Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ.

Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active.

Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma.

Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.

microRNA-2117 Negatively Regulates Liver Cancer Stem Cells Expansion and Chemoresistance Via Targeting SOX2.

Cancer stem cells (CSCs) are involved in the regulation of tumor initiation, progression, recurrence, and chemoresistance. However, the role of microRNAs (miRNAs) in liver CSCs has not been fully understood. Here we show that miR-2117 is downregulated in liver CSCs and predicts the poor prognosis of hepatocellular carcinoma (HCC) patients. Biofunction studies found that knockdown miR-2117 facilitates liver CSCs self-renewal and tumorigenesis. Conversely, forced miR-2117 expression suppresses liver CSCs self-renewal and tumorigenesis. Mechanistically, we find that transcription factor SOX2 is required for miR-2117-mediated liver CSCs expansion. The correlation between miR-2117 and SOX2 was confirmed in human HCC tissues. More importantly, miR-2117 overexpression HCC cells are more sensitive to CDDP treatment. Analysis of patients' cohort further demonstrates that miR-2117 may predict transcatheter arterial chemoembolization benefits in HCC patients. Our findings revealed the crucial role of miR-2117 in liver CSCs expansion, rendering miR-2117 as an optimal therapeutic target for HCC.

Elevated SLC1A5 associated with poor prognosis and therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor, and glutamine is vital for tumor cells. The role of glutamine transporter SLC1A5 in tumor progression and transarterial chemoembolization (TACE) efficacy is under study. This research seeks to determine the impact of SLC1A5 expression on the prognosis and TACE efficacy of HCC and elucidate its mechanisms. METHODS: SLC1A5 expression in HCC, correlation with patient outcomes, and response to TACE were studied in an open access liver cancer dataset and confirmed in our cohort. Additionally, the correlation between SLC1A5 expression and hypoxia, angiogenesis and immune infiltration was analyzed and verified by immunohistochemistry, immunofluorescence and transcriptome sequencing. Liver cancer cell lines with SLC1A5 expression knockdown or overexpression were constructed, and cell proliferation, colony formation, apoptosis, migration and drug sensitivity as well as in vivo xenograft tumor were measured. A gene set enrichment analysis was conducted to determine the signaling pathway influenced by SLC1A5, and a western blot analysis was performed to detect protein expression alterations. RESULTS: SLC1A5 expression was higher in HCC tissue and associated with poor survival and TACE resistance. Hypoxia could stimulate the upregulation of glutamine transport, angiogenesis and SLC1A5 expression. The SLC1A5 expression was positively correlated with hypoxia and angiogenesis-related genes, immune checkpoint pathways, macrophage, Tregs, and other immunosuppressive cells infiltration. Knockdown of SLC1A5 decreased proliferation, colony formation, and migration, but increased apoptosis and increased sensitivity to chemotherapy drugs. Downregulation of SLC1A5 resulted in a decrease in Vimentin and N-cadherin expression, yet an increase in E-cadherin expression. Upregulation of SLC1A5 increased Vimentin and N-cadherin expression, while decreasing E-cadherin. Overexpression of ß-catenin in SLC1A5-knockdown HCC cell lines could augment Vimentin and N-cadherin expression, suppress E-cadherin expression, and increase the migration and drug resistance. CONCLUSIONS: Elevated SLC1A5 was linked to TACE resistance and survival shortening in HCC patients. SLC1A5 was positively correlated with hypoxia, angiogenesis, and immunosuppression. SLC1A5 may mediate HCC cell migration and drug resistance via Epithelial-mesenchymal transition (EMT) pathway.

Survival benefit of adjuvant TACE for patients with hepatocellular carcinoma and child-pugh B7 or B8 after hepatectomy.

BACKGROUND & AIMS: The benefit of postoperative adjuvant transcatheter arterial chemoembolization (pTACE) for patients with hepatocellular carcinoma (HCC), especially those with Child-Pugh (CP) B, remains controversial. This study aimed to assess the survival benefit of pTACE for HCC patients with CP B. METHODS: Data from 297 HCC patients with CP B7 or B8 were analyzed, dividing them into groups with and without pTACE (70, 23.6% vs. 227, 76.4%). Propensity score matching (PSM) was used to control for confounding bias, and competing-risk regression was applied to address bias from non-cancer-specific death (NCSD). RESULTS: Preliminary findings suggest that pTACE did not increase the incidence of severe complications in HCC patients with CP B7 or B8. Survival analysis indicated that the group receiving pTACE had better overall survival and recurrence-free survival than the group without pTACE after PSM. Furthermore, competitive risk analysis revealed that pTACE was an independent prognostic factor associated with reduced cancer-specific death incidence (subdistribution hazard ratio [SHR] 0.644, 95%CI: 0.378-0.784, P = 0.011) and recurrence (SHR 0.635, 95% CI: 0.379-0.855, P = 0.001). Importantly, pTACE did not increase NCSD. Subgroup analysis corroborated these results. CONCLUSION: Adjuvant TACE demonstrates the potential to significantly enhance the long-term prognosis of HCC patients with CP B7 or B8 following hepatectomy, particularly those with multiple tumors, large tumor size, macrovascular or microvascular invasion, and narrow resection margin. Hence, pTACE should be considered for patients at high risk of recurrence following thorough evaluation.

Construction of a prognostic model for hepatocellular carcinoma patients receiving transarterial chemoembolization treatment based on the Tumor Burden Score.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) who undergo transarterial chemoembolization (TACE) may have varied outcomes based on their liver function and tumor burden diversity. This study aims to assess the prognostic significance of the tumor burden score (TBS) in these patients and develop a prognostic model for their overall survival. METHODS: The study involved a retrospective analysis of 644 newly diagnosed HCC patients undergoing TACE treatment. The individuals were assigned randomly to a training cohort (n = 452) and a validation cohort (n = 192). We utilized a multivariate Cox proportional risk model to identify independent preoperative predictive factors. We then evaluated model performance using the area under the curve (AUC), consistency index (c-index), calibration curve, and decision curve analysis (DCA) methods. RESULTS: The multivariate analysis revealed four prognostic factors associated with overall survival: Tumor Burden Score, Tumor Extent, Types of portal vein invasion (PVI), and Child-Pugh score. The total score was calculated based on these factors. The model demonstrated strong discriminative ability with high AUC values and c-index, providing high net clinical benefits for patients. Based on the model's scoring results, patients were categorized into high, medium, and low-risk groups. These results were validated in the validation cohort. CONCLUSIONS: The tumor burden score shows promise as a viable alternative prognostic indicator for assessing tumor burden in cases of HCC. The new prognostic model can place patients in one of three groups, which will estimate their individual outcomes. For high-risk patients, it is suggested to consider alternative treatment options or provide the best supportive care, as they may not benefit significantly from TACE treatment.

Liver abscess after drug-eluting bead transarterial chemoembolization for hepatic malignant tumors: Clinical features, pathogenesis, and management.

AIM: The study aimed to investigate the clinical features, incidence, pathogenesis, and management of liver abscess after drug-eluting bead transarterial chemoembolization (DEB-TACE) for primary and metastatic hepatic malignant tumors. METHODS: From June 2019 to June 2021, patients with liver abscess after DEB-TACE for primary and metastatic hepatic malignant tumors were reviewed and evaluated at our hospital. Demographic and clinical data, radiological findings, management approaches, and prognosis were retrospectively analyzed. RESULTS: In total, 419 DEB-TACE procedures were carried out in 314 patients with primary and metastatic liver tumors at our medical center. Twelve patients were confirmed to have liver abscesses after DEB-TACE through clinical manifestations, laboratory investigations, and imaging. In this study, the incidence of liver abscess was 3.82% per patient and 2.86% per DEB-TACE procedure. After percutaneous drainage and anti-inflammatory treatments, 10 patients recovered, and the remaining 2 patients died due to direct complications of liver abscess, such as sepsis and multiple organ failure. The mortality rate of liver abscesses after DEB-TACE was 16.7% (2/12). CONCLUSION: The incidence of liver abscess after DEB-TACE is relatively high and can have serious consequences, including death. Potential risk factors could include large tumor size, history of bile duct or tumor resection, history of diabetes, small DEB size (100-300 µm). Sensitive antibiotics therapy and percutaneous abscess aspiration/drainage are effective treatments for liver abscess after DEB-TACE.

AFP-DIAM Score to Predict Survival in Patients with Hepatocellular Carcinoma Before TACE: A French Multicenter Study.

BACKGROUND: Transarterial chemoembolization (TACE) is recommended as a palliative treatment for patients of the B stage of the Barcelona Clinic Liver Cancer (BCLC) classification. AIMS: To identify clinical, biological, and radiological predictors of survival in patients undergoing TACE and develop a pre-therapeutic prognostic score. METHODS: 191 adult cirrhotic patients treated for HCC with TACE at the University Hospital (UH) of Clermont-Ferrand (France) from 2007-2017 were retrospectively included. We investigated the impact of baseline liver function, patient characteristics, and tumor burden on overall survival and developed a prognostic score. RESULTS: Patients had a median age of 66 years and 126 patients were Child A. The AFP-DIAM score distinguishes two groups with a significant difference in survival time (median OS 28.3 months in patients with a score = 0 versus 17.7 months in patients with a score > 0). AFP-DIAM was validated on an external cohort, is well calibrated, and has the best discrimination capacity (C-index) as compared to NIACE, HAP, STATE, and SIX TO TWELVE. AFP-DIAM and SIX TO TWELVE are the more easy-to-use scores. When AFP-DIAM and the SIX TO TWELVE scores were tested in the same statistical model, results confirmed a better AFP-DIAM performance. CONCLUSIONS: The AFP-DIAM is an easy-to-use score which allows to distinguish two groups with different prognosis before the first TACE session. Its use could provide further support to BCLC system to guide the therapeutic strategy of patients with HCC.

Abnormal expression of serum miR-4746-5p in liver cancer patients after interventional chemotherapy and its possible mechanism.

Interventional chemotherapy is a common operation in the clinical treatment of liver cancer. The aim of this study was to investigate the expression and molecular mechanism of serum miR-4746-5p in liver cancer patients before and after interventional chemotherapy. The levels of miR-4746-5p and CDKN1C in serum samples from liver cancer patients were detected using real-time fluorescence quantitative polymerase chain reaction. Receiver operating characteristic curves revealed the diagnostic value of miR-4746-5p in tumors. Differences in clinical indicators between liver cancer patients and healthy controls were assessed using Pearson correlation analysis. Luciferase reporter gene assays confirmed the targeted interaction between miR-4746-5p and CDKN1C. In vitro cellular assays were validated by Cell Counting Kit-8, Transwell assay, and chemoresistance assay. Serum miR-4746-5p levels were increased in liver cancer patients but were downregulated after chemotherapy intervention. CDKN1C expression showed the opposite trend. Low levels of miR-4746-5p mediated cell growth and metastasis by targeting and negatively regulating CDKN1C expression, while silencing CDKN1C restored cell activity. Inhibition of miR-4746-5p reduced chemoresistance, while downregulation of CDKN1C affected cell sensitivity. miR-4746-5p may be a potential therapeutic factor for liver cancer diagnosis and interventional chemotherapy.

Plasma metabolomic analysis of human hepatocellular carcinoma before and after transcatheter arterial chemoembolization.

Introduction: Hepatocellular carcinoma (HCC) is the fourth most prevalent cancer in China. Transcatheter arterial chemoembolization (TACE) is a common interventional therapy for HCC. In this study, we aimed to explore specific metabolites that can accurately predict prognosis after TACE in patients with HCC. Methods: Patients with HCC and healthy volunteers (n = 20 each) were recruited to our study; plasma samples were collected from patients before and after TACE and from healthy volunteers. Plasma samples were subjected to untargeted ultra-high performance liquid chromatography-high resolution mass spectrometry metabolomics analysis, to identify metabolites significantly associated with the prognosis of patients with HCC after TACE. Results: Orthogonal filtered partial least squares discriminant analysis confirmed significant separation of the pre-TACE, post-TACE, and healthy groups, and 34 differential metabolites were identified between the pre-TACE and post-TACE groups. KEGG analysis revealed that phenylalanine, tyrosine, and tryptophan biosynthesis pathways and the phenylalanine metabolism pathway were potentially altered in HCC genesis and during TACE. Phenylalanine and tyrosine are involved in both pathways and were increased in the pre-TACE group relative to controls, with phenylalanine further increased in the post-TACE group. Receiver operating characteristic (ROC) curve analysis indicated that PC 36:4|PC 18:2_18:2 (area under the ROC curve (AUC) = 0.798) is a potential marker for assessment of prognosis in patients with HCC after TACE. Moreover, ROC curve analysis indicated that palmitoylcarnitine (AUC = 1) is a marker with potential value for HCC diagnosis. Conclusions: Limited studies had been conducted on the detection of metabolites in the plasma of HCC patients before and after TACE. PC 36:4|PC 18:2_18:2 is a potential marker for evaluation of the therapeutic effects of TACE. This finding may be beneficial for the treatment of patients with HCC after TACE.

Detection of hepatocellular carcinoma feeding vessels: MDCT angiography with 3D reconstruction versus digital subtraction angiography.

BACKGROUND: Accurate detection of Hepatocellular carcinoma (HCC) feeding vessels during transcatheter arterial chemoembolization (TACE) is important for an effective treatment, while limiting non-target embolization. This study aimed to investigate the feasibility and accuracy of pre-TACE three dimensional (3D) CT angiography for tumor-feeding vessels detection compared to DSA. METHODS: Sixty-nine consecutive patients referred for TACE from May 2022 to May 2023 were included. (3D) CT images were reconstructed from the pre-TACE diagnostic multiphasic contrast enhanced CT images and compared with non-selective digital subtraction angiography (DSA) images obtained during TACE for detection of HCC feeding vessels. A "Ground truth" made by consensus between observers after reviewing all available pre-TACE CT images, and DSA and CBCT images during TACE to detect the true feeding vessels was the gold standard. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), accuracy and ROC curve with AUC were calculated for each modality and compared. RESULTS: A total of 136 active HCCs were detected in the 69 consecutive patients included in the study. 185 feeding arteries were detected by 3D CT and DSA and included in the analysis. 3D CT detection of feeding arteries revealed mean sensitivity, specificity, PPV, NPV and accuracy of 91%, 71%, 98%, 36%, and 90%, respectively, with mean AUC = 0.81. DSA detection of feeding arteries revealed mean sensitivity, specificity, PPV, NPV, and accuracy of 80%, 58%, 96.5%, 16.5% and 78%, respectively, with mean AUC = 0.69. CONCLUSIONS: Pre-TACE 3D CT angiography has shown promise in improving the detection of HCC feeding vessels compared to DSA. However, further studies are required to confirm these findings across different clinical settings and patient populations. TRIAL REGISTRATION: This study was prospectively registered at Clinicaltrials.gov with ID NCT05304572; Date of registration: 2-4-2022.

Clinical evaluation of oxaliplatin-loaded drug-eluting callispheres beads transarterial chemoembolization for unresectable or recurrent esophageal carcinoma.

BACKGROUND: A majority of esophageal carcinoma patients are diagnosed at an advanced stage and are no longer suitable for surgical resection. Drug-eluting beads transarterial chemoembolization (DEB-TACE) with oxaliplatin-loaded CalliSpheres beads (CB) have been used for advanced hepatocellular carcinoma and lung cancer, but they have not been reported for the treatment of unresectable or recurrent esophageal carcinoma. METHODS: DEB-TACE was performed on 22 patients with unresectable or recurrent esophageal carcinoma between March 2019 and May 2022. The clinical outcomes, complications, and efficacy were retrospectively recorded and analyzed. RESULTS: A total of 39 sessions of DEB-TACE were performed in 22 patients, with a technical success rate of 92.3% and clinical success rate of 65.0%. No severe complications such as procedure-related death, esophageal rupture or paraplegia were observed. Complete response, partial response, and stable disease were observed in 14.3% (2/14), 42.9% (6/14), and 21.4% (3/14) of patients 6 months after DEB-TACE, respectively. The objective response rates were 62.5%, 42.9% and 57.1% respectively at 1-, 3-, and 6-month after DEB-TACE. Subsequent interventional treatments were administered to 12 patients, including DEB-TACE for hepatic metastasis in 3 (13.6%), esophageal stenting in 5 (22.7%), and airway stent placement in 5 (22.7%). Two patients were lost to follow up. A total of 9 patients died due to tumor progression (n = 5), pneumatic infection (n = 1), and tumor-related massive esophageal hemorrhage (n = 3). The median overall survivals were 13.9 months and 26.5 months from the first session of DEB-TACE and the diagnosis of esophageal carcinoma, respectively. CONCLUSIONS: DEB-TACE with oxaliplatin-loaded CB is suggested as a safe and effective treatment of unresectable or recurrent esophageal carcinoma, and more studies are required to confirm its efficacy and safety.

Systemic chemotherapy plus transarterial chemoembolization versus systemic chemotherapy alone for unresectable intrahepatic cholangiocarcinoma: a multicenter retrospective cohort study.

PURPOSE: Systemic chemotherapy (SYS) is the first-line treatment of unresectable intrahepatic cholangiocarcinoma (ICC). However, the survival benefit of SYS is still limited. This study compared the efficacy and safety of patients with unresectable ICC treated with transarterial chemoembolization (TACE) plus SYS to SYS alone. MATERIAL AND METHODS: The multicenter retrospective cohort study included patients aged ≥ 18 years old with pathologically diagnosed ICC. Patients with unmeasurable lesions, not receiving SYS treatment, Child-Pugh grade C, Eastern Cooperative Oncology Group performance status score of 3 or higher, prior liver resection, incomplete medical information, or discontinuation of the first SYS treatment were excluded. Data collection was mainly from the hospital system, and the survival outcome of patients was obtained through follow-up. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Propensity score matching at a 1:1 ratio using the nearest neighbor matching algorithm was performed to reduce selection bias between the TACE plus SYS and SYS alone groups. The Cox proportional hazards model was used to identify prognostic factors associated with OS and to estimate their hazard ratios. Modified Response Evaluation Criteria in Solid Tumors criteria were utilized to evaluate the response of tumors to therapy. RESULTS: Between June 2016 and February 2023, 118 unresectable ICC patients from three hospitals were included in this study. Of them, 37 were in the TACE plus SYS group and 81 were in the SYS alone group. The median OS in the combination group was 11.3 months, longer than the 6.4 months in the SYS alone group (P = 0.011). A greater objective response rate (ORR) and disease control rate (DCR) were observed in the combination group than in the SYS alone group (ORR, 48.65 vs. 6.17%, P < 0.001; DCR, 89.19 vs. 62.96%, P = 0.004). There were 16 patients in each group after matching, and the matched results remained consistent regarding OS and tumor response. Adverse events (AEs) were similar in the two groups after matching. CONCLUSION: Compared to SYS alone, the combination treatment of TACE plus SYS was more effective than SYS alone in improving OS, ORR, and DCR without any significant increase in AEs. TACE plus SYS may be a viable treatment option for patients with unresectable ICC.

Two-dimensional perfusion angiography permits direct visualization of redistribution of flow in hepatocellular carcinoma during b-TACE.

OBJECTIVES: To demonstrate in vivo redistribution of the blood flow towards HCC's lesions by utilizing two-dimensional perfusion angiography in b-TACE procedures. MATERIAL AND METHODS: In total, 30 patients with 35 HCC nodules treated in the period between January 2019 and November 2021. For each patient, a post-processing software leading to a two-dimensional perfusion angiography was applied on each angiography performed via balloon microcatheter, before and after inflation. On the colour map obtained, reflecting the evolution of contrast intensity change over time, five regions of interests (ROIs) were assessed: one on the tumour (ROI-t), two in the immediate peritumoural healthy liver parenchyma (ROI-ihl) and two in the peripheral healthy liver parenchyma (ROI-phl). The results have been interpreted with a novel in silico model that simulates the hemodynamics of the hepatic arterial system. RESULTS: Among the ROIs drawn inside the same segment of target lesion, the time-to-peak of the ROI-t and of the ROI-ihl have a significantly higher mean value when the balloon was inflated compared with the ROIs obtained with deflated balloon (10.33 ± 3.66 s vs 8.87 ± 2.60 s (p = 0.015) for ROI-t; 10.50 ± 3.65 s vs 9.23 ± 2.70 s (p = 0.047) for ROI-ihl). The in silico model prediction time-to-peak delays when balloon was inflated, match with those observed in vivo. The numerical flow analysis shows how time-to-peak delays are caused by the obstruction of the balloon-occluded artery and the opening of intra-hepatic collateral. CONCLUSION: The measurements identify predictively the flow redistribution in the hepatic arteries during b-TACE, supporting a proper positioning of the balloon microcatheter.

A multi-institutional study to predict the benefits of DEB-TACE and molecular targeted agent sequential therapy in unresectable hepatocellular carcinoma using a radiological-clinical nomogram.

OBJECTIVE: Exploring the efficacy of a Radiological-Clinical (Rad-Clinical) model in predicting prognosis of unresectable hepatocellular carcinoma (HCC) patients after drug eluting beads transcatheter arterial chemoembolization (DEB-TACE) to optimize the targeted sequential treatment. METHODS: In this retrospective analysis, we included 202 patients with unresectable HCC who received DEB-TACE treatment in 17 institutions from June 2018 to December 2022. Progression-free survival (PFS)-related radiomics features were computationally extracted from HCC patients to build a radiological signature (Rad-signature) model with least absolute shrinkage and selection operator regression. A Rad-Clinical model for postoperative PFS was further constructed according to the Rad-signature and clinical variables by Cox regression analysis. It was presented as a nomogram and evaluated by receiver operating characteristic curves, calibration curves, and decision curve analysis. And further evaluate the application value of Rad-Clinical model in clinical stages and targeted sequential therapy of HCC. RESULTS: Tumor size, Barcelona Clinic Liver Cancer (BCLC) stage, and radiomics score (Rad-score) were found to be independent risk factors for PFS after DEB-TACE treatment for unresectable HCC, with the Rad-Clinical model being the greatest predictor of PFS in these patients (hazard ratio: 2.08; 95% confidence interval: 1.56-2.78; P < 0.001) along with high 6 months, 12 months, 18 months, and 24 months area under the curves of 0.857, 0.810, 0.843, and 0.838, respectively. In addition, compared to the radiomics and clinical nomograms, the Radiological-Clinical nomogram also significantly improved the classification accuracy for PFS outcomes, based on the net reclassification improvement (45.2%, 95% CI 0.260-0.632, p < 0.05) and integrated discrimination improvement (14.9%, 95% CI 0.064-0.281, p < 0.05). Based on this model, low-risk patients had higher PFS than high-risk patients in BCLC-B and C stages (P = 0.021). Targeted sequential therapy for patients with high and low-risk HCC in BCLC-B stage exhibited significant benefits (P = 0.018, P = 0.012), but patients with high-risk HCC in BCLC-C stage did not benefit much (P = 0.052). CONCLUSION: The Rad-Clinical model may be favorable for predicting PFS in patients with unresectable HCC treated with DEB-TACE and for identifying patients who may benefit from targeted sequential therapy.

Percutaneous thermal segmentectomy for liver malignancies over 3 cm: mid-term oncological performance and predictors of sustained complete response from a multicentric Italian retrospective study.

INTRODUCTION: Percutaneous thermal segmentectomy is a single-step combination of microwave ablation, performed during arterial occlusion obtained with a balloon micro catheter, followed in the same session by balloon-occluded TACE. The aim of this multicenter retrospective study is to report the mid-term oncological performance of this technique for liver malignancies > 3.0 cm and to identify risk factors for the loss of sustained complete response. METHODS: Oncological results were evaluated with CT or MRI according to m-RECIST (HCC) and RECISTv1.1 (metastasis/intra-hepatic cholangiocarcinoma, iCC) at 1-month, 3-6-month and then at regular-6-month intervals. To identify predictive variables associated with not achieving or losing complete response two mixed-effects multivariable logistic regression models were constructed. RESULTS: Sixty-three patients (40/23, male/female) with primary liver malignancies (HCC = 49; iCC = 4) and metastasis (n = 10) were treated. Median diameter of target lesion was 4.5 cm (range 3.0-7.0 cm). The median follow-up time was 9.2 months. At one-month follow-up, 79.4% of patients presented with a complete response and the remaining 20.6% were partial responders. At the 3-6-month follow-up, reached by 59 of the initial 63 patients, 83.3% showed a sustained complete response, while 10.2% had a partial response and 8.5% a local recurrence. At the last follow-up, 69.8% of the lesions showed a complete response. The initial diameter of the target lesion ≥ 5.0 cm was the only independent variable associated with the risk of failure in maintaining a complete response at 6 months (OR = 8.58, 95% CI 1.38-53.43; P = 0.02). CONCLUSION: Percutaneous thermal segmentectomy achieves promising oncological results in patients with tumors > 3.0 cm, with tumor dimension ≥ 5.0 cm being the only risk factor associated with the failure of a sustained complete response.

Radiomics as a tool for prognostic prediction in transarterial chemoembolization for hepatocellular carcinoma: a systematic review and meta-analysis.

INTRODUCTION: Transarterial chemoembolization (TACE) is one of the predominant locoregional therapeutic modalities for addressing hepatocellular carcinoma (HCC). However, achieving precise prognostic predictions and effective patient selection remains a challenging pursuit. The primary objective of this systematic review and meta-analysis is to evaluate the efficacy of radiomics in forecasting the prognosis associated with TACE treatment. METHODS: A comprehensive exploration of pertinent original studies was undertaken, encompassing databases of PubMed, Web of Science and Embase. The studies' quality was meticulously evaluated employing the quality assessment of diagnostic accuracy studies 2 (QUADAS-2), the radiomics quality score (RQS) and the METhodological RadiomICs Score (METRICS). Pooled statistics, along with 95% confidence intervals (95% CI), were computed for sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR). Additionally, a summary receiver operating characteristic curve (sROC) was generated. To discern potential sources of heterogeneity, meta-regression and subgroup analyses were performed. RESULTS: The systematic review incorporated 29 studies, comprising a total of 5483 patients, with 14 studies involving 2691 patients qualifying for inclusion in the meta-analysis. The assessed studies exhibited commendable quality with regard to bias risk, with mean RQS of 12.90 ± 5.13 (35.82% ± 14.25%) and mean METRICS of 62.98% ± 14.58%. The pooled sensitivity was 0.83 (95% CI: 0.78-0.87), specificity was 0.86 (95% CI: 0.79-0.92), PLR was 6.13 (95% CI: 3.79-9.90), and NLR was 0.20 (95% CI: 0.15-0.27). The area under the sROC was 0.90 (95% CI: 0.87-0.93). Significant heterogeneity within all the included studies was observed, while meta-regression and subgroup analyses revealed homogeneous and promising findings in subgroups where principal methodological variables such as modeling algorithms, imaging modalities, and imaging phases were specified. CONCLUSION: Radiomics models have exhibited robust predictive capabilities concerning prognosis subsequent to TACE, thereby presenting promising prospects for clinical translation.

Combined transarterial chemoembolization and thermal ablation in candidates to liver transplantation with hepatocellular carcinoma: pathological findings and post-transplant outcome.

OBJECTIVES: Evaluating the pathological response and the survival outcomes of combined thermal ablation (TA) and transarterial chemoembolization (TACE) as a bridge or downstaging for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) > 3 cm. MATERIALS AND METHODS: A retrospective review encompassed 36 consecutive patients who underwent combined TA-TACE as bridging or downstaging before LT. Primary objectives included necrosis of the target lesion at explant pathology, post-LT overall survival (OS) and post-LT recurrence-free survival (RFS). For OS and RFS, a comparison with 170 patients subjected to TA alone for nodules <3 cm in size was also made. RESULTS: Out of the 36 patients, 63.9% underwent TA-TACE as bridging, while 36.1% required downstaging. The average node size was 4.25 cm. All cases were discussed in a multidisciplinary tumor board to assess the best treatment for each patient. Half received radiofrequency (RF), and the other half underwent microwave (MW). All nodes underwent drug-eluting beads (DEB) TACE with epirubicin. The mean necrosis percentage was 65.9% in the RF+TACE group and 83.3% in the MW+TACE group (p-value = 0.099). OS was 100% at 1 year, 100% at 3 years and 94.7% at 5 years. RFS was 97.2% at 1 year, 94.4% at 3 years and 90% at 5 years. Despite the different sizes of the lesions, OS and RFS did not show significant differences with the cohort of patients subjected to TA alone. CONCLUSIONS: The study highlights the effectiveness of combined TA-TACE for HCC>3 cm, particularly for bridging and downstaging to LT, achieving OS and RFS rates significantly exceeding 80% at 1, 3 and 5 years.

Natural Killer Cells Reprogram Myeloid-Derived Suppressor Cells to Induce TNF-α Release via NKG2D-Ligand Interaction after Cryo-Thermal Therapy.

In our previous studies, a novel cryothermal therapy (CTT) was developed to induce systemic long-term anti-tumor immunity. Natural killer (NK) cells were found to play an important role in CTT-induced long-term immune-mediated tumor control at the late stage after CTT, but the underlying mechanism is unclear. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that have potent immunosuppressive effects on T cells and weaken the long-term benefits of immunotherapy. Consequently, overcoming MDSC immunosuppression is essential for maintaining the long-term efficacy of immunotherapy. In this study, we revealed that NK cells considerably diminish MDSC accumulation at the late stage after CTT, boost T cell production, increase T cell activation, and promote MDSC maturation, culminating in Th1-dominant CD4+ T cell differentiation and enhancing NK and CD8+ T cell cytotoxicity. Additionally, NK cells activate ERK signaling in MDSCs through NKG2D-ligand interaction to increase the activity of tumor necrosis factor (TNF)-α converting enzyme (TACE)-cleaved membrane TNF-α. Furthermore, Increased TACE activity releases more soluble TNF-α from MDSCs to promote MDSC maturation. In our studies, we propose a novel mechanism by which NK cells can overcome MDSC-induced immunosuppression and maintain CTT-induced persistent anti-tumor immunity, providing a prospective therapeutic option to improve the performance of cancer immunotherapy.

Biodegradable Microspheres for Transarterial Chemoembolization in Malignant Liver Disease.

Transarterial chemoembolization (TACE) has revolutionized the treatment landscape for malignant liver disease, offering localized therapy with reduced systemic toxicity. This manuscript delves into the use of degradable microspheres (DMS) in TACE, exploring its potential advantages and clinical applications. DMS-TACE emerges as a promising strategy, offering temporary vessel occlusion and optimized drug delivery. The manuscript reviews the existing literature on DMS-TACE, emphasizing its tolerability, toxicity, and efficacy. Notably, DMS-TACE demonstrates versatility in patient selection, being suitable for both intermediate and advanced stages. The unique properties of DMS provide advantages over traditional embolic agents. The manuscript discusses the DMS-TACE procedure, adverse events, and tumor response rates in HCC, ICC, and metastases.