A two-step strategy to expand primary human hepatocytes in vitro with efficient metabolic and regenerative capacities.

BACKGROUND: Primary human hepatocytes (PHHs) are highly valuable for drug-metabolism evaluation, liver disease modeling and hepatocyte transplantation. However, their availability is significantly restricted due to limited donor sources, alongside their constrained proliferation capabilities and reduced functionality when cultured in vitro. To address this challenge, we aimed to develop a novel method to efficiently expand PHHs in vitro without a loss of function. METHODS: By mimicking the in vivo liver regeneration route, we developed a two-step strategy involving the de-differentiation/expansion and subsequent maturation of PHHs to generate abundant functional hepatocytes in vitro. Initially, we applied SiPer, a prediction algorithm, to identify candidate small molecules capable of activating liver regenerative transcription factors, thereby formulating a novel hepatic expansion medium to de-differentiate PHHs into proliferative human hepatic progenitor-like cells (ProHPLCs). These ProHPLCs were then re-differentiated into functionally mature hepatocytes using a new hepatocyte maturation condition. Additionally, we investigated the underlying mechanism of PHHs expansion under our new conditions. RESULTS: The novel hepatic expansion medium containing hydrocortisone facilitated the de-differentiation of PHHs into ProHPLCs, which exhibited key hepatic progenitor characteristics and demonstrated a marked increase in proliferation capacity compared to cells cultivated in previously established expansion conditions. Remarkably, these subsequent matured hepatocytes rivaled PHHs in terms of transcriptome profiles, drug metabolizing activities and in vivo engraftment capabilities. Importantly, our findings suggest that the enhanced expansion of PHHs by hydrocortisone may be mediated through the PPARα signaling pathway and regenerative transcription factors. CONCLUSIONS: This study presents a two-step strategy that initially induces PHHs into a proliferative state (ProHPLCs) to ensure sufficient cell quantity, followed by the maturation of ProHPLCs into fully functional hepatocytes to guarantee optimal cell quality. This approach offers a promising means of producing large numbers of seeding cells for hepatocyte-based applications.

6-Phosphogluconate dehydrogenase promotes glycolysis and fatty acid synthesis by inhibiting the AMPK pathway in lung adenocarcinoma cells.

Abnormal metabolism has emerged as a prominent hallmark of cancer and plays a pivotal role in carcinogenesis and progression of lung adenocarcinoma (LUAD). In this study, single-cell sequencing revealed that the metabolic enzyme 6-phosphogluconate dehydrogenase (PGD), which is a critical regulator of the pentose phosphate pathway (PPP), is significantly upregulated in the malignant epithelial cell subpopulation during malignant progression. However, the precise functional significance of PGD in LUAD and its underlying mechanisms remain elusive. Through the integration of TCGA database analysis and LUAD tissue microarray data, it was found that PGD expression was significantly upregulated in LUAD and closely correlated with a poor prognosis in LUAD patients. Moreover, in vitro and in vivo analyses demonstrated that PGD knockout and inhibition of its activity mitigated the proliferation, migration, and invasion of LUAD cells. Mechanistically, immunoprecipitation-mass spectrometry (IP-MS) revealed for the first time that IQGAP1 is a robust novel interacting protein of PGD. PGD decreased p-AMPK levels by competitively interacting with the IQ domain of the known AMPKα binding partner IQGAP1, which promoted glycolysis and fatty acid synthesis in LUAD cells. Furthermore, we demonstrated that the combination of Physcion (a PGD-specific inhibitor) and metformin (an AMPK agonist) could inhibit tumor growth more effectively both in vivo and in vitro. Collectively, these findings suggest that PGD is a potential prognostic biomarker and therapeutic target for LUAD.

Identification and validation of inflammatory subtypes in intrahepatic cholangiocellular carcinoma.

BACKGROUND: Inflammation plays a critical role in tumor development. Inflammatory cell infiltration and inflammatory mediator synthesis cause changes in the tumor microenvironment (TME) in several cancers, especially in intrahepatic cholangiocellular carcinoma (ICC). However, methods to ascertain the inflammatory state of patients using reliable biomarkers are still being explored. METHOD: We retrieved the RNA sequencing and somatic mutation analyses results and the clinical characteristics of 244 patients with ICC from published studies. We performed consensus clustering to identify the molecular subtypes associated with inflammation. We compared the prognostic patterns, clinical characteristics, somatic mutation profiles, and immune cell infiltration patterns across inflammatory subtypes. We performed quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) to confirm gene expression. We performed logistic regression analyses to construct a nomogram predicting the inflammatory status of patients with ICC. RESULTS: Our results confirmed that ICC can be categorized into an inflammation-high subtype (IHS) and an inflammation-low subtype (ILS). Patients from each group had distinct prognosis, clinical characteristics, and TME composition. Patients with ICC in the IHS group showed poorer prognosis owing to the immunosuppressive microenvironment and high frequency of KRAS and TP53 mutations. Cancer-associated fibroblast (CAF)-derived COLEC11 reduced myeloid inflammatory cell infiltration and attenuated inflammatory responses. The results of qRT-PCR and IHC experiments confirmed that COLEC11 expression levels were significantly reduced in tumor tissues compared to those in paracancerous tissues. Patients with ICC in the IHS group were more likely to respond to treatment with immune checkpoint inhibitors (ICIs) owing to their higher tumor mutational burden (TMB) scores, tumor neoantigen burden (TNB) scores, neoantigen counts, and immune checkpoint expression levels. Finally, we developed a nomogram to effectively predict the inflammatory status of patients with ICC based on their clinical characteristics and inflammatory gene expression levels. We evaluated the calibration, discrimination potential, and clinical utility of the nomogram. CONCLUSION: The inflammatory response in IHS is primarily induced by myeloid cells. COLEC11 can reduce the infiltration level of this group of cells, and myeloid inflammatory cells may be a novel target for ICC treatment. We developed a novel nomogram that could effectively predict the inflammatory state of patients with ICC, which will be useful for guiding individualized treatment plans.

Prediction Model for Immunotherapy Efficacy in Hepatocellular Carcinoma Based on Alternative Splicing Sequencing Data.

Background: Integrating immune checkpoint inhibitors with multi-target tyrosine kinase inhibitors presents an innovative and hopeful strategy in liver cancer treatment. Nonetheless, a degree of resistance to this treatment is noticeable in certain patients. Alternative splicing (AS) represents a common biological process that controls the variety of life functions via isoforms. Purpose: Investigating how gene AS affects the effectiveness of combined immunotherapy in treating hepatocellular carcinoma (HCC). Methods: Our retrospective examination focused on AS's effect on immune therapy effectiveness, utilizing accessible tissue sequencing and clinical records for HCC. For corroborating our results, we gathered samples of drug-resistant HCC tissue, nearby tissues, HCC tissue with high drug responsiveness, and healthy liver tissue from clinical studies. Results: The study revealed a link between the frequency of AS occurrences, the expression levels of programmed cell death 1 ligand 1, and the resistance to tumor medications. Our study detailed the AS occurrences in HCC, leading to the creation of a risk-assessment function and a predictive model using AS data. The results of our study revealed that the risk score effectively distinguished between various immune subtypes and the effectiveness of immune therapy. Additional examination of the chosen AS occurrences uncovered their effects on both the immune microenvironment and cellular immunity. Our investigation also delved into the regulatory framework of AS, uncovering the role of stringently controlled splicing factors in the emergence of tumors and the modulation of the body's immune response. Conclusions: Increased AS in HCC diminishes the efficacy of immunotherapy; conversely, more AS in peritumoral tissue elevates the likelihood of tumor immune evasion.

CCL5/CCR5/CYP1A1 pathway prompts liver cancer cells to survive in the combination of targeted and immunological therapies.

Combination therapy of anti-programmed cell death protein-1 (PD-1) antibodies and tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis for hepatocellular carcinoma (HCC), but many patients still have unsatisfactory outcomes. CD8 T cells are known to exert a pivotal function in the immune response against tumors. Nevertheless, most CD8 T cells in HCC tissues are in a state of exhaustion, losing the cytotoxic activity against malignant cells. Cytokines, mainly secreted by immune cells, play an important role in the occurrence and development of tumors. Here, we demonstrated the changes in exhausted CD8T cells during combination therapy by single-cell RNA sequencing (scRNA-seq) analysis on tumor samples before and after treatment. Combination therapy exerted a substantial impact on the exhausted CD8T cells, particularly in terms of cytokine expression. CCL5 was the most abundantly expressed cytokine in CD8T cells and exhausted CD8T cells, and its expression increased further after treatment. Subsequently, we discovered the CCL5/CCR5/CYP1A1 pathway through RNA sequencing (RNA-seq) on CCL5-stimulated Huh7 cells and verified through a series of experiments that this pathway can mediate the resistance of liver cancer cells to lenvatinib. Tissue experiments showed that after combination therapy, the CCL5/CCR5/CYP1A1 pathway was activated, which can benefit the residual tumor cells to survive treatment. Tumor-bearing mouse experiments demonstrated that bergamottin (BGM), a competitive inhibitor of CYP1A1, can enhance the efficacy of both lenvatinib and combination therapy. Our research revealed one mechanism by which hepatoma cells can survive the combination therapy, providing a theoretical basis for the refined treatment of HCC.

A combined model based on radiomics features of Sonazoid contrast-enhanced ultrasound in the Kupffer phase for the diagnosis of well-differentiated hepatocellular carcinoma and atypical focal liver lesions: a prospective, multicenter study.

OBJECTIVE: The objective of this study was to develop a combined model based on radiomics features of Sonazoid contrast-enhanced ultrasound (CEUS) during the Kupffer phase and to evaluate its value in differentiating well-differentiated hepatocellular carcinoma (w-HCC) from atypical benign focal liver lesions (FLLs). METHODS: A total of 116 patients with preoperatively Sonazoid-CEUS confirmed w-HCC or benign FLL were selected from a prospective multiple study on the clinical application of Sonazoid in FLLs conducted from August 2020 to March 2021. According to the randomization principle, the patients were divided into a training cohort and a test cohort in a 7:3 ratio. Seventy-nine patients were used for establishing and training the radiomics model and combined model. In comparison, 37 patients were used for validating and comparing the performance of the models. The diagnostic efficacy of the models for w-HCC and atypical benign FLLs was evaluated using ROCs curves and decision curves. A combined model nomogram was created to assess its value in reducing unnecessary biopsies. RESULTS: Among the patients, there were 55 cases of w-HCC and 61 cases of atypical benign FLLs, including 28 cases of early liver abscess, 16 cases of atypical hepatic hemangioma, 8 cases of hepatocellular dysplastic nodules (DN), and 9 cases of focal nodular hyperplasia (FNH). The radiomics model and combined model we established had AUCs of 0.905 and 0.951, respectively, in the training cohort, and the AUCs of the two models in the test cohort were 0.826 and 0.912, respectively. The combined model outperformed the radiomics feature model significantly. Decision curve analysis demonstrated that the combined model achieved a higher net benefit within a specific threshold probability range (0.25 to 1.00). A nomogram of the combined model was developed. CONCLUSION: The combined model based on the radiomics features of Sonazoid-CEUS in the Kupffer phase showed satisfactory performance in diagnosing w-HCC and atypical benign FLLs. It can assist clinicians in timely detecting malignant FLLs and reducing unnecessary biopsies for benign diseases.

Integrating IASLC grading and radiomics for predicting postoperative outcomes in stage IA invasive lung adenocarcinoma.

BACKGROUND: The International Association for the Study of Lung Cancer (IASLC) Pathology Committee introduced a histologic grading system for invasive lung adenocarcinoma (LUAD) in 2020. The IASLC grading system, hinging on the evaluation of predominant and high-grade histologic patterns, has proven to be practical and prognostic for invasive LUAD. However, there are still limitations in evaluating the prognosis of stage IA LUAD. Radiomics may serve as a valuable complement. PURPOSE: To establish a model that integrates IASLC grading and radiomics, aimed at predicting the prognosis of stage IA LUAD. METHODS: We conducted a retrospective analysis of 628 patients diagnosed with stage IA LUAD who underwent surgical resection between January 2015 and December 2018 at our institution. The patients were randomly divided into the training set (n = 439) and testing set (n = 189) at a ratio of 7:3. Overall survival (OS) and disease-free survival (DFS) were taken as the end points. Radiomics features were obtained by PyRadiomics. Feature selection was performed using the least absolute shrinkage and selection operator (LASSO). The prediction models for OS and DFS were developed using multivariate Cox regression analysis, and the models were visualized through nomogram plots. The model's performance was evaluated using area under the curves (AUC), concordance index (C-index), calibration curves, and survival decision curve analysis (DCA). RESULTS: In total, nine radiomics features were selected for the OS prediction model, and 15 radiomics features were selected for the DFS prediction model. Patients with high radiomics scores were associated with a worse prognosis (p < 0.001). We built separate prediction models using radiomics or IASLC alone, as well as a combined prediction model. In the prediction of OS, we observed that the combined model (C-index: 0.812 ± 0.024, 3 years AUC: 0.692, 5 years AUC: 0.792) achieved superior predictive performance than the radiomics (C-index: 0.743 ± 0.038, 3 years AUC: 0.633, 5 years AUC: 0.768) and IASLC grading (C-index: 0.765 ± 0.042, 3 years AUC: 0.658, 5 years AUC: 0.743) models alone. Similar results were obtained in the models for DFS. CONCLUSION: The combination of radiomics and IASLC pathological grading proves to be an effective approach for predicting the prognosis of stage IA LUAD. This has substantial clinical relevance in guiding treatment decisions for early-stage LUAD.

Surgical treatment improves overall survival of hepatocellular carcinoma with extrahepatic metastases after conversion therapy: a multicenter retrospective study.

Systemic therapy is typically the primary treatment choice for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. Some patients may achieve partial response (PR) or complete response (CR) with systemic treatment, leading to the possibility of their primary tumor becoming resectable. This study aimed to investigate whether these patients could achieve longer survival through surgical resection of their primary tumor. We retrospectively collected data from 150 HCC patients with extrahepatic metastases treated at 15 different centers from January 1st, 2015, to November 30th, 2022. We evaluated their overall survival (OS) and progress-free survival (PFS) and analyzed risk factors impacting both OS and PFS were analyzed. Patients who received surgical treatment had longer OS compared to those who did not (median OS 16.5 months vs. 11.3 months). However, there was no significant difference in progression-free survival between the two groups. Portal vein invasion (P = 0.025) was identified as a risk factor for poor prognosis in patients, while effective first-line treatment (P = 0.039) and surgical treatment (P = 0.005) were protective factors. No factors showed statistical significance in the analysis of PFS. Effective first-line treatment (P = 0.027) and surgical treatment (P = 0.006) were both independent protective factors for prolonging patient prognosis, while portal vein invasion was an independent risk factor (P = 0.044). HCC patients with extrahepatic metastases who achieve PR/CR with conversion therapy may experience longer OS through surgical treatment. This study is the first to analyze the clinical outcomes of patients receiving surgical treatment for HCC with extrahepatic metastases.

COSMIC-based mutation database enhances identification efficiency of HLA-I immunopeptidome.

BACKGROUND: Neoantigens have emerged as a promising area of focus in tumor immunotherapy, with several established strategies aiming to enhance their identification. Human leukocyte antigen class I molecules (HLA-I), which present intracellular immunopeptides to T cells, provide an ideal source for identifying neoantigens. However, solely relying on a mutation database generated through commonly used whole exome sequencing (WES) for the identification of HLA-I immunopeptides, may result in potential neoantigens being missed due to limitations in sequencing depth and sample quality. METHOD: In this study, we constructed and evaluated an extended database for neoantigen identification, based on COSMIC mutation database. This study utilized mass spectrometry-based proteogenomic profiling to identify the HLA-I immunopeptidome enriched from HepG2 cell. HepG2 WES-based and the COSMIC-based mutation database were generated and utilized to identify HepG2-specific mutant immunopeptides. RESULT: The results demonstrated that COSMIC-based database identified 5 immunopeptides compared to only 1 mutant peptide identified by HepG2 WES-based database, indicating its effectiveness in identifying mutant immunopeptides. Furthermore, HLA-I affinity of the mutant immunopeptides was evaluated through NetMHCpan and peptide-docking modeling to validate their binding to HLA-I molecules, demonstrating the potential of mutant peptides identified by the COSMIC-based database as neoantigens. CONCLUSION: Utilizing the COSMIC-based mutation database is a more efficient strategy for identifying mutant peptides from HLA-I immunopeptidome without significantly increasing the false positive rate. HepG2 specific WES-based database may exclude certain mutant peptides due to WES sequencing depth or sample heterogeneity. The COSMIC-based database can effectively uncover potential neoantigens within the HLA-I immunopeptidomes.

Long-term survival and portal vein patency with novel PVTT surgery approach in advanced HCC patients with Vp3/4 PVTT following combination therapy of TKIs and PD-1 inhibitors.

BACKGROUND: It is controversial whether patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) should undergo salvage surgery following the combination therapy of tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors. This study aimed to elucidate the efficiency and safety of salvage surgery following combination therapy, while also summarizing a novel surgical approach for Vp3/4 PVTT. METHODS: Between April 2019 and December 2022, a consecutive series of unresectable HCC patients with PVTT who received salvage surgery following combination therapy were enrolled. Evaluation included perioperative and long-term follow-up outcomes. The complete removal of Vp3/4 PVTT was achieved using a novel surgical approach characterized by "longitudinal incision and transverse suturing" and "angle-to-straight conversion". RESULTS: Forty patients including 22 patients with Vp3 and 18 patients with Vp4 were included. Long-term follow-up showed similar rates of portal vein patency (Vp3: 95.5%, Vp4:94.4%, p = 0.900), and 3-year portal vein patency rates were 95.0%. There were no significant differences observed in combination therapy-related adverse events (p = 0.253) and perioperative complications (p = 0.613) between the Vp3 and Vp4 groups. The recurrence patterns were similar between the two groups (p = 0.131). There were no significant differences in overall survival (OS) and recurrence-free (RFS) survival between the Vp3 and Vp4 groups (OS p = 0.457, RFS p = 0.985). Patients who achieved a pathological complete response had significantly better RFS (p = 0.011). CONCLUSION: Salvage surgery after combination therapy demonstrated favorable efficacy and safety. The novel surgical approach for PVTT can effectively achieve complete removal of PVTT and ensured long-term portal vein patency.

Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition).

Background: Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages: The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial.

BACKGROUND: Over 70% of the patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage and lose the opportunity for radical surgery. Combination therapy of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death protein-1 (PD-1) antibodies has achieved a high tumor response rate in both the first-line and second-line treatment of advanced HCC. However, few studies have prospectively evaluated whether TKIs plus anti-PD-1 antibodies could convert unresectable intermediate-advanced HCC into resectable disease. METHODS: This single-arm, phase II study enrolled systemic therapy-naïve adult patients with unresectable Barcelona Clinic Liver Cancer stage B or C HCC. Patients received oral lenvatinib one time per day plus intravenous anti-PD-1 agents every 3 weeks (one cycle). Tumor response and resectability were evaluated before the fourth cycle, then every two cycles. The primary endpoint was conversion success rate by investigator assessment. Secondary endpoints included objective response rate (ORR) by independent imaging review (IIR) assessment per modified RECIST (mRECIST) and Response Evaluation Criteria in Solid Tumors, V.1.1 (RECIST 1.1), progression-free survival (PFS) and 12-month recurrence-free survival (RFS) rate by IIR per mRECIST, R0 resection rate, overall survival (OS), and safety. Biomarkers were assessed as exploratory objectives. RESULTS: Of the 56 eligible patients enrolled, 53 (94.6%) had macrovascular invasion, and 16 (28.6%) had extrahepatic metastasis. The median follow-up was 23.5 months. The primary endpoint showed a conversion success rate of 55.4% (31/56). ORR was 53.6% per mRECIST and 44.6% per RECIST 1.1. Median PFS was 8.9 months, and median OS was 23.9 months. Among the 31 successful conversion patients, 21 underwent surgery with an R0 resection rate of 85.7%, a pathological complete response rate of 38.1%, and a 12-month RFS rate of 47.6%. Grade ≥3 treatment-related adverse events were observed in 42.9% of patients. Tumor immune microenvironment analysis of pretreatment samples displayed significant enrichment of CD8+ T cells (p=0.03) in responders versus non-responders. CONCLUSION: Lenvatinib plus anti-PD-1 antibodies demonstrate promising efficacy and tolerable safety as conversion therapy in unresectable HCC. Pre-existing CD8+ cells are identified as a promising biomarker for response to this regimen. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR1900023914.

Comprehensive analysis and immune landscape of chemokines- and chemokine receptors-based signature in hepatocellular carcinoma.

Background: Despite encouraging results from immunotherapy combined with targeted therapy for hepatocellular carcinoma (HCC), the prognosis remains poor. Chemokines and their receptors are an essential component in the development of HCC, but their significance in HCC have not yet been fully elucidated. We aimed to establish chemokine-related prognostic signature and investigate the association between the genes and tumor immune microenvironment (TIME). Methods: 342 HCC patients have screened from the TCGA cohort. A prognostic signature was developed using least absolute shrinkage and selection operator regression and Cox proportional risk regression analysis. External validation was performed using the LIHC-JP cohort deployed from the ICGC database. Single-cell RNA sequencing (scRNA-seq) data from the GEO database. Two nomograms were developed to estimate the outcome of HCC patients. RT-qPCR was used to validate the differences in the expression of genes contained in the signature. Results: The prognostic signature containing two chemokines-(CCL14, CCL20) and one chemokine receptor-(CCR3) was successfully established. The HCC patients were stratified into high- and low-risk groups according to their median risk scores. We found that patients in the low-risk group had better outcomes than those in the high-risk group. The results of univariate and multivariate Cox regression analyses suggested that this prognostic signature could be considered an independent risk factor for the outcome of HCC patients. We discovered significant differences in the infiltration of various immune cell subtypes, tumor mutation burden, biological pathways, the expression of immune activation or suppression genes, and the sensitivity of different groups to chemotherapy agents and small molecule-targeted drugs in the high- and low-risk groups. Subsequently, single-cell analysis results showed that the higher expression of CCL20 was associated with HCC metastasis. The RT-qPCR results demonstrated remarkable discrepancies in the expression of CCL14, CCL20, and CCR3 between HCC and its paired adjacent non-tumor tissues. Conclusion: In this study, a novel prognostic biomarker explored in depth the association between the prognostic model and TIME was developed and verified. These results may be applied in the future to improve the efficacy of immunotherapy or targeted therapy for HCC.

Factors influencing the prognosis patients with Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma undergoing salvage surgery after conversion therapy.

Background: The aim of this study was to investigate the prognostic factors influencing the outcome of patients with Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma (HCC) receiving salvage surgery after conversion therapy based on tyrosine kinase inhibitors (TKIs) and anti-programmed death-1 (PD-1) antibodies. Methods: From June 2018 to December 2022, patients receiving salvage surgery after conversion therapy based on PD-1 and TKIs at the Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital were retrospectively recruited for this study. Overall survival (OS) and recurrence-free survival (RFS) were observed as the primary end point in the Cox analysis of prognostic factors among this study. Results: The 6- and 12-month RFS rates were 77.0% and 64.8%, respectively, while the 6-, 12-, 24-, and 36-month OS rates were 98.4%, 93.4%, 76.8%, and 69.8%, respectively. The median OS and RFS were not reached. On multivariable Cox regression analyses, low serum alpha fetoprotein (AFP) level (≤20 ng/mL) after conversion therapy [hazard ratio (HR) 0.186, 95% CI: 0.039-0.887; P=0.035) and microvascular invasion (MVI) grade II (HR 3.054, 95% CI: 1.000-9.329; P=0.050) were independent factors associated with a higher OS and RFS. Conclusions: For patients with Barcelona Clinic Liver Cancer stage C (BCLC-C) HCC, lower AFP level after conversion therapy (<20 ng/mL) and MVI II were associated with a higher OS and lower RFS rate, respectively.

Nomogram based on Sonazoid contrast-enhanced ultrasound to differentiate intrahepatic cholangiocarcinoma and poorly differentiated hepatocellular carcinoma: a prospective multicenter study.

OBJECTIVES: The aim of this study was to develop a predictive model based on Sonazoid contrast-enhanced ultrasound (SCEUS) and clinical features to discriminate poorly differentiated hepatocellular carcinoma (P-HCC) from intrahepatic cholangiocarcinoma (ICC). PATIENTS AND METHOD: Forty-one ICC and forty-nine P-HCC patients were enrolled in this study. The CEUS LI-RADS category was assigned according to CEUS LI-RADS version 2017. Based on SCEUS and clinical features, a predicated model was established. Multivariate logistic regression analysis and LASSO logistic regression were used to identify the most valuable features, 400 times repeated 3-fold cross-validation was performed on the nomogram model and the model performance was determined by its discrimination, calibration, and clinical usefulness. RESULTS: Multivariate logistic regression and LASSO logistic regression indicated that age (> 51 y), viral hepatitis (No), AFP level (≤  20 µg/L), washout time (≤  45 s), and enhancement level in the Kupffer phase (Defect) were valuable predictors related to ICC. The area under the receiver operating characteristic (AUC) of the nomogram was 0.930 (95% CI: 0.856-0.973), much higher than the subjective assessment by the sonographers and CEUS LI-RADS categories. The calibration curve showed that the predicted incidence was more consistent with the actual incidence of ICC, and 400 times repeated 3-fold cross-validation revealed good discrimination with a mean AUC of 0.851. Decision curve analysis showed that the nomogram could increase the net benefit for patients. CONCLUSIONS: The nomogram based on SCEUS and clinical features can effectively differentiate P-HCC from ICC.

Corrigendum: The role of 18F-FDG PET in predicting the pathological response and prognosis to unresectable HCC patients treated with lenvatinib and PD-1 inhibitors as a conversion therapy.

[This corrects the article DOI: 10.3389/fimmu.2023.1151967.].