Intermediate-stage Hepatocellular Carcinoma Patients Research Articles

Evaluation of doxorubicin administrations in hepatocellular carcinoma in terms of genetic polymorphism, case study: Egypt

PurposeThis scientific article aims to evaluate the efficacy of the drug Doxorubicin for treating hepatocellular carcinoma (HCC) in Egypt. The study analyzes data from patients referred to a multi-disciplinary consultation at the National Cancer Institute, Cairo University. The study includes 40 intermediate-stage HCC patients who underwent treatment with either Doxorubicin-Lipiodol or Doxorubicin-loaded drug-eluting beads-trans-arterial chemoembolization (DEB-TACE).Design/methodology/approachPatients referred to a multi-disciplinary consultation at the National Cancer Institute, Cairo University with a possible diagnosis of HCC in the intermediate stage were eligible for the study.FindingsThe study finds that the plasma peak concentration of Doxorubicin is significantly higher in patients treated with Lipiodol compared to those treated with DEB-TACE. The median plasma peak concentration of patients treated with Lipiodol was significantly higher 424 (202.5–731) than the peak level of patients treated with beads 84.95 (26.6–156.5) with p-value = 0.036. However, there is no significant difference in other pharmacokinetic parameters between the two treatment groups. The research article also investigates the genetic polymorphisms in HCC patients treated with Doxorubicin-Lipiodol and Doxorubicin-loaded DEB-TACE. It identifies a significant association between the ABCB1 gene (C3435T) and the concentration of Doxorubicin in plasma. Patients with the CCand computed tomography (CT) genotypes of ABCB1 have higher concentrations of Doxorubicin compared to those with the TT genotype. Furthermore, the study examines the progression-free survival rates and tumour response in the two treatment groups. It demonstrates that DEB-TACE patients have a higher progression-free survival rate compared to cTACE patients. DEB-TACE also leads to better tumour regression.Originality/valueThe current study helps to increase the understanding of the genetic factors that may contribute to HCC susceptibility in the Egyptian population. However, it is essential to consider that genetic polymorphism is just one aspect of HCC risk, and other factors such as environment, lifestyle and viral infections also play crucial roles. Further research is needed to elucidate the complex interactions between genetic and environmental factors in HCC development among Egyptians.

Influence of serum Gas6 levels on prognosis in patients with hepatocellular carcinoma.

The prediction of prognosis in hepatocellular carcinoma patients is important for switching treatment. The association between circulating growth arrest-specific 6 levels and prognosis in hepatocellular carcinoma patients is unknown. We retrospectively analysed the association between serum growth arrest-specific 6 levels and clinical findings in 132 patients with hepatocellular carcinoma. Serum growth arrest-specific 6 levels were measured using enzyme-linked immunosorbent assay. Amongst 132 patients, the Barcelona Clinic Liver Cancer stage was classified as 0, A, B, C and D in 19, 48, 41, 18 and 6 patients, respectively. Serum growth arrest-specific 6 levels in hepatocellular carcinoma patients were higher than those in healthy controls (28.4ng/mL vs. 19.6ng/mL, P<0.001), and growth arrest-specific 6 levels were positively correlated with soluble Axl levels. In the entire cohort, high growth arrest-specific 6 levels were associated with a shorter survival period (hazard ratio: 1.78 per 20ng/mL, 95% confidence interval: 1.01-3.16, P=0.045). In early and intermediate-stage hepatocellular carcinoma patients treated with transcatheter arterial chemoembolization (n=59), we determined a cut-off value of 36.4ng/mL based on the receiver operating characteristic curve to predict death within 3years, and high growth arrest-specific 6 levels were associated with a high cumulative incidence of portal vein tumour thrombosis (Gray's test: P=0.010) and shorter overall survival (log-rank: P=0.005). Serum growth arrest-specific 6 levels were associated with prognosis in hepatocellular carcinoma patients. In early and intermediate-stage hepatocellular carcinoma patients who underwent transcatheter arterial chemoembolization, high growth arrest-specific 6 levels were associated with a high incidence of portal vein tumour thrombosis. Circulating growth arrest-specific 6 levels may be a useful prognostic marker in hepatocellular carcinoma patients.

DNA Methylation Biomarkers as Prediction Tools for Therapeutic Response and Prognosis in Intermediate-Stage Hepatocellular Carcinoma.

Alfa-fetoprotein (AFP), as the main serum tumor marker of hepatocellular carcinoma (HCC), is limited in terms of specificity and ability to predict outcomes. This study investigated the clinical utility of DNA methylation biomarkers to predict therapeutic responses and prognosis in intermediate-stage HCC. This study enrolled 72 patients with intermediate-stage HCC who underwent locoregional therapy (LRT) between 2020 and 2021. The immediate therapeutic response and disease status during a two-year follow-up were recorded. Analysis was performed on 10 selected DNA methylation biomarkers via pyrosequencing analysis of plasma collected before and after LRT. Analysis was performed on 53 patients with complete responses and 19 patients with disease progression after LRT. The mean follow-up duration was 2.4 ± 0.6 years. A methylation prediction model for tumor response (MMTR) and a methylation prediction model for early progression (MMEP) were constructed. The area under the curve (AUC) for sensitivity and specificity of MMTR was 0.79 for complete response and 0.759 for overall survival. The corresponding AUCs for sensitivity and specificity of AFP and protein induced by vitamin K absence-II (PIVKA-II) were 0.717 and 0.708, respectively. Note that the MMTR index was the only significant predictor in multivariate analysis. The AUC for sensitivity and specificity of the MMEP in predicting early progression was 0.79. The corresponding AUCs for sensitivity and specificity of AFP and PIVKA-II were 0.758 and 0.714, respectively. Multivariate analysis revealed that platelet count, beyond up-to-7 criteria, and the MMEP index were strongly correlated with early tumor progression. Combining the indexes and serum markers further improved the predictive accuracy (AUC = 0.922). Multivariate analysis revealed the MMEP index was the only independent risk factor for overall survival. This study indicates that these methylation markers could potentially outperform current serum markers in terms of accuracy and reliability in assessing treatment response and predicting outcomes. Combining methylation markers and serum markers further improved predictive accuracy, indicating that a multi-marker approach may be more effective in clinical practice. These findings suggest that DNA methylation biomarkers may be a useful tool for managing intermediate-stage HCC patients and guiding personalized treatment, particularly for those who are at high risk for close surveillance or adjuvant treatment after LRT.

Validation of the ALBI-TAE model and comparison of seven scoring systems for predicting survival outcome in patients with intermediate‐stage hepatocellular carcinoma undergoing chemoembolization

BackgroundThe ALBI-TAE model was recently proposed as a scoring system to select suitable patients with intermediate-stage hepatocellular carcinoma (HCC) for transarterial chemoembolization (TACE). However, this scoring system has not been externally validated. Therefore, we validated this score and compared it with six scoring systems in terms of prognostication.MethodsWe retrospectively enrolled 480 patients with intermediate-stage HCC who underwent TACE at a tertiary care center between January 2008 and December 2019. Seven scores, which included the ALBI-TAE model, Bolondi’s subclassification, HAP score, mHAP-II score, tumor burden score, six-and-twelve score, and seven-eleven criteria, were calculated and a head-to-head comparison was made in terms of prognostic power using Harrell’s C-index. Prognostic factors associated with survival were analyzed.ResultsALBI-TAE group A had the longest median overall survival (OS) of 40.80 months, followed by ALBI-TAE groups B, C, and D of 20.14 months, 10.58 months, and 7.54 months, respectively, with significant differences (P < 0.001). Among the seven scores, the ALBI-TAE model had the best predictive performance (Harrell’s C-index 0.633) in differentiating OS in intermediate-stage HCC patients. Moreover, the ALBI-TAE model was identified as an independent prognostic factor for survival outcome in multivariate analysis.ConclusionOur study confirmed the value of the ALBI-TAE model with excellent prognostic discriminatory power in intermediate-stage HCC patients. The ALBI-TAE model is a simple and valuable predictive tool to identify patients with good prognosis who can get the most benefit from TACE.

FAIL-T (AFP, AST, tumor sIze, ALT, and Tumor number): a model to predict intermediate-stage HCC patients who are not good candidates for TACE.

Patients with un-resectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) are a diverse group with varying overall survival (OS). Despite the availability of several scoring systems for predicting OS, one of the unsolved problems is identifying patients who might not benefit from TACE. We aim to develop and validate a model for identifying HCC patients who would survive <6 months after their first TACE. Patients with un-resectable HCC, BCLC stage 0-B, who received TACE as their first and only treatment between 2007 and 2020 were included in this study. Before the first TACE, demographic data, laboratory data, and tumor characteristics were obtained. Eligible patients were randomly allocated in a 2:1 ratio to training and validation sets. The former was used for model development using stepwise multivariate logistic regression, and the model was validated in the latter set. A total of 317 patients were included in the study (210 for the training set and 107 for the validation set). The baseline characteristics of the two sets were comparable. The final model (FAIL-T) included AFP, AST, tumor sIze, ALT, and Tumor number. The FAIL-T model yielded AUROCs of 0.855 and 0.806 for predicting 6-month mortality after TACE in the training and validation sets, respectively, while the "six-and-twelve" score showed AUROCs of 0.751 (P < 0.001) in the training set and 0.729 (P = 0.099) in the validation sets for the same purpose. The final model is useful for predicting 6-month mortality in naive HCC patients undergoing TACE. HCC patients with high FAIL-T scores may not benefit from TACE, and other treatment options, if available, should be considered.

Treatment Strategy for Intermediate-Stage Hepatocellular Carcinoma: Transarterial Chemoembolization, Systemic Therapy, and Conversion Therapy

Transarterial chemoembolization (TACE) has been standard treatment for intermediate-stage hepatocellular carcinoma (HCC). However, all intermediate-stage HCC patients did not benefit from TACE treatment because intermediate-stage HCC encompasses a wide variety of HCCs. Owing to remarkable progress in systemic therapy, including molecular-targeted therapy for advanced-stage HCC, the standard treatment of HCC has recently shifted to systemic therapy. However, it remains controversial as to which treatment should be initially performed for intermediate-stage HCC. In addition, although curative treatment can be considered when the tumor shrinks, the timing of conversion therapy remains uncertain. This review summarizes the advances of HCC treatment and discusses treatment strategies for intermediate-stage HCC.

Systemic treatment for unresectable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease. Advanced HCC has a poor prognosis. For many years, the only proven therapy for unresectable HCC (uHCC) was sorafenib, a tyrosine kinase inhibitor. Recently, the synergistic effect of an immune checkpoint inhibitor, atezolizumab, and bevacizumab outperformed sorafenib alone in terms of survival, making it the recommended first-line therapy. Other multikinase inhibitors, lenvatinib and regorafenib, were also recommended as first and second-line drugs, respectively. Intermediate-stage HCC patients with retained liver function, particularly uHCC without extrahepatic metastasis, may benefit from trans-arterial chemoembolization. The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function. Indeed, all study patients had a Child-Pugh class A, and the best therapy for other individuals is unknown. Additionally, in the absence of a medical contraindication, atezolizumab could be combined with bevacizumab for uHCC systemic therapy. Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs, and the first findings are encouraging. The paradigm of uHCC therapy is changing dramatically, and many obstacles remain for optimum patient management in the near future. The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.

Apatinib plus drug-eluting bead transarterial chemoembolization as bridging therapy to surgical resection displays an acceptable efficacy and safety profile in hepatocellular carcinoma patients.

Apatinib exhibits a synergistic effect with transarterial chemoembolization (TACE) by inhibiting TACE-induced neoangiogenic reaction in hepatocellular carcinoma (HCC) patients. But apatinib plus drug-eluting bead TACE (DEB-TACE) is rarely reported as a bridging therapy to surgery. This study aimed to evaluate the efficacy and safety of apatinib plus DEB-TACE as a bridge to surgical resection in intermediate-stage HCC patients. Thirty-one intermediate-stage HCC patients who received apatinib plus DEB-TACE as a bridging therapy to surgery were enrolled. After the bridging therapy, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and objective response rate (ORR) were evaluated; meanwhile, relapse-free survival (RFS) and overall survival (OS) were determined. After the bridging therapy, three (9.7%), twenty one (67.7%), seven (22.6%), and twenty four (77.4%) patients achieved CR, PR, SD, and ORR, respectively; besides, PD did not occur. The successful downstaging rate was 18 (58.1%). The median (95% confidence interval [CI]) accumulating RFS was 33.0 (19.6 - 46.6) months. Besides, the median (95% CI) accumulating OS was 37.0 (24.8 - 49.2) months. HCC patients with successful downstaging showed a higher accumulating RFS rate ( P = 0.038) and similar accumulating OS rate ( P = 0.073) compared to those without successful downstaging. The overall incidence of adverse events was relatively low. Besides, all the adverse events were mild and controllable. The most frequent adverse events included pain (14 [45.2%]) and fever (9 [29.0%]). Apatinib plus DEB-TACE as a bridging therapy to surgical resection displays good efficacy and safety profile in intermediate-stage HCC patients.

Clinical Effect of Lenvatinib Re-Administration after Transcatheter Arterial Chemoembolization in Patients with Intermediate Stage Hepatocellular Carcinoma.

The present study clarified the prognosis of intermediate-stage hepatocellular carcinoma (HCC) patients who received lenvatinib (LEN) followed by transcatheter arterial chemoembolization (TACE) on demand. We retrospectively evaluated 88 intermediate-stage HCC patients who received LEN. The median age was 74 (range: 47-92) years old, 67 patients were male, and 82 were classified as Child-Pugh A. LEN was administered until disease progression or discontinuation due to adverse events (AEs). The mean duration of LEN treatment was 7.0 months. The response and disease control rates were 51.1% and 89.8%, respectively. The median progression-free survival and overall survival (OS) after the initiation of LEN were 6.8 months and 29.9 months, respectively. The OS in patients for whom LEN was re-administered after TACE (TACE-LEN) was better than that in patients who received other therapies (e.g., only TACE, TACE-other therapy, or only other therapy) even with propensity score matching (p = 0.008). A Cox proportional hazard analysis showed that TACE-LEN was most strongly associated with the OS (hazard ratio: 0.083, 95% confidence interval: 0.019-0.362, p = 0.001). LEN was administered for approximately 11.1 months after TACE. In intermediate-stage HCC patients who can tolerate LEN without discontinuation due to AEs, TACE-LEN may prolong the prognosis.

Possible Use of miR-223-3p as a Prognostic Marker in Transarterial Chemoembolization Treatment of Hepatocellular Carcinoma Patients

Transcatheter chemoembolization (TACE) is the recommended therapy for intermediate stage hepatocellular carcinoma patients. Unfortunately, one of the main reasons for its failure is the emergence of multidrug resistance (MDR). Therefore, this study explored the possibility of using MDR-related miRNA as a response biomarker in HCC patients treated with doxorubicin drug-eluting bead TACE (DEB-TACE). Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to evaluate the expression level of 14 MDR-related miRNAs in doxorubicin-resistant HepG2 cells (HepG2/Dox) developed by single-dose of doxorubicin mimicking the situation of liver cells surviving TACE. The sera level of miR-223-3p, which was the most significantly downregulated in the HepG2 cells, was determined in 60 primary HCC patients undergoing TACE. Restoring miR-223-3p in HepG2/Dox cell line was achieved by its mimic transfection. Cell sensitivity was measured by SRB assay. Cell apoptosis and doxorubicin uptake were assessed by flow cytometry. The expression of miR-223-3p target protein, P-glycoprotein, was evaluated using qRT-PCR and western blotting. We detected a significant downregulation of circulating miR-223-3p in patients non-responders to TACE treatment compared with responders. The expression of miR-223-3p was markedly decreased in resistant HepG2/Dox cells compared to the parental control. In addition, the expression of miR-223-3p was found to be inversely correlated with P-glycoprotein expression thus confirming the role of miR-223-3p in MDR. Furthermore, overexpression of miR-223-3p suppressed P-glycoprotein which promoted cellular uptake of doxorubicin and increased apoptosis. Our data suggest a potential role for miR-233-3p as a prognostic as well as a therapeutic target for HCC.

Clinical-radiomics predictors to identify the suitability of transarterial chemoembolization treatment in intermediate-stage hepatocellular carcinoma: A multicenter study

BackgroundAlthough transarterial chemoembolization (TACE) is the first-line therapy for intermediate-stage hepatocellular carcinoma (HCC), it is not suitable for all patients. This study aimed to determine how to select patients who are not suitable for TACE as the first treatment choice. MethodsA total of 243 intermediate-stage HCC patients treated with TACE at three centers were retrospectively enrolled, of which 171 were used for model training and 72 for testing. Radiomics features were screened using the Spearman correlation analysis and the least absolute shrinkage and selection operator (LASSO) algorithm. Subsequently, a radiomics model was established using extreme gradient boosting (XGBoost) with 5-fold cross-validation. The Shapley additive explanations (SHAP) method was used to visualize the radiomics model. A clinical model was constructed using univariate and multivariate logistic regression. The combined model comprising the radiomics signature and clinical factors was then established. This model's performance was evaluated by discrimination, calibration, and clinical application. Generalization ability was evaluated by the testing cohort. Finally, the model was used to analyze overall and progression-free survival of different groups. ResultsA third of the patients (81/243) were unsuitable for TACE treatment. The combined model had a high degree of accuracy as it identified TACE-unsuitable cases, at a sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of 0.759, 0.885, 0.906 [95% confidence interval (CI): 0.859-0.953] in the training cohort and 0.826, 0.776, and 0.894 (95% CI: 0.815-0.972) in the testing cohort, respectively. ConclusionsThe high degree of accuracy of our clinical-radiomics model makes it clinically useful in identifying intermediate-stage HCC patients who are unsuitable for TACE treatment.

Investigating Up-to-Seven Criteria and APRI (AST Platelet Ratio) as Prognostic Factors in Intermediate-Stage Hepatocellular Carcinoma Patients Who Received Transarterial Chemoembolization.

Transarterial chemoembolization (TACE) is one of the locoregional treatments for intermediate-stage hepatocellular carcinoma (HCC). Multidetector computed tomography (MDCT) is a widely used diagnostic tool for HCC. It can also evaluate tumor size, tumor number, and tumor invasion. This study aimed to determine the median survival time in intermediate-stage HCC patients who underwent TACE and to find out prognostic factors influencing patients' survival time after TACE. A computerized search of medical record database in Maharaj Nakorn ChiangMai Hospital from January 2016 to December 2019 revealed 187 intermediate-stage HCC patients who received TACE as the first-line treatment. The median survival time of patients in this study was 9.9 months (95% CI: 8.3-11.6). The patients with aspartate aminotransferase-to-platelet ratio (APRI) less than 0.5 had a significantly better median survival time as compared with patients with APRI ratio more than 0.5; (13.2 months versus 9.9 months, p-value < 0.05). Univariate and multivariate Cox regression analysis demonstrated that tumor number > 7 and tumor size > 5 centimeters (cm) could be considered as independent parameters predicting poor overall survival time in the sufferers (HR 2.64 95%CI 1.68-4.15 and HR 2.38 95%CI 1.32-4.31, respectively). Based on our findings, patients with intermediate-stage HCC who received TACE had a lower median survival time compared to previous studies. However, we identified APRI less than 0.5, tumor size less than 5 cm, and tumor number less than 7 as prognostic factors improving survival time in intermediate-stage HCC patients.

Development and validation of a deep learning model for survival prognosis of transcatheter arterial chemoembolization in patients with intermediate-stage hepatocellular carcinoma

PurposeWe aimed to develop a deep learning-based approach to evaluate both time-to-progression (TTP) and overall survival (OS) prognosis of transcatheter arterial chemoembolization (TACE) in treatment-naïve patients with intermediate-stage hepatocellular carcinoma (HCC) and compare the approach’s performance with those of radiomics and clinical models. MethodsEfficientNetV2 was used to build a prognosis model for treatment-naïve patients with HCC. Data of 414 intermediate-stage HCC patients from one participant center were collected to construct the training and validation datasets (70%:30%) for TTP prognosis, while data of 129 intermediate-stage HCC patients from another participant center were collected as the test dataset for both TTP and OS prognosis. Three radiomics and three clinical models were then constructed for comparison. ResultsPatients with EfficientNetV2-based model score ≤ 0.5 had better TTP than those with higher scores (hazard ratio [HR]: 0.32, 95%CI: 0.22–0.46, P < 0.0001; HR: 0.28, 95%CI: 0.20–0.41, P < 0.0001; and HR: 0.55, 95%CI: 0.36–0.88, P = 0.005 in the training, validation, and test datasets, respectively). Patients with model score ≤ 0.5 had better OS (38.8 months vs 20.9 months, HR: 0.58, 95%CI: 0.37–0.90, P = 0.008). Compared with the radiomics (intra-tumoral and peri-tumoral) and three clinical models, the EfficientNetV2-based model showed better survival prognosis for TACE (P < 0.05) in the test dataset. ConclusionsThe EfficientNetV2-based model enables assessment of both TTP and OS prognosis of TACE in treatment-naïve, intermediate-stage HCC. Patients with lower scores will benefit from TACE. The model can potentially be used by clinicians to improve decision making regarding TACE treatment choices.

A Nomogram Based on Preoperative Lipiodol Deposition after Sequential Retreatment with Transarterial Chemoembolization to Predict Prognoses for Intermediate-Stage Hepatocellular Carcinoma.

(1) Background: Conventional transarterial chemoembolization (cTACE) is the mainstay treatment for patients with Barcelona Clinic Liver Cancer (BCLC) B-stage hepatocellular carcinoma (HCC). However, BCLC B-stage patients treated with cTACE represent a prognostically heterogeneous population. We aim to develop and validate a lipiodol-deposition-based nomogram for predicting the long-term survival of BCLC B-stage HCC patients after sequential cTACE. (2) Methods: In this retrospective study, 229 intermediate-stage HCC patients from two hospitals were separately allocated to a training cohort (n = 142) and a validation cohort (n = 87); these patients underwent repeated TACE (≥4 TACE sessions) between May 2010 and May 2017. Lipiodol deposition was assessed by semiautomatic volumetric measurement with multidetector computed tomography (MDCT) before cTACE and was characterized by two ordinal levels: ≤50% (low) and >50% (high). A clinical lipiodol deposition nomogram was constructed based on independent risk factors identified by univariate and multivariate Cox regression analyses, and the optimal cutoff points were obtained. Prediction models were assessed by time-dependent receiver-operating characteristic curves, calibration curves, and decision curve analysis. (3) Results: The median number of TACE sessions was five (range, 4–7) in both cohorts. Before the TACE-3 sessions, the newly constructed nomogram based on lipiodol deposition achieved desirable diagnostic performance in the training and validation cohorts with AUCs of 0.72 (95% CI, 0.69–0.74) and 0.71 (95% CI, 0.68–0.73), respectively, and demonstrated higher predictive ability compared with previously published prognostic models (all p < 0.05). The prognostic nomogram obtained good clinical usefulness in predicting the patient outcomes after TACE. (4) Conclusions: Based on each pre-TACE lipiodol deposition, two sessions are recommended before abandoning cTACE or combining treatment for patients with intermediate-stage HCC. Furthermore, the nomogram based on pre-TACE-3 lipiodol deposition can be used to predict the prognoses of patients with BCLC B-stage HCC.

Neoadjuvant transarterial chemoembolization (TACE) plus PD-1 inhibitor bridging to tumor resection in intermediate-stage hepatocellular carcinoma patients.

Programmed cell death protein 1 (PD-1) inhibitor is widely utilized in advanced-stage carcinomas including hepatocellular carcinoma (HCC), while its neoadjuvant application plus transarterial chemoembolization (TACE) in HCC remains unexplored. Thereby, the current study aimed to investigate the efficacy and safety of TACE plus PD-1 inhibitor as neoadjuvant therapy bridging to surgical resection in intermediate-stage HCC patients. Twenty intermediate-stage HCC (China Liver Cancer (CNLC) stage II) patients treated with neoadjuvant TACE plus PD-1 inhibitor (camrelizumab or sintilimab) bridging to surgery were consecutively enrolled. The objective response rate (ORR) and disease control rate (DCR) to neoadjuvant therapy were 75.0% and 100.0%, respectively; meanwhile, alpha-fetoprotein (AFP) was decreased after the neoadjuvant therapy (P < 0.001). Moreover, 14 (70.0%) patients had successful downstaging (patients converted to CNLC stage I). Neither median disease-free survival (DFS) nor median overall survival (OS) was reached; additionally, the 1-year accumulating DFS rate was 86.6%; meanwhile, the 1-year and 2-year accumulating OS rates were 100.0% and 76.4%, separately. Moreover, patients with successful downstaging had a prolonged DFS (P = 0.014) compared to patients with failed downstaging; meanwhile, this trend was also observed in assessing accumulating OS (P = 0.067) (without statistical significance). Main adverse events included pain (50.0%), fever (25.0%), neutropenia (25.0%), nausea and vomiting (25.0%), fatigue (25.0%), peripheral neuropathy (20.0%), anemia (15.0%), thrombopenia (15.0%), diarrhea (15.0%), anorexia (15.0%), and rash (15.0%). Neoadjuvant TACE plus PD-1 inhibitor realizes a satisfying downstaging rate, acceptable survival profile, and tolerance in intermediate-stage HCC patients.

Real-time automatic prediction of treatment response to transcatheter arterial chemoembolization in patients with hepatocellular carcinoma using deep learning based on digital subtraction angiography videos

BackgroundTranscatheter arterial chemoembolization (TACE) is the mainstay of therapy for intermediate-stage hepatocellular carcinoma (HCC); yet its efficacy varies between patients with the same tumor stage. Accurate prediction of TACE response remains a major concern to avoid overtreatment. Thus, we aimed to develop and validate an artificial intelligence system for real-time automatic prediction of TACE response in HCC patients based on digital subtraction angiography (DSA) videos via a deep learning approach.MethodsThis retrospective cohort study included a total of 605 patients with intermediate-stage HCC who received TACE as their initial therapy. A fully automated framework (i.e., DSA-Net) contained a U-net model for automatic tumor segmentation (Model 1) and a ResNet model for the prediction of treatment response to the first TACE (Model 2). The two models were trained in 360 patients, internally validated in 124 patients, and externally validated in 121 patients. Dice coefficient and receiver operating characteristic curves were used to evaluate the performance of Models 1 and 2, respectively.ResultsModel 1 yielded a Dice coefficient of 0.75 (95% confidence interval [CI]: 0.73–0.78) and 0.73 (95% CI: 0.71–0.75) for the internal validation and external validation cohorts, respectively. Integrating the DSA videos, segmentation results, and clinical variables (mainly demographics and liver function parameters), Model 2 predicted treatment response to first TACE with an accuracy of 78.2% (95%CI: 74.2–82.3), sensitivity of 77.6% (95%CI: 70.7–84.0), and specificity of 78.7% (95%CI: 72.9–84.1) for the internal validation cohort, and accuracy of 75.1% (95% CI: 73.1–81.7), sensitivity of 50.5% (95%CI: 40.0–61.5), and specificity of 83.5% (95%CI: 79.2–87.7) for the external validation cohort. Kaplan-Meier curves showed a significant difference in progression-free survival between the responders and non-responders divided by Model 2 (p = 0.002).ConclusionsOur multi-task deep learning framework provided a real-time effective approach for decoding DSA videos and can offer clinical-decision support for TACE treatment in intermediate-stage HCC patients in real-world settings.

Incidence of acute kidney injury and assessment of its associated risk factors in patients undergoing transarterial chemoembolisation for hepatocellular carcinoma.

To determine the incidence of acute kidney injury in intermediate stage hepatocellular carcinoma patients undergoing trans-arterial chemoembolisation, and to analyse various causative factors. The retrospective study was conducted at the Shaukat Khanum Cancer Memorial Hospital, Lahore, Pakistan,, and comprised data from January 2012 to December 2015 of adult patients of either gender with intermediate stage hepatocellular carcinoma and undergoing trans-arterial chemoembolisation with Child-Pugh score A. Outcomes were measured in the form of development of acute kidney injury, and its causative factors. Data was analysed using SPSS 20. Of the 133 patients, 90(67.6%) were male. The overall mean age of the sample was 59±8.4 years (range: 26-86 years). Of these, 19(14%) developed acute kidney injury. Higher alpha-fetoprotein levels and lower albumin levels were found to be the significant causative factors (p<0.05). The incidence of trans-arterial chemoembolisation-related acute kidney injury was 14%. Higher baseline alpha-fetoprotein and lower baseline albumin levels were found to be the significant risk factors.

GALNT14 genotype-guided chemoembolization plus sorafenib therapy in hepatocellular carcinoma: a randomized trial.

GALNT14-rs9679162 "TT" genotype is associated with favorable clinical outcomes in hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE). We investigated whether patients with GALNT14-rs9679162 "non-TT" unfavorable genotype benefited from chemoembolization plus sorafenib combination therapy. Intermediate stage HCC patients were recruited for GALNT14-rs9679162 genotyping before TACE. Patients with "TT" genotype received only TACE, labeled as TT (TACE) group. Patients with "non-TT" genotype ("GG" or "GT") were randomized to receive either TACE alone, labeled as Non-TT (TACE) group, or TACE plus sorafenib, labeled as Non-TT (TACE + Sora) group. The latter group received sorafenib 400mg daily plus TACE. From October 2015 to April 2019, 103 HCC patients scheduled to receive chemoembolization were screened. Of them, 84 met inclusion criteria and were assigned to TT (TACE) (n = 25), Non-TT (TACE) (n = 30) and Non-TT (TACE + Sora) (n = 29) groups according to their GALNT14 genotypes. Repeated TACE sessions were performed on-demand and patients were followed until November 2020. It was found that TT (TACE) and Non-TT (TACE + Sora) patients had shorter time-to-complete response compared with that in Non-TT (TACE) patients (p < 0.001 and 0.009, respectively). These two groups also had longer time-to-TACE progression (p < 0.001 and 0.006, respectively) and longer progression-free survival (p = 0.001 and 0.021, respectively). However, TT (TACE) patients harbored longer overall survival compared with those in non-TT (TACE + Sora) and non-TT (TACE) patients (p = 0.028, < 0.001, respectively). Combination of sorafenib and TACE for "non-TT" patients partially overcame the genetic disadvantage on treatment outcomes in terms of time-to-complete response, time-to-TACE progression and progression-free survival. ClinicalTrials.gov NCT02504983.

Real-life data on the impact of successful downstaging in patients with hepatocellular carcinoma: A Dutch Multicenter Study

Patients with Barcelona Clinic Liver Cancer intermediate stage hepatocellular carcinoma (HCC) theoretically are an excellent group to consider downstaging using locoregional therapy (LRT) since they do not have extrahepatic spread or vascular invasion. Once successful, this can change the treatment strategy from palliative to curative intention. Although downstaging therapy is suggested in guidelines, it is still not widely accepted. Moreover, studies on downstaging are mainly performed in high-incidence HCC countries. Therefore, our aim was to gain insight in therapeutic strategies in patients with intermediate stage HCC and their impact on intention-to-treat survival in a real-life setting in a low-incidence HCC country.We retrospectively analyzed data from the national Dutch HCC registry. From this database, consisting of 1409 patients with a diagnosis of HCC between 2005-2013 in 5 Dutch tertiary referral centers, we identified 165 patients with intermediate stage HCC. Out of these patients, 63 (38%) were not offered LRT, whereas 102 (62%) did receive LRT. Subsequently, 50 (49%) of the 102 patients who received LRT were successfully downstaged. Eleven patients (22% of successfully downstaged patients) eventually underwent liver transplantation. Cox regression analysis showed that a lower MELD score, an AFP value <100 ng/ml, successful downstaging and liver transplantation (all ≤p = 0.01) were positively associated to overall survival.In conclusion, our results demonstrate that LRT is not routinely offered to intermediate stage HCC patients in the Netherlands. Nevertheless, we showed that patients with intermediate stage HCC who are successfully downstaged have a survival benefit compared to those who were not.

Simple Scoring System for Predicting TACE Unsuitable among Intermediate-Stage Hepatocellular Carcinoma Patients in the Multiple Systemic Treatment Era

Background/Aim: With the development of systemic treatment methods for unresectable hepatocellular carcinoma (uHCC), the concept of unsuitable for transcatheter arterial chemoembolization (TACE) has become important. This study aimed to establish a simple predictive scoring system for determining TACE unsuitable status. Materials/Methods: From 1998 to 2015, 196 patients with intermediate-stage uHCC with Child-Pugh A (score 5:6 = 108:88) and given TACE as the initial treatment were enrolled. At the baseline, tumor burden (Milan criteria-out, up-to-7 in/out, and up-to-11 in/out: 0–2 points) and modified albumin-bilirubin grade 1/2a or 2b (0–1 point) were added to determine the score for TACE unsuitable (CITRUS-MICAN score; low <2 and high ≥2). In addition, a previously reported tumor marker (TM) score, in which alpha-fetoprotein (AFP) was ≥100 ng/mL, fucosylated AFP ≥10%, and des-gamma-carboxy prothrombin ≥100 mAU/mL (each 1 point) (total 0, 1, or ≥2 points), was used for additionally evaluating tumor malignancy potential. Prognosis was retrospectively evaluated based on those scores. Results: Median survival time (MST) was better for low compared to high CITRUS-MICAN score (42.0 vs. 26.4 months) (p = 0.002). A 2-step evaluation using the combination of CITRUS-MICAN and TM scores showed an MST of 43.2 months for low CITRUS-MICAN/TM score 0/1 (rank-A) and 39.6 months for low CITRUS-MICAN/TM score ≥2 (rank-B2), while it was 46.8 months for high CITRUS-MICAN/TM score 0 (rank-B1), 28.8 months for high CITRUS-MICAN/TM score 1 (rank-B2), and 22.8 months for high CITRUS-MICAN/TM score ≥2 (rank-C). For rank-A cases (n = 51), MST was 43.2 months, while it was 46.8 months for rank-B1 (n = 12), 31.2 months for rank-B2 (n = 82), and 22.8 months for rank-C (n = 51) (p = 0.001). Conclusion: The results showed that rank-C indicates absolute TACE unsuitable status. For rank-A patients, good prognosis with TACE can be expected, while TACE refractoriness status during the clinical course should be carefully evaluated so as to anticipate the appropriate timing for switching to systemic treatment in rank-B1 and -B2 patients.