transcatheter arterial chemoembolization (TACE). Serum STIP1 was detected by enzyme-linked immunosorbent assay (ELISA). Optimal cutoff values for serum STIP1 in resection and TACE groups were determined by receiver operating characteristic (ROC) analysis. Prognostic value was assessed by Kaplan-Meier, log-rank, and Cox regression analyses. Predictive values of STIP1 for objective response (OR) to TACE and MVI were evaluated by ROC curves and logistic regression.Results: Serum STIP1 was significantly increased in HCC patients when compared with chronic hepatitis B patients or health donors (both P < 0.05). Optimal cutoff values for STIP1 in resection and TACE groups were 83.43 and 112.06 ng/ml, respectively. High pretreatment STIP1 was identified as an independent prognosticator. Dynamic changes in high STIP1 status were significantly associated with long-term prognosis, regardless of treatment approaches. Moreover, post-TACE STIP1 was identified as an independent predictor for OR, with a higher area under ROC curve (AUC-ROC) than other clinicopathological features. Specifically, pretreatment STIP1 was significantly increased in patients with microvascular invasion (MVI), and was confirmed as a novel, powerful predictor for MVI.Conclusions: Serum STIP1 is a promising biomarker for outcome evaluation, therapeutic response assessment, and MVI prediction in HCC. Integration serum STIP1 detection into HCC management might facilitate early clinical decision making to improve the prognosis of HCC.

Reproducibility of LI-RADS treatment response algorithm for hepatocellular carcinoma after locoregional therapy

PurposeTo determine inter-reader agreement in categorizing hepatocellular carcinoma (HCC) treated with locoregional therapy using the Liver Imaging Reporting and Data System (LI-RADS) treatment response (LR-TR) algorithm. Materials and methodsA total of 93 patients with a total of 112 HCC nodules that were treated using thermal ablation or transarterial chemoembolization were prospectively included. There were 79 men and 14 women with a mean age of 55±2.6 (SD)years (range: 48–63years). All patients underwent magnetic resonance imaging (MRI) examination of the liver and MR images were analyzed by two independent observers. Treated HCC nodules were categorized into four groups according to LR-TR scoring system including: (i) LR-TR non-evaluable (treated, response not evaluable); (ii) LR-TR nonviable (treated, probably or definitively not viable); (iii) LR-TR equivocal (treated, equivocally viable) and (iv) LR-TR viable (treated, probably or definitively viable). The inter-observer agreement in LR-TR categorization was assessed using the kappa statistics. ResultsThere was excellent inter-observer agreement between the two reviewers for overall treated HCC according to LR-TR algorithm (kappa=0.938; 95% CI: 0.89–1.00; P=0.001) with 97.31% agreement. The LR-TR categories by both reviewers were non-viable (77/112; 69.6% and 76/112; 67.9%), viable (30/112; 26.8% and 32/112; 27.7%) and equivocal (5/112; 4.4% and 4/112; 3.6%). There was excellent inter-observer agreement for LR-TR nonviable (kappa=0.938; 95% CI: 0.87–1.0; P=0.001) with 97.3% agreement, LR-TR viable (kappa=0.955; 95% CI: 0.89–1.00; P=0.001) with 98.2% agreement and good inter-observer agreement for LR-TR equivocal (kappa=0.700; 95% CI: 0.28–1.0; P=0.001) with 97.3% agreement. ConclusionLR-TR algorithm conveys high degrees of inter-observer agreement for the evaluation of treatment response of HCC after thermal ablation and transarterial chemoembolization.

Evaluation of treatment response in hepatocellular carcinoma in the explanted liver with Liver Imaging Reporting and Data System version 2017.

To investigate the performance of Liver Imaging Reporting and Data System (LI-RADS) v2017 treatment response algorithm for predicting hepatocellular carcinoma (HCC) viability after locoregional therapy (LRT) using the liver explant as reference. One hundred fourteen patients with 206 HCCs who underwent liver transplantation (LT) after LRT for HCCs were included in this retrospective study. Two radiologists independently evaluated tumor viability using the LI-RADS and modified RECIST (mRECIST) with CT and MRI, respectively. The sensitivity and specificity of arterial phase hyperenhancement (APHE) and LR-TR viable criteria (any of three findings: APHE, washout, and enhancement pattern similar to pretreatment imaging) were compared using logistic regression. Receiver operating characteristics (ROC) analysis was used to compare the diagnostic performance between LI-RADS and mRECIST and between CT and MRI. The sensitivity and specificity for diagnosing viable tumor were not significantly different between APHE alone and LR-TR viable criteria on CT (p = 0.054 and p = 0.317) and MRI (p = 0.093 and p = 0.603). On CT, the area under the ROC curve (AUC) of LI-RADS was significantly higher than that of mRECIST (0.733 vs. 0.657, p < 0.001). On MRI, there was no significant difference in AUCs between LI-RADS and mRECIST (0.802 vs. 0.791, p = 0.500). Intra-individual comparison of CT and MRI showed comparable AUCs using LI-RADS (0.783 vs. 0.795, p = 0.776). LI-RADS v2017 treatment response algorithm showed better diagnostic performance than mRECIST on CT. With LI-RADS, CT and MRI were comparable to diagnose tumor viability of HCC after LRT. • Using Liver Imaging Reporting and Data System (LI-RADS) v2017 treatment response algorithm, the viability of hepatocellular carcinoma (HCC) after locoregional therapy (LRT) can be accurately diagnosed. • LI-RADS v2017 treatment response algorithm is superior to modified Response Evaluation Criteria in Solid Tumors for evaluating HCC viability using CT. • Either CT or MRI can be performed to assess tumor viability after LRT using LI-RADS v2017 treatment response algorithm.

The Roles of GSK-3β in Regulation of Retinoid Signaling and Sorafenib Treatment Response in Hepatocellular Carcinoma.

Rationale: Glycogen synthase kinase-3β (GSK-3β) plays key roles in metabolism and many cellular processes. It was recently demonstrated that overexpression of GSK-3β can confer tumor growth. However, the expression and function of GSK-3β in hepatocellular carcinoma (HCC) remain largely unexplored. This study is aimed at investigating the role and therapeutic target value of GSK-3β in HCC.Methods: We firstly clarified the expression of GSK-3β in human HCC samples. Given that deviated retinoid signalling is critical for HCC development, we studied whether GSK-3β could be involved in the regulation. Since sorafenib is currently used to treat HCC, the involvement of GSK-3β in sorafenib treatment response was determined. Co-immunoprecipitation, GST pull down, in vitro kinase assay, luciferase reporter and chromatin immunoprecipitation were used to explore the molecular mechanism. The biological readouts were examined with MTT, flow cytometry and animal experiments.Results: We demonstrated that GSK-3β is highly expressed in HCC and associated with shorter overall survival (OS). Overexpression of GSK-3β confers HCC cell colony formation and xenograft tumor growth. Tumor-associated GSK-3β is correlated with reduced expression of retinoic acid receptor-β (RARβ), which is caused by GSK-3β-mediated phosphorylation and heterodimerization abrogation of retinoid X receptor (RXRα) with RARα on RARβ promoter. Overexpression of functional GSK-3β impairs retinoid response and represses sorafenib anti-HCC effect. Inactivation of GSK-3β by tideglusib can potentiate 9-cis-RA enhancement of sorafenib sensitivity (tumor inhibition from 48.3% to 93.4%). Efficient induction of RARβ by tideglusib/9-cis-RA is required for enhanced therapeutic outcome of sorafenib, which effect is greatly inhibited by knocking down RARβ.Conclusions: Our findings demonstrate that GSK-3β is a disruptor of retinoid signalling and a new resistant factor of sorafenib in HCC. Targeting GSK-3β may be a promising strategy for HCC treatment in clinic.

Contrast-enhanced Ultrasonography: The Third Modality for Differentiation of Liver Mass

Contrast-enhanced ultrasonography (CEUS) using microbubble ultrasonography contrast agent can show the vascular structure and unique contrast enhancement patterns of focal liver lesions, including hepatocellular carcinoma (HCC). CEUS shows three phases, similar to a vascular pattern on computer tomography (CT), and typical arterial enhancement and portal or late phase washout in HCC. CEUS can show real-time images without nephrotoxicity or radiation hazard and can be used as guidance for loco-regional treatment and estimation of treatment response of HCC. In addition, some data recently revealed the usefulness of CEUS in the early estimation of response to anti-cancer pharmacological (i.e., sorafenib) therapy in advanced HCC. Although CEUS has limitations in clinical practice and more investigation is needed for its validation, it is recommended as a main diagnostic modality in a few major clinical practice guidelines for HCC. Thus, greater understanding of CEUS is necessary to extend its application in real practice for diagnosis and management of diseases. (J Liver Cancer 2019;19:91-96)

Hepatocellular carcinoma response to transcatheter arterial chemoembolisation using automatically generated pre-therapeutic tumour volumes by a random forest-based segmentation protocol

To demonstrate the feasibility of correlating pre-therapeutic volumes and residual liver volume (RLV) with clinical outcomes: time to progression (TTP) and overall survival (OS) in hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolisation (TACE). TTP was calculated from a database of 105 patients, receiving first-line treatment with TACE. TTP cut-off for stratifying patients into responders and non-responders was 28 weeks. Pre-treatment tumour and liver volumes were correlated with the TTP and OS following treatment. Univariate cox-regression model was used to assess whether these volumes could predict TTP and/or OS. Kaplan-Meier analysis with log-rank test was used to compare the TTP between high and low volume groups for viable, necrotic, and total tumour. Kaplan-Meier analysis was performed comparing the OS of 10 patients with the longest TTP (mean=122 weeks) in the responder group and 10 patients with the shortest TTP (mean=7 weeks) in the non-responder group. HCC in high tumour volume groups had a shorter TTP than lesions in low tumour volume groups (p=0.05, p=0.04, p=0.02, for enhancing, non-enhancing, total tumour groups, respectively). A negative (correlation coefficient [CC] 0.3) linear correlation between TTP and tumour volumes, and a positive linear correlation between TTP and residual liver volumes were also demonstrated (CC 0.3). Patients with the longest TTP had a higher OS than with the shortest TTP (p=0.03). This demonstrates the feasibility of predicting treatment response of HCC to TACE using volumetric measurements of pre-treatment lesion and the feasibility of correlating RLV with TACE outcome data in HCC patients.

The value of dynamic subtraction MRI technique in the assessment of treatment response of hepatocellular carcinoma to transcatheter arterial chemoembolization

BackgroundHepatocellular carcinoma is considered to be the fifth most common cancer worldwide. Resection and liver transplantation have a high survival in the correct clinical scenarios; however, locoregional therapy has many advantages over tumor resection like preservation of hepatic parenchyma and overall less morbidity and mortality. Our aim was to present the role of dynamic subtraction MRI technique in the assessment of treatment response of hepatocellular carcinoma to transarterial chemoembolization.MethodsThe study consisted of 43 patients with 55 hepatocellular carcinoma lesions who underwent transarterial chemoembolization procedure and followed up by dynamic MRI of the liver with post processing to obtain subtraction images 1–1.5 months after the procedure. If no signs of disease activity, another follow up study was preformed 2–4 months later. Five patients were excluded due to misregistration artifact at the subtraction images. The final cohort is 38 patients having 50 lesions. Precontrast T1, T2, dynamic contrast enhanced, and diffusion-weighted images were acquired. Subtracted dynamic images were created on the workstation. Sequences were assessed by three experienced readers in hepatic imaging. The sensitivity, specificity, positive predictive value, negative predictive value, 95% confidence interval, and overall agreement were calculated for the dynamic and subtracted dynamic images.ResultsThe subtraction images have sensitivity of 96%, specificity of 100%, PPV of 100%, and NPV of 100% Compared to 96%, 100%, 100%, 96%, and 96%, 100%, 100% 96% for the three readers respectively. On the other hand, the dynamic images has sensitivity of 92%, specificity of 96%, PPV of 95%, and NPV of 92.3% compared to 92%, 96%, 95%, 92.3% and 80%, 68%, 71.4%, and 77.2% for the three readers respectively.ConclusionSubtraction technique is a useful confirmative tool as it had higher sensitivity, specificity, PPV, and NPV values compared to the dynamic and diffusion images with high level of agreement between the readers and also associated with significantly higher reader confidence levels.

Response Evaluation Criteria in Cancer of the Liver version5 (RECICL 2019 revised version).

Response Evaluation Criteria in Solid Tumors (RECIST) is inappropriate to assess the direct effects of treatment on hepatocellular carcinoma (HCC) by locoregional therapies, such as radiofrequency ablation and transarterial chemoembolization. Therefore, establishment of response evaluation criteria solely devoted to HCC is needed in clinical practice, as well as in clinical trials of HCC treatment, such as systemic therapies, which cause necrosis of the tumor. Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2019 by the Liver Cancer Study Group of Japan based on the 2015 version of RECICL, which was commonly used in Japan. The major revised points of the RECICL 2019 are as follows: (i) CEA and CA19-9 have been newly added as tumor markers that should be recorded for use as criteria in the response evaluation for intrahepatic cholangiocarcinoma; (ii) the criteria now state that the details of molecular targeted therapy should be specified; and (iii) specific methods for overall evaluation are now described. Also, as an assessment of overall TE4 requires that TE4 is achieved in all nodules (even non-target lesions), the same calculation methods described above are used. We hope this new treatment response criteria, RECICL, proposed by the Liver Cancer Study Group of Japan will benefit the HCC treatment response evaluation in the setting of daily clinical practice and clinical trials as well, not only in Japan, but also internationally.

The Roles of GSK-3β in Regulation of Retinoid Signaling and Sorafenib Treatment Response in Hepatocellular Carcinoma

Background: Glycogen synthase kinase-3β (GSK-3β) is recently demonstrated to be a tumor promoter and a potential drug target in several tumors. However, the implication and mechanism of GSK-3β in hepatocellular carcinoma (HCC) remain unexplored. Methods: We firstly clarified the expression of GSK-3β in human HCC samples. Given that deviated retinoid signalling is critical for HCC development, we investigated where GSK-3β could be involved in the regulation. Since sorafenib is currently used to treat HCC, the involvement of GSK-3β in sorafenib treatment response was determined. Coimmunoprecipitation, GST pull down, in vitro kinase assay, luciferase reporter and chromatin immunoprecipitation were used to study the molecular mechanism. The biological readouts were examined with MTT, flow cytometry and animal experiments. Findings: We demonstrated that GSK-3β is highly expressed in HCC and associated with shorter overall survival (OS). Tumor-associated GSK-3β is correlated with reduced expression of retinoic acid receptor-β (RARβ), which is caused by GSK-3β-mediated phosphorylation and heterodimerization abrogation of retinoid X receptor (RXRα) with RARα on RARβ promoter. Overexpression of functional GSK-3β impairs retinoid response and represses sorafenib anti-HCC effect. Inactivation of GSK-3β by tideglusib can potentiate 9-cis-RA enhancement of sorafenib sensitivity (tumor inhibition: from 48.3% to 93.4%). Efficient induction of RARβ by tideglusib/9-cis-RA is required for enhanced therapeutic outcome of sorafenib, which effect is greatly inhibited by knocking down RARβ. Interpretation: Our findings suggest that overexpression of GSK-3β may confer HCC growth through interfering retinoid signalling. Targeting GSK3β can be a promising strategy for designing improved treatment of sorafenib in HCC. Funding Statement: This work is supported by grants from Natural Science Foundation of China (No. 81673467, 31471273, 31461163002/RGC N_HKU 740/14), the 10th Singapore-China Joint Research Program (S2014GR0448), Natural Science Foundation of Fujian Province (2019I0002) and Leading Talents in Scientific and Technological Innovation, Double Hundred Talents Program of Fujian Province. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All the use of human samples and study protocols were approved by the Hospital Ethics Committee. All patients signed an informed consent form in prior to sample collection.

Emerging role of 18F-fluorodeoxyglucose positron emission tomography for guiding management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of major causes of cancer mortality worldwide. For decades, 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been widely used for staging, predicting prognosis, and detecting cancer recurrence in various types of malignant diseases. Due to low sensitivity of FDG PET for detecting intrahepatic HCC lesions, the clinical value of FDG PET in HCC patients has been limited. However, recent studies with diverse analytic methods have shown that FDG PET has promising role in aiding management of HCC patients. In this review, we will discuss the clinical role of FDG PET for staging, predicting prognosis, and evaluating treatment response in HCC. Further, we will focus on recent clinical studies regarding implication of volumetric FDG PET parameters, the significance of FDG uptake in HCC for selecting treatment and predicting treatment response, and the use of radiomics of FDG PET in HCC.

Transcatheter embolization of hepatocellular carcinoma with epirubicin-loaded DC beads in Chinese patients

Background: This study evaluated the safety and efficacy of transcatheter chemoembolization with drug eluting beads (DEB-TACE) and compared it to the conventional TACE (cTACE) therapy method for hepatocellular carcinoma (HCC) in Chinese patients. Methods: Seventy-four patients were treated with DEB-TACE using the DC bead, and 80 patients were treated with cTACE for HCC. The modified response evaluation criteria in solid tumors (mRECIST) criteria were used to evaluate clinical response, with adverse events assessed according to the Common Terminology Criteria for Adverse Events (CTCAE). Results: Post-TACE, 9 patients (12.2%) achieved complete response (CR) and 44 (59.5%) achieved partial response (PR), with an overall tumor response rate (ORR) of 71.6% in the DEB-TACE group. Twelve patients (15%) achieved CR, and 38 (47.5%) achieved PR, with an ORR of 62.5% in the cTACE group. However, there was no significant difference in ORR between the two groups (P=0.229). Univariate logistic regression analysis determined that more than 3 nodules, higher Barcelona clinic liver cancer (BCLC) stage, portal vein invasion, previous chemotherapy (cTACE), and previous surgery were correlated with a worse ORR. Most common adverse events were not severe. Conclusions: DEB-TACE by DC bead was efficient and well-tolerated compared to cTACE in Chinese HCC patients. However, the present study showed no significant difference in ORR between the DEB-TACE and cTACE in the patient group with HCC. The BCLC stage, number of nodules, portal vein invasion, cTACE, and surgery history could possibly be a predictive factor for HCC treatment response.