Endoscopic ultrasound-guided tissue acquisition for focal liver lesions in patients with a history of multiple primary malignant neoplasms.

Objective: This study aimed to investigate the usefulness of endoscopic ultrasound-guided tissue acquisition (EUS-TA) for diagnosing focal liver lesions in patients with a history of multiple primary malignant neoplasms. Methods: Among patients who underwent EUS-TA for focal liver lesions between 2016 and 2022, those with a history of multiple malignant neoplasms were included. A histologically confirmed malignant tumor within the past 5 years before EUS-TA was defined as a history of malignant neoplasm. The primary outcomes were diagnostic ability and adverse events of EUS-TA. Results: This study included 16 patients (median age, 73 [33-90] years), the median tumor size was 32 (6-51) mm, 14 had a history of double malignant neoplasms, whereas two had triple malignant neoplasms. Malignant neoplasms were detected histologically or cytologically in all cases. Immunohistochemistry was performed in 75% (12/16), and the final diagnosis of EUS-TA was metastatic liver tumor in 12 patients, and primary malignant liver tumor in four patients. The primary site could be identified in 11 of 12 metastatic tumor cases. The diagnostic yield of EUS-TA was 100% (16/16) for differentiating benign and malignant tumors and 94% (15/16) for confirming the histological type including the primary site of metastatic lesions. No adverse events were associated with the procedure. Conclusion: EUS-TA is a useful diagnostic modality for focal liver lesions in patients with a history of multiple malignant neoplasms, allowing for the differential diagnosis of primary and metastatic tumors and identification of the primary site of metastatic lesions.

Metabolic reprogramming in hepatocellular carcinoma: a bibliometric and visualized study from 2011 to 2023.

Background and aims: Metabolic reprogramming has been found to be a typical feature of tumors. Hepatocellular carcinoma (HCC), a cancer with high morbidity and mortality, has been extensively studied for its metabolic reprogramming-related mechanisms. Our study aims to identify the hotspots and frontiers of metabolic reprogramming research in HCC and to provide guidance for future scientific research and decision-making in HCC metabolism. Methods: Relevant studies on the metabolic reprogramming of HCC were derived from the Web of Science Core Collection (WoSCC) database up until November 2023. The bibliometrix tools in R were used for scientometric analysis and visualization. Results: From 2011 to 2023, a total of 575 publications were obtained from WoSCC that met the established criteria. These publications involved 3,904 researchers and 948 organizations in 37 countries, with an average annual growth rate of 39.11% in research. These studies were published in 233 journals, with Cancers (n = 29) ranking first, followed by Frontiers in Oncology (n = 20) and International Journal of Molecular Sciences (n = 19). The top ten journals accounted for 26% of the 575 studies. The most prolific authors were Wang J (n = 14), Li Y (n = 12), and Liu J (n = 12). The country with the most publications is China, followed by the United States, Italy, and France. Fudan University had the largest percentage of research results with 15.48% (n = 89). Ally A's paper in Cell has the most citations. A total of 1,204 keywords were analyzed, with the trend themes such as "glycolysis," "tumor microenvironment," "Warburg effect," "mitochondria," "hypoxia ," etc. Co-occurrence network and cluster analysis revealed the relationships between keywords, authors, publications, and journals. Moreover, the close collaboration between countries in this field was elucidated. Conclusion: This bibliometric and visual analysis delves into studies related to metabolic reprogramming in HCC between 2012 and 2023, elucidating the characteristics of research in this field, which has gradually moved away from single glycolipid metabolism studies to the integration of overall metabolism in the body, pointing out the trend of research topics, and the dynamics of the interaction between the tumor microenvironment and metabolic reprogramming will be the future direction of research, which provides blueprints and inspirations for HCC prevention and treatment programs to the researchers in this field.Systematic Review Registration: [https://www.bibliometrix.org].

Liver stiffness in hepatocellular carcinoma and chronic hepatitis patients: Hepatitis B virus infection and transaminases should be considered.

BACKGROUND: Liver condition is a crucial prognostic factor for patients with hepatocellular carcinoma (HCC), but a convenient and comprehensive method to assess liver condition is lacking. Liver stiffness (LS) measured by two-dimensional shear wave elastography may help in assessing liver fibrosis and liver condition. Chronic hepatitis B (CHB) is an important risk factor for HCC progression, but LS was found to be less reliable in assessing liver fibrosis following hepatitis viral eradication. We hypothesize that the status of hepatitis virus infection would affect the accuracy of LS in assessing the liver condition. AIM: To test the feasibility and impact factors of using LS to assess liver condition in patients with HCC and CHB. METHODS: A total of 284 patients were retrospectively recruited and classified into two groups on the basis of serum CHB virus hepatitis B virus (HBV)-DNA levels [HBV-DNA ≥ 100.00 IU/mL as Pos group (n = 200) and < 100.00 IU/mL as Neg group (n = 84)]. Correlation analyses and receiver operating characteristic analyses were conducted to evaluate the relationship between LS and liver condition. RESULTS: A significant correlation was found between LS and most of the parameters considered to have the ability to evaluate liver condition (P < 0.05). When alanine aminotransferase (ALT) concentrations were normal (≤ 40 U/L), LS was correlated with liver condition indices (P < 0.05), but the optimal cutoff of LS to identify a Child-Pugh score of 5 was higher in the Neg group (9.30 kPa) than the Pos group (7.40 kPa). When ALT levels were elevated (> 40 U/L), the correlations between LS and liver condition indices were not significant (P > 0.05). CONCLUSION: LS was significantly correlated with most liver condition indices in patients with CHB and HCC. However, these correlations varied according to differences in HBV-DNA and transaminase concentrations.

Ultrasomics in liver cancer: Developing a radiomics model for differentiating intrahepatic cholangiocarcinoma from hepatocellular carcinoma using contrast-enhanced ultrasound.

BACKGROUND: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) represent the predominant histological types of primary liver cancer, comprising over 99% of cases. Given their differing biological behaviors, prognoses, and treatment strategies, accurately differentiating between HCC and ICC is crucial for effective clinical management. Radiomics, an emerging image processing technology, can automatically extract various quantitative image features that may elude the human eye. Reports on the application of ultrasound (US)-based radiomics methods in distinguishing HCC from ICC are limited. AIM: To develop and validate an ultrasomics model to accurately differentiate between HCC and ICC. METHODS: In our retrospective study, we included a total of 280 patients who were diagnosed with ICC (n = 140) and HCC (n = 140) between 1999 and 2019. These patients were divided into training (n = 224) and testing (n = 56) groups for analysis. US images and relevant clinical characteristics were collected. We utilized the XGBoost method to extract and select radiomics features and further employed a random forest algorithm to establish ultrasomics models. We compared the diagnostic performances of these ultrasomics models with that of radiologists. RESULTS: Four distinct ultrasomics models were constructed, with the number of selected features varying between models: 13 features for the US model; 15 for the contrast-enhanced ultrasound (CEUS) model; 13 for the combined US + CEUS model; and 21 for the US + CEUS + clinical data model. The US + CEUS + clinical data model yielded the highest area under the receiver operating characteristic curve (AUC) among all models, achieving an AUC of 0.973 in the validation cohort and 0.971 in the test cohort. This performance exceeded even the most experienced radiologist (AUC = 0.964). The AUC for the US + CEUS model (training cohort AUC = 0.964, test cohort AUC = 0.955) was significantly higher than that of the US model alone (training cohort AUC = 0.822, test cohort AUC = 0.816). This finding underscored the significant benefit of incorporating CEUS information in accurately distinguishing ICC from HCC. CONCLUSION: We developed a radiomics diagnostic model based on CEUS images capable of quickly distinguishing HCC from ICC, which outperformed experienced radiologists.

Selective bronchial occlusion for acquired bronchobiliary fistula caused by treatment of hepatocellular carcinoma: A case series.

Acquired bronchobiliary fistula (ABBF) is very rare among the complications that occur in patients with hepatocellular carcinoma (HCC) after treatment. Although surgery and drainage have been the main methods for treating ABBF for a long time, they are not entirely suitable for patients with refractory ABBF resulting from HCC therapy. In this study, we present four cases of ABBF caused by HCC treatment, who were treated using selective bronchial occlusion (SBO). Among the 4 patients with ABBF treated with SBO, 3 cases successfully blocked ABBF with SBO, and the treatment success rate was 75%. All successfully treated patients reported disappearance of symptoms of bilioptysis and cough was alleviated. No life-threatening adverse reactions were reported following SBO intervention, and no deaths occurred. We believe that the use of video bronchoscopy to place a self-made silicone plug in the bronchus to treat refractory ABBF is a feasible palliative treatment, which can significantly improve the condition of ABBF patients.

Nomogram based on liver stiffness and spleen area with ultrasound for posthepatectomy liver failure: A multicenter study.

BACKGROUND: Liver stiffness (LS) measurement with two-dimensional shear wave elastography (2D-SWE) correlates with the degree of liver fibrosis and thus indirectly reflects liver function reserve. The size of the spleen increases due to tissue proliferation, fibrosis, and portal vein congestion, which can indirectly reflect the situation of liver fibrosis/cirrhosis. It was reported that the size of the spleen was related to posthepatectomy liver failure (PHLF). So far, there has been no study combining 2D-SWE measurements of LS with spleen size to predict PHLF. This prospective study aimed to investigate the utility of 2D-SWE assessing LS and spleen area (SPA) for the prediction of PHLF in hepatocellular carcinoma (HCC) patients and to develop a risk prediction model. AIM: To investigate the utility of 2D-SWE assessing LS and SPA for the prediction of PHLF in HCC patients and to develop a risk prediction model. METHODS: This was a multicenter observational study prospectively analyzing patients who underwent hepatectomy from October 2020 to March 2022. Within 1 wk before partial hepatectomy, ultrasound examination was performed to measure LS and SPA, and blood was drawn to evaluate the patient's liver function and other conditions. Least absolute shrinkage and selection operator logistic regression and multivariate logistic regression analysis was applied to identify independent predictors of PHLF and develop a nomogram. Nomogram performance was validated further. The diagnostic performance of the nomogram was evaluated with receiver operating characteristic curve compared with the conventional models, including the model for end-stage liver disease (MELD) score and the albumin-bilirubin (ALBI) score. RESULTS: A total of 562 HCC patients undergoing hepatectomy (500 in the training cohort and 62 in the validation cohort) were enrolled in this study. The independent predictors of PHLF were LS, SPA, range of resection, blood loss, international normalized ratio, and total bilirubin. Better diagnostic performance of the nomogram was obtained in the training [area under receiver operating characteristic curve (AUC): 0.833; 95% confidence interval (95%CI): 0.792-0.873; sensitivity: 83.1%; specificity: 73.5%] and validation (AUC: 0.802; 95%CI: 0.684-0.920; sensitivity: 95.5%; specificity: 52.5%) cohorts compared with the MELD score and the ALBI score. CONCLUSION: This PHLF nomogram, mainly based on LS by 2D-SWE and SPA, was useful in predicting PHLF in HCC patients and presented better than MELD score and ALBI score.

Enhancing prognostic prediction in hepatocellular carcinoma post-TACE: a machine learning approach integrating radiomics and clinical features.

Objective: This study aimed to investigate the use of radiomics features and clinical information by four machine learning algorithms for predicting the prognosis of patients with hepatocellular carcinoma (HCC) who have been treated with transarterial chemoembolization (TACE). Methods: A total of 105 patients with HCC treated with TACE from 2002 to 2012 were enrolled retrospectively and randomly divided into two cohorts for training (n = 74) and validation (n = 31) according to a ratio of 7:3. The Spearman rank, random forest, and univariate Cox regression were used to select the optimal radiomics features. Univariate Cox regression was used to select clinical features. Four machine learning algorithms were used to develop the models: random survival forest, eXtreme gradient boosting (XGBoost), gradient boosting, and the Cox proportional hazard regression model. The area under the curve (AUC) and C-index were devoted to assessing the performance of the models in predicting HCC prognosis. Results: A total of 1,834 radiomics features were extracted from the computed tomography images of each patient. The clinical risk factors for HCC prognosis were age at diagnosis, TNM stage, and metastasis, which were analyzed using univariate Cox regression. In various models, the efficacy of the combined models generally surpassed that of the radiomics and clinical models. Among four machine learning algorithms, XGBoost exhibited the best performance in combined models, achieving an AUC of 0.979 in the training set and 0.750 in the testing set, demonstrating its strong prognostic prediction capability. Conclusion: The superior performance of the XGBoost-based combined model underscores its potential as a powerful tool for enhancing the precision of prognostic assessments for patients with HCC.

The prognostic role of an optimal machine learning model based on clinical available indicators in HCC patients.

Although methods in diagnosis and therapy of hepatocellular carcinoma (HCC) have made significant progress in the past decades, the overall survival (OS) of liver cancer is still disappointing. Machine learning models have several advantages over traditional cox models in prognostic prediction. This study aimed at designing an optimal panel and constructing an optimal machine learning model in predicting prognosis for HCC. A total of 941 HCC patients with completed survival data and preoperative clinical chemistry and immunology indicators from two medical centers were included. The OCC panel was designed by univariate and multivariate cox regression analysis. Subsequently, cox model and machine-learning models were established and assessed for predicting OS and PFS in discovery cohort and internal validation cohort. The best OCC model was validated in the external validation cohort and analyzed in different subgroups. In discovery, internal and external validation cohort, C-indexes of our optimal OCC model were 0.871 (95% CI, 0.863-0.878), 0.692 (95% CI, 0.667-0.717) and 0.648 (95% CI, 0.630-0.667), respectively; the 2-year AUCs of OCC model were 0.939 (95% CI, 0.920-0.959), 0.738 (95% CI, 0.667-0.809) and 0.725 (95% CI, 0.643-0.808), respectively. For subgroup analysis of HCC patients with HBV, aged less than 65, cirrhosis or resection as first therapy, C-indexes of our optimal OCC model were 0.772 (95% CI, 0.752-0.792), 0.769 (95% CI, 0.750-0.789), 0.855 (95% CI, 0.846-0.864) and 0.760 (95% CI, 0.741-0.778), respectively. In general, the optimal OCC model based on RSF algorithm shows prognostic guidance value in HCC patients undergoing individualized treatment.

An unusual occurrence of multiple primary malignant neoplasms: a case report and narrative review.

Introduction: Multiple primary malignant neoplasms (MPMNs) are cancers presenting distinct pathological types that originate from different tissues or organs. They are categorized as either synchronous or metachronous. Nowadays, the incidence of MPMN is increasing. Patients and methods: We present a case of a 71-year-old male patient with a medical history of hepatitis B and a family history of breast and endometrial cancers. The patient reported a nasal tip skin lesion with recurrent bleeding, and the history disclosed lower urinary tract symptoms. Further investigations revealed the coexistence of four primary cancers: basosquamous carcinoma of the nasal lesion, prostatic adenocarcinoma, hepatocellular carcinoma, and clear cell renal cell carcinoma. Results: A multidisciplinary team cooperated to decide the proper diagnostic and therapeutic modules. Conclusion: To the best of our knowledge, the synchronization of these four primary cancers has never been reported in the literature. Even so, multiple primary malignant neoplasms, in general, are no longer a rare entity and need proper explanations, a precise representation of definition and incidence, further work-up approaches, and treatment guidelines as well.

Influencing factors and risk prediction model for emergence agitation after general anesthesia for primary liver cancer.

BACKGROUND: General anesthesia is commonly used in the surgical management of gastrointestinal tumors; however, it can lead to emergence agitation (EA). EA is a common complication associated with general anesthesia, often characterized by behaviors, such as crying, struggling, and involuntary limb movements in patients. If treatment is delayed, there is a risk of incision cracking and bleeding, which can significantly affect surgical outcomes. Therefore, having a proper understanding of the factors influencing the occurrence of EA and implementing early preventive measures may reduce the incidence of agitation during the recovery phase from general anesthesia, which is beneficial for improving patient prognosis. AIM: To analyze influencing factors and develop a risk prediction model for EA occurrence following general anesthesia for primary liver cancer. METHODS: Retrospective analysis of clinical data from 200 patients who underwent hepatoma resection under general anesthesia at Wenzhou Central Hospital (January 2020 to December 2023) was conducted. Post-surgery, the Richmond Agitation-Sedation Scale was used to evaluate EA presence, noting EA incidence after general anesthesia. Patients were categorized by EA presence postoperatively, and the influencing factors were analyzed using logistic regression. A nomogram-based risk prediction model was constructed and evaluated for differentiation and fit using receiver operating characteristics and calibration curves. RESULTS: EA occurred in 51 (25.5%) patients. Multivariate analysis identified advanced age, American Society of Anesthesiologists (ASA) grade III, indwelling catheter use, and postoperative pain as risk factors for EA (P < 0.05). Conversely, postoperative analgesia was a protective factor against EA (P < 0.05). The area under the curve of the nomogram was 0.972 [95% confidence interval (CI): 0.947-0.997] for the training set and 0.979 (95%CI: 0.951-1.000) for the test set. Hosmer-Lemeshow test showed a good fit (χ 2 = 5.483, P = 0.705), and calibration curves showed agreement between predicted and actual EA incidence. CONCLUSION: Age, ASA grade, catheter use, postoperative pain, and analgesia significantly influence EA occurrence. A nomogram constructed using these factors demonstrates strong predictive accuracy.

Association of preoperative antiviral treatment with incidences of post-hepatectomy liver failure in hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: Post-hepatectomy liver failure (PHLF) is a common consequence of radical partial hepatectomy in hepatocellular carcinoma (HCC). AIMS: To investigate the relationship between preoperative antiviral therapy and PHLF, as well as assess the potential efficacy of hepatitis B virus (HBV) DNA level in predicting PHLF. METHODS: A retrospective study was performed involving 1301 HCC patients with HBV who underwent radical hepatectomy. Receiver operating characteristic (ROC) analysis was used to assess the capacity of HBV DNA to predict PHLF and establish the optimal cutoff value for subsequent analyses. Logistic regression analyses were performed to assess the independent risk factors of PHLF. The increase in the area under the ROC curve, categorical net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to quantify the efficacy of HBV DNA level for predicting PHLF. The P < 0.05 was considered statistically significant. RESULTS: Logistic regression analyses showed that preoperative antiviral therapy was independently associated with a reduced risk of PHLF (P < 0.05). HBV DNA level with an optimal cutoff value of 269 IU/mL (P < 0.001) was an independent risk factor of PHLF. All the reference models by adding the variable of HBV DNA level had an improvement in area under the curve, categorical NRI, and IDI, particularly for the fibrosis-4 model, with values of 0.729 (95%CI: 0.705-0.754), 1.382 (95%CI: 1.341-1.423), and 0.112 (95%CI: 0.110-0.114), respectively. All the above findings were statistically significant. CONCLUSION: In summary, preoperative antiviral treatment can reduce the incidence of PHLF, whereas an increased preoperative HBV DNA level has a correlative relationship with an increased susceptibility to PHLF.

Application of radioactive iodine-125 microparticles in hepatocellular carcinoma with portal vein embolus.

BACKGROUND: Radioactive iodine-125 (125I) microparticle therapy is a new type of internal radiation therapy that has shown unique advantages in the treatment of malignant tumors, especially hepatocellular carcinoma. Patients with hepatocellular carcinoma frequently experience portal vein embolism, which exacerbates the difficulty and complexity of treatment. 125I particles, used in local radiotherapy, can directly act on tumor tissue and reduce damage to surrounding healthy tissue. Through retrospective analysis, this study discussed the efficacy and safety of radioactive 125I particles in portal vein embolization patients with hepatocellular carcinoma in order to provide more powerful evidence supporting clinical treatment. AIM: To investigate the effect of transcatheter arterial chemoembolization combined with portal vein 125I particle implantation in the treatment of primary liver cancer patients with portal vein tumor thrombus and its influence on liver function. METHODS: The clinical data of 96 patients with primary liver cancer combined with portal vein tumor thrombus admitted to our hospital between January 2020 and December 2023 were retrospectively analyzed. Fifty-two patients received treatment with transcatheter arterial chemoembolization and implantation of 125I particles in the portal vein (combination group), while 44 patients received treatment with transcatheter arterial chemoembolization alone (control group). The therapeutic effects on tumor lesions, primary liver cancer, and portal vein tumor embolisms were compared between the two groups. Changes in relevant laboratory indexes before and after treatment were evaluated. The t test was used to compare the measurement data between the two groups, and the χ 2 test was used to compare the counting data between groups. RESULTS: The tumor lesion response rate in the combination group (59.62% vs 38.64%) and the response rate of patients with primary liver cancer complicated with portal vein tumor thrombus (80.77% vs 59.09%) were significantly greater than those in the control group (χ 2 = 4.196, 5.421; P = 0.041, 0.020). At 8 wk after surgery, the serum alpha-fetoprotein, portal vein main diameter, and platelet of the combined group were significantly lower than those of the control group, and the serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin were significantly greater than those of the control group (t = 3.891, 3.291, 2.330, 3.729, 3.582, 4.126; P < 0.05). The serum aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels of the two groups were significantly greater than those of the same group 8 wk after surgery (P < 0.05), and the peripheral blood platelet, alpha-fetoprotein, and main portal vein diameter were significantly less than those of the same group before surgery (P < 0.05). CONCLUSION: In patients with primary liver cancer and a thrombus in the portal vein, transcatheter arterial chemoembolization plus portal vein 125I implantation is more effective than transcatheter arterial chemoembolization alone. However, during treatment it is crucial to pay attention to liver function injury caused by transcatheter arterial chemoembolization.

Large language models' responses to liver cancer surveillance, diagnosis, and management questions: accuracy, reliability, readability.

PURPOSE: To assess the accuracy, reliability, and readability of publicly available large language models in answering fundamental questions on hepatocellular carcinoma diagnosis and management. METHODS: Twenty questions on liver cancer diagnosis and management were asked in triplicate to ChatGPT-3.5 (OpenAI), Gemini (Google), and Bing (Microsoft). Responses were assessed by six fellowship-trained physicians from three academic liver transplant centers who actively diagnose and/or treat liver cancer. Responses were categorized as accurate (score 1; all information is true and relevant), inadequate (score 0; all information is true, but does not fully answer the question or provides irrelevant information), or inaccurate (score - 1; any information is false). Means with standard deviations were recorded. Responses were considered as a whole accurate if mean score was > 0 and reliable if mean score was > 0 across all responses for the single question. Responses were also quantified for readability using the Flesch Reading Ease Score and Flesch-Kincaid Grade Level. Readability and accuracy across 60 responses were compared using one-way ANOVAs with Tukey's multiple comparison tests. RESULTS: Of the twenty questions, ChatGPT answered nine (45%), Gemini answered 12 (60%), and Bing answered six (30%) questions accurately; however, only six (30%), eight (40%), and three (15%), respectively, were both accurate and reliable. There were no significant differences in accuracy between any chatbot. ChatGPT responses were the least readable (mean Flesch Reading Ease Score 29; college graduate), followed by Gemini (30; college) and Bing (40; college; p < 0.001). CONCLUSION: Large language models provide complex responses to basic questions on hepatocellular carcinoma diagnosis and management that are seldomly accurate, reliable, or readable.

Addition of contrast in ultrasound screening for hepatocellular carcinoma.

Objective: Screening ultrasound for hepatocellular carcinoma (HCC) identifies lesions which require further characterization by a contrast-enhanced exam to non-invasively diagnose HCC. While ultrasound is recommended in screening, some HCC can be occult on grayscale imaging. The purpose of this study was to determine if the addition of ultrasound contrast (sulfahexafluoride) to screening ultrasound for HCC can identify more HCC lesions than grayscale sonographic imaging alone. Methods: All HCC screening ultrasounds that also had contrast were evaluated in this retrospective study. Patients with a focal lesion seen only after administration of contrast (OAC) were noted, as well as any follow-up imaging or pathology results. Additional variables collected included patient demographics, cirrhosis type, and laboratory values. Results: 230 unique patients were included, of which 160 had imaging or pathology follow-up. 18 of these patients had an OAC lesion, of which 17 had follow-up. Among these OACs, there was one LIRADS M lesion (1/18, 5.6 %) and one bland portal vein thrombus identified, which were both confirmed on follow-up imaging. All LIRADS 4 OAC lesions were downgraded. No additional HCC were identified on follow-up imaging or pathology of these patients. Conclusion: Addition of contrast to screening ultrasound did identify additional lesions, portal vein thrombus, and high grade malignancy. However, as the incidence of OAC lesions was low (7.8 %, 18/230) and most of the lesions were not malignant, addition of post contrast sweeps through the liver is of low value in the low to medium at-risk cirrhotic population in identifying occult HCC.

Transarterial embolization is an acceptable bridging therapy to hepatocellular carcinoma prior to liver transplantation.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that requires liver transplantation (LT). Despite patients with HCC being prioritized by most organ allocation systems worldwide, they still have to wait for long periods. Locoregional therapies (LRTs) are employed as bridging therapies in patients with HCC awaiting LT. Although largely used in the past, transarterial embolization (TAE) has been replaced by transarterial chemoembolization (TACE). However, the superiority of TACE over TAE has not been consistently shown in the literature. AIM: To compare the outcomes of TACE and TAE in patients with HCC awaiting LT. METHODS: All consecutive patients with HCC awaiting LT between 2011 and 2020 at a single center were included. All patients underwent LRT with either TACE or TAE. Some patients also underwent percutaneous ethanol injection (PEI), concomitantly or in different treatment sessions. The choice of LRT for each HCC nodule was determined by a multidisciplinary consensus. The primary outcome was waitlist dropout due to tumor progression, and the secondary outcome was the occurrence of adverse events. In the subset of patients who underwent LT, complete pathological response and post-transplant recurrence-free survival were also assessed. RESULTS: Twelve (18.5%) patients in the TACE group (only TACE and TACE + PEI; n = 65) and 3 (7.9%) patients in the TAE group (only TAE and TAE + PEI; n = 38) dropped out of the waitlist due to tumor progression (P log-rank test = 0.29). Adverse events occurred in 8 (12.3%) and 2 (5.3%) patients in the TACE and TAE groups, respectively (P = 0.316). Forty-eight (73.8%) of the 65 patients in the TACE group and 29 (76.3%) of the 38 patients in the TAE group underwent LT (P = 0.818). Among these patients, complete pathological response was detected in 7 (14.6%) and 9 (31%) patients in the TACE and TAE groups, respectively (P = 0.145). Post-LT, HCC recurred in 9 (18.8%) and 4 (13.8%) patients in the TACE and TAE groups, respectively (P = 0.756). Posttransplant recurrence-free survival was similar between the groups (P log-rank test = 0.71). CONCLUSION: Dropout rates and posttransplant recurrence-free survival of TAE were similar to those of TACE in patients with HCC. Our study reinforces the hypothesis that TACE is not superior to TAE as a bridging therapy to LT in patients with HCC.

GPAT3 is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma.

Background: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), but acquired resistance during the treatment greatly limits its clinical efficiency. Lipid metabolic disorder plays an important role in hepatocarcinogenesis. However, whether and how lipid metabolic reprogramming regulates sorafenib resistance of HCC cells remains vague. Methods: Sorafenib resistant HCC cells were established by continuous induction. UHPLC-MS/MS, proteomics, and flow cytometry were used to assess the lipid metabolism. ChIP and western blot were used to reflect the interaction of signal transducer and activator of transcription 3 (STAT3) with glycerol-3-phosphate acyltransferase 3 (GPAT3). Gain- and loss-of function studies were applied to explore the mechanism driving sorafenib resistance of HCC. Flow cytometry and CCK8 in vitro, and tumor size in vivo were used to evaluate the sorafenib sensitivity of HCC cells. Results: Our metabolome data revealed a significant enrichment of triglycerides in sorafenib-resistant HCC cells. Further analysis using proteomics and genomics techniques demonstrated a significant increase in the expression of GPAT3 in the sorafenib-resistant groups, which was found to be dependent on the activation of STAT3. The restoration of GPAT3 resensitized HCC cells to sorafenib, while overexpression of GPAT3 led to insensitivity to sorafenib. Mechanistically, GPAT3 upregulation increased triglyceride synthesis, which in turn stimulated the NF-κB/Bcl2 signaling pathway, resulting in apoptosis tolerance upon sorafenib treatment. Furthermore, our in vitro and in vivo studies revealed that pan-GPAT inhibitors effectively reversed sorafenib resistance in HCC cells. Conclusions: Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib.

Single cell analyses reveal the PD-1 blockade response-related immune features in hepatocellular carcinoma.

Background: Immunotherapy has demonstrated its potential to improve the prognosis of patients with hepatocellular carcinoma (HCC); however, patients' responses to immunotherapy vary a lot. A comparative analysis of the tumor microenvironment (TME) in responders and non-responders is expected to unveil the mechanisms responsible for the immunotherapy resistance and provide potential treatment targets. Methods: We performed sequencing analyses using 10x Genomics technology on six HCC patients who responded to anti-PD-1 therapy and one HCC patient who did not respond. Additionally, we obtained single cell data from untreated, responsive, and nonresponsive HCC patients from public databases, and used part of the datasets as a validation cohort. These data were integrated using algorithms such as Harmony. An independent validation cohort was established. Furthermore, we performed spatial transcriptomic sequencing on the tumor adjacent tissues of three HCC responsive patients using 10x Genomics spatial transcriptomic technology. Additionally, we analyzed data about three HCC patients obtained from public databases. Finally, we validated our conclusions using immunofluorescence, flow cytometry, and in vivo experiments. Results: Our findings confirmed the presence of "immune barrier" partially accounting for the limited efficacy of immunotherapy. Our analysis revealed a significant increase in TREM2+ Macrophages among non-responsive patients expressing multiple immunosuppressive signals. anti-Csf1r monoclonal antibodies effectively eliminated these macrophages and augmented the therapeutic effects of anti-PD-1 therapy. TCR+ Macrophages possessed direct tumor-killing capabilities. IL1B+ cDC2 was the primary functional subtype of cDC2 cells. Absence of THEMIShi CD8+ T subtypes might diminish immunotherapeutic effects. Furthermore, CD8+ T cells entered a state of stress after anti-PD-1 treatment, which might be associated with CD8+ T cell exhaustion and senescence. Conclusions: The profiles of immune TMEs showed differences in HCC patients responsive, non-responsive and untreated. These differences might explain the discounted efficacy of immunotherapy in some HCC patients. The cells and molecules, which we found to carry unique capabilities, may be targeted to enhance immunotherapeutic outcomes in patients with HCC.

Diagnostic and prognostic role of LINC01767 in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a primary contributor to cancer-related mortality on a global scale. However, the underlying molecular mechanisms are still poorly understood. Long noncoding RNAs are emerging markers for HCC diagnosis, prognosis, and therapeutic target. No study of LINC01767 in HCC was published. AIM: To conduct a multi-omics analysis to explore the roles of LINC01767 in HCC for the first time. METHODS: DESeq2 Package was used to analyze different gene expressions. Receiver operating characteristic curves assessed the diagnostic performance. Kaplan-Meier univariate and Cox multivariate analyses were used to perform survival analysis. The least absolute shrinkage and selection operator (LASSO)-Cox was used to identify the prediction model. Subsequent to the validation of LINC01767 expression in HCC fresh frozen tissues through quantitative real time polymerase chain reaction, next generation sequencing was performed following LINC01767 over expression (GSE243371), and Gene Ontology/Kyoto Encyclopedia of Genes and Genomes/Gene Set Enrichment Analysis/ingenuity pathway analysis was carried out. In vitro experiment in Huh7 cell was carried out. RESULTS: LINC01767 was down-regulated in HCC with a log fold change = 1.575 and was positively correlated with the cancer stemness. LINC01767 was a good diagnostic marker with area under the curve (AUC) [0.801, 95% confidence interval (CI): 0.751-0.852, P = 0.0106] and an independent predictor for overall survival (OS) with hazard ratio = 1.899 (95%CI: 1.01-3.58, P = 0.048). LINC01767 nomogram model showed a satisfied performance. The top-ranked regulatory network analysis of LINC01767 showed the regulation of genes participating various pathways. LASSO regression identified the 9-genes model showing a more satisfied performance than 5-genes model to predict the OS with AUC > 0.75. LINC01767 was down-expressed obviously in tumor than para-tumor tissues in our cohort as well as in cancer cell line; the over expression of LINC01767 inhibit cell proliferation and clone formation of Huh7 in vitro. CONCLUSION: LINC01767 was an important tumor suppressor gene in HCC with good diagnostic and prognostic performance.

Prognostic insights, immune infiltration, and therapeutic response: Cytoplasmic poly(A) tail regulators in hepatocellular carcinoma.

The presence of a poly(A) tail is indispensable for the post-transcriptional regulation of gene expression in cancer. This dynamic and modifiable feature of transcripts is under the control of various nuclear and cytoplasmic proteins. This study aimed to develop a novel cytoplasmic poly(A)-related signature for predicting prognosis, clinical attributes, tumor immune microenvironment (TIME), and treatment response in hepatocellular carcinoma (HCC). Utilizing RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA), non-negative matrix factorization (NMF), and principal-component analysis (PCA) were employed to categorize HCC patients into three clusters, thus demonstrating the pivotal prognostic role of cytoplasmic poly(A) tail regulators. Furthermore, machine learning algorithms such as least absolute shrinkage and selection operator (LASSO), survival analysis, and Cox proportional hazards modeling were able to distinguish distinct cytoplasmic poly(A) subtypes. As a result, a 5-gene signature derived from TCGA was developed and validated using International Cancer Genome Consortium (ICGC) HCC datasets. This novel classification based on cytoplasmic poly(A) regulators has the potential to improve prognostic predictions and provide guidance for chemotherapy, immunotherapy, and transarterial chemoembolization (TACE) in HCC.

Hepatocyte transformation is induced by laminin γ2 monomer.

Serum laminin-γ2 monomer (Lm-γ2m) is a potent predictive biomarker for hepatocellular carcinoma (HCC) onset in patients with hepatitis C infection who achieve a sustained virologic response with liver cirrhosis (LC) and for the onset of extrahepatic metastases in early-stage HCC. Although Lm-γ2m involvement in late-stage cancer progression has been well investigated, its precise roles in HCC onset remain to be systematically investigated. Therefore, we analyzed an HCC model, human hepatocytes and cholangiocytes, and surgically resected liver tissues from patients with HCC to understand the roles of Lm-γ2m in HCC onset. Ck-19- and EpCAM-positive hepatic progenitor cells (HPCs) in the liver of pdgf-c transgenic HCC mouse model with ductular reaction showed ectopic expression of Lm-γ2m. Forced expression of Lm-γ2m in hepatocytes adjacent to HPCs resulted in enhanced tumorigenicity, cell proliferation, and migration in immortalized hepatocytes, but not in cholangiocytes in vitro. Further, pharmacological inhibition of epidermal growth factor receptor (EGFR) and c-Jun activator JNK suppressed Lm-γ2m-induced hepatocyte transformation, suggesting the involvement of EGFR/c-Jun signaling in the transformation, leading to HCC development. Finally, immunohistochemical staining of HCC tissues revealed a high level of Lm-γ2 expression in the HPCs of the liver with ductular reaction in normal liver adjacent to HCC tissues. Overall, HPC-derived Lm-γ2m in normal liver with ductular reaction acts as a paracrine growth factor on surrounding hepatocytes and promotes their cellular transformation through the EGFR/c-Jun signaling pathway. Furthermore, this is the first report on Lm-γ2m expression detected in the normal liver with ductular reaction, a human precancerous lesion of HCC.